DK158664B - METHOD OF ANALOGUE FOR THE PREPARATION OF BENZOXAZINONES AND BENZOXAZOLINONES AND RELATIONS FOR USING THE PROCEDURE. - Google Patents

Description

. DK 158664B

The invention relates to an analogous process for the preparation of novel heterocyclic benzo compounds which can be used as active ingredients in pharmaceuticals.

The novel compounds have the general for flour I (see claim 1), wherein A represents a single bond, the group = C or the group.

Xr4 represents -CH2 "CH2- / represents OH, O-acyl, chlorine or hydrogen, R2 represents hydrogen, methyl or ethyl, H2H2" (CH2) m ~ \ 7R ^ represents -C-CH2 - - * or -C- (CH2) n-Rg K R8

II III

m is 2, 3 or 4, n is 1, 2 or 3, represents hydrogen or lower alkoxy, R 5 represents hydrogen, lower alkyl or further phenyl, if R 1 represents hydrogen,

Represents hydrogen or methyl, R7 represents hydrogen or methyl,

Rg represents hydrogen or methyl,

Rg represents hydrogen, Ar, OAr, NH-CO-Ar, 25 Ar represents or R10 - <§c - R12 35 Ri0 'R11 ° 9 R12' which may be the same or different, represent hydrogen, hydroxy, methyl, methoxy , Halogen, methylenedioxy, NH-R13 or CONH2, R13 '' represent hydrogen, acyl or lower alkyl sulphony.

They can be in the form of racemates, enantiomers and

DK 158664B

2 optionally diastereomeric antipode pairs as free bases or as acid addition salts.

In this specification, "lower alkyl" means an alkyl group having 1-4 carbon atoms, "halogen" means 5 fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, to 6 carbon atoms or an optionally substituted benzoyl group.

In a preferred embodiment of the invention, A represents a single bond, -CH2, = CH (CHg), = C (CHg) 2, or = ch (c2h5), R4 represents OH or Oacyl at the m or p position to the side. Represents the H, CHg or CgH ^,

Rg represents the groups listed above II or III, m is 2 or 3, n is 1, 2 or 3, Rg, Ry and Rg are hydrogen or methyl,

Rg represents H, Ar or KH-CO-Ar,

Ar represents the group of formula IV, 2-pyridyl or 4-pyridyl, R 10 represents H. OH, CH 3 or, together R 2, methylenedioxy, R 3 represents H. OH, CH 3 or, together with R 2, methylene -dicxy, K12 bleaches H, and R3 represents acetyl or methanesulfonyl.

Particularly preferred are compounds wherein 30 A represents = C (CH 2) 2 or -CH 2 -, R 1 represents OH in the p or m position to the side chain, R 2 represents H, CH 2 or C 6 H 9,

Rg is isopropyl, tart. butyl, cyclopentyl, 1-methylcyclopentyl or the group of formula III, n is 1 or 2,

R og and Rg represent hydrogen or methyl,

Rg represents phenyl, 4-hydroxyphenyl, 2-pyridyl, 4-pyridyl or z-hydroxyphenyl,

DK 158664B

3 hh-co- ^ Q \>, hh-co - <^ Q \ 5 CH3, ο ko) -08 and CH3 CH3 The analogous method of the invention is not condemnable by the characterizing part of claim 1.

The reduction of process variant a) is carried out in a sufficiently stable solvent, e.g. in a lower alcohol such as ethanol. Hydrogen and hydrogenation catalysts (such as palladium, platinum or Raney nickel) or hydrides (such as sodium borohydride or diborane) are used as reducing agents. By appropriate choice of reducing agent (catalytic reduction or reduction with hydrides) formation of predominantly either the erythro or threo form can be achieved.

On the central amino group or on a phenolic hydroxyl group, optionally present hydrogenolytically cleavable protecting groups, e.g. benzyl or substituted benzyl is removed during or after the reduction in the usual manner.

The novel compounds of formula V which serve as starting materials can be obtained by known methods, e.g. as shown in the following reaction scheme:

DK 158664 B

4

o2n oh 02n OH

hq- ^^ Friedel-Crafts ^ H0_ ^ S ^ -CO-CH-,>

° 2? ? H HpN OH

^ - \? 2 ^ h

Sz-O- ^ \ -CO-CH 2 - »Bz-O -, / \ -CO-CH 2 10

ClCQ-CR ^ R ^ Cl ^ CICO-OPh

Bz = Benzyl now

Ph = Phenyl 0 Λ-V5 A.

15 h /)> hA Xo V = \ * 2 Av

Bz-O- / \ -CO-CH2 Bz-O- / \ -CO-CH2 20 ^ Br2 | Br2

ISLAND

Λ-Λ «, A

25 _ / ° · r My_ / r2

Bz-O- ^ λ, -CO-cl-Br BzO- ^ -CO-CH-Br 30 VI Will

Corresponding bromo ketones with the (protected) OH group in the m-position to the side chain can be obtained as follows: 35 '

DK 158664 B

5

OH

0H I o I R2 / 9% in 2 <% \ - CoiH2 - »/ ^ - CO-CH2 in Bz-0

OH

° ή f V », 2 / Λ®ί% _, _ J Bz-0

Bz-0 0 0 R '! 0-¾ y ^> · “^ 2

Bz-0 Bz-0 ^ o

0 r4 II

»/ V

\ / R \ = / H2) ==% 12 / \ -CO-CH-Br / \ - CO-CH-Br \ / / Bz-0

Bz-0 VIII IX

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6

The brom ketones obtained in this way or by other conventional methods of the formula 0 1 5a 5 h / \ V === \ R, 10 1 wherein A, and have the above meaning, although phenolic OH groups may be protected by hydrogenolytic leaving groups, e.g. benzyl can be reacted with amines of formula R 'i

HN-R3 XI

wherein R 1 is as defined above and R 1 is hydrogen or a hydrogenolytically leaving group, e.g. benzyl or substituted benzyl, to give compounds of the formula

ISLAND

V_A

HN 0 R «R * va

25 V = <| 2 I

R 1 X> S-CH-N-R 3 wherein A, R 2, R 3, R 2 and R 1 have the above meanings.

The reaction is carried out in suitable solvents, e.g., ecetonitrile or acetic acid ethyl ester in the presence of an acid-binding agent, e.g. sodium carbonate or excess amine. Protective groups present in the reaction product may be removed thereafter or after further reaction.

Reaction by process variant b) of phenylglyoxals or semi-acetals of the formula:

DK 158664B

7

X O

Aa h / o XI1

AA

* 1 10 wherein R 1 and A have the above meanings and Q represents -CHO or

CH

O-lower alkyl 15 with amines of the formula

h2n-r3 XIII

wherein R 1 has the above meaning under the conditions of reductive amination.

Instead of Components XII and XIII, the Schiff bases of formula 0 A- \

25 XIV

/ y-C 0 -CH = N-Rj

RX

30 wherein A, R 1 and R 2 have the above meanings are subject to reduction.

As reducing agents, complex hydrides, preferably sodium borohydride, or hydrogen and hydrogenation catalysts such as platinum, palladium or nickel are used.

Phenolic hydroxy groups present in the starting materials may be protected by conventional hydrogenolytically leaving groups. These protective

DK 158664 B

8 groups can be removed hydrogenolytically during or after the reduction in the usual manner.

End products are obtained in which R 2 represents hydrogen.

The compounds of formula XII used as starting materials can be obtained from acetophenone derivatives of formula 0

II-a

10 HH X0 XV

xy "" "'R1 wherein and A are as defined above by oxidation with selenium dioxide in aqueous dioxane. Depending on whether crystallization from water or lower alcohols 20, glyoxals or half-acetals are obtained.

The amines of formula XIII are known or can be readily prepared by known methods.

Removal of hydrogenolytically cleavable protecting groups by process variant c) from compound compounds of the formula -

HN 0 XVI

R2 r «30 / -CH-CH-N-R *

\ / 1 · 3 X ^^ OH

R 'which can be obtained by reducing compounds of the formula 35 V or Va as described above and wherein A and R 2 have the above meaning and R 1 represents R 1 or a OH group protected by a hydrogenolytic leaving group, R 1 the same meaning as R ^, though 9

DK 158664B

an OH group optionally present in Rg may be protected by a hydrogenolytic leaving group, and R 'represents hydrogen or a hydrogenolytic leaving group. Preferred hydrogenolytically cleavable protecting groups are benzyl or substituted benzyl.

If desired, the compounds obtained according to a) to c) can be separated by the usual methods into the enantiomers and optionally also the diastereomeric antipode pairs, first obtained bases can be transferred to acid addition salts and first obtained acid addition salts can be transferred to bases or salts with other acids .

The compounds of the invention are useful as pharmaceuticals. Among other things, they have broncholytic, spasmolytic and antiallergic effects and increase ciliary activity and attenuate the inflammatory exudation reaction. They are thus applicable to all types of asthma and bronchitis as well as to urticaria, conjunctivitis, hay fever and colds. In addition, they act relaxing on the uterine musculature so that they are suitable for preventing difficulties before birth. The compounds can also be used to treat cardiovascular disorders, e.g. high blood pressure, peripheral vascular disease and arrhythmias. As additional effects are observed inhibition of gastric secretion and antidepressant effects on the central nervous system.

The therapeutic and prophylactic dose depends on the nature and severity of the disease state and the mode of administration.

To an adult, the following dosages are indicated for the following indications.

As broncholytics, 0.05-5 mg orally, inhalation 0.01-1.0 mg and subcutaneously 0.02-0.5 mg are given orally.

As a uterus agent, oral 10-50 mg or as 35 infusion solution ampoules (10 ml) containing 0.1-1 mg are given.

For vascular enlargement, 20-100 mg orally and for intramuscular injection vials of 20-40 mg are used. As blood

DK 158664B

Oral pressure reducing agent is given orally 200 mg to 1.8 g.

The pharmaceutical compositions contain active ingredients, pharmaceutically acceptable carriers and optionally other therapeutic ingredients.

Thus, broncholytics may be combined with theophyllines, parasympatholytics (e.g., ipratropium bromide), secretolytics (e.g., bromhexine), muscularotropic spasmodics (e.g., paraverin), corticosteroids, and anti-allergy. Uterus relaxants can be combined with corticoids.

For oral administration, capsules, tablets, solutions and suspensions are suitable. When administered by inhalation, dry powder having a particle diameter of 0.5-7 µ is preferably brought to the bronchial region by propellant gases 15. For parenteral administration, sterile isotonic aqueous solutions are suitably used. For topical use, lotions, creams, ointments, emulsions and sprays are used.

Preparation Example:

tablets

Composition of a tablet

Active ingredient according to the invention 20 mg

Colloidal silicic acid 10 mg 25 Milk sugar 118 mg

Potato starch 60 mg

Polyvinylpyrrolidone 6 mg

Sodium cellulose glycolate 4 mg

Magnesium stearate 2 mg 30 220 mg 35

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11

ampoules

Composition of the solution in an ampoule Active compound of the invention 10 mg

Sorbit 40 mg 5 Distilled water to 10 ml

suppositories

Composition of a suppository

Active ingredient according to the invention 100 mg

Suppository mass (cocoa butter) 1600 mg 10 1700 mg

Inhalation powder In each hard gelatin capsule for insertion, 0.5 mg of active ingredient according to the invention and 19.5 mg of 15 lactose are filled with a particle diameter between 0.5 and 7 µm.

For the pharmacological tests, the usual test methods and test animals or organs are used. Pharmacologically, the compounds of the invention are in part very distinctly different from commercial products 20 with the same indication. In addition to a long duration of action, they exhibit e.g. a particularly evident selectivity in the ratio of broncholysis to increase in heart rate.

Eg. for the compound of Example 1, ED 1, g i.v. Thus, in guinea pigs for heart rate increase, 25 more than 10 times the ED, _q i.v. [ug / kg] for broncholysis, which is only 0.045 ug / kg. The resorption conditions are usually also favorable. Thus, the resorption ratio of ED50 Ρ · ° · 30 ED50 is e.g. for compound 7 in Table 3, only 1.1, so that the oral effect is practically as great as the intravenous. The values of LD ^ q are, e.g. for mice so high above the therapeutic dose that there is a favorable therapeutic width.

12

DK 158664B

The broncholytic ability and selectivity of the compounds can be seen in the following test results obtained by intravenous administration to guinea pigs:

Compound ED5Q [ug / kg] Selectivity 5

Table I No. 6 0.08 8.8 No. 7 0.12 4.2 No. 9 0.12

Table II No. 3 0.9 10 Table III No. 14 0.06

Example 3 0.3

The invention is further illustrated by the following examples.

Depending on which solvent the substances mentioned in the following 15 are crystallized, they contain, in part, still determined amounts of the solvent bound in the crystal. The melting points indicated are uncorrected.

Regarding Process a) Example 10ho-Q-ch-ch / CH2'CH3 XHC1XH20 25 OH N'NHCH (CH3) 2 16.1 g of 5'-benzyloxy-81 - (1-oxo-2-bromo butyl) -2H-1,4-benzoxazine-3- (4H) -one and 7.5 g of isopropylamine are stirred in 100 ml of acetonitrile for 4 hours at 60 ° C. After acidification with concentrated hydrochloric acid and addition of 100 ml of water, 51-benzyloxy-81 - (1-oxo-2-isopropylamino-butyl) -2H-1,4-benzoxazine-3- (4H) -one hydrochloride (m.p. .

229-232 ° C).

6 g of this compound is entbenzylated in methanol 35 with the addition of palladium carbon as a catalyst to 5'-hydroxy-8 '- (1-oxo-2-isopropylamino-butyl) -2H-1,4-benz-oxazine-3 (4H) -one hydrochloride dihydrate (mp 242-245 ° C).

By hydrating 3.3 g of this compound in 13

DK 158664 B

methanol with platinum as catalyst gives 3 g of erythro-5'-hydroxy-81 - (1-hydroxy-2-isopropylamino-butyl) -2H-1,4-benzoxazine-3- (4H) -one hydrochloride. hydrate (yield 90% of theory), melting at 208-210 ° C.

Example 1 a

Process c) 0 δΡ2Η5 -CH-CH-NH-CH (CH3) 2 x HCl (threo)

OH

32.4 g of 5'-benzyloxy-81- (1-oxo-2-bromo-butyl) -2H-1,4-benzoxazine-3- (4H) -one and 72 g of benzylisopropylamine are stirred for 15 hours at 100 ° C. After addition of water, the precipitated oil is taken up in ether and diluted with petroleum ether; crystallizing 5'-benzyloxy-81 - (1-oxo-2-benzylisopropylamino-butyl) -2H-1,4-benzoxazine-3- (4H) -one.

11.6 g of this compound are added to a mixture of 60 ml of ethanol and 60 ml of acetonitrile with 1 g of sodium borohydride and stirred for 3 hours. Then, 250 ml of ice water and 100 ml of acetic acid ethyl ester are added, 25 and after cleavage of the sodium borohydride with concentrated acetic acid with stirring, make alkaline with concentrated ammonia solution, the acetic acid ethyl ester ash is separated, dried and evaporated by rotary evaporation. The oily residue is dissolved in ether which is cooled and the precipitated threo-51-benzyloxy-81- (1-hydroxy-2-benzyliso-propylamino-butyl) -2H-1,4-benzoxazine-3- (4H) - on (mp 89-92 ° C) is suctioned.

4.8 g of this compound is hydrogenated in 100 ml of methanol with palladium carbon as catalyst. After completion of uptake, the catalyst is aspirated, the mother liquor is evaporated in a rotary evaporator, the oily residue is dissolved in acetone / ethanol and acidified with the calculated amount of hydrochloric acid. Dilute the solution with ether and the 14

DK 158664B

precipitated threo-5'-hydroxy-8 '- (1-hydroxy-2-isopropylamino-butyl) -2H-1,4-benzoxazine-3- (4H) -one hydrochloride (yield 74% of theory) filtered off with suction; after evaporation from methanol / ether it melts at 202-205 ° C.

5

Example 20 HQ GH3 10 CH-CH2-NH-C-CH3 x HCl OH CH3 10 g 5'-benzyloxy-8 '- (1-oxo-2-bromo-ethyl) -2H-1,4-benzoxazine-3 - (4H) -one and 8.75 g of benzyl tert-butylamine are heated under reflux in 100 ml of acetonitrile for 3 hours. After cooling, the precipitated crystals are aspirated and washed with 200 ml of warm water. The crystals are acidified in acetonitrile with ethereal hydrochloric acid; after dilution with acetic acid ethyl ester, 51-benzyloxy-81- (1-oxo-2-benzyl-tert.-butylamino-ethyl) -2H-1,4-benzoxarine-3- (4H) -one hydrochloride (m.p. 185) -189 ° C).

7 g of this compound is entbenzylated at 5 bar and 50 ° C in 100 ml of methanol with the addition of palladium carbon as a catalyst to 5'-hydroxy-81- (1-oxo-2-tert).

(Butylaminoethyl) -2H-1,4-benzoxazine-3- (4H) -one hydrochloride (mp 237-240 ° C).

Catalytic hydrogenation of 2.2 g of this compound in methanol with platinum gives 1.6 g of 5'-hydroxy-8 1- (1-hydroxy-2-tert-butylamino-ethyl) -2H-1,4-benz -30 oxazine-3- (4H) -one hydrochloride (yield: 72.5% of theory), melting at 185-187 ° C.

35

DK 158664 B

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DK 158664B

Continuous Procedure b)

Example 3 0 5 Ht) “3 ™

Ha-y 2 V-CH-CH 2 -NH-C-CH 2 -CH 2 - ^^ X HCl ^ OH CH 3 5 g 5, -benzyloxy-8, - (1-oxo-2-hydroxy-2-ethoxyethyl) ) -2H-1,4-benzoxazine-3- (4H) -one, 2.2 g of 1,1-dimethyl-3-phenylpropylamine and 50 ml of alcohol are heated to 50-60 ° C for 3 hours. After cooling the reaction mixture, the precipitated Schiff base (mp 138-140 ° C) is suctioned off.

15

To 4.5 g of this compound in 100 ml of alcohol is added 1 g of sodium borohydride and stirred for 2 hours at room temperature. After the addition of 100 ml of water, the precipitated 51-benzyloxy-8 '[1-hydroxy-2- (4-phenyl-2-methyl-butylamino) -ethyl] -2H-1,4-benzoxazine-3- (4H ) -one 20 (mp 162-164 ° C) and the hydrochloride (mp 205-207 ° C) are prepared with ethereal hydrochloric acid.

Catalytic hydrogenation of this compound in 50 ml of methanol under normal conditions with palladium carbon as catalyst gives 2.7 g of 5'-hydroxy-81-25 [1-hydroxy-2- (4-phenyl-2-methyl-butylamino) -ethyl] -2H-1,4-benzoxazine-3- (4H) -one hydrochloride (mp 159 ~ 161 ° C, yield: 90% of theory).

Example 4

30 / V

H1 (jP CH3? - CH-CH2-NH-C-CH3 x Ha cr in H ilf3 5.8 g of 6, -chloro-8 '- (1-oxo-2-hydroxy-2-ethoxy-eth. Yl) -2H-1,4-benzoxazine-3- (4H) -one, 1.5 g of tert-butylamine, 60 ml of dioxane and 60 ml of alcohol are heated to 50 ° C for 2 hours.

DK 158664B

21

Then cool and add 2 g of sodium borohydride to the solution at 10-20 ° C. The solution is stirred for 1 hour at room temperature, then 500 ml of ice water is added and poured with 150 ml of acetic acid ethyl ester.

After cleavage of the sodium borohydride with stirring with concentrated acetic acid, make alkaline with ammonia water, separate the acetic acid ethyl ester phase, dry with sodium sulfate and evaporate by rotary evaporation. The oily residue is dissolved in 15 ml of alcohol which is acidified with ethereal hydrochloric acid and the precipitated 6'-chloro-8 '- [1-hydroxy-2- (tert-butylamino) ethyl] -2H-1.4 -benzoxazine-3- (4H) -one hydrochloride (yield: 38% of theory) is aspirated. After reacting twice from methanol with the addition of activated carbon, the substance has a melting point above 300 ° C (melting point of the base: 173-177 ° C).

DK 158664 B

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DK 158664B

26

About procedure c)

Example 5

ISLAND

5 HiOp

Cj - CH-CH₂-NHC₂H5 x HCl

oT ° H

4.3 g of 5'-benzyloxy-8 '- (1-hydroxy-2-benzylethylaminoethyl) -2H-1,4-benzoxazine-3- (4H) -one hydrochloride (m.p. 235 ° C) is hydrogenated in 125 ml of methanol with the addition of 0.5 g of 5% 1s palladium carbon. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the solution is distilled off under reduced pressure. When the residue is triturated with acetonitrile, 2.5 g of 5'-hydroxy-8 (1-hydroxy-2-ethylamino-ethyl) -2H-1,4-benzoxazine-3- (4H) -one hydrochloride are obtained (yield : 86.7% of theory), which after melting from methanol / ether after melting at 240-242 ° C.

Example 60

Hy ° CH3 0 25 H0 - / - y-CH-CH2-NH-C-CH2-CH2-NHC. ^ 3 x HC \ W OH CH Hydroxy-2- (4-picoline-acid-amido-2-methyl-2-butylamino) -ethyl] -2-benzoxazolone (m.p. 130-133 ° C) is hydrogenated in 125 ml of methanol with the addition of 1 g. 5% palladium carbon. After completion of recording, the catalyst is filtered off and the clear solution is evaporated by rotary evaporation under reduced pressure. The oily residue is dissolved in 10 ml of alcohol and 0.58 g of formic acid is added. After 5 hours, the precipitated 41-hydroxy-7 '- [1-hydroxy-2- (4-picolinic acid amido-2-methyl-2-butylamino) -

DK 158664 B

27 2-benzoxazolinone formate (yield: 78.5% of theory, m.p. 166-168 ° C).

DK 158664 B

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35 In the following are listed intermediates of formula V which can be obtained according to the above scheme.

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Claims (3)

An analogous process for the preparation of compounds of the general formula: 5 o II, «/%> - (h 10. tf in 3 p ^ v OH R1 s * R5 wherein A represents a single bond, the group = C \ R or the group 4 15 is δ represents OH, Oacyl, chlorine or hydrogen, R 2 represents hydrogen, methyl or ethyl, CH 2 - (CH 2) m R3 represents -C - CH-, e is C- (CH2) n -Rg R6 H II III m means 2, 3 or 4, 25. means 1, 2 or 3, R 4 represents hydrogen or lower alkyl, R c represents hydrogen, lower alkyl and further phenyl if R 1 represents hydrogen, R 9 represents hydrogen or methyl, Represents hydrogen or methyl, Rg represents hydrogen or methyl, Rg represents hydrogen, Ar, OAr or NH-CO-Ar, Ar being -00). -0 · “DK 158664 B R10 -dr 5 R12 R10f R11 ° 9 R12 ^ which are the same © Here different) denotes hydrogen, hydroxy, methyl, methoxy, halogen, methylenedioxy, NH-R ^ or CONI ^ where hydrogen, acyl or lower alkylsulfonyl, in the form of racemates, enantiomers and optionally 15 diastereomeric antipode pairs which may be available as free bases or as acid addition salts, characterized by a) reducing a compound of the formula 0 2 ° Jt A HN OW b / \ -C-CH-NH -R, X / 11 3 π ^ 0 K is wherein A, R 2, R 2 and R 2 are as defined above, wherein phenolic OH groups may be protected by hydrogenolytically cleavable protecting groups and optionally further protecting groups present may be deprived or b) reacting phenylglyoxal or half-acetal of the formula 35 wherein 158 and A have the above meaning, although phenolic OH groups may be protected by hydrogenolytically cleavable protecting groups and Q represents -CHO or -CH ( OH) -O-lower alkyl, with an amine of the formula 15 h2n-r3 XIII wherein Rg has the above meaning, wherein any OH groups present may be protected by hydrogenolytically cleavable protecting groups, under conditions of reductive amination, and optionally thereafter leaving further protecting groups present, or c) from a compound of formula 0 25 IU-AX HN 0 XVI) = <? 2f Cy'HH-CH-4.R · 30 wherein A and R 2 have the above meaning and R 1 represents R 2 or a protected OH group protected by a hydrogenolytic leaving group. group, R3 means R3, wherein an OH group optionally present in R3 may be protected by a hydrogenolytically cleavable protecting group, and R 'represents DK 158664 E hydrogen or a hydrogenolytic cleavable protecting group and wherein at least one compound of formula XVI is present in the compound of formula XVI leaving the protecting groups present, removing the protecting groups by conventional methods and optionally separating the compounds obtained in (a) to (c) into the enantiomers, optionally also in the diastereomeric antipode pairs, and transfer first obtained bases in acid addition salts. and first obtained acid addition salts in bases or salts with other acids. Compound for use in the method of claim 1, characterized in that it has the formula: 0) - HN 0 V 20> = / h / \ _c_ch-NH-R, X7i 3 R1 wherein A, R 1, R 2 and R 2 have the above meaning. 30 35