NO128994B - - Google Patents

Description

Analogy method for the production of new, therapeutically effective benzodioxole compounds.

The present invention relates to an analogue method for the production of hitherto unknown benzodioxole compounds with valuable pharmacological properties. The benzodioxole compounds referred to here have the general formula:

where R<1> is an amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidino or dialkylamino-alkylamino group or a group of the formula OR g,

where R 9 is a hydrogen atom, an alkyl group with at most 4 carbon atoms or a pharmaceutically acceptable inorganic or organic cation,

2 3

R and R are the same or different and each represents a hydrogen atom or an alkyl group,

4 5 6

R , R and R are the same or different and mean each

a hydrogen atom, fluorine atom or chlorine atom or a tri-fluoromethyl, nitro or hydroxy group or an alkyl or alkoxy group,

R 7 means hydrogen or an alkyl group,

where the above-mentioned alkyl and alkoxy groups each contain no more than 4 carbon atoms,

R Q is an alkyl or alkenyl group with 2-8 carbon atoms or a cycloalkyl group with at most 8 carbon atoms, optionally monosubstituted with Cl, OH or alkoxy with at most 4 carbon atoms; or a phenyl group, which is optionally substituted with no more than three identical or different substituents selected from Cl, alkyl groups and alkoxy groups with no more than 4 carbon atoms, or is optionally substituted with 3,4-methylene dioxide; or R together with R 7 and the carbon atom in the 2-position in the benzodioxole ring form a cycloaliphatic ring with at most 7 carbon atoms.

The compounds in question here have valuable anti-inflammatory and/or analgesic and/or antipyretic properties.

The pharmacological properties of the compounds of formula (I) vary according to the position and nature of the individual substituents, and they can advantageously be compared with such known anti-inflammatory agents as acetylsalicylic acid, phenylbutazone and indomethacin.

The compounds with the general formula (I), where R 2 denotes H and R 3 denotes H or CH 3 , show a particularly strong effect in pharmacological tests that indicate anti-inflammatory action. Such stronger effectiveness is also demonstrated by compounds where R 7 stands for H or CH3>

The compounds produced according to the invention are effective in pharmacological tests that are usually used for determining anti-inflammatory action ("Aerosil"-edema test as described by Th. Wagner-Jauregg et. al. Heiv. Physiol. Acta 21, 65

(1963), carrageenin-edema test as described by C.A.Winter et. eel. Proc.Soc. Exp. Biol. With. 111 544-47 (1962), analgesic activity (the torsion test as described by R. Koster et al. Fed. Proe. 18, 412 (1959)) and anti-pyretic activity (the yeast fever test in rats as described by CA. Winter in Non-steroidal Anti-inflammatory Drugs (S. Garattini and M.N. Dukes Eds) page 190, Excerpta Medica Foundation 1965).

The method according to the invention is characterized by

a) a carbonyl compound of the general formula

7 8

where R and R have the above meanings,

or a reactive derivative derived therefrom is treated with a dihydroxy compound of the general formula

or a reactive derivative derived from this, where R"'"0 means 24 11 12 13 or -C0R and R , R and R mean respectively R<4>, R5 and R6 or means NH2, CH2OR<17> or C00R<18 >, 16 17 where R -R has the above meaning, R means alkyl, aralkyl, aryl, alkylsulfonyl, arylsulfonyl, 18 alkylcarbonyl or arylcarbonyl; R denotes hydrogen, 19 alkyl, aralkyl or aryl; R hydrogen, alkoxy, aryloxy, chlorine, bromine, cyano, trichloromethyl, dichloromethyl, arylcarbonyloxy, aralkylcarbonyloxy, cycloalkylcarbonyloxy and (higher) alkylcarbonyloxy; R 20 denotes hydrogen, 21 alkyl, aryl or aralkyl; R is carboxyl, cyano, carbamoyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, hydroxy, chlorine, bromine, arylmethoxy; R lower 23 alkenyl; R hydrogen, lower alkyl or lower alkenyl 22 23 or R and R together form a methylene group (CH9=) and 24 R denotes methyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl, whereby a compound of the general formula IV is obtained

where R<7>, R<8>, R10, R11, R12 and R13 have previously indicated

meanings,

or

b) a carbonyl compound of the general formula (II),

7 8

where R and R have the meanings given above, or a reactive derivative thereof is treated with a dihydroxy compound of the general formula VI

or a reactive derivative thereof, whereby a compound of the general formula VII is obtained

.after which this compound (VII) is acetylated in the 5-position and the obtained acetyl derivative by means of Willgerodt rearrangement and hydrolysis is transferred to a compound with the

1 2 "3

general formula I, where R is OH, R = R = H

or

c) a compound with the general formula

where R<15> means H or CH3 and R<16> is CH3, or both

R1<5> and R<16> mean aryl groups, and R<10> - R<13> have the

previously stated meaning.

is converted to a compound of the general formula (IV) by transacetalization of a carbonyl compound of the general formula (II) in the presence of an acetalization catalyst,

after which, if necessary, the groups R"<*>"<0>, K*~^~, R^ and R"<*>"<3> are converted by usual methods into respectively

R<4>, R<5> and R6

where r\ R 2 , R 3 , R 4 , R 1 and R 2 have previously been indicated

importance,

and/or, if desired, when R^" is an OH group, transfer this in a manner known per se to other forms within the definition of R"<*>-, and/or, if desired, cleave a racemic mixture in the stereoisomeric forms.

As a reactive derivative derived from the carbonyl compound of formula (II), an acetal of a lower aliphatic alcohol or a gem dichloride or a gem dibromide can be used.

Enol ethers with a lower aliphatic alcohol of the carbonyl compounds of general formula (II) which can exist in enol form can also be used as such reactive derivatives.

As a reactive derivative derived from the dihydroxy compound of formula (III), cyclic sulfuric acid or carboxylic acid esters can be used.

If a carbonyl compound of the general formula (II) itself

or an acetal or an enol ether derived from it is used by reaction with a dihydroxy compound of general formula (III) or a reactive derivative thereof, the method can conveniently be carried out in the presence of a common acetalization catalyst such as sulfuric acid, phosphoric acid, polyphosphoric acid, hydrochloric acid or trifluacetic acid, pyridine hydrochloride, calcium chloride or an aliphatic or aromatic sulphonic acid or phosphoric acid or an ion exchanger bearing sulphonic acid groups.

The method is preferably carried out at a temperature between 0°C and the boiling point of the reaction mixture in an inert solvent such as a hydrocarbon, chlorinated hydrocarbon, ether or ester. The carbonyl compound of formula (II) itself or the reactive derivative thereof can be used as a solvent.

If the reactive derivative derived from the carbonyl compound of formula (II) is the corresponding gem dichloride or gem dibromide, the reaction is preferably carried out in the presence of a hydrogen ion acceptor such as hydroxide, carbonate or hydrogen carbonate of an alkali metal or alkaline earth metal or a tertiary amine.

Also compounds with the general formula

where R 15 denotes H or CH, and R 16 is CH, or both

R and R 16 denote aryl groups,

can be converted to a compound of the general formula (IV) by transacetalization with a carbonyl compound of the general formula II, in the presence of an acetalization catalyst.

Compounds of the general formula (I) containing asymmetric carbon atoms can, if desired, be resolved into their stereoisomers by conventional methods such as fractional crystallization of compounds of formula (I), where R is an -OH group, in form of salts with optically active bases. Such stereoisomers can also be prepared by using optically active starting substances in the synthesis.

Benzodioxole compounds are described in Danish patent no.

109 713. The compounds known from this<1> patent differ in structural terms significantly from the compounds present here in that the known compounds in the benzodioxole ring clearly contain a methylene group, while after near-7 8

being the invention, the substituents R and R cannot simultaneously be hydrogen.

The known compounds also differ from those present here at the other end of the molecule in that the carbonyl group is direct

in

bound to the benzene nucleus, while in the compounds according to the present invention there is always a carbon atom between the benzene nucleus and the carbonyl group.

in

Performed research! have shown that in order for the compound to exhibit an anti-inflammatory effect, it is essential that at least one hydrogen in the methylene group in the dioxor ring is

in

substituted by alkyl' of at least 2 carbon atoms. Thus, for example, benzodioxoacetic acid provides a demonstrable anti-inflammatory

in

toric effect, while, on the other hand, the corresponding compound substituted with lower alkyl in the 2-position clearly exhibits such an effect.

t

In the following, the results from a number of experiments carried out are reproduced:

in

j

IN

IN

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The following examples illustrate the present invention.

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Example 1.

To a mixture consisting of 10 mg of methyl-oc-methyl (3,4-dihydroxyphenyl)-acetate! 6.6 g of 3-pentanone and 50 ml of toluene are added to 7.25 g of phosphorus pentoxide all at once with vigorous stirring. The reaction mixture is refluxed for one hour and then cooled to room temperature. The solution containing the product is decanted and passed through a short column of activated alumina and then evaporated to dryness in vacuo, yielding a residue of methyl-oc-methyl-(2,2-diethyl-1,3-benzodioxole)-5- acetate as an oil (boiling point 115-135°C at 0.7 mm). The crude ester is hydrolysed with 100 ml of 2 molar potassium hydroxide in methanol by refluxing for 1.5 hours.

in

o -Methyl-(2,2-diethyl-1,3-benzodioxole)-5-acetic acid crystallizes as the morpholine salt; melting point 81.5°C.

The method described above is used for the preparation of: 2,2-diethyl-1,3-benzodiIoxol-5-acetic acid, m.p. 77-78 oC

2-ethyl-2-methyl-1,3-benzodioxole-5-acetic acid (ethanolamine salt, m.p. 104°C) in

! ■

in

spiro-[1,3-benzodioxole-2,1'-cyclopentane]-5-acetic acid (ethanolamine salt, m.p. 108°C

in

spiro-[1,3-benzodioxol-2,11-cyclohexane]-5-acetic acid, m.p. 88°C;

2-methyl-2-tert.butyl-1,13-benzodioxole-5-acetic acid, m.p. 88°C

2-methyl-2-phenyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 110°C)

2-phenyl-1,3-benzodioxole-5-acetic acid, m.p. 117°C

2-isopropyl-1,3-benzodioxole-5-acetic acid, m.p. 70°C

2-isopropyl-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 102°C)

2-methyl-2-propyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 82°C)

2-isobutyl-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 95°C)

2-butyl-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 90°C)

2,2-dipropyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 62°C)

α-Methyl-[2-ethyl-2-methyl-1,3-benzodioxole]-5-acetic acid, m.p. 77.5°C

α-Methyl-[2-isopropyl-2-methyl-1,3-benzodioxole]-5-acetic acid

(morpholine salt, m.p. 112-112.5°C)

α-Methyl-[2-methyl-2-propyl-1,3-benzodioxole]-5-acetic acid (morpholine salt, m.p. 104-104.5°C)

α-Methyl-[2-hexyl-2-methyl-1,3-benzodioxole]-5-acetic acid (morpholine salt, m.p. 87.5-88°C)

α-Methyl-Spiro-[1,3-benzodioxole-2,1'-cyclohexane]-5-acetic acid, m.p. 113-114.5°C

α-Methyl-(2-methyl-2-phenyl-1,3-benzodioxole)-acetic acid (morpholine salt, m.p. 132-134°C)

2-(4-Methoxyphenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 83°C)

2-(2-Methoxyphenyl)-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 92°C)

2-(4-Methoxyphenyl)-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 107°C) : 2-(3,4-methylenedioxyphenyl)-2-methyl-1,3-benzodioxole- 5-acetic acid (morpholine salt, m.p. 108°C)

2-(4-chlorophenyl)-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 108-110°C)

oe,a-dimethyl-(2,2-diethyl-1,3-benzodioxole)-5-acetic acid (morpholine salt, m.p. 73°C)

2-ethyl-2-phenyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 96°C)

2-(2-n-butyl)-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 97°C)

2-(3-n-pentyl)-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 103°C)

2-cyclohexyl-2-ethyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 89-90°C)

in

2-n-propyl-2-phenyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 96°C)

2-(3-chlorophenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 85°C)

2-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-benzodioxole-5-acetic acid

(morpholine salt, m.p. 84°C)

2-(4-chlorophenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 115°C)

2-(2-chlorophenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 104°C)

2-(3-Methoxyphenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 94°C)

2-(2-Methoxyphenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 110°C

2-(3-Methoxyphenyl)-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 89°C)

2-(2,6-dichlorophenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 100°C)

2-(3,4-dimethoxyphenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 112°C)

2-(4-tolyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 118°C)

2-(3,4-methylenedioxyphenyl)-1,3-benzodioxole-5-acetic acid, m.p. 108°C)

2-cyclopropyl-2-methyl-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 85°C)

2,2-diethyl-6-chloro-1,3-benzodioxole-5-acetic acid, m.p. 95°C

2-isopropyl-2-methyl-6-chloro-1,3-benzodioxole-5-acetic acid, m.p. 118°C

α,α-dimethyl-(2-isopropyl-2-methyl-1,3-benzodioxole)-5-acetic acid

(morpholine salt, m.p. 82°C)

α,α-Dimethyl-(2-phenyl-1, 3-benzodioxole)-5-acetic acid (morpholine-

salt, s.p. 103-104°C)

α,α-dimethyl-(2-methyl-2-phenyl-1,3-benzodioxole)-5-acetic acid

(morpholine salt, m.p. 101-103°C)

2-ethyl-2-methyl-7-chloro-1,3-benzodioxole-5-acetic acid, m.p. 117.5-118°C

2-methyl-2-phenyl-7-chloro-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p. 118-119°C)

α-Ethyl (2-butyl-2-methyl-1,3-benzodioxole)-5-acetic acid, sodium salt, (morpholine salt, m.p. 102-104°C)

7-fluoro-2-ethyl-2-methyl-1,3-benzodioxole-5-acetic acid, sodium 20

salt, (the free acid, nD = 1.5265)

7-nitro-2,2-diethyl-1,3-benzodioxole-5-acetic acid, sodium salt, 20

(the free acid, n£ = 1.5485)

7-Trifluoromethyl-2-ethyl-2-methyl-1,3-benzodioxole-5-acetic acid, sodium salt, (the free acid, n£ 20 = 1.5432)

2-(2-Hydroxyethyl)-2-methyl-1,3-benzodioxole-5-acetic acid, sodium salt, (morpholine salt, m.p. 88-90°)

2-(2-Methoxy-n-butyl)-2-methyl-1,3-benzodioxole-5-acetic acid, calcium salt, (morpholine salt, m.p. 91-93.5°C)

2-propenyl-1,3-benzodioxole-5-acetic acid, calcium salt, (morpholine salt, m.p. 101-103°C)

2-(2-Chloropropyl)-2-methyl-1,3-benzodioxole-5-acetic acid, Caladum salt (morpholine salt, m.p. 89-91°C)

Example 2.

A mixture consisting of 13.6 parts of benzodioxol-2-ene (pyro-catechol carbonate), 9.8 parts of cyclohexanone is refluxed

Jknuv

until no more carbon dioxide is evolved. The residue is distilled in vacuo to give spiro-(1,3-benzodioxole-2,1'-cyclohexane). Boiling point 116-119°c/ll mm Hg; melting point 97°C

This compound can also be prepared in the following way:

A mixture consisting of 15.0 parts of 2,2-dimethyl-1,3-benzodioxole, 14.7 parts of cyclohexanone, 100 parts of toluene and 2 parts of p-toluenesulfonic acid is slowly distilled at atmospheric pressure, until all acetone formed has been distilled off. The reaction mixture is cooled to room temperature, washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and distilled in vacuo, thereby obtaining spiro-(1,3-benzodioxole-2,1'-cyclohexane), b.p. 116-119°C/11 mm Hg.

20.4 parts of acetic anhydride are then added to 19.4 parts of spiro-(1,3-benzodioxole-2,1'-cyclohexane). After cooling in an ice bath, 28.2 parts of boron trifluoride-acetic acid complex (BF3"(CH3COOH)2) are added while stirring. Stirring is continued for 30 minutes in the ice bath and then for 90 minutes at room temperature.

The reaction mixture is then poured into an excess of saturated aqueous sodium acetate solution and then extracted with ether. The ether extract is treated with activated carbon, washed over anhydrous sodium sulfate and distilled in vacuo to give spiro-(5-acetyl-1,3-benzodioxole-2,1'-cyclohexane). Boiling point 192-193°C, m.p. 52°C.

(Willgerodt's rearrangement) A mixture consisting of 11.1 g of spiro-(5-acetyl-1,3-benzodioxole-2,1'-cyclohexane), 2.6 g of amorphous sulfur and 7.3 g of morpholine is refluxed for 10 hours. The reaction mixture is poured into 30 ml of absolute ethanol, after which the morpholide of spiro-(1,3-benzodioxole-2,1'-cyclohexane)-5-thioacetic acid is crystallized and filtered off. The product obtained in this way is then hydrolysed by reflux treatment in 200 ml of a solution of 5% sodium hydroxide in 50% ethanol for 10 hours. The reaction mixture is then acidified and extracted with ether, treated with activated carbon and evaporated to dryness.

hot in vacuum. The residue is crystallized from hexane to give spiro-(1,3-benzodioxole-2,1'-cyclohexane)-5-acetic acid, m.p. 88°C.

Example 3.

A mixture consisting of 36.4 g of methyl-3,4-dihydroxyphenylacetate, 29.4 g of cyclohexanone, 0.2 g of p-toluenesulfonic acid and 200 ml of xylene is refluxed with a water separator until the calculated amount of water has been collected. The reaction mixture is then extracted with an aqueous solution of sodium hydroxide and evaporated to dryness in vacuo to give methyl spiro-(1,3-benzodioxole-2,1"-cyclohexane)-5-acetate as an oil with a boiling point of 138-140°C/ 0.15 mm Hg.

Example 4.

10 parts of 2-ethyl-2-methyl-1,3-benzodioxole-5-acetyl chloride are dissolved in 50 parts of methanol and 0.05 parts of concentrated sulfuric acid are added. The reaction mixture is refluxed for 30 minutes and then cooled to room temperature.

The reaction mixture is then dissolved in ether, washed with aqueous sodium hydrogen carbonate solution. The ether solution is dried with anhydrous sodium sulfate and evaporated to dryness. The residue is distilled in vacuum and gives methyl-(2-ethyl-2-methyl-1,3-benzodioxole)-5-acetate, b.p.Q 2 108.5-109°C as an oil.

The same procedure can be used for the production of the following

the compounds: isopropyl-(2-ethyl-2-methyl-1,3-benzodioxole)-5-acetate, oil, boiling point Q > 143°C.

n-butyl-(2-ethyl-2-methyl-1,3-benzodioxole)-5-acetate, oil, boiling point Q 2 190-192°C.

Example 5.

10 parts of 2-ethyl-2-methyl-1,3-benzodioxole-5-acetyl chloride are dissolved in 100 parts of anhydrous ether and shaken with 100 parts of concentrated ammonia.

The ethereal phase is separated, washed with water, dried

over anhydrous sodium sulfate and evaporated to dryness in vacuo.

The residue is crystallized from ether-petroleum ether and gives 2-ethyl-2-methyl-1,3-benzodioxole-5-acetamide, melting point 90-91°C.

The same procedure is used for the preparation of N-(2-ethyl-2-methyl-1,3-benzodioxole-5-acetyl)-morpholine, in the form of an oil, n<20> =1.5470.

The compounds produced according to the invention are generally characterized by the pharmacological activity indicated above, which makes them useful for counteracting certain physiological abnormalities in the living body. Effective amounts of the pharmacologically active compounds can be administered to a living animal by any of a variety of routes, for example orally or parenterally and in some cases intravenously. Other routes of administration are cutaneous, subcutaneous, buccal, intramuscular and intraperitoneal.

As examples of living beings that can be treated with compounds produced according to the invention to alleviate the same and/or similar conditions as those described, in addition to humans, the following can be mentioned: Domestic animals, such as dogs and cats, agricultural animals such as horses, cows, sheep and goats.

Although relatively small amounts of the active compounds prepared according to the invention, even as low as 5.0 mg, can be used in cases of administration to persons having a relatively low body weight, the unit doses are preferably 5 mg or more and preferably 25, 50 or 100 mg also higher, depending on the weight of the person being treated and the particular result desired, as would be clear to professional

the man in the area. Larger intervals are 1 to 3000 mg per unit dose. It will be appreciated that multiple unit dosage forms may be administered approximately simultaneously. The precise individual doses as well as daily doses in a particular case will of course be determined according to well-established medical and/or veterinary principles. As a rule, however, when used therapeutically in humans, the compounds prepared according to the present invention can be administered in an amount of 25 to 5000 mg per day and patient, divided into 1 to 4 doses over a time period of 1 day to 1 year.

Claims (1)

Analogous process for the preparation of new, therapeutically active benzodioxole compounds of the general formula I where R1 is an amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidino or dialkylamino-alkylamino group or a group with the formula OR9, where Rg is a hydrogen atom, an alkyl group with at most 4 carbon atoms or a pharmaceutical acceptable inorganic or organic cation, 2 3 R and R are the same or different and each represent a hydrogen atom or an alkyl group, 4 5 6 R , R and R are the same or different and each represent a hydrogen, fluorine or chlorine atom or a trifluoride -methyl, nitro or hydroxy group or an alkyl or alkoxy group, R 7 means hydrogen or an alkyl group, where the above-mentioned alkyl and alkoxy groups each contain at most 4 carbon atoms, R Q. is an alkyl or alkenyl group with 2-8 carbon atoms or a cycloalkyl group with at most 8 carbon atoms, optionally monosubstituted with Cl, OH or alkoxy with at most 4 carbon atoms; or a phenyl group, which is optionally substituted with no more than three identical or different substituents selected from Cl, alkyl groups and alkoxy groups with no more than 4 carbon atoms, or is optionally Q substituted with 3,4-methylene dioxide; or R together with R 7 and the carbon atom in the 2-position in the benzodioxole ring forms a cycloaliphatic ring with at most 7 carbon atoms, characterized in that a) a carbonyl compound with the general formula II 7 8 where R and R have the meanings indicated above, or a reactive derivative derived therefrom is treated with a dihydroxy compound of the general formula III or a reactive derivative derived from this, where R"*-0 means or -COR24 and R11, R12 and R13 mean respectively R<4>, R<5> and R6 or means NH„, CH0OR<17> or COOR<13 >, 16 17 where R -R has the above meaning, R means alkyl, aralkyl, aryl, alkylsulfonyl, arylsulfonyl, 18 alkylcarbonyl or arylcarbonyl; R denotes hydrogen, 19 alkyl, aralkyl or aryl; R hydrogen, alkoxy, aryloxy , chlorine, bromine, cyano, trichloromethyl, dichloromethyl, arylcarbonyloxy, aralkylcarbonyloxy, cycloalkylcarbonyloxy and Qoyere-) alkylcarbonyloxy; R 20 denotes hydrogen, 21 alkyl, aryl or aralkyl; R carboxyl, cyano, carbamoyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxy- 22 carbonyl, hydroxy, chlorine, bromine, arylmethoxy; R lower alkenyl; R" hydrogen, lower alkyl or lower alkenyl 22 ^3 or R and R" together form a methylene group (CH0=) and 24 z R denotes methyl, cyano, carboxyl , alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl, thereby obtaining a compound with the g eneral formula IV where R<7>, R<8>, R10, R11, R12 and R13 have the above meanings, or b) a carbonyl compound of the general formula (II), 7 8 where R and R have the above meaning, or a reactive derivative thereof is treated with a dihydroxy compound with the general formula VI or a reactive derivative thereof, whereby a compound of the general formula VII is obtained after which this compound (VII) is acetylated in the 5-position and the acetyl derivative obtained by means of Willgerodt rearrangement and hydrolysis is transferred to a compound of the 1 2 3 general formula I, where R is OH, R = R = H or c) a compound of the general formula where R<15> means H or CH3 and R<16> is CH3, or both R^ and R^ mean aryl groups, and R"*"° - R"*"3 has the above meaning, is converted to a compound of the general formula (IV) by transacetalization of a carbonyl compound of the general formula (II) in the presence of an acetalization catalyst, after which, if necessary, the groups R"*-0, R^, R^"<2> and R"<*>"<3> are converted by usual methods into respectively where r\ R2, R3, R4, R and R^ have previously indicated . importance, and/or, if desired, when R"*" is an OH group, transfer this in a manner known per se to other forms within the definition of R"*", and/or, if desired, cleave a racemic mixture in the stereoisomeric forms.