NO814191L - PROCEDURE FOR THE PREPARATION OF INDOLOKINOLIZIN DERIVATIVES - Google Patents

Abstract

Indolo-quinolizine compounds of general formula. wherein A represents H and B represents H or an alkyl group, or A and B form a bridge of formula. wherein H is alkoxycarbonyl and R is H or alkyl, alkoxycarbonyl or arylcarbonyl. The compounds have pharmacological action. Their preparation is described.

Description

The present invention relates to a method for the production of pharmacologically active indolo-quinolizine compounds with the general formula (I)

in which

R means hydrogen, C 1-4 alkyl, 4-alkyl-carbonyl or

arylcarbonyl, especially benzoyl,

A means hydrogen,

'b means hydrogen or alkyl,

or A and B together form a group with formula

means hydrogen or C 1 -C 1 - 6 alkoxycarbonyl.

as well as their addition salts with pharmaceutically acceptable acids, and the distinctive feature of the method according to the invention is the steps in which

■ a) 1, 2/3, 4, 6, 7,12-hexahydro-indolo!'2,3-a quinolizine

with formula

is nitrosated to a nitroso derivative (III) with formula b) this nitroso derivative is treated in a strongly acidic environment to form an unsaturated hydroxyimino derivative (IV) of formula

in which Z~ represents a residue of a strong acid,

c) the unsaturated hydroxyimino derivative (IV) is reduced

- either first with sodium borohydride in alcoholic solution and

final reduction of the thus obtained compound (V) with formula

with lithium aluminum hydride or bis-(2-methoxyethoxy)sodium aluminum hydride in solution in ether, or

- by catalytic hydrogenation

to obtain a compound (Ia) of formula

and

d) the obtained compound (Ia) is converted into other compounds of formula (I) in which B and R have the indicated

meanings other than H, using classical reactions.

These features of the invention appear in the patent claim.

The compounds have a pharmacological effect and are particularly useful in the vascular area.

The addisjoir salts can be formed, e.g. with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, maleic acid, formic acid, fumaric acid, acetic acid, succinic acid, lactic acid, citric acid, tartaric acid, glutamic acid, malic acid and with metal salts of acids such as disodium orthophosphate and monopotassium sulfate.

The hydrogen atoms linked to the carbon atoms I and 12b can exist as cis, or trans and for one and the same compound

each of these two structures may comprise two optical antipodes. The invention also includes the preparation of racemic mixtures as well as the optical isomers.

The preferred compounds have trans structure.

For the alkylation reactions refer to "The Chemistry and the Amino Group" by Brian C. Challis of A.R. Butler, (published by Saul Patai - Interscience Publisher 1968)

Certain compounds of formula I can be obtained by classical reactions with either alkylation or with an acylation reaction followed by a reduction reaction.

Monoalkylation of the compounds Ia can thus be achieved either

by conversion to the amide or to the carbamate followed by a reaction (see e.g. J.Org.Chem. 1965, 30, 2483), or by means of the classical sequence comprising a preceding protection, an alkylation and a deprotection (see e.g. .ex.

J. Chem. Soc, Series C, 1969, 2223 or J. Am. Chem. Soc.

1956, 78, 4778).

Alkylation of the thus obtained secondary amine can be carried out either by direct alkylation or by conversion to amide or carbamate followed by a reduction.

The compounds of formula I in which the groups A and B are linked can be obtained starting from compounds Ia by means of cyclization reactions within the general range

with reactions involving acylation, acylation/reduction and alkylation.

The compounds I in which A and B form a bridge

can be obtained by reaction of the compounds la with a suitable substituted aldehyde in neutral or acidic environment. The compounds of formula I, wherein A and B form a bridge

can

is obtained by conversion to carbamate of the compounds I with subsequent ring closure.

The compounds of formula I in which the groups A and B form a

bro - CH2- CO- can be obtained by reaction of the compounds Ia

with α--halogenated acid halides especially with catalysis by means of phase transfer.

With regard to the compounds of formula I in which A and B form a bridge j-C^ - CH2", these can be obtained by reaction of the compounds Ia with bi-functional reactants of the type α-diesters or α-dicarbonyl compounds.

They can also be obtained by reduction of corresponding carbonylated derivatives.

In the following examples, examples 1-3 illustrate the preparation of intermediate products and examples 4-25 illustrate the preparation of the compounds of formula I.

EXAMPLE 1

1-nitros o-2, 3, 4, 6, 7, 12-hexahydro-indolo j^2 , 3-a~j-"quinoliz in (formula III).

At ordinary temperature, 150 ml of isoamyl nitrite is added to a suspension of 220 g of 2,3,4,6,7,12-hexahydro-indolo 2,3-a quinolizine prepared according to the method described by R.N. Schut and T.J. Leipzig (J. Het. Chem. 1966, 3, 101) in a

1.2 liters of methanol. After 16 hours' rest, the dark crystals formed are isolated by filtration, cleaned and dried. 210 g of product is obtained (yield = 83%).

The product crystallizes with 1/2 molecule of ethanol.

Melting point = 195°C.

EXAMPLE 2

1-hydroxy γ-imino-1, 2,3,4,6,7,12-heptahydro-indolo Jj2, 3-aj quinolizinium chloride (formula IV)

To a suspension of 210 g of 1-nitroso-2,3,4,6,7,12-hexahydro-indolo-2,3-a-quinolizine (ex. 1) in 1.5 liters of methanol, . kept at approximately the reflux temperature, carefully add 120 ml of concentrated hydrochloric acid. The mixture is then put away for 16 hours in a freezer. By filtration, 120 g of orange crystals are recovered (yield = 79%).

The product crystallizes with 2/3 molecules of water.

Melting point =215°C.

EXAMPLE 3

(+)-1-Hydroxyimino-1,2,3,4,6,7,12,12b-octahydro-indolo-1 J2,3-a^j quinolizine (formula IV).

To 8.7 g of 1-hydroxyiiTU.ni._i, 2, 3, 4, 6, 7, 12-heptahydro-indolo-[2,3-a]quinolizinium chloride (Example 2) in solution in 200 ml of methanol is added at ordinary temperature and in small portions and with stirring sodium borohydride until total decolorization of the orange solution. The mixture is then poured into water and extracted with methylene chloride. The organic phase is washed with water, dewatered over anhydrous sodium sulfate and evaporated. 7.5 g of oxime are recovered (yield = 98%).

Preparation of hemifumarate.

The oxime (0.02 mol) is dissolved in methanol and fumaric acid (0.01 mol) in solution in methanol is added. The solution is evaporated and set aside for crystallization.

Melting point = 192°C.

EXAMPLE 4

( + ) -1-amino-1, 2,3,4,6,7,12, 12b-octahydro-indolo-|^2 , 3-aj-quinolizine.

At normal temperature, 14 g of lithium aluminum hydride are brought into suspension in 500 ml of tetrahydrofuran and a solution of 50 g ( + ) is then added dropwise over the course of 1 hour. hydroxyimino 1,2,3,4,6,7,12,12b-octahydro-indolo-[j2,3-a_J-quinolizine (Example 3) in 500 ml of tetrahydrofuran. During vigorous stirring, excess hydride is split by careful addition of a saturated solution of sodium sulphate. The mixture is kept under reflux for 1/4 hour. The precipitate formed is filtered off, cleaned with methylene chloride and the filtrate is poured into water and extracted several times with methylene chloride. After drying and evaporation of the organic phase, a residue (43 g) is obtained.

This residue dissolved in methylene chloride is chromatographed on a silica column. One elutes with the solution of methylene chloride containing increasing amounts of methanol (0-5%).

This fractionation yields 15 g of pure amine (21%).

Preparation of the di-fumarate.

The amine (0.01 mol) is dissolved in methanol and fumaric acid (0.02 mol)

1 solution in methanol is added. The solution is evaporated and set aside for crystallization.

Melting point = 178°C.

EXAMPLE 5

( + )-l-benzamido-12,3,4,6,7,12,12b-octahydro-indolo-\\, 3-aH quinolizine. 2 g (±) 1-amino-12, 3, 4, 6, 7, 12, 12b-octahydro-indolo-Q>, 3-a| quinolizine (Example 4) is dissolved in 100 ml of methylene chloride in the presence of 1.15 ml of triethylamine. 0.95 ml of benzoyl chloride is then added and the mixture is left in contact for 5 minutes. The solvent is evaporated and the residue obtained in dissolved methylene chloride is chromatographed on silica. Elution is carried out in accordance with example 4, and 2.4 g of benzamide is isolated (yield = 84%).

Preparation of fumarate.

The amide is dissolved in methanol (0.01 mol) and fumaric acid (0.01 mol) in solution in methanol is added.

The solution is evaporated and set aside for crystallization.

o

Melting point = 245 C.

EXAMPLE 6

( + ) -\ jL, lFj^iminomethano-l, 2,3,4, 6, 7, 12, 12b-octahydro-indolo-[^2, 3-aj quinolizine.

To 2.5 g (+)-1-amino-1,2,3,4,7,12,12b-octahydro-indolo-jj!, 3-aJ quinolizine (Example 4) in solution in 40 ml of tetrahydrofuran, 1 ml of acetic acid and 1 ml of 30% formalin solution in water are added. The solution is refluxed for 1 hour and, after cooling, the reaction mixture is poured into alkaline water and extracted with methylene chloride. After usual treatment of the organic phase, 2.5 g of a residue is obtained which is chromatographed on silica in accordance with example 4 and gives 2 g of pure product (76%).

Preparation of the dihydrochloride.

The amine is dissolved in methanol (0.01 mol) and hydrochloric acid (0.02 mol) is added to the methanolic solution. It is evaporated and the dihydrochloride crystallizes with 1 molecule of water.

o

Melting point = 250 C (decomposition).

EXAMPLE 7

(+)-14-ethoxycarbonyl-1,12-imino-methano-1,2,3,4,6,7,12,12b-octahydro-indolo-2,3-a quinolizine.

At room temperature, 3 ml of ethyl chloroformate are added with stirring to a solution of 3.6 g of (+)-imino-methano-(1, 12]-1, 2, 3, 4, 6, 7, 12,12b-octahydro-indolo - 2,->3-a quinolizine (Example 6) in 100 ml methylene chloride The methylene chloride phase is washed with alkaline water, dried and evaporated and 4 g urethane (84%) is obtained.

EXAMPLE 7A

Preparation of the fumarate of the compound from example 7. This is prepared as described in example 5.

Melting point = 195-196°C.

EXAMPLE 7B

Preparation of the methanesulfonate of the compound from Example 7.

IN

The aqueous solution of the methanesulfonate is freeze-dried.

Pour point: 228-231°C.

EXAMPLE 8

( + )-14-benzoyl-imino-methano-jl, 12^j-l, 2, 3, 4 , 6 , 7,12, 12b-octahydro-indolo-[j>, 3-aj quinolizine.

A benzoylation is carried out under analogous conditions

with the conditions .in example 5.

EXAMPLE 9

(+)-14-oxo-iminoethane-1,2,3,4,6,7,12,12b-octahydro-indolo-P,3-aj-quinolizine.

At normal temperature, 4 ml of ct-bromo-acetyl-bromide is added dropwise to a solution of 10 g of (+):1-amino-1,2,3,4,6,7,12,12b-octahydro-indolo-[2, 3-aj'wquinolizine (Example 4) in 250 ml of methylene chloride with vigorous stirring. After 10 minutes, 100 ml of caustic soda (33%) and 0.2 g of tetrabutylammonium hydrogensulphate are added and the mixture is allowed to stand for 1/2 hour with vigorous stirring. In the reaction mixture as well as away, a white precipitate appears in the aqueous phase and this is recovered by filtration and washed well with water. After drying, 4 g of product (38%) are obtained.

Preparation of fumarate.

This is produced as in example 5.

The fumarate crystallizes with 1 molecule of water.

Melting point more than 250°C.

EXAMPLE 10

(+) imino-ethano- 1,12 -1,2,3,4,6,7,12,12b-octahydro-indolo-

\ j2 , 3-a}"quinolizine.

3g ( + )-14-oxo-iminoethanol-lyl, li]-1, 2 , 3, 4, 6 , 7, 12 , 12b-octahydro-indolo-L2,3-al-quinolizine (Example 9) is suspended in 250 ml of tetrahydrofuran. In small amounts, an excess of lithium aluminum hydride is added. The mixture is maintained for 3 hours under reflux

and cool. 80 ml of a saturated solution of sodium sulphate are added with vigorous stirring taking care not to

split hydride excess. The mixture is kept under reflux again for 1/4 hour, cooled and filtered. The precipitate is purified with methylene chloride and after the usual treatment of the organic phase, 2.3 g of product (80%) are recovered.

Preparation of the dihydrochloride.

This is produced as in example 6.

Melting point more than 250°C.

EXAMPLE 11

(+)-1-amino-1,2,3,4,6,7,12,12b-octahydro-indolo-|_2_,3-a]quinolizine.

30g of 1-hydroxyimino-1, 2,3,4,6,7, 12-heptahydro-indolo-J~2 , 3-a quinolizinium chloride (Example 2) in solution in 300 ml of acetic acid are brought into a hydrogenation apparatus in presence of 6g 5% palladium on carbon, under pressure 200 bar and normal temperature.

When the absorption of hydrogen is finished, the mixture is filtered. The catalyst is cleaned several times with a mixture of acetic acid/methanol 50/50. The filtrate is poured into aqueous ice-mixed alkaline water and extracted with methylene chloride.

After drying and evaporation of the organic phase, 25 g of crude product is obtained as chromatographed in solution in methylene chloride on

an alumina column by elution with methylene chloride containing increasing amounts of methanol (0-5%) in 17.5 pure amine (73%).

Preparation of difumarate.

This is produced in accordance with example 4.

Melting point = 115°C (decomposition).

IN

EXAMPLE 12

imino-methano- [1,12]- 1,2,3,4,6,7,12,12b-octahydro-indolo-

[2, 3-a}-quinolizine.

A loop closure is carried out under conditions analogous to those in example 6.

EXAMPLE 13

(+) 13-Methoxycarbonyl-iminomethano-Q, 12_|~1, 2 , 3, 4,6, 7,12,12b-octahydro-indolo-2,3-a quinolizine.

6g (±) 1-amino-1, 2, 3, 4, 6, 7, 12, 12b-octahydro-indolo-[2'3-a]-1 quinolizine (Example 11) is dissolved in 60 ml tetrahydrofuran and 20 ml acetic acid. 33 ml of methyl dimethoxy acetate are quickly added and the mixture is kept under reflux for 6 hours. The mixture is then poured into alkaline water and extracted several times with methylene chloride. After the usual treatment of the methylene chloride phase, the residue is chromatographed on silica as in example 4, yielding 2.55 g of product (34%).

Preparation of hemi-fumarate.

This is produced in accordance with example 3.

Melting point = 187°C.

EXAMPLE 14

( + )-1-ethoxy-carbonyl-amino-1,2,3,4,6,7,12,12b-octahydro-indolo-[j2,3-aJ-quinolizine.

The reaction is carried out under conditions analogous to the conditions in example 7.

EXAMPLE 15

( + )-1-benzamido-1,2,3,4,6,7,12,12b-octahydro-indolo- [2,3-a]—quinolizine.

The reaction is carried out under analogous conditions as in example 5.

EXAMPLE 16

( + )-1-methylamino-1,2,3,4,6,7/12,12b-octahydro-indolo-jj2,3-'a]-'quinolizine.

To 4.94 g of (+)-1-ethoxy-carbonyl-amino-1,2,3,4,6,7,12,12b-octahydro-indolo-|3,3-a]-quinolizine (Example 14) dissolved in 100 ml of tetrahydrofuran, an excess of lithium aluminum hydride is added while stirring in small portions. After the addition has been completed, the suspension is kept under reflux for 2 hours.

After cooling, excess hydride is removed by adding a saturated solution of sodium sulphate. The mixture is kept under reflux for 15 minutes. It is filtered and purified several times with methylene chloride. The filtrate is poured into water and extracted several times with methylene chloride. After usual treatment of the organic phase, 3.9 g of product is obtained which is chromatographed on silicon oxide (as in example 4).

Preparation of disulfate.

This is produced as in example 2.

Di-sulphate crystallizes with 1/2 molecule of water.

Melting point = 175°C (decomposition).

EXAMPLES 17 - 21

The various reactions are carried out under analogous conditions as in the previous examples.

EXAMPLE 22

{ + ) -13-oxo-imino-methano-[l_, 12^] -—1, 2, 3, 4,6, 7,12,12b-octahydro indolo- 2,3-a quinolizine.

4g of 1-ethoxycarbonamino-1,2,3,4,6,7,12,12b-octahydro-indolo-2,3-fa-quinolizine is dissolved in 50 ml of tetrahydrofuran. lg sodium hydride (50% suspension in oil) is added in small portions and the mixture is kept under reflux. After 1 hour the reaction is

completely, excess hydride is removed with a saturated

solution of sodium sulfate. The mixture is poured into acidified water and extracted with ether. The aqueous solution is made alkaline and extracted with dichloromethane. The washed organic phase is dried and evaporated to give 3.3g of ring-closed product (92.3%).

Preparation of the hydrochloride.

This is produced as in example 8.

The hydrochloride crystallizes with 1/2 molecule of water.

Melting point = 241 - 244°C.

EXAMPLE 2 3

(+) N-methyl-iminomethano-Qu 12_J~1, 2,3,4,6,7, 12,12b-octahydro indolo-{^2, 3-a]—quinolizine.

The reaction is carried out under conditions analogous to the example

16. EXAMPLE 24 (+)-13-oxo-imino-methano-1,12^J—1,2,3,4,6,7,12,12b-octahydro-indolo-2,3-a quinolizine. a) In 100 ml of dichloromethane dissolve 5 g (+)-1-amino-1,2,3,4,6,7,12,12b-octahydro-indolo-|_2, 3-aj-- quinolizine (example 4) and 3 ml of triethylamine. The mixture is kept at 0°C and 2 ml of ethyl chloroformate is added dropwise. The mixture is kept under stirring and brought back to normal temperature within 1 hour. After adding 1 ml of ethyl chloroformate, stirring is continued for a further 1 hour.

The chloromethylene phase is then washed with water that has been made alkaline

and dried and evaporated and 5g of (+)-1-ethoxy-carbonyl-amino-1, 2,3,4,6,7,12,12b-octahydro-indolo-Qji, 3-a~|- quinolizine is isolated

(77%) . b) 5g (+)-1-ethoxy-carbonylamino-1,2,3,4,6,7,12,12b-octahydro-indolo-jT; 3-α~|-quinolizine prepared earlier is brought into suspension in 100 ml of tetrahydrofuran. In small portions, sodium hydride (50% suspension in oil) is added to the mixture which is kept under reflux until a new product appears by thin layer chromatography.

After completion of the reaction, excess hydride is split with methanol and the mixture is poured into water that has been acidified. After washing with ether, the aqueous solution is made alkaline and extracted with dichloromethane. The usual treatment of the organic phase allows the isolation of a residue which after chromatography on a column of silicon oxide (as in example 4) yields 2 g of product (45%).

Production of sulphate.

This is produced as in example 17.

The sulfate crystallizes with 1/2 molecule of water.

Melting point = 265-268°C.

EXAMPLE 25

(+)-13-N-methyl-oxo-imino-rnetano- {T, 12_J-1, 2, 3,4,6,7,12,12b-octahydro-indolo- 12, 3-"a"|- quinolysine.

Starting from the compound obtained in example 24a, a reduction is carried out in accordance with example 16, an ethoxy-carbonylation in accordance with example 7, and a ring closure in accordance with example 22.

The following table reproduces the structures and physical properties of the compounds from the examples and also indicates the relative position of the hydrogen atoms attached to the carbon atoms 1 and 12b. The compounds of formula I and their addition salts with pharmaceutically acceptable acids have interesting pharmacological properties and in particular anti-anoxia properties and/or as vasodilators with prolonged action.

Among other things, the compounds have a toxicity that only appears at much larger doses than the pharmacologically active doses and this allows their use in therapy.

In the following, results are given for toxicological and pharmacological experiments which clearly show these characteristics.

I - acute toxicity in mice

The compounds are administered orally in increasing doses (arithmetic or geometric increase) to groups of 3 to 15 female mice of the strain Swiss and average weight 25 g.

For this, the compounds are brought into suspension in 10% gum arabic solution.

LD^q is calculated by the method of Behrens (B) and i Karber (C.) (Arch. Exp. Path. Pharmakol. 1935, 177, 379-388).

The number of animals that survive in the different groups is definitively confirmed 15 days after administration of the compound.

LD50 determined in this way is from 500 mg/kg to more than

1000 mg/kg.

II - demonstration of an antianoxia effect and cerebral vasoregulatory effect: Experiments with hypobaric hypoxia in mice

Male Charles River mice with an average weight of 25 g are used

distributed in groups of 6-10 animals. The compounds are administered orally in solution in distilled water or suspension in 10% gum arabic solution 30 minutes before the experiment. The comparison compound is vincamine dissolved in the form of the tartrate and administered in doses of 200 mg/kg per os.

The mice are introduced in groups of 3 (1 mouse as control, 1 mouse

with vincamine supply and 1 mouse treated with compounds prepared in accordance with the invention) in an atmosphere made poor in oxygen by establishing a partial negative pressure in a hermetically sealed container where the pressure is reduced to 185 mm Hg for 40 seconds by means of a vacuum pump.

The survival time for the mice is determined, as cessation of respiration is taken as a sign of death. These survival times are increased by means of agents capable of favoring the oxygenation of the cerebral tissue.

The mean survival time is determined for all control animals

and for each of the treated groups. The percentage increase in survival time in relation to the values observed in the control animals is calculated.

The static analysis of the results is carried out using the non-parametric test of Mann and Whitney (the comparisons are carried out in relation to the controls) ..... o

The magnitude of the antianoxia effects of the compounds of formula I is judged in relation to the values obtained with the usual active dose of 200 mg/kg per os. of vincamine.

It is then established that for doses of active substances from

20 mg/kg to 100 mg/kg the survival time for the experimental animals is of the same order of magnitude or longer than the survival times obtained with vincamine at 200 mg/kg.

III - demonstration of a peripheral vasodilatory effect: Examination of the cardiovascular system in anesthetized dogs

The investigation of the compounds of formula I was carried out

in non-pure breed male dogs weighing between 16 and 28 kg, anesthetized with pentobarbita (30 mg/kg i.v.) while anesthesia was maintained during the experiment by means of a slow discontinuous perfusion of pentobarbital (2-5 mg/kg/ hour in a volume of 1.2 - 3 ml).

The animals are placed in an assisted ventilator.

The peripheral vasodilatory effects were investigated by recording the variations in mean delivery volume of a femoral artery.

The compounds dissolved in distilled water are administered by injection into the saphenous vein in doses corresponding to approximately 1/800, 1/400, 1/200, 1/100, 1/50, 1/20 and 1/10 of the LD5Q determined by intravenous administration in mice.

The compounds of formula I quite strongly increase the peripheral vascular flow rates from small doses and prove particularly interesting for the duration of their action.

The compounds of formula I and their addition salts with pharmaceutically acceptable acids can be used in therapy, in particular in the treatment of vascular cerebral disorders, circulatory cerebral insufficiency, circulatory disturbances in the extremities and arteriopathy in the limbs.

The compounds and their addition salts with pharmaceutically acceptable acids can be administered to humans orally, rectally or parenterally, especially in connection with pharmaceutically acceptable adjuvants.

substances.

The compounds can be administered: in the form of tablets, gels or any other form intended for oral administration, or in the form of suppositories, or in the form of preparations for parenteral administration.

The compounds can be added in unit doses of between 1 and 50 mg of the active ingredient.

Administration in humans can be carried out in doses of 5 mg to 250 mg per day and night.

Claims (1)

Process for the preparation of pharmacologically active indolo-quinolizine compounds of the general formula (I) in which R means hydrogen, C₁ -C₁ alkyl, C₁ -C₁ alkoxycarbonyl or arylcarbonyl, especially benzoyl, A means hydrogen, B means hydrogen or C₁-C₁ alkyl, or A and B together form a group with formula wherein R₁ means hydrogen or C₁ -C₁ alkoxycarbonyl, as well as their addition salts with pharmaceutically acceptable acids, characterized by the steps of at a) a 2,3,4,6,7,12-hexahydro-indolo 2, 3-aj-quinolizine with formula nitrosated to a nitroso derivative (III) with formula • b) this nitroso derivative is treated in a strongly acidic environment to an unsaturated hydroxyimino derivative (IV) wherein Z represents a residue of a strong acid, c) this unsaturated hydroxyimino derivative (IV) is reduced, - either first with sodium borohydride in alcoholic solution and with final reduction of the compound (V) thus obtained with formula by means of lithium aluminum hydride or bis(2-methoxy-ethoxy)-sodium aluminum hydride in solution in ether, or -by catalytic hydrogenation which leads to a compound (Ia) of formula and d) the compound Ia is optionally converted into other compounds of formula I in which B and R have the indicated meanings other than H, by means of classical reactions.