DE2828396A1 - BENZOFURAN AND DIHYDROBENZOFUR DERIVATIVES - Google Patents

Description

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Patent application

/ uiiuslder: SHJiLL ΙΙΜΪΈΚΜATIONALE RJ-JSEARCH MAATSCHAPPIJ B.V. Carel van Bylandtlaan 30, The Hague, Netherlands

Title: Benzofuran or Dihydrobenzofuran derivatives

6292

809882/0977

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PATENT LAWYERS

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1A-51 063

Applicant: Shell Int.

description

The invention relates to benzofuran and 2,3-dihydrobenzofuran derivatives, Process for their preparation and their use as lipogenesis inhibitors in warm-blooded animals.

The invention relates, inter alia, to an inhibitor the lipogenesis of warm-blooded animals, comprising a pharmacologically acceptable carrier and A) a benzofuran derivative of the formula

(I)

in which R is bonded to a carbon atom in the 5- or 6-position and is a cycloalkyl group with 3 to 6 carbon atoms, an alkyl group with 4 to 8 carbon atoms, an alkoxy group with 4 to 8 carbon atoms, a phenyl, phenoxy, Benzyl or benzoyl group, where each of the last-mentioned T groups optionally by 1 or 2 substituents from the group of nitro groups, chlorine or bromine atoms or alkyl groups with 1 to 6 carbon atoms R can be a hydroxy or benzoyl group or an alkoxy group having 1 to 4 carbon atoms or an alkenyloxy or

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Alkynyloxy group or a cycloalkyloxy group, where the last-mentioned group has 3 to 6 carbon atoms or B) a 2,3-dihydrobenzofuran derivative of the formula

(II)

in which R has the meaning given for formula I and R likewise has the meaning given in formula I or is an allylamino group.

In these compounds, each alkyl, alkyloxy, alkenyloxy and alkynyloxy group can be straight or branched chain. Preferably each such alkenyloxy and alkynyloxy group contains 2 to 4 carbon atoms.

The 2,3-dihydrobenzofuran derivatives of the formula II can be due to their asymmetrical configuration in the 2-position of the molecule in the form of two optically active isonies. The invention therefore relates to agents which contain an optically active isomer and various combinations of the individual optically active isomers.

Because of their particularly high activity in inhibiting lipogenesis, 5-phenyl-2-benzofurancarboxylic acid and 2,3-dihydro-5-phenyl-2-benzofurancarboxylic acid are used and 2,3-dihydro-5-phenyl-N-2-allyl-2-benzofurancarboxamide preferred.

The preparation of typical compounds of the formulas .1 and II is illustrated in the examples. Other typical

• j compounds of the formula I are those in which R and R have the following meanings:

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a) 6-phenoxy OH b) 5- (4-chloro-pheny1) OH c) 5-cyclohexyl OH d) 5- (P-ToIyI) OH e) 5-benzoyl OH f) 5-benzyl QH G) 5- (2 _J ⁱ l-dichlorophenoxy) OH H) . 5- (2-methylpropyl) OH x) 5- (l, l, 3,3-ltetramethylbut ; yl) OH j) 5-hexyloxy OH k) 5- (4-nitrophenyl) OH D. 5-phenyl fiutoxy m) 5-phenyl Cyclopropyloxy n) 5-phenyl 2-propynyloxy O) 5-phenyl 2-propenyloxy p) 5-phenyl Cyclohexyloxy q) 5-phenyl Benzyloxy r) S- phenoxy OH s) 5-benzyl OH t) . 5- (2-methylpropyl) OH u) 5-cyclohexyl OH v) 6-phenoxy .'iutoxy v;) 5-hexyloxy OH

809882/0977

5-benzyl -X- 1A-51 063 ALlyloxy 6-phenoxy 2-propynyloxy χ) ' 5-phenyl Cyclopropyloxy y) 5-phenyl Benzyloxy ζ) aa)

Other typical compounds of formula II are those at

-1

where R is an allyl aino group and R has the following meaning:

bb) 6-phenoxy

cc) 5- (JJ-Cilor-phenoxy)

dd) 5-cyclohexyl

ee) 5-Cp-ToIyI)

ff) 5-benzoyl

gg) 5-benzyl

hh) 5- (2 ₃ i) -Dichlorophenoxy)

Ii) 5- (2-methylpropyl)

JJ ") 5- (1,1,3,3-tetramethylbutyl)

klc) 5-hexyloxy

11) 5 - (^

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282839a

The following four compounds included in the invention Agents used as inhibitors are known:

S-phenyl ^ -benzofurancarboxylic acid,

Ethyl ~ 5-phenyl-2-benzofurancarboxylate, 2,3-dihydro-5-phenyl-2-benzofurancarboxylic acid and ethyl 2,3-dihydro-5-phenyl-2-benzofurancarboxylate.

These four compounds are described by Witiak, D.T., et al., 1976 Lipids 11 (5): 384-391. Processes for their production are also given there.

The invention also relates to benzofuran derivatives of the formula I and 2,3-dihydrobenzofuran derivatives of the formula II, except for 5-phenyl-2-benzofurancarboxylic acid and 2,3-dihydro-5-phenyl-2-benzofurancarboxylic acid and their esters.

The ethyl 2-benzofuran carboxylates of the formula

(III)

is bonded in the R (A) in the 5- or 6-position and one Cycloalkyl group with 3 to 6 carbon atoms, an alkyl group with 4 to 8 carbon atoms, an alkoxy group with 4 to 8 carbon atoms, denotes a phenoxy, benzyl or benzoyl group, the last-mentioned three groups optionally by one or two identical or different nitro groups, chlorine or bromine atoms or alkyl groups with 1 to 6 carbon atoms may be substituted or (B) is bonded to a carbon atom in the 6-position and a phenyl group, optionally by 1 or 2 identical or different nitro groups, chlorine or bromine atoms or alkyl groups with 1 to 6 carbon atoms can be substituted, means can be prepared by reacting a salicylaldehyde of the formula

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ΛΧ

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2Β2Β3Μ

-OH -C-H

I!

(IV)

in which R has the meaning given in formula III with Diethyl bromomalonate in the presence of anhydrous potassium carbonate. This procedure corresponds to Kurkudar and Rao, Indian Acad. Sci., Section A, 58 (1963) 336 and Witiak D.T., et al., 1976 Lipids 11 (5): 384-391.

The 2-benzofurancarboxylic acids of the formula

(V)

in which R has the meaning given for formula III, can be prepared by hydrolysis of an ethyl ester of Formula III. This procedure corresponds to that of Kurkudar and Rao, Indian Acad. Sci., Section A, 58 (1963) 336.

Furthermore, the 2,3-dihydro-2-benzofurancarboxylic acids of the formula

(VI)

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in which R has the meaning given for formula III, are prepared by reducing a 2-benzofurancarboxylic acid of formula V in the presence of sodium amalgam and an aqueous solution of an alkali hydroxide. Sodium hydroxide is a suitable one Alkali hydroxide. This method corresponds to that according to Fredga, Acta Chem. Scan., 9 (1955) 719.

The 2-benzofuran carboxylates according to the invention can also be used the formula

(VII)

or 2,3-dib.ydro-benzofurancarboxylate of the formula

(VIII)

where R has the meaning given in formula III, R a Benzyloxy group or an alkoxy group having 1 to 4 carbon atoms or an alkenyloxy or alkynyloxy group or a cycloalkyl group, the last-mentioned 3 to 6 Has carbon atoms or, alternatively, R is in the 5-position and denotes a phenyl group, which is optionally replaced by 1 or 2 identical or different nitro groups, Chlorine or bromine atoms or alkyl groups with 1 to 6 carbon atoms is substituted and R is a benzyloxy group or a Alkyloxy group with 1, 3 / ^^ carbon atoms or an alkenyloxy or alkynyloxy group or a cycloalkyloxy group, the latter having 3 to 6 carbon atoms are made by reacting a 2 ~ benzofurancarboxylic acid of the formula

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(IX)

or a 2,3-dihydro-benzofurancarboxylic acid of the formula

(X)

where in the formulas IX, X and XI R and R are those in formula VIII Have given meaning, in the presence of a solvent such as toluene and a catalytic amount of an acid such as Sulfuric acid, hydrochloric acid or p-toluenesulfonic acid. This The process corresponds to the so-called Fischer-Speier esterification.

The invention also relates to a process for the preparation of 2,3-dihydrobenzofuran derivatives of the formula II, in which R is a Allylamino group means, where one is a 2,3-dihydro-2-benzofurancarboxylate of the formula

(XII)

in which R has the meaning given in formula II and R is an alkyl group, reacts with allylamine in the presence of a solvent. The alkyl group in the allyl ester desirably contains 1 to 5 carbon atoms and / especially one Ethyl group. Ethanol is a suitable solvent. The reaction takes place at room temperature, higher temperatures can but can also be used to reduce the response time.

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add, ζ. B, the equipment can be refluxed will. Preferably about a 4 "to 6-fold excess is used of the amine applied. The desired product can be obtained by evaporating off the solvent and excess Amine and subsequent application of customary processes, such as selective extraction, recrystallization and / or Chromatography on a dry column to isolate the desired product.

The salicylaldehydes of Formula IV can be prepared by treating the corresponding phenol with chloroform under strongly basic conditions according to the Reimer-Tiemann reaction (References are given in Merck Index, 9th Ed. Pp. ONR-74 and Russell, A. and Lockhart, L.B., Organic Synthesis, 22, 63 (1942).

Many of the precursor phenols are known compounds. Others can be made by conventional methods. So are the phenols for the compounds (a), (r), (v), (yy) and (bb), (h), (t) and (ii), (c), (u) and (dd), ( e) and (ff) and (i) and (jj) are commercially available. The phenols for that

(ε)

Connections (j), (w) and (kk), (b), / and (hh) and (cc) can are produced by diazotization of the corresponding anilines; the phenols for the compounds (s), (x) and (f) and (gg) can be prepared by Y / olff-Kisehner reduction the phenols for compounds (a) and (ff); the phenols for compounds (d) and (ee) and (k) and (11) are given in Beilstein. If necessary, e.g. B. when R is a phenoxy group, as in the case of compound (g), the aniline can be produced by reacting the sodium salt of R-phenyl with the corresponding chloronitrobenzene and reduction (hydrogen, Palladiura-on-carbon catalyst, Ethanol or acetic acid as solvent) the nitro group to the amino group.

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The benzofuran derivatives of the formula I and 2,3-dihydrobenzofuran derivatives of the formula II can be used to control lipogenesis in warm-blooded animals, e.g. B. in domestic animals, zoo animals, herd animals (cattle), fur animals, etc., such. B. dogs, cats, mink, sheep, goats, pigs, cattle, horses, mules, donkeys and poultry. The effect is achieved by administering an effective amount of one or a mixture of two or more of the compounds of the formula I or II, orally or parenterally. The compounds can be administered as such or as an active ingredient in a conventional medicament. The agents according to the invention are therefore suitable for inhibiting lipogenesis in warm-blooded animals if an effective amount of a compound of the formula I or II or an agent containing such a compound is administered to such animals.

The compounds of formula I or II or agents that contain them Compounds containing compounds can be administered orally in any suitable manner. So they can be administered orally are considered a solution through intubation, in food and the Water for the animal, in a food additive or in a preparation specifically for administering the drug is determined. Suitable preparations include solutions, suspensions, dispersions, emulsions, tablets, BoIi, powders, Capsules, syrups and elixirs. For parenteral administration, the agents can be in the form of a solution, suspension, dispersion or emulsion. They can be in the form of an implant or some other preparation for controlled, delayed Active ingredient delivery-to be applied. Inert pharmacologically acceptable Carriers, such as water, oils suitable for food, Gelatin, lactose, starch, magnesium stearate, talc and / or vegetable gums can be used.

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The dose of compound of formula I or II required to inhibit lipogenesis depends on the particular applied compound and the specific animal to be treated. In general, however, the results will be satisfactory achieved when the compounds are administered at a dose of from about 1 to about 500 mg per kg of body weight. They can be taken as a single dose or in one Series of doses can be administered on the same day or over several days. There should be one for each specific animal special dosage according to individual needs, the particular compound used, and the experience of the person receiving the administering the agent or monitoring the administration will.

The invention is illustrated in more detail by the following examples. In the production examples, the identity was of the product and the precursor confirmed by appropriate chemical and spectroscopic analyzes.

example 1

Ethyl - ^ - phenyl-E-benzofurancarboxylate (compound 1)

22 g of p-phenylphenol were dissolved in 95% strength ethanol. A solution of 40 g sodium hydroxide in 80 ml v / water was added quickly. The resulting solution was heated to 75 to 80 ⁰ C and 20 ml of chloroform was added within 1 h and the mixture was heated slightly under reflux. The mixture was then stirred for 3 hours, cooled and ethanol and excess chloroform evaporated under reduced pressure. The resulting residue was cooled and poured into cold water. The resulting mixture was acidified by the slow addition of hydrochloric acid and extracted with diethyl ether. The solvent was evaporated from the extract under reduced pressure, the residue was poured into twice the volume of saturated sodium metabisulfite solution and the mixture was shaken vigorously for 45 minutes.

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The resulting semi-solid bisulfite addition compound was Left to stand for 1 h, filtered in the dark and treated with small amounts of ethanol and diethyl ether to remove the Phenol washed. The bisulfite addition compound was decomposed with dilute sulfuric acid, the mixture on the Heated water bath for 30 min, extracted the cooled mixture with diethyl ether and dried over Na ^ SO / and the solvent evaporated under reduced pressure. The residue was treated with activated charcoal and recrystallized from ethanol / water. 5-phenylsalicylaldehyde compound was obtained 1A, as yellow crystals, m.p. 98-99 ° C.

A mixture of 0.99 g of compound 1A, 0.096 g of diethyl bromomalonate and 1.25 g of anhydrous potassium carbonate in 20 ml of 2-butanone was refluxed for 10 hours. The solvent was evaporated off under reduced pressure, the residue was cooled, poured into 100 ml v / water and extracted with diethyl ether. The extract was washed with cold 5 % sodium hydroxide solution and with water and then evaporated under reduced pressure. The residue was recrystallized from ethanol. C. gave compound 1 as white crystals, mp. 109-110 ⁰

Example 2

5-phenyl-2-benzofurancarboxylic acid (compound 2)

A mixture of 1.3 g of compound 1 and 50 ml of 10% alcoholic Potassium hydroxide solution was refluxed for 4 hours. The solvent was evaporated under reduced pressure and the residue washed with diethyl ether and dissolved in water. The basic solution was made with dilute hydrochloric acid acidified and extracted with diethyl ether. The ether layer was extracted with dilute sodium hydrogen carbonate solution. The aqueous solution was again with dilute salt

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acidified and extracted with diethyl ether. The ether extract was _{dried over Ua 2} SO ^ and evaporated under reduced pressure. The residue was recrystallized from ethanol. Connect / as a white solid, mp. 220-221 ⁰ C. This gave

Example 3

2,3-Dihvdro-5-phenyl-2-benzofurancarboxylic acid (compound 3)

5.0 g of compound 2 were mixed with 90 ml of 10-6 strength sodium hydroxide solution. Sodium amalgam (prepared from 1.5 g of sodium and 50 g of mercury) was then added to the mixture over a period of 1 hour with stirring. The mixture was then stirred for 24 hours and allowed to stand for a further 24 hours at room temperature. The mercury was separated off, the solution was neutralized with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with dilute sodium bicarbonate solution, the aqueous layer separated, acidified again with dilute hydrochloric acid and extracted with diethyl ether. The extract was dried over NapSO, and evaporated under reduced pressure. The residue was recrystallized from ethanol. The compound 3 as white crystals, mp was obtained. 186-187 ⁰ C.

Example 4

2,3-dihydro-5-phenyl-benzofuran »2-carboxylate (compound 4)

A mixture of 2.5 g of compound 3, 60 ml of ethanol, 20 ml of dry benzene and 2 ml of concentrated sulfuric acid was made Heated under reflux for 7 h, during which the water formed was removed. The resulting mixture was concentrated and the Residue dissolved in diethyl ether. The solution was saturated with Sodium bicarbonate solution and washed with water.

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The aqueous portion was extracted with diethyl ether. The combined organic layers were dried over Na 2 SO 4 and the solvent removed under reduced pressure. The residue was distilled. To give compound 4 as a colorless liquid, b.p. 180-181 ⁰ C, 47 Pa.

Example 5

2,3-Dihvdro-5-phenyl-N ~ 2 - propenyl ~ 2-benzofurancarboxamide (compound 5)

An ethanolic solution of 4 and an excess of allylamine was refluxed for 2.5 days. The excess amine and solvent were evaporated under reduced pressure and the resulting gummy product recrystallized from methylene chloride / hexane. 5 was obtained as a white solid, melting point 112 ^° C.

Examples 6 to 10 Attempts to demonstrate the inhibition of lipogenesis;

The effectiveness of compounds 1 to 5 for inhibiting the Lipogenesis in tissue from warm-blooded animals was determined by placing samples of pig fat tissue in a liquid Medium containing radioactive glucose and the compound to be examined immersed for a while and then the lipid of the treated tissue and determined the uptake of radioactive carbon by scintillation counting. The experiments were carried out on adipose tissue from pigs, because in pigs the main lipogenesis site seems to be the adipose tissue. In detail, the experiments were carried out according to the following general procedures carried out:

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150 rag sections of pig adipose tissue were shaken for 2 h in 3 ml Krebs-Ringer bicarbonate solution containing half the normal calcium concentration, 60 μmol glucose, 0.5 / μCi glucose-U C and 300 μU insulin and 5 % dimethyl sulfoxide (DMSO ) incubated. The compounds to be examined were added as a solution or suspension in DMSO and were present in a concentration of 100 / Ug / ml with the incubation gel.

The incubation was terminated by adding 0.25 ml of 1 η sulfuric acid. The resulting mixture was extracted with a total of 25 ml of chloroform: methanol (2: 1 by volume). The extracts are washed according to Folch et al. (J. Biol. Chem., 226, 497-509, (1957.)), air dried and placed in a liquid scintillation counter with 15 ml of counting liquid (2 parts of toluene, containing 0.4 % w / v, New England Nuclear Omnifluor and 1 part Triton X-100) counted. The experiments were run in triplicate and were accompanied by comparative experiments in which all ingredients, amounts and conditions were the same with the exception that no test compound was added. From the data obtained, the percent inhibition of lipid synthesis by the test compound was calculated. The values obtained in the experiments are reported in Table I as the percentage inhibition of lipogenesis compared to the results obtained in the comparative experiments in which only the test compound was omitted.

Table I.

Example No. Compound No. Percent Inhibition

6 1 12

7 2 49

8 3 50

9 4 21 10 5 59

Claims (9)

Claims "\ J Benzofuran or 2,3-dihydrobenzofuran derivatives of the general formula (D bindiong indicates, in which the dotted line is a possibly existing double the R / is a carbon atom in the 5- or 6-position in the Molecule is bound and a cycloalkyl group with 3 to 6 carbon atoms, an alkyl group with 4 to 8 carbon atoms, an alkoxy group having 4 to S carbon atoms, a phenyl, phenoxy, benzyl or benzoyl group, any of the the last-mentioned four groups, optionally with one or two nitro groups, chlorine or bromine atoms / or alkyl groups -ι can be substituted with 1 to 6 carbon atoms and R a hydroxyl or benzyloxy group or an alkyloxy group with 1 to 4 carbon atoms or an alkenyloxy or alkynyloxy or a cycloalkoxy group, the latter group having 3 to 6 carbon atoms, and R if it is is a 2,3-dihydrobenzofuran, optionally one Is allylamino group. 2. 2,3-Dihydro-5-phenyl-N-2-allyl-2-benzofurancarboxamide. 80988 2/0 9 77 2028390 - 2 ~ 1A-51 063 3. Process for the preparation of ethyl 2-benzofurancarboxylates according to claim 1 of the formula , C-OC ₂ H ₅ (III) in R (A) to a carbon atom in the 5- or 6-position is bonded in the molecule and a cycloalkyl group with 3 to 6 carbon atoms, an alkyl group with 4 to 8 carbon atoms, an alkoxy group containing 4 to 8 carbon atoms, a phenoxy, benzyl or benzoyl group, each the last-mentioned three groups optionally by one or two nitro groups, chlorine or bromine atoms / or Alkyl groups having 1 to 6 carbon atoms can be substituted, or (B) on a carbon atom in 6-position is bound in the molecule and has a phenyl group, optionally by one or two nitro groups, chlorine and / or bromine atoms or alkyl groups with 1 to 6 carbon atoms Can be substituted, means, characterized in that a ^ salicylic acid aldehyde of J.'O sleeves (IV) in which R has the meaning given in formula III, reacts with diethyl bromomalloBt in the presence of anhydrous potassium carbonate. 809882/0977 282839S 1Ä-51 063 4. Process for the preparation of 2-benzofurancarboxylic acids according to Claim 1 of the formula (V) in which R has the meaning given for formula III, characterized in that one is an ethyl ester of formula III hydrolyzed. 5 »Process for the preparation of 2,3-dihydro-2-benzofurancarboxylic acids according to claim 1 of the formula (VI) in which R has the meaning given for formula III, characterized in that a 2-benzofurancarboxylic acid is used of formula V in the presence of sodium amalgam and an aqueous solution of an alkali metal hydroxide. 6. Process for the preparation of 2-benzofuran carboxylates according to claim 1 of the formula (VII) or 2,3-dihydro-benzofuran carboxylates of the formula 809882/0977 1-51 063 282839S (VIII) in which R has the meaning given for formula III and R is a benzyloxy group or an alkoxy group with 1 to 4 carbon atoms or an alkenyloxy or alkynyloxy group or a cycloalkyloxy group, the latter Has 3 to 6 carbon atoms, or R is located on the carbon atom in the 5-position in the molecule and a phenyl group, optionally, by one or two Nitro groups, chlorine or bromine atoms / or alkyl groups with 1 to 6 carbon atoms is substituted and R is a benzyl or 4 'oxy or an alkyloxy group with 1, 3 / carbon atoms or an alkenyloxy or alkynyloxy group or a cycloalkyloxy group, the last-mentioned 3 to Has 6 carbon atoms, characterized in that a 2-benzofurancarboxylic acid of the formula (IX) or a 2,3-dihydro-benzofurancarboxylic acid of the formula reacts with an alcohol of the formula ROH (XI) - 5 -809882/0977 - 5 - 1A-51 063 where in the formulas IX, X and XI R and R ^{1 have} the meaning given for formula VIII, in the presence of a solvent and a catalytic amount of an acid. 7. Process for the preparation of 2,3-dihydrobenzofuran derivatives of formula II according to claim 1, wherein R is an allylamino group, characterized thereby e t that one is an alkyl dihydro-2-benzofurancarboxylate the formula (XII) in which R has the meaning given for formula II and R is an alkyl group, reacts with an allylarain in Presence of a solvent. 8. The method according to claim 7, characterized in that R in formula XII 1 to 5 Kohlenotc contains atoms, is preferably an ethyl group. 9. Medicines for inhibiting lipogenesis, characterized in that they are at least as active ingredient a compound according to claim 1, optionally together with the usual carriers and / or additives. 809882/0977