Substituted benzosulfimide, method for their production and pharmaceutical drugs based on them


(57) Abstract:

The proposed substituted benzosulfimide formula I, where R(l) - (C1-C6) alkyl, R(2) - (C1-C6)alkoxy, R(3) is hydrogen, R(4), R(5) R(6) is hydrogen, aryl or (C1-C6)alkyl, E is a sulfur atom, X is oxygen, Y is (CH2-)group, and their pharmaceutically tolerated salts have the property to inhibit potassium channels in the heart with a heightened sensitivity to ATP (antiarrhythmic effect). Also proposed is a method of obtaining compounds of formula I by the interaction of benzosulfimide formula II or its salt III with R(l) substituted by isothiocyanato R(1)-N = C = S, where R(l) - R(6), X, Y described above, and M is an ion of an alkaline or alkaline-earth metal, and pharmaceutical drug that has anti-arrhythmic action. 3 S. and 6 C.p. f-crystals, 1 PL.

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The invention relates to substituted benzosulfimide formula I

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where mean:

R(1) - alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

R(2) - alkoxy with 1, 2, 3, 4, 5 or 6 C-atoms;

R(3) - hydrogen;

R(4), R(5) R(6) - independently from each other hydrogen, aryl or alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

E - sulfur;

X is oxygen;

Y - CH2group,

and their pharmaceutically who adnie remains straight or branched chain.

Aryl refers to aromatic systems phenyl, thienyl, furyl, pyrrolyl, thiazolyl, naphthyl, pyridyl, which, depending on the circumstances, may be substituted by one to three substituents as alkyl with 1 or 2 C-atoms, alkoxy with 1 or 2 C-atoms, Cl, Br, F; especially phenyl, naphthyl and thienyl.

Next, sometimes in the alkyl chains Y, R(3), R(4), R(5) R(6) can receive connections with centers of chirality. In this case, the invention belong as individual antipodes by themselves, and the mixture of both enantiomers in different ways, belong here metasediment or mixture of metasediment, enantiomers or diastereomers.

Like sulfonylureas with reducing sugar content in the blood is known from patent application Belgium 754454 and unaccepted bids Germany 1198354. In applications for patents Germany P 4341655.1 (HOE 93/F 399) and P 4344957.3 (HOE 93/F 439) offer benzosulfimide and-thiourea, which, however, do not have the cyclo-group matching containing the Y ring.

There describe the reducing sugar content in the blood of the action of the sulfonylureas. The prototype of such reducing sugar content in the blood of the sulfonylureas is glibenclamide, which is used in therapy as a means dlsueac sensitive to ATP potassium channels. Along with reducing the sugar content in the blood by the action of glibenclamide has other actions that still could not be used in therapy, but all of which together amount to a blockade just those sensitive to ATP potassium channels. This includes especially directed against the atrial action on the heart. However, in the treatment of ventricular fibrillation of the heart or its preliminary stages simultaneously decreasing the amount of sugar in the blood would be undesirable or even dangerous, as it can worsen the condition of the patient.

Therefore, the present invention was to obtain compounds that have the same good effect on the heart as glibenclamide, but the sugar content in the blood is effective for heart doses or concentrations do not affect or influence significantly less than glibenclamide.

As experimental animals to confirm such actions are suitable, for example, mice, rats, Guinea pigs, rabbits, dogs, monkeys or pigs.

The compounds of formula I are used as active substances of medicinal products for human and veterinary medicine. Further, they can be used as intermediate products for the manufacture of other will acrobatyour:

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

R(2) - methoxy or ethoxy,

R(3) is hydrogen,

R(4), R(5) R(6) - independently from each other hydrogen, aryl or alkyl with 1, 2, 3, 4, 5, 6, C-atoms,

E - sulfur,

X is oxygen,

Y - CH2.

Especially preferred compounds of formula I, in which mean:

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

R(2) - methoxy or ethoxy,

R(3) is hydrogen,

R(4) and R(5) independently from each other hydrogen, alkyl with 1, 2, 3, 4, 5, 6 C-atoms,

R(6) - aryl,

E - sulfur,

X is oxygen,

Y - CH2.

The compounds of formula I of this invention are valuable medicines to treat heart rhythm disorders of different Genesis and to prevent due to arrhythmia sudden death from cardiac arrest, and so they may find use as antiarrhythmic funds. Examples of arrhythmic heart disorders are supraselective arrhythmias, such as tachycardia fibrillation, atrial flutter or paroxysmal supraselective arrhythmias, or ventricular arrhythmias like ventricular extrasystole, but especially life-threatening ventricular tachycardia or especially dangerous Mercan the coronary vessel, as for example, angina or during acute myocardial infarction or appear as a consequence of chronic myocardial infarction. Therefore, they are used especially in postinfarction patients to prevent sudden death from cardiac arrest. Other clinical pictures, which play a role similar arrhythmias and/or sudden, caused by arrhythmia death from cardiac arrest, are, for example, heart failure or cardiac hypertrophy as a consequence of chronic high blood pressure.

In addition, the compounds of formula I can have a positive effect on the contractility of the heart. Thus we can talk about disease caused by the weakening of the contractility of the heart, for example, in case of insufficiency of the heart, but also about acute cases, as the fall of cardiac activity when exposed to shock. Similarly, when a heart transplant after the operation, the heart can be faster and more reliable again to resume its functional ability. The same applies to operations on the heart, which necessitates a temporary cardiac arrest due to cardioplegic solutions, and connections can be used to protect organs, Nacimiento.

The invention relates then to a production method of benzosulfimide formula I, which is characterized by the fact that benzosulfimide formula II

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or its salt of the formula III

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interacting with R(1) substituted by isothiocyanato formula VI

R(1) - N = C = S

where R(1), R(2), R(3), R(4), R(5), R(6), X, Y described above.

The cation M in the salts of the formula (III) take into account the ions of alkali and alkaline earth metals.

As the drying means, you can apply all appropriate to obtain the amide bonds of connection, such as dicyclohexylcarbodiimide, carbonimidoyl, anhydride propriospinal acid. As solvents are used inert nephratonia solvents, such as THF, QMF, simple, diethyl ether, dichloromethane, and mixtures of these solvents.

The compounds of formula I and their physiologically not cause fear salts are valuable therapeutic agents, which are suitable not only as antiarrhythmic funds, but also for the prevention during the disorders of the cardiovascular system, heart failure, heart transplant, or diseases of the blood vessels of the brain in humans or mammals (N. the state of fear salts of compounds of formulas I mean in Pharmaceutical science of Remmington, 17th edition, 1985, S. 14-18, compounds of formula X

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which can be derived from nontoxic organic and inorganic bases and benzosulfimide formula I.

While I prefer salt in which M(1) in formula X are ions of sodium, potassium, rubidium, calcium, magnesium, and also addition products of acids, basic amino acids, such as lysine or arginine.

Starting compound for the above-mentioned synthesis methods of benzosulfimide formula I get the known methods described in the literature (for example, in basic writings, as Houben-Weyl. Methods of organic chemistry, Georg Thieme-Verlag, Stuttgart; Organic reactions, John Wiley & Sons, Inc., New York; and in the above patent applications, namely in terms of reactions, which are known and suitable for the mentioned transformations. You can use also known, but not mentioned here more options. The source of the substance, if necessary, can be formed also in place so that they are not isolated from the reaction mixture, and immediately turn on.

So, correspondingly substituted carboxylic acid of formula XI according to scheme 1 (see the end of the description) can pstway with the corresponding amines R(3), R(4), NH after activation of the carboxylic acid group to a carboxylic acid amide of formula II.

As methods of activation are applied to obtain the acid chloride of the carboxylic acid or mixed anhydrides, carboxylic acid halides of formic acid. You can then apply known to obtain the amide bonds of the reactants, as for example, carbonimidoyl, dicyclohexylcarbodiimide and anhydride propriospinal acid.

Obtained in scheme 1 as intermediate products sulfonamides of formula XII can interact with the corresponding isocyanates of the formula R(1) - N = C = E to carboxylic acids of benzosulfimide formula IX according to scheme 2 (see the end of the description).

The compounds of formula I may have one or more chiral centers. Therefore, when manufacturing them can be obtained as racemates or, if used optically active substances are also in optically active form. If the compounds have one or more chiral centers, they can get in the synthesis as mixtures of racemates, from which the individual isomers can be isolated in pure form, for example, by recrystallization from inert solvents. Separate the racemates, if required the houtem interaction with optically active dividing means it is possible to form diastereomers. As release agents for basic compounds are used, for example, optically active acids, as R - or R, R and S, respectively S,S - forms of tartaric acid, dibenzoyltartaric acid, diatsetilvinny acid, camphor sulphonic acids, almond acid, malic acid or lactic acid. Further, carbinol using chiral reagents acylation, for example, R - or S-methylbenzenesulfonate, you can lidirovat and then separate. Various forms of the diastereomers can in a known manner, for example, fractional crystallization, separating, and enantiomers of the formula I can in a known manner to release. The enantiomers could then be separated by chromatography on optically active substances-carriers.

Compounds according to the invention of the formula I and their physiologically not cause fear salts can be used for the manufacture of pharmaceutical preparations. They could, however, along at least one solid or liquid carrier or auxiliary substance, alone or in combination with other effective circulation with heart medicines such as calcium antagonists, NO-donors or ACE-inhibitors, bring in the proper dosage form. These products can be used when sportsouth organic or inorganic substances, suitable for intestinal (e.g. oral), parenteral, such as intravenous administration or for local applications, and which do not react with the new compounds, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates as lactose or starch, magnesium stearate, talc, lanolin, petrolatum. For oral administration are especially tablets, coated tablets, capsules, syrups, juices or drops; for rectal use solutions, mainly oily or aqueous solutions, then suspensions, emulsions or implants; for topical application are ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example, in alcohols as ethanol or isopropanol, acetonitrile, 1,2-propandiol or their mixtures with each other or with water) or powder. New connections can be subjected to lyophilization and apply lyophilizate, for example, for the manufacture of drugs for injection. In particular, for local use also use liposomal preparations, stabilizers and/or substances with a high surface activity, emulsifiers, salts and/or auxiliary substances, such as lubricants, preservatives, their substance. They can optionally also contain one or more other active substances, for example one or more vitamins.

The dosage required for the treatment of cardiac arrhythmias with compounds of the formula I depends on used for acute therapy or for prevention. Generally carry a range of doses of at least about 0.1 mg, mostly minimally 1 mg, up to a maximum of 100 mg, predominantly up to a maximum of 10 mg per 1 kg and 1 day, if prevention is conducted. Mainly the dose range is from 1 to 10 mg per 1 kg and 1 day in relation to an adult with an average weight of 75 kg, this dose can be divided into oral or parenteral single dose or four single doses. If you treat acute cases of cardiac arrhythmias, for example in a hospital, it may be beneficial to the parenteral administration. In this case, the preferred range of doses in critical situations can be from 10 to 100 mg, and the dose may be administered, for example, as prolonged intravenous infusion.

According to the invention can also be obtained, except as described in the examples of implementation of the compounds, the following compounds:

1) N-methylamide 3 sulfonylamino-N-(malinakerman) -4-methoxyphenyl-cyclopropanecarbonyl acid;

3) N-1-propylamide 3 sulfonylamino-N,N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

4) N-2 - propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

5) N-1-butylamide 3 sulfonylamino-N -(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

6) N-2-butylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

7) N-1-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

8) N-2-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

9) N-3-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

10) N-1-butyl-2-methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

11) N-1-butyl-3-methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

12) N-1-hexylamine 3 sulfonylamino-N-(methylaminomethyl) -4 - methoxyphenyl-cyclopropanecarbonyl acid;

13) N-2-hexylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid

15) N-1-heptylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

16) N-2-heptylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

17) N-3-heptylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

18) N-1-octylated 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

19) N-2-octylated 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

20) N-1-adamantylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

21) N-2-adamantylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

22) N di methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

23) N-methyl-N'-ethylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

24) N-methyl-N'-1-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

25) N-methyl-N'-2-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropane inkarbaeva acid;

27) N-methyl-N'-2-butylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

28) N-di-ethylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

29) N-ethyl-N'-1-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

30) N-ethyl-N'- 2-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

31) Pyrrolidinium 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

32) Piperidine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

33) Morphodynamic 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

34) (N-methylpiperazine)amide 3-sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

35) 4-thio-morpholinyl 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

36) N-methylamide 3 sulfonylamino-N -(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

37) N-ethylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxy shall Setenil-cyclopropanecarbonyl acid;

39) N-2-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

40) N-1-butylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

41) N-2-butylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

42) N-1-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

43) N-2-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

44) N-3-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

45) N-1-butyl-2-methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

46) N-1-butyl-3-methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

47) N-1-hexylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

48) N-2-hexylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

49) N-C-exiled 3 sulfonylamino-N-(methylaminomethyl) -4-methoxy shall Setenil-cyclopropanecarbonyl acid;

51) N-2-heptylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

52) N-3-heptylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

53) N-1-octylated 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

54) N-2-octylated 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

55) N-adamantylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

56) N-2-adamantylamine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

57) N di methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

58) N-methyl-N'-ethylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

59) N-methyl-N'-1-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

60) N-methyl-N'-2-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

61) N-methyl-N'-1-butylamide 3 sulfonylamino-N-(methylamino eliminationchamber) -4-methoxyphenyl-cyclopropanecarbonyl acid;

63) N-di-ethylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

64) N-ethyl-N'-1-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

65) N-ethyl-N'-2-propylamide 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

66) Pyrrolidinium 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

67) Piperidine 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

68) Morphodynamic 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

69) (N-methyl-piperazinil)amide 3-sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

70) 4-thio-morpholinyl 3 sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl-cyclopropanecarbonyl acid;

71) N-methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

72) N-ethylamide 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid:

73) N-1-propylamide 3 sulfonylamino-N-(mediumistic arbonyl) -4-were-cyclopropanecarbonyl acid;

75) N-1 - butylamide 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

76) N-2-butylamide 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

77) N-1-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

78) N-2-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

79) N-3-pencilled 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

80) N-1-butyl-2-methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

81) N-1-butyl-3-methylamide 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

82) N-1-hexylamine 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

83) N-2-hexylamine 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

84) N-3-hexylamine 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

85) N-1-heptylamine 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl the new acid;

87) N-3-heptylamine 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

88) N-1-octylated 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

89) N-2-octylated 3 sulfonylamino-N -(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

90) N-1-adamantylamine 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

91) N-2-adamantylamine 3 sulfonylamino-N-(methylaminomethyl) -4-were-cyclopropanecarbonyl acid;

Receipt of the initial substances.

Getting 2-(3-sulfonylamino-4-methoxyphenyl) cyclopropanecarboxylic acids.

4-substituted esters phenylcarbinol acid is added under stirring parts to excess chlorosulfonic acid. Stirred for 30 min at room temperature, then poured on ice and suck educated sulfonic acid chloride. The latter is dissolved in an ammonia solution, stirred for 30 min at room temperature and neutralize the solution with 2 n hydrochloric acid. The resulting product is sucked off. The obtained ester is stirred with an excess of lithium hydroxide in a mixture of tetrahydrofuran is firom get the desired acid.

In this method get:

complex ethyl ester of 2-(3-sulfonylamino-4-methoxyphenyl) cyclopropanecarboxylic acid;

the melting point 154oC

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2-(3-sulfonylamino-4-methoxyphenyl)cyclopropanecarbonyl acid;

the melting point of 160oC

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Example 1.

N-1-phenyl-1-butyramide 2-[3-sulfonylamino-N-(methylaminomethyl) -4-methoxyphenyl)-4-methoxyphenyl]cyclopropanecarbonyl acid.

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250 g N-1-phenyl-1-butylamine 2-(3-sulfonylamino-4-methoxyphenyl) -cyclopropanecarbonyl acid are dissolved in 3 ml of dimethylformamide, mixed with 37 mg of NaOH and stirred for 30 min at 40oC. Then added 54 mg methylisothiocyanate and stirred for further 2 h at 70oC. After cooling and neutralization with 2 n hydrochloric acid, the product is sucked off and dried.

Melting point 110oC.

Pharmacological data.

therapeutic properties of the compounds of formula I may be evident on the basis of the following models.

1) the Duration of the action potential on the papillary muscle of the heart Guinea pigs:

a) Introduction.

State deficit of ATP, which monitored during ischemia in the cardiac muscle cell, Reentry, which can cause sudden death from cardiac arrest. The reason for this, consider opening sensitive to ATP potassium channels by reducing ATP.

b) Method.

To measure the action potential is applied to the standard method with microelectrodes. For this Guinea pigs of both sexes killed by a blow to the head, remove the heart, isolated papillary muscles of the heart and hung in the bath for bodies. Bath organs rinsing with ringer's solution (0.9% NaCl, 0,048% KCl, 0,024% CaCl20,02% NaHCO3and 0.1% glucose) and treated with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36oC. Papillary muscle excite via the electrodes with rectangular pulses of 1 V and with a duration of 1 MS, with a frequency of 2 Hz. Potential actions assign and register through the introduction into the cell of a glass microelectrode filled with a solution of 3 mmol of KCl. Subjects substances were added to the ringer's solution at a concentration of 2.2 10-5mol/L. the action Potential boost by means of the amplifier Hugo Sachs and present on the oscilloscope. The duration of the action potential is determined at the level of repolarization 95% (APD95). Reducing the duration of the action potential cause or deoxyglucose. Reducing the duration of the action potential effect of these substances is reduced or prevented by the simultaneous reception of the standard substances. The test substance was added as uterine solutions in propane diol to a solution of the bath. The stated values refer to measurements within 30 min after addition. Glibenclamide served in these dimensions are standard. The standard concentration is in all cases 2 10-6M

with the Results.

We measured the following values (see tab. 1).

1. Substituted benzosulfimide formula I

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where R (1) - alkyl with 1,2,3,4,5 or 6 C-atoms;

R (2) - alkoxy with 1,2,3,4,5 or 6 C-atoms;

R (3) - hydrogen;

R (4), R (5) R (6) - independently from each other hydrogen, aryl or alkyl with 1,2,3,4,5 or 6 C-atoms;

E - sulfur;

X is oxygen;

Y - CH2group,

and their pharmaceutically tolerated salts.

2. Substituted benzosulfimide formula I on p. 1, where R (1) - alkyl with 1,2,3 or 4 C-atoms, R (2) - methoxy or ethoxy, R (3) is hydrogen, R (4), R (5) R (6) - independently from each other hydrogen, aryl or alkyl with 1,2,3,4,5,6, C-atoms, S is sulfur, X is oxygen, Y is CH2.

3. Substituted benzosulfimide formula I on PP.1 and 2, where R (1) -sludge 1,2,3,4,5,6 C-atoms, R (6) - aryl, S is sulfur, X is oxygen, Y is CH2.

4. The method of obtaining substituted benzosulfimide formula I on PP.1 to 3, characterized in that benzosulfimide formula II

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or its salt of the formula III

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interacting with R (1) substituted by isothiocyanato formula VI

R (1) - N = C = S,

where R (1), R (2), R (3), R (4), R (5), R (6), X, Y described in paragraph 1;

M-ion alkaline or alkaline earth metal.

5. Substituted benzosulfimide formula I on PP.1 to 3, with anti-arrhythmic effect.

6. Substituted benzosulfimide formula I on PP.1 - 3, suitable for the production of a pharmaceutical preparation having anti-arrhythmic effect.

7. Substituted benzosulfimide formula I on PP.1 to 3, has the property to inhibit potassium channels in the heart with a heightened sensitivity to ATP.

8. Substituted benzosulfimide formula I on PP.1 - 3, suitable for the production of a pharmaceutical preparation for the prevention of sudden death from cardiac arrest.

9. Pharmaceutical drug that has anti-arrhythmic action, containing the active substance and conventional inert additives, the main quantity.


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where R1denotes A, CF3CH2F, CHF2C2F5, CN, NO2, Gal, CCH, or-X-R4;

R2and R3each, independently of one another, denote H, Gal A, -X-R4, CN, NO2, CF3CH2F, CHF2C2F5CH2CF3, -SOn-R6, -SO2NR4R5Ph or OPh;

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R4and R5together also denote alkylene with 4-5 C atoms, and one CH2the group may also be replaced by O, S, NH, N-A or N-CH2-Ph;

R6denotes A or Ph;

Het denotes a dual core, saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and/or S atoms, linked via N or C, which is unsubstituted or may be substituted by one, two or three times with Gal, CF3, A, -X-R4, CN, NO2and/or carbonyl oxygen;

A stands for Ala is atno replaced with A, OA, NR4R5, Gal or CF3phenyl;

"n" is 1 or 2; and

Gal denotes fluorine, chlorine, bromine or iodine,

and their physiologically acceptable salts
The invention relates to medicine, cardiology

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

Antiseptic ointment // 2134572
The invention relates to veterinary medicine and can be used in the treatment of lesions of skin and mucous membranes of the skin of animals of different etiology, and prevention of diseases of the udder

The invention relates to the field of veterinary medicine and the development of a drug for disinfection (disinfection) from pathogenic viruses and bacteria premises, equipment, implements, utensils, tools, instruments, solutions and environmentally corrosive-safe drug tevtropin and can be used on livestock farms, technology, engineering, manufacturing and warehouse facilities, research and medical institutions, enterprises of biological and food industry

The invention relates to new derivatives of N-methyldiethanolamine and, in more detail, the derivative of N-methyldiethanolamine, represented by the following formula and their salts:

< / BR>
where R represents the residue obtained by removal of COOH from C3-C7sugar carboxylic acids, present in the residue of the hydroxyl group can be protected by means of protective groups

FIELD: pharmaceutical agents, in particular glyburide containing composition.

SUBSTANCE: claimed composition contains 5-chloro-N-[2-[4-[[(cyclohexylamino) carbonyl]amino]sulfonyl]ethyl]-2-methoxybenzamide, known under generic name as glyburide, and has the next grain-size classification (%): undersize of 3-11 mum - 25; undersize of 6-23 mum - 50 %, and undersize of 15-46 mum - 75 %. Such grain-size classification affords the ability to increase glyburide dissolution rate and provide reproducible biological availability of glyburide.

EFFECT: pharmaceutical composition useful for treatment of II- type diabetes.

11 cl, 2 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying substituted benzenesulfonylureas and -thioureas of the formula (I) for preparing a medicinal agent used for treatment and prophylaxis of disturbances in vegetative nervous system. In particular, invention relates to treatment and prophylaxis of disturbances associated with vagus nerve, for example, in cardiovascular diseases, and to applying compounds of the formula (I) in combination with beta-receptor blocking agents. Also, invention relates to products and pharmaceutical compositions that comprise at least one substance among compounds of the formula (I) and at least one beta-receptor blocking agent, and to new compounds also. Invention provides enhancing effectiveness in treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

22 cl, 2 tbl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition made mainly as solid medicinal formulations and comprising therapeutically effective amount of gliclazide and the special additive in the amount 4.65-6.70 mass. p. per mass unit of active substance. The additive comprises hydroxypropylmethylcellulose, microcrystalline cellulose, aerosil and stearate taken in the following ratio of components, mass. p. per 1 m. p. of active substance: hydroxypropylmethylcellulose, 2.50-3.50; microcrystalline cellulose, 2.12-3.00; aerosil, 0.01-0.05, and stearate, 0.02-0.15. Proposed pharmaceutical composition provides the sustained-release of gliclazide and high bioavailability of active substance, a simple method for its preparing as compared with solid medicinal formulation of gliclazide known from the prior art.

EFFECT: improved and valuable properties of composition.

3 cl, 2 tbl, 3 ex

FIELD: medicine, endocrinology, in particular treatment of diabetus mellitus type 2 in patient didn't use anti-diabetic drugs.

SUBSTANCE: claimed method includes simultaneous administration of metformine in daily dose of 160-750 mg and gliburide in daily dose of 0.5-15 mg. Gliburide has grain-size classification wherein min.10 % particles have size less than 2 mum and max.10 % particles have size more than 60 mum.

EFFECT: treatment of improved effectiveness with decreased drug doses and reduced side effects.

24 cl, 10 dwg, 4 ex, 4 tbl

FIELD: medicine, endocrinology.

SUBSTANCE: invention elates to a method for treatment of diabetes mellitus type 2, method for declining the glucose content in patient blood and method for reducing resistance to insulin, diminishing the hemoglobin A1c content, enhancing the insulin level after eating, and reducing the amplitude change content ("mobility") of glucose in diabetic patients. Method involves administration of metformin to patient in the low dose (160-750 mg) in combination with the second anti-diabetic agent chosen from the group including glucose oxidase inhibitor, glucagons-like peptide-1 (GLP-1), insulin, α/β-double agonist of PRAP other than thiazolidinedione, meglitimide and inhibitor aP2 wherein the second anti-diabetic agent is administrated as a daily dose in interval between the initial daily dose comprising 20-60% of the initial daily dose of this anti-diabetic agent used in usual medicinal practice in therapy of the first order in treatment of diabetes mellitus up to the daily supporting dose comprising 40-60% of the daily supporting dose of this anti-diabetic agent used in usual medicinal practice as therapy of the first order in treatment of diabetes mellitus. Invention provides the effectiveness in treatment of diabetes mellitus that is equivalent practically to effectiveness of treatment by using combination of metformin and other indicated anti-diabetic agent used in doses prescribing in usual medicinal practice but with significantly less adverse effects.

EFFECT: improved method for treatment of diabetes mellitus.

7 cl, 10 dwg, 4 tbl, 3 ex