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


(57) Abstract:

The proposed substituted benzosulfimide formula I, where R(1) - (C1-C6)alkyl; R(2) - (C1-C6)alkyl or (C1-C6)alkoxy; R(3) and R(4) is hydrogen, (C1-C6)alkyl or together form a chain (-CH2)2-5-; E is a sulfur atom; X is an oxygen atom; Y is a chain -(CH2)1-2-; Ar is phenyl or naphthyl, not substituted or substituted (C1-C2)alkyl or (C1-C2)alkoxy, has the property to inhibit potassium channels in the heart with a heightened sensitivity to ATP (antiarrhythmic effect). Also proposed is a method of obtaining derivatives benzosulfimide formula I by the interaction of benzosulfimide II or its salt III, where M is an ion of an alkaline or alkaline earth metal, ammonium or tetraalkylammonium ion, with R(1) substituted by isothiocyanato R(1)-N = C = S, and pharmaceutical drug that has anti-arrhythmic action. 3 S. and 7 C.p. f-crystals., 1 PL.

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The invention relates to substituted benzosulfimide formula I

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where R(1) is alkyl with 1-6 C-atoms;

R(2) is alkyl with 1-6 C atoms or alkoxy with 1-6 C-atoms;

R(3) and R(4), Odinak is/BR> E represents a sulfur atom;

X represents an oxygen atom;

Y represents a chain -(CH2)1-2-;

Ar represents phenyl or naphthyl, which can be unsubstituted or substituted by one or two substituents from the group of alkyl with 1 or 2 C atoms, alkoxy with 1 or 2 C-atoms.

The concept of alkyl describes if there are no other indications, saturated hydrocarbon residues with a straight or branched chain.

Next, sometimes in the alkyl chains Y, R(2), R(3) and R(4) can receive connections with centers of chirality. In this case, the invention includes both the individual antipodes by themselves, and the mixture of both enantiomers in different ways, and also belong here metasediment or mixture of metasediment, enantiomers or diastereomers.

Like sulfonylureas with reducing sugar content in the blood is known from the patent Belgium 754454.

Compounds 1 are used as active ingredients of drugs in medicine and in veterinary medicine. Further, they can be used as intermediate products for the manufacture of other active substances of medicines.

Preferred are compounds 1, in which the transport is different and represent hydrogen, alkyl with 1-6 C-atoms;

E - sulfur;

X is oxygen;

Y is a hydrocarbon chain of the formula (CH2)1-2;

Ar is phenyl or naphthyl, which can be unsubstituted or substituted by 1-2 substituents selected from the group consisting of alkyl with 1 or 2 C atoms, alkoxy with 1 or 2 C-atoms.

Especially preferred compounds 1, in which mean:

R(1) - alkyl with 1 or 2 C-atoms;

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

R(3) and R(4) is the same or different and represent hydrogen or methyl;

E - sulfur;

X is oxygen;

Y is a hydrocarbon chain of the formula (CH2)1-2;

Ar is naphthyl, which can be respectively unsubstituted or substituted by 1-2 substituents selected from the group consisting of alkyl with 1 or 2 C atoms, alkoxy with 1 or 2 C-atoms.

Hereinafter, the preferred group is formed by compounds 1, in which mean:

R(1) - alkyl with 1 or 2 C-atoms;

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

R(3) and R(4) is the same or different and represent hydrogen or methyl;

E - sulfur;

X is oxygen;

Y is a hydrocarbon chain of the formula (CH2)1-2;

Ar is phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting and predstavlyaet valuable medicines to treat heart rhythm disorders of different Genesis and to prevent due to arrhythmia sudden death from cardiac arrest, therefore they can be used as antiarrhythmic drugs. Examples of arrhythmic heart disorders are supraselective disorders of heart rhythm such as atrial tachycardia, atrial flutter or paroxysmal supraselective disorders of rhythm or ventricular rhythm disorders, as ventricular extrasystoles, but especially life-threatening ventricular tachycardia or especially dangerous flicker of the heart ventricles. They are used especially for such cases, where arrhythmias are the result of narrowing of the coronary vessel, such as angina or acute myocardial infarction, or as a consequence of chronic myocardial infarction. Therefore, they are used especially for patients with postinfarction to prevent sudden death from cardiac arrest. Other clinical picture, where they play the role of rhythm disorders and/or suddenly caused by arrhythmia death from cardiac arrest, are, for example, heart failure or cardiac hypertrophy as a consequence of chronically elevated blood pressure.

In addition, the compounds can have a positive impact on the reduced contractility of the heart. Thus m is Enza, but also about acute cases, such as heart failure upon impact of the shock. Similarly, when the heart transplant after the operation, the heart can be faster and more reliable again to resume its performance. The same applies to operations on the heart, which necessitates a temporary suspension of cardiac activity due to cardioplegic solutions.

Further, the invention relates to a method of compounds 1, characterized in that the aromatic sulfonamides of the formula II

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or their salts of the formula III

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interact with R(1) substituted by isothiocyanates (VI):

R(1) - N = C = S, (VI)

where R(1), R(2), R(3), R(4), X, Y and Ar have the above values.

As the cation M in the salts of the formula III take into account the alkaline, alkaline earth, ammonium and tetraalkylammonium ions.

The unsubstituted benzosulfimide 1 b [R(1) = H, X = S] can be obtained by transformation of aromatic benzosulfimide II or its salt III with trimethylsilylcyanation or tetrastichinae silicon and splitting (hydrolysis) initially formed kremnezemistye benzosulfimide. Further, the aromatic benzosulfimide II or his solicitiation can interact with the aqueous solution of mineral acid 1 b [R(1) = H, E = S]. Such methods are described in J. Med. Chem. 1992, 35, 1137-1144.

Compounds 1 and their physiologically not cause fear salts are valuable therapeutic agents, which are used not only as the beginning of pregnancy, but also as a prophylactic for disorders of the cardiovascular system, heart failure, heart transplant, or diseases of cerebral vessels in humans or mammals (for example, monkeys, dogs, mice, rats, rabbits, Guinea pigs and cats). Under physiologically acceptable concerns salts of compounds 1 mean on Remington Pharmaceutical Science, 17th edition, 1985, pages 14 to 18, compounds of formula XII,

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which can be derived from nontoxic organic and inorganic bases and substituted benzosulfimide 1. While I prefer salt in which M in the formula XII are ions of sodium, potassium, rubidium, calcium, magnesium, ammonium, and addition products of basic amino acids, such as men or arginine.

Starting compound for the above-mentioned synthesis methods of benzosulfimide 1 get well-known methods, which are described in the literature (for example, in basic writings, as Houben-Weyl. Methods of organic chemistry, is vcah on patents), namely, in the reaction conditions which are known and suitable for the mentioned transformations. You can use also known, but not mentioned here more options. The initial substance 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 the formula XIII

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can be subjected to halogen sulfonation and received subsequent ammonolysis of the sulfonamide XIV

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interacting with the appropriate amine R(3)R(4)NH after activation of the carboxylic acid group in a carboxylic acid amide of the formula II

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As methods of activation are suitable obtain acid chloride of carboxylic acid, or a complex ester 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.

Sulfonamides XIV receive well-known methods, namely the reaction conditions which are known and suitable for the mentioned transformations. If this IP is in one two or more stages. Especially preferred ways in which the acid of formula XIII using electrophilic reagents in the presence or in the absence of inert solvents, translated at temperatures from -10oC to 120oC, mainly from the 0oC to 100oC, aromatic sulfonic acids and their derivatives, as the halides, sulfonic acids. For example, it is possible to carry out the sulfonation with sulfuric acid or fuming sulfuric acid halide sulphonation halogencontaining, reaction with sulfurylchloride in the presence of anhydrous metal halides or thionylchloride in the presence of anhydrous metal halides followed, carried out in a known manner by okisleniya to aromatic sulfonic acid chlorides. If sulfonic acids are the primary reaction products, the latter either directly or by treatment of the tertiary amines, such as pyridine or trialkylamines, or hydroxides of alkaline or alkaline earth metals, or chemicals that these basic compounds can form in the location, you can translate in a known manner through galodamadruga acid, as fosfortrichloride, photocatalysed, phosphorochloridate in sulfonamides exercise known from the literature by the way, mainly sulfonic acid chlorides turn in inert solvents at temperatures from 0oC to 100oC with a water solution of ammonia in acetone or TNG. In addition, aromatic sulfonamides of the formula XIV as described in the literature methods can be synthesized from the acid of formula XIII or their esters by transformation with organic reagents alkaline or alkaline earth metals in inert solvents and in the atmosphere of inert gas, at temperatures from -100oC to 50oC, preferably from -100oC to 30oC, with sulfur dioxide and subsequent heat treatment NH2donor, such as, for example, aminosalicylates.

The compounds of formula I according to the invention and their physiologically not cause fear salts can be used for the manufacture of pharmaceutical preparations, especially non-chemical way. When they are together at least solid, liquid carrier or auxiliary substance, alone or in combination with other active drugs for circulatory heart, as for example, calcium antagonists, NO-donors or ACE-inhibitors can form a suitable dosage form. These drugs can be used as medicines in the matter, used for intestinal (e.g. oral), parenteral, such as intravenous purpose, or for local applications, and which do not react with the new compounds, for example, vegetable oils, benzyl alcohols, polyethylene glycols, glyceryltrinitrate, gelatin, carbohydrate 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, spray, foams, aerosols, solutions (for example, in alcohols as ethanol or isopropanol, acetonitrile, dimethylformamide, dimethylacetamide, 1,2-propandiol or their mixtures with each other or with water) or dry powder. The new compounds can also be lyophilized and the resulting products lyophilization to apply, for example, for the manufacture of drugs for injection. In particular, for local use use of liposomal drugs. The preparations may contain stabilizers and/or substances with a high surface activity, emulsifiers salt group buffer substances, colorants and flavorings and/or aromatic substances. They can, if necessary, also contain one or more other active substances, for example one or more vitamins.

The dosage required for the treatment of cardiac arrhythmias compounds of formula I, depend on, have therapeutic treatment or prophylactic. Generally carry a range of doses approximately minimum 0.1 mg, mostly minimally 1 mg from up to 100 mg, mostly 10 mg, per 1 kg and 1 day if prevention is conducted. This dose can be divided into oral or parenteral single dose or as four single doses. If you treat acute cases of cardiac arrhythmias, for example, in a hospital intensive care may be beneficial to the parenteral administration. In this case, the preferred range of doses may be in critical situations from 10 to 100 mg and assign, for example, prolonged intravenous infusion.

Except as described in the embodiments of the compounds according to the invention can be obtained in the following connection table 1:

1). N-5-(1-phenylethyl)aminocarbonylmethyl-2-propoksifen is ultimatemenu;

3). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

4). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

5). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

6). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

7). N-5-(1-(3-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

8). N-5-(1-(2-thiazolyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

9). N-5-(1-(3-thiazolyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

10). N-5-(1-(2-furyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

11). N-5-(1-(3-furyl)-ethyl) aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

12). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - metacafemichael-N'-metallocene;

13). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

14). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

15). N-5-(1-(3-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

16). N-5-(1-(2-tionality-2 - methylphenylsulfonyl-N'-metallocene;

18). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

19). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

20). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

21). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

22). N-5-(1-(3-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-urea;

23). N-5-(1-(2-thiazolyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

24). N-5-(1-(3-thiazolyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

25). N-5-(1-(2-furyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

26). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

27). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

28). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

29). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

30). N-5-(1-(3-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

31). N-5-(1-(2-thiazolyl)-ethyl)aminocarbonylmethyl-2 - the Nile-N'-metallocene;

33). N-5-(1-(2-furyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

34). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

35). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

36). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

37). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

38). N-5-(1-(3-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N-methylthymidine;

39). N-5-(1-(2-thiazolyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

40). N-5-(1-(3-thiazolyl-)ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

41). N-5-(1-(2-furyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

42). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

43). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

44). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

45). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;
48). N-5-(1-(2-furyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

49). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

50). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

51). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

52). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

53). N-5-(1-(3-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

54). N-5-(1-(2-thiazolyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

55). N-5-(1-(3-thiazolyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

56). N1-5-(1-(2-furyl-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

57). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

58). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

59). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

60). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

61). N-5-(1-(3-pyrrolyl)-ethyl) - is-2 - ethoxyphenylacetic-N'-metallocene;

63). N-5-(1-(2-furyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

64). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

65). N-5-(1-(2-thienyl)-ethylaminomethyl-2 - propoxyethanol-N'-methylthymidine;

66). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

67). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

68). N-5-(1-(3-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

69). N-5-(1-(2-thiazolyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

70). N-5-(1-(3-thiazolyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

71). N-5-(1-(2-furyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

72). N-5-(1-(3-furyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

73). N-5-(1-(2-thienyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

74). N-5-(1-(3-thienyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

75). N-5-(1-(2-pyrrolyl)-ethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;
78). N-5-(1-phenylpropyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

79). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

80). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N-methylthymidine;

81). N-5-(1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

82). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

83). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

84). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

85). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

86). N-5-(1-(3-thiazolyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

87). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

88). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

89). N-5- (1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

90). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-IU/BR> 92). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

93). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

94). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

95). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

96). N-5-(1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

97). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

98). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

99). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

100). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

101). N-5-(1-(3-thiazolyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

102). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

103). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

104). N-5-(1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

105). the Il)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

107). N-5- (1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

108). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

109). N-5-(1-(3-thiazolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

110). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

111). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

112). N-5-(1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

113). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

114). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

115). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

116). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

117). N-5-(1-(3-thiazolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

118). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

119). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - metelli the N'-metallocene;

121). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

122). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

123). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

124). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

125). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

126). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

127). N-5-(1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

128). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

129). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

130). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

131). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

132). N-5-(1-(3-thiazolyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

133). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenyl;

135). N-5-(1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

136). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - etsyversary-N'-metallocene;

137). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

138). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

139). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

140). N-5-(1-(2-furyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

141). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

142). N-5-(1-(2-thienyl)propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

143). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

144). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

145). N-5-(1-(3-pyrrolyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

146). N5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

147). N-5-(1-(3-thiazolyl)-propyl)aminocarbonylmethyl-2 - propoxyphenyl the urea;

149). N-5-(1-(3-furyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

150). N-5-(1-(2-thienyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

151). N-5-(1-(3-thienyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

152). N-5-(1-(2-pyrrolyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

153). N-5-(1-(3-pyrrolyl) propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

154). N-5-(1-(2-thiazolyl)-propyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

155). N-5-(1-phenyl-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

156). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

157). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

158). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

159). N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

160). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

161). N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

163). N-5-(1-(3-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine;

164). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

165). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

166). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

167. N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

168. N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

169). N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

170). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-metallocene;

171). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

172). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

173). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

174). N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

175). N-5-(1-(2-pyrrolyl)-1-methylethyl)arylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

177). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

178). N-5-(1-(3-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine;

179). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

180). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

181). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

182). N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

183). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

184. N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N-metallocene;

185). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-metallocene;

186). N-5-(1-(3-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

187. N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

188). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

189). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonyl methyldiphenylamine-N'-methylthymidine;

191). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

192). N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

193). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

194. N-5-(1-(3-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-methylthymidine;

195). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

196). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

197). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

198). N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

199). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonyl-2 - methyldiphenylamine-N'-metallocene;

200). N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

201). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - methyldiphenylamine-N'-metallocene;

202). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

203). N-5-(1-(3-futil)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

205). N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

206). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

207). N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

208). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonyl-2 - ethoxyphenylacetic-N'-methylthymidine;

209). N-5-(1-(3-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-methylthymidine;

210). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

211). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

212). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

213). N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

214). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

215). N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonyl-2 - ethoxyphenylacetic-N'-metallocene;

216). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - ethoxyphenylacetic-N'-metallocene;

217). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-N'-methylthymidine;

219). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

220). N-5-(1-(3-thienyl-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

221). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

222). N-5-(1-(3-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

223). N-5-(1-(2-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

224). N-5-(1-(3-thiazolyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-methylthymidine;

225). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

226). N-5-(1-(2-furyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

226). N-5-(1-(3-furyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

227). N-5-(1-(2-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

228). N-5-(1-(3-thienyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

229). N-5-(1-(2-pyrrolyl)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metallocene;

230). N-Lil)-1-methylethyl)aminocarbonylmethyl-2 - propoxyethanol-N'-metalmachine.

Obtaining raw materials

Obtaining 3-sulfamoylbenzoic acids

4-substituted phenylalkylamine acid add parts under stirring to an excess of chlorosulfonic. Stirred for 30 minutes at room temperature, then poured on ice and suck educated sulfonic acid chloride. The latter is dissolved in an ammonia solution, stirred for 30 minutes at room temperature, and the solution is neutralized using 2 N. hydrochloric acid. The resulting product is sucked off.

In this method get:

3-sulfamyl-4-methoxyphenyl-3-propionic acid.

The melting point 172-176oC.

3-sulfamyl-4-methoxyphenylalanine acid.

The melting point 164oC.

Obtaining 3-sulfonylamino-N-(methylaminomethyl)-4 - methoxyphenylacetic acid

5 g of 3-sulfamyl-4-methoxy-phenylacetic acid are dissolved in 3 ml of dimethylformamide and stirred with 245 mg of sodium hydroxide for 30 minutes at 40oC. Add 328 mg methylisothiocyanate and stirred for further 2 hours at 70oC. To the cooled solution add 2 N. hydrochloric acid and the product is sucked off. The melting point of 174oC.

Obtaining N-5-(snoi acid and 4.0 g of triethylamine are dissolved in 25 ml of dimethylformamide and mixed under ice cooling with anhydride papapostolou acid (0,15 mol; 50% in NF) and then 1.2 g (0,01 mol) 1-phenethylamine. Stirred for 3 hours at room temperature and sending the mixture in water. After some time the product crystallizes and can be used many times without further purification for the other transformations.

Similarly get:




Melting point: 156-158oC.


Melting point: 117 - 118oC.


Melting point: 143 - 145oC.

General working method to obtain sulfonyl (thio)ureas 1 of sulfonamides 2: A).

0,01 mol sulfonamida II is dissolved in 25 ml of dimethylformamide and mixed with 0,006 mol K2CO3. Under stirring add to 0.011 mol ISO(thio)cyanate and heat the mixture for about 2 - 6 hours at 60 - 80oC. Pour the mixture into ice water and acidified with 2 N. HCl. The precipitated crystals are sucked off and, if necessary, purified by recrystallization or chromatogra is after acidification in a pure form. B).

The sulfonamide add 2 CS2and KOH in dimethylformamide, and then to Pikalevo salt add triphosgene. Finally add the ammonia, and the solution is acidified.


Example 1:

N-5-(1-phenylethyl)aminocarbonylmethyl-2-methoxybenzenesulfonyl - N'-methylthymidine.

Melting point: 175 -176oC.

Example 2:

N-5-(1-phenylethyl)aminocarbonylmethyl-2-ethoxyphenylacetic-N'- methylthymidine.

Melting point: 156 - 158oC.

Example 3:

N-5-(1-phenylethyl)aminocarbonylmethyl-2-methylphenylsulfonyl - N'-methylthymidine.

Example 4:

N-5-(1-naphtalate)aminocarbonylmethyl-2-methoxybenzenesulfonyl - N'-methylthymidine.

Melting point: 188 - 190oC.

Example 5:

N-5-(phenylpropyl)aminocarbonylmethyl-2-methoxybenzenesulfonyl - N'-methylthymidine.

Melting point: 125 - 127oC.

Example 6:

N-5-(1-Perelmuter)aminocarbonylmethyl-2-methoxybenzenesulfonyl - N'-methylthymidine.

The melting point of 128-130oC.

Example 7:

N-5-(1-vinylcyclopropyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine.

Melting point: 195 - 197oC. moonvine.

Melting point: 181 - 183oC.

Example 9:

N-5-(1-(2-methoxyphenyl)ethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine.

Melting point: 178 - 179oC.

Example 10:

N-5-(1-fenilpentil)aminocarbonylmethyl-2-methoxybenzenesulfonyl - N'-methylthymidine.

Melting point: 143 - 145oC.

Example 11:

N-5-(1-phenylpropyl)aminocarbonylmethyl-2-methylsulphonyl-N'- methylthymidine.

Melting point: 117 - 118oC.

Example 12:

N-5-(1-phenyl butyl)aminocarbonylmethyl-2-methylsulphonyl-N'- methylthymidine.

Melting point: 112 - 113oC.

Example 13:

N-5-(1-vinylcyclopropyl)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine.

Melting point: 130 - 131oC.

Example 14:

N-5-(1-phenylcyclohexylamine)aminocarbonylmethyl-2 - methylphenylsulfonyl-N'-methylthymidine.

Melting point: 145 - 147oC.

Example 15:

N-5-(2-(1,1 R-phenylethyl)aminocarbonyl)ethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine.

Melting point: 88oC.

Example 16:

N-5-(2-(1,1 S-phenylethyl)aminocarbonyl)ethyl-2 - methoxybenzenesulfonyl-N'-meta metil-2 - methoxybenzenesulfonyl-N'-methylthymidine.

Melting point: 150 - 152oC.

Example 18:

N-5-(1,1 S-phenylethyl)aminocarbonylmethyl-2 - methoxybenzenesulfonyl-N'-methylthymidine.

Melting point: 150 - 152oC.

Example 19:

N-5-(1,1 S-phenylbutyl)aminocarbonyl)ethyl - 2-methoxybenzenesulfonyl-N'-methylthymidine.

Melting point: 171oC.

Pharmacological data:

therapeutic properties of the compounds of formula 1 become apparent based on 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 (adenosine triphosphate), which monitored during ischemia in the cell of the heart muscle, lead to a reduction in the duration of the action potential. They are considered one of the reasons the so-called Reentry-arrhythmias that can cause sudden death from cardiac arrest. The reason for this is considered an open-sensitive ATP-channels by reducing the APR.

(b). Method.

To measure the action potential is applied to the standard method with microelectrodes. For this shot in the head kill Guinea pigs of both sexes, take heart, separate SOS,9 NaCl, 0,048% KCl, 0,024% CaCl2, 0,02% NaHCO3and 0.1% Glucose) and treated with a mixture of 95% oxygen and 5 % carbon dioxide at a temperature of 36oC. Muscle excite via the electrodes with rectangular pulses of 1 V and with a duration of 1 MS at a frequency of 2 Hz. The action potential is measured and recorded is entered into the cell glass microelectrodes, which is filled with a solution of 3 mmol of KCl. To test substances added to the ringer's solution at a concentration of 2.2 10-5mol per liter. The action potential boost by means of the amplifier Hugo Sachs and recorded on an oscilloscope. The duration of the action potential is determined at the level of repolarization 95% (APD 95).

Reducing the duration of the action potential cause or addition of 1 μm-molar solution of the discoverer of potassium channels Noah 234 (J. Kaiser, H. Gegelein, Naunyn-Schmiedebergs Arch. Pharm. 1991, 343, R59) or by addition of 2-deoxyglucose. The effect of shortening the potential duration of these substances is prevented or reduced its simultaneous reception of the test substances. The test substances were added as uterine solutions in propane diol to a solution of the bath. The stated values refer to measurements after 30 minutes after the addition. Glibenclamide is used in AIX). The results are presented in the table.

1. Substituted benzosulfimide formula I

< / BR>
where R(1) represents alkyl with 1 to 6 C-atoms;

R(2) is alkyl with 1 to 6 C-atoms or alkoxy with 1 to 6 C-atoms;

R(3) and R(4), the same or different, represent hydrogen, alkyl with 1 to 6 C-atoms or together form a chain -(CH2)2-5-;

E represents a sulfur atom;

X represents an oxygen atom;

Y represents a chain -(CH2)1-2-;

Ar represents phenyl or naphthyl, which can be unsubstituted or substituted by one or two substituents from the group of alkyl with 1 or 2 C-atoms, alkoxy with 1 or 2 C-atoms.

2. Substituted benzosulfimide formula I under item 1, where the radicals have the following meanings: R(1) - alkyl with 1 or 2 C-atoms; R(2) - alkoxy with 1, 2, 3, 4, 5 or 6 C-atoms; R(3) and R(4) is the same or different and represent hydrogen, alkyl with 1 to 6 C-atoms;

E - sulfur;

X is oxygen;

Y is a hydrocarbon chain of the formula (CH2)1-2;

Ar is phenyl or naphthyl, which can be unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of alkyl with 1 or 2 C-atoms, alkoxy with 1 or 2 C-Aromamedia: R(1) - alkyl with 1 or 2 C-atoms; R(2) - alkoxy with 1, 2, 3, 4, 5 or 6 C-atoms; R(3) and R(4) is the same or different and represent hydrogen or methyl; S is sulfur; X is oxygen; Y is a hydrocarbon chain of the formula (CH2)1-2; Ar is naphthyl, which can be respectively unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of alkyl with 1 or 2 C-atoms, alkoxy with 1 or 2 C-atoms.

4. Substituted benzosulfimide formula I according to one of paragraphs.1 to 3, where the radicals have the following meanings: R(1) - alkyl with 1 or 2 C-atoms; R(2) - alkoxy with 1, 2, 3, 4, 5 or 6 C-atoms; R(3) and R(4) is the same or different and represent hydrogen or methyl; S is sulfur; X is oxygen; Y is a hydrocarbon chain of the formula (CH2)1-2; Ar is naphthyl, which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of alkyl with 1 or 2 C-atoms, alkoxy with 1 or 2 C-atoms.

5. The method of obtaining derivatives benzosulfimide formula I under item 1, characterized in that benzosulfimide formula II

< / BR>
or its salt of the formula III

< / BR>
interacting with R(1) substituted by isothiocyanato VI

R(1) - N = C = S,

where R(1), R(2), R(3), R(4), X, Y, and Ar are specified in paragraph 1 values;

M - ion alkaline or selecetion formula I on PP.1 - 4, has antiarrhythmic action.

7. Substituted benzosulfimide formula I on PP.1 - 4, suitable for the production of a pharmaceutical preparation having anti-arrhythmic effect.

8. Substituted benzosulfimide formula I on PP.1 - 4, suitable for the production of a pharmaceutical preparation for preventing sudden death from cardiac arrest.

9. Substituted benzosulfimide formula I on PP.1 to 4, have the property to inhibit potassium channels in the heart with a heightened sensitivity to ATP.

10. Pharmaceutical drug that has anti-arrhythmic action, containing the active substance and conventional inert additives, characterized in that the active substance it contains a compound of General formula I on PP.1 to 4 in an effective amount.


Same patents:

The invention relates to medicine, in particular to derivatives of diazepine formula, where the values of the radicals A, R1X, Y, and R4specified in the claims, to a pharmaceutical composition having anti-arrhythmic activity, and to a method of treating arrhythmia

The invention relates to ortho-substituted heterocyclyl-benzoyl-guanidine formula (I)

< / BR>
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;

R4denotes H, a, cycloalkyl with 5-7 C atoms, cycloalkenyl with 6-8 C atoms, CF3CH2F, CHF2CH2CF3Ph or-CH2-Ph;

R5denotes H or A, or, however,

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

FIELD: medicine, pharmaceuticals, in particular compositions for treatment of insulin-independent II type diabetus mellitus.

SUBSTANCE: claimed composition represents single solid dosed pharmaceutical for oral administration and contains effective dose of metformin and glibenclamide, wherein said glibenclamide contains powdery particles with specific surface of 1.7-2.2 m2/g. Also disclosed are method for treatment of insulin-independent diabetes or hyperglycemia; method for providing and enhancing of glibenclamide bioavailability in human body (variants).

EFFECT: composition with increased glibenclamide bioavailability.

68 cl, 3 ex, 7 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine and pharmacology, particularly a solid dosed formulation for treatment of pancreatic diabetes, the said formulation including a highly stable and solid combination of therapeutically effective quantities of metformin and glyclazide at the ratio of 6.2-12.5 with target additives such as sorbitol, polyvinylpyrrolidone, stearic acid and/or stearate, sodium croscarmellose as active substance.

EFFECT: obtaining solid formulation for treatment of pancreatic diabetes.

4 cl, 5 ex

FIELD: medicine.

SUBSTANCE: combined medical form with controlled release for peroral introduction, which contains a) part with controlled release, which contains metformin or its pharmacologically acceptable salt as active ingredient, and combination of polyethylenoxide and natural pitch as carrier for controlled release and b) part with quick release, which contains anti-diabetic medication based on sulfonylurea as active ingredient, applied on part with controlled release, intended for diabetes treatment.

EFFECT: possibility to support effective concentration of medications in blood at constant level.

19 cl, 21 ex, 18 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns area of medical products, in particular to structure for oral tablets with the modified release, containing fine gliclazide for depression of level of a glucose in blood with defined granulat metric structure, and also the agent modifying liberation, for gliclazide release control; and fine gliclazide for depression of level of a glucose in blood has certain profiles of dissolution in the cleared water. Besides the invention concerns the way of reception of the specified structure.

EFFECT: decrease of level of glucose in the blood during long period of time.

8 cl, 3 dwg, 9 tbl, 8 ex

FIELD: veterinary.

SUBSTANCE: medication includes the following components, wt %: Sulfadimezinum 11.5-15; Trimethoprim 2.0-3.6; Colistin 2.0-3.5; glucose up to 100. Before application the medication is dissolved in warm water or colostrums at 35-37°C or fed with forage. The medication is applied daily twice in the dosage of 100 mg/kg of body weight for 3-5 days, or for 5-7 days under severe course of disease.

EFFECT: enhanced efficiency of colibacteriosis treatment for form animals.

12 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to synthesis of new biologically active substance, namely, to γ-hydroxypropylammonium-5-hydroxynicotinate of the formula (I): , eliciting an anti-ischemic, anti-arrhythmic and hypolipidemic activity. This compound shows low toxicity and absence of cardiodepressive effect. Compound of the formula (I) is prepared by interaction of 5-hydroxynicotinic acid with 3-amino-1-propanol in the presence of a solvent at heating.

EFFECT: valuable medicinal properties of compound.

1 cl, 7 tbl, 3 ex