Title of Invention

SUBSTITUTED BENZENESULFONYLUREAS AND -THIOUREAS, PROCESSES FOR THEIR PREPARATION, THEIR USE FOR THE PRODUCTION OF PHARMACEUTICAL PREPARATIONS, AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM

Abstract Substituted benzenesulfonylureas and -thioureas, processes for preparation, their use for their production of pharmaceutical preparations, and pharmaceutical preparations containing them substituted benzenesulfonylureas and -thioureas of formula I in which R(1), R(2), R(3), E, X, Y and Ar have the meanings indicated in the patent claims, exhibit effects on the cardiovascular system.
Full Text

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Hoechst Aktiengesellschaft HOE 95/F 020 Dr. v. F.
Description
Substituted benzenesulfonylureas and -thioureas/ pro¬cesses for their preparation, their use for the produc¬tion of pharmaceutical preparations, and pharmaceutical preparations containing them
The invention relates to substituted benzenesulfonylureas and -thioureas of the formula I

in which:
R(l) is hydrogen, alkyl having 1, 2, 3, 4, S or 6 carbon atoms or cycloalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
R (2) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms or (C1-C8) chains in which one to three carbon atoms can be replaced by heteroatoms selected from the group consisting of O, NH and S;
R(3) and R(4)
(identical or different) are hydrogen, alkyl having 1, 2, 3,4, 5 or 6 carbon atoms, or together form a
(CH2)2-5 chain; E is oxygen or sulfur; X is oxygen or sulfur; Y is a hydrocarbon chain of the formula [CR(S)2]m,
R(5) is hydrogen or alkyl having 1 or 2 carbon atoms;
m is 1 or 2;

Ar is phenyl, thienyl, furyl, pyrrolyl, thiazolyl, naphthyl, pyridyl, which in each case is unsubstitu-ted or substituted by one to 3 substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, C1, Br and P.
The term alkyl describes, if not stated otherwise, straight-chain or branched saturated hydrocarbon radicals. The cycloalkyl radical can additionally carry an alkyl substituent. Halogen substituents which can be employed are the elements fluorine, chlorine, bromine and iodine. Furthermore, compounds having centers of chirality, for example in the alkyl chains Y, R(2}, R(3} and K(4), can occur. In this case, the invention includes both the individual antipodes per se, and a mixture of the two enantiomers in different proportions, and also the associated meso compounds or mixtures of meso compounds, the enantiomers or diastereomers.
Similar sulfonylureas having hypoglycemic action are disclosed in Belgian Patent 754 454.
The compounds I are used as pharmaceutical active com¬pounds in human and veterinary medicine. They can further be used as intermediates for the production of further pharmaceutical active compounds.
Preferred compounds I are those in which:
R(l) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
R (2) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms or (C1-C8) chains in which 1 to 3 carbon atoms can be replaced by heteroatoms selected from the group consisting of 0, NH and S;

R(3) and R{4)
(identical or different) are hydrogen, alkyl having 1, 2, 3,4, 5 or 6 carbon atoms or together form a (CH2) 2-5 chain;
E is sulfur;
X is oxygen;
Y is a hydrocarbon chain of the formula [CR(5)2]1-2
R(5) is hydrogen or alkyl having 1 or 2 carbon atoms; Ar is phenyl, thenyl, furyl, pyrrolyl, thiazolyl, naphthyl, pyridyl,
which in each case is unsubstituted or substi¬tuted by one to 3 substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, C1, Br and F.
Very particularly preferred compounds I are those in
which:
R(l) is hydrogen or alkyl having 1 or 2 carbon atoms;
R(2) is alkoxy having 1, 2, 3, 4, S or 6 carbon atoms;
R(3) and R(4)
(identical or different) are hydrogen, alkyl having
1, 2, 3, 4, 5 or 6 carbon atoms; E is sulfur; X is oxygen;
Y is a hydrocarbon chain of the formula (CH2)1-2;
Ar is phenyl, thenyl, furyl, pyrrolyl, thiazolyl, naphthyl, pyridyl,
which in each case is unsubstituted or substi¬tuted by one to 3 substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, C1, Br and F.
In addition, the compounds I form a preferred group in which:
R(l) is hydrogen or alkyl having 1 or 2 carbon atoms;

R(2) is alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms; R(3) and R(4)
(identical or different) are hydrogen or methyl; E is sulfur; X is oxygen;
Y is a hydrocarbon chain of the formula (CH2)1-2
Ar is thienyl, furyl, pyrrolyl, thiazolyl, naphthyl, pyridyl,
which in each case is unsubstituted or substi¬tuted by one to 3 substituents selected from the group consisting of alkyl having 1 or
2 carbon atoms, alkoxy having 1 or 2 carbon
atoms, Cl/ Br and F.
Likewise preferred compounds of the formula I are those in which:
R(l) is hydrogen or alkyl having 1 or 2 carbon atoms; R(2) is alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms; R(3) and R(4)
(identical or different) are hydrogen or methyl; E is sulfur; X is oxygen;
Y is a hydrocarbon chain of the formula (CH1)1-2;
Ar is phenyl,
which is unsubstituted or substituted by one to
3 Substituents selected from the group consist¬
ing of alkyl having 1 or 2 carbon atoms, alkoxy
having 1 or 2 carbon atoms, Cl, Br and F.
The compounds of the present invention are useful pharma¬ceuticals for the treatment of cardiac arrhythmias of all types of origin and for the prevention of sudden heart death due to arrhythmia and can therefore be used as antiarrhythmics. Examples of arrhythmic disorders of the heart are supraventricular arrhythmias such as atrial tachycardias, atrial flutters or paroxysmal supraventri¬cular arrhythmias or ventricular arrhythmias such as ventricular extrasystoles, but in particular life-threatening ventricular tachycardias or the particularly

dangerous ventricular fibrillation. They are suitable, in particular, for those cases where arrhythmias are the consequence of a constriction of a coronary vessel, such as occur in angina pectoris or during an acute cardiac infarct or as a chronic consequence of a cardiac infarct. They are therefore particularly suitable in postinfarct patients for the prevention of sudden heart death* Further syndromes where arrhythmias of this type and/or sudden heart death due to arrhythmia play a part are, for example, cardiac insufficiency or cardiac hypertrophy as a consequence of a chronically increased blood pressure. Moreover/ the compounds can positively affect a decreased contractility of the heart. This can include a disease-related fall in cardiac contractility, such as in cardiac insufficiency, but also acute cases such as heart failure in the case of the effects of shock. Likewise, in the case of a heart transplantation, after operation has taken place the heart can resume its operational capacity more rapidly and reliably. The same applies to operations on the heart, which necessitate a temporary stopping of cardiac activity by means of cardioplegic solutions.
The invention furthermore relates to a process for the preparation of the compounds I, which comprises
(a) reacting aromatic sulfonamides of the formula II

or their salts of the formula XXI


with R(l)-siibatituted isocyanates of the formula IV
R(l) -N=C=0 to give sxibstituted benzenesulfonylureas I a (E = oxygen)

Suitable cations M in the salts of the formula III are alkali metal/ alkaline earth metal, ammonium and tetra-alkylammonium ions. Equivalently to the R(l)-substituted isocyanates IV, R(1) substituted carbamic acid esters, R(l)-substituted carbamoyl halides or R(l)-substituted ureas can be employed.
(b) Unsubstituted benzenesulfonylureas I a [R(l) = H, E = O]
can be prepared by reaction of an aromatic benzenes-
ulfonamide of the formula II or of its salt III with
trialkylsilyl isocyanate or silicon tetraisocyanate and
cleavage (e.g. hydrolysis) of the primary silicon-substi¬
tuted benzenesulfonylureas.
It is furthermore possible to convert a benzenesulfon-amide II or its salt III into a benzenesulfonylurea I a by reaction with cyanogen halides and hydrolysis of the primarily formed N-cyanosulfonamides with mineral acids at temperatures from O°C to 100°C.
(c) A benzenesulfonylurea X a (where E = oxygen) can be
prepared from an aromatic benzene sulfonamide II or its
salt III using an R(l)-substituted trichloroacetamide of
the formula V


in the presence of a base in an inert solvent according to Synthesis 1987, 734-735 at temperatures from 25°C to 150°C.
Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides or alternatively alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassitim amide, sodium methoxide, sodium ethoxide, potassium methoxide or potas¬sium ethoxide. 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, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoramide, sulfoxides such as DMSO, sul-fones such as sulfolane, hydrocarbons such as benzene, toluene, xylenes. Furthermore, mixtures of these solvents with one another are also suitable.

is prepared from a benzenesulfonamide II or its salt III and an R(l)-substituted isothiocyanate VI
R(l)-N=C=S.
An unsubstituted benzenesulfonylthiourea lb [R(l) = H, X - S] can be prepared by reaction of an aromatic benz-

enesulfonamide II or its salt III with trimethylsilyl isothiocyanate or silicon tetraisothiocyanate and cleav¬age (hydrolysis) of the primarily formed silicon-substi¬tuted benzenesulfonylurea. Furthermore, it is possible to react an aromatic benzenesulfonamide IX or its salt III with benzoyl isothiocyemate and to react the intermediate benzoyl-substituted benzenesulfonylthiourea with an aqueous mineral acid to give I b [R(l) = H, E = S] * Similar processes are described in J. Med, Chem. 1992/ 35/ 1137-1144. A further variant consists in reacting the N-cyanosulfonamides mentioned under process 1 with hydrogen sulfide.
(e) A substituted benzenesulfonylurea of the formula I a
(E = oxygen) can be prepared by a conversion reaction of
a benzenesulfonylthiourea of the structure lb (E = S) .
The replacement of the sulfur atom by an oxygen atom in
the appropriately substituted benzenesulfonylthiourea can
be carried out, for example, with the aid of oxides or
salts of heavy metals or also by use of oxidants such as
hydrogen peroxide, sodium peroxide or nitrous acid. A
thiourea can also be desulfurized by treatment with
phosgene or phosphorus pentachloride. The intermediate
compounds obtained are chloroformamidines or carbo-
diimides, which are converted into the corresponding
substituted benzenesulfonylureas, for example, by hydro¬
lysis or addition of water. During desulfurization,
isothioureas behave like thioureas and can accordingly
also be used as starting substances for these reactions.
(f) A benzenesulfonylurea I a can be prepared from a
benzenesulfonyl halide of the formula VII


using an R(l)-substituted urea or an R(l)-substituted bis(trialkylsilyl)urea. Furthermore, the sulfonyl chlor¬ide VII can be reacted with parabanic acid to give a benzenesulfonylparabanic acid whose hydrolysis with mineral acids yields the corresponding benzenesulfonyl-urea I a.
(g) A benzenesulfonylurea I a can be prepared by reaction of an amine of the formula R(l) -NH2 with a benzenesul-fonyl isocyanate of the formula VIII

Likewise, an amine R(l) -NH2 can be reacted with a benzenesulfonylcarbamic acid ester, a -carbamoyl halide or a benzenesulfonylurea I a [where R(l) = H] to give the compounds I a.
(h) A benzenesulfonylthiourea I b can be prepared by reaction of an amine of the formula R(1)-NH2 with a benz¬enesulfonyl isothiocyanate of the formula IX

Likewise, an amine R(1)-NH2 can be reacted with a benz¬enesulfonylcarbamic acid thioester or a thiocarbamoyl halide to give the compounds I b.
The sulfonyl isothiocyanates were prepared by reaction of a corresponding sulfonamide with eguimolar amounts of alkali metal hydroxide and carbon disulfide in an organic solvent, such as DMF, DMSO or N-methylpyrrolidone • The di-alkali metal salt of the sulfonyldithiocarbamic acid obtained is reacted in an inert solvent with a slight

excess of phosgene/ or substitute of the same, such as triphosgene, a chlorofonnic acid ester (2 equivalents) or thionyl chloride. The solution of the sulfonyl isothlo-cyanate obtained can be reacted directly with the corre¬sponding amines or ammonia
(i) An appropriately substituted benzenesulf enyl- or -sulfinylurea can be oxidized to give the benzene-sulfonylurea I a using an oxidant, such as hydrogen peroxide, sodium peroxide or nitrous acid.
(j) A benzenesulfonylurea I a can be prepared from a
benzenesulfonylurea of the formula X

and R(3)R(4)NH using a dehydrating agent/or by activation with a carbonyl mixde or with a mixed anhydride.
The dehydrating agents employed can be all compounds suitable for the preparation or amide bonds, such as dicyclohexylcarbodiimide, carbonyldiimidazole or pro-panephosphoric anhydride. The solvents used are inert nonprotic solvents such as THF, DMF, diethyl ether, dichloromethane, as well as mixtures of these solvents.
(k) A benzenesulfonylthiourea I b can be prepared from a benzenesulf onyl thiourea of the formula xI

and R(3)R(4)NH using a dehydrating agent or by activation with a carbonyl halide or with a mixed anhydride.

The compounds I and their physiologically acceptable salts are useful therapeutics which are suitable not only as antiarrhythmics/ but as prophylaxis in disorders of the cardiovascular system, cardiac insufficiency, heart transplantation or cerebral vascular disorders in humans or mammals (for example monkeys, dogs, mice, rats, rabbits, guinea-pigs and cats), Physiologically accept¬able salts of the compounds X are understood according to Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14-18 as meaning compounds of the formula XII

which can be prepared from nontoxic organic and inorganic bases and substituted benzenesulfonylureas I. Salts are preferred in this context in which M in the formula XII is a sodium, potassium, rubidium, calcium, magnesium or ammonium ion, and can also be the acid addition products of basic amino acids, such as lysine or arginine.
The starting compounds for the mentioned synthesis processes of the benzenesulfonylureas I are prepared by methods known per se, as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley St Sons, Inc., New York; and also in the patent applications indicated above), namely under

reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but not mentioned here in more detail. If desired, the starting substances can also be formed in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further.
The starting compounds for the mentioned synthesis processes of the benzenesulfonyl(thio)ureas I are pre¬pared by methods known per se, as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; and also in the patent applications indicated above), namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but not mentioned here in more detail. If desired, the starting substances can also be formed in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further.
Suitably substituted carboxylic acids of the formula XIII

can thus be subjected to a halosulfonation and the sulfonamide XIV
obtained by subseguent ammonolysis can be reacted with an

appropriate amine R(3}R(4)MH after activation o£ the carboxylic acid group to give the carboxaxmide of the formula II
Suitable activation methods are the preparation of the carbonyl chloride or of the ester or mixed carboxylic anhydrides using formyl halides. In addition, the reagents known for amide bond preparation such as carbonyldiimidazole, dicyclohexylcarbodiimide and pro-panephosphoric anhydride can be used.
The sulfonamides XIV are prepared by known methods, namely voider reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known but not mentioned here in more detail. If desired, the syntheses can be carried out in one, two or more steps. In particu¬lar, processes are preferred in which the acid XIII is converted into aromatic sulfonic acids and their derivat¬ives, such as sulfonyl halides, by electrophilic reagents in the presence or absence of inert solvents at tempera-tures from -10°C to 120°C, preferably from 0°C to 100°C, For example, sulfonations can be carried out using sulfuric acids or oleum, halosulfonations using halo-sulfonic acids, reactions with sulfuryl halides in the presence of anhydrous metal halides or with thionyl halides in the presence of anhydrous metal halides with subsequent oxidations, which are carried out in a known manner, to give aromatic sulfonyl chlorides. If sulfonic acids are the primary reaction products, these can be converted into sulfonyl halides in a known manner by acid halides, such as phosphorus trihalides, phosphorus pentahalides, phosphorus oxychloride, thionyl halides or

oxalyl halides, either directly or by treatment with tertiary amines, such as pyridine or trialkylamines, or with alkali metal or alkaline earth metal hydroxides or reagents which form these basic compounds in situ. The sulfonic acid derivatives are converted into sulfonamides in a manner known from the literature, preferably sulfonyl chlorides are reacted in inert solvents with aqueous ammonia in acetone or THF at temperatures from 0°C to 100°C. Furthermore, aromatic sulfonamides XIV can be synthesized according to processes described in the literature from the acids XIII or their esters by reac¬tions with organic reagents of alkali metals or alkaline earth metals in inert solvents and under an inert gas atmosphere at temperatures from -100°C to 50°C, prefer-ably from -100°C to 30C, with sul fur dioxide and subsequent thermal treatment with an NH2 donor, such as sulfamic acid.
The compounds I according to the invention and their physiologically acceptable salts can be used for the production of pharmaceutical preparations, in particular by a nonchemical route. In this context, they can be brought into a suitable dose form together with at least one solid or liquid excipient or auxiliary on their own or in combination with other pharmaceuticals having cardiovascular activity, such as calcium antagonists, NO donors or ACE inhibitors. These preparations can be used as pharmaceuticals in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration, for example intravenous administration, or topical applications and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin and petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, juices or drops are used for oral administration, solutions, preferably oily or aqueous solutions, and also

suspensions, emulsions or implants, are used for rectal administration, and creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1, 2-propanediol or their mixtures with one another or with water) or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. In particular for topical application, liposomal prepara¬tions are also suitable. They contain stabilizers and/or wetting agents, emulsifiers, salts and/or auxiliaries such as lubriccants, preservatives, salts for affecting the osmotic pressure, buffer substances, colorants and flavorings and/or aromatic substances. If desired, they can also contain one or more further active compounds, for example one or more vitamins.
The doses which are necessary for the treatment of cardiac arrhythmias with the compounds I depend on whether the therapy is acute or prophylactic. Normally, a dose range of approximately at least 0.1 mg, preferably at least 1 mg, up to at most 100 mg, preferably up to at most 10 mg, per kg per day is adequate if prophylaxis is conducted. The dose can in this case be divided as an oral or parenteral individual dose or else in up to four individual doses* l£ acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration can be advantageous. A preferred dose range in critical situations can then be 10 to 100 mg and be administered, for example, as an intravenous continuous infusion.
According to the invention, in addition to the compounds described in the working examples, the compounds I compiled in the following Table can be obtained:
1) N-5-(1-Phenylethyl)aminocarbonylmethyl-2-propoxy-phenylsulfonyl-N'-methylthiourea





N-5-(1-(2-Furyl)ethyl)aminocarbonylmethyl-2-methyl-thiophenylsulfonyl-N'-methylurea
42) N-5- (1- (3-Furyl) ethyl)aminocarbonylmethyl-2-methyl-thiophenylsulfonyl-N'-methylurea
43) N-5-(1-(2-Thienyl)ethyl)aminocarbonylmethyl-2-methyl-thiophenylsulfonyl-N'-methylurea
44) N-5- (1- (3-Thienyl)ethyl)aminocarbonylmethyl-2-methyl-thiophenylsul£onyl-N'-methylurea

45) N-5- (1-{2-Pyrrolyl)ethyl)aminocarbonylmethyl-2-methyl-thiophenylsulfonyl-N'-methylurea
46) N-5- (1- (3-Pyrrolyl) ethyl) aminocarbonylmethyl-2-methyl-thiophenylsulfonyl-N'-methylurea
47) N-5- (1-(2-Thiazolyl)ethyl)aminocarbonylmethyl-2-
methylthiophenylsulfonyl-N'-methylurea
48) N-5- (1- (2-Furyl)ethyl)aminocarbonylmethyl-2-ethoxy-phenylsulfonyl-N'-methylthiourea
49) N-5-(1-(3-Furyl)ethyl) auninocarbonylmethyl-2-ethoxy-phenylsulfonyl-N'-methylthiourea
50) N-5- (1- (2-Thienyl) ethyl) aminocarbonylmethyl-2-ethoxy-phenylsulfonyl-N'-methylthiourea
51) N-5- (1- (3-Thienyl) ethyl) aminocarbonylmethyl-2-ethoxy-phenylsulfonyl-N'-methylthiourea

52) N-5-(1-(2-Pyrrolyl)ethyl)aminocarbonylmethyl-2-ethoxyphenylsul£onyl-N' -methylthiourea
53) N-5-(1-(3-Pyrrolyl)ethyl)aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N' -methylthiourea

54) N-5- (1- (2-Thiazolyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N' -methylthiourea
55) N-5-(1-(3-Thiazolyl)ethyl)aminocarbonylmethyl-2-ethoxyphenylsul£onyl-N'-methylthiourea

56) N-5-(1-(2-Furyl)ethyl) euninocarbonylmethyl-2-ethoxy¬phenylsulfonyl-N' -methylurea
57) N-5-(1-(3-Furyl)ethyl)aminocarbonylmethyl-2-ethoxy¬phenylsulfonyl-N' -methylurea
58) N-5-(1- (2-Thienyl)ethyl)aminocarbonylmethyl-2-ethoxy¬phenylsulfonyl-N' -methylurea
59) N-5- (1- (3-Thienyl) ethyl) aminocarbonylmethyl-2-ethoxy-phenylaulfonyl-N'-methylurea
60) N-5-(1-{2-Pyrrolyl)ethyl)aminocarbonylmethyl-2-

ethoxyphenylsulfonyl -N'-methylurea
61) N-5-(1-(3-Pyrrolyl)ethyl)aminocarbonylmethyl-2-
ethoxyphenylsulfonyl- N' -methylurea
62) N-5-(1-(2-Thiazolyl)ethyl)aminocarbonylmethyl-2-
ethoxyphenylsulfonyl -N' -methylurea
63) N-5-(1-(2-Furyl)ethyl)aminocarbonylmethyl-2-propoxy-phenylsulfonyl-N' -methylthiourea
64) N-5-(1-(3-Furyl)ethyl)aminocarbonylmethyl-2-propoxy-phenylsulfonyl-N' -methylthiourea

65) N-5- (1- (2-Thienyl) ethyl) aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea
66) N-5- (1- (3-Thienyl) ethyl) aminocarbonylmethyl-2-pro-poxyphenlylsulfonyl-N' -methylthiourea

67) N-5- (1- (2-Pyrrolyl) ethyl) aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N' -methylthiourea
68) N-5-(1-(3-Pyrrolyl)ethyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea

69) N-5-(1-(2-Thiazolyl)ethyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea
70) N-5-(l-(3-Thiazolyl)ethyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea
71) N-5-(1-(2-Furyl)ethyl)aminocarbonylmethyl-2-propoxy-phenylsulfonyl-N' -methylurea
72) N-5-(1-(3-Furyl)ethyl) auninocarbonylmethyl-2-propoxy-phenylsulfonyl-N'-methylurea

73) N-5-(1-(2-Thienyl)ethyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylurea
74) N-5-(1-(3-Thienyl)ethyl)aminoGarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylurea

75) N-5-(1- (2-Pyrrolyl)ethyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylurea
76) N-5-(1-(3-Pyrrolyl)ethyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N' -methylurea
77) N-5-(1-{2-Thiazolyl)ethyl)aminocarbonylmethyl-2-pro-
poxyphenylsulfonyl-N'-methylurea
78) N-5-(l-Phenylpropyl)aminocarbonylmethyl-2-propoxy-
phenylsulfonyl-N'-methylthiourea
79) N-5-(1-(2-Furyl)propyl)aminocarbonylmethyl-2-methoxy-
phenylsulfonyl-N'-methylthiourea

80) N-5- (1- (3-Furyl)propyl)aminocarbonylmethyl-2-methoxy-
phenylsulfonyl-N'-methylthiourea
81) N-5- (1- (2-Thienyl) propyl) aminocarbonylinethyl-2-methoxyphenylsulfonyl-N' -methylthiourea
82) N-5-(1-(3-Thienyl)propyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N' -methylthiourea

83) N-5- (1- (2-Pyrrolyl) propyl) aminocarbonylmethyl-2-methoxyphenylsul£onyl-N' -methylthiourea
84) N-5-(1-(3-Pyrrolyl)propyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

85) N-5- (1-(2-Thiazolyl)propyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea
86) N-5- (1- (3-Thiazolyl)propyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

87) N-5- (1- (2-Furyl)propyl)aminocarbonylmethyl-2-methoxy-phenylsulfonyl-N'-methylurea
88) N-5- (1- (3-Furyl)propyl) aminocarbonylmethyl-2-methoxy¬phenylsulfonyl-N' -methylurea

89) N-5-(1-(2-Thienyl)propyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N' -methylurea
90) N-5-(1-(3-Thienyl)propyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea
91) N-5- (1- (2-Pyrrolyl)propyl)aminocarbonylmethyl-2-meth-
oxyphenylsulfonyl-N'-methylurea
92) N-5-(1-(3-Pyrrolyl)propyl) aminocarbonylmethyl-2-
methoxyphenylsulfonyl-N'-methylurea
93) N-5-(1-(2-Thiazolyl)propyl)aminocarbonylmethyl-2-
methoxyphenylsulfonyl-N'-methylurea
94) N-5- (1- (2-Furyl)propyl) aminocarbonylmethyl-2-methyl-phenylsulfonyl-N'-methylthiourea
95) N-5- (1- (3-Furyl) propyl) aminocarbonylmethyl-2-methy 1-phenylsulfonyl-N'-methylthiourea

96) N-5- (1-(2-Thienyl)propyl)aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea
97) N-5-(1-(3-Thienyl)propyl)aminoGarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea

98) N-5- (1-(2-Pyrrolyl)propyl)aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea
99) N-5-(1-(3-Pyrrolyl)propyl)aminocarbonylmethyl-2-

methylphenylsulfonyl-N'-methylthiourea
100) N-5- (1- (2-Thiazolyl)propyl)aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea
101) N-5-(1-(3-Thiazolyl)propyl)aminocarbonylmethyl-2" methylphenylsulfonyl-N'-methylthiourea

102) N-5- (1- (2-Furyl) propyl) aminocarbonylmethyl-2-methyl¬phenylsulfonyl-N' -methylurea
103) N-5- (1- (3-Furyl) propyl) aminocarbonylmethyl-2-methyl-phenylsulfonyl-N'-methylurea

104) N-5-(l-(2-Thienyl)propyl)aminoGarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea
105) N-5-(l-(3-Thienyl)propyl)aminocarbonylmethyl-2 -methylphenylsulfonyl-N'-methylurea

106) N-5-(1-(2-Pyrrolyl)propyl)aminocarbonylmethyl-2-methylphenylsulfonyl-N' -methylurea
107) N-5-(1-(3-Pyrrolyl)propyl)aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea

108) N-5-(l-(2- Thiazolyl) propyl) aminocarbonylmethyl - 2 -methylphenylsulfonyl-N' -methylurea
109) N-5-(l- (3-Thiazolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N' -methylurea

110) N-5- (1- (2-Furyl) propyl) aminocarbonylme thyl-2-methyl-thiophenylsulfonyl-N'-methylthiourea
111) N-5- (1- (3-Furyl) propyl) aminocarbonylme thyl-2-methyl-thiophenylsulfonyl-N'-methylthiourea

112) N-5-(1-(2-Thienyl)propyl)aminocarbonylmethyl-2-methyl thiophenylsulfonyl-N' -methylthiourea
113) N-5- (1- (3-Thienyl) propyl) aminocarbonylmethyl-2-me thyl thiophenylsulfonyl-N' -methylthiourea

114) N-5- (1- (2-Pyrrolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea
115) N-5-(1-(3-Pyrrolyl)propyl)aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea

116) N-5- (1- (2-Thiazolyl) propyl) aminocarbonylmethyl-2-me thyl thiophenylsulfonyl-N' -methylthiourea
117) N-5-(1-(3-Thiazolyl)propyl)aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea
118) N-5- (1- (2-Furyl) propyl) aminocarbonylme thyl-2-me thyl-
thiophenylsulfonyl-N'-methylurea

119) N-5- (1- (3-Furyl)propyl) aminocarbonylmethyl-2-methyl-
thiophenylsulfonyl-N'-methylurea
120) N-5- (1- (2-Thienyl) propyl) aminocarbonylinethyl-2-methylthiophenylsulfonyl-N' -methylurea
121) N-5-(1-(3-Thienyl)propyl)aminoGarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea

122) N-5-(1-(2-Pyrrolyl)propyl)aminocarbonylmethyl-2-methy1thiophenylsulfonyl-N'-methylurea
123) N-5- (1- (3-Pyrrolyl)propyl) aminocarbonylmethyl-2-methylthiophenylsul£onyl-N'-methylurea
124) N-5- (1-(2-Thiazolyl)propyl)aminocarbonylmethyl-2-
methylthiophenylsulfonyl-N'-methylurea
125) N-5- (1- (2-Furyl)propyl)aminocarbonylmethyl-2-ethoxy-phenylsul£onyl-N'-methylthiourea
126) N-5- (1- (3-Furyl) propyl)aminocarbonylmethyl-2-ethoxy-phenylsulfonyl-N'-methylthiourea

127) N-5-(1-(2-Thienyl)propyl)aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea
128) N-5- (1- (3-Thienyl) propyl) ajninocarbonylmethyl-2-ethoxyphenylsulfonyl-N' -methylthiourea

129) N-5- (1- (2-Pyrrolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N' -methylthiourea
130) N-5- (1- (3-Pyrrolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N' -methylthiourea

131) N-5- (1-(2-Thiazolyl) propyl)aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea
132) N-5- (1- (3-Thiassolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea

133) N-5- (1- (2-Fury 1) propyl) aminocarbonylmethyl-2-ethoxy¬phenylsulfonyl-N' -methylurea
134) N-5- (1- (3-Puryl) propyl) aminocarbonylmethyl-2-ethoxy-
phenylaulfonyl-N'-methylurea
135) N-5-(1-(2-Thienyl)propyl)aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea
136) N-5-(1-(3-Thienyl)propyl)aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea

137) N-5-(1-(2-Pyrrolyl)propyl) auninocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea
138) N-5-{l-(3-Pyrrolyl)propyl)aminocarbonylmethyl-2-

ethoxyphenyl0ulfonyl-N' -methylurea
139) N-5- (1- (2-Thiazolyl) propyl) aminocarbonylinethyl-2-ethoxyphenylsulfonyl-N' -methylurea
140) N-5- (1- (2-Puryl) propyl) aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N' -methylthiourea
141) N-5-(1-(3-Furyl)propyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea

142) N-5-(1-(2-Thienyl)propyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea
143) N-5-(1-(3-Thienyl)propyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea

144) N-5- (1- (2-Pyrrolyl) propyl) aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N' -methylthiourea
145) N-5- (1- (3-Pyrrolyl)propyl)aminocarbonylmethyl-2-pro-poxyphenylsulfonyl-N'-methylthiourea

146) N-5- (1- (2-Thiazolyl) propyl)aminocarboiiylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea
147) N-5-(1-(3-Thiazolyl)propyl)aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea
148) N-5-(1-(2-Puryl)propyl)aminocarbonylmethyl-2-pro¬poxyphenylsulfonyl-N' -methylurea
149) N-5-(1-(3-Fury1)propyl) suainocarbonylmethyl-2-pro¬poxyphenylsulfonyl-N' -methylurea

150) N-5-(1-(2-Thienyl)propyl)aminocarbonylmethyl-2-pro¬poxyphenylsulfonyl-N' -methylurea
151) N-5-(l- (3-Thienyl) propyl) aminocarbonylmethyl-2-pro¬poxyphenylsulfonyl-N' -methylurea

152) N-5- (1- (2-Pyrrolyl)propyl)aminocarbonylmethyl-2-pro¬poxyphenylsulfonyl-N' -methylurea
153) N-5- (1- (3-Pyrrolyl) propyl) aminocarbonylmethyl-2-pro¬poxyphenylsulfonyl-N' -methylurea
154) N-5-(1-(2-Thiazolyl)propyl)aminocarbonylmethyl-2-
propoxyphenylsulfonyl-N'-methylurea
155) N-5-(1-Phenyl-l-methylethyl)aminocarbonylmethyl-2-
propoxyphenylsul£onyl-N'-methylthiourea
156) N-5-(1-(2-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methoxyphenylaul£onyl-N' -methylthiourea
157) N-5'(1-(3-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

158) N-5- (1- (2-Thienyl) -1-methylethyl) aminocarbonyl-methyl-2-methoxyphenylsulfonyl-N' -methylthiourea
159) N-5-(1-(3-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-lnethoxyphenylsulfonyl-N' -methylthiourea

160) N-5-(1-(2-Pyrrolyl)-1-methylethyl)aminocarbonyl-methyl-2-methoxyphenylsulfonyl'N'-methylthiourea
161) N-5-(1-(3-Pyrrolyl)-l-methylethyl)aminocarbonyl-methyl-2-methoxyphenylsulfonyl*N' -methylthiourea

162) N-5-(1-{2-Thiazolyl)-1-methylethyl)aminocarbonyl-methyl-2-methoxyphenylsulfonyl-N'-methylthiourea
163) N-5-(1-(3-Thiazolyl)-1-methylethyl)aminocarbonyl-methyl-2-methoxyphenylsulfonyl-N'-methylthiourea

164) N-5-(1-{2-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methoxyphenylaulfonyl-N'-methylurea
165) N-5- (1- (3-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea

166) N-5-(l-(2-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-methoxyphenylsul£onyl-N' -methylurea
167) N-5-(1-(3-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-methoxyphenylsulfonyl-N'-methylurea

168) N-5-(l-(2-Pyrrolyl)-1-methylethyl)aminocarbonyl-methyl-2-methoxyphenylsulfonyl-N'-methylurea
169) N-5-(1-(3-Pyrrolyl)-1-mathylethyl) ajninocarbonyl-methyl-2-methoxyphenylsulfonyl-N'-methylurea
170) N-5-(1-(2-Thiazolyl)-1-methylethyl)aminocarbonyl-
methyl-2-methoxyphenylsulfonyl-N'-methylurea
171) N-5-(1-(2-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea
172) N-5-(1-(3-Furyl)-1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea

173) N-5-(1-(2-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylthiourea
174) N-5-(1-(3-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylthiourea

175) N-5-(1-(2-Pyrrolyl)-1-methylethyl) auninocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylthiourea
176) N-5-(1-(3-Pyrrolyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylthiourea
177) N-5-(1-(2-Thiazolyl)-1-methylethyl)aminocarbonyl-

methyl-2-methylphenylsulfonyl-N'-methylthiourea
178) N-5- (1- (3-Thiazolyl) -1-methylethyl) aminocarbonyl-
methyl-2-methylphenylsulfonyl-N'-methylthiourea
179) N-5- (1- (2-Furyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea
180) N-5-(1-(3-Furyl)-l-methylethyl)aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea

181) N-5-(1-(2-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylurea
182) N-5-(1-(3-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylurea

183) N-5-(1-(2-Pyrrolyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylurea
184) N-5-(1-(3-Pyrrolyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylurea

185) N-5-(1-(2-Thiazolyl)-1-methylethyl)aminocarbonyl-methyl-2-methylphenylsulfonyl-N'-methylurea
186) N-5-(1-(3-Thiazolyl)-1-methylethyl)aminocarbonyl-methyl-2-methylthiophenylsulfonyl-N'-methylurea

187) N-5- (1- (2-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea
188) N-5-(1-(3-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea

189) N-5- (1-(2-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-methyl thiophenylsulf onyl-N' -methyl thiourea
190) N-5- (1-(3-Thienyl)-1-methylethyl) aminocarbonyl-methyl-2-methylthiophenylsulfonyl-N'-methylthiourea

191) N-5- (1-(2-Pyrrolyl)-1-methylethyl) aminocarbonyl-methyl-2-methyl thiophenylsulf onyl-N' -methylthiourea
192) N-5-(l- (3-Pyrrolyl) -1-methylethyl) aminocarbonyl-methyl-2-methyl thiophenylsulf onyl-N' -methylthiourea

193) N-5- (1- (2-Thiazolyl) -1-methylethyl) aminocarbonyl-methyl-2-methyl thiophenylsulf onyl-N' -methylthiourea
194) N-5-(1-(3-Thiazolyl)-1-methylethyl) aminocarbonyl-methyl-2-methyl thiophenylsulf onyl-N' -methylthiourea

195) N-5- (1- (2-Furyl) -1-methylethyl) aminocarbonylmethyl-2 -methylthiophenylsulf onyl -N' -methylurea
196) N-5-(1-(3-Furyl)-1-methylethyl)aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea



methyl-2-ethoxyphenylsulfonyl-N' -methylurea
217) N-5- (1- (2-Furyl) -1-methylethyl) alIlinocarbonylmethyl-2-propoxyphenylsulfonyl-N' -methylthiourea
218) N-5- (1-(3-Furyl)-1-methylethyl)aminocarbonylmethyl-2-propoxyphenylsulfonyl-N' -methylthiourea

219) N-5-(1-(2-Thienyl)-1-methylethyl)aminocarbonyl-methyl-2-propoxyphenylsulfonyl-N'-methylthiourea
220) N-5- (1- (3-Thienyl) -1-methylethyl) aminocarbonyl-methyl-2-propoxyphenylsulfonyl-N' -methylthiourea

221) N-5-(l-(2-Pyrrolyl)-1-methylethyl) aminocarbonyl-methyl-2-propoxyphenylsulfonyl-N'-methylthiourea
222) N-5-{l-(3-Pyrrolyl)-1-methylethyl)aminocarbonyl-methyl-2-propoxyphenylsulfonyl-N'-methylthiourea

223) N-5-(1-(2-Thiazolyl)-1-methylethyl)aminocarbonyl-methyl-2-propoxyphenylsulfonyl-N'-methylthiourea
224) N-5-(1-(B-Thiazolyl)-1-methylethyl) aminocarbonyl-methyl-2-propoxyphenylsulfonyl-N'-methylthiourea

225) N-5-(l-{2-Furyl)-1-methylethyl)aminocarbonylmethy1-2-propoxyphenylsulfonyl-N'-methylurea
226) N-5-(l-(3-Furyl)-1-methylethyl)aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylurea

227) N-5-(1-(2-Thienyl)-1-methylethyl)aminocarbonyl¬methyl -2 -propoxyphenylsulfonyl-N' -methylurea
228) N-5-(1-(3-Thienyl)-1-methylethyl)aminocarbonyl¬methyl -2 -propoxyphenylsulfonyl-N' -methylurea

229) N-5-(l-(2-Pyrrolyl)-1-methylethyl)aminocarbonyl¬methyl -2 -propoxyphenylsulfonyl-N' -methylurea
230) N-5-(l-(3-Pyrrolyl)-1-methylethyl)aminocarbonyl¬methyl -2 -propoxyphenylsulfonyl-N' -methylurea
231) N-5-(1-(2-Thiazolyl)-1-methylethyl)aminocarbonyl¬
methyl -2 -propoxyphenylsulfonyl-N' -methylurea
Preparation of the starting materials
Preparation of 3-sulfamoylphenylalkanecarboxylic acids
The 4-substituted phenylalkanecarboxylic acids are added in portions with stirring to an excess of

chlorosulfonic acid. The mixture is stirred for 30 min¬utes at room temperature, then poured onto ice and the resulting sulfonyl chloride is filtered off with suction. The latter is dissolved in ammonia solution, stirred at room temperature for 3 0 minutes, and the solution is neutralized using 2N hydrochloric acid. The product obtained is filtered off with suction.
Prepared according to this method: 3 -Sulfamoyl-4-methoxyphenyl-3-propionic acid M.p. 172-176°C
3-Sulfamoyl-4-methoxyphenylacetic acid M.p. 164°C
Preparation of 3-sulfonyl2unino-N- (methylaminothio-carbonyl)-4-methoxyphenylacetic acid
5 g of 3-sulfamoyl-4-methoxyphenylacetic acid are dis-solved in 3 ml of DMF and stirred at 40°C for 3 0 minutes with 245 mg of sodium hydroxide. 328 mg of methyl iso-thiocyanate are added thereto and the mixture is stirred for a further 2 h at 70°C. 2N hydrochloric acid is added to the cooled solution and the product is filtered off with suction. M.p. 174°C.
Preparation of N-5-(l-phenylethyl)aminocarbonylmethyl-2-
methoxysulfamoylbenzene
2 .45 g (0 .01 mol) of 3-sulf amoyl-4-me thoxyphenyl-ace tic
acid and 4.0 g of trie thy lamine are_ dissolved in 25 ml of DMF and treated with propanephosphonic anhydride (0.015 mol; 50 % str_ength in DMF) and then with 1.2 g (0.01 mol) 1-phenylethy 1-amine with ice cooling. The mixture is stirred for 3 hours at RT and poured onto water. After some time, the product crystallizes and can fr_equently be used without further-purification for further reactions.
The following are obtained analogously
N-5- (1-Phenylethyl) aminocarbonylmethyl-2-ethoxy


A)
0.01 mol of a sulfonamide II are dissolved in 25 ml of
DMF and treated with 0.006 mol of K2CO3, 0.011 mol of an
iso(thio)cyanate is added with stirring and the mixture
is heated at 60-80°C for approximately 2-6 hours. The
mixture is poured onto ice water and acidified with 2 N
HCl. The deposited crystals are filtered off with suction
and optionally purified by recrystallization or by
chromatography on silica gel. In many cases, however, the
reaction is quantitative or the product crystallizes out
in pure form after acidifying.
B)
CS2 and KOH in DMF are added to sulfonamide 2, then
triphosgene to the dipotassium salt. Finally, ammonia is
added and the solution is acidified.
Examples:
Example 1:
N-5- (1-Phenylethyl) aminocarbonylmethyl-2-methoxyphenyl-
sulfonyl-N'-methylthiourea
M.p.: 175-176°C

Example 2:
N-5-(1-Phenylethyl)aminocarbonylmethy1-2 -ethoxypheny1-
sulfonyl-N'-methylthiourea
M,p.: 156-158°C
Example 3
N-5-(1-Phenylethyl) aminocarbonylmethyl-2-methylphenyl-
sulfonyl-N'-methylthiourea
Example 4
N-5- (1-Naphthylethyl) aminocarbonylmethyl-2-methoxyphenyl-
sulfonyl-N'-methylthiourea
M.p.: 188-190°C
Example 5
N-5- (1-Phenylpropyl) aminocarbonylmethyl-2-methoxyphenyl-
aulfonyl-N'-methylthiourea
M.p.: 125-127°C
Example 6
N-5 - (1 - Phenylbutyl) aminocarbonylmethyl - 2 -me thoxyphenyl -
sulfonyl-N'-methylthiourea
M.p.: 128-130°C
Example 7
N-5-(1-Phenyleyclobutylmethyl)aminocarbonylmethyl-2-
methoxyphenylsulfonyl-N'-methylthiourea
M.p.: 195-197°C
Example 8
N-5-(l-Phenylcyclohexylmethyl)aminocarbonylmethyl-2-
methoxyphenylsulfonyl-N'-methylthiourea
M.p.: 181-183°C
Example 9
N-5 - (1- (2 -Methoxyphenyl) ethyl) aminocarbonylmethyl-2 -
methoxyphenylsulfonyl-N' -methylthiourea
M.p.: 178-179°C

Example 10
N-5- (l-Phenylpentyl) aminocarbonylmethyl-2-methoxyphenyl-sulfonyl-N'-methylthiourea M,p.: 143-145°C
Example 11
N-5 - (1 - Phenylpropyl) aminocarbonylme thyl - 2 -methylsulfonyl -
N' -methylthiourea
M.p.: 117-118°C
Excunple 12
N-5- (l-Phenylbutyl) aminocarbonylmethyl-2-me thylsulf onyl-
N'-methylthiourea
M.p.: 112-113°C
Example 13
N-5-(1-Phenylcyclobutylmethyl)aminocarbonylmethyl-2 -
methylphenylsulfonyl-N' -methylthiourea
M.p.: 130-131°C
Example 14
N-5-(l-Phenylcyclohexylmethyl)aminocarbonylmethyl-2 -
methylphenylsulfonyl-N'-methylthiourea
M.p.: 145-147°C
Example 15
N-5- (2- (1, IR-Phenylethyl) aminocarbonyl) ethyl-2-methoxy-
phenylsulfonyl-N'-methylthiourea
M.p.: 88°C
Example 16
N-5- (2- (1, IS-Phenylethyl) aminocarbonyl) ethyl-2-methoxy-
phenylsulfonyl-N'-methylthiourea
M,p.: 85°C
Example 17
N-5- (2- (1, IR-Phenylethyl) aminocarbonylmethyl-2-methoxy-phenylsulfonyl-N' -methylthiourea M.p.: 150-152°C


The therapeutic properties of the compounds I can be revealed using the following models:
(1) Action potential duration on the papillary muscle of the guinea-pig:
(a) Introduction
ATP deficiency states, as are observed during ischemia in the cardiac muscle cell, lead to a reduction of the action potential duration. They count as one of the causes of so-called reentry arrhythmias, which can cause sudden heart death. The opening of ATP-sensitive K channels as a result of the fall of ATP counts as causal here*
(b) Method
To measure the action potential, a standard micro-electrode technique is employed. For this, guinea-pigs of both sexes are killed by a blow to the head, the hearts are removed, and the papillazry muscles are separated out and suspended in an organ bath. The organ bath is irrigated with Ringer solution (0.9% NaCl, 0.048% KCl, 0.024% CaCl2, 0-02% NaHCO3 and 0.1% glucose) and aerated with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 3 6°C. The muscle is stimulated by means of

an electrode using square-wave impulses of 1 V and 1 ms duration and a frequency of 2 Hz, The action potential is derived and recorded by means of a glass microelectrode inserted intracellularly, which is filled with 3 mM KCl solution. The substances to be tested were added to the Ringer solution in a concentration of 2.2-10-5 mol per liter. The action potential is amplified using an amplifier from Hugo Sachs and shown on an oscilloscope. The duration of the action potential is determined at a degree of repolarization of 95% (APD95)-
Action potential reductions are produced either by addition of a 1 µm-strength solution of the potassium channel opener Hoe 234 (J, Kaiser, H. Gogelein, Naunyn-Schmiedebergs Arch. Pharm. 1991, 343/ R 59) or by addi¬tion of 2-deoxygluGose. The action potential-reducing effect of these substances was prevented or reduced by the simultaneous addition of the test substances. Test substances were added to the bath solution as stock solutions in propanediol. The values indicated relate to measurements 30 minutes after addition. Glibenclamide was used in these measurements as a standard. The test concentration in all cases is 2 x 10-6 M.
(c) Results:




Patent claims HOE 9S/F 020 Dr. v. F,
1. A substituted benzenesulfonylurea or -thiourea o£ the formula I

in which:
R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 1, 2, 3/ 4, 5 or € carbon atoms;
R (2) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms or (C1-C8) chains in which one to three carbon atoms can be replaced by hetero-atoms selected from the group consisting of O, NH and S;
R(3) and R(4)
(identical or different) are hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or together form a (CH2)2-5 chain;
E is oxygen or sulfur;
X is oxygen or sulfur;
Y is a hydrocarbon chain of the formula
[CR(5)2]m; R(5) is hydrogen or alkyl having 1 or 2 carbon
atoms;
m is 1 or 2;
Ar is phenyl, thienyl, furyl, pyrrolyl, thiazolyl,
naphthyl, pyridyl, which in each case is unsub-
stituted or substituted by one to 3 substitu-
ents selected from the group consisting of
alkyl having 1 or 2 carbon atoms, alkoxy having
1 or 2 carbon atoms, C1, Br and F.

2, A compound of the formula I as claimed in claim 1,
wherein:
R(I) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
R(2) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms or (C1-C8) chains in which 1 to 3 carbon atoms can be replaced by heteroatoms selected from the group consisting of 0, NH and S;
R(3) and R(4)
(identical or different) are hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or together form a (CH2) 2 - 5 chain;
E is sulfur;
X is oxygen;
Y is a hydrocarbon chain of the formula
[CR(5)2]1-2' R(5) is hydrogen or alkyl having 1 or 2 carbon
atoms;
Ar is phenyl, thenyl, furyl, pyrrolyl, thiazolyl,
naphthyl, pyridyl,
which in each case is unsubstituted or
substituted by one to 3 substituents
selected from the group consisting of
alkyl having 1 or 2 carbon atoms, alkoxy
having 1 or 2 carbon atoms, Cl, Br and F.
3. A compound of the formula I as claimed in one of
claims 1 and 2, wherein:
R (1) is hydrogen or alkyl having 1 or 2 carbon
atoms; R (2) is alkoxy having 1, 2, 3, 4, 5 or 6 carbon
atoms; R(3) and R(4)
(identical or different) are hydrogen, alkyl

having 1, 2, 3, 4, 5 or 6 carbon atoms;
E is sulfur;
X is oxygen;
Y is a hydrocarbon chain of the formula (CH2)1-2
Ar is phenyl, thenyl, furyl, pyrrolyl, thiazolyl, naphthyl,pyridyl,
which in each case is unsubstituted or substituted by one to 3 substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, C1, Br and F,
4. A compound of the formula I as claimed in one of
claims 1 to 3, wherein:
R(l) is hydrogen or alkyl having 1 or 2 carbon
atoms; R(2) is alkoxy having 1, 2, 3, 4, 5 or 6 carbon
atoms; R(3) and R(4)
(identical or different) are hydrogen or methyl; E is sulfur; X is oxygen;
Y is a hydrocarbon chain of the formula (CH2)i_2; Ar is thienyl, furyl, pyrrolyl, thiazolyl, naphthyl, pyridyl,
which in each case is unsubstituted or substituted by one to 3 substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, C1, Br and F.
5. A compound of the formula I as claimed in one of
claims 1 to 4, wherein:
R(l) is hydrogen or alkyl having 1 or 2 carbon
atoms; R(2) is alkoxy having 1, 2, 3, 4, 5 or 6 carbon
atoms; R(3) and R(4)

(identical or different) are hydrogen or methyl;
E is sulfur;
X is oxygen;
y is a hydrocarbon chain of the formula (CH2)1-2;
Ar is phenyl,
which is unsubstituted or substituted by one to 3 stibstituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, C1, Br and P.
6. A process for the preparation of a compound I as claimed in claim 1, which comprises
(a) reacting an. aromatic sulfonamide of the for¬mula II

in which R(2), R(3), R(4), M and Ar have the mean¬ings indicated in claim 1,
with an R(l)-substituted isocyanate of the formula IV
R(l) -N=C=O in which R(l) has the meaning indicated in claim 1, to give substituted a benzenesulfonylurea I a (E = oxygen)


or
(b) preparing an unsubstituted benzenesulfonylurea
la [R(l} a H, E = O] by reaction o£ an aromatic
benzenesulfonamide of the formula II or of its salt
III with trialkylsilyl isocyanate or silicon tetra-
isocyanate and cleavage (e.g. hydrolysis) of the
primary silicon-substituted benzeneaulfonylureas;
or
(c) preparing a benzenesulfonylurea I a (E = oxygen)
from an aromatic benzenesulfonamide II or its salt
III using an R(l)-substituted trichloroacetamide of
the formula V

in the presence of a base in an inert solvent; or
(d) preparing a benzenesulfonylthiourea lb (E = S)

from a benzenesulfonamide II or its salt III and an R(l)-substituted isothiocyanate VI
R(l) .N=:C=S; or
(e) preparing a substituted benzenesulfonylurea of
the formula I a (E = oxygen) by a conversion

reaction of a benzenesulfonyl thiourea of the Structure lb (E=S); or
(f} preparing a benzenesulfonylurea I from a benzene¬sulfonyl halide of the formula VII

using an R(l) -substituted urea or an R(l) -sub-stituted bis(trialkylsilyl)urea; or
(g) preparing a benzenesulfonylurea I a by reaction of an amine of the formula R(1}-NH2 with a benzene¬sulfonyl isocyanate of the formula VIII

or
(h) preparing a benzenesulfonyl thiourea I b by reaction of an eunine of the formula R(1}-NH2 with a benzenesulfonyl isothiocyanate of the formula IX

or
(i) oxidizing a benzenesulfenyl- or -sulfinylurea
using an oxidant to give the benzenesulfonylurea
I a;
or

(j) preparing a benzenesulfonylurea I a from a benzenesulfonylurea of the formula X

and R(3)R(4)NH using a dehydrating agent or by-activation with a carbonyl halide or with a mixed anhydride; or
(k) preparing a benzenesulronlthiourea I b from a benzenesulfonylthiourea of the formula XI

and R(3)R(4)NH using a dehydrating agent or by activation with a carbonyl halide or with a miked anhydride
7. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of cardiac arrhythmias.
8. The use of a compound I as claimed in claim 1 for the production of a medicament for the prevention of sudden heart death.
9. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of ischemic conditions of the heart.
10. The use of a compound I as claimed in claim 1 for

the production of a scientific tool for the inhibition of ATP-sensitive potaasium channels,
11. The use of a compound I for the production of a medicament for the treatment of weakened cardiac power.
12. The use of a compound I for the production of a
medicament for the improvement of heart function
after heart transplantation.
13. A medicament comprising an effective amount of a
compound of the formula I as claimed in claim 1
14. A substituted benezenesulfonylurea or -thiourea of
the formula I, substantially herein described and exemplified.
15. A medicament comprising an effective amount of a
compound of the formula I substantially as herein described and
exemplified.


Documents:

141-mas-1996-abstract.pdf

141-mas-1996-claims filed.pdf

141-mas-1996-claims granted.pdf

141-mas-1996-correspondnece-others.pdf

141-mas-1996-correspondnece-po.pdf

141-mas-1996-description(complete) filed.pdf

141-mas-1996-description(complete) granted.pdf

141-mas-1996-form 1.pdf

141-mas-1996-form 26.pdf

141-mas-1996-form 3.pdf

141-mas-1996-other documents.pdf

141.jpg


Patent Number 211558
Indian Patent Application Number 141/MAS/1996
PG Journal Number 50/2007
Publication Date 14-Dec-2007
Grant Date 05-Nov-2007
Date of Filing 30-Jan-1996
Name of Patentee M/S. HOECHST AKTIENGESELLSCHAFT
Applicant Address D-65926 FRANKFURT AM MAIN,
Inventors:
# Inventor's Name Inventor's Address
1 DR. HEINRICH ENGLERT, ET.AL., STORMSTRASSE 13, D-65719 HOFHEIM,
PCT International Classification Number C07 C 311/58
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 195 04 379.0 1995-02-10 Germany