Oxetanones

The present invention relates to new oxetanones, processes for their preparation, pharmaceutical preparations which contain such oxetanones, and the use of these oxetanones in the production of pharmaceutical preparations.

These oxetanones have the formula<chemistry id="chem0001" num="0001"><img file="EP0444482B1_D0001.tif" /></chemistry> wherein Q is a group of the formula         (R³, R⁴) NCO (X) n-CO-Q1         (R³, R⁴) NCO-X'- Q2 or<chemistry id="chem0002" num="0002"><img file="EP0444482B1_D0002.tif" /></chemistry> is and R 1 and R 1 to 3 halogen atoms substituted alkyl with up to 18 carbon atoms or optionally interrupted by a 1,4-arylene group, optionally substituted by an aryl group in the ω-position and optionally substituted by an aryl-C₁₋₄-alkyl group Are alkenyl, alkynyl or alkadienyl groups with up to 20 C atoms, where R¹ can be interrupted by an O or S atom or by a sulfinyl or sulfonyl group other than the α position to an unsaturated C atom, or R¹ can be an aryl-NH- or aryl-C₁₋₄- group alkyl-OCONH, R³ and R⁴ are hydrogen or C₁₋₄-alkyl or together with the N atom to which they are attached, a saturated 3- to 6-membered, optionally an O or S atom in another form the ring containing the α position to the N atom, n is the number 1 or 0, X is an alkylene group which is optionally interrupted by an O or S atom or by a sulfinyl or sulfonyl group and which contains up to 6 carbon atoms and optionally by a hydroxy, mercapto, aryl, aryloxy, arylthio, aryl -C₁₋₄-alkyl, aryl-C₁₋₄-alkoxy-, aryl-C₁₋₄-alkylthio, aryl-C₁₋₄-alkylidene, C₃₋₇-cycloalkylidene or C₁₋₆-alkylidene group or by one or two C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylthio groups is substituted, where two C₁₋₆-alkyl, C₁₋₆-alkoxy or C₁₋₆-alkylthio groups bonded to the same carbon atom or to two adjacent carbon atoms can form an optionally monounsaturated 3 to 7-membered ring and an optionally present one Hydroxy or mercapto group or optionally present unsaturated carbon atom must be in a position other than the α position to an optionally present O or S atom or an optionally present sulfinyl or sulfonyl group, or X is a group of the formula         = CHN (R, R^O) or -CHN (R, R^O) CH₂- R and R^O Hydrogen, C₁₋₄-alkyl, C₁₋₄-alkyl (CO or OCO) -, aryl, aryl (CO or OCO) -, aryl-C₁₋₄-alkyl or aryl-C₁₋₄-alkyl (CO or OCO) - are and X 'is an alkylene group containing up to 6 C atoms, which is substituted by a C₁₋₄ alkoxy, aryl, aryloxy, arylthio, aryl C₁₋₄ alkyl, aryl C₁₋₄ alkoxy or Aryl-C₁₋₄-alkylthio group or by one or two C₁₋₆-alkyl group (s) may be substituted, wherein two C₁₋₆-alkyl groups bonded to adjacent C atoms can form a 3- to 7-membered ring.

The esterastine and its derivatives described in FR 2426679 and FR 2379531 contain an ester group of the formula:         OC (O) CH [NHC (O) CH₃] CH₂C (O) NH₂ In contrast, the present OQ¹ ester group has the formula:         OC (O) CH [N (R, R^O)] C (O) N (R³, R⁴) or         OC (O) CH₂CH [N (R, R^O)] C (O) N (R³, R⁴), depending on X a group of the formula         CHN (R, R °) or CHN (R, R^O) CH₂ is.

The alkyl, alkenyl and alkadienyl groups can be straight-chain or branched. Examples of alkyl groups are methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, undecyl and heptadecyl.

"Aryl" and "arylene" denote phenyl or phenylene or phenyl or phenylene substituted by up to 5 halogen atoms or up to 3 C₁₋₄-alkyl, C₁₋₄-alkoxy or nitro groups.

Preferred oxetanones of the formula I are those in which Q is a group Q 1, R 1 and R optionally alkyl which is interrupted by a 1,4-phenylene group, is optionally substituted by a phenyl group in the ω-position and is optionally substituted by a phenyl-C₁₋₄-alkyl group, Are alkenyl or alkadienyl groups with up to 20 C atoms, where R 1 may be interrupted by an O or S atom in a position other than the α position to an unsaturated C atom, X is an alkylene group which is optionally interrupted by an O or S atom and contains up to 6 C atoms and optionally by a hydroxy, mercapto, phenyl, phenoxy, phenylthio, phenyl-C₁₋₄-alkyl , Phenyl-C₁₋₄ alkoxy, phenyl-C₁₋₄-alkylthio, phenyl-C₁ alkyl-alkylidene, C₃₋₇-cycloalkylidene or C₁₋₆-alkylidene group or by one or two C₁₋₆-alkyl -, C₁₋₆-alkoxy or C₁₋₆-alkylthio groups is substituted, two C₁₋₆-alkyl groups bonded to the same C atom, C₁₋₆-alkoxy or C₁₋₆-alkylthio groups can form a 3- to 7-membered ring and an optionally present hydroxyl or mercapto group must be present in a position other than the α-position to an optionally present O or S atom , or X is a group = CHN (R, R^O), R and R^O Are hydrogen, C₁₋₄-alkyl, C₁₋₄-alkyl- (CO or OCO) -, phenyl or phenyl- (CO or OCO) - and n, R³ and R⁴ have the meaning given above.

Further preferred oxetanones of the formula I in which Q is a group Q 1 are those in which R 1 and R are alkyl, alkenyl, alkynyl, or alkadienyl groups with up to 20 C atoms which are optionally substituted by an aryl group in the ω-position, where R¹ can be interrupted by an S atom in a position other than the α position to an unsaturated C atom, or R¹ anilino, alkyl substituted by a halogen atom with up to 18 C atoms or a group of phenyl-C₁₋₄-alkyl -OCONH-, R³ and R⁴ are hydrogen or C₁₋₄-alkyl or together with the N atom to which they are attached, a saturated O or S atom in a 6-membered ring containing a position other than the α position to the N atom form, n is the number 1 or 0, X is an alkylene group which may be interrupted by an O or S atom or by a sulfinyl group and contains up to 6 C atoms and optionally by one or two C₁₋₆ alkyl or C₁ ₋₆-alkoxy groups is substituted, where two C₁₋₆-alkyl or C₁₋₆-alkoxy groups bonded to the same C atom or to two adjacent C atoms can form an optionally monounsaturated 3 to 7-membered ring, or X a group = CHN (R, R °) or -CHN (R, R^O) CH₂-, and R and R ° are hydrogen, C₂₋₅ alkanoyl or benzyloxycarbonyl.

Also preferred are the oxetanones of the formula I in which Q is a group Q; R¹ and R are C₁₋₂₀ alkyl, R³ and R⁴ are hydrogen and X 'is an alkylene group containing up to 6 C atoms, which can be substituted by a C₁₋₄ alkoxy or by one or two C₁₋₆ alkyl groups , wherein two C₁₋₆ alkyl groups bonded to adjacent C atoms can form a 3- to 7-membered ring.

Also preferred are the oxetanones of formula I, wherein Q is a group Q³; R³ is hydrogen and R¹ and R are C₁₋₂₀ alkyl, especially hexyl or undecyl.

Particularly preferred among the oxetanones of the formula I in which Q is a group Q 1 are those in which R 1 is methyl, ethyl, propyl, hexyl, 2-butenyl, 3-methyl-2-butenyl, 2-propynyl, methylthio, pentylthio, 5 -Chlorpentyl, benzyl, phenylthio, benzylthio, pentafluorobenzyl, anilino or benzyloxycarbonylamino, R undecyl, heptadecyl or 8,11-heptadecadienyl, R³ and R⁴ are hydrogen, methyl or isopropyl or together with the N atom form a morpholino or thiomorpholino group, n is 1 or 0, and X is (CH₂) ₁₋₈, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopentylidene, t-butylmethylene, dimethylvinylidene, cyclopentylidene, cyclohexylidene, phenethylidene, phenylpropylidene, 1,2- Cyclohexylene, cyclohex-3-en-1,6-ylene, acetamidomethylene, benzyloxycarbonylaminomethylene, 1-benzyloxycarbonylamino-1,2-ethylene, methyleneoxymethylene, methylenethiomethylene, methylenesulfinylmethylene, ethylenethioethylene, ethylenesulfinylethylene, Are methoxymethylene or ethylene or propylene dioxymethylene.

Particularly preferred among the oxetanones of formula I in which Q is a group Q are those in which R 1 is hexyl, R undecyl and X 'ethylene, 1-methoxy-1,2-ethylene or 1,2-cyclohexylene.

Examples of such connections are as follows:<ul id="ul0001" list-style="none" compact="compact"><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate,</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-carbamoylvalerate,</li><li>(all Z, S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl- (S) -2-isopropylmalonamate,</li><li>(S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate,</li><li>(S) -1 - [[(2S, 3S) or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl- [S: R (2: 1)] - 2-isopropylmalonamate,</li><li>(S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (S or R) -2-t-butylmalonamate,</li><li>(S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-1-carbamoylcydopentane carboxylate,</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-benzylmalonamate,</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-3 - [(2-carbamoylethyl) thio] propionate,</li><li>5-oxo-D-prolin (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester,</li><li>5-oxo-L-prolin (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester and in particular</li><li>(S) 1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-isopropylmalonamate,</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-carbamoylvalerate (epimers 1: 1),</li><li>(all Z, S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl- (S or R) -2-isopropylmalonamate,</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-carbamoyl-4-methylvalerate (epimers 1: 1),</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-1-carbamoylcyclohexane carboxylate,</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-methyl malonamate (epimers 1: 1),</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-ethylmalonamate (epimers 1: 1),</li><li>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-butylmalonamate (epimers 1: 1),</li><li>(S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-1-carbamoylcyclohexane carboxylate,</li><li>(S) -1 [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl- [S: R or R: S (2: 1)] - 2- isopropyl malonamate,</li><li>(S) -1 - [[(2R, 3R) -3-benzyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-isopropylmalonamate.</li></ul>

The oxetanones of the formula I contain at least three asymmetric carbon atoms and can therefore be present as optically active enantiomers, as mixtures thereof, for example as racemates or as diastereomers.

The oxetanones of the formula I can be prepared in a manner known per se by<ul id="ul0002" list-style="none"><li>a) an alcohol of the formula<chemistry id="chem0003" num="0003"><img file="EP0444482B1_D0003.tif" /></chemistry> with an acid of formula Q^a-OH, where Q^a is a group of formula Q¹ or Q³, esterified or</li><li>b) an acid of the formula         (QO, R) CHCH₂CH (OH) CH (R¹) -COOH IIb cyclized or</li><li>c) in an acid of the formula<chemistry id="chem0004" num="0004"><img file="EP0444482B1_D0004.tif" /></chemistry> wherein T is a group of the formula         HOCO (X)_n-CO- T¹ or         HOCO-X'- T, is, the carboxy group in group T converts into an amide group (R³, R⁴) and</li><li>d) if desired, an epimer mixture of the formula I is separated into the individual epimers.</li></ul>

The esterification a) can be carried out in the presence of triphenylphosphine and an azodicarboxylic acid diester, such as the di-t-butyl or diisopropyl ester, in a solvent, for example an ether, such as tetrahydrofuran (THF), at room temperature or with cooling, for example to 0 to Carry out at -5 ° C.

The cyclization b) can be carried out in a solvent such as methylene chloride, dimethylformamide (DMF) or acetonitrile with a molecular sieve, for example in the presence of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU ) and from a base, such as triethylamine, at room temperature or at a temperature up to 50 ° C.

The amidation c) can be accomplished with a solution of ammonia or an amine of the formula (R³, R⁴) NH, for example in acetonitrile, in the presence of HBTU at room temperature or at a temperature up to 40 ° C.

The optional separation of an epimer mixture of the formula I can be carried out, for example, by chromatography on silica gel with ethyl acetate / hexane / methylene chloride as the eluent.

The alcohols of the formula IIa are known, for example from European patent application No. 0 185 359 A2, or they can be prepared analogously to the known alcohols of the formula IIa or as described in Examples A to I, M and O to T.

The starting acids of the formulas IIb and IIc can be prepared in a manner known per se, for example starting from corresponding alcohols of the formula IIa as described below in Examples J and K (for the acids IIb) or K, L and N (for the acids IIc ) described.

Example A

<ul id="ul0003" list-style="none"><li>a) 465 g of methyl acetoacetate and then 458 g of ethyl bromide are added to 720 g of 30% sodium methylate solution in 1200 ml of methanol. The reaction mixture is then boiled under reflux. After the methanol has been distilled off, the residue is poured onto ice water. Then it is extracted with n-hexane and water. The organic phases are combined and dried. After evaporation of the solvent and distillation, 328 g of methyl 2-acetylbutyrate are obtained, bp 77-79 ° / 15 torr.</li><li>b) 144.17 g of the methyl ester of a) are added under argon at 0-5 ° C. to a suspension of 26.4 g of sodium hydride in 1250 ml of THF. After stirring for 1.5 hours at 0-5 ° C, the mixture is cooled to -10 ° C. At this temperature, 675 ml of 1.56M butyllithium in hexane are added. After stirring for 30 minutes at -10 ° C., a solution of 149.3 g of methyl stearate in 250 ml of THF is added dropwise. After stirring at -10 ° C. for 1.5 hours, the reaction solution is added to 250 ml of 37% hydrochloric acid and 300 g of ice under argon. It is extracted with hexane and water. The combined organic phases are dried, filtered and evaporated. The residue is dissolved in 2500 ml of THF, 76.1 g of 1,8-diazabicyclo- [5.4.0] undec-7-ene (1.5-5) (DBU) are added and the mixture is refluxed under argon. The cooled reaction solution is extracted with 37% hydrochloric acid and then with saturated sodium chloride solution. The combined organic phases are dried and evaporated. The product is dissolved in ethyl acetate. The solution is cooled to room temperature and stirred at 25 ° C. overnight. The crystals are filtered off, washed with ethyl acetate and dried. The result is 122.5 g of 3-ethyl-6-heptadecyl-4-hydroxy-2H-pyran-2-one, mp. 101-102 ° C.</li><li>c) 100 g of Raney nickel and 2000 ml of THF are added to 100 g of the pyrone from b). After 3 days of hydrogenation at 25 °, the catalyst is filtered off and washed with THF. The filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and stirred at 10 ° for 17 hours. The crystals are filtered off, washed with -10 ° cold ethyl acetate and dried at 40 ° C for 17 hours. The result is 90.54 g of rac- (2RS, 3RS, 5SR) -2-ethyl-5-heptadecyl-3-hydroxy-δ-valeriolactone, mp. 101-102 ° C.</li><li>d) 138.5 g of benzoic anhydride and then 2.5 ml of 70% perchloric acid are added to a suspension of 191.3 g of the δ-lactone from c) in 1250 ml of toluene. After stirring for 2.5 hours, the reaction mixture is extracted in toluene with 1N sodium hydroxide solution in 20% sodium chloride solution and then with saturated sodium chloride solution. The organic phases are combined, dried and evaporated. The result is 243.4 g of rac- (2RS, 3RS, 5SR) -3-benzoyloxy-2-ethyl -5-heptadecyl-δ-valeriolactone, mp. 64.5-66 ° C.</li><li>e) 243 g of the benzoate from d) are dissolved in 450 ml of toluene at 40 ° C. under argon. There are 1000 ml of methanol and then 2.5 ml of conc. Sulfuric acid is added and the reaction mixture is stirred at 25 ° C. for 20 hours. After neutralizing the sulfuric acid with triethylamine, the solvent is evaporated off. The residue is dissolved in t-butyl methyl ether and washed with water. The aqueous phase is extracted with t-butyl methyl ether and the organic phases are combined and dried over sodium sulfate, the drying agent is filtered off with suction and washed with t-butyl methyl ether and then evaporated. The result is 257 g of rac- (2RS, 3RS, 5SR) -3-benzoyloxy-2-ethyl -5-hydroxydocosanoic acid methyl ester.</li><li>f) Under argon, 257 g of the hydroxy ester from e) in 1250 ml of n-hexane are mixed with 152 g of benzyl-2,2,2-trichloroacetimidate. Then 3.2 ml of trifluoromethanesulfonic acid are added. After stirring for 18 hours, the precipitate is filtered off and washed with n-hexane. The filtrate is extracted with 5% sodium bicarbonate solution and water. The combined hexane phases are dried, filtered and concentrated. After stirring for 20 hours at -20 ° C., the crystals are filtered off, washed with n-hexane and discarded. The filtrate is evaporated. The result is 239.6 g of rac- (2RS, 3RS, 5SR) -3-benzoyloxy-5-benzyloxy -2-ethyldocosanoic acid methyl ester.</li><li>g) A solution of 140 g of potassium hydroxide in 1250 ml of 95% (v / v) methanol / water is added to 239.6 g of the benzyl ether from f) under argon and the mixture is stirred at 40 ° C. for 17 hours. The mixture is then concentrated at 40 ° C., the suspension is taken up in t-butyl methyl ether and washed in succession with 10% sodium chloride solution, 1N hydrochloric acid and again with 10% sodium chloride solution. The organic phase is dried with sodium sulfate, the drying agent is filtered off and washed with t-butyl methyl ether. The filtrate is evaporated. The result is 182.1 g of rac- (2RS, 3RS, 5SR) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid.</li><li>h) 33.3 g of (S) - (-) - α-methylbenzylamine are added dropwise to a solution of 182.1 g of the β-hydroxy acid of g) in 1250 ml of methyl acetate. The solution is inoculated with 50 mg of phenethylamine salt of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid and left to stand for 20 hours. The crystals are filtered off with suction, washed with methyl acetate at -20 ° C. and then dried. This 1st Crystallizate is dissolved in hot methyl acetate, cooled to 45 ° C. and inoculated with 50 mg phenethylamine salt of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid. The solution is left to stand at room temperature for 20 hours. The crystals are filtered off with suction, washed with methyl acetate at -20 ° C. and dried. The same procedure as with the 1st crystals is repeated with the 2nd crystals. The result is 39.4 g of phenethylamine salt of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid, mp. 92-95 ° C.</li><li>i) 39.4 g of the phenethylamine salt from h) are mixed with 400 ml of t-butyl methyl ether and 80 ml of 1N hydrochloric acid and dissolved with stirring. The organic phase is washed with water, dried, filtered and concentrated. The result is 31.4 g (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid, mp. 62-63.5 ° C.</li><li>j) 17.6 g of benzenesulfonyl chloride are added dropwise under argon to a solution of 24.5 g of the β-hydroxy acid from i) in 250 ml of pyridine at 0 ° C. After 20 hours of stirring at 0 ° C., 5 ml of water are added dropwise to the solution. The mixture is stirred at room temperature for 1 hour. The pyridine is evaporated. The crystal slurry is taken up in t-butyl methyl ether and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and 10% sodium chloride solution. The organic phase is dried over sodium sulfate and then stirred with activated carbon. Desiccant and activated carbon are sucked off and the filtrate is evaporated. 23.4 g of (3S, 4S) -4 - [(R) -2-benzyloxynonadecyl] -3-ethyl-2-oxetanone result.</li><li>k) A solution of 23.4 g of the oxetanone from j) in 250 ml of THF is mixed with 2.3 g of Pd / C 10%. After 5 hours of hydrogenation, the hydrogenation solution is filtered off with suction. After washing with THF, the filtrate is evaporated, the residue is dissolved in n-hexane and inoculated with (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone. After 18 hours, the crystals are filtered off, washed with hexane and dried. 16.1 g of (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone, mp. 66.5-68 ° C, the starting alcohol of Example 1.</li></ul>

Example B

<ul id="ul0004" list-style="none"><li>a) 50 g of methyl (R) -3-hydroxytetradecanoate, 35 g of t-butyld ester , 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine are dissolved in 200 ml of methylene chloride and stirred for 30 hours at room temperature and 16 hours under reflux. A further 2 g of t-butyldimethylchlorosilane are then added. After a further 24 hours under reflux, the precipitated triethylamine hydrochloride salt is filtered off, washed with ether and the filtrate is concentrated. The residue is dissolved in ether and successively with water, 0.5M citric acid, again with water and saturated. Washed sodium chloride solution, dried, concentrated and then freed from volatile material at 50 ° C in a high vacuum for 5 hours. 71.8 g of (R) -3- (t-butyldimethylsiloxy) tetradecanoic acid methyl ester, IR (cm -1): 1745, 1254, 895, 776.</li><li>b) 18.63 g of the product from a), dissolved in 100 ml of ether, are mixed with 65 ml of 1M diisobutylaluminum hydride solution in hexane at a temperature of -70 ° C. to -75 ° C. and then stirred at this temperature for 1 hour. Then 2.5 ml isopropanol, 10 ml water and 50 ml 0.5M citric acid solution at max. 10 ° C added dropwise. The ether phase is separated off, the water phase is extracted with ether, the combined ether phases are washed with brine, dried and concentrated. The residue is chromatographed on silica gel with pentane / ether (5: 1) and 14.47 g of (R) -3- (t-butyldimethylsiloxy) tetradecanal, IR (cm -1): 1728, 1254, 836, 775.</li><li>c) A solution of 2.55 ml of diisopropylamine in 45 ml of THF is mixed with 22.5 ml of a solution of 1.6M n-butyllithium in hexane at 0 ° C. and, after stirring for 15 minutes, cooled to -75 ° C. A solution of 2.92 g of pentylthioacetic acid in 9 ml of THF is then added dropwise. After stirring for 10 minutes, the reaction mixture is allowed to warm to room temperature, stirred for 5 minutes and cooled again to -75 ° C. A solution of 2.4 g of the aldehyde from b) in 9 ml of THF is added dropwise at this temperature. After stirring for 20 minutes, the reaction mixture is poured onto saturated ammonium chloride solution and extracted with hexane. The hexane phase is dried and concentrated. 3.89 g (2R / S, 3R / S, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxy-2-pentylthiohexadecanoic acid are obtained as a mixture of 4 diastereomers.</li><li>d) A solution of 3.89 g of the product of c), 3.18 g of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2 g of 4 Å molecular sieve and 3 ml of triethylamine in a mixture of 130 ml of methylene chloride and 6 ml of DMF is stirred for 2 hours. It is then filtered, the filtrate is concentrated, the residue is dissolved in water / methanol (3: 7) and extracted with hexane. The hexane phase is dried and concentrated, 3.57 g of (3R / S, 4R / S) -4 - [(R) -2- (t-butyldimethylsiloxy] tridecyl] -3-pentylthio-2-oxetanone are obtained as a mixture of 4 diastereomers.</li><li>e) A solution of 4.59 g of the product from d) in 200 ml of acetonitrile is mixed with 15 ml of 40% hydrofluoric acid and stirred for 18 hours. Then sodium bicarbonate solution is added, then extracted with hexane and the hexane phase dried and concentrated. The residue is chromatographed on silica gel with 1-5% ether in methylene chloride. 699.9 mg of 3R, 4R (or 3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone, mp. 43 ° C and 691.2 mg of 3S, 4S (or 3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone, mp. 71 ° C, the starting alcohols of Examples 5 and 6.</li></ul>

Example C

<ul id="ul0005" list-style="none"><li>a) 18 ml of a 1M solution of lithium bis (trimethylsilyl) amide in THF are added under argon at -75 ° C with 1.8 ml of ethyl acetate, stirred for 30 minutes at this temperature and then with 4.8 g (R) - 3-Benzyloxytetradecanal in 15 ml of THF and stirred for half an hour at -78 ° C. A solution of 3.8 ml of conc. Hydrochloric acid added dropwise in 6 ml of water. The solution obtained is extracted with ethyl acetate, the combined organic phases are washed with 10% sodium bicarbonate and water, dried, filtered and concentrated. Ethyl (3R, 5R and 3S, 5R) -5-benzyloxy-3-hydroxyhexadecanoate (1: 1) is obtained.</li><li>b) A solution of 4 ml of diisopropylamine in 12.5 ml of THF is mixed with 17 ml of a 1.6M solution of n-BuLi in n-hexane under argon at 0 ° C. After stirring for 15 minutes, 5 g of the product from a) in 2.5 ml of THF are added dropwise at -50 ° C. After 10 minutes at -10 ° C., the temperature is reduced to -50 ° C. and, after a solution of 3.18 g of benzyl bromide in 3.1 ml of hexamethylphosphoric triamide is added dropwise, the mixture is stirred at -50 ° C. for 15 minutes. The cooling bath is then removed and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is cooled to 0 ° C. and 50 ml of saturated sodium chloride solution are added, the mixture is extracted with t-butyl methyl ether, the extracts are dried, filtered and the solvent is evaporated off. The residue is chromatographed on silica gel with n-hexane / ethyl acetate (4: 1). The residue is dried. Ethyl (2R, 3R, 5R and 2S, 3S, 5R) -5-benzyloxy-2-benzyl-3-hydroxyhexadecanoate are obtained as 1: 1 threo-diastereomers.</li><li>c) A solution of 3.1 g of the product from b) and 26 ml of 2.5N sodium hydroxide solution in 37.2 ml of ethanol is refluxed for 50 minutes and then neutralized at room temperature with 26 ml of 2.5N hydrochloric acid. The ethanol is distilled off and the residue is extracted with t-butyl methyl ether and water. The combined organic phases are dried and concentrated. A solution of 3 g of the residue in 109 ml of methylene chloride is stirred under argon and mixed with 2.59 g of HBTU and 2.74 g of molecular sieve. 5.5 ml of DMF and 2.8 ml of triethylamine are then added and the reaction mixture is stirred for 1 hour, filtered and concentrated. The residue is taken up in n-hexane, then the solution is extracted with water, dried and concentrated in vacuo. Chromatography on silica gel with methylene chloride gives a 1st trans-diastereomer, (3S, 4S or 3R, 4R) -3-benzyl-4 - [(R) -2-benzyloxytridecyl] -2-oxetanone, Rf value: 0.45 (thin layer chromatography on silica gel 5-40 µ with Methylene chloride) and a 2nd trans diastereomer, (3R, 4R or 3S, 4S) -3-benzyl-4 - [(R) -2-benzyloxytridecyl] -2-oxetanone, Rf value: 0.50 (thin layer chromatography over Silica gel 5-40 µ with methylene chloride).</li><li>d) A solution of 646 mg of the second trans-diastereomer from c) in 65 ml THF is hydrogenated in the presence of 646 mg Pd / C 10% for 1 hour. The reaction mixture is filtered and concentrated. A trans-diastereomer is obtained: (3R, 4R) -3-benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, the starting alcohol in Example 7.</li><li>e) As described under d), the trans-diastereomer is obtained from the 1st trans-diastereomer from c): (3S, 4S) -3-benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, the starting alcohol in Example 8.</li></ul>

Example D

A solution of 3.0 ml of diisopropylamine in 50 ml of THF is mixed with 0.0 ° C with 12.0 ml of a solution of 1.6M n-butyllithium in hexane and cooled to -75 ° C after stirring. A solution of 1.26 g of Z-glycine in 10 ml of THF is then added dropwise. Then the reaction mixture is allowed to warm up to room temperature and cooled again to -75 ° C. 0.70 g of (R) -3- (t-butyldimethylsiloxy) tetradecanal in 5 ml of THF are then added dropwise at -75 ° C. The reaction mixture is stirred for 1 hour at -75 ° C, 1/2 hour at -40 ° to -50 ° C, then warmed to 5 ° C, cooled again to -75 ° C and poured onto dilute potassium hydrogen sulfate solution and extracted with ether. The ether phase is dried, concentrated and chromatographed on silica gel using methylene chloride / methanol. This results in 540 mg (2R / S, 3R / S, 5R) -2- [1- (benzyloxy) formamido] -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoic acid as a mixture of 4 diastereomers.

In analogy to B) d), the above product is benzyl-4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -2-oxo-3-oxetane carbamate as a 1: 1 mixture of the two trans-diastereomers β- Lactones obtained, MS: 476 (M⁺ • -C₄H₉ •).

In analogy to B) e), the above mixture (3S, 4S or 3R, 4R) -benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxo-3-oxetane carbamate, the starting alcohol in Example 15, mp 122-124 ° C, and (3R, 4R or 3S, 4S) -benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxo-3-oxetane carbamate, mp 98-99 ° C.

Example E

Analogously to Example B, thiophenoxyacetic acid and (R) -3 - [(1,1-dimethylethyl) dimethylsilyloxy] tetradecanal are obtained<ul id="ul0006" list-style="none"><li>a) (2R / S, 3R / S, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxy-2- (phenylthio) hexadecanoic acid (mixture of 4 diastereomers) and</li><li>b) (3R / S, 4R / S) -4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -3- (phenylthio) -2-oxetanone (mixture of 4 diastereomers), IR (cm⁻¹ ): 2927, 2855, 1833, 1254,    das (3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone, mp. 79 ° C (ether) and (3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone, mp. 47 ° C. (ether) the starting alcohols of Example 16.</li></ul>

Example F

<ul id="ul0007" list-style="none"><li>a) 270 ml of stearic acid chloride are added dropwise at a maximum of 15 ° C. to a solution of 117 g of Meldrum's acid and 131 ml of pyridine in 1.5 l of methylene chloride. After stirring, the reaction mixture is washed with 4N hydrochloric acid, the aqueous phase is extracted with methylene chloride, the methylene chloride phase is dried and concentrated. The residue is taken up in methanol and stirred under reflux. After cooling, the precipitated crystals are filtered off, dissolved in methylene chloride and chromatographed on silica gel with methylene chloride. 175 g of methyl 3-oxoeicosanoate, mp 52-54 ° C. are obtained.</li><li>b) A solution of 9.1 mg of [(R) -2,2'-bis (diphenylphosphino) -6,6'-dimethylbiphenyl] ruthenium diacetate in 20 ml of methylene chloride gives 1.84 mg of acetyl chloride in 1.84 ml of methanol admitted. The solution obtained is hydrogenated together with 39.8 g of the keto ester of a) and 170 ml of methanol at 35 bar hydrogen and 60 ° C. After adding methylene chloride, the mixture is evaporated to dryness. Chromatography on silica gel with ether and recrystallization from n-hexane provides 35.7 g of (R) -3-hydroxyyeicosanoic acid methyl ester, mp. 64-64.5 ° C.</li><li>c) Analogously to Example B, the product of b) is obtained via<ul id="ul0008" list-style="none"><li>Methyl- (R) -3- (t-butyldimethylsiloxy) eicosanoate, IR (cm⁻¹): 1745, 1255, 836,</li><li>(R) -3- (t-butyldimethylsiloxy) eicosanal, IR (cm -1): 1728, 1463, 1255, 1104, 836, 775,</li><li>(2R / S, 3R / S, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxy-2- (methylthio) -docosanoic acid (mixture of 4 diastereomers) MS: 533 (M + H) ⁺,</li><li>4 - [(R) -2- (t-butyldimethylsiloxy) nonadecyl] -3- (methylthio) -2-oxetanone, (1: 1 mixture of two trans diastereomers), IR (cm⁻¹): 1834, 1463 , 1256, 1106, 836 and</li><li>4 - [(R) -2- (t-butyldimethylsiloxy) nonadecyl] -3- (methylthio) -2-oxetanone (1: 1 mixture of two cis-diastereomers), IR (cm⁻¹): 1834, 1463, 1256, 1106, 1066, 836,</li></ul> the following starting alcohols from Example 17:<ul id="ul0009" list-style="none" compact="compact"><li>(3S, 4R or 3R, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, mp. 65 ° C (from methylene chloride)</li><li>(3R, 4S or 3S, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, mp. 67 ° C (from methylene chloride)</li><li>(3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, mp. 71 ° C (from ether)</li><li>(3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, mp. 80 ° C (from ether).</li></ul></li></ul>

Example G

Analogously to Example B, (benzylthio) acetic acid and (R) -3 - [(1,1-dimethylethyl) dimethylsilyloxy] tetradecanal are obtained via<ul id="ul0010" list-style="none"><li>(2R / S, 3R / S, 5R) -2- (benzylthio) -5 - [(1,1-dimethylethyl) dimethylsilyloxy] -3-hydroxyhexadecanoic acid (mixture of 4 diastereomers) and</li><li>(3R / S, 4R / S) -3- (benzylthio) -4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -2-oxetanone (mixture of 4 diastereomers), MS: 506 (M⁺)</li></ul> the following starting alcohols of Examples 19 and 20:<ul id="ul0011" list-style="none"><li>the (3S, 4S or 3R, 4R) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone, mp. 65 ° C (ether),</li><li>(3R, 4R or 3S, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone, MS: 374 (M⁺ • -H₂O) and</li><li>das (3R, 4S and 3S, 4R) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone (1: 1 diast.), MS: 374 (M⁺ • -H₂O) .</li></ul>

Example H

<ul id="ul0012" list-style="none"><li>a) 104 g of mother liquor from the 1st crystallization in Example Ah) are dissolved in water and methylene chloride. Under ice cooling, the addition of conc. HCl acidified to pH 1, the methylene chloride phase separated, the water phase extracted with methylene chloride, the methylene chloride phase washed with water, dried and concentrated. The result is 86.7 g of enriched (2R, 3R, 5S) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid, which is dissolved in 500 ml of ethyl acetate and cooled with 20.6 g of (R) - (+) - α -Methylbenzylamin be added. After addition of ethyl acetate, the mixture is heated to reflux, filtered and crystallized out. The crystals obtained are recrystallized from ethyl and methyl acetate. The result is 70.0 g of phenethylamine salt of (2R, 3R, 5S) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid, mp. 88-91 ° C.</li><li>b) Analogous to example Ai) j) k), the above salt is via<ul id="ul0013" list-style="none"><li>(2R, 3R, 5S) -5-benyzloxy-2-ethyl-3-hydroxydocosanoic acid, mp. 61.5-63 ° C and</li><li>(3R, 4R) -4 - [(S) -2-benzyloxynonadecyl] -3-ethyl-2-oxetanone, mp 38-40 ° C</li><li>received the (3R, 4R) -3-ethyl-4 - [(S) -2-hydroxynonadecyl] -2-oxetanone, mp. 66-68 ° C.</li></ul></li><li>c) A solution of 14.2 g of the product obtained and 8.65 g of triphenylphosphine in 250 ml of THF is mixed with 1.19 ml of formic acid at + 5 ° C. and then with a solution of 5.12 g of diethyl azodicarboxylate in 20 ml of THF . Then 0.4 ml of formic acid, 2.9 g of triphenylphosphine and 1.7 ml of diethyl azodicarboxylate are added again. The reaction mixture is concentrated and the residue is chromatographed on silica gel with hexane / ethyl acetate; this results in 13.1 g of (R) -1 - [[(2R, 3R) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl formate. The product obtained is dissolved in 150 ml of methanol and 0.114 g of p-toluenesulfonic acid monohydrate are added at 15 ° C. After stirring, the reaction mixture is concentrated, the residue is partitioned between methylene chloride and aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride phase is dried and concentrated, and the residue is recrystallized from ethyl acetate. 9.5 g of (3R, 4R) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone, mp. 80-82 ° C., the starting alcohol in Example 21 are obtained.</li></ul>

Example I

<ul id="ul0014" list-style="none"><li>a) 187.5 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 42.5 ml of diisopropylamine in 500 ml of THF at -20 ° C. After stirring, the solution at max. -65 ° C added dropwise to a suspension of 39.9 g (S) - (-) - 2-hydroxy-1,2,2-triphenylethyl acetate in 600 ml THF. The reaction mixture is then warmed to 0 ° C., stirred, cooled to -70 ° C. and a solution of 51.2 g of (R) -3 - [(t-butyl) dimethylsilyloxy] eicosanal in 400 ml of THF is added. After stirring, 500 ml of saturated ammonium chloride solution are added dropwise at -70 ° C., then warmed up to room temperature and stirred. The reaction mixture is concentrated, partitioned between water and ether and extracted with ether, the ether phase washed with water, concentrated, taken up in 1 l of methylene chloride, dried and concentrated. The result is 91.9 g of (S) -2-hydroxy-1,2,2-triphenylethyl- [3R: 3S (4: 1), 5R] -5- (t-butyldimethylsiloxy) -3-hydroxydocosanoate, IR (cm ⁻¹): 3525, 1719, 1448, 1250, 1159, 838, 697.</li><li>b) A solution of 90.8 g of the product obtained above in 1 l of methanol is mixed with 22.15 ml of 5.4M sodium methylate in methanol. After stirring, the solution is concentrated, the residue is partitioned between ether and saturated ammonium chloride solution and extracted with ether. The ether phase is dried, concentrated and chromatographed on silica gel using hexane / ethyl acetate. This results in 42.7 g of methyl (3R, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxydocosanoate, IR (cm -1): 3521, 3468, 1738, 1254, 1168, 1137, 1105.</li><li>c) Analogous to Example Be) and Cb), c) the latter compound via methyl (2R, 3R, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxy-2-methyldocosanoate, IR (cm⁻¹): 3522 , 1739, 1464, 1254, 1066 and (3R, 4R) -4 - [(R) -2- (t-butyldimethylsiloxy) nonodecyl] -3-methyl-2-oxetanone, IR (cm -1): 1830, 1464 , 1254, 1129, 1071 into the (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-methyl-2-oxetanone, mp. 82.5-84 ° C (from EtOAc / hexane) Starting alcohol converted in Example 22.</li></ul>

Example J

<ul id="ul0015" list-style="none"><li>a) 1.1 g (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, 1.6 g triphenylphosphine, 0.825 g salicylamide and 3 g molecular sieve (4Å) are with 20 ml of THF are added and the mixture is cooled to 0.degree. 1.4 g of di-t-butyl azodicarboxylic acid are then added. After warming to room temperature and stirring, the reaction mixture is concentrated and the residue is partitioned between methanol / water (70:30) and hexane and extracted with hexane. The hexane phase is dried and concentrated, and the residue is chromatographed on silica gel using hexane / ethyl acetate (4: 1). This results in 0.727 g of o - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] benzamide, MS: 474 (M + H) ⁺.</li><li>b) 972 mg of the product obtained above are dissolved in 12 ml of methanol and mixed with 0.2 g of potassium carbonate. After stirring, the reaction mixture is concentrated and the residue is partitioned between methanol / water (7: 3) and hexane and extracted with hexane. The hexane phase is dried and concentrated. This results in 854 mg of methyl (2S, 3S, 5S) -5- (o-carbamoylphenoxy) -2-hexyl-3-hydroxyhexadecanoate, MS: 369 (M⁺ • - (o-carbamoylphenoxy).</li><li>c) 850 mg of the product obtained above are dissolved in 12 ml of methanol / water (98: 2), with 800 mg of 5 percent. Rhodium on alumina and hydrogenated at 100 ° C and 100 bar hydrogen. The reaction mixture is filtered, concentrated and chromatographed on silica gel with hexane / ethyl acetate (1: 1). This gives 213 mg of methyl (2S, 3S, 5S) -5 - [[(cis) -2-carbamoylcydohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoate (1. Diast.), MS: 367 [M⁺ • - (H₂NCOC₆H₁₀ • ⁺H₂O)]; 204 mg mixed fraction and 142 mg methyl- (2S, 3S, 5S) -5 - [[(cis) -2-carbamoylcyclohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoate (2nd diast.), MS: 367 [M ⁺ • - (H₂NCOC₆H₁₀ • + H₂O)].</li><li>d) 210 mg of the 1st diastereomer obtained above are dissolved in 10 ml acetone, mixed with 3 ml 1N potassium hydroxide. After stirring, the reaction mixture is poured onto potassium hydrogen sulfate solution and extracted with ether. The ether phase is dried and evaporated. 277 mg (2S, 3S, 5S) -5 - [[(cis) -2-carbamoylcydohexyl] oxyl] -2-hexyl-3-hydroxyhexadecanoic acid (1st diast.), The starting acid in Example 23a), are obtained.</li><li>e) As described in d), the (2S, 3S, 5S) -5 - [[(cis) -2-carbamoylcyclohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoic acid (2. Diast.), The starting acid obtained in Example 23b).</li></ul>

Example K

<ul id="ul0016" list-style="none"><li>a) Analogously to Example Hc), (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and formic acid are obtained via (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl formate, IR (cm⁻¹): 1826, 1725, 1177, 1122, the (3S, 4S) -3-hexyl-4 - [(S) - 2-hydroxytridecyl] -2-oxetanone, mp 63-64 ° C (from hexane).</li><li>b) 1.8 g of the hydroxy-β-lactone prepared above, 1.3 g of pyridinium p-toluenesulfonate and 2 g of molecular sieve (4 Å) are stirred in 10 ml of methyl 3,3-dimethoxypropionate at 100 ° C. under argon, then that The reaction mixture was filtered off, the residue was concentrated and the residue was chromatographed on silica gel using ether / methylene chloride. The result<ul id="ul0017" list-style="none"><li>1. 213 mg of methyl- (E) -3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] -dodecyl] oxy] acrylate, IR (cm ⁻¹): 1827, 1714, 1643, 1622, 1192, as well</li><li>2nd 826 mg of methyl (R / S) -3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] -3-methoxypropionate (1: 1 mixture of epimers), IR (cm -1): 1824, 1743, 1438, 1117.</li></ul></li><li>c) 235 mg of the product from b) 2. are suspended in 25 ml of 0.02N NaOH and the reaction mixture is diluted with acetone. After stirring for 24 hours with 5 percent. Acidified potassium hydrogen sulfate solution and extracted with ether. The ether phase is dried, concentrated and the residue is chromatographed on silica gel with methylene chloride / methanol. This gives 60 mg (2S, 3S, 5S) -2-hexyl-3-hydroxy-5 - [(R / S) -1-methoxy-2- (methoxycarbonyl) ethoxy] hexadecanoic acid, MS: 337 (M⁺ • - (H₂O + • O- (CH₃O) -CH₂-COOCH₃).</li><li>d) A solution of 58 mg of the above compound in 4 ml of condensed ammonia is heated in an autoclave at 50 ° C. The ammonia gas is then allowed to escape, potassium hydrogen sulfate solution is then added and the mixture is extracted with methylene chloride. The methylene chloride phase is dried and concentrated. 42.5 mg (2S, 3S, 5S) -5 - [(R / S) -2-carbamoyl-1-methoxyethoxy] -2-hexyl-3-hydroxyhexadecanoic acid, starting acid from Example 24, result.</li></ul>

Example L

A solution of 200 mg of the product from Example Kb) 1. in 10 ml THF is hydrogenated with 200 mg Pd / C (10%). Then it is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with 1% ether in methylene chloride. The result is 99 mg of methyl 3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] propionate, MS: 285 (M⁺ • - (C₁₁H₂₃ •)).

Acetonitrile is added to a suspension of 544 mg of this compound in 49 ml of 0.02N sodium hydroxide. The resulting solution is acidified with aqueous potassium hydrogen sulfate, the reaction mixture is extracted with ether and the ether phase is dried and concentrated. Chromatography on silica gel with 2% ether in methylene chloride and then 5% methanol in methylene chloride provides 43.7 mg of 3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl ] methyl] dodecyl] oxy] propionic acid, IR (cm -1): 1823, 1715, 1466, 1105, starting acid in Example 25.

Example M

Analogously to examples Cb) and c), methyl- (3R, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxydocosanoate (Example Ib) with proparyl bromide becomes methyl- (2R, 3R, 5R) -5- (t-butyldimethylsiloxy ) -3-hydroxy-2- (2-propynyl) docosanoate, IR (cm⁻¹): 3310, 2120, 1740, 1255, converted and the latter to (2R, 3R, 5R) -5- (t-butyldimethylsiloxy) - 3-hydroxy-2- (2-propynyl) docosanoic acid, IR (cm⁻¹): 3315, 2120, 1715, 1255 saponified and to (3R, 4R) -4 - [(R) -2- (t-butyldimethylsiloxy) nonadecyl] -3- (2-propynyl) -2-oxetanone, IR (cm⁻¹): 3315, 2130, 1830, 1255 cyclized.

After removal of the protective group analogously to Example Be), the (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (2-propynyl) -2-oxetanone, mp. 62-63 ° C ( from ethyl acetate), the starting alcohol in Example 60.

Example N

Analogously to Example 1, (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and monobenzyl malonate give the benzyl- (S) -1 - [[(2S, 3S) - 3-hexyl-4-oxo-2-oxetanyl] methyl] dodecylmalonate, IR (cm -1): 1824, 1734, 1149, 1125.

A solution of 430 mg of this product in 15 ml of THF is mixed with 100 mg Pd / C and then hydrogenated. The reaction mixture is filtered and the filtrate is concentrated. The result is 361 mg (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl hydrogenmalonate, IR (cm -1): 1824, 1745, the starting acid of example 26.

Example O

A solution of 1.96 g of the alcohol product from Example M in 50 ml of ethyl acetate is with 0.25 g of 10 percent. Pd / C hydrogenated, then the reaction mixture was filtered and the residue was chromatographed on silica gel with ethyl acetate / hexane. This gives 1.44 g of (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-propyl-2-oxetanone, mp. 84-85 ° C (from ethyl acetate / hexane), the starting alcohol in Example 61

Example P

<ul id="ul0018" list-style="none"><li>a) From (R) -3- (t-butyldimethylsiloxy) tetradecanal (Example Bb), analogously to Example Ca) b) c) via ethyl- (3R and 3S, 5R) -5- (t-butyldimethylsiloxy) -3- hydroxyhexadecanoate (mixture of epimers),<ul id="ul0019" list-style="none"><li>Ethyl (R and S) -2 - [(1R and 1S, 3R) -3- (t-butyldimethylsiloxy) -1-hydroxytetradecyl] -5-methyl-4-hexenoate (1: 1 threo-diastereomers)</li><li>the (3R, 4R and 3S, 4S) -4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -3- (3-methyl-2-butenyl) -2-oxetanone (1: 1 trans diastereomers ).</li></ul></li><li>b) 6.2 ml of 40% hydrofluoric acid are added to a solution of 1.87 g of the product from a) in 50 ml of acetonitrile. After stirring, sodium bicarbonate solution is added, then extracted with methylene chloride and the methylene chloride phase is dried and concentrated. The residue is chromatographed on silica gel with 1 ethyl acetate / 4.5 methylene chloride / 4.5 n-hexane. The chromatography gives the starting alcohols for Examples 62-65:<ul id="ul0020" list-style="none"><li>a 1st trans-diastereomer, (3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3- (3-methyl-2-butenyl) -2-oxetanone, Rf value: 0.31 and</li><li>a 2nd trans diastereomer, (3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3- (3-methyl-2-butenyl) -2-oxetanone, Rf value: 0.26 (thin layer chromatography over silica gel 5-40 µ with 1 ethyl acetate / 4.5 methylene chloride / 4.5 n-hexane).</li></ul></li></ul>

Example Q

Ethyl (3R, 5R and 3S, 5R) -5-benzyloxy-3-hydroxyhexadecanoate (1: 1) (Example Ca) is obtained analogously to Example Cb) to e) via ethyl- (2R, 3R, 5R and 2S, 3S, 5R) -5-benzyl-2- (5-chloropentyl) -3-hydroxyhexadecanoate (threo diastereomers),<ul id="ul0021" list-style="none"><li>a 1st trans-diastereomer, (3S, 4S or 3R, 4R) -4 - [(R) -2- (benzyloxy) tridecyl] -3- (5-chloropentyl) -2-oxetanone, Rf value: 0, 47,</li><li>and a second trans-diastereomer, (3R, 4R or 3S, 4S) -4 - [(R) -2- (benzyloxy) tridecyl] -3- (5-chloropentyl) -2-oxetanone, Rf value: 0 , 28 (thin layer chromatography on silica gel 5-40 μ with methylene chloride), the starting alcohols for Examples 66-69:</li><li>(3R, 4R or 3S, 4S) -3- (5-chloropentyl) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone, and</li><li>(3S, 4S or 3R, 4R) -3- (5-chloropentyl) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone.</li></ul>

Example R

From (R) -3- (t-butyldimethylsiloxy) tetradecanal (Example Bb) one obtains analogously to Example Cb) and c) via ethyl- (R and S, E) -2 - [(1R and 1S, 3R) -3- (t-butyldimethylsiloxy) tetradecyl] -4-hexenoate (1,1 threo diastereomers) and<ul id="ul0022" list-style="none"><li>(3R, 4R and 3S, 4S) -3 - [(E) -2-butenyl] -4 - [(R) -2- (t-butyldimethylsiloxy) - tridecyl] -2-oxetanone (1: 1 trans diastereomers ) the starting alcohols for Examples 70-73:</li><li>a 1st trans-diastereomer, (3S, 4S or 3R, 4R) -3 - [(E) -2-butenyl] -4 - [(R) -2-hydroxytridecyl] -2-oxetanone, Rf value: 0.475 and</li><li>a 2nd trans-diastereomer, (3R, 4R or 3S, 4S) -3 - [(E) -2-butenyl] -4 - [(R) -2-hydroxytridecyl] -2-oxetanone, Rf value: 0 , 44 (Chromatography and thin layer chromatography on silica gel with 1 ethyl acetate / 2 methylene chloride / 2 n-hexane.</li></ul>

Example S

From ethyl (3R, 5R and 3S, 5R) -5-benzyloxy-3-hydroxyhexadecanoate (1: 1) (Example Ca) is obtained analogously to Example Cb) and c) via ethyl- (2R, 3R and 2S, 3S, 5R) -5- (benzyloxy) -3-hydroxy-2- (2,3,4,5,6-pentafluorobenzyl) hexadecanoate (threo diastereomers) and<ul id="ul0023" list-style="none"><li>(3R, 4R and 3S, 4S) -4 - [(R) -2- (benzyloxy) tridecyl] -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanone (trans diastereomers) Starting alcohols of Examples 74-77:</li><li>a 1st trans diastereomer, (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanone, Rf -Value: 0.43 and</li><li>a 2nd trans diastereomer, (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanone, Rf -Value: 0.39 (chromatography and thin layer chromatography on silica gel with 1 ethyl acetate / 4.5 methylene chloride / 4.5 n-hexane).</li></ul>

Example T

<ul id="ul0024" list-style="none"><li>a) A solution of 0.5 ml of diisopropylamine in 15 ml of THF is mixed with 0 ml of a solution of 1.6M n-butyllithium in hexane at 0 ° C and cooled to -75 ° C after stirring. A solution of 765 mg of N-benzyl-N-phenylglycine methyl ester in 3 ml of THF is then added. After stirring, a solution of 700 mg of (R) -3- (t-butyldimethylsiloxy) tetradecanal (Example Bb) in 5 ml of THF is added dropwise. After stirring at -75 ° C, the reaction mixture is poured onto aqueous potassium hydrogen sulfate and extracted with ether. The ether phase is dried, concentrated, partitioned between hexane and methanol / water (7: 3), the hexane phase dried and concentrated and the residue is chromatographed on silica gel with pentane / ether (5: 1). 96.3 mg of methyl (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoate, diastereomer A, MS: 540 (M⁺ • -C₄H₉ •) and 142.8 are obtained mg methyl- (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoate, diastereomer B, MS: 540 (M⁺ • -C₄H₉ •) and 313.4 mg mixture of the above two diastereomers .</li><li>b) 134 mg of diastereomer B are suspended in 3 ml of 0.1N NaOH and sufficient acetonitrile is added to give a clear solution. After stirring, the mixture is poured onto aqueous potassium hydrogen sulfate and extracted with ether, and the ether phase is dried and concentrated. After chromatography on silica gel with methylene chloride / methanol (9: 1), 108 mg (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoic acid, diastereomer B, MS: 526 (M⁺ • C₄H₉ •).</li><li>c) Analogously, the diastereomer A obtained from a) (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoic acid, diastereomer A, MS: 526 (M⁺ • -C₄H₉ •) .</li><li>d) 1.1 g of diastereomer B from b), 1.1 g of HBTU, 0.5 g of triethylamine and 2 g of 4 Å molecular sieve are stirred in 50 ml of acetonitrile. After filtration and concentration, the product is chromatographed on silica gel with methylene chloride. This results in 1.04 g of 3R, 4R (or 3S, 4S) -3- (N-benzylanilino) -4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -2-oxetanone, diastereomer B, MS: 566 (M + H) ⁺.</li><li>e) Analogously, the diastereomer A from c) gives 3S, 4S (or 3R, 4R) -3- (N-benzylanilino) -4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -2-oxetanone , Diastereomer A, MS: 566 (M + H) ⁺.</li><li>f) 1.0 g of diastereomer B from d) and 0.8 g of Pd / C (10%) are hydrogenated in 30 ml of THF. It is then filtered and concentrated. This gives 834 mg of 3R, 4R (or 3S, 4S) -3-anilino-4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -2-oxetanone, diasteromer B, MS: 475 (M⁺ • ).</li><li>g) Analogously, the diastereomer A of e) gives 3S, 4S (or 3R, 4R) -3-anilino-4 - [(R) -2- (t-butyldimethylsiloxy) tridecyl] -2-oxetanone, diastereomer A, MS: 475 (M⁺ •).</li><li>h) The products of f) and g) are individually analogous to Be) in 3R, 4R (or 3S, 4S) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, diastereomer B, mp . 104 ° C or</li></ul>

3S, 4S (or 3R, 4R) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, diastereomer A, mp 60-62 ° C, the starting alcohols for Example 79, converted.

The acids of formula Q_q-OH are known or can be prepared analogously to the known acids, for example by saponification of a corresponding lower alkyl ester in a solvent, such as acetone or methanol, with an alkali metal hydroxide, such as potassium hydroxide, in an alcohol, such as ethanol or methanol. The starting acid of Examples 2d) and 2e) below can be prepared as follows:

A solution of 3.8 g of ethyl 2-propylmalonamide in 30 ml of acetone is mixed with 22 ml of 1N KOH in ethanol and stirred for 4 hours, then concentrated, taken up in sodium bicarbonate solution and extracted with ethyl acetate. The water phase is acidified to pH 2 with hydrochloric acid at 0 ° and extracted with ethyl acetate. The ethyl acetate phase is washed with brine, dried, concentrated and the residue is recrystallized from ethyl acetate / ether. 1.96 g of 2-propylmalonic acid monoamide, mp. 137 ° C.

Analogously, 2-phenethylmalonamic acid, mp. 141.5 ° C., the starting acid for Example 58-59 is prepared from ethyl 2-phenethylmalonamate.

The (+) and (-) 2-isopropylmalonic acid monoamide (starting amide from Example 11) can be prepared as described below:

5.5 g rac-2-isopropylmalonic acid monoamide and 12.0 g quinidine are dissolved in 100 ml of boiling water, inoculated with a few crystals of the quinidine salt of (S) - (+) - 2-isopropylmalonic acid monoamide and then crystallized out. The crystals are filtered off, washed with water and ether and dried; 8.3 g of quinidine salt of (S) - (+) - 2-isopropylmalonic acid monoamide result. This salt is in 10 percent. Hydrochloric acid dissolved and left at 5 ° C, the precipitated crystals are filtered off, washed with water, dried and recrystallized again from water with the addition of a few drops of 1N hydrochloric acid. This gives 720 mg (S) - (+) - 2-isopropylmalonic acid monoamide, mp. 174 ° C., [α]<maths id="math0001" num=""><math display="inline"><mrow><mfrac><mrow><mtext>20</mtext></mrow><mrow><mtext>589</mtext></mrow></mfrac></mrow></math><img file="EP0444482B1_D0005.tif" /></maths>= + 45.6 ° (ethanol, c = 1).

The mother liquor obtained in the crystallization of the quinidine salt is 10 percent. Hydrochloric acid acidified and left at 5 ° C, the precipitated crystals are filtered off, washed with water, dried and recrystallized from water with the addition of a few drops of 1N hydrochloric acid. This gives 850 mg of (R) - (-) - 2-isopropylmalonic acid monoamide, mp. 176 ° C., [α]<maths id="math0002" num=""><math display="inline"><mrow><mfrac><mrow><mtext>20</mtext></mrow><mrow><mtext>589</mtext></mrow></mfrac></mrow></math><img file="EP0444482B1_D0006.tif" /></maths>= -45.6 ° (ethanol, c = 1).

The starting acid for example 42 can be produced as follows:<ul id="ul0025" list-style="none"><li>a) 20.6 g of thiomorpholine are added dropwise to a solution of 13.6 g of methyl malonate monochloride in 100 ml of methylene chloride. After stirring, the mixture is diluted with 200 ml of methylene chloride, washed in a separating funnel with water, then dried, filtered and evaporated. The residue is purified by chromatography on silica gel with methylene chloride and then methylene chloride / acetone (1: 1). 17.6 g of methyl tetrahydro-β-oxo-4H-1,4-thiazine-4-propionate are obtained.</li><li>b) 85 ml of 1N potassium hydroxide solution are added dropwise to a solution of 17.3 g of the ester from a) in 170 ml of acetone. After stirring and filtering, the mixture is evaporated, the residue is stirred in 200 ml of acetone and then filtered. The filter cake is washed with acetone and dried. An aqueous solution of the resulting potassium salt is chromatographed on a cation exchange column with water. The eluate is evaporated to dryness, the residue is pasted with ether and filtered off. 13 g of tetrahydro-β-oxo-4H-1,4-thiazine-4-propionic acid are obtained, mp. 119-120 ° C.</li></ul>

The starting acid for example 44 is produced as follows:<ul id="ul0026" list-style="none"><li>a) 33 ml of 1N potassium hydroxide solution are added dropwise to a solution of 5.6 g of methyl 1-carbamoylcyclopentane carboxylate in 66 ml of acetone. After stirring, the mixture is mixed with 250 ml of acetone, the precipitated potassium salt is filtered off and then washed with acetone and dried.</li><li>b) A solution of the 5.79 g of potassium salt obtained in 35 ml of water is concentrated at 0 ° C with 4 ml. Acidified hydrochloric acid to pH 1. The precipitate is filtered off, washed with water and then diethyl ether. After drying, 3.5 g of 1-carbamoylcyclopentane carboxylic acid are obtained.</li></ul>

The starting acid of Example 46 can be prepared as follows:

To 26 ml 25 percent. aqueous ammonia, a solution of 10.4 g of methyl methoxymalonate in 70 ml of methylene chloride is added dropwise at -10 ° C. After stirring, the mixture is evaporated, the residue is dissolved in water and chromatographed on a cation exchanger with water. The eluate is concentrated, the residue is pasted with diethyl ether and filtered off. The precipitate is washed with ether and dried. 8.9 g of methoxymalonamic acid, mp. 128-130 ° C., are obtained.

The starting acid for example 49 can be produced as follows:

A solution of 1.79 g of carbamoylmethylthioacetic acid in 42 ml of water is mixed with 3.71 g of monoperoxyphthalic acid magnesium salt hexahydrate. After stirring, the mixture is filtered, the filtrate is concentrated and concentrated with 2 ml. Acidified hydrochloric acid. After filtering off, the filtrate is percolated over a cation exchanger, eluted with water and the eluate is evaporated to dryness. The residue is slurried with acetone and filtered off. It is washed with acetone and dried. 1.65 g of rac - [(carbamoylmethyl) sulfinyl] acetic acid, mp. 137-138 ° C. result.

The acids of formula Q^aLower alkyl esters corresponding to OH are known or can be prepared analogously to the known esters, for example as described below, starting from the monoester of the formula H- (X)_n-COOR ", in which R" is lower alkyl, via the dicarboxylic acid monoester of the formula HOCO- (X)_n-COOR ". The starting acid of Example 2f) can be prepared as follows:<ul id="ul0027" list-style="none"><li>a) 48 ml of a 1.6M n-butyllithium solution in hexane are added dropwise to 11 ml of diisopropylamine and 5 g of 4 Å molecular sieve in 75 ml of THF at -15 ° C. After 15 minutes, the reaction mixture is cooled to -78 ° C. and a solution of 9.5 g of ethyl 1,3-dioxolane-2-carboxylate in 50 ml of THF is added dropwise. After stirring for 20 minutes, CO₂ is introduced at a temperature below -70 ° C. After saturation, the mixture is stirred at -75 ° C. for 20 minutes and then warmed up to room temperature. After the CO₂ gas has evaporated, the reaction mixture is concentrated, the residue is mixed with saturated bicarbonate solution and ethyl acetate, the ethyl acetate phase is discarded, the aqueous phase is acidified to pH 2 with potassium hydrogen sulfate and extracted with ethyl acetate. The ethyl acetate phase is dried and concentrated.</li><li>b) 0.93 ml of isobutyl chloroformate in 5 ml of THF are added dropwise to a solution of 1.08 g of the product of a), 1.1 ml of triethylamine and 3 g of molecular sieve 4Å in 30 ml of THF at 0 ° C. After stirring for 40 minutes, ammonia gas is introduced for 10 minutes and the reaction mixture is then stirred overnight. It is then filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with methylene chloride / methanol (95: 5). This results in 420 mg of ethyl 2-carbamoyl-1,3-dioxolane-2-carboxylate, mp. 99-100 ° C.</li><li>c) A solution of 190 mg of the product from b) in 10 ml of methanol is mixed with 1 ml of 2N KOH in methanol and stirred for 90 minutes at room temperature. A solution of 280 mg of potassium hydrogen sulfate in 1 ml of water is then added, the reaction mixture is filtered off with suction and the filtrate is evaporated. This gives the 2-carbamoyl-1,3-dioxolane-2-carboxylic acid.</li></ul>

The 2-carbamoyl-m-dioxane-2-carboxylic acid (starting acid for example 3m) is obtained analogously from the ethyl-m-dioxane-2-carboxylate.

The acids of the formula (R³, R⁴) NCO (X)_n-COOH, where X is a group = CHN (R, R^O), can be prepared from the corresponding dicarboxylic acid monoesters of the formula HOCO-X-COOR "via a corresponding succinimide and the corresponding amide ester of the formula H₂NCO-X-COOR", for example as described below for the starting acid of Example 9.<ul id="ul0028" list-style="none"><li>a) 4.54 g of dicyclohexylcarbodiimide, 4.16 g of acetamino-monoethylmalonate and 2.53 g of N-hydroxysuccinimide are added to 54 ml of THF at 0 ° C. After stirring for 1 hour, the mixture is allowed to warm to room temperature and stirred overnight. Then it is cooled to 0 ° C. and filtered. The filtrate is mixed with 20 ml of 25% aqueous ammonia solution, left at room temperature during the day and at 4 ° C. overnight. Then the solution is evaporated, the remaining aqueous solution is mixed with sodium bicarbonate. The aqueous phase is separated off, the organic phase is washed with saturated sodium chloride solution, then dried and concentrated. The residue is filtered in hexane containing ethyl acetate. The resulting crystals are washed with ether and then dried. 1.2 g of [D, L] -N-acetyl-2-carbamoylglycine ethyl ester are obtained, mp. 126-128 ° C.</li><li>b) A solution of 5.8 ml of 1N potassium hydroxide solution is added dropwise to a suspension of 1.09 g of the amide ester from a) in 7 ml of acetone. After stirring for 3 hours, the mixture is concentrated and the residue is dissolved in aqueous sodium bicarbonate solution. The solution is extracted with ethyl acetate, the aqueous phase is acidified to pH 3 with cooling with hydrochloric acid and then percolated via an ion exchanger. The eluate is evaporated to dryness and the residue is pasted with acetone. 500 mg of [D, L] -N-acetyl-2-carbamoylglycine, mp. 120 ° C. (decomposition) are obtained.</li></ul>

Starting acids of the formula (R³, R⁴) NCO (X)_n-COOH, in which at least one of R³ and R⁴ is different from H, can be obtained by reacting the corresponding acid ester of the formula HOC (O) - (X)_n-C (O) OR "with an amine HN (R³, R⁴) produce.

The starting acid of Example 10d) can be prepared as follows:

A solution of 3 g of monomethyl malonate in 15 ml of 40% aqueous dimethylamine is concentrated after stirring for 18 hours, filtered through a strongly acidic cation exchanger, evaporated to dryness and crystallized from chloroform. Concentration of the mother liquor and crystallization from ether yield 1.3 g of dimethylcarbamoylacetic acid, mp. 72-76 ° C.

The oxetanones of the formula I have valuable pharmacological properties. They inhibit pancreatic lipase in particular and can accordingly be used to combat or prevent obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

The inhibition of pancreatic lipase by the oxetanones of the formula I can be demonstrated experimentally by titrimetrically recording the oleic acid released when triolein is cleaved by porcine pancreatic lipase. To an emulsion containing 1 mM taurodeoxycholate, 9 mM taurocholate, 0.1 mM cholesterol, 1 mM eilezithin, 15 mg / ml BSA, 2 mM Tris-HCl, 100 mM sodium chloride, 1 mM calcium chloride and the substrate triolein are added the compound of formula I dissolved in ethanol or dimethyl sulfoxide (10% of the emulsion volume) and starts the reaction by adding 1-3 µg of porcine pancreatic lipase. The pH is kept at 8 during the reaction by adding sodium hydroxide solution. The IC₅₀ is calculated from the consumption of sodium hydroxide solution determined over 10 minutes. The IC₅₀ is the concentration at which the lipase activity is half maximally inhibited. The following table contains the IC₅₀ values ​​determined for the compounds of the formula I in µg / ml.<tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="13" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="12.11mm" /><colspec colnum="2" colname="col2" colwidth="12.11mm" /><colspec colnum="3" colname="col3" colwidth="12.11mm" /><colspec colnum="4" colname="col4" colwidth="12.11mm" /><colspec colnum="5" colname="col5" colwidth="12.11mm" /><colspec colnum="6" colname="col6" colwidth="12.11mm" /><colspec colnum="7" colname="col7" colwidth="12.11mm" /><colspec colnum="8" colname="col8" colwidth="12.11mm" /><colspec colnum="9" colname="col9" colwidth="12.11mm" /><colspec colnum="10" colname="col10" colwidth="12.11mm" /><colspec colnum="11" colname="col11" colwidth="12.11mm" /><colspec colnum="12" colname="col12" colwidth="12.11mm" /><colspec colnum="13" colname="col13" colwidth="12.11mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left"><b>example</b></entry><entry namest="col2" nameend="col2" align="left">1a, 11a</entry><entry namest="col3" nameend="col3" align="left">1b, 11b</entry><entry namest="col4" nameend="col5" align="left">2b, 12b</entry><entry namest="col6" nameend="col7" align="left">2d</entry><entry namest="col8" nameend="col9" align="left">2e</entry><entry namest="col10" nameend="col11" align="left">2f</entry><entry namest="col12" nameend="col12" align="left">2g1,13a</entry><entry namest="col13" nameend="col13" align="left">2g2</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">IC₅₀</entry><entry namest="col2" nameend="col2" align="char" char=",">0,032</entry><entry namest="col3" nameend="col3" align="char" char=",">0,025</entry><entry namest="col4" nameend="col5" align="char" char=",">0,063</entry><entry namest="col6" nameend="col7" align="char" char=",">0,12</entry><entry namest="col8" nameend="col9" align="char" char=",">0,051</entry><entry namest="col10" nameend="col11" align="char" char=",">0,47</entry><entry namest="col12" nameend="col12" align="char" char=",">0,052</entry><entry namest="col13" nameend="col13" align="char" char=",">0,013</entry></row></tbody></tgroup><tgroup cols="13" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="12.11mm" /><colspec colnum="2" colname="col2" colwidth="12.11mm" /><colspec colnum="3" colname="col3" colwidth="12.11mm" /><colspec colnum="4" colname="col4" colwidth="12.11mm" /><colspec colnum="5" colname="col5" colwidth="12.11mm" /><colspec colnum="6" colname="col6" colwidth="12.11mm" /><colspec colnum="7" colname="col7" colwidth="12.11mm" /><colspec colnum="8" colname="col8" colwidth="12.11mm" /><colspec colnum="9" colname="col9" colwidth="12.11mm" /><colspec colnum="10" colname="col10" colwidth="12.11mm" /><colspec colnum="11" colname="col11" colwidth="12.11mm" /><colspec colnum="12" colname="col12" colwidth="12.11mm" /><colspec colnum="13" colname="col13" colwidth="12.11mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left"><b>example</b></entry><entry namest="col2" nameend="col2" align="left">3c</entry><entry namest="col3" nameend="col3" align="left">3d</entry><entry namest="col4" nameend="col5" align="left">3e</entry><entry namest="col6" nameend="col7" align="left">3f</entry><entry namest="col8" nameend="col9" align="left">3g</entry><entry namest="col10" nameend="col11" align="left">3h</entry><entry namest="col12" nameend="col12" align="left">3i</entry><entry namest="col13" nameend="col13" align="left">3y</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">IC₅₀</entry><entry namest="col2" nameend="col2" align="char" char=",">0,39</entry><entry namest="col3" nameend="col3" align="char" char=",">0,90</entry><entry namest="col4" nameend="col5" align="char" char=",">1,41</entry><entry namest="col6" nameend="col7" align="char" char=",">0,083</entry><entry namest="col8" nameend="col9" align="char" char=",">0,294</entry><entry namest="col10" nameend="col11" align="char" char=",">2,1</entry><entry namest="col12" nameend="col12" align="char" char=",">0,42</entry><entry namest="col13" nameend="col13" align="char" char=",">0,16</entry></row></tbody></tgroup><tgroup cols="13" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="12.11mm" /><colspec colnum="2" colname="col2" colwidth="12.11mm" /><colspec colnum="3" colname="col3" colwidth="12.11mm" /><colspec colnum="4" colname="col4" colwidth="12.11mm" /><colspec colnum="5" colname="col5" colwidth="12.11mm" /><colspec colnum="6" colname="col6" colwidth="12.11mm" /><colspec colnum="7" colname="col7" colwidth="12.11mm" /><colspec colnum="8" colname="col8" colwidth="12.11mm" /><colspec colnum="9" colname="col9" colwidth="12.11mm" /><colspec colnum="10" colname="col10" colwidth="12.11mm" /><colspec colnum="11" colname="col11" colwidth="12.11mm" /><colspec colnum="12" colname="col12" colwidth="12.11mm" /><colspec colnum="13" colname="col13" colwidth="12.11mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left"><b>example</b></entry><entry namest="col2" nameend="col2" align="left">3k</entry><entry namest="col3" nameend="col3" align="left">3l</entry><entry namest="col4" nameend="col5" align="left">4a</entry><entry namest="col6" nameend="col7" align="left">6b, 14c</entry><entry namest="col8" nameend="col9" align="left">7b</entry><entry namest="col10" nameend="col11" align="left">10a</entry><entry namest="col12" nameend="col12" align="left">10b</entry><entry namest="col13" nameend="col13" align="left">10c</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">IC₅₀</entry><entry namest="col2" nameend="col2" align="char" char=",">0,12</entry><entry namest="col3" nameend="col3" align="char" char=",">0,78</entry><entry namest="col4" nameend="col5" align="char" char=",">0,16</entry><entry namest="col6" nameend="col7" align="char" char=",">0,056</entry><entry namest="col8" nameend="col9" align="char" char=",">0,079</entry><entry namest="col10" nameend="col11" align="char" char=",">0,083</entry><entry namest="col12" nameend="col12" align="char" char=",">0,042</entry><entry namest="col13" nameend="col13" align="char" char=",">0,1</entry></row></tbody></tgroup><tgroup cols="13" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="12.11mm" /><colspec colnum="2" colname="col2" colwidth="12.11mm" /><colspec colnum="3" colname="col3" colwidth="12.11mm" /><colspec colnum="4" colname="col4" colwidth="12.11mm" /><colspec colnum="5" colname="col5" colwidth="12.11mm" /><colspec colnum="6" colname="col6" colwidth="12.11mm" /><colspec colnum="7" colname="col7" colwidth="12.11mm" /><colspec colnum="8" colname="col8" colwidth="12.11mm" /><colspec colnum="9" colname="col9" colwidth="12.11mm" /><colspec colnum="10" colname="col10" colwidth="12.11mm" /><colspec colnum="11" colname="col11" colwidth="12.11mm" /><colspec colnum="12" colname="col12" colwidth="12.11mm" /><colspec colnum="13" colname="col13" colwidth="12.11mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left"><b>example</b></entry><entry namest="col2" nameend="col2" align="left">10d</entry><entry namest="col3" nameend="col3" align="left">10e</entry><entry namest="col4" nameend="col4" align="left">10f</entry><entry namest="col5" nameend="col6" align="left">37</entry><entry namest="col7" nameend="col8" align="left">43</entry><entry namest="col9" nameend="col10" align="left">45</entry><entry namest="col11" nameend="col11" align="left">51</entry><entry namest="col12" nameend="col12" align="left">78c</entry><entry namest="col13" nameend="col13" align="left">78d</entry></row></thead><tbody valign="top"><row rowsep="1"><entry namest="col1" nameend="col1" align="left">IC₅₀</entry><entry namest="col2" nameend="col2" align="char" char=",">0,47</entry><entry namest="col3" nameend="col3" align="char" char=",">0,027</entry><entry namest="col4" nameend="col4" align="char" char=",">0,32</entry><entry namest="col5" nameend="col6" align="char" char=",">0,034</entry><entry namest="col7" nameend="col8" align="char" char=",">0,12</entry><entry namest="col9" nameend="col10" align="char" char=",">0,047</entry><entry namest="col11" nameend="col11" align="char" char=",">0,36</entry><entry namest="col12" nameend="col12" align="char" char=",">0,28</entry><entry namest="col13" nameend="col13" align="char" char=",">0,051</entry></row></tbody></tgroup></table></tables>

The acute toxicity (after a single oral administration to mice) is more than 5000 mg / kg for the products of Examples 3d, 3h, 3i, 3l, 4a and 10a, b, e and f.

The oxetanones of the formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.

For the production of pharmaceutical preparations, the products according to the invention can be administered with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as such carriers for tablets, coated tablets, coated tablets and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-fat and liquid polyols; Depending on the nature of the active ingredient, no carriers are required at all in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose.

The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.

As mentioned at the outset, medicaments containing an oxetanone of the formula I are also the subject of the present invention, and also a process for the preparation of such medicaments, which is characterized in that an oxetanone of the formula I and, if appropriate, one or more other therapeutically valuable substances brings a pharmaceutical formulation. As mentioned, the compounds of the formula I can be used in combating or preventing diseases, in particular in combating or preventing obesity, hyperlipaemia, atherosclerosis and arteriosclerosis. The dosage can vary within wide limits and must of course be adapted to the individual circumstances in each individual case. In general, a daily dose of about 0.1 mg to 100 mg / kg body weight should be appropriate for oral administration.

The oxetanones of the formula I can also be added to industrially manufactured foods, fats, oils, butter, margarine, chocolate and other confectionery products being particularly suitable. Such industrially manufactured foods, which can contain about 0.1 to 5% by weight of an oxetanone of the formula I, and their production are also the subject of the present invention.

The following examples are intended to explain the present invention in greater detail, but in no way limit its scope. All temperatures are given in degrees Celsius.

example 1

A solution of 574 mg (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone, 525 mg triphenylphosphine, 290 mg 2-isopropylmalonic acid monoamide and 2 g molecular sieve (4Å) in 10 ml THF is mixed with 0.4 ml of diisopropyl azodicarboxylic acid while stirring at 0 °. After 30 minutes of stirring at 0 ° and 1 hour at room temperature, the reaction mixture is filtered off, the molecular sieve is washed with ether and the solvents are evaporated off. The residue is dissolved in hexane and extracted with methanol / water (7: 3). The hexane phase is diluted with ether, dried and evaporated. The residue is chromatographed on silica gel using methylene chloride / ether (9: 1). You get<ul id="ul0029" list-style="none"><li>a) 239 mg (S) - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (R or S) -2-isopropylmalonamate, mp. 115 ° and</li><li>b) 266 mg (S) - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (S or R) -2-isopropylmalonamate, mp 118 °.</li></ul>

Example 2

Analogously to Example 1, (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-isopropylmalonic acid monoamide are obtained<ul id="ul0030" list-style="none"><li>a) (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - (R or S) -2-isopropylmalonamate, mp. 136 ° and</li><li>b) (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - (S or R) -2-isopropylmalonamate, mp 82 °;</li><li>c) from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and isopropylidene malonic acid monoamide (S) -1 - [[(2S, 3S) -3-hexyl-4- oxo-2-oxetanyl] methyl] -dodecyl -2-carbamoyl-3-methylcrotonate, m.p. 108-111 °;</li><li>d) from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-propylmalonic acid monoamide the (S) -1 - [[(2S, 3S) -3-hexyl -4-oxo-2-oxetanyl] methyl] -dodecyl- (RS) -2-carbamoylvalerate (epimers 1: 1), mp 92-94 °;</li><li>e) from (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone and 2-propylmalonic acid monoamide the (S) -1 - [[(2S, 3S) -3-ethyl -4-oxo-2-oxetanyl] methyl] octadecyl - (RS) -2-carbamoylvalerate (epimers 1: 1), mp 78-80 °;</li><li>f) from (3S, 4S) -ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone and 2-carbamoyl-1,3-dioxolane-2-carboxylic acid the (S) -1 - [[( 2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl -2-carbamoyl-1,3-dioxolane-2-carboxylate, mp 95 °;</li><li>g) from (3S, 4S) -3-ethyl-4 - [(R, 10Z, 13Z) -2-hydroxy -10,13-nonadecadienyl] -2-oxetanone and 2-isopropylmalonic acid monoamide</li><li>1. (all Z, S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl (R or S) -2-isopropylmalonamate, m.p. 87 -88 ° (from ether) and</li><li>2nd (all Z, S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl- (S or R) -2-isopropylmalonamate, IR: 3393, 1840, 1716, 1647, 1185 cm -1.</li></ul>

Example 3

Analogously to Example 1, the following ester amides are obtained by reacting the (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone with the following amides:<ul id="ul0031" list-style="none"><li>a) with the 4-carbamoylbutyric acid the 4-carbamoylbutyric acid- (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester, mp. 67-68 °</li><li>b) with the 3-carbamoylpropionic acid the 3-carbamoylpropionic acid- (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester, mp. 50.5-51 °</li><li>c) with the 2-carbamoylacetic acid the 2-carbamoylacetic acid- (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester, mp. 86.5-87 °</li><li>d) with the oxalic acid monoamide, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyloxamate, mp 77-78 °</li><li>e) with the methylcarbamoylacetic acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl -N-methylmalonamate, mp. 63-67 °</li><li>f) with the rac-2-carbamoyl-4-methylvaleric acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - (RS) -2- carbamoyl-4-methylvalerate (epimers 1: 1), mp 102-104 °</li><li>g) with the 1-carbamoylcydohexanecarboxylic acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl -1-carbamoylcydohexanecarboxylate, mp. 50-52 °</li><li>h) with 2,2-dimethylmalonamic acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl -2,2-dimethylmalonamate, [α]<maths id="math0003" num=""><math display="inline"><mrow><mfrac><mrow><mtext>20</mtext></mrow><mrow><mtext>D</mtext></mrow></mfrac></mrow></math><img file="EP0444482B1_D0007.tif" /></maths>= -23.8 ° (CHCl₃, c = 0.9%)</li><li>i) with the rac-2-methylmalonamic acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - (RS) -2-methylmalonamate (epimers 1 : 1), mp 107-108 °</li><li>j) with the rac-2-ethylmalonamic acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - (RS) -2-ethylmalonamate (epimers 1 : 1), mp 87-90 °</li><li>k) with the rac-2-butylmalonamic acid the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - (RS) -2-butylmalonamate (epimers 1 : 1), m.p. 96-98 °</li><li>l) with the 2,2-diethylmalonamic acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl -2,2-diethylmalonamate, [α]<maths id="math0004" num=""><math display="inline"><mrow><mfrac><mrow><mtext>20</mtext></mrow><mrow><mtext>D</mtext></mrow></mfrac></mrow></math><img file="EP0444482B1_D0008.tif" /></maths>= -21.1 ° (CHCl₃, c = 1%)</li><li>m) with the 2-carbamoyl-m-dioxane-2-carboxylic acid, the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl -2-carbamoyl- m-dioxane-2-carboxylate, mp 51 °.</li></ul>

Example 4

Analogously to Example 1, (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone and<ul id="ul0032" list-style="none"><li>a) from the 1-carbamoylcydohexanecarboxylic acid the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl -1-carbamoylcyclohexanecarboxylate, mp. 78-79 ° and</li><li>b) from the 2-carbamoyl-m-dioxane-2-carboxylic acid, the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl -2-carbamoyl- m-dioxane-2-carboxylate, mp 79 °.</li></ul>

example

5

Analogously to Example 1, (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone and 2-isopropylmalonamide are obtained<ul id="ul0033" list-style="none"><li>a) the (S) -1 - [[(2R, 3R or 2S, 3S) -4-oxo-3-pentylthio-2-oxetanyl] methyl] -dodecyl- (R or S) -2-isopropylmalonamate, MS: 354 [M⁺ • - (2-isopropylmalonic acid amide)]; IR (cm⁻¹): 3397, 2924, 1829, 1731, 1657, 1120 and</li><li>b) the (S) -1 - [[(2R, 3R or 2S, 3S) -4-oxo-3-pentylthio-2-oxetanyl] methyl] -dodecyl- (S or R) -2-isopropylmalonamate, m.p. 77-78 ° (diethyl ether).</li></ul>

Example 6

Analogously to Example 1, (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone and 2-isopropylmalonamide are obtained<ul id="ul0034" list-style="none"><li>a) the (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl- (R or S) -2-isopropylmalonamate, mp. 133 ° (ethyl acetate) and</li><li>b) the (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] -dodecyl- [S: R or R: S (2: 1 )] - 2-isopropylmalonamate, m.p. 102-104 ° (ethyl acetate).</li></ul>

Example 7

Analogously to Example 1, an epimer mixture is obtained from (3R, 4R) -3-benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-isopropylmalonic acid monoamide, which mixture is chromatographed on silica gel with ethyl acetate / hexane / methylene chloride ( 1: 2: 2) is separated into<ul id="ul0035" list-style="none"><li>a) (S) -1 - [[(2R, 3R) -3-benzyl-4-oxo-2-oxetanyl] methyl] dodecyl- (R or S) -2-isopropylmalonamate, mp 85-87 ° (methylene chloride ) and</li><li>b) (S) -1 - [[(2R, 3R) -3-benzyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-isopropylmalonamate, mp. 108-110 ° (methylene chloride ).</li></ul>

Example 8

Analogously to Example 1, an (3S, 4S) -3-benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-isopropylmalonic acid monoamide is used to obtain an epimer mixture which is purified by chromatography on silica gel with ethyl acetate / hexane / methylene chloride ( 1: 2: 2) is separated into<ul id="ul0036" list-style="none"><li>a) (S) -1 - [[(2S, 3S) -3-benzyl-4-oxo-2-oxetanyl] methyl] dodecyl- (R or S) -2-isopropylmalonamate, mp. 107-108 ° (methylene chloride ) and</li><li>b) (S) -1 - [[(2S, 3S) -3-benzyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-isopropylmalonamate, mp 148-149 ° (methylene chloride ).</li></ul>

Example 9

A suspension of 1.06 g (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, 480 mg [D, L] -N-acetyl, cooled to -10 ° C -2-carbamoylglycine, 1.1 g triphenylphosphine and 1.2 g molecular sieve 4Å in 12 ml THF, 1.03 g azodicarboxylic acid di-t-butyl ester are added. After stirring for 1 hour at 0 ° C. and overnight at room temperature, the reaction mixture is worked up similarly to that described in Example 1. You get<ul id="ul0037" list-style="none"><li>a) 190 mg (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (R or S) -2-acetamidomalonamate, mp 125-126 ° and</li><li>b) 100 mg (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-acetamidomalonamate (epimers 1: 1), mp. 110-116 °, [α]<maths id="math0005" num=""><math display="inline"><mrow><mfrac><mrow><mtext>25</mtext></mrow><mrow><mtext>D</mtext></mrow></mfrac></mrow></math><img file="EP0444482B1_D0009.tif" /></maths>= -8 ° (c = 0.5, CHCl₃).</li></ul>

Example 10

Analogously to Example 1, but using the following amides, the following ester amides are obtained:<ul id="ul0038" list-style="none"><li>a) from the oxalic acid monoamide the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyloxamate, mp. 99-100 °</li><li>b) from the 2-carbamoylacetic acid the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecylmalonamate, mp 90.5-91.5 °</li><li>c) from the methyl carbamoylacetic acid, the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-N-methylmalonamate, mp. 84-85 °</li><li>d) from the dimethylcarbamoylacetic acid the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-N, N-dimethylmalonamate, mp. 66-67 °</li><li>e) from the rac-2-methylmalonamic acid, the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (RS) -2-methylmalonamate (epimers 1 : 1), m.p. 91.5-92 °</li><li>f) from the 3-carbamoylpropionic acid the (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl succinamate, mp. 74.5-75.7 ° .</li></ul>

Example 11

Analogously to Example 1, but using (S) - (+) - or (±) -2-isopropylmalonic acid monoamide, is obtained<ul id="ul0039" list-style="none"><li>a) (S) - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (R) -2-isopropylmalonamate, mp. 115 ° and</li><li>b) (S) - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, mp 118 °.</li></ul>

Example 12

Analogously to Examples 1, 2a) b) and 11, (3S, 4S) -3-hexyl-4 - [(R) -2hydroxytridecyl] -2-oxetanone and (±) - or (S) - (+) -2-isopropylmalonic acid monoamide<ul id="ul0040" list-style="none"><li>a) (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, mp. 136 ° or</li><li>b) (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, mp 82 °</li><li>c) from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-propylmalonic acid monoamide after chromatographic separation on silica gel with methylene chloride / acetonitrile (85:15)<ul id="ul0041" list-style="none"><li>1. the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (R or S) -2-carbamoylvalerate, mp. 113 ° (from methanol / water ) and</li><li>2nd the (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-carbamoylvalerate, mp 85 °.</li></ul></li></ul>

Example 13

Analogously to Examples 1, 2g) and 11, (3S, 4S) -3-ethyl-4 - [(R, 10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone and (±) - or (S) - (+) - 2-isopropylmalonic acid monoamide<ul id="ul0042" list-style="none"><li>a) (all Z, S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl- (R) -2-isopropylmalonamate, m.p. 87-88 ° (from ether) and</li><li>b) (all Z, S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl- (S) -2-isopropylmalonamate, m.p. 109 ° (from aqueous methanol).</li></ul>

Example 14

Analogously to Examples 1, 6 and 11, (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone and (±) - or (S) - (+) - 2-isopropylmalonic acid amide<ul id="ul0043" list-style="none"><li>a) the (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, mp. 133 ° ( Ethyl acetate)</li><li>b) the (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, mp. 93 ° ( Diethyl ether / hexane) and</li><li>c) the (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl- [S: R (2: 1)] - 2- isopropyl malonamate, m.p. 102-104 ° (ethyl acetate).</li></ul>

Example 15

Analogously to Examples 1 and 11, (3S, 4S or 3R, 4R) -benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxo-3-oxetane carbamate and (S) - (+) - 2- Isopropylmalonic acid monoamide the (S) -1 - [[(2S, 3S or 2R, 3R) -3- [1- (benzyloxy) formamido] -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate , Mp 133 ° (from ether / hexane).

Example 16

Analogously to Examples 1 and 11 one obtains<ul id="ul0044" list-style="none"><li>a) from (3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone and (S) - (+) - 2-isopropylmalonic acid monoamide the (S) -1- [ [(2R, 3R) -4-oxo-3- (phenylthio) -2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, mp. 88 ° (ether)</li><li>b) from (3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone and 2-isopropylmalonic acid monoamide the (S) -1 - [[(2S, 3S) -4 -Oxo-3- (phenylthio) -2-oxetanyl] methyl] dodecyl- (RS) -2-isopropylmalonamate (1: 1 epimers), mp. 109 ° (ether)</li><li>c) from (3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone and 2-isopropylmalonic acid monoamide the same product as under a) and the (S) -1- [ [(2R, 3R) -4-oxo-3- (phenylthio) -2-oxetanyl] methyl] dodecyl-2-isopropylmalonamate (R: S = 7: 1), mp 85 ° (ether).</li></ul>

Example 17

Analogously to Examples 1 and 11, the following esters are obtained from (S) - (+) - 2-isopropylmalonic acid monoamide and from the following alcohols:<ul id="ul0045" list-style="none"><li>a) from (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone the (S) -1 - [[(2S, 3S or 2R, 3R) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, mp. 133 ° (from ether)</li><li>b) from (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone the (S) -1 - [[(2R, 3R or 2S, 3S) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, mp. 103 ° (from ether) and</li><li>c) from (3S, 4R or 3R, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone the (S) -1 - [[(2R, 3S or 2S, 3R) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, mp. 96 ° (from ether / hexane)</li><li>d) from (3R, 4S or 3S, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio] -2-oxetanone the (S) -1 - [[(2S, 3R or 2R, 3S) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, mp. 120 ° (from ether / hexane).</li></ul>

Example 18

Analogously to Examples 1 and 11, (R) - (-) - 2-isopropylmalonic acid monoamide and<ul id="ul0046" list-style="none"><li>a) from (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone the (S) -1 - [[(2S, 3S or 2R, 3R) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl- (R) -2-isopropylmalonamate, mp. 96 ° (from ether)</li><li>b) from (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone the (S) -1 - [[(2R, 3R or 2S, 3S) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl- (R) -2-isopropylmalonamate, mp. 87 ° (from ether / hexane).</li></ul>

Example 19

Analogously to Examples 1 and 11, the following esters are obtained from (S) - (+) - 2-isopropylmalonic acid monoamide and from the following alcohols:<ul id="ul0047" list-style="none"><li>a) from (3S, 4S or 3R, 4R) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone the (S) -1 - [[(2S, 3S or 2R, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, mp. 84 ° (from pentane)</li><li>b) from (3R, 4R or 3S, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone the (S) -1 - [[(2R, 3R or 2S, 3S) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, mp. 65 ° (from ether / pentane)</li><li>c) from (3S, 4R and 3R, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone<ul id="ul0048" list-style="none"><li>1. the (S) -1 - [[(2S, 3R or 2R, 3S) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, mp 69 ° ( from pentane)</li><li>2nd the (S) -1 - [[(2R, 3S or 2S, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, mp. 106 ° ( from hexane).</li></ul></li></ul>

Example 20

Analogously to Examples 1 and 11, the following esters are obtained from (R) - (-) - 2-isopropylmalonic acid monoamide and from the following alcohols:<ul id="ul0049" list-style="none"><li>a) from (3S, 4S or 3R, 4R) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone the (S) -1 - [[(2S, 3S or 2R, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, mp. 130 ° (from ether / pentane)</li><li>b) from (3R, 4R or 3S, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone the (S) -1 - [[(2R, 3R or 2S, 3S) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, mp. 119 ° (from hexane / pentane)</li><li>c) from (3S, 4R and 3R, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone</li><li>1. the (S) -1 - [[(2S, 3R or 2R, 3S) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, mp. 132 ° ( from ether / pentane)</li><li>2nd the (S) -1 - [[(2R, 3S or 2S, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, mp. 102 ° ( from ether / pentane).</li></ul>

Example 21

Analogously to Examples 1 and 11, reaction of (3R, 4R) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone is obtained<ul id="ul0050" list-style="none"><li>a) with (S) - (+) - 2-isopropylmalonic acid monoamide the (S) -1 - [[(2R, 3R) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (S) -2 -isopropylmalonamate, mp. 116-118 ° (methylene chloride),</li><li>b) with 1-carbamoylcyclohexane carboxylic acid, the (S) -1 - [[(2R, 3R) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-1-carbamoylcydohexane carboxylate, mp. 71-74 °.</li></ul>

Example 22

Analogously to Examples 1 and 11, one obtains<ul id="ul0051" list-style="none"><li>a) from (S) - (+) - 2-isopropylmalonic acid monoamide and (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-methyl-2-oxetanone the (S) -1 - [[( 2R, 3R) -3-methyl-4-oxo-2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, mp. 124-126 ° (from ethyl acetate / hexane)</li><li>b) from rac-2-t-butylmalonic acid monoamide and (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-methyl-2-oxetanone the (S) -1 - [[(2R, 3R) -3-methyl-4-oxo-2-oxetanyl] methyl] octadecyl- (RS) -2-t-butylmalonamate (epimers 1: 1), mp. 51-54 ° (ethyl acetate / hexane).</li></ul>

Example 23

A solution of 277 mg (2S, 3S, 5S) -5 - [[(cis) -2-carbamoylcydohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoic acid (Example Jd) in 24 ml methylene chloride and 3 ml DMF is mixed with 2 g molecular sieve (4Å), 240 mg HBTU and 240 mg triethylamine. After stirring, 300 mg of HBTU and 300 mg of triethylamine are added. Then it is filtered and the filtrate is concentrated. The residue is partitioned between methanol / water (7: 3) and hexane and extracted with hexane. The hexane phase is diluted with methylene chloride, then dried and concentrated and the residue is recrystallized from ether / hexane. The result<ul id="ul0052" list-style="none"><li>a) 96 mg (1R or S, 2S or R) -2 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] cydohexane carboxamide (1st cis diastereomer), mp. 102 ° (from ether / hexane)</li><li>b) Analogously, (2S, 3S, 5S) -5 - [[(cis) -2-carbamoylcydohexyl] oxy] -2-hexyl-3-hydroxyh exadecanoic acid (2nd diast. acid) in Example Je) becomes (1S or R, 2R or S) -2 - [[(S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] cyclohexane carboxamide (2nd cis- Diastereomer), mp. 94 ° (from ether / hexane).</li></ul>

Example 24

A solution of 42.5 mg (2S, 3S, 5S) -5 - [(R / S) -2-carbamoyl-1-methoxyethoxy] -2-hexyl-3-hydroxydecanoic acid (Example Kd) in 10 ml methylene chloride / acetonitrile (1: 1) is mixed with 1 g molecular sieve (4 Å), 0.1 ml triethylamine and 50 mg HBTU. After stirring, the reaction mixture is filtered, concentrated and the residue is partitioned between hexane and methanol / water (1: 1); the aqueous methanolic phase is extracted with hexane, the hexane phase is dried and concentrated; then the residue on silica gel with 5 percent. Chromatographed methanol in methylene chloride. This results in 21 mg (R / S) -3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] -3-methoxypropionamide (Epimers 3: 1), mp 54 °.

Example 25

In a solution of 40 mg of 3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] propionic acid (Example L) in 2, 5 ml of acetonitrile is blown in until ammonia gas is saturated and then 50 mg of HBTU are added. Then it is filtered and evaporated and the residue on silica gel with 5 percent. Chromatographed methanol in methylene chloride. The result is 32.5 mg (3S, 4S) -4 - [(S) -2- (2-carbamoylethoxy) tridecyl] -3-hexyl-2-oxetanone, mp. 35 °.

Example 26

A solution of 33.5 mg (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl hydrogen malonate (Example N) in 2 ml of acetonitrile is mixed with 60 mg HBTU and 75 mg of isopropylamine were added. After stirring, the reaction mixture is filtered off, the filtrate is concentrated and the residue is chromatographed on silica gel with hexane / methylene chloride / ethyl acetate (2: 2: 1). The result is 31.1 mg (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-N-isopropylmalonamate, mp 59 °.

The following compounds are prepared in a manner analogous to Example 1:<ul id="ul0053" list-style="none" compact="compact"><li><u>Example 27</u>: (S) -1 - [[(2S, 3S) -3-hexyl-oxo-2-oxetanyl] methyl] dodecyl-5-carbamoylvalerianate, mp 50-51 °,</li><li><u>Example 28:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-6-carbamoylhexanoate, mp 52-53 °,</li><li><u>Example 29</u>: (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-7-carbamoylheptanoate, mp 40-43 °,</li><li><u>Example 30</u>: (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-9-carbamoyl nonanoate, mp. 29-30 °,</li><li><u>Example 31</u>: (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-4-carbamoylbutyrate, mp 74-75 °,</li><li><u>Example 32:</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl adipamate, mp 63.5-64.5 °,</li><li><u>Example 33:</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-6-carbamoylhexanoate, mp 71.5-72.5 °,</li><li><u>Example 34:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-oxetanyl] methyl] dodecyl (R or S) -2-t-butylmalonamate, mp. 53-54 °,</li><li><u>Example 35:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-t-butylmalonamate, [α]<maths id="math0006" num=""><math display="inline"><mrow><mfrac><mrow><mtext>20</mtext></mrow><mrow><mtext>D</mtext></mrow></mfrac></mrow></math><img file="EP0444482B1_D0010.tif" /></maths>= -16.4 ° (c = 0.8, CHCl₃),</li><li><u>Example 36:</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (R or S) -2-t-butylmalonamate, mp 48-49 °,</li><li><u>Example 37:</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (S or R) -2-t-butylmalonamate, mp 81-82 °,</li><li><u>Example 38:</u>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (S) -3- [1- (benzyloxy) formamido] succinamate, m.p. 72- 73 °,</li><li><u>Example 39:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-cis-6-carbamoyl-3-cyclohexene-1-carboxylate, mp 55-59 ° ,</li><li><u>Example 40:</u>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-cis-2-carbamoylcyclohexane carboxylate, mp 76-77 °,</li><li><u>Example 41:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-β-oxo-4-morpholine propionate, mp 49-51 °,</li><li><u>Example 42:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-tetrahydro-β-oxo-4H-1,4-thiazine-4-propionate, m.p. 59-61 °,</li><li><u>Example 43:</u>(S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl-1-carbamoylcyclopentane carboxylate, mp 62-63 °,</li><li><u>Example 44:</u> (S) -1 - [[(2S, 2S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-1-carbamoylcyclopentane carboxylate, mp 40-41 °,</li><li><u>Example 45:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-benzylmalonomat (epimers 1: 1), mp 86-92 ° ,</li><li><u>Example 46:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-methoxymalonamate (epimers 1: 1), mp 65-67 ° ,</li><li><u>Example 47:</u>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - [(carbamoyl) thio] acetate, mp 58-60 °,</li><li><u>Example 48:</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl - [(carbamoylmethyl) thio] acetate, mp 83-84 ° C,</li><li><u>Example 49:</u>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl - [(RS) - (carbamoylmethyl) sulfinyl] acetate (epimers 1: 1), m.p. 55-59 °,</li><li><u>Example 50:</u>(S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl - [(RS) - (carbamoylmethyl) thio] acetate S-oxide, m.p. 80- 82 °,</li><li><u>Example 51:</u>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-3 - [(2-carbamoylethyl) thio] propionate, mp. 73-74 °,</li><li><u>Example 52:</u> (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl-3 - [(RS) - (2-carbamoylethyl) sulfinyl] propionate (epimers 1: 1 ), Mp. 48-51 °,</li><li><u>Example 53:</u> (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (carbamoylmethoxy) acetate, mp 52-53 °,</li><li><u>Example 54:</u>(S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (carbamoylmethoxy) acetate, mp. 75-76 °,</li><li><u>Example 55:</u> (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2- [1- (benzyloxy) formamido] malonamate (epimers 1: 1 ), Mp 94-95 °,</li><li><u>Example 56:</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (RS) -2-isobutylmalonamate (epimers 1: 1), mp 96-99 ° ,</li><li><u>Example 57a)</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (RS) -2-benzylmalonamate (epimers 1: 1), mp. 96-103 ° ,</li><li><u>Example 57b)</u> (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (R or S) -2-benzylmalonamate, mp. 118-120 °,</li><li><u>Example 58:</u>(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl- (RS) -2-phenethylmalonamate (epimers 1: 1), mp 92-93 ° ,</li><li><u>Example 59:</u>(S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl- (RS) -2-phenethylmalonamate (epimers 1: 1)), mp 97-98 °.</li></ul>

Example 60

Analogously to Examples 1 and 11, (S) - (+) - 2-isopropylmalonic acid monoamide and (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (2-propynyl) -2-oxetanone ( Example M) the (S) -1 - [[(2R, 3R) -4-oxo-3- (2-propynyl) -2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, m.p. 92- 95 ° C (from ethyl acetate / hexane).

Example 61

Analogously to Examples 1 and 11, (S) - (+) - 2-isopropylmalonic acid monoamide and (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-propyl-2-oxetanone (Example O) give that (S) -1 - [[(2R, 3R) -4-oxo-3-propyl-2-oxetanyl] methyl] octadecyl- (S) -2-isopropylmalonamate, mp 90-93 ° (from ethyl acetate / hexane) .

The following compounds are prepared in a manner analogous to Examples 1 and 11:<ul id="ul0054" list-style="none" compact="compact"><li><u>Example 62:</u> (S) -1 - [[(2S, 3S) -3- (3-methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (R or S) -2-isopropylmalonamate, m.p. 100-102 °,</li><li><u>Example 63:</u>(S) -1 - [[(2S, 3S) -3- (3-methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-isopropylmalonamate, m.p. 120-121 °,</li><li><u>Example 64:</u> (S) -1 - [[(2R, 3R) -3- (3-methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (R or S) -2-isopropylmalonamate, m.p. 60-62 °,</li><li><u>Example 65:</u> (S) -1 - [[(2R, 3R) -3- (3-methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2-isopropylmalonamate, m.p. 76-78 °,</li><li><u>Example 66:</u> (S) -1 - [[(2S, 3S or 2R, 3R) -3- (5-chloropentyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, m.p. 66- 72 °,</li><li><u>Example 67:</u> (S) -1 - [[(2S, 3S or 2R, 3R) -3- (5-chloropentyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, mp 130 ° ,</li><li><u>Example 68:</u> (S) -1 - [[(2R, 3R or 2S, 3S) -3- (5-chloropentyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, m.p. 44- 50 °,</li><li><u>Example 69:</u> (S) -1 - [[(2R, 3R or 2S, 3S) -3- (5-chloropentyl) -4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, m.p. 85- 87 °,</li><li><u>Example 70:</u> (S) -1- (2S, 3S or 2R, 3R) - [[3 - [(E) -2-butenyl] -4-oxo-2-oxetanyl] methyl] dodecyl- (R or S) -2- isopropylmalonamate, m.p. 105-107 °,</li><li><u>Example 71:</u> (S) -1- (2S, 3S or 2R, 3R) - [[3 - [(E) -2-butenyl] -4-oxo-2-oxetanyl] methyl] dodecyl- (S or R) -2- isopropylmalonamate, mp 96-98 °,</li><li><u>Example 72:</u> (S) -1- (2R, 3R or 2S, 3S) - [[3 - [(E) -2-butenyl] -4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, Mp 89-90 °,</li><li><u>Example 73:</u> (S) -1- (2R, 3R or 2S, 3S) - [[3 - [(E) -2-butenyl] -4-oxo-2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, Mp 60-63 °,</li><li><u>Example 74:</u> (S) -1 - [[(2R, 3R or 2S, 3S) -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, Mp 107-109 °,</li><li><u>Example 75:</u> (S) -1 - [[(2R, 3R or 2S, 3S) -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, M.p. 115-118 °,</li><li><u>Example 76:</u> (S) -1 - [[(2S, 3S or 2R, 3R) -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanyl] methyl] dodecyl- (R) -2-isopropylmalonamate, Mp 88-90 °,</li><li><u>Example 77:</u> (S) -1 - [[(2S, 3S or 2R, 3R) -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate, Mp 52-55 °.</li></ul>

Example 78

Analogously to Examples 1 and 2, but using (R) - or (S) -2-pyrrolidone-5-carboxylic acid instead of 2-isopropylmalonic acid monoamide<ul id="ul0055" list-style="none"><li>a) 5-Oxo-D-prolin (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, 1 H-NMR (CDCl₃): 0 , 88 (m, 6H); 1.26 (m, 26H); 1.55-1.9 (m, 4H); 1.95-2.55 (m, 6H); 3.21 (m, 1H); 4.25 (m. 1H); 4.31 (m, 1H); 5.14 (m, 1H); 5.80 (s, 1H) ppm.</li><li>b) 5-Oxo-L-prolin (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, mp 51-52 °</li><li>c) 5-oxo-D-prolin (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester, mp. 55 ° (diethyl ether)</li><li>d) 5-Oxo-L-prolin (S) -1 - [[(2S, 3S) -3-ethyl-4-oxetanyl] methyl] octadecyl ester, mp 57-58 °.</li></ul>

Example 79

Analogously to Examples 1 and 11, (S) - (+) - 2-isopropylmalonic acid monoamide and<ul id="ul0056" list-style="none"><li>a) from 3R, 4R (or 3S, 4S) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, diastereomer B (Example T) the (S) -1 - [[(2R , 3R or 2S, 3S) -3-anilino-4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate (diastereomer B), mp. 92 °, and</li><li>b) from 3S, 4S (or 3R, 4R) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, diastereomer A (example T) the (S) -1 - [[(2S , 3S or 2R, 3R) -3-anilino-4-oxo-2-oxetanyl] methyl] dodecyl- (S) -2-isopropylmalonamate (diastereomer A), mp. 77 °.</li></ul>

Pharmaceutical preparations of the following composition are produced in a manner known per se:

Example A

<tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">Soft gelatin capsules:</entry></row><row><entry namest="col1" nameend="col1" /><entry namest="col2" nameend="col2" align="center">Amount per capsule</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">An oxetanone of formula I.</entry><entry namest="col2" nameend="col2" align="right">50 mg</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Medium chain triglyceride</entry><entry namest="col2" nameend="col2" align="right">450 µl</entry></row></tbody></tgroup></table></tables>

Example B

<tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">Hard gelatin capsule:</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" /></row><row><entry namest="col1" nameend="col1" align="left">An oxetanone of formula I.</entry><entry namest="col2" nameend="col2" align="char" char=",">20.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Milk sugar krist.</entry><entry namest="col2" nameend="col2" align="char" char=",">37.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Microcrystalline cellulose</entry><entry namest="col2" nameend="col2" align="char" char=",">20.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Polyvinyl polypyrrolidone</entry><entry namest="col2" nameend="col2" align="char" char=",">8.5 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Sodium salt of starch carboxymethyl ether</entry><entry namest="col2" nameend="col2" align="char" char=",">8.5 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Talk</entry><entry namest="col2" nameend="col2" align="char" char=",">4.5 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Magnesium stearate</entry><entry namest="col2" nameend="col2" align="char" char=",">1.5 mg</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">   Capsule fill weight</entry><entry namest="col2" nameend="col2" align="char" char=","><maths id="math0007" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>100.0 mg</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP0444482B1_D0011.tif" /></maths></entry></row></tbody></tgroup></table></tables>

Example C

<tables id="tabl0004" num="0004"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">Tablet:</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" /></row><row><entry namest="col1" nameend="col1" align="left">An oxetanone of formula I.</entry><entry namest="col2" nameend="col2" align="char" char=",">30.0 g</entry></row><row><entry namest="col1" nameend="col1" align="left">Milk sugar anhydrous</entry><entry namest="col2" nameend="col2" align="char" char=",">118,8</entry></row><row><entry namest="col1" nameend="col1" align="left">Microcrystalline cellulose</entry><entry namest="col2" nameend="col2" align="char" char=",">30,0</entry></row><row><entry namest="col1" nameend="col1" align="left">Polyvinyl pyrrolidone</entry><entry namest="col2" nameend="col2" align="char" char=",">10,0</entry></row><row><entry namest="col1" nameend="col1" align="left">Polymer of carboxymethyl cellulose</entry><entry namest="col2" nameend="col2" align="char" char=",">10,0</entry></row><row><entry namest="col1" nameend="col1" align="left">Magnesium stearate</entry><entry namest="col2" nameend="col2" align="char" char=",">1,2</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">   Tablet weight</entry><entry namest="col2" nameend="col2" align="char" char=","><maths id="math0008" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>200.0 mg</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP0444482B1_D0012.tif" /></maths></entry></row></tbody></tgroup></table></tables>

Example D

<tables id="tabl0005" num="0005"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">Tablet with controlled release of active ingredient and increased residence time in the stomach:</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" /></row><row><entry namest="col1" nameend="col1" align="left">An oxetanone of formula I.</entry><entry namest="col2" nameend="col2" align="char" char=",">60.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Milk sugar powder.</entry><entry namest="col2" nameend="col2" align="char" char=",">70.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Hydroxypropylmethyl cellulose</entry><entry namest="col2" nameend="col2" align="char" char=",">52.5 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Polyvinyl pyrrolidone</entry><entry namest="col2" nameend="col2" align="char" char=",">7.5 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Talk</entry><entry namest="col2" nameend="col2" align="char" char=",">8.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Magnesium stearate</entry><entry namest="col2" nameend="col2" align="char" char=",">1.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">colloidal silica</entry><entry namest="col2" nameend="col2" align="char" char=",">1.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">   Core weight</entry><entry namest="col2" nameend="col2" align="char" char=","><maths id="math0009" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>200.0 mg</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP0444482B1_D0013.tif" /></maths></entry></row><row><entry namest="col1" nameend="col1" /></row><row><entry namest="col1" nameend="col1" align="left">Hydroxypropylmethyl cellulose</entry><entry namest="col2" nameend="col2" align="char" char=",">2.5 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Talk</entry><entry namest="col2" nameend="col2" align="char" char=",">1.25 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Titanium dioxide</entry><entry namest="col2" nameend="col2" align="char" char=",">1.25 mg</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Weight of the film cover</entry><entry namest="col2" nameend="col2" align="char" char=","><maths id="math0010" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>5.0 mg</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP0444482B1_D0014.tif" /></maths></entry></row></tbody></tgroup></table></tables>

Example E

<tables id="tabl0006" num="0006"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">Reconstitutable powder:</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" /></row><row><entry namest="col1" nameend="col1" align="left">An oxetanone of formula I.</entry><entry namest="col2" nameend="col2" align="char" char=",">200.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Ethyl vanillin</entry><entry namest="col2" nameend="col2" align="char" char=",">10.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Aspartame</entry><entry namest="col2" nameend="col2" align="char" char=",">30.0 mg</entry></row><row><entry namest="col1" nameend="col1" align="left">Spray skimmed milk powder</entry><entry namest="col2" nameend="col2" align="char" char=",">4,760.0 mg</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Total</entry><entry namest="col2" nameend="col2" align="char" char=","><maths id="math0011" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>5,000.0 mg</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP0444482B1_D0015.tif" /></maths></entry></row></tbody></tgroup></table></tables>