FI107917B - A process for the preparation of therapeutically useful derivatives of 2-oxo-3-pyrrolinylcarboxamidoethylbenzenesulfonyl urea and thiourea urea - Google Patents

Abstract

There are described substituted benzenesulphonylureas and -thioureas of the formula I <IMAGE> where R(1) is H, (cyclo)(CH2)a(fluoro)alk(en)yl, R(2) is H, Hal, (fluoro)(mercapto)(CH2)e(cyclo)alk(oxy)(yl), NR(4)R(5) where R(4) and R(5) together are a (CH2)2-7 chain, or R(4), R(5), R(6) are H, (alkyl)(cyclo)(fluoro)alk(en)yl, E is O, S; Y is -[CR(7)2]n-R(3) <IMAGE> B is (C3-C6)-alkenyl, or R(3) is <IMAGE> X is H, Hal, alkyl; Z is Hal, (cyclo)alk(yl)(oxy). Compounds I are used for the treatment of cardiac arrhythmias and for the prevention of sudden heart death caused by arrhythmia and can therefore be used as antiarrhythmics. They are particularly suitable in those cases in which arrhythmias are the result of constriction of a coronary vessel, such as in angina pectoris or in acute cardiac infarct.

Description

107917

The present invention relates to novel therapeutically useful 2-oxo-3-pyrrolinylcarboxybenzamido-2-oxo-3-pyrrolidinylcarboxybenzamido-carboxylic manufacture of thiourea derivatives,

10 H H H

MO - N / N 's ° 2 γ ^ γ'0 "2 · 0112" "y R (J) 1 1U) 0 (I) 15 wherein R (1) is C 1 -C 6 alkyl; R (2) is F, Cl, Br, I or C 1-6 alkoxy; and R (3) is a group of the formula

·.:. · 1 11 jT

fv> ^ R (5) ·: ··· o · · · 25 where R (4) and R (5) are C1.44 alkyl.

Preference is given to compounds of formula I wherein: R (1) is (C 1 -C 4) alkyl, and R (2) is F, Cl or (C 1 -C 4) alkoxy, *: 1 (1); ·· .1. Theses wherein ··· R (1) is C 1-4 alkyl and C 1-4 fluoroalkyl; R (2) is F or Cl.

· »· The term alkyl means straight or branched chain saturated hydrocarbon residues, unless otherwise stated. : 35 Aunt.

• ·· m · 107917 2

Similar sulfonylureas are known from DE-A-2 413 514, DE-A-1 518 874 and EP-A-0 031 058. DE-A-2,413,514 and EP-A-0 031 058 describe blood glucose lowering agents only having a p-substitution on the central phenyl group. There is no indication of m-substitution.

The compounds describe a blood glucose lowering effect. The prototype of such blood glucose-lowering sulfonyl ureas is glibencenclide, which is used as a medicine for the treatment of diabetes mellitus and a very important science in the study of so-called ATP-sensitive potassium channels. In addition to its blood glucose lowering properties, gli-15 benclamide has other effects that cannot yet be exploited, but which are all based on the ability to block these ATP-sensitive potassium channels. These include, in particular, the anti-ventricular action of the heart. Decreasing blood glucose levels concurrently with the treatment of ventricular fibrillation or its precursors would not be desirable, or even dangerous, as it may further worsen the patient's condition.

Thus, it was an object of the invention to synthesize compounds which have a cardiac effect similar to glicen · · · 25 benclamide, but which do not, or at a lower level, affect blood glucose than glibenclamide at cardiovascular doses or concentrations. .

Mice, rats, guinea pigs, rabbits, dogs, monkeys are suitable as experimental animals for the demonstration of such effects. 30 or pigs.

· · ·

The active compounds of the formula I can be used in human and veterinary medicine. In addition, they may be used as intermediates for other active pharmaceutical ingredients. den.

• · · · • · · ··· · * 3 107917

The compounds of formula I are valuable drugs for the treatment of various cardiac arrhythmias and for the prevention of sudden cardiac death associated with arrhythmias, and may thus find use as anti-arrhythmic agents. Examples of disorders of irregular heartbeat include supraventricular arrhythmias such as atrial fibrillation, supraventricular arrhythmias, or ventricular arrhythmias such as ventricular arrhythmias, or ventricular arrhythmias, but They are particularly suitable for cases where arrhythmias are due to coronary artery stenosis, such as angina pectoris got-15 in iron, or where they occur during acute myocardial infarction or as a chronic consequence of myocardial infarction. Thus, they are particularly suitable for post-infarction after-care to prevent a patient's sudden cardiac death. Other conditions where such arrhythmias and / or sudden cardiac death due to rhythm 20 may contribute, include, for example, heart failure due to hypertension or heart failure.

In addition, compounds of formula I may positively affect reduced cardiac contractility.

• · · 25 This may be due to a reduction in the ability of the heart to contract due to illness, such as heart failure, but also in acute cases such as refusal of the heart to respond to shock. Similarly, in ♦; ·· {transplantation of the heart, the heart may be resumed after surgery. * ··. 30 get faster and more reliable performance. The same applies to cardiac surgery where it is necessary to temporarily suspend the active activity of the heart with cardiac ·· ♦ treatment solutions so that the compounds can be used in the body. to protect them during treatment with physiological hematopoietic pathways or when stored in hematopoietic fluids, as well as for transplantation of organs into the recipient organism.

Compounds of formula I may be prepared by preparing 5 (a) substituted benzenesulfonylthiourea derivatives of formula (Ib), H H CH 2 - CH 2 - [X / R (3) 10 R (1) - ΗγΝ - SO 2 | 0 S R (2) (Ib) 15

benzenesulfonamide II or a salt thereof III

ph CH ^ H H

20 -w'j- “Y8m - * χτ Ύ * ** ** ** ** ** ** (II) (III) · 9 25 where M is an alkali metal or alkaline earth metal cation, is reacted with R (1) -substituted isocyanate of the formula R (1) - N = C = S (VI) • «. 30 ··· • or • ·: * · * (b) for the preparation of substituted benzenesulphonyl ureas of formula (Ia), · · »m 9 9 9 9 9 9 • 99 • 9 9 9 9 5 107917

'H H H

The benzenesulfonylthiourea derivative of the formula (Ib) is reacted with an oxidant to MO - ΝγΝ - so2V - (-) - (γ) 5 - R (2) - (-) - (Ia).

As the cations of the salts of the formula III, the alkali and alkaline earth metal ions, in particular Na \ K +, Ca ++, Mg ++, are suitable.

Substituted benzenesulfonyl ureas of formula Ia can be prepared by structural modification reactions of benzenesulfonyl thioureas of formula Ib. The sulfur atom can be replaced by an oxygen atom in the correspondingly substituted benzenesulfonylthiourea of formula Ib, for example, by the use of oxides or salts of heavy metals or by the use of oxidants such as hydrogen peroxide, sodium peroxide or nitric acid.

Thiourea can also be desulfurized by treatment with phosgene or phosphorus pentachloride. Intermediates provide chloroformic acid amidines or carboximidides, for example, which, for example by saponification and addition of water, are converted to the corresponding benzenesulfonylureas of formula Ia. Isothioproteins behave in desulfurization ···. As with thiourea, they can also be used as starting materials in these reactions.

·· 1 “The compounds of the formula I and their physiologically acceptable salts are valuable drugs which can be used not only as antiarrhythmic agents. ·: 35 but also as prophylactic agents in humans and other mammals. • 10,779 hands (eg, monkeys, dogs, mice, rats, rabbits, guinea pigs and cats) in cardiovascular disorders, heart failure, heart transplants or cerebrovascular disease.

The physiologically acceptable salts of Formula I are compounds of Formula IX according to Remmington's Pharmaceutical Science, 17th Edition, 1985, pages 14-18.

10 H M (1) H

»(O - V" - - N Y ()

Ϊ I

(Y = CH 2 CH 2) (IX) which may be prepared from non-toxic organic and inorganic bases and from substituted benzenesulfonyl ureas of formula (I).

Preferred salts are those wherein M (1) is of formula. IX is acid addition salts formed with sodium, potassium, rubidium, calcium, magnesium ion, and basic amino acids such as lysine, arginine or the like.

* * The starting materials used in the said synthesis methods of the benzenesulfonyl urea compounds of formula I are prepared in a manner known per se, such as in the literature (for example, standard works such as Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart, Organic Reaction). Wiley & * ··, 30 Sons, Inc., New York) as well as in the aforementioned patents are described and under reaction conditions known and suitable for said reactions.

···;. #. Σ However, variants known per se which are not mentioned here may also be used.

«··; 35 If desired, the starting materials can also be formed in situ without being isolated from the reaction mixture and used immediately for further reactions.

Amine X is first converted to an isocyanate or reactive carbonic acid derivative (Reaction Scheme 1).

Conversion of amine X to isocyanate is accomplished in known manner by reacting amine X with a carbonic halide such as phosgene or thiophosgene in the presence of a tertiary alkylamine or pyridine in an inert solvent. Suitable inert solvents are ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether (diglyme), ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, N-dimethylformamide (N-dimethylformamide) , Phosphoric acid hexamethyl triamide, sulfoxides such as DMSO, sulfones such as sulfolane, hydrocarbons such as benzene, toluene, xylenes. Mixtures of these solvents with each other are also suitable. Suitable reactive carbonic acid derivatives are those which can be synthesized from chloroformic acid alkyl esters. amines X and suitable tertiary alkyl amines or pyridine. In addition, N, N-carbonyldiimidazole and analogous reactive derivatives (Staab, HA: 25 Synthesen mit heterocyclischen Amiden (Azoliden), Ange *: 1 wandte Chemie 74 ( 1962), No. 12, pp. 407-423).

·· # · • · · r R (2) ^^ M2) ♦ ·· ♦ · • · 1 (y = ch2ch2) (X) (xi) ♦ • · • ♦ • · · # • · · · · · • · 8 107917

Reaction Scheme 1

Isocyanate XI or the corresponding urethanes are coupled with another molecular component (Justus Liebigs Ann. Chem. 1956, 598, p. 203) in the presence or absence of an inert solvent at 100-170 ° C to give acyl urea derivatives XII (reaction -chart 2) "—-, / ΤΤ '' (XI) (XII) 15 (Y = CH 2 CH 2)

Reaction Scheme 2

Compounds XII synthesized according to Reaction Scheme 2 can be converted to sulfonamides II in a manner known per se according to Reaction Scheme 3. The sulfonamides II are prepared by methods known per se and under reaction conditions known and suitable for carrying out the reactions mentioned. However, variants known per se which are not specifically mentioned herein may also be used. Syntheses can be carried out in one, two or more steps if desired. Eri- • ·· · • * j *. Particularly preferred are processes wherein the acyl urea agent XII is converted by electrophilic reagents in the presence or absence of an inert solvent at -10 to 120 ° C, preferably 0 to 100 ° C, ar *; * as a sulfonic acid or a derivative thereof, such as a sulfonic acid halide. Halosulfonations can be carried out, for example, on halosulfonic acid. In this case, ortho and meta isomers may be formed which • ··. 35 can be separated by standard methods (e.g., 10 · 107917 column chromatography using an inert support or crystallization from an inert solvent). The conversion of the sulfonic acid derivatives to the sulfonamides of the formula II is carried out in a manner known in the literature, preferably by reacting the sulfonic acid chlorides in an inert solvent at a temperature of 0 to 100 ° C with aqueous ammonia.

"Jcr-'V -r-xr-V ·" '0 R (2 (XIII) (II) 15 (Y = CH 2 CH 2)

Reaction Scheme 3 The thus prepared sulfonamide-disubstituted acyl urea derivatives or their acid addition compounds can be prepared in the above manner from benzenesulfonyl of formula I

* «· * Urine. R (1), R (2), R (3) and E, respectively

Depending on the nature of the ···: *. *, One or more of the above methods for the preparation of the compounds I are inappropriate in individual cases or require at least measures to protect the active ··· groups. Such are relatively rare

• IM

the cases can be readily identified by one of ordinary skill in the art, and in such cases there is no difficulty in using any of the other synthetic routes described.

The compounds of formula I may have one or more chiral centers. They may thus be obtained as racemates or, if used optically, during their preparation. : ***; active starting materials, also in optically active form ··· ./. If the compounds have two or more chiral *. *, 35 centers, so that they can be obtained in the synthesis as mixtures of racemates, from which various isomers can be isolated in pure form, for example by crystallization from an inert solvent. The racemates obtained may, if desired, be mechanically or chemically separated into their enantiomers by methods known per se. In this way, the racemate can be reacted with an optically active resolving agent to form diastereomers. For example, optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetyl tartaric acid, camphorsulfonic acid, mandelic acid, malic acid or lactic acid are suitable as the separating agents for basic compounds. In addition, the carbinols are further amidated by chiral acylation reagents, for example R or S-α-methylbenzyl isocyanate, and then resolved. The various forms of diastereomers may be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of formula I may be liberated from the diastereomers in a manner known per se. In addition, the enantiomers are resolved by chromatography on optically active carriers.

The compounds of the formula I and their physiologically acceptable salts can be used for the preparation of pharmaceutical products. In this case they may be combined with at least one solid or liquid carrier *! **: or an excipient alone or in combination with other cardiovascular active agents such as ··· · ♦. for example, calcium antagonists, NO donors, or ACE · «·» inhibitors, forms a suitable dosage form. These preparations can be used as medicines in humans. or veterinary medicine. Carriers include organic or inorganic substances suitable for administration by the gastrointestinal tract (for example, orally), as an example, ** *; • for intravenous or local use and does not react with new compounds such as water, • «*. "35 olive oils, benzyl alcohols, polyethylene glycols, glycine, glycerol, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly. , syrups, 5 juices or drops, for rectal administration as drugs, solutions, preferably oily or aqueous solutions, also can be used as suspensions, emulsions or implants, topical use of ointments, creams, pastes, water, gels, sprays, foams, aerosols, solutions of 10 ( for example, alcohols such as ethanol or isopropanol, 1,2-propanediol or mixtures thereof with one another or with water) or powders, etc. The novel compounds may also be lyophilized and the resulting lyophilisates used, for example, for injection. The formulations may also contain stabilizers and / or surfactants, emulsifiers, salts and / or adjuvants such as lubricants, preservatives, stabilizers and surfactants, emulsifiers, salts with osmotic agents. pressure regulators, buffers, colorants and flavorings and / or flavorings. If desired, they may also contain one or more other influences; *, · Weighing agent, for example one or more vitamins.

* i * '· The dose of ϊ 2 5 compounds of formula I required to treat cardiac arrhythmias depends on ··· whether it is an acute event or a preventive treatment.

····

Normally an adequate daily dose is at least about 0.001, preferably 0.01, especially about 0.1 mg to a maximum of about 100 mg, preferably about 10 mg, especially 1 mg / • · 30 kg in the case of preventive treatment . Affordable • ·; _ ·· ♦ * The dose range is 1 to 10 mg / kg / day. The dose may then be administered orally or parenterally as a single dose or divided into up to four individual doses. In the treatment of acute cardiac arrhythmias, for example, in the ICU, the gastrointestinal dosing may be preferred. In critical situations, the preferred dosage range may be 10-100 mg, for example, for intravenous infusions. .

In accordance with the invention, in addition to the compounds described in Exemplary Examples 5, the compounds of formula I, assembled in the following Table 1, may be prepared: 1- {2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl) -1] -carboxamido) ethyl] phenylsulfonyl} -3-ethylstream substance, 1- {2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl) -1- carboxamido) ethyl] phenylsulfonyl} -3- (1-propyl) urea, 1- {2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl) -1-carboxamido) ethyl] phenylsulfonyl} -3- (2-propyl-15-yl) urea, 1- {2-ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3) -pyrrolinyl-1-carboxamido) ethyl] phenylsulfonyl} -3-ethyl flux, 1- {2-ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl) -20i-1-carboxamido) ethyl] phenylsulfonyl} -3- (1-propyl) urea, 1- {2-ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo) -3-pyrrolinyl-1 · (1-carboxamido) ethyl] phenylsulfonyl} -3- (2-propyl: 1: 1) urea; 1- {2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido) -ethyl] -phenylsulfonyl} -3-ethyl-styrofoam; ···. Sa, • · · 1- {2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl-1-carboxamido) ethyl] phenylsulfonyl} -3- (1-Propyl) urea, ··· '· · ··· 1- {2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl) - · 1 · · 1 · 1 -Carboxamido) ethyl] phenylsulfonyl} -3- (2-propyl-2 · 1 · l) urea, ··· ··· • · 1 · · · · · • ·· 2 • · 13 107917 1- {2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl-1-carboxatnido) ethyl] phenylsulfonyl} -3 - (Cyclopropyl) urea, 1- {2-ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl-5'-1-carboxamido) ethyl] phenylsulfonyl} -3-ethyl-thiourea, 1- {2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl-1-carboxamido) ethyl] phenylsulfonyl} -3 - (1-Propyl) thiourea, 10 1- {2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido) ethyl] phenylsulfonyl} -3- (1-propyl) thiourea, 1- {2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl) -1-carboxamido) ethyl] phenylsulfonyl} -3- (2-propyl-15-yl) thiourea, 1- {2-ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3) -pyrrolinyl-1-carboxamido) ethyl] phenylsulfonyl} -3-ethylthiourea, 1- {2-ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl) -20i-1-carboxamido) ethyl] phenylsulfonyl} -3- (1-propyl) thiourea, 1- {2-ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo) -3-Pyrrolinyl ···.

• l-1-carboxamido) ethyl] phenylsulfonyl} -3- (2-propyl *: 1: 1) thiourea ,; 1- {2-Ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl] -1H-carboxamido) ethyl] phenylsulfonyl} -3- (cyclopropyl ·········································································································································································································································································· · carboxamido) ethyl] phenylsulfonyl} -3-ethyl-thiourea, 1- {2-fluoro-5- [2- (3-ethyl-4-methyl-2-oxo) 3-Pyrrolinyl-1-carboxamido) ethyl] phenylsulfonyl} -3- (1-propyl) thiourea, ··· * {2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl-1-carboxamido) ethyl] phenylsulfonyl} -3- (2-propyl) thiourea , 1- {2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolidinyl-5H-1-carboxamido) ethyl] phenylsulfonyl} -3- (cyclopropyl) thiourea -substance,

Example 1 1- {2-Methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolyl-1-carboxamido) ethyl] phenylsulfonyl) -3-melo-thiol urea

H H H

0.25 g (0.58 mmol) of 2-methoxy-5- [2- (3-ethyl) -? -4-Methyl-2-oxo-3-pyrrolinyl-1-carboxamido) ethyl] benzenesulfonamide is dissolved in 10 ml of acetone and 25 mg of NaOH and 50 μl of water are added to solution 20. To the well-stirred reaction mixture is added 45 mg (0.6 * · mmol) of methyl isothiocyanate under ice-cooling, and stirring is continued. After the addition of V for 1 hour at room temperature and *: **: then the solvent is removed under reduced pressure. Obtained:: 1: 25 Evaporation residue is purified by column chromatography (Kie- · · ··· on Sel 60) using ethyl acetate (Rp = ♦ ♦♦ · 0.4) as solvent to give 0.18 g of the desired product colorless. · As crystals having m.p. 65-70 ° C.

Preparation of the starting compound • 4.5 g (30 mmol) of 4-methoxy-5-phenylethylamine · 1 n are added dropwise to a solution of triphosgene (2.96 g, 10.0 mmol) in anhydrous tetrahydrofuran (30 mL). ) and reflux for 2 hours. The solution, cooled to room temperature, is filtered and the filtrate is evaporated to dryness. 35 in a vacuum. The residual colorless oil was purified by distillation (balloon condenser) at 267 Pa (2 torr) at a bath temperature of 220 ° C to give 1.1 g of 4-meth, toxic-S-phenylethyl-. diisocyanate.

0.7 g (4.0 mmol) of 4-methoxy-5-phenylethyl isocyanate and 0.4 g (3.5 mmol) of 3-ethyl-4-methyl-2-oxo-3-pyrroline are mixed with each other. and the mixture is heated for one hour at 150 ° C. The cooled reaction mixture is dissolved in a minimum amount of ethyl acetate and purified by column chromatography (Kieselgel 60) using ethyl acetate (RF = 0.5) as solvent. Evaporation of the eluent under reduced pressure gives 0.25 g of methoxy-4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido) ethyl] benzene, which is added portionwise to cold (0 ° C). C) chlorosulfonic acid. After stirring for 1 hour at 0 ° C, the reaction mixture is poured onto ice. The precipitated sulfonic acid chloride is dissolved in ethyl acetate. The organic phase is dried over sodium sulfate, evaporated in vacuo, the crude sulfonic acid chloride is dissolved in acetone, and by treating the acetone solution with aqueous ammonia, the sulfonic acid chloride is converted to 2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo) 3-pyrrolinyl-1-carboxamido) ethyl] benzenesulfonamide. Sulfonamidine Γν sp. 204-205 ° C.

Example 2; 1- {2-Methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrimidin-4-yl-rolinyl-1-carboxamido) ethyl] phenylsulfonyl) -3-methyl - ··· ·; ·. style urine • · ::: “‘ Y ’o 0 0» ·· 1 • · 1 · • 16 107917 0.25 g (0.55 mmol) 1- {2-methoxy-5- [2- ( 3-Ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido) ethyl] phenylsulfonyl} -3-methylthiovirus is suspended in aqueous NaOH (45 mg NaOH and 0.5 mL water) 5% aqueous H 2 O 2 solution is added and the reaction mixture is stirred for 30 minutes at 80 ° C. At room temperature, dichloromethane is added to the reaction mixture, the mixture is acidified (pH = 2-3) with about 2 M aqueous HCl and the organic phase is dried over sodium sulfate. The organic phase 10 is evaporated in vacuo to give 0.22 g of 1- {2-methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido) ethyl] phenylsulfonyl } -3-methyl urea as colorless crystals, m.p. 184-187 ° C.

Example 3 1- {2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolyl-1-carboxamido) ethyl] phenylsulfonyl) -3-methylthiovirus The material S F '' 'is synthesized according to the method of Example 1 *: 1: 1- {2-Fluoro-5- [2- (3-ethyl-4-methyl-2)] -Oxo-3-pyrrolidinyl: 1'-1-carboxamido) ethyl] phenylsulfonyl} -3-methylthio-4'-urea (m.p. 90 ° C, decomposes) starting from 4-fluoro-B-phenyl- · ♦ · # Ethyl amine: Fluoro-4- [2- (3-ethyl-4-methyl-2-oxo-1β) -3-pyrrolinyl-1-carboxamido) ethyl] benzene [m.p.

. 141 ° C), 2-Fluoro-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolyl-1-carboxamido) ethyl] benzenesulfonic acid chloride (m.p. 147 ° C), 2-Fluoro-5- [2- (3-ethyl-4-methyl-2- [1,2-oxo-3-pyrrolinyl-1-carboxamido) ethyl] benzenesulfone-3. amide (m.p. 136 ° C).

»« »• • • • • ♦♦ · • ♦ · 2 • · · 3 • · 17 107917

Example 4 1- {2-Ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolyl-1-carboxamido) ethyl] phenylsulfonyl} -3-methylthiovirus 5 ( mp 176-178 ° C) is obtained analogously to Example 1.

Example 5 1- {2-Ethoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolyl-1-carboxamido) ethyl] phenylsulfonyl} -3-methyl-10-urine (m.p. 160-165 ° C) is obtained analogously to Example 2.

Pharmacological data

The following models can be used to demonstrate the therapeutic properties of the compounds of formula I-15: (1) Duration of action potential in guinea pig nystic muscle (a) Introduction ATP deficiencies observed in myocardial cells during anemia lead to a reduction in action potential duration. They are considered to be one of the so-called. reentry arrhythmias that can lead to ·· · • '. · sudden cardiac death. Opening *: · * of ATP-sensitive K channels is considered to be the cause of ATP reduction.

♦ ·· (b) Method e · · ·

Standard · · · standard microelectrode technology is used to measure the action potential. In this case, both sexes. half-guinea pigs are struck in the head, the hearts are taken from them, the nymph muscles are separated and hung in a • · ··· 'bath. Ringer's solution (0.9% NaCl, 0.048% KCl, 0.024% CaCl2, 0.02% NaHCO3, and. ***. 0.1% glucose) is passed through the organ bath and gasified at 36 ° C. .. · Gas mixture containing 95% oxygen and 5% carbon dioxide. Muscle is stimulated through an electrode with IV and l ms · · · * · * J durable rectangular pulses at 2 Hz. The action potential is passed through a microelectrode filled with intracellular glass 18107917 filled with 3 mM KCl solution and recorded. Test compounds were added to Ringer's solution at a concentration of 2.210-5 mol / liter. The action potential is described by an oscilloscope amplified with a Hugo Sacchs amplifier-5. The duration of action potential is determined at 95% repolarization rate (APD95). Reductions in action potential are achieved either by the addition of 1 μΜ of potassium channel opener Hoe 234 (Rilmakalim) [W. Linz, E. Klaus, U. Albus, R.H.A. Becker, D. Mania, 10 H.C. Englert, B.A. Schölkens, Arzneimittelforschung / Drug Research, Vol. 42 (II), 1992, pp. 1180-1185) or by adding 2-deoxyglucose (DEO). In experimental physiology, 2-desoxyglucose induces ATP deficient states by blocking glucose metabolism. The action-reducing effect of these agents on action-15 was inhibited or reduced by the simultaneous administration of test compounds. Test compounds were added to the bath solution as stock solutions in propanediol. The values given are for measurements 30 minutes after the addition. As control, 20 APD95 values in the presence and absence of DE0 or HOE 234 are considered as control.

* ·. ·. · (C) Results: • · · • 1 ϊ The following values were measured: • ·

25 Γ Measurement I APD95-DEO1 'IAPD95-HOE 234al I

··· [ms] [ms] ···· ^ _____ _ I Control <40 <40

Example 1 60 ± 22 (162 ± 7) 119 ± 16 30 n = 3 (162 ± 16) -: n = 3! '·· Example 2 110 (155) 125 (185) ··· n = 1 n = 1 (A) After the measurement values for the n tests, the corresponding blank values are shown in parentheses. The blank values are the APD95 values at the start of the experiment in Ringer's solution without DEO, HOE 234 and test compound.

5 (2) Membrane Potential in Isolated S-Cells: (a) Introduction

The mechanism of action of blood glucose-lowering sulfonylureas has been largely elucidated. The target organ is the pancreatic β-cells, which produce additional insulin production to the blood glucose lowering hormone. Insulin release is controlled by cell membrane potential. Glibenclamide exerts a depolarizing effect on the cell membrane, which promotes insulin release due to increased influx of calcium ions. This cell membrane depolarization measure Λϋ15 for some of the compounds of the invention was determined on RINm5F cells of the pancreatic cancer cell line. In this model, the potency of the compound predicts the potency of the blood glucose lowering effect of this compound.

(b) Method 20 Cell culture of RIfcaSF cells RINm5F cells were cultured at 37 ° C in RPMI 1640 medium (Flow) supplemented with 11 mM glucose: * ·]: 10% v / v fetal calf serum, 2 mM gluten. - ·; ··; and 50 μg / ml gentamycin. Cells for experiments. . ·. 25 were isolated by incubation (ca. 3 min) in Ca 2+ -free medium containing 0.25% trypsin and stored ... on ice.

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Measuring method

The isolated RINm5F cells were placed in a Plexiglas chamber of an inversion microscope with differential in-30 contrast-contrast optics. By microscopic observation (400x magnification), micromanipulates were placed on the cells. a micropipette, fire-polished using an aperture, with an aperture 1 diameter of approximately 1 μτη. By applying a Patch pipette to a mild vacuum, the glass and cell membrane were initially formed at 107917 Lille's high electrical seal and then, by increasing the vacuum, the membrane under the measuring pipette was ruptured. In this whole-cell system, the potential of the cell-5 was recorded using a Patch-Clamp amplifier (L / M EPC 7) and the current was measured throughout the cell by increasing the voltage.

Solutions: Patch pipette was filled with KCl solution (millimoles): 140 KCl, 10 NaCl, 1.1 MgCl2, 0.5 EGTA, 1 Mg-ATP, 10 HEPES, pH = 7.2, and the bath contained NaCl solution -10 (millimoles): 140 NaCl, 4.7 KCl, 1.1 MgCl2, 2 CaCl2, 10 HEPES, pH = 7.4. Stock solutions (100 mM concentration) in dimethylsulfoxide (DMSO) and corresponding dilutions in NaCl solution were prepared from the test compounds. Cellular potential was not affected by DMSO alone. To stabilize the cellular potential of cell-15 under control conditions, the ATP-sensitive K + channel opener, diazoxide (100 μΜ) was added to the bath solution in all experiments. All experiments were performed at 34 ± 1 ° C.

(c) Results (Concentrations of the compounds of the invention in the assays are 10'5 moles / liter. Measurement AU (mV) ai ··· _____: 1 · 1: Example 1 2 (-80) n = 6 • ·

Example 2 12 (-71) n = 6. 25 ---- -; - ··· (a) The blank values corresponding to the results of the n tests are given in brackets. Blank values are diazoc

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the cell potentials obtained after the application of cid.

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Claims (4)

21 107917 M A process for the preparation of therapeutically useful derivatives of 2-oxo-3-pyrrolinylcarboxamidoethylbenzene sulfonyl-5 urine and thiourea urea having the formula "O)" - H v / N - SO 2 - »V 11111 n RmAJ Ϊ ER ( 2) (I) wherein R (1) is C 1-6 alkyl; R (2) is F, Cl, Br, I or C 1-6 alkoxy; E is oxygen or sulfur; and R (3) is a group of the formula 20. JT V ^ R <5) where R (4) and R (5) are C 1 -C 4 alkyl,. 25 is known for • · *. ·. (a) for the preparation of substituted benzenesulfonylthiourea derivatives of formula (Ib), 30. H CH2 * CH2 _ J / R (3) v Y; ···. sr (2) • ♦ ··· φ m ·: * ·· 35 (Ib) • ♦ • · · e »« • · 22 107917 Benzenesulfonamide II or a salt thereof III CH CH HH CH.-CH, H 5 niy ^ 0 0 (II) (III) 10 wherein M is an alkali metal or alkaline earth metal cation, is reacted with an R (1) substituted isocyanate of the formula R (1) - N = C = S (VI) 15 or (b) ) for the preparation of substituted benzenesulfonyl ureas according to formula (Ia), 20. H H MO - NwN - S02 “N \ / R (3) ·· 1 Ϊ XJ n • ·’ 1 • 1. The benzenesulfonylthiourea derivative of formula (Ib) is reacted with an oxidant. A process according to claim 1, characterized in that a ··· ... · compound of formula (I) is prepared, wherein R 1 is (C 1 -C 4) alkyl; and. ···. R (2) is F, Cl or C 1-4 alkoxy. • · ··· φ # • · · · · · · · · · · · · · · · · · · · · · · · 23 Process according to Claim 1, characterized in that a compound of formula (I) is prepared wherein R (1) is C 1-6 alkyl; and R (2) is F or Cl. Process according to claim 1, characterized in that a compound of formula (I) is prepared wherein R (1) C 1-4 alkyl; and R (2) is C 1-4 alkoxy. · · · · * * ♦ ♦ ♦ ♦ ♦ ♦ «« «« «« • · »· · · · · · · · · · · · · · · · · · · · · · · · · · · · ···