DE1912848A1 - Process for the preparation of new derivatives of sulfanilamide - Google Patents

Description

Process for the preparation of new derivatives of the sulfanilamida

The present invention relates to new derivatives of sulfanilamide, processes for their preparation, pharmaceuticals, ■ which the new connections contain and their use.

Compounds of general formula I,

. ■. "*: 'CH ₉ CH ₉

Il

(I)

CH ₉ CH ₉

Il

- A "^ i - H ₁ I"

IL

V-H

in which ; IL is an alkylA / cycloalkyl or cycloalkenyl group of

means at most 7 carbon atoms, and their addition salts m %% inorganic or organic acids

have not yet become known. -—-...

As has now been found, these connections are worth »

full pharmacological properties, especially 1-sulfanilyl « 2-imino-3-butyl-, l-3ulfanilyl ~ 2-imino-3-tert-butyl- and dae l-sulfanilyl - ^ - imino - ^ - oyclohexyl-iaidasolidin indicate peroral or parenteral administration on hypoglycanic effect, which they characterize as suitable for the treatment of diabetes. The hypoglycanic effect is demonstrated in standard experiments

909840/1747

Detected in warm-blooded animals, e.g. on rabbits and rats.

In the compounds of general formula I, R _n can be used as lower alkyl groups, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isqbutyl, pentyl, isopentyl, 2 , 2-di-ethyl-propyl, 1-ethyl-butyl, 1-ethyl-propyl, 1,2-dimethyl-propyl, group. IL can also be, for example: as the cycloalkyl group, the cyolopropyl, cyclopropylmethyl, 2-cyclopropyl-ethyl, ^ -cyclopropyl-propyl, cyclohutyl, öyclobutylniethyl, 2-glyclobutyl-ethyl, 3-cyclobutylpropyl, cyclopentyl , 1-ethyl-cyclopentyl-, 2-methyl-cyolopentyl-, 3-methyl-cyclopentyl-, 1-ethyl-cyclopentyl-, 2-ethyl-cyclopentyl-, 3-ethyl-cyclopentyl-, cyclopentylmethyl-, 2-methyl- cyclopentylmethyl, ^ -Methyl-cyclopentyljnethyl-, Cyclohexyl-, 1-Methylcyclohexyl-, 2-Methyl-cyclohexyl-, ^ -Methyl-cyclohexyl-, 4-Methylcyclohexyl-, Oyclohexylmethyl- or the cycloheptyl group and as the cycloalkenyl group the 2-Cyclopenten- 1-yl- _f 2-methyl-2-cyclopenten-1-yl-, 3-methyl-2-cyclopenten-1-yl-, 2-ethyl ~ 2-cyclopenten-1-yl- ,, 3-ethyl-2 -cyclopenten-1-yl ~, 3-cyclopenten-1-yl-, 2-methyl-3-cyclopenten-1-yl-, 3-methyl-3-cyclopenten-1-yl-, 2-ethyl-3-cyclopentene -1-yl-, 3-ethyl-3-cyclopentene-l ~ 3'-l-, 2-cyclohexen-1-yl-, l-methyl-2-cyclohexen-l ~ yl-, 2-methyl-2 ~ cyclohexen-1-yl-, 3-methyl-2-cyc lohexen-l-yl-, 4-methyl-2-cyclohexen-l-yl-, 3-cyclohexen-1-yl-, l-methyl-3-cyclohexen-l-yl-, 2-methyl-3-cyclo- hexen-l-yl-, 3-ίίethyl-3-cyclohexen-l-yl-, 4-methyl-3-cyclohexen-1-yl-, the 2- or 3-cyclopenten-l-ylmethyl-, the 2-, 3- or 4-Cyclohexea-1-ylmethyl-, 2-Cyclohepten »,

909840/1747

l-yl-, ^ -Cyclohepten-l-yl- or the 4-cyclohepten-l-yl group ^

According to a first method according to the invention a compound of the general formula I is produced by a compound of the general formula II,

CH ₀ CE ₀

Χ— (Γ \ - SO ₀ -N KR ₁ (II)

in which

R _{1 has} the meaning given under formula I, Rp hydrogen, an arylmethyl, diarylmethyl or a

Triarylmethyl group, the methyl or the allyl group, X one by hydrolysis or reduction into the free

Amino group convertible radical means or, if Rp is hydrogen, also means the free amino group, Reacts and cyclizes with a reactive cyanic acid derivative, if necessary, the reaction product is hydrolyzed or reduced to convert the group X into the free amino group and optionally converting the compound obtained into an addition salt with an inorganic or organic acid.

Rp is an arylmethyl, diarylmethyl or triarylmethyl group for example the benzyl, benzhydryl or trityl group.

Suitable reactive oyanoic acid derivatives are cyanide kalogenates, such as cyanogen chloride or cyanogen bromide, or cyanic acid esters, especially phenyl cyanate. The implementation takes place

909840/1747

Zugsvreis in the presence of a water-miscible or immiscible inert organic solvent in the presence or absence of water. Suitable inert organic solvents are, for example, hydrocarbons, such as. Benzene, toluene or xylene, lower alkanols such as methanol or Aethahol, äthorartige liquids vie ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as Kethylenchlcrid, MeDeRe ketones, such as acetone or methyl ethyl ketone, Carbonsäureester such as ethyl acetate, carboxylic acid nitriles, such as acetonitrile, or sulfones such as tetrahydro-thiophene-II-dioxide. The reaction can be carried out in the presence or absence of an acid-binding agent. Inorganic bases or salts, for example alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates or alkali metal phosphates, such as the corresponding sodium or potassium compounds, are suitable as acid-binding agents. Calcium carbonates as well as calcium phosphates and magnesium carbonate can also be used.

The subsequent conversion of group X of the reaction product in (you free amino groups which this into a Compound of general formula I converted, depending on the Type of group X carried out by hydrolysis, reduction or reductive cleavage.

Convertible into the free amino group by hydrolysis Residues X Bind, for example, acylamino residues, such as z * B. the acetamido group. Perneij are such radicals lower alkoxycarbonyl

amino radicals, such as Z ₈ B. the ethoxycarbonylamino group, aryloxycarbonylamino radicals, such as the phenoxycarbonylamino radical, or aryliaethoxycarbonylamino radicals, such as the benzyloxycarbonylamino radical, or radicals of corresponding thiocarbonic acid derivatives. Further examples are substituted methyleneamino radicals, such as the benzylideneamino or the p-dimethylamino-benzylideneamino group. The hydrolysis to liberate the amino group can take place in an acidic medium, for example in methanolic hydrochloric acid, or in dilute aqueous hydrochloric acid or sulfuric acid, or, if X is represented by an alkoxycarbonylamino radical, also under mild alkaline conditions, for example by means of 1-n. or 2-n. Caustic soda.

An example of a radical X which can be converted into the amino group by reduction is the nitro group and examples for those radicals which lead to the amino group by reductive cleavage, the phenylazo or p-dimethylamino-phenyl azo groups are. The reduction of these residues can generally be catalytic, e.g. by means of hydrogen in the presence of Raney nickel, palladium or platinum charcoal, in an inert solvent such as ethanol. In addition to these, there are other common ones Reduction processes into consideration, for example the reduction of nitro groups or the reductive cleavage of azo groups using iron in acetic acid or hydrochloric acid.

Suitable starting materials of the general formula II are those compounds whose symbols R ,, R «and X with the

Groups übercinstiffiinen, "the anischliessend to Tor.-i. ':''tr-r Tj enumerated Such starting materials sini ll- (2-ÄLiL. Io-ä ^J Chyl) -... Benzolsulfonaaide whose benzene ring by the radical X is in the para position and its amino group _{is substituted by the radicals R, and R 0.} These compounds can be, for example, her / r?.; · Be divided if one starts out from a l-phenylsulfonylaziridine which is substituted by the radical X, and the aziridine is reacted with a primary or secondary amine which contains the radicals R ₁ and R 2. Representatives of the aziridines mentioned are described in the literature, for example 4 ^l - (aziridin-1-ylsulfonyl) acetanilide [cf. R. Lehmann et al., Bull.Soc.Chim.Beiges 55 »52-97 (1946; OA 41» 5475 f (1947)]. Further aziridines of this type can be prepared analogously.

According to a second method according to the invention compounds of the general formula I produced by a Compound of the general formula III,

(III)

fh which

X denotes the amino group or a radical which is through Hydrolysis or reduction converted into the amino group can be,

with a compound of the general formula IV, "" "

f ^M ÖAO OR (QiNAU

in \ · ί which IL has the meaning given under Foxsael I, or Kit an alkali metal or alkaline earth metal derivative of such Compound condenses and cyclizes, if necessary that Reaction product for converting the group X into the free amino group hydrolyzed or reduced and optionally the compound obtained with an inorganic or organic one Säivre transferred to an addition sala.

Suitable alkali metal or alkaline earth metal derivatives of the general formula IV are sodium, potassium, lithium and / or. Caleium derivatives. The condensation is preferably carried out in a ethereal liquid, e.g. in ether, tetrahydrofuran, dioxane, anisole or ethylene glycol dimethyl ether.

The group X has the same meaning as in the first Procedure. Their conversion into the free amino group, which is the reaction product in a compound of the general formula I. transferred, can take place as set out in the description of that method. .

Suitable starting materials of the general formula III are, for example, those compounds whose symbol X corresponds to the groups matches, which are listed after formula II. A production possibility for such connections is already available has been explained following the first procedure.

According to a third process according to the invention, compounds of the general formula I are prepared by using a

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Compound of the general formula V,

(V)

in which '

X denotes the amino group or a radical which can be converted into the free amino group by hydrolysis or reduction,

with a reactive ester of a hydroxy compound of general formula VI,

OH N-IL (VI)

i ^

O = N

in which R, which has the meaning given under formula I , condenses and cyclizes, if necessary the reaction product is hydrolyzed or reduced to convert the radical X into the free amino group and, if appropriate, the compound obtained is converted into an addition salt with an inorganic or organic acid.

Suitable reactive esters of hydroxyl compounds of the general formula VI are, for example, halides, in particular chlorides or bromides, and also sulfonic acid esters, for example the o- or p-toluenesulfonic acid ester or the methanesulfonic acid ester. The condensation is preferably carried out in one with

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Water-miscible or immiscible solvents in the presence or absence of water. Alkanols such as butanol, ethereal liquids such as dioxane, diethylene glycol monomethyl ether, carboxamides such as ^, ii-dimethylformamide, or sulfoxides can be used as solvents _. such as dimethyl sulfoxide can be used. It is advantageous to carry out the condensation in the presence of an acid-binding agent. Those compounds which are named after the first process can be used as such, as well as tertiary organic bases, such as, for example,, Ν-diisopropylethylamine ..

The & ruppe Σ has the same meaning as in the first procedure. Their conversion into the free amino groups which convert the reaction product into a compound of the general formula I can take place as set out in the description of that process.

As starting products of the third process, aB, the reactive esters or hydroxy compounds of the general formula VI listed above can be used, the symbol JL of which corresponds to the groups * which are listed after formula I. A ßrupp © bromides of all "" common formula VI can ζ, Β "warden received? If you have a 1-alkyl or 1-Gycloalkyl-aziridine [cf. _A. Weissenberger, Heterocyclic Compounds with Three and EOur-membered ring , Part One5 John Wiley Sons Ine, London (1964)] with cyanogen bromide in dioxane.

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According to a fourth method according to the invention compounds of the general formula I are established, inoes aan one reactive ester of a compound of the general Formula VII,

-N OH (YII)

. ΟδΗ

in which

X ^! means a residue obtained by hydrolysis or reduction

can be converted into the free amino group, with an amine of the general formula VIII »

t ¥ III)

in which R, the «earlier formula I has given meaning» condensed land oyclisiert. taid nötigaafalls eyelet Resktioiisprodukt Ueberführusig sur des-Best X ¹ in the free amino group is hydrolyzed or reduced gegebenöiifalls the srhaltexi © ^ sait compound ¹ of inorganic or organic acid into an addition salt.

Suitable reactive esters of a hydroxy compound of the general formula VII z, B _e halides, in particular chlorides or bromides, or the like. Sulphonic acid ester »in particular a benzenesulforic acid ester which is substituted in the para-3tposition by the radical X '. The condensation is preferably carried out in a solvent. _{Z 9} B _{8 are the} same as such

909840/1747

BATHROOM OBlGlNAL

- ■ M. -

Solvents used in the third method.

It is advantageous to carry out the reaction in the presence of a slurry-binding agent. As an acid-binding agent excess bases of the general formula VIII are preferably suitable.

The radical X ^s , as radical * which can be converted into the free amino lip by hydrolysis or reduction, has the same meaning as the radical X of the first process. The conversion of the radical X ¹ into the free amino group, which converts the reaction product into a compound of the general '! Formula I 'can also be carried out as set out in the first method for the Eest X.

The starting materials for this process are e.g.

the reactive esters of the hydroxy compounds of the general formula VII ₉ listed above, the symbol X ^{$ of} which corresponds to the groups which are also listed in formula II. Such connections are made, for example, as follows:

One starts from aziridine and sets this with cyanogen bromide in ether to ¥ - {2-bromo-ethyl) -cyanamide; this cyanamide one condenses. in acetone with a benzenesulfonyl chloride, which is substituted in the para position by the radical X ', in the presence of dilute sodium hydroxide solution with elimination of hydrogen chloride to form a corresponding N- (2-bromo-ethyl) -N-cyanobenzenesulfonamide.

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Each receives a fifth method according to the invention one a compound of the general formula I, if one. an addition salt of the general formula IX, ^

CH ₀ CH,

I ² © I ² (ΙΣ)

in which R has the meaning given under formula I, X 'denotes a radical which has been obtained by hydrolysis or reduction

can be converted into the free amino group, and Y is halogen,

cyclized by heating, if necessary the reaction product obtained to convert the radical X 'into the free amino group hydrolyzed or reduced and optionally the obtained Compound with an inorganic or organic acid in an Idditionssals transferred.

As a halogen, Y can mean, for example, bromine or chlorine.

The condensation can be carried out by etching in a solvent or without such. Suitable solvents are high-boiling liquids, e.g. ethers, such as diethylene glycol dimethyl ether, or carboxamides, such as N, N-dimethyl-f ο rtnamid.

The radical X 'has as a radical that can be converted into the free amino group by hydrolysis or reduction, same meaning as residue X of the first method. the

90 * 9840/1747

Conversion of the radical X ¹ into the free amino group, which converts the reaction product into a compound of the general formula I, can also be carried out as is explained for the radical X in the description of the first process.

Suitable starting materials for the process are compounds of the general formula IX, the symbols R ,, XV and Y correspond to the groups subsequent to formulas I _t II and IX are enumerated. Can be a group "of such starting materials such as _o be prepared by reacting of benzenesulfonyl chlorides _f represented by the radical X 'are para substituted, goes out and this with Binätriumeyanamid in water to the sodium derivative of the' corresponding N" ~ öyana-benzolsulfanamide condensed j these condensation products are then reacted with N- (2-chloro-ethyl) -amine- ° hydrochlorides »which are substituted on the nitrogen by the radical R»

Times a sixth process of this invention one provides a compound of general formula I * forth by reacting a compound of the general Foirael X,

SO «- K ■ Έ - IL '(X)

in which

' an alkenyl group of 3-5 carbon atoms or a cycloalkenyl group of 5-7 carbon atoms and

the amino group or a radical means » by 909840/1747

Hydro.lyse or reduction converted into the free amino group can be,

reduced and optionally converted a compound obtained with an inorganic or organic acid in an addition.

The reduction is preferably carried out with hydrogen in the presence of a catalyst in a solvent. Suitable catalysts are, for example, _e Edelsetallkatalysatoren such as palladium, which is used for example on carbon, and further Raney nickel. Alkanols, such as methanol or ethanol, and also dioxane, for example, can be used as solvents. It is advantageous to carry out the reduction at normal pressure and room temperature.

The group X has the same meaning as in the first method. Their conversion into the free amino group, which the Reaction product converted into a compound of the general formula I can be carried out as in the description of that Procedure is set out.

Starting materials of general formula X can be prepared analogously to the first method, be prepared by starting from a l ~ phenylsulphonyl-aziridine, which is substituted by aen radical X and example of this aziridine with an alkenyl or Gycloalkenyl-amine to a corresponding through the rest of X substituted N- (2-alkenylaraino-ethyl) - or

909840/1747

ORtGiNALtNSPECTED

iT_ (2-Gycloalkenyla: aino-ätiiyl) -benzenesulfonamide converts and this condensed with cyanogen bromide and cyolized.

ITac-h represents a seventh method according to the invention a compound of the general formula I is produced by a compound of the general formula XI,

HH \ - SO ₂ - N ^> - R ₁ (XI)

N-H

in which R, has the meaning given under formula I and X ^{1 is} a radical which can be converted into the free amino group by hydrolysis or reduction, with a reactive diester of ethylene glycol, if necessary the reaction product for converting the radical X ¹ into the hydrolyzed or reduced free amino group and optionally converted the compound obtained with an inorganic or organic acid into an addition salt.

Suitable reactive diesters of ethylene glycol are for example halides, in particular dichlorides or dibromides, also sulfonic acid esters, e.g. bis-o- or p-tolucl sulfonic acid esters or bis-methanesulfonic acid esters.

The reaction is preferably carried out in an inert solvent. Suitable inert solvents are, for example, aromatic hydrocarbons, such as benzene, toluene or the xylenes, halogenated hydrocarbons, such as

909840/1747

Methylene chloride, chloroform or carbon tetrachloride, ether, such as tetrahydrofuran, dioxane or diethylene glycol monomethyl ether, Carboxamides, such as Ιί, Ν-dimethylformamide, K, N-diethylformamide or Ιϊ, Ν-diethylacetaraid, or sulfoxides, such as dimethyl sulfoxide.

The implementation can be in the presence or absence of one additional acid-binding agent. as acid-binding agents are inorganic bases or salts, e.g. alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates or alkali metal phosphates, such as the corresponding iiatrium or potassium compounds. Furthermore can also Calcium carbonates as well as calcium phosphates and magnesium carbonate can be used. Suitable organic tertiary nitrogen bases, such as Ν, Η-diisopropylethylamine, can be used as acid-binding Serving means. '

The radical X ¹ , as a radical which can be converted into the free amino group by hydrolysis or reduction, has the same meaning as the radical X of the first process. The conversion of the radical X 'into the free amino group, which converts the reaction product into a compound of the general formula I, can also be carried out as set out for the radical X in the first process.

A starting material of the general formula XI, the l- (p-acetamido-phenylsulfonyl) -3-butyl-guanidine »was τοπ B.G., Boggiano et al. [see. J. Fhara, and Pharmacol. 12 * 567-

909040/1747

574 (1961)]. Further starting materials of the general

■ - *

my formula XI can be produced analogously «

Subject an eighth method according to the invention compounds of the general formula I are produced by compounds of the general formula XII,

H (XII)

in which

X 'one by hydrolysis or reduction into the free Amino group convertible radical means

. with a reactive ester of a hydroxy compound of general formula XIIX,

OH -

in which

R, an alkyl group with a maximum of 7 carbon atoms

means, .

converted, if necessary the reaction product for converting the group X ¹ into the free amino group is hydrolyzed or reduced and, if necessary, the compound obtained is converted into an addition salt with an inorganic or organic acid.

Suitable reactive derivatives of hydroxy compounds

90984 0/1747

of the general Porniel-XIII-are for example K ^ lcr ^ nide, in particular Chlorides or bromides, also sulfonic acid esters, e.g. the o ~ or p-toluenesulfonic acid ester or the kethanesulfonic acid ester.

The reaction is preferably carried out in an inert solvent. Suitable inert solvents are for example aromatic hydrocarbons ,. such as benzene, toluene Or the xylenes, halogenated hydrocarbons like methylene chloride, Chloroform or carbon tetrachloride, ethers such as fetrahydrofuran, dioxane or diethylene glycol monomethyl ether, Carboxamides, such as Ν, Ν-bimethylformamide, Ν, ίί-diethylforinamide or KjN diethylacetamide, or sulfoxides, such as dimethyl- Sulfoxide,

The implementation can be in the presence or absence of one additional acid-binding agent can be made. Inorganic bases or salts are suitable as acid-binding agents, e.g. alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates or alkali metal phosphates, such as the corresponding Sodium or potassium compounds, furthermore can also Calcium carbonates as well as calcium phosphates and magnesium carbonate can be used. Also suitable organic tertiary nitrogen Bases, such as Ν, Ν-diisopropylethylamine, can act as acid-binding agents Serving means.

The radical X ¹ , as a radical which can be converted into the free amino group by hydrolysis or reduction, has the same meaning as the radical X of the first process. the

909840/174 7

BATH ORIGINAL

Conversion of the radical X ¹ into the free amino group, which converts the reaction product into a compound of the general formula I, can also be carried out as set out in the first process for the radical X.

Starting compounds of the general formula XII wer.ien obtained, for example, if a benzenesulfonyl chloride which ^{is substituted by the radical X 1} in the para position, for example H-acetyl-sulfanil chloride, with 2-amino-2-i / aidazoline hydrochloride in Reacts the presence of sodium hydroxide solution.

The obtained by the process according to the invention Compounds of general formula I are then if desired into their salts with inorganic ones as well as organic acids transferred. These salts are produced, for example, by reacting the compounds of the general Formula I with the equivalent amount of an acid in a suitable aqueous-organic or organic Solvents such as methanol, ethanol, diethyl ether, chloroform or methylene chloride.

909840/1747

For use as drugs rather than a <sr free compounds of general formula I may whose pharEja & eu "table acceptable salts are used with acids. Suitable idditiona salts are, for example, salts with hydrochloric acid, hydrobral acid, sulfuric acid, phosphoric acid, methanesulfonic acid. acid, ethanesulfonic, .beta.-hydroxy-äthansulfoneäurej acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, AEPF elsäure, tartaric acid, citric acid, benzoic acid, salicylic acid Ri "iylessigsäure, mandelic acid and embonic acid.

The new active ingredients are preferably administered orally. The daily doses range between 100 and 500 mg for adult patients with normal weight _β Suitable dosage unit forms, such as dragees, tablets preferably contain 50-500 mg of an active ingredient according to the invention, namely 20 to 80 μS of a compound of the general formula I.

To produce them, the active ingredient s.B. with solid powdery carriers such as lactose, sucrose, Sorbitol, mannitol; Starches, such as potato starch, or corn starch Amylopectin, also Laminaria powder or Gitruapulpenpulverj Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights to tablets or to dragons. The latter are coated, for example with concentrated sugar solutions, which e.g. may contain Arabic gumrai, talc and / or titanium dioxide, or with a

_; 909840/174 7

in volatile organic solvents or mixtures of acidic agents dissolved paint. Dyes can be used for these coatings can be added, e.g. to identify different doses of active ingredients.

Ala more oral Doseneinheitsfora are filled capsules consisting of (Jelatine as well as soft, sealed capsules made of gelatin and a plasticiser, such as glycerol. The plug capsules contain the active compound, preferably as granulate, for example in admixture with filler _ene-f as corn starch, and / ODSR lubricants "as Talc or MagnesiisiBstearati and optionally stabilizers «, such as latriuEraetaMstxXfit (Na ₀ S ₀ O _8. ) Or ascorbic acid _o In weionea

c. d 3>

Capsules are the active ingredient -? ATSisgs ¥ ®is © dissolved in suitable liquids, such as liquid SöljrEtlriylengljkoIeap oö © r sus- ..-. We also use stabilizers

end © a ¥ © rseiirl £ t © & solleia fii®

a) 1000 s X-

ιΐΘτύ @ η with 5 © © §! setose and 270 g potato starch dl © HiSGhuijfg ait © ines ¹ aqueous solution τοπ 8 _f 0 g ®- © l®tiSG gg «hissed and granulated through a sieve-o laugh the fröslmss. Islsclit 60.0 g of Kart-off®lstäifee ₆ 6O ₉ O g talc, 10 _s 0 g Bfegnesitim stearate and 20 »0 g colloidal silicon dioxide and presses the mixture into IQ'OOQ tablets of 200 ng weight and 100 mg active ingredient content, which, if desired, can be provided with partial notches for more precise adjustment of the dosage »

909840/174

b) From 1000 g of l-3ulfanilyl-2-: üaino-3-tert.butylimidazolidine, 345 g of lactose and the aqueous solution of 6.0 g of gelatin, granules are produced, which after drying with 10.0 g of colloidal Silica, 40.0 g talc, 40.0 g
Mix potato starch and 5.0 g magnesium stearate and ^{press into 10 1} 000 coated tablets. These are then connected with a concentrated syrup made from 533 g of crystalline. Sucrose, 2O _r O g shellac, 75,0.g gum arabic, 250 g talc, 20 g of colloidal silica UHD I ₈ 5 g of dye Hfe srssg © © © n imcl gstrsefaieto Bi
hold® «, Bsragdfes weigh j © 24S es w & iä ejatfeeisea J ©
material, ' .. '

the ne & £ 3 lbgsiaiEEgeE, eat ³ Gllgeaeijags. Sssiel 21 mm & ^v m

Called läesöldETiGisories.

Jji

90984.0 / 174 7 ° R ^ nal, nspecthd

example 1

a) 31 # 3 g of N ¹ - {2-ButylaEiino-ethyl) -N ^ -acetyl-sulfanil are dissolved in 100 ml of 2N sodium hydroxide solution and mixed with 10.6 g of Broiseyan while cooling at 20-30 ° The crude product immediately precipitates in crystalline form. It is abgenutssht after 30 minutes and from Ν, Ν-Diffiethylformaraid, urakristallisiert · Xtes resulting 4 ^l "(2-Imitto" 3-totjl-iraidagoXidin ^ yl £ ul £ © phenyl) - "estaalUft melts tel 243-2H ^0th . '

b) 33 * 8 g & m after a) obtainable © B aoetanilids are

the one with 100 ml 2-n. ä & lEsSure a stunäe at 80 ° © s ^ färait.

. Ans © Sts @ sstnd cools to the HealctionsgemiBgli to 20 ^ö and adjusts © s 2 ~ n _e iiatröialauge alkaliseh * Di © unusual, Bas © roh® is abfllt ^ ated "with Wasses ⁰ g @ wasefo © ra uaä from

c) Bie starting compound w & a b.) wtod as follows

get

24.0 g 4 '"i (Aziridin-1-ylsulfonyl) -acetanilide R _e Lehmann et al", Bull.Soc.Chim.Beiges 55, 52-97 CA. fil, 5475 f (1947) ^ 7 are dissolved in 100 ml of dioxane and 15 ml of water in the cold and the solution is added dropwise to 100 ml of butylamine. The reaction mixture is then refluxed for one hour and &&& excess butylarain and the dicxan are distilled off. The crystalline residue is recrystallized from ethyl acetate, whereupon the pure N (2-3atylamir.o-ethyl) -H * -acetylr-sulfanilamide melts at 97-98 °

909840/1747

- 24 - ■ · ν

Example 2 *

i &) Analogous to Example 1 a) one obtains also 27 * 1 g of N- (2-MethyianlRO-Stthjl) -N ^ -ac * t3rl-8uIfanllaraid and 10.6 g of broacyan das 4 '* (2-2mino-3 -aethyl-iaiaaaoliiin-1 -yleulfonylj-aoet anilide from sap · S66 .- 267 °. "

b) 29.6 g of the acetanilides obtained after a) are mixed with 200 ttl 8-jio Ithanollechiw? Hydrochloric acid 48 8fcun4 «i to« i 20 ° 8tehengel ** B * n. Because does Wt & is HeftlctiouegfiliUiöti in one, solves the crietalline back & Tii % n Vasbo? and makes solution alt 2-n * caustic soda * alkaline. Oils free «, raw E ** e falls AU8 | §4 · is abgenutssht ui% d au "M" THANOL-1i »isör ■ t» _e llieiert which dao pure lbei 209-211 °

c) / The Auagangipro-lukte dat. M ¹ - (2 <»ltethyiaftlno-Kthyl) -K ^ -acetyl-ealfaailaeiä τοα Sap » 100 -102 ° (au * SeelgeKure & thyletter) «becomes« nclog example Ie) g * -A * iridine (X-ylsulfonyl) -ftc »ter.ilId and 100% kothylaissin.

909IÄ0- / 1741

'Example 3

a) Analogous to example la). «r is based on

1 4

28.5 SN - (S-Aethylaralno-afchyl) - «-acetyl-sulfanilainid of m.p. Ethyl-lnüdasolidin-1-ylsulfonyl-acetanilide of Snp ", 2β7 - 269 ° (from ethanol) _fl of the 31 * 0 g analogous to Example X b) with 100 ral 2-N" Hydrochloric acid susi final product Sulphanilyl * §-imiao-5-Sthyl * itoidftaolidin of m.p. 171 I72 ⁰ (from methanol-water} hydrol is iert 0

. b) The starting substance of a) * is obtained analogously Example Ic) from 24.0 g of 4 * - {A »iridin-1-ylsulfonyl) acetanilide and 100 ml of ethylassin »

909840/1747

Example 4 . . ~

a) Analogously to example la) one obtains, looking from 29.9 β N ¹ - (2-propylemitto-ethyl) -N-aoetyl-sulphonimide vora Snip. 89 - 90 ° (from ethyl acetate) * r> it 1O ₃ 6 g Broraoyan das 4 ^l - {2 * .Iraino-3-propyl-iaiiöazolidin-l "yleulfonyl)"& cetanili5l from Srcp. 253 - 255 °, of the 52.4 g analogous to example 2 b) with 8-n «. ät | ianoliseher Balxaäur · as the end product l ~ sulfanilyl-2-iiBino-3 -? ^ pyl-i "iA *" oliÄiil νοβ Scip. 16 ^ - 166 ° (from methanol) can be hydrolyzed «'

b) The Auegangeeubstpnz. from a) is obtained analogously to Example 1 c) from 2K, k g ^ • -.faziridin-1-ylsulfonylJ-acetanilide and 100 ml propylaniin.

909840/1747

Example 5 - "

a) Analogous example i &) crhUlt san, also from

a It

29 »9 6 N - (2-l8opropylaalno-ethyl} -n -acetyl-Äulfanilamld of m.p. 91-93 ° (from Sseigsüureäthyleeter) with 6.2 g of cyanogen chloride the ^ .'- (2-Isiino-3-i» oprop7l ~ i9ida2olidin-l-yl3uifonyl) -acetanilid vota Sap · 253 - 2S & °, from <5ea 32 * 4 g analogous to Belipitl 2 b) Bit 200 ml S ^ n. Thauolischcr Salxeäure suo Sndprodulct l-Sulph * nilyl-S-iBino-3-i * opiHipyl-iisidiizolidin vom Step «183 -

b) IHf Au "2 * B3e" ul5ei; ens voa a> «Rhtlt is analogous

1 o> aue 24.0 s V- (Asii? I4iu-i-yl «ulfonyl) -toetanilide "Aft 100 al

900840 / f TO-

Example € . '

a) Analogously to Example It) trhUlt AAEN "starting from 31.5 6 H ¹ - (2-Isobutvlaniino-äthyI) -M ^if -aoetyl-suirftailac: id VOA .-. M.p. 70 - 72 ° (from 36sigs & ure & thylfst «r ~ Aftth« t * ^ nlfc 10 «(S χ Bronoy & n das ^ '» (a-I't .-. InoO-ieobutyl-imidazoliain-l-yleulfocjja) -aeotanilId vom M.p. 264-255 ° (from methanol) / of the 33% g. Analogous to Example 2 b) cit 200 ml of 8-n -lr.idiizoIidin voa

M.p. 146 - 147 ° (from methanol *} fc ^ tfol ^ nltrt ».rerden.

b) The starting subiuaiis of a) is obtained analogously to Example 1 o) from 27 # 6 $ H ^l * ita ⁱⁱ i amide and 100 toi isobutyltmin

909040/17 * 7

BAD ORJQINAU

Example 7

a) Analogously to Example la), starting from 31.12 g of N - (2-see.Butylamino-ethyl) -N -acetyl-sulfanilamide with a melting point of 70-72 °, with 10.6 g of cyanogen bromide the 4 ^l - (2-Imino-3-sec.butylimidazolidin-1-ylsulfonyl) -acetanilla of m.p. 265-266 ° (from methanol), of which 33 * 8 g analogously to Example 2b) with 200 ml 8-n. Ethanol-based hydrochloric acid to the end product l-sulfanilyl-2-imino-3-sec. butyl-imldazolidine with a melting point of 1-3-173.5 ° (from methanol) can be hydrolyzed.

b) The starting substance of a) is obtained analogously to Example 1 o) from 24.0 g of 4 ^l - (aziridin-l-ylsulfonyl) aoetanilide and 100 ml of see. Butylamine.

909840/1747

Example 8

a) Analogous to example la) one obtains, starting from

ι h.

31.3 ß N - (2-tert-butylamino-ethyl) -N -acetyl-sulfanilarnid vom Snip, 98-101 ° (from ethyl acetate), with 6.5 g Cyanogen chloride, instead of cyanogen bromide, the 4'- (2-Imiuo «-3-tert. butyl-imidazolidln-.l-.ylsulfonyl) -aeetanilid vom Snip »2 ^ 5 2 ^ 7 ° (also methanol-water), of which 33 * 8 g analogously to Example Ib). with 100 ml 2-n. Hydrochloric acid to the end product l-sulfanilyl-2-imino-3-tert. butyl-imidazolidine with a melting point of I87 - 189 ° (from methanol-water) be hydrolyzed.

b) The starting substance "of a) is obtained analogously Example 1 o) from 2 ^, 0 g ^ '- (Aziridin-i-ylsulfonyl ^ acetanilide and 100 ml tert. Butylamine.

Example 9

a) Analogously to Example 1 a), starting from 32.7 g of W - (2-pentylamino-ethyl} -lr-acetyl-sulfanilamide vom Mp. 103-104 ° (from ethyl acetate), with 10.6 g of cyanogen bromide the 4 '- (2-imino-3-pentyl-imidasolidin-l ~ ylsulfonyl) -acetanilide vom.Smp. 248-250 ° (from methanol).

b) 35 »2 g of the acetanilide obtained according to a) are added to 125 g of 50% sulfuric acid heated to 40 °, with stirring. The mixture is heated to 50 for 2 hours and then poured into 750 μl of water with stirring, the crude product precipitating as sulfate. The reaction mixture is mixed with 10-n. Sodium hydroxide solution _{adjusted to pH 6 f} 3, with the exception of minor impurities, solution entering. Seed addition of 2 g of activated charcoal is stirred for 15 minutes and filtered through Hyflo. The Piltrat is with 10-n. Sodium hydroxide solution made alkaline. The crude product is filtered off, washed with water, dried at 90 ° la vacuum and recrystallized from methanol. The l-sulfanilyl-2-ifflino-3-pentyl-imidazo-idin obtained has a melting point of 167 * 168 °.

c) The starting substance of a) is obtained analogously to Example 1 c) from 24.0 g of 4 '* ^: {A2iridin- * l'-ylsulfonyl5-acetanilide and 100 ml of bentylamine. -.

901140/174 7

Example 10

a) Analogously to Example 1 a) is obtained, starting from

1 4 ^%

J54, 1 g of N - (2-hexylamino-ethyl) -N -acetyl-sulfanilamide of melting point.

98-99 (from ethyl acetate) with 11.9 S phenylcyanate, instead of cyanogen bromide, the 4 '- (2-Iniino-3-imidazolidin-1-ylsulfonyl) -acetanilide of m.p. 2 ^ 6 - 2 ^ 8, from the 36.6 g analogously to Example 2 b) are hydrolyzed with 200 ml of ethanolic hydrochloric acid to give the end product l-sulfanilyl-2-imino-j5-hexyl-imidazolidine with a melting point of 182-183.

b) The starting substance of a) is obtained analogously to Example 1 c) from 24.0 g of 4 '- (aziridin-1-ylsulfonyl) acetanilide and 200 ml of hexylamine.

90 014.0 / 1 Ii f.

Example 11

a) Analogous to example la) one obtains, starting from

l 4

32.5 β N - (S-Cyclopentylamino-Kthyl) - ^ -acetyl-aulfanilamld (Snip, dee Hydrochloride: 215 - 217 °), with 10.6 g of cyanogen bromide the h '- (S ^ Imino-J-cyclopentyl- imidazolidin-1-ylsulfonylJ-aeetanilide of m.p. "261-263 °" of the 35 "0 g analogous to Example 1 to) with 100 ml of 2-n. Hydrochloric acid can be hydrolyzed to the end product Sulph & nilyl-2-lraipo · 3-cyclopentyl-imidazolidine with a melting point of 192 ° -193 °.

b) The starting substance of a) is obtained analogously

Example Ic) from 24.0 g of 4 ^l - (atiridin ~ 1-yleulfonyl) acetanIII and 100 ml of cyclopentylamine.

90984 0/17 4 Ψ ^

Example 12

a). Analogously to Example 1 a), starting from 33.7 g of ^ - ^ - ^ - cyclohexen-1-ylaminoi-ethyl-1r-acetylsulfanilamide with a melting point of 121-122 with 10.6 g of Broincyan, the 4 '- [2-imino-3- (3-cyciohexen-1-yl) -imidazolidin-1-ylsulfonyl] -acetanilide of melting point 283-284 °, of which 36.2 g as in Example 2 b) with 200 ml 8-n. ethanolic hydrochloric acid to the end product l-sulfanilyl-2-imino-3- (3-cyclohexen-l-yl) imidazolidine from M.p. 172-173 (from methanol) can be hydrolyzed »

b) The starting substance of a) is obtained analogously Example 1 c) from 24.0 g of 4 '- (aziridin-1-ylsulfonyl) acetanilide and 100 ml (5-cyclohexen-1-yl) amine.

909840/1747

ORIGINAL INSPIÖH ©

Example 13

a) Analogously to Example 1 a) is obtained from 30.1 g

N- (2-Cyclohe: xylamino-ethyl) -p-nit: ro-Denzenesulfonamid (crude product) and 10.6 g of cyanogen bromide in 100 ml of 2-n. Caustic soda the l- (p ~ Nitro-phenylsulfonyl) -2-imino-3-cyclohexyl-imidazolidine from M.p. 98-99 ° (from benzene).

b) 35.2 g of the nitro compound inclined to a) are dissolved in one liter of ethanol and in the presence of palladium-charcoal (5Q £ palladium) with hydrogen at 20 ° and Normal pressure Ms hydrogenated to a standstill. The catalyst is then filtered off, washed with ethanol and the filtrate is removed evaporated in vacuo. Recrystallization of the residue from dioxane water gives the pure 1-sulfanilyl-2-imino-3-cyclohexyl-imidazolidine from m.p. 181-183

c) The starting material used in a) is analogous to Example 1 c) from 22.8 g of l- (p-nitrophenylsulfonyl) aziridine and obtained 150 ml of cyclohexylamine.

90 * 840/174

Example. 14 -

a) 38.9 g of N - [2 ~ (N-isopropyl-benzylamino) ethyl] -

N -acetyl-sulfanilamide are dissolved in 500 ml of benzene. Man the solution is mixed with 10.6 g of cyanogen bromide, the reaction mixture is stirred for 3 hours at room temperature and it is evaporated. Man represents the residue with 2-n. Caustic soda alkaline. Crystals precipitate, which are washed with water and made from methanol-ether be recrystallized. The pure 4 '- (2-imino-3-isopropyl-imidazolidin-1-ylsulfonyl) acetanilide obtained melts at 253.degree. C. The acetanilide obtained is hydrolyzed according to Example 5 to the l-sulfanilyl ^ -imino ^ -isopropyl-imidazolidine of m.p. 183-184 °.

The starting product is manufactured as follows:

b) 24.0 g of 4 '- (aziridin-1-ylsulfonyl) acetanilide are dissolved in 100 ml of dioxane and 20 ml of water and refluxed with 15.0 g of N-benzyl-isopropylarain with stirring for 5 hours cooked. Then the reaction mixture is evaporated. The received OeI crystallizes in ethyl acetate. From ethyl acetate recrystallized, the pure N- [2- (N-isopropyl-benzylamino) -ethyl} -N ^ & ifetyl-sulfanilamide melts at 85-86 °.

9Q9840 / T747

example

a) A solution of 25.5 g of N - (2-CyclOpropylamino-ethyl) -sulfanilaraid in 100 ml. dioxane is mixed with a solution of 11.9 g of phenyl cyanate in 50 ml within 10 minutes while cooling at 10 ° Aether displaced. The suspension obtained is refluxed for 1.5 hours and then evaporated in vacuo. Man the residue is mixed with methylene chloride and 2-n. Caustic soda. The insoluble crude product is filtered off, the organic phase separated off the piltrate, dried over sodium sulfate and evaporated in vacuo. The residue is combined with the one obtained Crude product and the mixture crystallized from methanol, after which the l-sulfanilyl ^ -imino-J-cyclopropyl-imidazolidine melts at 202-204 °.

The starting product is obtained as follows:

b) 7.1 g of 1-sulfanilyl-aziridine with a melting point of 124-126 ⁰ , which is prepared by catalytic reduction of 1- (p-nitro-phenylsulfonyl) -aziridine with Raney nickel in dioxane, are dissolved [cf.

R. Lehmann et al., Bull. Soc. Chim. Beiges 5J>, 52 (1946)], in 70 ml Dioxane and this solution is added dropwise to 18.2 g of boiling Oyclopropylamin within one hour. The mixture is boiled for a further 2 hours continue under reflux, then the excess is distilled Cyclopropylamine from and the reaction mixture evaporated in vacuo. The residue is crystallized from ethyl acetate to, after which the N - (2-Cyclopropylamino-ethyl) -sulfanilaraid obtained from m.p. 91-94 °. ·

909840/1747

Example 16

a) Analogously to Example 15 a), from 27 _{t of} 1 gB- (2-butylamino-ethyl) -sulfanilamide with a melting point of 76-78 ° with a solution of 11.9 g of phenyl cyanate in 50 ml of ether, 1-sulfanilyl- 2-imino-3-butyl-imidazolidine with a melting point of 179-181 °.

The starting product is manufactured as follows:

b) 31.3 g of N ¹ - (2-butylanino-ethyl) -H ⁴ -acetylsulfanilamide are shaken with 300 ml of ethanolic hydrochloric acid, the crystals initially dissolving. After an interval of a few minutes, crystals will precipitate again. The suspension is left to stand for 16 hours at room temperature and then evaporated in vacuo. The residue is dissolved in a little water and with 2-n. Sodium hydroxide solution carefully adjusted to pH, whereby the solution becomes milky cloudy. The solution is extracted three times with 200 ml of chloroform each time. The chloroform solution is washed with a little water, dried with sodium sulfate and evaporated. The residue is recrystallized from ethyl acetate, after which the N - (2-butylamino-ethyl) sulfanilamide obtained melts at 76 ° -78 °.

909840/1747

Example 17

Analogously to Example 15 a), 28.3 g of N - (2-cyclopentylamino-ethyl) sulfanilamide are obtained, its hydrochloric! "at I9O-I9I melts, and a solution of 11.9 g of phenyl cyanate in 50 ml of ether the l-sulfanilyl ^ -imino - ^ - cyclopentylimidazolidine from m.p. 192-193

The starting product is made analogously to Example 11 "b)

1 4

32.5 g of N - (2-cyclopentylamino-ethyl) -B -acetyl-sulfanilamide (See. Example 10 a) with 300 ml of ethanolic hydrochloric acid obtain.

909840/1747

Example 18

27.1 g of N - (2-butylamino-ethyl) sulfanilamide will be in 120 ml 2-n. Sodium hydroxide solution is dissolved and 10.6 g of cyanogen bromide are added. Crystals precipitate. The reaction mixture is stirred one hour at room temperature and then filtered the crystals off. Recrystallization of the crude product from methanol gives the pure l-sulfanilyl-2-imino-3-butylimidazolidine of m.p. 179-181 °.

909840/1747

Example 19

Analogously to Example 18, starting from 120 ml of 2-n. Caustic soda:

a) with 25.7 g of Nr- (Oyclopropylamino-ethyl) sulfanilamide and 10.6 g of cyanogen bromide l-sulfanilyl ~ 2 ~ imino-3-cyclopropylimidazolidine from m.p. 202-204 ° and

b) with 28.3 g of N - (cyclopentylamino-ethylV-sulfanilamide and 6.2 g of cyanogen chloride l-sulfanilyl - ^ - imino - ^ - cyelopentylimidazolidine of m.p. 192-193 °.

909840/1747

example 2D

A solution of 14.6 g of butylamine in 100 ml abs. Ether is stirred at -10 to -5 within 50 minutes with a solution of 10.6 g of cyanogen bromide in 50 ml of abs. Aether moves »Man. The reaction mixture is stirred for a further 30 minutes and the butylamine hydrochloride which has precipitated is filtered off. The filtrate, in which the butyl cyanamide obtained is dissolved, is added, with further cooling, with a suspension of 2.8 g of sodium hydride in 40 ml of abs. Ether. The suspension, which is cooled further to the same temperature, is stirred for a further 30 minutes and 24.0 g of 4 ^l - (aziridin-l-ylsulfonyl) acetanilide are then added to the suspended sodium derivative of butyl cyanamide. The mixture is warmed to room temperature and stirred for 15 hours at this temperature. The reaction mixture is then slowly mixed with 2-n. Hydrochloric acid and separates the two phases formed. The acidic, aqueous phase is washed twice with ether, purified with activated charcoal, filtered and concentrated at 0 with conc. Sodium hydroxide solution made alkaline. The precipitated 4 '- (2-imino-3-butyl-imidazolidin-1-ylsulfonyl) acetanilide is filtered off and recrystallized from methanol, after which it melts at 243-244.

The acetanilide obtained is according to Example Ib) for 1-sulfanilyl-2-imino-3-butyl-imidazolidine with a melting point of 179-101 ° hydrolyzed.

909840/1747

Example 21

Analogous to example 20 one obtains:

a) from 6.2 g of methylamine in 100 ml of ether with 10.6 g of cyanogen bromide, the N-methyl-cyanamide, which with 2.8 g of sodium hydride is converted into the sodium derivative in 40 ml of ether; this gives with 24.0 g of 4 '- (aziridin-l-ylsulfonyl) acetanilide that 4- (2 ~ Imino-3-methyl-iinidazolidin-1-ylsulfonyl) -acetanilide from Mp. 266-267 °, which according to Example 2 b) to l-sulfanilyl-2-imino-3-methyl-imidazolidine is hydrolyzed with m.p. 209-211;

b) N-ethyl-cyanamide from 9.0 g of ethylamine in 100 ml of ether with 10.6 g of cyanogen bromide, which is converted into the sodium derivative with 2.8 g of sodium hydride in 40 ml of ether; this gives with 24.0 g ^ - (aziridin-l-ylsulfonylJ-acetanilide the 4- (2-imino-3-ethyl-imidazolidin-l-ylsulfonyl) -acetanilide of melting point 267-269 °, which according to Example 3 for 1-sulfanilyl-2-iinino-3-ethyl-imidazolidine with a melting point of 171-172 ° is hydrolyzed;

c) propyl cyanamide from 11.8 g of propylamine in 100 ml of ether with 10.6 g of cyanogen bromide, which with 2.8 g of sodium hydride is converted into the sodium derivative in 40 ml of ether; this gives with 24.0 g of 4- (aziridin-1-ylsulfonyl) acetanilide 4- (2-Imino-3-propyl-imidazolidin-1-ylsulfonyl) -acetanilide vom Mp. 253-255 °, which according to Example 4 to l-sulfanilyl-2-imino-3-propyl-imidazolidine is hydrolyzed from m.p. 164-166 °;

909840/1747

d) from 14.6 g of tert-butylamine in 100 ml of ether with 10.6 g of cyanogen bromide tert-butyl-cyanamide, which with 2.8 g Sodium hydride in 40 ml of ether converted into the sodium derivative " will; With 24? 0 g of 4- (aziridin-1-ylsulfonyl) -acetanilide this gives 4- (2 ~ imino-3-tert-butyl-imidazolidin-lylsulfonyl) -acetanilide from m.p. 245-247 »which according to Example 8 a) to the l-sulfanilyl ~ '2-imino-3-tert-butyl-imidazolidine from M.p. 187-189 ° is hydrolyzed;

e) from 17 | 0 g of cyclopentylamine in 100 ml of ether with 10.6 g of cyanogen bromide cyclopentyl-eyanamide, which with 2.8 g Sodium hydride in 40 ml of ether is converted into the sodium derivative; this gives with 24.0 g of 4- (aziridin-1 «ylsulfonyl) acetanilide 4- (2-Imino ~ 3-cyclopentyl-imidazolidin-1-ylsulfonyl) -acetanilide from m.p. 261-263, which according to Example 11 a) to the l-sulfanilyl-2-imino-3-cyclopentyl-imidazolidine from M.p. 192-193 ° is hydrolyzed;

f) from 19.8 g of cyclohexylamine in 100 ml of ether with 10.6 g of cyanogen bromide. The Oyclohexyl-cyanamid, which with 2.8 g Sodium hydride in 40 ml of ether is converted into the sodium derivative; this gives 24.0 g of 4 '- (aziridin-1-ylsulfonyl) acetanilide 4- (2-Imino-3-cyclohexyl-imidazolidin-1-ylsulfonyl) acetanilide from the smp "283-284 °, which is analogous to example Ib) is hydrolyzed to l-sulfanilyl-2-imino-3-cyclohexyl-imidazolidine of melting point 178-179 °, and

909840/1747

g) pentylcyanamide from 1714 g of pentylamine in 100 ml of ether with 10.6 g of cyanogen bromide, which is converted into the sodium derivative with 2.8 g of sodium hydride in 40 ml of ether; With 24.0 g of 4 ^l - (aziridin-1-ylsulfonyl) acetanilide, this gives 4 '- (2-imino-3-pentyl-imidazolidin-1-ylsulfonyl) -acetanilide of melting point 248-250, which according to Example 9b) is hydrolyzed to 1-sulfanilyl-2-imino-3-pentyl-imidazolidine with a melting point of 167-168 °.

908840/1747

~ 46 ~

Example 22

With stirring and cooling to -5 Ms -10 is added a solution of 10.6 g of cyanogen bromide in 50 ml of absolute ether dropwise a solution of 14> 6 g butylamine in 100 ial abs. AeVr.ar too. To The butylamine hydrochicride precipitates out for a few minutes. It will filtered off. The piltrate, in which the butyl cyananide is dissolved 2.8 g of sodium hydride in 40 ml of absolute ether are added in portions. A precipitate separates out. You dilute the Suspension with 200 ml of abs. Ether and 200 ml of Dioxari and stir them for 10 minutes at room temperature. Then add 19.8 g of 1-sulfanilyl-aziridine are added and the gray suspension is stirred Continue for 15 hours and give another 30 ml 2-n. Hydrochloric acid too. Man separates the organic phase. It is played twice with 2-n. Hydrochloric acid extracted. The aqueous, acidic phases are combined, cleaned with activated charcoal and filtered. The reaction mixture is neutralized with solid sodium hydrogen carbonate, whereby a brown resin precipitates. The resin is filtered off through cellite (purified diatomaceous earth) and the colorless, clear solution with kpnz. Sodium hydroxide solution made alkaline. The reaction mixture is left to stand at 0 ° for one hour and the precipitated products are filtered off Crystals that are recrystallized from ethanol. You get l-sulfanilyl-2-imino-3- "butyl-imidazolidine with a melting point of 179-181 °.

909840/1747

Example 23

Analogous to example 22 one obtains:

a) from 6.2 g of methylamine in 100 ml of ether with 10.6 g of cyanogen bromide methyl cyanamide, which with 2.8 g of sodium hydride is converted into the sodium derivative in 40 ml of ether; With 19.8 g of 1-sulfanilyl-aziridine, this gives l-sulfanilyl-2-imino-3-methyl-imidazolidine of m.p. 209-211;

b) from 9) 0 g of ethylamine in 100 ml of ether with 10.6 g of cyanogen bromide, ethyl cyanamide, which is converted into the sodium derivative with 2.8 g of sodium hydride in 40 ml of ether; With 19.8 g of 1-sulfanilylaziridine, this gives l-sulfanilyl-2-imino-3-ethyl-iinidazolidine with a melting point of ₀ 171-172;

c) from 11.8 g of propylamine in 100 ml of ether with 10.6 g Cyanogen bromide propyl cyanamide, which with 2.8 g of sodium hydride is converted into the sodium derivative in 40 ml of ether; this gives l-sulfanilyl-2-imino-3-propyl-imidazolidine with 19.8 g of 1-sulfanilylaziridine from m.p. 164-166;

d) tert-butyl-cyanamide from 14.6 g of tert-butylamine in 100 ml of ether with 10.6 g of broracyan, which is converted into the sodium derivative with 2.8 g of sodium hydride in 40 ml of ether; With 19.8 g of 1-sulfanilyl-aziriditi, this gives l-sulfanilyl-2-imino-3-tert-butyl-imidazolidine with a melting point of 187-189 °;

e) from 17.0 g of cyclopentylamine in 100 ml of ether with 10.6 g of cyanogen bromide cyclopentyl cyanamide, which with 2.8 g

909840/1747

-, 48 -

Sodium hydride converted into the sodium derivative in 40 ml of ether will; this provides 19.8 g of 1-sulfanilyl-aziridine l-sulfanilyl-2-imino-3-cyclopentyl-imidazolidine from Snip. . 192-193 °, and

f) from 19.8 g of cyclohexylamine in 100 ml of ether with 10.6 g of cyanogen bromide the cyclohexyl-cyanamide, which with 2.8 g Sodium hydride in 40 ml of ether is converted into the sodium derivative; this provides 19.8 g of 1-sulfanilyl-aziridine F l-sulfanilyl-2-imino-3-cyclohexyl-imidazolidine with a melting point of 178 ° -179 °.

0-9 840/1747

Example 24

9.9 g of l-tert-butyl aziridine [cf. A. Weissberger, Heterocyclic Compounds with Three and Four-Membered Rings, John Wiley & Sons Inc., London (1964), page 530] are dissolved in 60 ml of dioxane, and 10.6 g of cyanogen bromide are added. In a An exothermic reaction is a solution of N- (2-bromo-ethyl) -N-tert.t) utyl-cyanamide obtained, which is added with stirring to a solution of 21.4 g of 4'-sulfamoyl acetanilide in 100 ml of l-n. Sodium hydroxide drips. The reaction mixture is refluxed for one hour and then evaporated in vacuo to the half volume. The precipitated crystals are filtered off, washed with water, dried at 60 in a vacuum and recrystallized from ethyl acetate. The 4 '- (2-imino-3-tert-butyl-imidazolidin-1-ylsulfonyl) -acetanilide obtained Melts at 245-247 ° and, according to Example 8, becomes 1-sulfanilyl-2-imino-3-tert-butyl-imidazolidine hydrolyzed from m.p. 187-189 °.

909840/1747

Example 25

Analogous to example 24 one obtains:

a) from 5.7 g of 1-methylaziridine and 10.6 g of cyanogen bromide

in 60 ml of dioxane the N- (2-broa-ethyl) -! T-methyl-cyanainia, which with 21.4 g of 4'-sulfainoyl acetanilide in 100 ml of 1N sodium hydroxide solution the 4- {2-imino-3-methyl-imidazolidin-l-ylsulfonyl) acetanilide vom Snip * 266-267 supplies; this is according to Example 2 b) for l-sulfanilyl-2-imino-3-methyl-imidazolidine from sap ", 209-211 ° hydrolyzed;

b) from 7 »1 g of 1-ethyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -lT-ethyl-cyanamide, which with 21.4 g of 4'-sulfamoyl acetanilide in 100 ml of 1-n. Caustic soda the 4- (2-imino-3-ethyl-imidazolidin-l-ylsulfonyl) acetanilide vom Provides m.p. 267-269 °; according to Example 3, this becomes 1-sulfanilyl-2-imino-3-ethyl-imidazolidine hydrolyzed from m.p. 171-172 °;

c) from 8.5 g of 1-propyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-propyl-eyanamide, which with 21.4 g of 4'-sulfamoyl-acetanilide in 100 ml of 1-n. Caustic soda 4- (2-Iraino-3-propyl-imidazolidin ~ l-ylsulfonyl) -acetanilide from Provides m.p. 253-255; according to Example 4, this becomes 1-sulfanilyl-2-imiho-3-propyl-imidazolidine of m.p. 164-166 hydrolyzed.

909840/1747

d) from 8.5 g of 1-isopropyl aziridine and 10.6 g of cyanogen bromide in 60 nil dioxane the N- (2-bromo-ethyl) -N-isopropyl-cyanajnid, which with 21.4 g of 4'-sulfamoyl acetanilide in 100 ml of l-n " Sodium hydroxide solution 4- (2-imino-3-isopropyl-imidazolidin-l-ylsulfonyl) acetanilide with a melting point of 253-254 °; this will after Example 5 for 1-sulfanilyl-2-imino-3-isopropyl-imidazolidine hydrolyzed from Smpo 183-184;

e) from 9 »9 g of 1-isobutyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-isobutyl-cyanamide, which with 21.4 g of 4'-sulfamoyl acetanilide in 100 ml of l-n " Sodium hydroxide solution 4- (2-imino ~ 3-isobutyl- "imidazolidin-1-ylBUlfonyl) ~ acetanilide of m.p. 264-265 provides; this is according to Example .6 to l-sulfanilyl-2-imino-3-isobutyl-imidazolidine hydrolyzed from melting point 146-147 °:

f) from 9 »9 g of 1-seco-butyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N- (2-bromo-ethyl) -N-sec.butyl-cyanamide, which with 21 ₅ 4 g of 4 ^! ~ Sulfamoyl ~ acetanilide in 100 ml 1-n. Sodium hydroxide solution 4- (2-imino ~ 3 ~ sec.butyl-imidazolidin ~ l-yl-sulfonyl) -

909840/1747

acetanilide of m.p. 265-266 provides; this will after Example 7a) for l-sulfanilyl-2-imino-3-sec-butyl-imidazolidine hydrolyzed from m.p. 173-173.5 °;

g) from 11.3 g of 1-pentyl aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-pentyl- ~ cyanamide, which with 21.4 g of 4'-sulfamoyl acetanilide in 100 ml of 1N sodium hydroxide solution the 4 - ^ - Imino ^ -pentyl-imidazolidin-l-ylsulfonyl) -acetanilid vom M.p. provides 248-250 °; according to example 9b) this becomes 1-sulfanilyl-2-imino-3-pentyl-imidazolidine hydrolyzed from m.p. 167-168;

h) from 12.7 g of 1-hexyl aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-hexyl-cyanamide, which with 21.4 g of 4'-sulfamoyl-acetanilide in 100 ml of 1-n. Caustic soda the 4- (2-imino-3-hexyl-imidazolidin-l-ylsulfonyl) -acetanilide from Provides m.p. 236-238 °; according to example 10a) this becomes 1-sulfanilyl-2-imino-3-hexyl-imidazolidine hydrolyzed from m.p. 182-183 °;

i) from 11.1 g of l-cyclopentyl aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, the N- (2-bromo-ethyl) -N-cyclopentylcyanamide, which with 21.4 g of 4'-sulfamoyl acetanilide in 100 ml of ln _o sodium hydroxide solution yields 4- (2-imino-3-cyclopentyl-imidazolidin-1-ylsulfonyl) -acetanilM with a melting point of 261-263 °; this is hydrolyzed according to Example 11a) to l-sulfanilyl-2-imino-3-cyclopentyl-imidazolidine of melting point 192-193 °, and

90984 0/1747

J) from 12.5 g of i-cyclohexyl-aziriiin and 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -ii-eyclohexylcyanamidj which with 21.4 g of 4'-sulfamcyl-acetanilide in 100 ml 1-n. Katronlauge 4- _(i? Exyl-imidazolidin-l 2-imino-3-cyclo - ylsulfonyl) acetanilide provides mp "283-284; this will after
Example 2Lf) hydrolyzed to l-sulfanilyl-2-imino-3-cyclohexyl-i-inidazolidine of Smpo 178-179.

90Ö840 / 1747

Example 26

12.5 g of 1-cyclohexyl-aziridine are dissolved in 60 ml of dioxane, and 10.6 g of cyanogen bromide are added. In an exothermic reaction, the N- (2-bromo-ethyl) -N-cyclohexyl-cyanamide is formed, which in the reaction solution with stirring to a solution of 17.2 g of sulfanilamide in 100 ml of 1-n. Given caustic soda
will. The reaction mixture is refluxed for one hour and evaporated in vacuo. The residue is with
Water is added, the resulting precipitate is filtered off and recrystallized from ethyl acetate. The received
l-sulfanilyl-2-imino-3-cyclohexyl-imidazolidine melts at
178-179 °.

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Example 27

Analogous to example 26 one obtains:

a) from 5.7 g of 1-methylaziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-methyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imino-3-methyl-imidazolidine sodium hydroxide solution provides from m.p. 209-211 °;

b) from 7.1 g of 1-ethyl aziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane, the N- (2-bromo-ethyl) -N-ethyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imino-3-ethyl-imidazolidine sodium hydroxide solution from m.p. 171-172 ° results;

c) from 8.5 g of 1-propyl-aziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane N- (2-bromo-ethyl) -N-propyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imino-3-propyl-imidazolidine sodium hydroxide solution provides from m.p. 164-166 °;

d) from 8.5 g of 1-isopropyl aziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-isopropyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imino-3-isopropyl-imidazolidine sodium hydroxide solution from m.p. 183-184 ° results ;;

e) from 9 »9 g of 1-butyl aziridine with 10.6 g of broracyan in 60 ml of dioxane the N- (2-bromo-ethyl) -N-butyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imino-3-butyl-imidazolidine sodium hydroxide solution of m.p. 179-181 °;

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f) from 9 »9 S 1-isobutylaziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane, N- (2-BroE-ethyl) -! T-isobutyl - cyanamide, which with 17» 2 g of sulfanilamide in 100 ml 1-n. Sodium hydroxide solution gives l-3ulfanilyl-2-imino-3-isobutyl-imidazolidine with a melting point of 146-147 °;

g) from 9 »9 g of 1-sec-butyl-aziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-sec.butyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imino-3-sec-butyl-imidazolidine with a melting point of 173-173.5 ° supplies;

h) from 11.3 g of 1-pentyl aziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-pentyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imine D-3-pentyl-imidazolidine sodium hydroxide solution of m.p. 167-168 ° results; .

i) from 12.7 g of 1-hexyl aziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane, the N- (2-bromo-ethyl) -N-hexyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. 1-sulfanilyl-2-imino-3-hexyl-imidazolidine sodium hydroxide solution of m.p. 182-183 °;

j) from 11.1 g of 1-cyclopentyl-aziridine with 10.6 g of cyanogen bromide in 60 ml of dioxane the N- (2-bromo-ethyl) -N-cyclopentyl-cyanamide, which with 17.2 g of sulfanilamide in 100 ml of 1-n. Caustic soda that L-sulfanilyl-2-imino-3-cyclopentyl-imidazolidine with a melting point of 192-193 ° provides.

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Example 28

A mixture of 16.0 g of N- (2-chloro-ethyl) -IT-tert-butylcyanamide, 5.6 g potassium hydroxide and 17.2 g sulfanilamide in 100 ml Diethylene glycol monomethyl ether is heated in a 160-170 bath for 30 minutes. The reaction mixture is then poured onto ice and the suspension is filtered. The filter residue will be in 2-n. Dissolved hydrochloric acid, the solution decolorized with activated charcoal, filtered and made alkaline with concentrated sodium hydroxide solution. The precipitated crystals are filtered off, washed with water and recrystallized from ethanol. You get that 1-sulfanilyl-imino-tert-butyl-imidazolidine with a melting point of 188-190 °.

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Example 29

a) 34.6 g of N ¹ - (2-bromo-Ä.thyl) -li ¹ -cyano-N ⁴ -acetylsulfanilaraid are dissolved in 500 ml of ethanol and 7.3 g of butylamine and refluxed for 17 hours Reaction mixture, and takes the residue in chloroform and 2-n. Hydrochloric acid. The acidic, aqueous extract is mixed with conc. Sodium hydroxide solution made alkaline. The crude product precipitates; it is filtered off and purified by recrystallization from ethanol and acetone. The 4 '- (2-imino-3-butyl ~ imidazolidinl-ylsulfonyl) acetanilide obtained melts at 249-251 °. This acetanilide is hydrolyzed according to Example Ib) to l-3ulfanilyl-2-imino-3-butylimidazolidine with a melting point of 179-181.

b) The sulfanilamide that was assumed can be can be made as follows

A solution of is added dropwise within 30 minutes at 0 ° 4.3 g of aziridine in 20 ml of ether to that of 10.6 g of cyanogen bromide in 30 ml of ether. The suspension obtained is evaporated in vacuo at a bath temperature below 40 °. One slurries that The residue is dissolved in 60 ml of water, and a solution of 25 g of N-acetyl-sulfanilyl chloride in 190 ml is added to the suspension Acetone. 4 »5 g of sodium hydroxide are then added dropwise to 10 ml of water within 10 minutes and the resulting mixture is refluxed for 30 minutes. After cooling, it crystallizes Raw product from. It is filtered off. The filtrate results in

809840/1747

Dilute a further amount of crude product with water, which is separated off and combined with the first fraction. Man the two fractions recrystallized from methanol, after which the N - (2-bromo-ethyl) -N -cyano-N -acetyl-sulfanilamide Melts at 177-179 °.

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example 30th

Analogously to Example 29, 34.6 g are obtained starting from 34.6 g N - (2-bromo-ethyl) -N -cyano-N -acetyl-sulfanilamide in 500 ml Ethanol:.

a) with 31.0 g of methj ^ lamin the 4 '- (2-imino-3-niethylimidazolidin-1-ylsulfonyl) acetanilide of m.p. 266-267 °, which according to Example 2b) to l-sulfanilyl-2-imino-3-methyl-imidazolidine is hydrolyzed with m.p. 209-211;

"b) with 45, Og ethylamine the 4 '- (2-imino-3-ethyl-

imidazolidin-: l-ylsulfonyl) acetanilide of melting point 267-269, which is hydrolyzed according to Example 3 to l-sulfanilyl-2-imino-3-ethyl-imidazolidine with a melting point of 171-172 °;

c) 4 '- (2-imino-3-propylimidazolidin-1-ylsulfonyl) acetanilide with 59.0 g of propylamine from m.p. 253-255 °, which according to Example 4 to l-sulfanilyl-2-imino-3-propyl-imidazolidine is hydrolyzed from m.p. 164-166 °;

d) 59, Og isopropylamine, the 4 '- (2-imino-3-isopropyl-imidazolidin-l-ylsulfonyl) -acetanirid _o mp 253-254 °, which according to Example 5 for l-sulfanilyl ^ -imino ^ -isopropylimidazolidin is hydrolyzed from m.p. 183-184 °;

e) 4 '- (2-imino-3-isobutylimidazolidin-1-ylsulfonyl) acetanilide with 73.0 g of isobutylamine of m.p. 264-265 °, which according to Example 6 to l-sulfanilyl-2-imino-3 ^ -isobutyl-imidazolidine is hydrolyzed from m.p. 146-147 °;

909840/1747

f) with 73.0 g of sec-butylaoin the 4 '- (2-imino-3-sec-butyl-imidazolidin-1-ylsulfonyl) -acetanilide from m.p. 265-266, which according to Example 7 to the l-sulfanilyl-2-imino ~ 3-sec-butyl-imidazolidine with a melting point of 173-173.5 hydrolyzed will; ·

g) with 73.0 g of t-butylamine, the 4 '- _e (2-imino-3-tert-butyl-imidazolidin-l-ylsulfonyl) acetanilide, mp "245-247 °, which according to Example 8 to l-Sulfanilyl- 2-imino-3-tertobutyl-imidazolidine with a melting point of 187-189 ° is hydrolyzed;

h) the 4 '- (2-imino-3-pentylimidazolidin-1-ylsulfonyl) acetanilide with 87.0 g of pentylamine from Smp «248-250, which according to Example 9b) is hydrolyzed to l-sulfanilyl-2-imino-3-pentyl-imidazolidine with a melting point of 167-168 °;

i) 4 '- (2-Imino-3-cyclopentyl-imidazolidin-1-ylsulfonylj-acetanilide) with 85.0 g of cyclopentylamine of m.p. 261-263, which according to Example H ^ to l ~ sulfanilyl-2-imino-3-cyclopentyl-imidazolidine is hydrolyzed from m.p. 192-193 °, and

j) with 99.0 g of cyclohexylamine, the 4 '- (2-imino-3-cyclohexyl-imidazolidin-1-ylsulfonyl) acetanilide of melting point 283-284 °, which according to Example 21 $ to l-sulfanilyl-2-imino-3-cyclohexyl-imidazolidine of m.p. 178-179 is hydrolyzed.

909840/1747

Example 31

a) 37.45 g addition salt of N-cyano-N -acetylsulfanilamide and N- (2-0hlor-ethyl) -tert, butylarain are heated for one hour in a bath of 145, the salt melting. The reaction mixture is cooled and the resinous cash register is triturated with 2-n. Hydrochloric acid and decant the solution from the insoluble resin. The solution is made with conc. Sodium hydroxide solution made alkaline _s the precipitated crude product filtered off, washed with water / water and recrystallized from ethanol. The 4 '- (2-imino-3-tert.butyl-imidazolidin-1-ylsulfonyl) -acetanilide from Srnp «242-244 °, which according to Example 8a) to the l-sulfanilyl-2-imino-3 ~ tert .butyl-imidazolidine with a melting point of 187-189 ° is hydrolyzed.

The starting compound is obtained as follows:

b) To a solution of 8.6 g of disodium cyanamide in 100 ml of water, 23.3 g of N-acetylsulfanilyl chloride are added in portions over 30 minutes, which gradually dissolves with a slightly exothermic reaction. The solution is stirred for one hour at room temperature, the sodium derivative of N-cyano-N ^ -acetyl-bulfanilamide being formed. Then 17.2 g of N- (2-0hlar-ethyl) -tert.butylamine hydrochloride are added in portions to the reaction mixture over a period of 15 minutes. After an interval of a few minutes, the addition salt of N-cyano-N falls -acetylsulf anilamid and N- (2-0hlor-ethyl) -tert _a butylamine from "The salt is filtered off, washed with water, recrystallized from isopropanol, after which it melts at 122-124.

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Example 32

The following end products are obtained analogously to Example 31 a):

a) from your addition salt of N -cyano-N -acetyl-bulfanilamide and N- (2-chloro-ethyl) -methylamine 4 '- (2-imino-3-methylimidazolidin-1-ylsulfonyl) acetanilide of m.p. 266-267 °, which according to Example 2 b) to l-sulfanilyl-2- imino-3-methyl-imidazolidine is hydrolyzed from m.p. 209-211 °;

(The addition salt used is analogous to Example 31 b) from N-cyano-N -acetyl-sulfanilamide sodium and N- (2-chloro-ethyl) -methylamine hydrochloride manufactured);

b) from the addition salt of N-cyano-N-acetyl-sulfanilamide and N- (2-chloro-ethyl) -butylamine the 4 '- (2-imino-3-butyl-imidazolidin-1-ylsulfonyl) -acetanilide of mp 243-244 °, which according to Example 1 b) is hydrolyzed to l-sulfanilyl-2-imino-3-butyl-imidazolidine with a melting point of 174-181 °;

(the addition salt used is analogous to Example 31 b) N -Cyano-N -acetyl-sulfanilamide sodium and N- (2-chloro-ethyl) -butylamine hydrochloride manufactured)}

14th

c) from the addition salt of N -Cyano-N -acetyl-sulfanilamide

and N- (2-chloro-ethyl) -cyclohexylamine 4 '- (2-imino-3-cyclohexylimidazolidin-1-ylsulfonyl) acetanilide from m.p. 283-284 °, which according to Example 21 f) to the l-sulfanilyl ^ -imino ^ -cyclohexylimidazolidine is hydrolyzed from m.p. 178-179 °; (The addition salt used is analogous to Example 31 b) N -Cyano-lP-acetyl-sulfanilamide sodium and N- (2-chloro-ethyl) -cyclohexylamine hydrochloride manufactured);

909840/1747

d) from the addition salt of N -Cyano-N -acetyl-sulfanilamide and N- (2-chloro-ethyl) -cyclopentylamine the 4 '- (2-imino-3-cyclopentyl-imidazolidin-1-ylstilfonyl) -aGetanilid of melting point 261-263 °, which according to Example 11 a) to l-sulfanilyl-2-imino-3-cyclopentyl-imidazolidine is hydrolyzed with m.p. 192-193;

(The addition salt used is analogous to Example 31 ″ b) N -Cyano-N -acetyl-sulfanilamide sodium and N- (2-chloro-ethyl) ~ cyclopentylamine produced), and

> 1 4

e) from the addition salt of N -Oyano-N -acetyl-sulfanilamide

and N- (2-chloroethyl) pentylamine 4 '- (2-imino-3-pentylimidazolidin-1-ylsulfonyl) acetanilide of m.p. is hydrolyzed from m.p. 167-168 °;

(The addition salt used is analogous to Example 31 b) N -Cyano-N -acetvl-sulfanilamide sodium and N- (2-chloro-ethyl) -pentylamine manufactured).

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1912843

For example 33 '.. · ■

a) 28.0 g of l-sulfanilyl-a-imino-J-allyl-imidazolidine from melting point 158-160 ° are in 350 ml of dioxane with 5.0 g of 5 ^ -iger Palladium carbon hydrogenated at room temperature and normal pressure. After the hydrogen uptake has ended, the catalyst is removed filtered off and evaporated the Piltrat. 1-sulfanilyl-2-imino-3-propyl-imidazolidine is obtained of m.p. 164-166 ° (from methanol). ·

b) The starting compound, the l-sulfanilyl-2-imino-3-allyl-imidazolidine _, is obtained analogously to Example la-c) starting from 4 '- (aziridin-l-ylsulfonyl) acetanilide via the intermediates N - (2 -Allylamino-ethyl) -N -acetylsulfanilamide (crude product) and 4 '- (2-imino-3-allyl-imidazolidin-1-ylsulfonyl) -acetanilide with a melting point of 247-249 ° (from methanol).

908840 / 17Ä7

Example 34

Analogously to Example 33 a), starting from 32.0g, nan receives l-sulfanilyl-2-imino-3- (3-eyelohexen-l-yl) -imidazolidine from m.p. 172-173 ° the l-sulfanilyl - ^ - imino ^ -cyclohexylimidazolidine from m.p. 181-183.

The following are also obtained analogously: l-sulfanilyl-2-imino-3-butyl-imidazolidine with a melting point of 179-181 °;

daa l-sulfanilyl-2-imino-3-isobutyl-imida2olidine of m.p. 146-147 ° and

l-sulfanilyl-2-imino-3-pentyl-imidazolidine with a melting point of 192-193 °.

908840/1747

Example 3 5

a) A reaction mixture consisting of 30 ^ 8 g of 1- (p-acetamidophenylsulfonyl) -3-butyl-guanidine with a melting point of 121 [cf. B.δ. Boggiano et al., J. Pharm. and Pharmacol. IJ ,, 567-574 (1961)], 18.8 g of ethylene dibromide and. 900 ml of dioxane is refluxed for 30 hours and then evaporated to dryness. The residue is mixed with 120 ml of 2N. Sodium hydroxide solution and extracted it with chloroform. The chloroform extract is chromatographed on a silica gel column. The fractions eluted with the solvent mixture methanol-chloroform (1: 4) are checked by thin-layer chromatography. The desired substance has an Rf value of 0.6 (silica gel, methanol: chloroform 1: 4). The fractions containing the desired substance in sufficient purity are combined and freed from the solvent. The resulting crude 4 ^l - (2-imino-3-butyl-imidazolidinl-ylsulfonyl) -acetanilide is recrystallized from alcohol and melts at 243-244 °.

b) 33.8 g of the compound obtained according to a) analogous to Example 1 b) to the l-sulfanilyl-2-imino-3-butylimidazolidine hydrolyzed from m.p. 179-181 °.

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Example 36

Analogously to Example 35 a), starting from 18.8 g of ethylene dibromide ϊ is obtained

a) and 27.0 g of l- (p-acetamidophenylsulfonyl) -3-methyl-guanidine with a melting point of 24.8-249 ° (cf. E. Havarth et al., J. Chem-Soc. 1147, 820-822) the 4M2-imino-3-methyl-imidazolidin-1-ylsulfonyl) aoetanilide of melting point 266-267 _t that of Example 2 b) for l-sulfanilyl-2-imino-3-ethyl-imidazolidine of melting point 209-211 ° is hydrolyzed;

to) and 32.2 g of l- (p-acetamidophenylsulfonyl) -3-pentyl-guanidine 4 '- (2-imino-3-pentyl-iraidazolidin-l-ylsulfonyl) -acetanilide of melting point 248-250 °, the according to Example 9 b) to 1-sulfanilyl »2-imino-3-pentyl-imidazolidine from 8mp. 167-168 ° is hydrolyzed l

c) and 33 # 8 g of l- (p-acetamidophenylsulfonyl) -3-oyolohexylguanidine the 4 '- {2-Iraino-3-oyolohezyl-imidazolldin-l-ylsulfonyl) · acetßnilid of melting point 283-284 ° »welöhea analogous to Example 21 f) for l-sulfanilyl-2-imino * 3-cyclohex: yl-imida2olidine with a melting point of 181-183 ° is hydrolyzed.

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Appendix 37

a) A reaction mixture consisting of 28.2 g 4 '~ (2-imino-imidazolidin-1-ylsulfonyl) acetanilide, 14.1 g Butyl bromide and 900 ml of dioxane are refluxed for 30 hours and then evaporated to dryness. One relocates the residue with 60 ml of 2-n. Sodium hydroxide solution and extracted it with chloroform. The chloroform extract is attached to a silica gel column chromatographed. The mixed with the solvent Methanol-chloroform (1: 4) eluted fractions are thin-layer chromatography checked. The desired substance has an Rf value of 0.6 (silica gel, methanol / solvent form 1: 4). Be the Fractions containing the desired substance in sufficient purity are combined and freed from the solvent. The received crude 4 '- (2-imino-3-butyl-imidazolidin-1-ylsulfonyl) acetanilide is recrystallized from ethanol and melts at 243-244 °.

b) For the saponification, 53.8 g of the obtained according to a) are obtained Acetanilids with 100 ml of 2-n. Hydrochloric acid heated to 80 for one hour. The reaction mixture is cooled to 20 and placed with 2-n. Caustic soda alkaline. The precipitated crude base is filtered off; washed with water and recrystallized from ethanol. The 1-sulfanilyl-2-imino-3-butyl-imidazolidine obtained, dried in vacuo melts at 179-181 °.

c) The starting material used under a) can be produced in the following way:

909840 / 1-747

To a solution of 23.2 g of N-acetylsulfanilyl chloride in 250 ml of acetone are 12.2 g of ^ -amino ^ -imidazoline hydrochloride, dissolved in 100 ml of water. A solution of 8 g of sodium hydroxide in 100 ml of water is then added, with a thick crystalline pulp precipitates. The reaction mixture is heated to 70 for one hour. The precipitated crystals are with 300 ml of hot water treated and insoluble in water 4- (2-Imidazolin-2-yl-sulfamoyl) -acetanilide (mp. 252-253 °) filtered off. Crystallized on cooling the filtrate to 0 ° the desired 4 '- (2-imino-imidazolidin-1-ylsulfonyl) -acetanilide. The crystals are filtered off and dried, mp 212-213 °.

9Q984Q / 17A7

Example 38

a) Analogously to Example 37 a), the 4 ^l - (2-imino-3-propyl-imidazolidine- l-ylsulfonyl) acetanilide with a melting point of 253-255 °.

b) For saponification, 32.4 g of the acetanilide obtained according to a) are mixed with 200 ml of 8-n. ethanolic hydrochloric acid 48 hours left to stand at 20 °. The reaction mixture is then evaporated

in a vacuum, dissolves the crystalline residue in water and
represents the aqueous solution with 2-n. Caustic soda alkaliseh. The resulting, crude base is filtered off with suction and recrystallized from methanol-water. The l-sulfanilyl-2-imino »3-propylimidazolidine obtained melts at 164-166 °.

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Example 59

a) In analogy to Example 37 a) from 28.2 g of 4 ^l - (2-Imlno-imidazolidin-l-ylsulfQnyl) acetanilide and 15 "5 g of pentyl bromide, the 4 '- (2-imino-3-pentyl-iinidazolidin- l-ylsulfonyl) acetanilide with a melting point of 248-250 °.

b) 35 »2 g of the acetanilide obtained according to a) are added to 125 g of 50% sulfuric acid heated to 40 °, with stirring. The mixture is heated to 50 for 2 hours and then poured into 750 ml of water with stirring, the crude product precipitating as sulfate. One sets the reaction mixture with 10-n. Caustic soda solution to pH 6.3, with the result that solution occurs except for minor impurities. After adding 2 g of activated carbon 15 Hinuten is stirred and filtered over Hyflo (diatomaceous earth). The filtrate is set with 10-n. Caustic soda alkaline. The boh product precipitates; it is filtered off, washed aii water, dried at 90 ° in vacuo and recrystallized from methanol. The l-bulfanilyl-2-iaino-3-pentylimidaBolidin obtained has a melting point of 167-168 ° »

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Example 40

a) Prepared in analogy to Example 37 c) l- (p-Nitro-phenylsulfonyl) -2-imino-imidazolidine is analogous Example 37 a) alkylated with butyl bromide. That after the chromatography The crude product obtained on a silica gel column is recrystallized from benzene. The pure l- (p-nitrophenyl3ulfonyl) -2-imino-3-butyl-imidazolidine obtained has a m.p. of 98-99 °.

b) 390 g of the nitro compound prepared according to a) are dissolved in 15 liters of ethanol and in the presence of platinum-charcoal (5 $ platinum) with hydrogen at 20 ° and normal pressure hydrogenated. The catalyst is filtered off and washed with ethanol. The piltrate is evaporated in a vacuum, the Residue with one liter of 2-n. Hydrochloric acid is added and the insoluble components are filtered off. The Piltrat is presented with 2-n. Caustic soda alkaline. The precipitated crystalline base is filtered off, washed with water and dried in vacuo at 90, The obtained l-sulfanilyl ^ -imino ^ -butyl-imidazolidine melts at 179-181 °.

909840/1747

Example 4 1

Analogously to Example 37 a), 28.2 g of 4 '- (2-iminoimidazolin-1-yl) acetanilide are obtained and 14.5 g of methyl iodide the 4 '- (2-IminQ-3-methyl-imidazolidin-1-ylsulfonyl) -acetanilide obtained from m.p. 266-267 °, which according to Example 2 b) to the l-sulfanilyl-2-imino-3-methyl-imidazolidine from m.p. 209-211 ° | is hydrolyzed.

909840/1747

Example 42

a) Analogously to Example 1 a) is obtained, starting from

1 4

33f9 g of K - (2-cyelohexylamino-ethyl) -N -acetyl-sulfanilamide of melting point 135-136 ° (from ethyl acetate), with 10.6 g
Cyanogen bromide 4 '- (S-Imino - ^ - cyclohexyl-imidazolidine-lylsulfonyl) -acetanilide from Sinp. 283-284 from methanol, of which 36.4 g are hydrolyzed analogously to Example 21 f) to the end product 1-sulfanilyl-2-imino-3-cyclohexyl-imidazolidine with a melting point of 178-179 °.

b) The starting substance from a) is obtained analogously to Example 1 c) from 24.0 g of 4 '- (aziridin-i-ylsulfonyl) acetanilide and 100 ml of cyclohexylamine.

909840/1747

Claims (6)

Claims 1 »Process for the preparation of new derivatives of the sulfanilamide of the general formula I," " - SO, CH. NO, (D Il N-H in which \ group e m j.t at most 5 carbon atoms »one / an alkylv cycloalkyl or öycloalkenyl group of means at most 7 carbon atoms, and their addition salts with inorganic or organic acids, characterized in that a compound of the general formula II, in) in which the meaning given under formula I has "hydrogen, an arylmethyl, diarylmethyl" or a triarylmethyl group xnt, the methyl or the AlIy! Group, one by hydrolysis or reduction to the free Amino group convertible radical means or, if Rg is hydrogen, including the free amine group means, 909840/1747 with a reactive cyanic acid derivative and cyclized, if necessary the reaction product 'hydrolyzed or reduced to convert the group X into the free amino group and optionally converting the compound obtained into an addition salt with an inorganic or organic acid . 2. Modification of the method according to claim 1, characterized characterized in that a compound of the general formula III, CH., (III) in which X denotes the amino group or a radical which is converted into the amino group by hydrolysis or reduction can be, with a compound of the general formula IV, H-N- (IV) 909840/1747 in which E, the given in claim 1 under formula I. Has meaning, or condensed with an alkali metal or alkaline earth metal derivative of such a compound and cyclized, if necessary hydrolyzed or reduced the reaction product to convert group 2 into the free amino group and optionally the compound obtained with a inorganic or organic acid converted into an addition salt. 3. Modification of the method according to claim 1, characterized characterized in that a compound of the general formula V, in which . X denotes the amino group or a radical which is through Hydrolysis or reduction can be converted into the free amino group, with a reactive ester of a hydroxy compound of the general formula VI, H IT- R ₁ (VI) Α .. in which R ^ given in claim 1 under formula I. Has meaning, condensed and cyclized, if necessary the reaction product to convert the radical X into the free Amino group hydrolyzed or reduced and optionally the compound obtained with an inorganic or organic 909840/1747 * ' Ganischen acid converted into an addition salt. 4. Modification of the method according to claim 1, characterized characterized dasβ one a reactive 3rd of a compound of the general formula VII, (VII) σ ξ ν in which X ¹ denotes a radical obtained by hydrolysis or reduction can be converted into the free amino group with an amine of the general formula VIII, (VIII) in which R- has the meaning given in claim 1 under formula I. Has, 9098A0 / 17A7 in which K. has the meaning given in claim 1 under formula I, condensed and cyclized, if necessary the reaction product to convert the radical X ¹ into the free afliino group hydrolyzed or reduced and optionally the compound obtained with an inorganic or organic acid in a Transferred addition salt. 5. Modification of the process according to claim 1, characterized in that an addition salt of the general formula IX, OH ₂ OH ι χ H ! X ¹ denotes a radical obtained by hydrolysis or reduction can be converted into the free amino group, and T halogen means Cycllsiert by heating, if necessary, the reaction product obtained to convert the radical X * into the free amino group hydrolyzed or reduced and optionally the compound obtained with an inorganic or organic acid in transferred to an addition salt. _ 6. Modification of the method according to claim 1, characterized characterized »that one is a compound of the general formula X, (X) - H in which an alkenyl group of 3 - 5 carbon atoms or a cycloalkenyl group of 5-7 carbon atoms and the amino group or »inen reads through in the Hydrolysis or reduction to the free amino group Can be transferred » unfl possibly a obtained connection with a inorganic or organic acid converted into an addition 7 »Modification of the method according to claim 1, characterized in that a compound of the general formula Xt ^,! H H - Jr "i SO ₂ - N NR ₁ ; (XI) N-H in which R has the meaning given in claim 1 under formula I. has and X 'denotes a radical which can be converted into the free amino group by hydrolysis or reduction, with a reactive diester of ethylene glycol, if necessary the reaction product to transfer the radical X ' hydrolyzed or reduced into the free amino group and optionally the compound obtained with an inorganic one or organic acid converted into an addition salt. 8 »Modification of the method according to claim 1, thereby characterized in that a compound of the general formula XII, OH,, (in) in which X ¹ denotes a radical which can be converted into the free amino group by hydrolysis or reduction, with a reactive ester of a hydroxy compound of the general formula XIII, OH-R ₁ (XIII) 909840/1747 in which IL is an alkyl group of at most 7 carbon atoms means, converts »if necessary hydrolyzes or reduces the reaction product to convert the group X ^f into the free amino group and, if necessary, converts the compound obtained into an addition salt with an inorganic or organic acid, 909840/1747