Cyclic sulfones, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

The invention relates to new heterocyclic condensed to benzoylpyridine General formula I, where R1and R2denote independently from each other H or A; X denotes CR4R5; C=Z or O, Y represents CR6R7Z denotes O or CH2, R4, R5, R6or R7denote independently from each other H, A, HE or OA, or R5and R6or R7and R8indicate link together, with each molecule may receive a maximum of only one such bond, or R4and R5indicate together O-(CH2)2-O or O-(CH2)3-O, or R8and R9denote independently from each other H or A; And denotes alkyl with 1 to 6 C-atoms; n represents 0 or 1, and their physiologically acceptable salts. Benzoylpyridine formula I are inhibitors of the cellular Na+/H+antinomies and used to obtain drugs. Also described is a method of obtaining compounds of formula I, pharmaceutical composition and method of reception. 4 C. and 1 C.p. f-crystals, 1 PL.

The invention relates to cyclic sulfones of the formula I

< / BR>
g the UB>2F5Hal, HE, OA, NH2, NHA, NA2, NO2or CN,

X represents-CR4R5, C=Z, O, S, NH, NA or NR3,

Y represents CR6R7, C=Z, O, NH, NA or NR3,

Z represents O, S, NH, NA, NOH, NOA, CH2, CHA CA2,

R4, R5, R6and R7denote, respectively independently of each other H, A, R3Hal, HE, OA, SH, SA, NH2, NHA or NA2or R5and R6? or R7and R8denote, respectively, along the relationship, with each molecule may receive only one such connection;

R4and R5indicate together also O-(CH2)2-O or O-(CH2)3"OH,

R8and R9denote, respectively independently of one another H or A,

A denotes alkyl with 1-6 C-atoms,

Hal denotes F, Cl, Br or I and

R3denotes unsubstituted or substituted one-, two -, or triple A, OA, NH2, NHA, NA2, F, Cl, Br and/or CF3phenyl or benzyl, and

n denotes 0 or 1,

and to their physiologically acceptable salts.

The objective of the invention is the search for new compounds with valuable properties, especially those that can be applied for the manufacture of medicines.

Was no pharmacological properties.

When new connections we are talking about the inhibitors of the cellular Na+H+antinomies, i.e. active substances which inhibit the mechanism of Na+H+-exchange cells (Dusing, etc., Med. Klin. 87, 378-384 (1992)) and are, therefore, good antiarrhythmic agent, which is suitable in particular for the treatment of arrhythmias, appearing as a consequence of hypoxia.

The most well-known active substance group acylhalides is amiloride. However, this substance shows, first of all, lowering blood pressure and salureticheskoe action, which is undesirable especially in the treatment of cardiac arrhythmias, while antiarrhythmic properties expressed only very weakly.

Benzoylpyridine described, for example, in German patent DE 4404183.

However, as described in the prior art compounds differ significantly in structure from the claimed compounds.

The subject invention are the compounds of formula I and their physiologically acceptable salts.

Matter of this application according to the invention show good cardiotoxin action and are therefore suitable in particular for the treatment of myocardial infarction, prophylaxis heart attack and to treat angina. Further, what can be treated primarily or secondarily caused by disease. Substances successfully used also for prevention.

Based on the protective action of these substances in pathological hypoxic or ischemic situations there are other possible use in surgical procedures to protect the temporarily less supplied with blood, organs, transplant organs taken to protect organs angioplasticheskih interventions in the blood vessels or heart, when ischemia of the nervous system, in the treatment of shock conditions and for preventive treatment of essential hypertension.

Further, the compounds can also be used as a therapeutic agent when due to cell proliferation diseases as arteriosclerosis, diabetic late complications, neoplastic disease, fibromya diseases, especially lung, liver, and kidney, as well as hypertrophy and hyperplasia of the bodies. In addition, substances used for diagnostic purposes for detection of diseases which are accompanied by increased activity of Na+/H+antinomies, for example, in erythrocytes, platelets or leukocytes.

Steps compounds can be determined using known methods, which are listed, for example, N. Escobales and J. experimental animals are used, for example, mice, rats, Guinea pigs, dogs, cats, monkeys or pigs.

The compounds can therefore be used as active substances of medicines in medicine and veterinary medicine. Further, they are used as intermediate products for the manufacture of other active substances of medicines.

In the above formulas, the group A represents a group of alkyl branched or unbranched chain with 1-6, preferably 1-4, especially 1, 2 or 3 C-atoms, particularly preferably methyl, further preferably ethyl, propyl, isopropyl, butyl, isobutyl, then preferably Deut.-butyl, tert. -butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).

R1denotes preferably A, especially methyl or ethyl, or hydrogen.

R2represents preferably hydrogen, while R3is preferably phenyl or benzyl.

X and Y respectively represent, independently of one another particularly preferably-CH2-, -CH(CH3)-, -C(=CH2)-, -C(CH3)2, -CH(OH)-, -SON(CH3)-, -C(OH)R3-, -C(OCH3)CH3-, -CH(OCH3)-, -C(OCH3R3-, -CHCl-, -CH(NH2)-, -CH(NA2)-, -CH(CN)-, -CO-, -C(=NOH)-, -C(=NOA)-, -C(O-CH2)-, =CH-CH2-, =C(CH3)-CH2- or =CH-CH(CH3)-.

R8and R9are mostly independent from each other H, methyl or ethyl.

R5and R6or R7and R8however respectively together can also represent a relationship, with, however, only one such connection can exist in one molecule.

Hal preferably denotes F, Cl or Br.

In General, this means that all residues, as for example, A, which can appear multiple times in the molecule, the same or different, i.e., can be independent from each other.

In accordance with the objects of the invention are particularly such compounds of the formula I, in which at least one of these residues has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following formulas Ia-Ig, which correspond to the formula I and in which an unnamed more residues are indicated for the formula I is, however, where

in Ia - X and Y denote, respectively, CH2and n = 0;

1b - n = 0 and X or Y denotes CH(CH3), respectively, and the remainder represents CH2;

in 1c - X and Y denoted by-CH2- or-CH2-C(CH3)2and n = 0;

in Id - Y denotes CH2and X is CHOH, C(CH3)OH, CR3OH, CHOCH3, CA(OCH3), CR3(OCH3), CHCl, CH(NH2), CH(NHA), CH(NA2), CH(CN), C=O, C(O-CH2CH2O), C(=NOH), or C(=NOA) and n = 0;

Ie - X = Oh, n = 0 and Y denotes CH2CH(CH3) or C(CH3)2;

in the If - X = NH, NA or NR3, Y denotes CH2CH(CH3) or C(CH3)2and n = 0;

in Ig group -(CR8R9)n- Y-X is-CH2-CH=CH - or-CH=CH-CH2-.

Further, particularly preferred such compounds, which are mentioned in paragraphs Ia-If preferred values, but in which n = 1 and CR8R9- is preferably CH2CH(CH3) or C(CH3)2.

Further, the subject invention is a method for producing compounds of the formula I in claim 1 and their salts, characterized in that the compound of formula II

< / BR>
where R1, R2, R8, R9X, Y and n have the above meanings and

Q denotes Cl, Br, OA, O-CO-A, O-CO-Ph, HE or another reactive esterified OH group or denotes easily nucleophile replaced the deleted group, is subjected to the interaction with guanidine, or that soutetsu or more recoverable groups and/or one or more additional C-C and/or C-N-bonds process regenerating means, or that corresponding generally to the formula I compound, which, however, instead of one or more hydrogen atoms contains one or more solvolysis groups, process solvolysis means, and/or that the received base of formula I by treatment with an acid converted into one of its salts.

However, the compounds of formula I get the known methods described in the literature (for example, in basic writings, as Houben-Weyl. Methods of organic chemistry, publisher Georg Thieme, Stuttgart; Organic reactions. John Wiley & Sons, Inc., New York; and in the above patent application), at reaction conditions which are known and suitable for these interactions. You can use also known not mentioned here more options.

Source materials can also be formed in Situ if desired, so that they are not isolated from the reaction mixture, and immediately turn on to compounds of formula I.

Preferably, the compounds of formula I is produced by interaction of the activated carboxylic acid derivative of the formula II, and Q is particularly preferably Cl or-O-CH3

Used as intermediate compounds carboxylic acids of the formula II and their derivatives can, for example, to get the

(a) catalyzed by bases intramolecular cyclization of 3-methyl-sulfonylmethane acids or derivatives of these acids, which contain in the 4-position carbonyl group or a cyanide, for example,

< / BR>
< / BR>
(b) reaction of Hakka suitable derivatives of 3-alkanesulfonyl-4-bromobenzoyl acid, for example,

< / BR>
(response Hecka see, for example, Organic reactions, 27, 345 (1982));

(C) an intramolecular nucleophilic substitution of 4 - halogencontaining acids or their derivatives, which in the 3-position contain suitable hydroxy-, amino - or mercaptoacetyltriglycine the remainder (R), for example,

< / BR>
(d) oxidation of cyclic sulfides of General formula

< / BR>
(e) attaching carbonyl compounds to mercaptophenyl or mercatoria and subsequent oxidation

< / BR>
or

(R = OH or NH2;

R1 and Q are as defined)

< / BR>
, the third edition, John Wiley & Sons (1985).

Thus obtained cyclic sulfones conventional methods can be turned into derivatives or collisional.

The interaction of a reactive carboxylic acid derivative of the formula II with guanidine carried out in a known manner, preferably in a proton or aprotic, polar or nonpolar, inert, organic solvent.

The preferred option is, however, that the components of the reaction directly without the addition of solvent, lead into reaction with each other.

Upon receipt II or in the interaction of II with guanidine it is also advisable to work in the presence of base or with an excess of the basic components. As the bases used are preferably, for example, hydroxides, carbonates, alkaline alcoholate or alkaline earth metals, or organic bases such as triethylamine or pyridine, which are also used in excess and which in this case can simultaneously serve as solvents.

As inert solvents are particularly alcohols as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers like diethyl ether, disop the ol or ethylglycol), etilenglikolevye ether (diglyme); ketones, such as acetone or butanone; NITRILES like acetonitrile; nitro compounds, as nitromethane or nitrobenzene; esters as ethyl acetate; amides, as hexamethylene phosphoric acid; sulfoxidov as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons like dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons as benzene, toluene or xylene. Next, apply a mixture of these solvents.

Particularly suitable solvents are methanol, THF, dimethoxyethane, dioxane, water or produced from these mixtures. The reaction is conducted, for example, at temperatures between 20oC and the boiling point of the solvent. The reaction time is from 5 minutes to 12 hours. Appropriate response to applied catcher acid. For this purpose these kinds of grounds that are not directly impede the reaction. However, particularly advantageous application of inorganic bases like potassium carbonate or organic bases like triethylamine or pyridine, or an excess of guanidine.

Further, the compounds of formula I can be obtained by releasing them from their functional derivatives by solvolysis, especially hydrolysis, or the SJ such substances, which typically correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxy-group, preferably such that instead of H-atom with a N-atom, contain a protective amino group, especially those who instead of HN-groups contain R'-N-group, where R' denotes a protective amino group, and/or such that instead of the H atom of the hydroxy-group containing a protected hydroxy-group, for example, those that correspond to the formula I, but instead of the OH-groups contain OR 'group, where R" represents a protected hydroxy-group.

In the molecule of the original substance can be several - same or different - protected amino and/or hydroxyl groups. If the existing protective groups differ from each other, they in many cases can selectively be chipped off.

The expression "protective amino group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group prior to chemical interaction, but which can be easily removed after the desired chemical reaction carried out on the other side of the molecule. Typical of such groups are especially resumes ethyl (CMV) or kalkilya group (for example, benzyl, 4-nitrobenzyl, triphenylmethyl). Because the protective amino group after the desired reaction (or sequence of reactions) are removed, their type and value is not however critical; however, prefer group with 1-20, especially with 1-8 C-atoms. The expression "acyl group" in connection with the present method should be considered in its broadest sense. It includes formed from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulfonic acids acyl group and especially alkoxycarbonyl, aryloxyalkyl and primarily alcoxycarbenium group. Examples of such acyl groups are alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluoyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tert. -butoxycarbonyl (BOC) 2-iodoxybenzoic; Uralelectromed as benzyloxycarbonyl (CBZ), 4-methoxy-benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred protective amino groups are BOC, DNP and BOM, then CBZ, benzyl and acetyl.

The expression "protective hydroxy-group" is also obsess is about which can be easily removed, after the desired chemical reaction carried out on the other side of the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, kalkilya or acyl group, then the alkyl group. The nature and magnitude of the protective hydroxy groups is not critical, because they are after the desired chemical reaction or sequence of reactions again removed; prefer group with 1-20, especially with 1-10 C-atoms. Examples for protective hydroxyl groups are, in particular, tert.-butyl, benzyl, p-nitrobenzyl, p-toluensulfonyl and acetyl, and especially preferred benzyl and acetyl.

Used as starting substances functional derivatives of compounds of formula I can be obtained by conventional methods, which are described, for example, called the fundamental papers and patent applications, for example, the conversion of compounds which correspond to the formulae II and III, however, and at least one of these compounds contains a protective group instead of the H atom.

The release of the compounds of the formula I from their functional derivatives is possible - depending on the use of protective groups - for example using strong acids, expediently Lana acid or sulfuric acid, strong organic carboxylic acids, as trichloroacetic acid or sulfonic acids, as benzene - or p-toluensulfonate. Perhaps, but it is not always necessary, the presence of an additional inert solvent. As the inert solvents used are preferably organic, for example carboxylic acids, as acetic acid, ethers, like tetrahydrofuran (THF) or dioxane, amides, as dimethylformamide (DMF), halogenated hydrocarbons like dichloromethane, then also alcohols as methanol, ethanol or isopropanol, and water. Next, apply a mixture of the above solvents. Triperoxonane acid is preferably used in excess without the addition of another solvent, perchloro acid in the form of a mixture of acetic acid and 70% perchloro acid in the ratio 9:1. Reaction temperatures for the cleavage are usually approximately between 0 and 50oC; preferably employs between 15 and 30oC (room temperature).

BOC-group can be split, for example, preferably 40% triperoxonane acid in dichloromethane or approximately 3-5 N. HCl in dioxane at 15-60oC, FMOC - group of approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-50oC. Use The P>C.

Removed by hydrogenolysis of the protective group (for example, BOM, CBZ or benzyl) can be split, for example, by treatment with hydrogen in the presence of a catalyst (e.g. catalyst based on a noble metal as palladium, expediently on a medium such as coal). At the same time as the solvent used, as described above, particularly, for example, alcohols, like methanol or ethanol, or amides, as DMF. The hydrogenolysis is carried out, as a rule, at temperatures between about 0 and 100oC and at pressures between about 1 and 200 bar, preferably at 20-30oC and at a pressure of 1-10 bar. Hydrogenolysis of CBZ-group is good at, for example, on 5-10% Pd-C in methanol at 20-30oC.

The basis of the formula I can then use acid to translate to the corresponding acid additive salt. For this interaction is used acids, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, halogen acids as hydrochloric acid or Hydrobromic acid, phosphoric acid, like phosphoric acid, sulfamic acid, then the organic acids, especially aliphatic, alicyclic, Analiticheskaya acid, for example, formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2 - or 3-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluene-acid, naphthalene-mono - and-disulfonate, louisanna acid.

The compounds of formula I contain one or more chiral centers and therefore may exist in racemic or in optically active form. Resulting racemates can be well-known methods to separate mechanically or chemically to the enantiomers. Preferably the racemic mixture by reacting with an optically active separating means are formed diastereomers. As release agents are used, for example, optically active acids, such as D - and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acids is Hakikat. Advantageous to separate the enantiomers using a column filled with optically active separation means (for example, dinitrobenzonitrile).

Of course, optically active compounds of formula I can also be obtained by the methods described above, and used the original substance, for example, formula (II), which are already optically active.

The compounds of formula I and their physiologically acceptable salts can be used for the manufacture of pharmaceutical dosage forms, especially non-chemical way. When they are brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance and, if necessary, in combination with one or more other active ingredients.

The subject invention are then tools, especially pharmaceutical dosage form containing an effective amount of at least one of the compounds of formula I and/or one of its physiologically acceptable salts.

These forms can be used as drugs in medicine or in veterinary medicine. As carriers use organic or inorganic Veselye not react with the new compounds, for example, water, vegetable oil, benzyl alcohol, glycols, glyceryltrinitrate, gelatin, carbohydrate as lactose or starch, magnesium stearate, talc, lanolin, petrolatum. For oral administration is particularly suitable tablets, coated tablets, capsules, syrups, juices or drops; for rectal use candles; for parenteral administration are solutions, preferably oily or aqueous solutions, then suspensions, emulsions or implants; for local application are ointments, creams, pastes, lotions, gels, sprays, foaming agents, aerosols, solutions (e.g. solutions in alcohols as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propandiol, or a mixture thereof among themselves and/or with water) or dry powder. New connections can be subjected to the freeze-drying and the resulting lyophilizate to apply, for example, to obtain drugs for injection.

In particular, for local applications also use liposomal dosage forms. These dosage forms can be sterilized, and they may contain and/or auxiliary substances as substances which impart lubricity, preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing osmotic given, also contain one or more other active substances, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be assigned to people or animals, especially mammals like monkeys, dogs, cats, rats or mice and therapeutic treatment of the human or animal, in the treatment of diseases, especially in the treatment and/or prevention of disorders of the cardiovascular system. Therefore, they are used to treat arrhythmias, especially when the latter caused by hypoxia, stroke, heart attacks, ischemia of the nervous system, such as stroke or brain edema, shock, and for preventive treatment.

Further, the substance can be used as therapeutic agent for diseases in which play the role of cell proliferation as arteriosclerosis, diabetic late complications, neoplastic diseases, fibrosis, and hypertrophy and hyperplasia of the authorities, in particular, diseases of the prostate.

When this substance according to the invention, as a rule, appoint by analogy with the known antiarrhythmic means, for example, aprindine, preferably in dosages between about to about of 0.0001 and 0.1, especially between 0,0003 and 0.01 mg/kg of body weight. However, the individual dose for each particular patient depends on various factors, for example, the effectiveness of the introduced compound, the age, body weight, General health, sex, food, time, and method of drug administration, rate of excretion, combination of drugs and the severity of the relevant disease for which treatment acts. Prefer oral administration.

In the following examples, "conventional processing" means:

add if you want water, extracted with an organic solvent like ethyl acetate, separate the organic phase, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography and/or crystallization.

Example 1:

Bring in a nitrogen atmosphere, with stirring and with the exclusion of moisture, and 1.9 g of sodium in 40 ml of dried methanol. The resulting solution is mixed at room temperature with 8.7 g of guanidine hydrochloride and stirred for 30 minutes. The suspension is filtered, the filtrate is mixed with 4 g of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxy-1-benzothiophen-6-carboxylic acid (obtained by cyclization met the slots and recovery of sodium borohydride obtained ketone) and stirred for 3 hours at 50oC. Then the reaction mixture while cooling with ice mixed with water, saturated with sodium chloride and extracted with complex ethyl ester of acetic acid. After the usual processing receive 1,1-dioxide, N-diamino-methylene-2,3-dihydro-3-hydroxy-1-benzothiophen-6-carboxamide, so pl. 240-241oC. Processing methansulfonate in methanol receive the corresponding methanesulfonate, so pl. 204-206oC.

Similarly, get:

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxy-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-5-methyl-1-benzothiophen-6-carboxamide, methanesulfonate: so pl. 266 - 267oC (from methanol);

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophen-6-carboxamide, so pl. 243-245oC, methanesulfonate: so pl. 214-216oC;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxy-3-ethyl-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-3-methyl-5-ethyl-1-benzothiophen-6-carboxamide, so pl. 126-128o, methanesulfonate: 218-220o;

of the 1.1-die N-diaminomethylene-2,3-dihydro-3-hydroxy-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxy-2,2,5-trimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-2,2,5-trimethyl-1-benzothiophen-6-carboxamide, so pl. 253o, methanesulfonate: 262-263o;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-chloro-3-methyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-chloro-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-chloro-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-chloro-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-chloro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-chloro-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-chloro-3-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-chloro-3-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-cyan-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-cyan-5-methyl-1-benzothiophen-6-carboxamide is the notes

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-cyan-3-methyl-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-cyan-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-cyan-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-cyan-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-cyan-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-cyan-3-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-cyan-3-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-amino-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-amino-5-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-amino-3-methyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-amino-3-methyl-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-amino-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-amino-5-et-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-amino-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-amino-3-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-amino-3-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N-methylamino-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N-methylamino-5-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N-methylamino-3-methyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N-methylamino-3-methyl-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N-methylamino-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N-methylamino-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N-methylamino-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N-methylamino-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N-methylamino-3-methyl-1-benzothiophen-6-carboxylic Cyclotimia difficult methyl ester of 2,3-dihydro-3-N,N-dimethylamino-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N-dimethylamino-5-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N,N-dimethylamino-3-methyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-3-methyl - 5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N,N-dimethylamino-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N,N-dimethylamino-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-N,N-dimethylamino-3-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-N,N-dimethylamino-3-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methyl-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-oxo-5-methyl is oxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-oxo-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-oxo-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-oxo-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-oxo-5-fluoro-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-oxo-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-oxo-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-oxo-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-oxo-5-trifluoromethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3,3-Ethylenedioxy-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-Ethylenedioxy-5-methyl-1-benzothiophen-6-carboxamide, so pl. 242oC, methanesulfonate: 285-287oC,

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3,3-Ethylenedioxy-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-Ethylenedioxy-5-ethyl-1-benzothieno-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-Ethylenedioxy-5-fluoro-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3,3-Ethylenedioxy-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-Ethylenedioxy-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3,3-Ethylenedioxy-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-Ethylenedioxy-5-trifluoromethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxyimino-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-methyl-1-benzothiophen-6-carboxamide; so pl. 250oC (methanesulfonate);

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxyimino-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxyimino-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-fluoro-1 - benzothiophen-6-carboxamide;

of 1,1-dioxide sloneg-diaminomethylene-2,3-dihydro-3-hydroxyimino-2,2,5-trimethyl-1-benzothiophen-6-carboxamide; so pl. 237-238oC (methanesulfonate);

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-hydroxyimino-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-trifluoromethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methoxyimino-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methoxyimino-5-methyl-1-benzothiophen-6-carboxamide; so pl. 284oC (methanesulfonate);

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methoxyimino-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3 - methoxyimino-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methoxyimino-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methoxyimino-5-fluoro-1-benzothiophen-6-carboxamide,

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methoxyimino-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methoxyimino-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methoxyimino-5-trifluoromethyl-1-benzo is iophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methoxy-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methoxy-1-benzothiophen-6-carboxamide, so pl. 193-194oC methanesulfonate: so pl. 234-236oC;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methoxy-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methoxy-5-methyl-1-benzothiophen-6-carboxamide, so pl. 224oC methanesulfonate: so pl. 249-251oC.

EXAMPLE 2:

Contribute with the exclusion of moisture, in a nitrogen atmosphere and with stirring, 1.24 g of sodium in 20 ml of dry methanol. Then mix the solution at room temperature with 5,64 g of guanidine hydrochloride and stirred for 30 minutes. Then filtered, the filtrate is concentrated in vacuo, mixed with 10 ml etilenpropilendienovogo ether (EDME) and again freed from solvent. The residue is absorbed in 8 ml EDME and under stirring at 5-10oC for 45 minutes to a suspension of 2.1 g of 1,1-dioxide acid chloride 2,3-dihydro-3,5-dimethyl-1-benzothiophen-6-carboxylic acid [obtained by the interaction of 1.9 g of 1,1-dioxide, 2,3-dihydro-3,5-dimethyl-1-benzothiophen-6-carboxylic acid with 10 ml chloride tiomila with the exclusion of moisture and with stirring over 4 cha is s, stirred for 1 hour, then mix with ice cooling with 60 ml of water and suck precipitate formed. After recrystallization

from dichloromethane/methanol receive 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,5-dimethyl-1-benzothiophen-6-carboxamide, so pl. 237-238oC. Processing the methane-acid in 30 ml of methanol at 40oWith over 2 hours to get the corresponding methanesulfonate: so pl. 245-248oC.

Similarly, get:

of 1,1-dioxide complex methyl ester of 2,3-dihydro-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-5-methyl-1-benzothiophen-6-carboxamide, etc., 299-301oC (methanesulfonate);

of 1,1-dioxide complex methyl ester of 2,3 - dihydro-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-5-ethyl-1-benzothiophen-6 - carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-5 - trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-5-trifluoromethyl-1 - benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3 - dihydro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-1-benzothiophen - 6-carboxamide, so pl. 223oC is R-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methyl-5-fluoro-1 - benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-isopropyl - 5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-isopropyl-5-methyl - 1-benzothiophen-6-carboxamide, so pl. 194-196oC,

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methyl-1 - benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3,3-dimethyl-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-dimethyl-5-fluoro-1-benzothiophen-6-carboxamide,

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3,3-dimethyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3,5-trimethyl-1 - benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3 - dihydro-3,3,5-trimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-dimethyl-5-fluoro-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3,3-dimethyl-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide methyl ester of 2,3-dihydro-3,3-dimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,3-dimethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2,2-dimethyl-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2,2-dimethyl-5-fluoro-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2,2-dimethyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2,2-dimethyl-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2,2,5-trimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2,2-dimethyl-5-fluoro-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2,2,5-trimethyl-3-methoxy-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2,2,5-trimethyl-3-methoxy-1-benzothiophen-6-carboxamide, so pl. 245oC, methanesulfonate: 284-285oC;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2,2-dimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2,2-dimethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2,5-dimethyl-1-benzothiophen-6-carboxylic who and complicated methyl ester of 2,3-dihydro-2-methyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2-methyl-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2-methyl-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2-methyl-5-trifluoromethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-2-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-2 - methyl-1-benzothiophen-6-carboxamide.

Example 3:

In nitrogen atmosphere, with stirring and with the exclusion of moisture contribute 213 mg of sodium in 5 ml of methanol. The resulting solution is mixed at room temperature with 975 mg of guanidine hydrochloride and stirred for 30 minutes. Then the suspension is filtered. After that, the filtrate is mixed with 500 mg of a complex of methyl ester of 4-acetyl-2-methyl-5-methylsulfonylbenzoyl acid and 1 hour of support when the phlegm. After one hour of additional stirring at room temperature are mixed under cooling with ice water, saturated with sodium chloride, extracted with acetic ether, the organic phase is washed with water, dried and concentrated. Recrystallization from methanol/acetic ether gives 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroscout after recrystallization from methanol/acetone corresponding methanesulfonate: so pl. 214-216oC.

Similarly, get:

from the complicated methyl ester 4-benzoyl-5 - methylsulfonylbenzoyl acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-phenyl-3-hydroxy-1-benzothiophen-6-carboxamide;

from the complicated methyl ester 4-benzoyl-2-methyl-5-methylsulfonylbenzoyl acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-phenyl-3-hydroxy-5-methyl-1-benzothiophen-6-carboxamide.

Example 4:

Obtained as described in example 3 from 547 mg sodium, 12 ml of methanol and 2.5 g of guanidine hydrochloride solution of guanidine mixed with 1.2 g of 1,1-dioxide complex methyl ester of 2,3-dihydro-5-methyl-3-methylene-1-benzothiophen-6-carboxylic acid [obtained by cyclization of complex methyl ester 4-acetyl-2-methyl-5-methylsulfonylbenzoyl acid and subsequent dehydration] and boil the mixture for one hour, then stirred for one hour at room temperature and processed as usual. Receive 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methoxy-3,5-dimethyl-1-benzothiophen-6-carboxamide. Treatment methansulfonate in methanol receive the corresponding methanesulfonate: so pl. 214-215oC.

Similarly, get:

of 1,1-dioxide complex of methyl ester of 3-phenyl-1-benzothiophen-6-carbons 1,1-dioxide complex methyl ester 5-methyl-3 - phenyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-phenyl-3-methoxy-5-methyl-1-benzothiophen-6-carboxamide.

Example 5:

Analogously to example 2 by their interaction with guanidine 1,1-dioxide acid chloride of 3,5-dimethyl-1-benzothiophen-6-carboxylic acid [obtained by the interaction of 1.9 g of 1,1-dioxide 3,5-dimethyl-1-benzothiophen-6-carboxylic acid with 10 ml chloride tiomila with the exclusion of moisture and with stirring over 4 hours at the boiling point] receive 1,1-dioxide, N-diaminomethylene-3,5-dimethyl-1-benzothiophen-6-carboxamide. Treatment methansulfonate in methanol receive the corresponding methanesulfonate.

Similarly, get:

of 1,1-dioxide complex methyl ester 5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-5-methyl-1 - benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester 5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester 5 - trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-5-trifluoromethyl-1-benzothiophen-6-carboxamide

of 1,1-dioxide complex methyl ester 1-benzothiophen-6-cammiloo ester 3-methyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-5-ethyl-1-benzo-thiophene-6-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyl-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-5-fluoro-1-benzothiophen-6-carboxamide

of 1,1-dioxide complex methyl ester 3-methyl-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-5-trifluoromethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex of methyl ester of 3-phenyl-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-phenyl-5-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex of methyl ester of 3-phenyl-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-phenyl-5-ethyl-1-benzothiophen-6-carboxamide

of 1,1-dioxide complex of methyl ester of 3-phenyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-phenyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,5-dimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-dia is benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-5-ethyl-1-benzothiophen-6-carboxamide

of 1,1-dioxide complex methyl ester of 2-methyl-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-5-trifluoromethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2-methyl-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-5-fluoro-1-benzothiophen-6-carboxamide

of 1,1-dioxide complex methyl ester of 2-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methylene-5-methyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methylene-5-methyl-1-benzothiophen-6-carboxamide, so pl. 208-212oC methanesulfonate: 230-235oC;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methylene-5-ethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methylene-5-ethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-oxo-2,2,5-trimethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-oxo-2,2,5-trimethyl-1-B2,3-dihydro-3-methylene-5-fluoro-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methylene-5-fluoro-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methylene-5-trifluoromethyl-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3 - methylene-5-trifluoromethyl-1-benzothiophen-6-carboxamide;

of 1,1-dioxide complex methyl ester of 2,3-dihydro-3-methylene-1-benzothiophen-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-methylene-1-benzothiophen-6-carboxamide;

Example 6:

Analogously to example 1 receive:

from 3,3-dioxide complex methyl ester 6-methyl-1,3-benzodithiol-5-carboxylic acid

3,3-dioxide, N-diaminomethylene-6-methyl-1,3-benzodithiol-5-carboxamide;

from 3,3-dioxide complex methyl ester of 1,3-benzodithiol-5-carboxylic acid

3,3-dioxide, N-diaminomethylene-1,3-benzodithiol-5-carboxamide;

from 3,3-dioxide complex methyl ester 6-ethyl-1,3-benzodithiol-5-carboxylic acid

3,3-dioxide, N-diaminomethylene-6-ethyl-1,3-benzodithiol-5-carboxamide;

from 3,3-dioxide complex methyl ester of 2,6-dimethyl-1,3-benzodithiol-5-carboxylic acid

3,3-dioxide, N-diaminomethylene-2,6-dimethyl-1,3-benzodithiol-5-carboxamide

from 3,3-dioxide complex is xation-5-carboxamide;

from 3,3-dioxide complex methyl ester of 2-methyl-6-ethyl-1,3-benzodithiol-5-carboxylic acid

3,3 - dioxide, N-diaminomethylene-2-methyl-6-ethyl-1,3-benzodithiol-5-carboxamide;

from 3,3-dioxide complex methyl ester 2,2,6-trimethyl-1,3-benzodithiol-5-carboxylic acid

3,3-dioxide, N-diaminomethylene-2,2,6-trimethyl-1,3-benzodithiol-5-carboxamide;

from 3,3-dioxide complex of methyl ether of 2,2-dimethyl-1,3-benzodithiol-5-carboxylic acid

3,3 - dioxide, N-diaminomethylene-2,2-dimethyl-1,3-benzodithiol-5-carboxamide

from 3,3-dioxide complex of methyl ether of 2,2-dimethyl-6-ethyl-1,3-benzodithiol-5-carboxylic acid

3,3-dioxide, N-diaminomethylene-2,2-dimethyl-6-ethyl-1,3-benzodithiol-5-carboxamide;

of 1,1-dioxide complex methyl ester of 2,5-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,5-dimethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester of 2-methyl-2,3-dihydro-benzothiazole-5-carboxylic acid

1,1 - dioxide, 6-N-diaminomethylene-2-methyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester of 2-methyl-6-ethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2-mate the evil-6-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2, 3,5-trimethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester of 2,3-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,3-dimethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester of 2,3-dimethyl-5-ethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,3-dimethyl-5-ethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 5-methyl-2,3-dihydrobenzofuran-6-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-5-methyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 6-ethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-6-ethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 3,5-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-3,5-dimethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 3-methyl-2,3-dihydrobenzo is 1,1-dioxide complex methyl ester 3-methyl-5-ethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-3-methyl-5-ethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 2,2,5-trimethyl-2,3-dihydrobenzofuran-6-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,2,5-trimethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,2-dimethyl-2,3-dihydro-of-benzothiazole;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl-6-ethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,2-dimethyl-6-ethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 2,2,3,5-tetramethyl-2,3-dihydrobenzofuran-6-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,2,3,5-tetramethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 2,2,3-trimethyl-2,3-dihydrobenzofuran-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,2,3-trimethyl-2,3-dihydrobenzofuran;

of 1,1-dioxide complex methyl ester 2,2,3-trimethyl-5-ethyl-2,3-dihydro-benzothiazole-5-carboxylic acid

1,1-dioxide, 6-N-diaminomethylene-2,2,3-trimethyl-5-ethyl-2,3-dihydrobenzofuran-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-metrognome-7-carboxamide;

of 1,1-dioxide complex methyl ester thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-7-carboxamide;

of 1,1-dioxide complex methyl ester 6-atitikimas-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-atitikimas-7-carboxamide;

of 1,1-dioxide complex methyl ester of 2,6-dimethylthiochroman-7 - carboxylic acid

1,1-dioxide, N-diaminomethylene-2,6-dimethylthiochroman-7-carboxamide;

of 1,1-dioxide complex methyl ester 2-methyldibromo-7 - carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyldibromo-7-carboxamide;

of 1,1-dioxide complex methyl ester of 2-methyl-6 - atitikimas-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-6-atitikimas-7-carboxamide;

of 1,1-dioxide complex methyl ester 2,2,6-trimethylchitosan-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2,6-trimethylchitosan-7-carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2-dimethylthiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2-dimethylthiochroman-7-carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl-6-utilties 1,1-dioxide complex methyl ester of 3,6-dimethylthiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,6-dimethylthiochroman-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyldibromo-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyldibromo-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyl-6-atitikimas-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-6-ethyl-thiochroman-7-carboxamide;

of 1,1-dioxide complex methyl ester of 4,6-dimethylthiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,6-dimethyl-thiochroman-7-carboxamide, so pl. 204 - 205oC methanesulfonate: 248-250oC;

of 1,1-dioxide complex methyl ester 4-methyldibromo-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-methyldibromo-7-carboxamide;

of 1,1 - dioxide complex methyl ester 4-methyl-6-atitikimas-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-methyl-6-atitikimas-7 - carboxamide;

of 1,1-dioxide complex methyl ester 3,3,6-trimethylchitosan-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,3,6-trimethylchitosan-7-carboxamide;

of 1,1 - dioxide complex methyl ester 3,3-dimethylthiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,3-dimethylthiochroman BR>
1,1 - dioxide, N-diaminomethylene-3,3-dimethyl-6-atitikimas-7-carboxamide;

of 1,1-dioxide complex methyl ester 4,4,6-trimethylchitosan-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,4,6-trimethylchitosan-7-carboxamide;

of 1,1-dioxide complex of methyl ether of 4,4-dimethylthiochroman-7 - carboxylic acid

1,1-dioxide, N-diaminomethylene-thiochroman-4,4 - dimethyl-7-carboxamide,

of 1,1-dioxide complex methyl ester 2,2,4,6-tetramethylchroman-7-carboxylic acid

1,1 - dioxide, N-diaminomethylene-2,2,4,6-tetramethylchroman-7-carboxamide, so pl. 256oC (methanesulfonate);

of 1,1-dioxide complex methyl ester of 4,4-dimethyl-6-atitikimas-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,4-dimethyl-6-atitikimas-7-carboxamide;

of 1,1-dioxide complex methyl ester 6-methyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-methyl-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 6-ethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,6-dimethyl-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex of methyl ester of 2-methyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester of 2-methyl - 6-ethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-6-ethyl-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 2,2,6-trimethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2,6-trimethyl-2H-1-benzothiophen - 7-carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2-dimethyl-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl - 6-ethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2-dimethyl-6-ethyl-2H-1-benzothiophen-7 - carboxamide;

of 1,1-dioxide complex methyl ester of 3,6 - dimethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,6-dimethyl-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyl-2H-1 - benzothiadiazide difficult methyl ester 3-methyl-6-ethyl-2H-1 - benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2H-1-benzothiophen-7-carboxamide-3-methyl-6-ethyl;

of 1,1-dioxide complex methyl ester of 4,6-dimethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,6-dimethyl-2H-1 - benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-methyl-2H-1-benzothiophen - 7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-methyl-2H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-methyl-6-ethyl-2H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-methyl-6-ethyl-2H-1 - benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 6-methyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-methyl-4H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 6-ethyl-4H - 1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-ethyl-4H-1-benzothiophen-7 - carboxamide;

of 1,1-dioxide complex methyl ester of 2,6-dimethyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diamine-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-4H-1-benzothiophen-7-carboxamide,

of 1,1-dioxide complex methyl ester of 2-methyl-6-ethyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-6-ethyl-4H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester of 3,6-dimethyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,6-dimethyl-4H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-4H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyl-6-ethyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-6-ethyl-4H-1-benzothiophen - 7-carboxamide;

of 1,1-dioxide complex methyl ester of 4,6-dimethyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,6-dimethyl-4H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-methyl-4H-1-benzothiophen-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-methyl-4H-1-benzothiophen-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-methyl-6-ethyl-4H-1 - benzothiophen-7-carboxylic is false methyl ester 3-hydroxy-6-methyl-thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-hydroxy-6-methyl-thiochroman-7 - carboxamide;

of 1,1-dioxide complex of methyl ester of 3-hydroxy-thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-hydroxy-thiochroman-7-carboxamide;

of 1,1-dioxide complex of methyl ester of 3-hydroxy-6 - ethyl-thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-hydroxy-6-ethyl-thiochroman-7-carboxamide;

of 1,1-dioxide complex of methyl ester of 4-hydroxy-6-methyl-thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-hydroxy-6-methyl - thiochroman-7-carboxamide;

of 1,1-dioxide complex of methyl ester of 4-hydroxy-thiochroman-7 - carboxylic acid

1,1-dioxide, N-diaminomethylene-4-hydroxy-thiochroman-7 - carboxamide;

of 1,1-dioxide complex of methyl ester of 4-hydroxy-6-ethyl - thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-hydroxy-6-ethyl-thiochroman - 7-carboxamide;

of 1,1-dioxide complex methyl ester 3-oxo-6-methyl-thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-oxo-6-methyl-thiochroman-7 - carboxamide;

of 1,1-dioxide complex methyl ester 3-oxo - thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-oxo-tiochrom>/BR>1,1-dioxide, N-diaminomethylene-3-oxo-6-ethyl-thiochroman-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-oxo-6 - methyl-thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-oxo-6-methyl-thiochroman-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-oxo-thiochroman-7 - carboxylic acid

1,1-dioxide, N-diaminomethylene-4-oxo-thiochroman-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-oxo-6-ethyl - thiochroman-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-oxo-6-ethyl-thiochroman-7-carboxamide;

Example 8:

Analogously to example 1 receive:

of 4,4-dioxide complex methyl ester 7-methyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-7-methyl-1,4-benzoxazin-6 - carboxamide;

of 4,4-dioxide complex methyl ester 7-ethyl - 1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-7-ethyl-1,4-benzoxazin-6-carboxamide;

of 4,4-dioxide complex of methyl ether 1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-1,4-benzoxazin-6-carboxamide;

of 4,4-dioxide complex methyl ether, 2,7 - dimethyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-2,7-dime the-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-2-methyl-7-ethyl-1,4 - benzoxazin-6-carboxamide;

of 4,4-dioxide complex methyl ester of 2-methyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-1,4-benzoxazin-2-methyl-6-carboxamide;

of 4,4-dioxide complex methyl ester of 3,7-dimethyl-1,4 - benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-3,7-dimethyl-1,4-benzoxazin-6-carboxamide

of 4,4-dioxide complex methyl ester 3-methyl-7-ethyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-3-methyl-7-ethyl-1,4-benzoxazin-6 - carboxamide;

of 4,4-dioxide complex methyl ester 3-methyl - 1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-3-methyl-1,4-benzoxazin-6-carboxamide;

of 4,4-dioxide complex methyl ester 2,2,7-trimethyl-1,4 - benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-2,2,7-trimethyl-1,4-benzoxazin-6 - carboxamide;

of 4,4-dioxide complex of methyl ether of 2,2-dimethyl-7-ethyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-2,2-dimethyl-7 - ethyl-1,4-benzoxazin-6-carboxamide;

of 4,4-dioxide complex of methyl ether of 2,2-dimethyl-1,4 - benzoxazin-6-carboxylic acid

4,Fira 3,3,7-trimethyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-3,3,7-trimethyl-1,4-benzoxazin-6 - carboxamide, so pl. 243-244o(Methane-sulfonate);

of 4,4-dioxide complex methyl ester of 3,3-dimethyl-7-ethyl-1, 4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-3,3-dimethyl-7-ethyl-1,4-benzoxazin - 6-carboxamide;

of 4,4-dioxide complex methyl ester of 3,3 - dimethyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-3,3-dimethyl-7-ethyl-1,4 - benzoxazin-6-carboxamide;

of 4,4-dioxide complex methyl ester 2-oxo-7-methyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-2-oxo-7-methyl-1,4 - benzoxazin-6-carboxamide;

of 4,4-dioxide complex methyl ester 2-oxo-7-ethyl-1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-2-oxo-7-ethyl-1,4-benzoxazin-6 - carboxamide;

of 4,4-dioxide complex methyl ester 2-oxo - 1,4-benzoxazin-6-carboxylic acid

4,4-dioxide, N-diaminomethylene-2-oxo-1,4-benzoxazin-6-carboxamide.

Example 9:

Analogously to example 1 receive:

of 1,1-dioxide complex methyl ester 6-methyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-methyl-3,1-benzoxazin-7 - carboxamide;

of 1,1-dioxide complex methyl ester 3,1 - benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,1-benzoxazin-7-carboxamide;

of 1,1-dioxide complex methyl ester of 2,6 - dimethyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,6-dimethyl-3,1-benzoxazin - 7-carboxamide;

of 1,1-dioxide complex methyl ester of 2-methyl-6-ethyl-3,1 - benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-6-ethyl-3,1-benzoxazin - 7-carboxamide;

of 1,1-dioxide complex methyl ester of 2-methyl - 3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,1-benzoxazin-2-methyl-7 - carboxamide;

of 1,1-dioxide complex methyl ester of 4,6 - dimethyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,6-dimethyl-3,1 - benzoxazin-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-methyl-6-ethyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-methyl-6-ethyl-3,1 - benzoxazin-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-methyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,1-benzoxazin-4-methyl-7-carboxamide;

of 1,1-dioxide complex metrolog Ossetian-7 - carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl-6-ethyl-3,1 - benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2-dimethyl-6-ethyl-3, 1-benzoxazin-6-carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2, 2-dimethyl-3, 1-benzoxazin-7-carboxamide;

of 1,1-dioxide complex methyl ester 4,4,6-trimethyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,4,6-trimethyl-3,1-benzoxazin-7 - carboxamide;

of 1,1-dioxide complex methyl ester of 4,4-dimethyl-6-ethyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,4-dimethyl-6-ethyl-3,1-benzoxazin-6 - carboxamide;

of 1,1-dioxide complex methyl ester of 4,4-dimethyl-3,1 - benzoxazin-6-carboxylic acid

1,1-dioxide, N-diaminomethylene-4,4-dimethyl-3,1-benzoxazin-6 - carboxamide;

of 1,1-dioxide complex methyl ester 4-oxo-6-methyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-oxo-6-methyl - 3,1-benzoxazin-7-carboxamide;

of 1,1-dioxide complex methyl ester 4-oxo-6-ethyl-3,1-benzoxazin-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-4-oxo-6-ethyl-3,1 - benzoxa

1,1-dioxide, N-diaminomethylene-4-oxo-3,1-benzoxazin-6-carboxamide.

Example 10:

Analogously to example 1 receive:

of 1,1-dioxide complex methyl ester 6-methyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-methyl-1,4-benzodithiol-7 - carboxamide;

of 1,1-dioxide complex methyl ester 6-ethyl - 1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-6-ethyl-1,4-benzodithiol-7-carboxamide;

of 1,1-dioxide complex of methyl ether 1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-1,4-benzodithiol-7 - carboxamide;

of 1,1-dioxide complex methyl ester of 2,6 - dimethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,6-dimethyl-1,4-benzodithiol - 7-carboxamide;

of 1,1-dioxide complex methyl ester of 2-methyl-6 - ethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-6-ethyl-1,4 - benzodithiol-7-carboxamide;

of 1,1-dioxide complex methyl ester of 2-methyl-1,4-benzodithiol - 7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-methyl-1,4-benzodithiol-7 - carboxamide;

of 1,1-dioxide complex methyl ester of 3,6 - dimethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxi the Teal-6 - ethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3 - methyl-6-ethyl-1,4 - benzodithiol-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-methyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-methyl-1,4-benzodithiol-7-carboxamide;

of 1,1-dioxide complex methyl ester 2,2,6 - trimethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2,6-trimethyl-1,4 - benzodithiol-7-carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2 - dimethyl-6-ethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2,2-dimethyl-6-ethyl-1,4 - benzodithiol-6-carboxamide;

of 1,1-dioxide complex of methyl ether of 2,2-dimethyl-1,4 - benzodithiol-7-carboxylic acid

1,1 - dioxide, N-diaminomethylene-2,2-dimethyl-1,4-benzodithiol-7 - carboxamide;

of 1,1-dioxide complex methyl ester 3,3,6-trimethyl-1,4 - benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,3,6-trimethyl-1,4 - benzodithiol-7-carboxamide;

of 1,1-dioxide complex methyl ester of 3,3-dimethyl-6-ethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3,3-dimethyl-6-ethyl-1,4 - benzodithiol-6-carboxamide;

of 1,1-dioxide complex methyl ester of 3,3-dimethyl-1,4-benzodithiol - 7-carboxylic acid
on ether 2-oxo-6-methyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-oxo-6-methyl-1,4-benzodithiol-7 - carboxamide;

of 1,1-dioxide complex methyl ester 2-oxo-6 - ethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-oxo-6-ethyl-1,4-benzodithiol - 7-carboxamide;

of 1,1-dioxide complex methyl ester 2-oxo-1,4 - benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-2-oxo-1,4-benzodithiol-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-oxo-6-methyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-oxo-6-methyl-1,4 - benzodithiol-7-carboxamide;

of 1,1-dioxide complex methyl ester 3-oxo-6-ethyl-1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-oxo-6-ethyl-1,4-benzodithiol-7 - carboxamide;

of 1,1-dioxide complex methyl ester 3-oxo - 1,4-benzodithiol-7-carboxylic acid

1,1-dioxide, N-diaminomethylene-3-oxo-1,4-benzodithiol-7-carboxamide.

Example 11:

Analogously to example 1 receive:

of 1,1-dioxide complex methyl ester 6-methyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-6 - methyl-3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 6-ethyl-3,4 is-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester of 3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester of 4,6 - dimethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-4,6-dimethyl-3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 4-methyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-4-methyl-6-ethyl-3,4 - dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 4-methyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-4-methyl-3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester of 3,6-dimethyl-3,4-dihydro - 2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,6-dimethyl-3,4 - dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 3-methyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3-methyl-6-ethyl-3,4 - dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 3-methyl-3,4-dihydro-2H-1,4-benzothiazin the C 1,1-dioxide complex methyl ester 3,4,6 - trimethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,4,6-trimethyl - 3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester of 3,4 - dimethyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,4-dimethyl-6 - ethyl-3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester of 3,4 - dimethyl-3,4-dihydro - 2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,4-dimethyl-3,4 - dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 3,3,6-trimethyl-3,4 - dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,3,6-trimethyl - 3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester of 3,3-dimethyl-6-ethyl-3,4 - dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,3-dimethyl-6-ethyl-3,4 - dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester of 3,3 - dimethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,3-dimethyl-3,4-dihydro - 2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 3,3,4,6 - tetramethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-Diamir 3,3,4-trimethyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,3,4-trimethyl-6-ethyl - 3,4-dihydro-2H-1,4-benzothiazine;

of 1,1-dioxide complex methyl ester 3,3,4-trimethyl-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,3,4-trimethyl-3,4 - dihydro-2H-1,4-benzothiazine.

Example 12:

Analogously to example 1 receive:

of 1,1-dioxide complex methyl ester 6-methyl-3,4-dihydro-2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-6-methyl-3,4-dihydro - 2H-1,3-benzothiazine;

of 1,1-dioxide complex methyl ester 6-ethyl-3,4-dihydro - 2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-6 - ethyl-3,4-dihydro-2H-1,3-benzothiazine;

of 1,1-dioxide complex methyl ester of 3,4-dihydro-2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,4-dihydro-2H-1,3-benzothiazine

of 1,1-dioxide complex methyl ester of 3,6-dimethyl-3,4-dihydro - 2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3,6-dimethyl-3,4 - dihydro-2H-1,3-benzothiazine;

of 1,1-dioxide complex methyl ester 3-methyl-6 - ethyl-3,4-dihydro-2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diamine is Teal-3,4-dihydro - 2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-3-methyl-3,4-dihydro - 2H-1,3-benzothiazine;

of 1,1-dioxide complex methyl ester 4-oxo-6 - methyl-3,4-dihydro-2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-4-oxo-6-methyl - 3,4-dihydro-2H-1,3-benzothiazine;

of 1,1-dioxide complex methyl ester 4-oxo-6 - ethyl-3,4-dihydro-2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-4-oxo-6-ethyl - 3,4-dihydro-2H-1,3-benzothiazine;

of 1,1-dioxide complex methyl ester 4-oxo-3,4-dihydro - 2H-1,3-benzothiazin-7-carboxylic acid

1,1-dioxide 7-N-diaminomethylene-carbarnoyl-4-oxo-3,4 - dihydro-2H-1,3-benzothiazine.

The following examples relate to pharmaceutical dosage forms.

Example a: ampoules for injection

A solution of 100 tonnes of active substance of the formula I and 5 g of dinitrigenoxide in 3 l of double distilled water using 2 N. hydrochloric acid adjusted to a pH of 6.5, sterile filtered, filled into ampoules for injection, subjected to freeze-drying under sterile conditions and closed under sterile conditions. Each ampoule for injection contains 5 mg of active substance.

Example B: candles

Melt a mixture of 20 g of the active substances is a contains 20 mg of active substance.

Example C: a solution of

Prepare a solution of 1 g of the active substance of the formula I, 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g benzalkonium chloride in 940 ml of double distilled water. Set pH to 6.8, made up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: ointment

Mix 500 mg of active substance of the formula I with 99.5 g of vaseline under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate formed into tablets in the usual way, so that each tablet contained 10 mg of active substance.

Example F: bean

Analogously to example E is formed into tablets, which are then applied in the usual way a coating of sucrose, potato starch, talc, tragant and dye.

Example G: capsules

2 kg of active substance of the formula I is administered in the usual way in capsules of hard gelatin, so that each capsule contained 20 mg of the active substance.

Example H: ampoules

A solution of 1 kg of active substance of the formula I in 60 liters of doubly distilled water filter is eriline conditions. Each ampoule contains 10 mg of active substance.

PHARMACOLOGICAL DATA

Defined inhibitory activity against Na+/H+-exchange compounds of General formula

< / BR>
where Me = methyl, Et = ethyl.

Inhibitory activity against Na+-absorption in rabbit erythrocytes was determined in accordance with the method described Duesing al., Med.Clin., 87, 378-384 (1992). Inhibitory activity represented by the IC50corresponding to 50% of the resultant inhibition of Na+/H+- exchange of Na+-absorption) in erythrocytes of rabbit. As can be seen from the obtained data are shown in table 1, proposed according to the invention the compounds of formula (I) have sufficient inhibitory activity against Na+/H+-exchange and thus suitable for the treatment of heart disease, as they lead to good cardiotoxicity effect. These compounds are suitable for the treatment of arrhythmia, angina, heart attacks and pathological hypoxic or ischemic disorders.

1. Cyclic sulfones of the formula I

< / BR>
where R1and R2denote independently from each other H or A;

X represents CR4R5C=Z or O;

Y represents CR6RUg from each other H, A, OH or OA, or R5and R6or R7and R8indicate link together, with each molecule may receive a maximum of only one such bond, or R4and R5indicate together O-(CH2)2-O or O-(CH2)3-O, or R8and R9denote independently from each other H or A;

A denotes alkyl with 1 to 6 C-atoms;

n denotes 0 or 1,

and their physiologically acceptable salts.

2. Connection on p. 1 representing:

(a) 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-1-benzothiophen-6-carboxamide;

(b) 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-5-methyl-1-benzothiophen-6-carboxamide;

(c) 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophen-6-carboxamide;

(d) 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-3-methoxy-3,5-dimethyl-1-benzothiophen-6-carboxamide;

(e) 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3,5-dimethyl-1-benzothiophen-6-carboxamide;

(f) 1,1-dioxide, N-diaminomethylene-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophen-6-carboxamide.

3. The method of obtaining cyclic sulfones of the formula I on p. 1 and their salts, characterized in that the compound of formula II

< / BR>
where R1, R2, R8>/BR>subjected to interaction with guanidine, followed by separation of the base of formula I or translate it into salt by the action of acid.

4. The method of obtaining pharmaceutical compositions, characterized in that the compound of formula I under item 1 and/or one of its physiologically acceptable salts is transferred into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary substance.

5. Pharmaceutical composition having inhibitory activity against Na+/H+exchange, characterized in that it contains at least one compound of General formula I under item 1 and/or one of its physiologically acceptable salts.

 

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< / BR>
where mean:

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R(3) - hydrogen;

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E - sulfur;

X is oxygen;

Y - CH2group,

and their pharmaceutically tolerable salts

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