DE2360027A1 - SPIRAL COMPOUNDS, METHOD OF MANUFACTURING THEM AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

Dr. Hans-Heinrich Willraih

Dr. Dieter Weber Dipl.-Phys. Klaus Seiffert

PATENT LAWYERS

D-62 WIESBADEN 27 NOV. 1973 P.O. Box 1327

Gustav-Freytag-Strasse £ 5 @ (06.121) 372720

Telegramraadressei VILLPATENT

LA 357-1

Astra Läkemedel Aktiebolag, Kvarnbergagatan 16, S-151 85 Södertälje

Spiro compounds, method for their Manufacture and medicines containing them

Priority: Patent application No. 15936/72 dated December 7, 1972 in Sweden

The invention relates to new compounds of the spiroamine type and Process for their manufacture. The invention also relates to pharmaceutical preparations which contain such compounds and methods for the pharmacological use of the compounds.

The main object of the invention is to obtain compounds having antidepressant properties and tranquilizing properties.

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A compound that is commonly used for depression control is imipramine

This connection is both mood-lifting and psycho-motive.

she

rically activating, but has several serious disadvantages. It is anticholinergic and causes anticholinergic symptoms such as dryness of the mouth, tremor, tachycardia and sweats. At higher doses it can cause serious cardiac arrhythmias, and at normal doses it can be toxic Cause disturbances in people with heart defects. Also, another disadvantage is treatment with imipramine the late onset of the antidepressant effect, which can only be observed after three weeks of treatment.

To the above mentioned disadvantages in the treatment of depression to overcome, is proposed according to the present invention, one or more of the following compounds or their to use pharmaceutically acceptable salts:

II

CH ₂ NHCH

III

CH ₂ N (CH

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CH ₂ KH ₂

VII

CH ₂ NHCH,

N (CH ₃ ) ₂

CHoNKCH.

VIII CH ₉ N (CH 1).

-CH ₂ N (CH ₃ )

IX

XI

The compounds described above that have an asymmetric
Containing carbon atoms exist as optically active forms and can be separated into their optical antipodes by methods known per se, for example by using optically active acids such as tartaric acid, camphor-10-sulfonic acid, dibenzoyl tartaric acid, etc.

The compounds described above can be used as mixtures of the mentioned isomeric forms or in the form of pure isomers will.

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Both organic and inorganic acids can be used to make non-toxic, pharmaceutically acceptable acid addition salts of the compounds of the invention. Examples of such acids are sulfuric acid, nitric acid, Phosphoric acid, hydrochloric acid, citric acid, acetic acid, lactic acid, tartaric acid, pamoic acid, ethanedisulfonic acid, sulfamic acid, Succinic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid and benzoic acid. These salts are easy to subside produce known methods.

In clinical practice the compounds according to the present invention are used Invention normally administered orally or by injection in the 'form of pharmaceutical preparations containing the active Component either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, such as the hydrochloride, Lactate, acetate, sulfamate, or the like, in association with a pharmaceutically acceptable carrier.

Thus, if here of the new compounds according to the invention In each case, both the free amine base and the acid addition salts are used for the general term and in individual cases the free base be meant, unless the overall context in which these terms are used as in the specific examples, is incompatible with this broader meaning. The carrier can be solid, semi-rigid or liquid diluent or a capsule. These pharmaceutical preparations form another aspect of this invention. Usually the active substance makes up 0.1 to 95% by weight of the preparation, more specifically 0.5 to 20% by weight

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Preparations for injection and 2 to 50% by weight for preparations for oral administration.

For the manufacture of pharmaceutical preparations containing a compound according to the invention in the form of dosage units for oral Administration included, the selected compound with a solid, fine-grained carrier, such as lactose, sucrose, Sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin, and one Lubricants such as magnesium stearate, calcium stearate, polyethylene glycol waxes and the like are mixed and then compressed into tablets. If coated tablets are required, the Ker * * * * ne, which have been prepared as described above, are coated with a concentrated sugar solution, for example Gum arabic. Gelatin, talc, titanium dioxide and the like

contains. Instead, the tablet can also be coated with a lacquer dissolved in a volatile organic solvent or a mixture of organic solvents is. Coloring agents can be added to these coatings to easily distinguish between tablets of different active substances or different amounts of the active compound.

For the production of soft gelatine capsules (pearl-shaped closed Capsules), which consist of gelatin and, for example, glycerine, or similar closed capsules the active substance can be mixed with a vegetable oil. Hardness Gelatin capsules can contain granules of the active substance in combination with solid, fine-grained carriers such as lactose, saccharose

4G9824 / 10S7

se, sorbitol, mannitol, starch (such as potato starch, Corn starch or amylopectin), cellulose derivatives or gelatine.

Liquid preparations for oral administration may be in the form of syrups or suspensions, such as Solutions containing about 0.2 to 20% by weight of the active substance described herein, the remainder being sugar with a Mixture of ethanol, water, glycerine and propylene glycol. If necessary, such liquid preparations can also Colorants, flavor enhancers, saccharin and carboxymethyl cellulose Contained as a thickener.

Solutions for parenteral administration by injection can be prepared by using an aqueous solution a water soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of about 0.5 to about 10% by weight prepares. This solution may also contain stabilizing agents and / or buffering agents, and conveniently be withdrawn on ampoules with different dosage units. When it comes to therapeutic treatment, they are suitable daily dosages of the compounds according to the invention at 5 to 500 mg, preferably at 50 to 250 mg, for oral administration and 1 to 100, preferably 10 to 50 mg, for parenteral administration.

Manufacturing methods
A. Implementation of a compound of the general formula

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where η means 1 or 2? m is O or 1 and Z is hydro xyl group, a halogen atom such as a chlorine atom, or another acidic residue, like an acid anhydride group, is, with nitrogen- ' hydrochloric acid (HN-) or an inorganic salt thereof according to the Schmidt reaction to form a primary amine and, if a secondary or tertiary amine is desired, conversion of the primary amine thus obtained into the corresponding secondary or tertiary amine in a manner known per se.

This method is applicable to all compounds according to the invention.

B. Implementation of a compound of the general formula

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where m and η have the above meaning, with hypobromite or Hypochlorite according to the conditions of the Hofmann reaction with formation of a primary amine and, if a secondary or tertiary amine Amine is desired, conversion of the primary amine obtained in a manner known per se into the corresponding secondary or tertiary amine.

This method is applicable to all compounds according to the invention.

C. Implementation of a compound of the general formula

where D is ^ C = O or ^ CHM and where M is a reactive ester group, with a compound of the general formula

R ¹¹ '-N

where R is a hydrogen atom or a methyl group and R " ^{1 is} a hydrogen atom or an acyl or sulfonyl group, with formation of one of the compounds of the formulas IV or V

NHCH,

N (CH

IV

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This method can also be used for the production of those compounds of the invention which contain a methylene group between the amino nitrogen and the hydrogenated ring. In this case a compound of the general formula

in which η is 1 or 2 and D is -CHO or -CH ₂ M, in which M is a reactive ester group, ^{reacted with a compound of the general formula R 11} ^ NRR in which R ¹ ' ^{1 has} the above meaning and R and R ¹ are identical or different and each represent hydrogen atoms or methyl groups.

Illustrative examples of reactive ester groups are -Cl, -Br, -I or -OSO ₂ R ¹¹ F in which-K * ^{r is} a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, such as a methyl group, or an aryl group, such as the phenyl radical or Tolyl radical, means.

D. Reduction of a compound of the general formula

where S ^ C-NOR ", ^ C-NOCOR",> C = NOS0 ₂ R ", ^ C ^ CHNRCOR", ^ CHNRCOOR ¹¹ , ^ CHN,, ^ CHNO ₉ or ^ C = NNHR ' ^f and R and R ^f 'are as defined above, forming one of the compounds of the following formulas

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NHCH,

This method can also be used for the preparation of those compounds according to the invention which have a methylene group between the amino nitrogen and the hydrogenated ring. In this case becomes a compound of the general formula

ZcH ₂ 7 _n

where η denotes 1 or 2 and E -CH = NOR ", -CH = NOCOR ¹ ', -CH = NOSO ₂ R", -CH = NR, -CH ₂ NRCOR ¹¹ , -CH ₂ NRCOOR ¹¹ , "CH ₃ N ₃ , -CH ₂ NO ₂ , -CH = NNHR ¹¹ or = CHNO ₂ and R and R "have the above meaning, reduced.

E. Reduction of a carboxylic acid derivative with at least one nitrogen atom in the group derived from the carboxyl group, as shown in a simplified manner by the following formula:

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1) -

where η has the above meaning and X is N, O, S or nothing at all means.

Illustrative examples of the above formula are:

CONRR '

where η is 1 or 2 and R and R * are identical or different and each represent a hydrogen atom or a methyl group, and

The reduction of the compound of the last formula gives a primary Amine. If a secondary or tertiary amine is desired, the primary amine can be converted into the corresponding secondary or tertiary amine can be converted.

This method is limited to the preparation of those compounds according to the invention in which a CH ₂ group lies between the amino nitrogen and the hydrogenated ring.

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2 * 60027

F. Reduction of a compound of the general formula

in which m, n, R and R ^{1 have} the above meaning and in which the carbonyl oxygen is always in a vicinal or adjacent position to the side chain of the hydrogenated ring.

If you use an acyl derivative or the like as an intermediate with one of the methods A to F, hydrolysis is required to obtain the compounds of the invention.

Some of the above methods are reductive methods. Suitable reducing agents that can be used in these methods are hydrogen in statu nascendi (sodium and some alcohol, Zinc and acetic acid), catalytically activated hydrogen gas (Pb, Pd, Ni are suitable catalysts) and hydrides.

The following examples serve to further illustrate the invention.

example 1

HCHO

HCOOH

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0.26 g (O _r OOl mol) of the compound (1), 0.35 g formalin. (37%), 0.25 g of formic acid (98%) and 0.10 g of sodium formate were mixed with one another and heated on a bath (115 ° C.) for 3 hours. After cooling, 10 ml of 0.2 M NaOH were added and the mixture was extracted with 3 × 30 ml of ether. This was followed by washing with 15 ml of water and extraction with 3 × 50 ml of 0.2 M HCl. The combined water solutions were washed with 20 ml of ether. 25 ml of 2M NaOH were added and the solution was extracted with 3 × 50 ml of ether. Washing with 50 ml of water, drying (Na ₂ SO ^) and evaporation gave 160 mg of an oil. Yield 55% of theory. The hydrochloride and maleate of compound V are hygroscopic. The oxalate of compound V was recrystallized from 15 ml of 2-propyl alcohol. Yield 80 mg, m.p. = 214 to 215 ° C.

Example 2

LiAlH ^
ether

-NHCOOCH ₃

(2)

NHCH

IV

0.50 g of compound (2) were dissolved in 20 ml of dry egg ether. 0.15 g of LiAlH ₄ were added in portions with stirring. The mixture was refluxed for 2 hours. To destroy the excess hydride, 2 ml of saturated aqueous solution of Na ₂ SO. added. After filtering and washing

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see with 2 × 50 ml of ether, 50 ml of water were added. the Organic layer (A) was extracted with 3 × 30 ml of 0.2 M HCl. The water layer was washed with 20 ml of ether and made alkaline with 2 M NaOH. The extraction with 3 χ 50 ml of ether, Drying and evaporation gave 0.3 g of an oil. The organic layer (A) gave 0.2 g of non-basic material. The oil was dissolved in ether and crystallized as maleate, recrystallization from 25 ml of isopropyl ether gave 185 mg of compound IV, m.p. = 172 to 175 ° C.

Example 3
a)

SOCl,

^C 6 ^H 6

COOH

COCl

(3)

(4)

0.88 g of compound (3), 10 ml of thionyl chloride and 10 ml of dry Benzene was mixed together and refluxed for 1.5 hours. The excess thionyl chloride was in vacuo evaporated together with benzene. The remaining 1.3 g of a yellow oil did not crystallize. The oil was therefore made for the next level used.

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NH (CH ₃ ), ^C 6 ^H 5

COCI

CON (CH _x ),

(4)

(5)

1.0 ml of dimethylamine was dissolved in 25 ml of benzene. To this solution 0.9 g of the acid chloride (4) / were mixed at room temperature with 25 ml of benzene added. After stirring at 60 ° C. for one hour, the precipitated dimethylamine hydrochloride was filtered and the filtrate shaken with 40 ml of water. Drying and evaporation gave 1.1 g of an oil.

'Et ₂ O

(5)

CON (CH ₃ ),

CH ₂ N (CH ₃ ) _?

III

0.55 g of the above crude product was dissolved in 25 ml of dry ether, 0.20 g of LiAlH ₄ was added and the mixture was stirred at room temperature for 18 hours. The excess LiAlH ₄ was destroyed by adding 5 ml of saturated Na ₂ SO ₄ solution. The ether solution was decanted while washing twice with ether and extracted with 3 × 20 ml 0.2 M HCl. The aqueous layer

4038 2 4/10 87

was made alkaline with 10 ml of 2 M NaOH and extracted with 3 × 50 ml of ether. Drying (over Na ₂ SO ₄ ) and evaporation gave 0.47 g of an oil. 50 ml of ether dried over sodium was added and 4M HCl in ether was added dropwise to the stirred solution until no further precipitate was observed. After one hour the mixture was filtered. The hydrochloride (0.50 g) was crystallized from 8 ml of 2-propyl alcohol and gave 250 mg of compound III, m.p. = 124 to 127 ° C. Two further recrystallizations from 2-propyl alcohol gave a melting point of m.p. = 122 to 125 ° C.

Example 4

COCl 'L-CH ₂ NHCH ₃

(4) II

The acid chloride (4) (prepared from 3.6 g - 0.012
Mol - the acid in 30 ml of benzene, as described for the compound (4) of Example 3a) added. The mixture was stirred at 20 ° C. for 3 hours. Filtering off and washing the filtrate with water and working up gave about 4 g of a residue. This was rubbed with ether and dried, yielding 2.4 g
(64%) of N-methylspiro- / 5H-dibenzo- (a, d) -cyclohepten-5,1'-cyclopenta]! / - ^ ¹ -carboxamide, m.p. = 195 to 197 ° C. Addition of
2.3 g (0.076 mole) of this compound, dissolved in 30 ml of tetrahydro-

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furan, to 0.75 g (0.020 mol) of LiAlH ₄ in 40 ml of tetrahydrofuran and boiling for 3 hours gave 1.2 g (55%) of the compound II F. = 76 to 80 ° C. after recrystallization from ether / n-hexane (1: 1). The compound II hydrochloride had a. Melting point F. = 226 to 228 ° C.

Example 5

HCHO

HCOOH

CH ₂ NHCH,

CH ₂ N (CH ₃

II

III

To the secondary amine hydrochloride II were 0.1 g of sodium formate, 0.3 g formalin (37%) and 0.2 g formic acid (98%) were added at ambient temperature. The stirred mixture was heated on a bath of 120 ° C for 2 hours. After cooling and after adding 20 ml of 0.2 M NaOH, the solution was extracted with ether. The organic layer was washed with water and extracted with 3 × 50 ml of 0.2 M HCl. The aqueous layer was made alkaline by treatment with 5% NaOH and with 3 χ 40 ml of ether extracted. Drying and evaporation gave 100 mg of an oil. Treatment with HCl / ether yielded 80 mg (F. = 192 to 195 ° C) of the hydrochloride. Recrystallization from 3 ml of isopropyl alcohol yielded 65 mg. F. = 194 to 195 ° C. Yield 80% of theory.

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Example 6 a)

TsCH ₀ NC

To a solution of spiro- / 5H-dibenzo- (a, d) -cyclohepten-5, l'-cyclohexan / -4'-one (5) (5.5 g, 20 mmol) and tosylmethyl isocyanide (3.9 g , 20 mmol), prepared according to van Leusen et al. Tetrahedron Letters No. 23, pages 2367 to 2368 (1972), in 50 ml of dry dimethoxyethane cooled to 0 ° C., a solution of 45 ml of 0.9 M potassium tertiary butoxide (40 mmol) in tertiary butanol was diluted with 45 ml dry dimethoxyethane added dropwise with stirring under a nitrogen atmosphere. The reaction mixture was stirred at 0 ° C for one hour and then allowed to reach room temperature. Stirring was continued for one hour. 100 ml of water was added and the aqueous phase was extracted with chloroform. The collected chloroform layers were dried (with saturated sodium chloride solution and magnesium sulfate) and evaporated in vacuo. The residue, which crystallized on cooling, was recrystallized from ethanol and yielded 5.5 g (96%) of pure spiro- ^ 5H-dibenzo- (a, d) -cyclohepten-5, l ^l -cyclohexan7-4 ^l -cyanide ( 6), F. = 224 to

226 ° C.

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LiAlH,

CH ₂ NH ₂ VI

A solution of the cyanide (6) (5.4 g, 19 mmol) in 100 ml of dry Tetrahydrofuran was added dropwise to one over 0.5 hour stirred lithium aluminum hydride slurry (1.52 g; 40 mmol) in 100 ml of dry ether was added at such a rate that a gentle reflux was maintained. After the addition the reaction mixture was heated to 60 ° C. for 5 hours. The mixture was cooled, and then 1.5 ml of water, 1.5 ml of 15% NaOH and 4.5 ml of water were added. The precipitated clay was filtered off and washed with several portions of ether. the Ether-THF solution was; dried (over saturated sodium chloride solution and magnesium sulfate) and evaporated in vacuo to give a colorless viscous oil. The hydrochloride was prepared and recrystallized from ethanol to give 5.1 g of the spiro- / 5H-dibenzo- (a, d) -cycloheptene-5,1'7cyclohexane / -4'-methylamine hydrochloride VI with a content of one equivalent of crystal ethanol (NMR) and a melting point F. = 174 C. Yield 73%.

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Example 7

Manufacture of tablets
Each tablet contained:

A compound according to the invention

in the salt form 10 mg

Lactose 60 mg

Strength 29 mg

Magnesium stearate I mg

The powders are mixed and pressed directly into tablets with a diameter of 6 mm.

Example 8

Manufacture of tablets
Each tablet contains:

A compound according to the invention 50 mg

Aerosil ^ S / (silicon dioxide) 20 mg

Lactose 100 mg

Strength 30 mg

Magnesium stearate 2 mg

The active compound is mixed with Aerosil ^. This mixture is added to the other powders. Tablets are compressed with a diameter of 10 ram.

Example 9 Manufacture of capsules

A compound according to the invention 20 mg

Peanut oil 60 mg

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The solution is filled into soft gelatin capsules. Any capsule contains 20 mg of the active compound.

Example 10

Manufacture of capsules "

A compound according to the invention 10 mg

Polyoxyethylene sorbitan monooleate 100 mg

The capsules are produced as in Example 9.

Pharmacological experiments

It is not possible to induce depression in laboratory animals by experimental means. In order to evaluate a possible antidepressant effect of new substances, one has to go to biochemical-pharmacological Resort to testing methods. One such method, which seems to give a good indication of the potential antidepressant effects of the test substances, is in Europ. J. Pharmacol. 17, page 107, 1972. This method consists of measuring the potentiation of the syndromes that in a laboratory animal with 5-hydroxytryptophan (5-HTP).

The lack of euphoric effects, i.e. the lack of centrally stimulating activity, is tested by the motor Activity in mice is measured after administration of the test substance.

5-HTP potentiation test

Inhibiting the uptake of 5-HT likely potentiates the effects of administered 5-hydroxytryptophan (5-HTP)

409824-1087

Increasing the amount of 5-HT on the receptor. Obtained three mice the test substances one hour (or 4 or 24 hours) before intravenous administration of dl-5-HTP in an amount of 90 mg / kg. 5-HTP alone gives only a mild behavioral syndrome, However, a characteristic behavioral syndrome can be seen in pre-treated mice that occurs within 5 minutes: Tremor, lordosis, muscle movement of the hind legs, head twitching.

The absence or presence of the syndrome in question is determined in groups of 10 mice. The compound was administered in at least five doses, and that quantitative Response was analyzed by sample analysis and determined by the Litchfield and Wilcoxon method.

Motor activity in mice

The study activity of mice was in an exercise cage recorded by counting the movements, in which the animals closed an electrical circuit in the base plate. The activity was stopped for 10 minutes, one hour after administration of the substance recorded. The animals were tested individually. Groups of 6 mice were used and the mice were used only once. The activity was expressed as a percentage of the activity of control groups which were examined at the same time. The compounds were administered in at least four doses.

The increase (+) or decrease (-) in activity compared to control groups was determined from the log dose-response curves certainly.

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Pharmacological effects link

Potentiation of 5-HTP, ED _ς mg / kg motor activity

+ = Increase
- = decrease
0 = no effect

DL ₁ . mg / kg

^ÜU iv in mice

NHCH,

> 25

> 25 30

25th

(SHa

JLCH ₂ -

Imipramine

> 25

28

0 9 8 2 4/1087.

Claims (6)

- 24 - '■ Claims 1. Connections of the formulas CH ₂ NH ₂ CH ₂ NHCH CH ₂ NH ₀ c. III CH ₂ N (CH ₃ ), NHCH ^ IV N (CH ₃ ) ₂ VI CH ₂ NHCH ₃ VII VIII CH ₂ NHCH ₃ IX XI 409824/1087 and their pharmaceutically acceptable salts. 2. Compounds according to claim 1 in the form of a substantially pure stereoisomer. 3. Process for the preparation of a compound of one of the formulas CH ₂ NHCH ₅ II IV -CH ₂ NH ₂ IX NHCH3 CH ₂ NHCH ₅ CH ₂ N (CH ₅ ), ..III N (CH ₅ ) ₂ VIII CH ₂ N (CH ₅ ) ₂ CH ₂ NHCH ₅ CH ₂ N (CH ₅ ). XI 409824/108 or pharmaceutically acceptable salts thereof, characterized / that one
a) a compound of the general formula where η denotes 1 or 2, m denotes O or 1 and Z denotes a hydroxyl group, a halogen atom or another acidic radical, with hydrazoic acid (HN-) or an inorganic salt thereof according to the Schmidt reaction to form a primary amine, and optionally this is converted into the corresponding secondary or tertiary amine in a manner known per se or
b) a compound of the general formula 409824/1087 where m and η have the above meaning, reacts with hypobromite or hypochlorite under the conditions of the Hofmann reaction to form a primary amine and converts this into the corresponding secondary or tertiary amine, if appropriate, in a manner known per se
c) a compound of the general formula where m and η have the above meaning, R and R 'the same or are different and each represents a hydrogen atom or a Mean methyl group and in which the carbonyl oxygen is in each case in an adjacent position to the side chain of the hydrogenated ring is reduced and the compounds obtained according to a) to c), if appropriate converted to a stereoisomer and / or a pharmaceutically acceptable salt. . 4. Process for the preparation of one of the compounds or N (CH ₅ ) ₂ UQ 9 8 2 4 / I or a pharmaceutically acceptable salt thereof, characterized in that one a) a compound of the general formula where D]> C = 0 or ^> CHM and M is a reactive ester group means with a compound of the general formula _R ,,, _ _N / ^CH 3
"^ R wherein R denotes a hydrogen atom or a methyl group and R ¹ · 'is a hydrogen atom, an acyl group or sulfonyl group, reacts or d) a compound of the general formula where E ^ C = NOR ", ^ = C = NOCOR", J = C = NOSO ₂ R ", = ^ C = NR, r = ^ CHNRCOR", ^ = CHNRCOOR ", ITrCHN ₃ , I = CIINO ₂ or I. = C = NNIIR "means, R has the above meaning and R" means a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or an aryl radical. U U »ü / UI IU87 and then optionally the compounds obtained according to a) or b) converted into, a stereoisomer and / or a pharmaceutically acceptable salt. 5. A process for the preparation of a compound of the formula CH ₂ NH ₂ CH ₂ NH ₂ VI IX CH ₂ NHCH VII CH ₂ NiICH ₅ III ; CH ₂ N (CH ₃ ) ₂ CH ₂ N (CH ₅ ) ₂ XI or pharmaceutically acceptable salts thereof, characterized in that one
a) a carboxylic acid derivative having at least one nitrogen atom in the group derived from the carboxyl group according to the following simplified formula where η means 1 or 2: and X means N / O, S or nothing, reduced, or b) a compound of the general formula where η denotes 1 or 2 and E -CH = NOR ", -CH-NOCOR", -CH = NOSO ₂ R ", -CH = NR, -CH 1 IRCOR", -CH ₂ NRCOOR ", -CH ₂ N ₃ , -CH = NNHR "or = CHNO ₂ , R is a hydrogen atom or a methyl group and R" is a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or an aryl radical, or c) a compound of the general formula 409824/1087 where η is 1 or 2 and D is -CHO or -CH ₂ M, where M is a reactive ester group, with a compound of the general formula R ¹ ' ¹ NRR ¹ , where R and R ^{1 have} the above meanings and R ¹ ' ^{1 is} a hydrogen atom, an acyl or sulfonyl group, and then the compounds obtained according to a) to c), if appropriate converted into a stereoisomer and / or a pharmaceutically acceptable salt. 6. Medicament containing at least one compound according to claim 1 and 2, preferably in combination with a pharmaceutically acceptable carrier material, U 0 9 8 2 k I 1 0 8 7