DE1912849A1 - Process for the preparation of new derivatives of sulfanilamide - Google Patents

Description

Dr. F. Zumsfein - Dr. E. Assmann

Dr. R. Koenigsberger Dipl. Phys. R. Holzhauer -

Patent Attorneys J. R. GEIGY A. G. BASEL 2 I Munich 2, Bräuhaussfra & e 4/111

4-278Ο »

Process for the preparation of new derivatives of sulfanilamide

The present invention relates to new derivatives of sulfanilamide, Process for their production, pharmaceuticals containing the new compounds and their use.

Compounds of general formula I,

(I)

in which

Typically an alkyl or alkenyl group of at most 5 carbon atoms or a cycloalkyl or cycloalkenyl group of at most 7 carbon atoms and Rp denotes the methyl or ethyl group, and their addition salts with inorganic or organic acids have not yet become known.

As has now been found, these compounds have valuable pharmacological properties, in particular 1-sulfanilyl-2-imino-3-butyl-5-ethyl, the 1-sulfanilyl-2 ~ imino-3-tert.butyl-4-methyl- and daa l-sulfanilyl-2-imino-3-tert-butyl-5-methyl-imida3olidine are hypoglycemic when administered orally or parenterally Effect on which they are considered suitable for treating the

909840/1748

Characterize diabetes. The hypoglycemic effect, will on standard experiments on warm-blooded animals, z.S. on rabbits and rats, proven.

In the compounds of general formula I, IL can be used as lower alkyl groups e.g. the methyl, ethyl, propyl, isopropyl, Butyl, sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, 2,2-dimethyl-propyl, 1-methyl-butyl, 1-ethyl-propyl, 1,2-dimethylpropyl group and as the alkenyl group, for example, the allyl, 1-, 2- or 3-buten-1-yl, 2-methyl-propenyl, methallyl or 3- or 4-penten-1-yl group. Furthermore, R, "can be, for example: as Cycloalkyl group, the cyclopropyl, cyclopropylmethyl, 2-cyclopropylethyl, 3-Gyclopropyl-propyl-, Gyclobutyl-, Cyclobutylmethyl-, 2-Cyclobutyl-ethyl-, ^ -Cyclobutyl-propyl-, cyclopentyl-, 1-methylcyclopentyl-, 2-methyl-cyclopentyl-, ^ -Methyl-cyclopentyl-, 1-ethyl-cyclopentyl-, 2-ethyl-cyclopentyl-, ^ -ethyl-cyclopentyl-, Cyclopentylmethyl-, 2-methyl-cyclopentylmethyl-, 3-methyl-cyclopentylmethyl-, Cyclohexyl-, 1-methyl-cyclohexyl-, 2-methyl-cyclohexyl-, 3-methyl-cyclohexyl-, 4-methyl-eyclohexyl-, cyclohexylmethyl- or the cycloheptyl group and, as the cycloalkenyl group, the 2-cyclopenten-l-yl-, 2-methyl-2-cyclopenten-l-yl-, 3-methyl-2-cyclopenten-1-yl-, 2-ethyl-2-cyclopenten-1-yl-, 3-ethyl-2-cyclopehten-1-yl-, 3-cyclopenten-l-yl-, 2-methyl-3-cyclopenten-l-yl-, 3-methyl-3-cyclopenten-1-yl-, 2 ~ ethyl-35 ~ cyclopenten-1-yl-, 3-ethyl-3-cyclopenten-1-yl-, 2-cyclohexen-l-yl-, l-methyl-2-cyclohexen-1-yl-, 2-methyl-2-cyclohexen-l-yl-, 3-methyl-2-cyclohexen-lyl-, 4-methyl-2-cyclohexen-l-yl -, ^ - cyclohexen-l-yl-, l-methyl-3 - cyclohexen-l-yl-, 2-methyl-3-cyclohexen-l-yl-, 3-methyl-3-cyclohexen-l-yl- » 4-methyl-3-c \ ü3loJißxen-l-Tl-e the 2- or 3-cyclopentene-l-

aU3840 / 1 / 4e

ORIGINAL INSPECTED

ylmethyl-, 2-, 3- or 4-Oyölohexen-l-ylmethyl-, 2-Gyclohepten-1-yl-, 3-Cyclohepten-1-yl or the 4-Cyclohepten-1-yl group.

According to a first process according to the invention, one sets a compound of the general formula I by adding a compound of the general formula II,

(II)

in which

R-. and Rp have the meaning given under formula I, R ~ hydrogen, the methyl or allyl group or a

Arylmethyl, diarylmethyl or an iriarylmethyl group and
X denotes a radical which can be converted into the free amino group by hydrolysis or reduction or, if R is hydrogen, also denotes the free amino group,

Reacts and eyclizes with a reactive cyanic acid derivative, if necessary, the reaction product to convert the group X into the hydrolyzed or reduced free amino group and optionally the compound obtained with an inorganic or organic acid converted into an addition salt.

R- is as, arylmethyl, diarylmethyl or triarylmethyl group for example the benzyl, benzhydryl or trityl group.

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

909ß40 / 17it

preferably in the presence of a water-miscible or immiscible inert organic solvent in an ore ab- * Essence of water. Suitable inert organic solvents bind, for example, hydrocarbons such as benzene, toluene or Xylene, lower alkenols such as methanol or ethanol, ethereal liquids such as ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, lower Ketones, such as acetone or methyl ethyl ketone, carboxylic acid esters, such as Ethyl acetate, carboxylic acid nitriles, such as acetonitrile, or sulfones, such as tetrahydro-thiophene-l ^ -dioxide. The implementation can be carried out in the presence or absence of an acid-binding agent. Inorganic ones are suitable as acid-binding agents Bases or salts, e.g. alkali metal hydroxides, alkali * - metal hydrogen carbonates, alkali metal carbonates or alkali metal * phosphates, such as the corresponding sodium or potassium compounds. Calcium carbonates and calcium phosphates can also be used and magnesium carbonate can be used.

The subsequent conversion of group X of the reaction product in the free amino group, which converts this into a compound of general formula I, depending on the Type of group X made by hydrolysis, reduction or reductive cleavage.

Convertible into the free amino group by hydrolysis X radicals are, for example, acylamino radicals, such as the acetamido group. Furthermore, such © radicals are lower alkoxycarbonyl

908840/1748

amino radicals, such as the ethoxycarbonylamino group, aryloxycarbonylamino radicals, like the phenoxycarbonylamino radical, or Arylmethoxycarbonylamino radicals, such as the benzyloxycarbonylamino radical, or radicals of corresponding thiocarbonic acid derivatives. Further examples are substituted methylene amino radicals, such as e.g. the benzylideneamino- or the p-dimethylamino-benzylidene- amino group. The hydrolysis to release the amino group can in acidic medium, e.g. in methanolic hydrochloric acid, or in dilute aqueous hydrochloric acid or sulfuric acid or, if X is represented by an alkoxycarbonylamino radical, even under mild alkaline conditions, e.g. using 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-phenylazo 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 are H ₁ , ^ ₂ '' ^ 3 ^ ^{4 X with}

Groups match that are listed after formula I or II. Such starting materials are N- (2-amino-ethyl) -benzenesulfonamides, their benzene ring through the radical X in para position, their amino group through the radicals R and R, and their ethyl group in the 1- or 2-position through the methyl or ethyl group is substituted. A group of such compounds can be 25.B. be prepared when 2-methyl-fonyl of a 1 Λ Phenylßul- or l-phenylsulfonyl-2-ethyl-asiridin aiisgeht which is substituted by the radical X, and the aziridine with a primary or secondary amine having the R-, and R contains, converts. Representatives of the aziridines mentioned are described in the literature [cf. A. Weissberger, Heterocyclic Compounds with Three- and Pour-Membered Rings, Part. One, John Wiley & Sons Inc. London (1964)] · Other aziridines of this type can be prepared analogously.

According to a second inventive method, w represents compounds of the formula I here, in which _R? occupies the 5-position by adding a compound of the general formula III,

(III)

in which Rp has the meaning given under formula I and X denotes the amino group or a radical which is converted into the amino group by hydrolysis or reduction can be, 9098 4 0/174 9

-ΐ-

with a compound of the general formula IV,

H-N-

I (IV)

σ ξ ν

in which R has the meaning given under formula I, or condensed and cyolized with an alkali metal or alkaline earth metal derivative of such a compound, if necessary that Reaction product for converting the group X into the free amino group hydrolyzed or reduced and optionally the The compound obtained is converted into an addition salt with an inorganic or organic acid.

Suitable alkali metal or alkaline earth metal derivatives of the general formula IV are sodium, potassium, lithium or Calcium derivatives. The condensation is preferably in one 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 method. Their conversion to 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.

Suitable starting materials of the general formula III are, for example _9, such compounds whose SymboleX and R ₂ correspond to the groups änsehliessend enumerated in Formula II. A production possibility for such connections

9 09 Wed '87 17 41 "'

1312849

is already explained after the first procedure been.

According to a third method according to the invention compounds of the general formula I can be prepared by egg Compound of the general formula V,

HR ₂

CK CH

ι ^l

C.

Jt

H-H

in which R ^ the meaning given under formula I, _r Rj 'has an alkenyl group of 3-5 carbon atoms or one

Gycloalkenyl group of 5-7 carbon atoms and X denotes the amino group or a radical which is through Hydrolysis or reduction can be converted into the free amino group,

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

The reduction is preferably carried out with hydrogen in the presence of a catalyst in a solvent. Suitable catalysts are, for example, noble metal catalysts, such as palladium, which is used, for example, on Kqhle and Raney nickel. As a solvent e.g.

909840/174 *

Alkanols, such as methanol or ethanol, and also dioxane are used will. 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 to 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 the general formula V can, for example, be prepared analogously to the first process if one of a l-phenylsulfonyl-2-methyl- or l-phenylsulfonyl-2-ethylaziridine starts out, which is substituted in the benzene ring by the radical X and this aziridine with an alkenyl or Gycloalkenyl-amine to a corresponding one in the benzene ring the radical X substituted N- (l-methyl-2-alkenylamino-ethyl) -, N- (l-ethyl-2-alkenylamino-ethyl) -, N- (2-methyl-2-cycloalkenylamino-ethyl) - or N- (2-ethyl-2-cycloalkenylamino-ethyl) -benzenesulfonamide and this is condensed with cyanogen bromide and cyclized.

Obtained according to a fourth inventive method one compounds of the general formula "I, by adding a reactive functional derivative of a sulfonic acid of the general Formula VI,

(VI) in which 909840/1741

X 'means a residue obtained by hydrolysis, reduction or reductive cleavage can be converted into an amino group,

with a compound of the general formula YII,

N CH

HH /
H ₂ H -

N CH

(VII)

in which R and Rp have the meaning given under formula I. have converted, hydrolyzed or reduced the reaction product to convert the group X into the free amino group and desired enf alls the compound obtained is converted into an addition salt with an inorganic or organic acid.

A suitable reactive functional derivative of a sulfonic acid of the general formula VI is, for example, a halide, fc in particular a chloride, or an anhydride of the general Formula VIa,

S0 ₂ ) ₂ 0 (VIa)

in which X ^{1 has} the meaning given under formula VT «

The reaction is preferably carried out in the presence of an inert organic which is miscible or immiscible with water Solvent in the presence or absence of water. Suitable inert organic solvents are, for example, carbon

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1S12849

hydrogen »such as benzene, toluene or xylene :, ethereal Liquids such as ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride and lower Ketones, such as acetone or methyl ethyl ketone. It is beneficial to add an acid-binding agent to the reaction solution .. As such are, for example, inorganic bases or salts, followed by are listed in the first procedure. Furthermore organic bases such as pyridime, trimethyl- or triethylamine, Ιί, Ιί-diisapropylethylamine or collidine, use those added in excess, also as solvents can be used.

The radical X ', 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 ¹ in the free amino group e, which the reaction product in a compound of the general; Formula I converted can also be carried out as set out for the radical X in the description of the first process.

Compounds, for example, can be used as starting materials for the process of the general formula VII are used, their Symbols R, and Rp match the groups that follow on formula I are listed.

A group of starting materials of the general formula VII are 2-amino-4-methyl - and ^ -

2-imidazolines, which are substituted in the 1-position by the radical R-. The IR, -2-amino-4-methyl-2-imidazolines mentioned can be obtained, for example, as follows; The starting point is 2-chloro-propionyl chloride and this chloride is reacted with primary amines of the formula HpU-R- to form N-R_ ~ 2 ~ chloropropionamides; these amides give with benzylamine NR -, - (2-benzylamino) -propionaraide _f which with lithium

12 ·

aluminum hydride "to N -R -, - N -benzyl-l ^ -propanediamines be reduced; the reduction products can be converted into the corresponding ones with palladium carbon and hydrogen N-R - debenzylate 1,2-propanediamines, which deal with Condense cyanogen bromide with ring closure. Homologues 1-R -, - 2-amino-4-ethyl-2-imidazolines can be prepared analogously starting from 2-chlorobutyryl chloride via the Intermediates N-R ^ -2-chloro-butyramide, N-R.-2-

1 2
benzylamino-butyramides, If -R.-N -benzyl-1,2-butanediamines and N -R.-1-4 -butanediamines.

Another group of starting materials of the general formula VII are 2-amino-5-methyl- as well as 2-Amino-5-ethyl-2-imidazoline, which in the 1-position by

the radical R 1 are substituted. The 1-R -, - 2-amino-5-methyl-2-imidazolines mentioned can be prepared, for example, from 2-chloro-propionyl chloride. For example, this carboxylic acid chloride is reacted with benzylamine to give N-benzyl-2-chloropropionamide, which with primary amines of the formula ELN-R, N-benzyl-2- (R, -amino) -propionamide gives these amides are reduced with Lithiumalum'iniumhydrid to N -Benzyl-N »R ₁ -l, 2-propan.diaminen, which with hydrogen in the presence of a catalyst

N -R ^ .- l, 2-propanediamines are debenzylated and Finally, the diamines obtained are condensed with cyanogen bromide and cyclized.

The compounds of general formula I obtained by the process according to the invention are then, if desired, converted into their salts with inorganic and organic acids. These salts are prepared, 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 solvent _p such as s * B. Methanol, ethanol, diethyl ether, chloroform or methylene chloride.

809840/1741

For use as medicinal substances, their pharmaceutically acceptable salts with acids can be used instead of the free compounds of the general formula I. Suitable addition salts are, for example, salts with hydrochloric acid. Hydrobromic acid. Sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid * ß-hydroxyethanesulfonic acid, acetic acid * lactic acid _; . Oxalic acid »succinic acid, fumaric acid _s maleic acid * malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenyl-p acetic acid. Mandelic Acid and Emboxylic Acid =

The new active ingredients are preferably administered orally. The daily doses range between 100 and 500 mg for adult patients of normal weight general formula I ₀

To produce them, one combines the active ingredient Z ₀ B.

k with solid, powdery carriers, such as lactose, sucrose, sorbitol, mannitol; Starches such as potato starch, corn starch or - amylopectin, also laminaria or Citruspulpenpulver? Cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or calcium stearate or poly -.-;., Ethylene glycols of suitable molecular weights to form tablets or dragee cores. May contain talc and / or titanium dioxide>. or with one

38 4 0 / $ 174

,. 15 -

Varnish dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, Z ₀ B ₀ to indicate different doses of active ingredients.

As a further oral unit dose form, push-fit capsules made of gelatin as well as soft, closed capsules made of gelatin and a plasticizer. Such as glycerine lubricants _s such as talc or magnesium stearate, and optionally Stabiiisatoren _s as Natriu2imetabisulfit (Na ^ S ^ opj or ascorbic acid "is in weienen capsules DER active compound, preferably in geeigTieten liquids, such as liquid Folyäthylenglykolenr, which stabilizers may also be added dissolved or suspended s"

The following regulations are intended to explain the manufacture of tablets and coated tablets in more detail?

a) 1000 g of l-sulfaralyl ^ 2 ^ imino-> tert.butyl-4-methyl- ± iddazolidin are mixed with 500 g of lactose and 270 g of potato starch, the mixture is _{moistened with an aqueous solution of 8% of} 0 g of gelatin and Granulated through a sieve »After drying, add 60.0 g of potato starch _f 60> 0 g of talc» 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide and press the mixture into 10,000 tablets, each weighing 200 mg 100 mg active ingredient content} which, if desired, can be provided with partial notches for finer adjustment of the dosage.

b) From 1000 g l-

methyl-imidazolidine, 345 g of lactose and the aqueous solution of 6.0 g of gelatin, granules are produced which, after drying, are mixed with 10.0 g of colloidal silicon dioxide, 40.0 g of talc, 40.0 g of potato starch and 5, Mix 0 g of magnesium stearate and ^{press into 10 1} 000 coated tablets. These are then with a concentrated syrup of 533.g crystall. Sucrose, 20.0 g shellac, 75% gum arabic, 25% talc, 20 g colloidal silicon dioxide and 1.5 g color coated and dried. The coated tablets each weigh 240 mg and each contain 100 mg of active ingredient.

c) Around 1000 capsules with 100 mg active ingredient content each prepare, mix 100 g of l-sulfanilyl-2-imino ~ 4-butyl- ■ 5-ethyl-imidazolidine with 173.0 g of lactose, the mixture evenly moistened with an aqueous solution of 2.0 g Gelatine and granulate it through a suitable sieve (e.g. Sieve III according to Ph.HeIv. V). The granulate is mixed with 10.0 g dried corn starch and 15.0 g talc and fill it evenly into 1000 hard gelatine capsules in size 1.

The following examples explain the production of the new compounds of general formula 1 and from so far Intermediate products not described in more detail, but are by no means the only embodiments of the same. The temperatures are given in degrees Celsius.

example 1

a) 32.7 g of N ^ -Cl-methyl-a-tert-butylamino-ethyl) -

N -acetyl-sulfanilamide in 100 ml of 2-n. Dissolved sodium hydroxide solution and treated with 10.6 g of cyanogen bromide while cooling at 20-30 °. The crude product immediately precipitates in crystalline form. It is suction filtered after 30 minutes and recrystallized from Ν, Ν-dimethylformamide. The 4 '- (2-imino-3-tert-butyl-5-methyl-imidazolidinl-ylsulfonyl) -acetanilide obtained melts at 243-244 °.

b) To 125 g of 50% sulfuric acid heated to 40 °, 35.2 g of the acetanilide obtained according to a) are added with stirring given. The mixture is heated to 50 ° for 2 hours and the solution is then poured into 750 ml of water with stirring. That The crude product precipitates as a sulfate. The pH of the reaction mixture is 10-n. Sodium hydroxide solution adjusted to 6.3. The mixture dissolves except for a small amount of contamination; it is stirred with 2 g of activated charcoal for 15 minutes and cleaned over Hyflo (purified Diatomaceous earth) filtered. One sets the filtrate with 10-n. Caustic soda alkaline. The crude product precipitates. It is filtered off, washed with water, dried at 90 ° and recrystallized from ethyl acetate. The 1-sulfanilyl-2-imino-3-tert-butyl-5-methyl-imidazolidine obtained melts at 145-146 ° ...

: -'- · ■ - c) is obtained from the mentioned under a) gangs compound such folgtt A solution of 23.3 g of N ^ -Aoetyl-sulfanilylchlorid in 70 ml of acetone under Bühren at -10 to 0 ° to ^Q. 5.6 g of 2-methyl-aziridine were added dropwise to 30 ml of 4- _no sodium hydroxide solution.

909840/174 "-,:

The reaction mixture is stirred at 0 for a further 2 hours then pour it onto 400 ml of ice water. The suspension obtained is filtered off, the precipitate, the crude 4- (2-methyl-aziridin-1-ylsulfonyl) acetanilide, washed with water and processed immediately, as it polymerizes easily,

d) The acetanilide obtained according to c) is dissolved in the cold in 100 ml of dioxane and 15 ml of water and added dropwise Solution 100 ml of tert-butylamine. Then the reaction mixture Boiled under reflux for one hour and the excess tert-butylamine and the dioxane are distilled off. One crystallizes the crystalline residue from ethyl acetate, after which the pure IT'-Cl-methyl-2-tert-butylamino-ethyl) -N acetyl-sulfanilamide melts at 93-95 °.

909840/1741

Example 2 "

a) Analogously to Example 1 a) is obtained starting from 28j 5 g of N - (1-methyl-2-methylamino-ethyl} -N-aoetyl-sulfanilamide (Crude product) with 10.6 g of cyanogen bromide the 4 '~ (2-Jmino-3y5-dimethyl-iinidazolidin-1-ylsulfonyl) -aetanilide of melting point 258-260, of which 31.0 g analogously to Example 1 b) with 125 g of 50% sulfuric acid to the end product l-sulfanilyl-2-imino-3,5-dimethylimidazolidine of m.p. 196-197 ° are hydrolyzed.

b) Me starting substance of a) is obtained analogously Example 1 c) from 25.4 g of 4 '- (2-methyl-aziridin-1-ylsulfonyl)> acetanilide (See. Example 1 c) and 200 ml of 33 ^^ β6Πΐ methylamine in ethanol.

S0 Ii mi ti u

Is it oil?

a) Starting from example la) one obtains;

29.9 g of N - (1-methyl-2-ethylamino-ethyl) - = IT-acetyl-sulfanilamiS (Crude product) with 10.6 g of cyanogen bromide 4 '- (2-imino-3-ethyl-5-methyl-imidazolidin-1-ylsulfonyl) acetanilide vom E! mp «229-23Ö, of the 32.4 g analogous to Example I b) with 125 g of 50 ^ -iger sulphuric acid to the end product l-sulfanilyl-2-imino-3-ethyl-5-methyiimidazolidine to be hydrolyzed »

b) The output sula of a) is obtained analogously Example 1 c) from 25.4 g of 4- (2-methyl-aziridin-1-ylsulforiyl) acetanilide (see. Example ί c) and 250 ml 2Ö? 5-igem Äethylamiii in benzene.

909840 / 1H8

Example 4

a) Analogously. Example 1 a) is obtained starting from 31-5 g of N - (1-Kethyl-2-propylaraino-ethyl) -N -acetyl-sulfanilamide from Smpο 162-163 with. 10.6 g of bromoyane das 4 '- (2-imino-3-propyl ~ 5-methyl-imidazolidin-1-ylsulfonyl) acetanilide of melting point. 254-255 °> of the 33.8 g analogous to example 1 b) with 125 g 50% Sulfuric acid to the end product

methyl-imidazolidine with a melting point of 146-148 ° can be hydrolyzed.

b) The starting substance of a) is obtained analogously to Example Ic) from 25.4 g of 4 ¹ - (2-methyl-aziridin-1-ylsulfonyl) acetanilide (cf. Example 1 c) and 100 ml of propylamine.

909840/1748

Example 5

a) Analogously to Example 1 a), 32.7 g of N - (1-methyl-2-butylamino-ethyl) -N -acetyl-sulfanilamide are obtained starting from 32.7 g of m.p. 166-167 ° with 10.6 g of Bromcyaii das 4 '- (2-imino-3-butyl-5-methyl - Imidazolidin-1-ylsulfonyl) -aeetanilid of melting point. 243-244 °, of which 35.2 g as in Example 1 b) with 125 g 50 $ - iger sulfuric acid to the end product l-9ulfanilyl-2-imino-3-butyl-5-methyl-imidazolidine of m.p. 125-126 are hydrolyzed.

b) The starting substance of a) is obtained analogously Example 1 c) from 25.4 g of 4- (2-methyl-aziridin-1-ylsulfonyl) acetanilide (see. Example Ic) and 100 ml of butylamine.

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191284t

Example 6

a) Analogously to example la) one obtains starting from

1 , - ■ ■: ν ■ ■ i

32.7 g of N- (1-methyl-2-s ek "tratylamine-3-ethyl) -N -acetylsulfanilamide of melting point 118-120 with 10.6 g of cyanogen bromide the 4 ^r - (2-ίmino-3-secobutyl -5-methyl-i] nidazΌl · idin-l-ylsυlfΌnyl) -acetaniliö of melting point> 242-244, of which 35 ^ 2 g as in Example 1 b) with 125 g of 50% sulfuric acid to the end product 1-sulfanilyl-2 -imino-3-sec "" butyl-5-methyi-imidazoiidi-n can be hydrolyzed by Ömp "194-195.

"b) The starting substance of a) is obtained analogously Example 1 c) from 25.4 g of 4 '- (2-methyl-aziridin-i-yisulforiyl) -acetanilide (cf. Example 1e} and loo ml sec »butylamine.

Example 7

a) Analogous to example la) one obtains starting from. 34.1 g of N ~ (1-methyl-2-pentylamino-ethyl) -K -acetyl-sulfanilamide (Crude product) with 10.6 g of cyanogen bromide 4 '- (2-imino-3-pentyl-5-methyl - imidazolidin-1-ylsulfonyl) acetanilide of m.p. 228-229 ». of the 36 * 4 g as in Example 1 b) with 125 g of 50% sulfuric acid to the end product l-sulfanilyl ^ -imino - ^ - pentyl-S-methylinidazolidine from M.p. 127-128.

b) The starting substance of a) is obtained analogously Example 1 c) from 25 »4 g of 4M2-methyl-aziridin-1-ylsulfonyl) acetanilide (see. Example Ic) and 100 ml of pentylamine ,,

90 9 840 / 1U8

_ 25 _ '

Example 8

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

1 4

35.1 g of N - (1-methyl-2-cyclohexylamino-ethyl) -N -acetyl-sulfanilamide (Crude product) 4 '- (2-imino-3-cyclohexyl-5-methyl-imidazolidin-1-ylsulfonyl) acetanilide with 10.6 g of cyanogen bromide vom Srap «235-237, of which 37.6 g analogous to Example Ib) with 125 g of 50% sulfuric acid to the end product ■ 1-sulfanilyl-2-imino-3-cyclohexyl-5-methyl-imidazolidine be hydrolyzed by Smpo 217-218-

b) The starting substance of a) is obtained analogously to Example 1 c) from 25.4 g of 4 '- (2-methyl-aziridin-1-ylsulfonyl) acetanilide (see. Example Ic) and 100 ml of cyclohexylamine.

909840/1748

Example 9

a) Analogously to example la), starting from 3 ^, 9 g of N ¹ - / tr ^/ iethyl-2- (3-Gyclohexen-l-ylamino) -äthyl7-N acetyl-sulfariilar: .id vom Sm ^. 139-1 ^ 1 in it 10.6 g bromine cyan the 4 '- / 2 -Im in ο - ^ - (p-cyclohexen-1-yl) -5-methyl-iraidazolidin-lylsulfonyl7-acetanilid of m.p. 270 -271 °, from the 37Λ Ζ analogously to example ic) with 125 g of 50 / ^ sulfuric acid initially final product l-sulfanilyl-2 "imino-3-O-cyclohexen-1-yl) -5-niethylimidazolidin of mp. 203-209 ° be hydrolyzed.

b) The initial value of a) is obtained analogously to Example 1 c) from 25.4 g of 4 ^t - (2-methyl-aziridin-1-ylsulfonyl) acetanilide (cf. Example Ic) and 100 ml (3-cyclohexene-1 -yl) -amine.

c) Furthermore, analogously to Example la), 1-sulfanilyl-2-imino-; 5-tert-butyl-4-methyl-imidazolidine with a melting point of 178-180 ⁰ (from isopropanol) and l-sulfanilyl-2-3 jnino-3 butyl-5'-aethylimidazolfäin of mp. I6I-I63 ⁰ produced.

909840/1748

Example 3-0

a) Analogously to Example Z a), starting from 32.7 g of N ¹ - (1-methyl-2-tert-butylamino-ethyl) -N ⁴ -acetylsulfanilamide of melting point 93-95 (from ethyl acetate) with 6.5 g Cyanogen chloride or, with 11.9 g of phenyl anate instead of cyanogen bromide, the 4 '- (2-imino-3-tert-butyl ~ 5-methyl-imidazQlidin-1-ylsulfonyl) -acetanilind of melting point 243-244 (from ^^ - Dimethylformamide), of which 35.2 according to Example 1 b) to the end product 1-sulfanilyl-2-imino-3-tert.butyl-5-methyl- ^ iiaidaaolidin from Sjap. 145-146 (from ethyl acetate) are hydrolyzed.

b) The starting substance of a) is obtained according to Example 1 c - d) from 24.0 g of 4 ^l - (2-methyl-aziridin-l-ylsulfonyl) acetanilide and 100 ml of tert "butylamine".

909-840 / 1748

Example II '

A solution of 14.6 gtert butylamine in 100 ml of abs. Ether is stirred at -10 ° to -5 ° within 30 minutes with a solution of 10.6 g of cyanogen bromide in 50 ml of abs. Aether displaced. The reaction mixture is stirred for a further 30 minutes and filtered the precipitated tert. Butylamine hydrobromide. away* The filtrate, in which the tert-butylcyanamide obtained is dissolved, with further cooling with a suspension of 2.8 g of sodium hydride in 40 ml of abs. Ether. You stir them Suspension, which is further cooled to the same temperature, for another 30 minutes and then adds to the resulting, suspended Sodium derivative of tert-butyl cyanamide 25.4 g of 4 '- (2-methylaziridin-1-ylsulfonyl) acetanilide to. The mixture is warmed to room temperature and stirred for 15 hours at this temperature. The reaction mixture is then slowly added 2-n. Hydrochloric acid and separates the two arias. the acidic, aqueous phase is washed twice with ether, cleaned with activated charcoal, filtered and concentrated at 0 ° with conc. Caustic soda made alkaline. The precipitated 4 '- (2-imino-3-tert-butyl-5-methyl-imidazolidin-1-ylsulfonyl) acetanilide is filtered off and it crystallizes from chloroform-ethanol, after which it melts at 238-240 °.

Acetanilide obtained Da3 is according to Example 1 b) for 1-Sulfanily 1-2 - ^^ 0-3-tert-butyl-5-methyl-imidazolidine vom M.p. 145-146 ° hydrolyzed.

909840 / 17ii

Example 12

Analogous to example 11 one obtains:

a) from 14.6 g of butylamine, in 100 ml of ether with 10.6 g Cyanogen bromide butylcyanamide, which with 2.8 g of sodium hydride. is converted into the sodium derivative in 40 ml of ether; this gives with 25.4 g of 4 '- (2-methyl-aziridin-1-ylsuifonyl) -ac etanilide 4 '- (2-imino-3-butyl-5-methyl-imidazolidin-lylsulfonyl) -acetanilide from m.p. 243-244 »which analogously to Example 1 b) to the l-sulfanilyl - ^ - imino ^ -butyl - ^ - methylimidazolidine is hydrolyzed from m.p. 125-126 °;

b) from 17.4 g of pentylamine in 100 ml of ether with 10.6 g Cyanogen bromide the pentylcyanamide, which with 2.8 g of sodium hydride is converted into the sodium derivative in 40 ml of ether; this gives with 25.4 g of 4 '- (2-methyl-aziridin-1-ylsulfonyl) -> acetanilide 4 '- (2-imino-3-pentyl-5-methyl-imidazolidin-lylsulfonyl) -acetanilide from m.p. 228-229 °, which analogously to Example Ib) for 1-i

imidazolidine of m.p. 127-128 ° is hydrolyzed;

c) from 19.6 g of 3-cyclohexen-1-ylamine in 100 ml of ether with 10.6 g of cyanogen bromide (3-cyclohexen-1-yl) cyanamide, which is mixed with 2.8 g of sodium hydride in 40 ml of ether Sodium derivative is converted; with 25.4 g of 4 '- (2-methylaziridin-1-ylsulfonyl) -acetanilide, this gives 4 ^l - [2-imino-3- (3-cyclohexenl-yl) -5-methyl-imidazolidin ~ l-ylsulfonyl] -aeetanilid of melting point 270-271 °, which analogously to Example 1 b) to 1-sulfanilyl-2-imino-3- (3-cyclohexen-1-yl) -5- "methyl-imidazolidine of melting point.

909840/1741
208-209 ° is hydrolyzed jf. . !

d) from 19 * 8 g of cyclohexylamine in 100 ml of ether with 10.6 g of cyanogen bromide cyclohexyl-cyanamide, which is converted into the sodium derivative with 2.8 g of sodium hydride in 40 ml of ether; With 25.4 g of 4 ¹ - (2-methyl-asiridinl-ylsulfonyl) -acetanilide this gives 4 '- (2-iniino-3-cyclohexyl-5-diethylimidazolidin-1-ylsulfonyl) -acetanilide with a melting point of 235-237 °, which is hydrolyzed analogously to Example 1 b) to l-sulfanilyl-2-imino-3-cyclohexyl-5-methyl-imidazolidine vcm melting point 217-218.

e) from 14.6 g of sec-butylamine in 100 ml of ether with 10.6 g of cyanogen bromide, butyl cyanamide, which is converted into the sodium derivative with 2.8 g of sodium hydride in 40 ml of ether; this provides 25 ₅ 4 g of 4 '- (2-methyl-aziridine-l-ylsulfonyl) acetanilide the 4 ^f - (2-Iming-j3-sec-butyl-5-methyl-iinidazolidinl-ylsulphonyl) acetanilide, mp 242-244, which is hydrolyzed analogously to Example 1 b) to l-sulfanilyl-2-imino-3-sec.butyl-5-methylimidazolidine with a melting point of 194-195 °, and '

f) butylcyanamide from 14.6 g of butylamine 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 26.8 g of 4 ^l - (2-ethyl-aziridin-1-ylsulfonyl) -acetanilide, this gives 4 '- (2-imino-3-butyl-5-ethyl-imidazolidin-1-ylsulfonyl) -aeetanilide (crude product ) of m.p. 107-111, which is hydrolyzed analogously to Example 1 b) to l-sulfanilyl ^ -iminoO-butyl ^ -ethyl-imidazolidine of m.p. 16l-16j5 °;

9098 ^ 0/1748

Example 13

33.5g 1-sulfanilyl ~ 2-imino-3- (3-cyclohexen-1-yl) -5-methyl-imidazolidine are in 350 ml of dioxane with 5 »0 g 5 # palladium carbon at room temperature and normal pressure hydrogenated. After the hydrogen uptake has ended, will filtered off from the catalyst and the filtrate evaporated. 1-sulfanilyl ~ 2-imino-3-cyclohexyl-5-methyl ~ is obtained imidazolidine of m.p. 217-218 (from methanol).

909840/1748

Example 1 4

a) 31 »0 g of crude N -tert.Butyl-l ^ -propanediamine dihydrobromide be, with a solution of 13.2 g of cyanogen bromide in 220 ml of ether are added. A solution of 11.4 g of sodium carbonate is added in portions to this mixture over the course of 5 minutes in 88 ml of water. The suspension obtained is stirred for 15 hours at room temperature and left to stand for 2 days. One separates the aqueous layer containing the l-tert-butyl ^ -amino ^ -methyl-2-imidazoline contains, of the ether solution and dilutes the aqueous phase with water to remove the precipitated sodium bromide to dissolve.-The aqueous solution is mixed with one of 23 »8 g of IT-Acetyl-sulf anilylchloride in 220 ml of acetone and also with a solution of 8.8 g of sodium hydroxide in 44 ml Water. The mixture is then refluxed for 30 minutes boiled, cooled, the precipitated crude product filtered off and recrystallized from Ohloroform ethanol. You get the 4 * - (2-imino-3-tert-butyl-5-methyl-imidazolidin-1-ylsulfonyl) acetanilide of melting point 238-240 °,

, "- ': -: - ■:'.".;)?) - 35.2 g of the acetanilide obtained according to a) are in 180 ml of 8-n. Dissolved ethanolic hydrochloric acid and this solution was left to stand for 2 days at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is filtered off and made alkaline with sodium hydroxide solution. The precipitated crystals are filtered off, washed with water and recrystallized from acetone-methanol, after which the 1-sulfanilyl-2-imino-3-tert-butyl-5-methyl-imidazolidine

melts at 145-146 °,

909840/17 ^ e

The starting product of a) can be produced as follows:

c) 16.35 g of N-tert-butyl-2-chloro-propionamide [cf. J.Am.Chem.Soc. 78, 6124 (1956)] and 25.0 g of benzylamine are heated to a bath temperature of 150-170 ° for 3.5 hours. Au3 Crystals precipitate out of the solution, which is initially homogeneous. The reaction mixture is cooled and 150 ml of 2-n are added. Caustic soda and chloroform too. The organic phase is separated off, washed with water, dried and evaporated. One distills the residue. After a first run of benzylamine, the N-tert-butyl-2-benzylamino-propionamide is obtained from 123-125 ° / O, 03 Torr. The hydrochloride melts at 158-162 °.

d) To a suspension of 9.0 g of lithium aluminum hydride in 200 ml of abs. Tetrahydrofuran is added dropwise within 15 minutes a solution of 23.4 g of the amide obtained according to c) in 80 ml of abs. Tetrahydrofuran. The suspension is then refluxed for 38 hours. It will initially turn raspberry red and then gray again over the course of 30 minutes. The reaction mixture is cooled, the excess lithium aluminum hydride is destroyed while cooling with ethyl acetate, then with water and with methanol, and the suspension is evaporated. The gray residue is extracted twice with boiling chloroform for 30 minutes and filtered. The combined chloroform solutions are dried over sodium sulfate and evaporated. The remaining oil is distilled. The lr-tert-butyl-N ² -benzyl-1,2-propanediamine distills at 72-86 ° / 0.005 Torr.

909840/1748

'- 34 -

191284%

e) 22.0 g of the amine obtained according to d) in 440 ml of distilled ethanol are mixed with 34.0 g of 48% pure hydrogen bromide and 8.8 g of 5 ° - ± ger palladium carbon and hydrogenated at room temperature and normal pressure. After 95% of the calculated amount of hydrogen have been absorbed, 8.8 g of 5% palladium carbon are added and hydrogenation is continued. After 17 hours the reaction mixture has taken up 98% of the calculated amount of hydrogen. The catalyst is filtered off, washed with ethanol and the filtrate is evaporated. The residue, the F ^ -tert.Butyl-l ^ -propanediamine dihydro- bromide is used as the crude product.

909840/1748

Ex iel_ ^15:::.

a) Analogously to Example 14 a-b) the following end product is obtained:

From N-butyl-1,2-propanediamine and cyanogen bromide l-butyl-2-amino-4-methyl-2-imida, zolidine hydrobromide (crude product), which with N-acetyl-sulfanilyl chloride the 4 '- (2-imino-3-buty3.-5-methyl-imidazolidin-1-ylsulfonyl) -acetanilide of m.p. of m.p. 125-126 results.

The starting product is leqjha ^ en as follows :. "; _: , ■■ ^ _,

b) One drips inside with good ice cooling

30 minutes 12.7 g of 2-chloropropionyl chloride η-20-at oleoroform to a solution of 16, -1 g of butylamine in 50 ml of GhIo röf ο im ^ The solution obtained is left to stand for 15 hours at room temperature, then washed several times with water -e -organic ■ phase -separated. Ma.fi dries the organic -pice ¹ over- ■ sodium sulphate "and evaporates it. Back blefbl-d'as-'röne H-butyl -2-chloro-propionamide.

c) Analogously to Example 14 c-e) is obtained starting from crude amide from b) via the intermediates N-butyl-2-benzylamino-propionamide of bp 151-154 ° / 0, 005 Torr and N-butyl-N benzyl-1,2-propanediamine with a boiling point of 98-104 ° / 0.04 Torr, 1,2-propanediamine.

909840/1748

Example 1 6

a) The following end product is obtained analogously to Example 14 a-b):

From IT -butyl-1,2-butanediamine (crude product) with

Cyanogen bromide l- butyl-2-amino-4-athyl-2-im.idasolin-dihydrobrora.id (Crude product), which with N-acetyl-sulfanilyl chloride the 4 '- (2-Imino-3-butyl "5-ethyl-imidazolidin-1-ylsulfonyl) -acetanilide (Crude product) of melting point 107-111 supplies, which leads to the l-sulfanilyl-2-imino-3-butyl-5-ethyl-imidazolidine from M.p. 161-163 is hydrolyzed.

The starting compound of a) is prepared as follows:

b) Analogously to Examples 15 b) and 14 c-e), starting from 2-chloro-butyryl chloride, the intermediate products are obtained N-butyl-2-chlorobutyramide (crude product), N-butyl-2-benzylaminobutyramide (Crude product) and N -butyl-N -benzyl-1,2-butanediamine (Crude product) N-butyl-1,2-butanediamine.

909840/174

Example 1 7

a) 23.6 g (0.1 mol) of 1-tert-butyl-2-aniino-5-methyl-2-imidazoline hydrobroride Werden.in 100 ml of water and 21.8 g (0.1 mol) of N-acetyl-sulfanilyl chloride added in 200 ml of acetone. A solution of 10.0 g of sodium hydroxide is then added dropwise over the course of 10 minutes 40 ml of water are added and the suspension obtained is refluxed for 45 minutes. The reaction mixture is then cooled and the acetone is evaporated off in vacuo. The residue is mixed with water and the precipitated oil is taken in methylene chloride on. The methylene chloride solution is dried over sodium sulfate and evaporated. The residue crystallizes one from methanol. The 4 '- (2-imino-3-tert-butyl-4-methyl-imidazolidin-1-yl) acetanilide obtained melts at 178-180

b) The reaction product obtained according to a) is analogous to Example 14 b) to l-sulfanil ^ -imino ^ -tert.butyl-4-methyl-imidazolidine hydrolyzed from m.p. 178-180 (from isopropanol).

The starting compound, das.l-tert-butyl-2-imino-5-methyl-2-imidazolidine, can be made as follows:

c) 12.7 g of 2-chloro-propio}> yl chloride are in 50 ml Dissolved chloroform. The solution is added dropwise within 45 minutes to a solution of 22 g of benzylamine in 70 ml of Ohioroform, the reaction mixture is stirred for one hour at room temperature

909840/1748

and then adds v / ater. The benzylamine dissolves. One separates the chloroform solution and washes it with water. The aqueous phase is washed once with water and this aqueous phase extracted with chloroform. The combined chloroform solutions are dried over sodium sulfate and evaporated. The residue is crystallized from methylene chloride-cyclohexane, after which the F-benzyl-2-chloro-propionamide melts at 74-76 °.

d) 19.75 g of the amide obtained according to c) are dissolved in 20 g of tert-butylamine and the resulting solution in Autoclave heated to 150 for 3.5 hours. Then the reaction mixture is diluted with ether and water. Separate the organic Phase off and extract it several times with 6-n. Hydrochloric acid. The aqueous phases are combined and under Cooling with conc. Sodium hydroxide solution made alkaline. The oil which precipitates is extracted with ether, the ethereal solution dried over sodium sulfate and evaporated. The remaining N-benzyl-2-tert.butylamino-propionamide is

distilled in a high vacuum, boiling point 119-12O ° / O, O1 Torr.

e) 23.4 g of the amide obtained in d). in 50 ml abs. Dissolved tetrahydrofuran. The solution is added dropwise to a suspension of within 30 minutes with cooling 9 g lithium aluminum hydride in 170 ml abs. Tetrahydrofuran and the suspension is refluxed for 39 hours. That The reaction mixture is cooled with 9 ml of water, 18 ml of aqueous

909840/1741

15/5 sodium hydroxide solution and 27 ml of water drop by drop offset. The resulting precipitate is filtered off, the filtrate is evaporated in vacuo and the residue is distilled

1 2

was under high vacuum. The resulting N -Benzyl-N -tert.butyl-1,2-propanediarnine boils at 74-80 ° / 0.01 torr.

f) 22 g of the diamine obtained according to e) are dissolved in 220 ml of ethanol. 34 g of pure conc. Hydrobromic acid and 5 g of 5% palladium carbon. Man hydrogenates the mixture with hydrogen at atmospheric pressure and room temperature. Two additions are made during the hydrogenation 3 g of palladium carbon each. After the hydrogen uptake has ended, the catalyst is filtered off and it is evaporated

Filtrate in vacuo. The crude oily N-tert-butyl-1,2-propanediamine hydrobromide obtained 12.7 g of cyanogen bromide in 150 ml of ether are added. Add to the suspension obtained a solution of 11 g is added dropwise over the course of 15 minutes Sodium carbonate in 50 ml of water. The OeI dissolves with the formation of carbon dioxide. The mixture is 15 hours at Room temperature stirred. The aqueous phase, which contains the crude 1-tert-butyl-2-amino-5-methyl-2-imidazoline, is used in a).

909 8 40/1748

Claims (1)

Patent claims 1. Process for the preparation of new derivatives of the sulfanilamide of the general formula I, MR, Γ
\ II. CH CH- N - I. i SO ₂ II (I) in which . R- is an alkyl or alkenyl group of at most 5 carbon atoms or a cycloalkyl or cycloalkenyl group of at most 7 carbon atoms and Rp denotes the methyl or ethyl group. and their addition salts with inorganic or organic Acids, characterized in that one is a compound of the general formula II, (II) in which and R _{2 have} the meaning given under formula I, Hydrogen, the methyl or allyl group or a Arylmethyl-, diarylmethyl- or a triarylmethyl- * group and 909840/1740 X one by hydrolysis or reduction into the free Amino group convertible. Means remainder or, if R, is hydrogen, also means the free amino group, Reacts and cyclizes with a reactive gyanoic 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. 2. Modification of the method according to claim 1, characterized characterized in that a compound of the general formula III, .OH - R ₀ / W ' ² (III) in which R2 has the meaning given in claim 1 under formula I and
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, (IV) in which R has the meaning given in claim 1 under formula I, or condenses and cyclizes with an alkali metal or alkaline earth metal derivative of such a compound, if necessary, the reaction product is hydrolyzed or reduced to convert the group X into the free amine group, and optionally The obtained compound is converted into an addition salt with an inorganic or organic acid. 3. Modification of the method geiaäss claim 1, characterized in that one compound of the general Formula V, (V) in what R _? has the meaning given in claim 1 under formula I,
R 'is an alkenyl group of 3-5 carbon atoms or a Cycloalkenyl group of 5-7 carbon atoms and X denotes the amino group or a radical which is through Hydrolysis or reduction-in the free amino group- ■ ■. can be led, reduced and optionally leads a compound obtained with an inorganic or organic acid into an addition salt, I . 4 · Modification of the method according to claim l _f thereby ■ ■ '■' ■ ■ ■ - "vf characterized daaa a reactive functional derivative of a sulfonic acid of the general formula VI, " 9098A0 / 1 748 in which X 'one. Remainder means that by hydrolysis, reduction or reductive cleavage converted into an amino group can be, with a compound of the general formula VII, • ^CH RR (VII) H .CH in which R, and R _? have the meaning given in claim 1 under formula I, the reaction product is hydrolyzed or reduced to convert the group X into the free amino group and, if desired, the compound obtained is converted into an addition salt with an inorganic or organic acid. 5. Compounds of the general formula I given in claim 1, in which R 1 and R _{2 have} the meaning given there, and their addition salts with inorganic or organic acids. 909840/1749