CA2035967C - Oxetanones - Google Patents

Abstract

Novel pancreas lipase-inhibiting oxetanones of the formula (see formula I) wherein Q, R1 and R2 have the significance given in the description, are manufactured starting from corresponding .beta.-hydroxycarboxylic acids.

Description

2~~~~~~r~

The present invention is concerned with novel oxetanones, a process for their manufacture, pharmaceutical preparations which contain such oxetanones as well as the use of these oxetanones in the manufacture of pharmaceutical preparations.
These oxetanones have the formula O
(~-OCFICHa ~C--.~ I
R2 R' Q is a group of the formula (R3,R4)NCO(X)n-CO- Q1 (R3,R4)NCO-X'- Q2 ~o or ~C~~~~
Il and R1 and R2 are alkyl with up to 18 C atoms substituted by 1 to 3 halogen atoms or alkyl, alkenyl, alkynyl or alkadienyl groups with up to 20 C
atoms optionally interrupted by a 1,4-arylene graup, optionally substitu-ted by an aryl group in the w-position and optionally substituted by an aryl-C1-4-alkyl group, whereby R1 can be interrupted by an O or S atom Me/ 16.1.91 ~03~~..~~'~
_2_ or by a sulphinyl or sulphonyl group in a position other than the a-position to an unsaturated C atom, or R1 is an aryl-NH- or aryl-C1-4-alkyl-OCONF-i- group, R3 and R'~ are hydrogen or C1_~-alkyl or together with the N atom to which they are attached farm a saturated 3- to 6-membered ring optionally containing an O or S atom in a position other than the a-pasition to the N atom, n is the number 1 or 0, X is an alkylene group which contains up to b C atoms, which is l0 optionally interrupted by an O or S atom or by a sulphinyl or sulphonyl group and which is optionally substituted by a hydroxy, mercapto, aryl, aryloxy, arylthio, aryl-C~-4-alkyl, aryl-C~-4-alkoxy, aryl-C~,-4-alkylthia, aryl-C1_~-alkylidene, Cg-~-cycloalkylidene or C1-(-alkylidene group or by one or two C1-~-alkyl, C1-~-alkoxy or C1-6-alkylthio groups, whereby two C1-6-alkyl, C1_6-alkoxy or C1-6-alkylthio groups on the same C atom or on two adjacent C atoms can form an optionally mono-unsaturated 3- to 7-membered ring and an optionally present hydroxy or mercapto group or an optionally present unsaturated C atom must be in a position other than the a-position to an optionally present O or S atom or to an zo optionally present sulphinyl or sulphonyl group, or X is a group of the formula =CI-IN(R,Ro) or -CHN(R,Ro)CH2-R and R~ are hydrogen C1-q;-alkyl, C1_~-alkyl(CO or OCO)-, aryl, aryl(CO
or OCO)-, aryl-C1..~-alkyl or aryl-C~_4-alkyl(CO or OCO)- and X' is an alkylene group containing up to 6 C atoms which can be substi-tuted by a (~1~-alkoxy, aryl, aryloxy, arylthio, aryl-C1-~-alkyl, aryl-C~_4-alkoxy or aryl-C~-4-alkylthio group or by one or two C1-f,-alkyl graups, whereby two C1-s-alkyl groups attached to adjacent C atoms can form a 3- to ~-membered ring.
3o The alkyl, alkenyl and alkadienyl groups can be straight-chain or branched. Methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, undecyl and heptadecyl are examples of alkyl groups.

"aryl" and "arylene" denote phenyl and, respectively, phenylene or phenyl and, respectively, phenylene substituted by up to 5 halogen atoms or up to 3 C1_,~-alkyl, CI_4-alkoxy or nitro groups.
Preferred oxetanones of formula I are those in which Q is a group QI, R1 and R2 are alkyl, alkenyl or alkadienyl groups with up to 20 C atoms optionally interrupted by a 1,4-phenylene group, optionally substituted by a phenyl group in the w-position and optionally subskituted by a phenyl-CI_~-alkyl group, whereby R1 can be interrupted by an O or S atom in a position other than the a-position to an unsaturated C atom, X is an alkylene group, which contains up to 6 C atoms, which is optionally interrupted by an O or S atom and which is optionally substituted by a hydroxy, mercapto, phenyl, phenoxy, phenylthio, phenyl-CI_4-alkyl, phenyl-CI_~-alkoxy, phenyl-CI-4-alkylthio, phenyl-CI-4-alkylidene, C3-~-cycloalkylidene or C1_6-alkylidene group or by one or two CI-6-alkyl, CI-6-alkoxy or CI-6-alkylthio groups, whereby two CI-g-alkyl, CI-6-alkoxy or CI_6-alkylthio groups attached to the same C atom can form a 3- to 7 membered ring and an optionally present hydroxy or mercapto group must be in a position other than the a-position to an optionally present O or S atom, or X is a group =CHN(R,R°), R and R° are hydrogen, C1_,~-alkyl, CI_~-alkyl-(CO or OCO)-, phenyl or phenyl-(CO or OCO)- and n, R3 and R4 have the significance given above.
Further preferred oxetanones of formula I, wherein Q is a group QI, are those in which R1 and R2 are alkyl, alkenyl, alkynyl or alkadienyl groups with up to 20 C atoms optionally substituted by an aryl group in the c~-position, whereby RI can be interrupted by a S atom in a position other than the a-position to an unsaturated C atom, or RI is anilino, alkyl with up to 18 C
atoms substituted by a halogen atom or a phenyl-CI_4-alkyl-OCONH- group, R3 and R4 are hydrogen or CI_4-alkyl or together with the N atom to which they are attached form a saturated 6-membered ring containing an 0 or S atom in a position other than the a-position to the N atom, n is the number I or O, X is an alkylene group, which contains up to 6 C atoms, which is optionally interrupted by an O or S atom or by a sulphinyl group and which is optionally substituted by one or two CI_6-alkyl or CI_~-alkoxy groups, whereby two CI-6-alkyl or CI_6-alkoxy groups attached to the same C atom or to two adjacent C
atoms can form an optionally mono-unsaturated 3- to 7-membered ring, or X
is a group =CHN(R,Ro) or -CHN(R,Ro)CH2- and R and Ro are hydrogen, C2-5-alkanoyl or benzyloxycarbonyl.

~~3~~~'~

There are further preferred the oxetanones of formula I in which Q is a group Q2, R1 and R2 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-~-alkoxy group or by one or two C1-6-alkyl groups, whereby two C1-6-alkyl groups attached to adjacent C atoms can form a 3- ko 7-membered ring.
The oxetanones or formula I in which Q is a group Q3, R3 is hydrogen and R1 and R2 are C1_2p-alkyl, especially hexyl or undecyl, are also preferred.
Especially preferred among the oxetanones of formula I in which Q is a group Q1 are those in which R1 is methyl, ethyl, propyl, hexyl, 2-butenyl, Zo 3-methyl-2-butenyl, 2-propynyl, rnethylthio, pentylthio, 5-chloropentyl, benzyl, phenylthio, benzylthio, pentafluorobenzyl, anilino or benzyloxycar-bonylamino, R2 is undecyl, heptadecyl or g,11-heptadecadienyl, R3 and R'1 are hydrogen, methyl or isopropyl or together with the N atom form a morpho-lino or thiomorpholino group, n is the number 1 or 0 and X is the group -(CH2)1-g-, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopentylidene, t-butylmethylene, dimethylvinylidene, cyclo-pentylidene, cyclohexylidene, phenethylidene, phenylpropylidene, 1,2-cyclo-hexylene, cyclohex-3-en-1,6-ylene, acetamidomethylene, benzyloxycar-bonylaminomethylene, 1-benzyloxycarbonylamino-1,2-ethylene, methylene-oxymethylene, methylenethiomethylene, methylenesulphinylmethylene, ethylenethioethylene, ethylenesulphinylethylene, methoxymethylene or ethylene- or propylenedioxymethylene.
Especially preferred among the oxetanones of formula I in which Q is a group Q2 are those in which R1 is hexyl, R2 is undecyl and X' is ethylene, 1-methoxy-1,2-ethylene or 1,2-cyclohexylene.
The following are examples of such compounds:
(S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropyl-malonamate, (S~1-[[(2S,3Sr3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-3o carbamoylvalerate, (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (S)-2-isopropylmalonamate, 2~~~:~~~
-5_ (S)-1-(((2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, (S)-1-[[(2S,3S) or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl (S:R(2:1 )]-2-isopropylmalonamate, (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (S or R)-2-t-butylmalonamate, (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 1-carbamoylcyclo-pentanecarboxylate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-benzyl-1o malonamate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 3-((2-carba-moylethyl)thio]propionate, 5-oxo-D-proline (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester, 15 5-oxo-L-proline (S)-1-([(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester and especially (S)-1-([(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-iso-propylmalonamate, (S)-1-([(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-carbamoyl-2o valerate (epimers 1;1), (all G,S)-1-(((zS,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (S
or R)-2-isopropylmalonamate, (S)-1-([(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-carbamoyl-4-methylvalerate (epimers 1:1), 25 (S)-1-([(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyll-carbamoylcyclo-hexanecarboxylate, (S)-1-[((2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-methyl-malonamate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-ethyl-malonamate (epimers 1:1), (S)-1-[((2S,3S)-3-hexyl-~4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-butyl-rnalonamate (epimers 1:1), (S)-1-[((2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyll-carbamoylcyclo-hexanecarboxylate, (S)-1-[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl [S:R
or R:S(2:1)]-2-isopropylmalonamate and (S)-1-[[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-iso-~o propylmalonamate.
The oxetanones of formula I contain at least three asymmetric C atoms and can accordingly be present as optically active enantiomers, as mixtures thereof, e.g. as racemates, or a diastereomers.
The oxetanones of formula I can be manufactured in a manner known per se by a) esterifying an alcohol of the formula o FI~CHCN2 \C---~ IIa R2 R' with an aeid of the formula Qa-OH, wherein Qa is a group of the formula Q1 or Q3, or 2o b) cyrlizing an acid of the formula (Q-O,RZ)CHCHZCH(OH)CH(R1 )-COOH llb or c) converting the carboxy group in the group T in an acid of the formula ~~3~~~~
Q
T-OCHCHx ~C=O IIc R2 Ri wherein T is a group of the formula I ~OCO(X)n-CO- T1 or HOCO-X'- T2, into an amide group (R3, R4)NCO-, and d) if desired, separating a mixhxre of epirners of formula I into the individual epimers.
The esterification a) can be carried out in the presence of triphenylphos-phine and an azodicarboxylic acid diester such as the di-t-butyl ester of diiso-1o propyl ester in a solvent, e.g. an ether such as tetrahydrofuran (THF), at room temperature or while cooling, e.g. to 0 to -SoC.
The cyclization b) can be carried out in a solvent such as rnethylene chloride,, dimethylformamide (DMF) or acetonitrile using a molecular sieve, e.g. in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium z5 hexafluorophosphate (HBTU) and of a base such as triethylamine at room temperature or at a temperature up to 50oC.
The amidation c) can be carried out using a solution of ammonia or of an amine of the f~rmula (R3,R4)NH, e.g. in acetonitrile, in the presence of HBTU
at room temperat<ire or at a temperature up to 40oC.
20 The optional separation of a mixture of epimers of formula I can be carried out e.g. by chromatography over silica gel with ethyl acetate,/hexane/methylene chloride as the eluting agenk.
The alcohols of formula lda are known, e.g. from European Patent Application No. 0 185 359 A2, or can be prepared in analogy to the kmown 25 alcohols of formula IIa or as described in Examples A to I, M and 0 to T.

The and starting materials of formulae IIb and IIc can be prepared in a manner known per se, e.g. starting from corresponding alcohols of formula IIa as described hereinafter in Examples J and K (for the acids IIb) and K, L, and N
(for the acids IIc).
Example A
a) 465 g of methyl acetoacetate and then 458 g of ethyl bromide are added under nitrogen to 720 g of 30% sodium methylate solution. The reaction mixture is subsequently boiled at reflux. After distilling off the methanol the residue is poured on to ice-water. Then, the mixture is extracted with n-hexane l0 and water. The organic phases are combined and dried. After evaporation of the solvent and distillation there are obtained 328 g of methyl 2-acetylbutyrate, b.p. 77-790/15 Torr.
b) 144.17 g of the methyl ester from a) are added under argon at 0-50C to a suspension of 26.4 g of sodium hydride in 1250 ml of THF. After stirring at 0-15 50C for 1.5 hours the mixture is cooled to -100C. At this temperature there are added 675 ml of 1.56M butyllithium in hexane. After stirring at -100C for 30 minutes a solution of 149.3 g of methyl stearate in 250 ml of THF is added dropwise. After stirring at -100C for 1.5 hours the reaction solution is added under argon to 250 ml of 37% hydrochloric acid and 300 g of ice. The mixture is 20 extracted with hexane and water. The combined organic phases are dried, filtered and evaporated.
The residue is dissolved in 2500 ml of THF, treated with 76.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene(1.5-5) (DBU) and boiled at reflux under argon.
The cooled reaction solution is extracted with 37% hydrochloric acid and then 25 with saturated sodium chloride solution. The combined organic phases are dried and evaporated. The product is dissoved in ethyl acetate. The solution is cooled to room temperature and stirred at 250C overnight. The crystallizate is filtered off under suction, washed with ethyl acetate and dried. There are obtained 122.5 g of 3-ethyl-6-heptadecyl-4-hydroxy-2H-pyran-2-one, m.p. 101-30 1020C.
c) 100 g of Raney-nickel and 2000 ml of THF are added to 100 g of the pyrone from b). After hydrogenation at 250 for 3 days the catalyst is filtered off under suction and washed with THF. The filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and stirred at 100 for I7 hours. The 35 crystallizate is filtered off under suction, washed with cold (-100) ethyl acetate * Trademark and dried at 40a for 17 hours. There axe obtained 90.54 g of rac-(2RS,2RS,5SR)-ethyl-5-heptadecyl-3-hydraxy-8-valerolactone, m.p. 101-102oC.
d) 138.5 g of benzaic anhydride and subsequently 2.5 ml of 70% perchloric acid are added to a suspension of 191.3 g of the d-lackone from c) in 1250 ml of toluene. After stirring fox 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 axganic phases are combined, dried and evaporated. There are obtained 243.4 g of rac-(2RS,3RS,5SR)-3-benzoyloxy-2-ethyl-5-heptadecyl-8-valerolactone, m.p. 64.5-66aC.
e) 243 g of the benzoate from d) are dissolved in 450 ml of toluene at 40oC
under argon. 1000 ml of methanol and thereafter 2.5 ml of cone sulphuric acid are added and the reaction mixture is stirred at 25oC for 20 houxs. After neutralization of the sulphuric acid with triethylamine the solvent is evaporated. The xesidue 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 sulphate, the drying agent is filtered off under suction and washed with t-butyl methyl ether and subsequently evaporated. There are obtained 257 g of methyl rac-(2RS,3RS,5SR)-3-benzoyloxy-2-ethyl-5-hydroxydocasanoate.
f) 257 g of the hydroxyester from e) in 1250 ml of n-hexane are treated under argon with 152 g of benzyl 2,2,2-trichloroacetimidate. Then, 3.2 rnl of tri-fluoromethanesulphoruc acid are added. After stirring for 18 hours the preci-pitate is filtered off under suction 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 starring at -20oC
for 20 hours the crystallizate is filtered off under suction, washed with n-hexane and discarded. The filtrate is evaporated. There are obtained 239.6 g of methyl rac(2RS,3RS,5SR)-3-benzoyloxy-5-benzyloxy-2-ethyldocosan oats.
g~ 239.6 g of the benzyl ether from f) are treated under argon with a solution of 140 g of potassium hydroxide in 1250 ml of 95% (v/v) methanol/water and stirred at 40oC for 17 hours. Subsequently, the mixture is concentrated at 40aC, the suspension is taken up in t-butyl methyl ether and washed in sequence with 10% sodium chloride solution, 1N hydrochloric acid and again with 10%
sodium chloride solution. The organic phase is dried with sodium sulphate, the drying agent is filtered off under suction and washed with t-butyl methyl ether. The filtrate is evaporated. There are obtained 182.1 g of rac-(2RS,3RS,5SR)-5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid.
h) 33.3 g of (S)-(-)-oc-methylbenzylamine axe added to a solution of 182.1 g of the [3-hydroxyadd from g) in 1250 ml of methyl acetate. The solution is seeded with 50 mg of the phenethylamine salt of (2S,3S,5R)-5-benzyloxy-2-ethyl-3-hydraxydocosanoic acid and left to stand for 20 hours. The crystallizate is filtered off under suction, washed with cold (-20aC) methyl acetate and then dried. Tlus 1st crystallizate is dissolved in hot methyl acetate, cooled to 45aC
and seeded with 50 mg of the pl~enethylarnine salt of (2S,3S,5R)-5-benzyloxy-2-1o ethyl-3-hydroxydocosanoic acid. The solution is left to stand at roam tempera-ture far 20 hours. The crystallizate is filtered off under suction, washed with cold (-20oC) methyl acetate and dried. The same procedure as with the 1st crystallizate is repeated with the 2nd crystallizate. There are obtained 39.4 g of the phenethylarnine salt of (2S,3S,5R)-5-benzyloxy-2-ethyl-3-hydroxy-docosanoic acid, m.p. 92-95oC.
i) 39.4 g of the phenethylamine salt from h) are treated with 400 rnl of t-butyl methyl ether and 80 ml of 1N hydrochloric acid and dissolved while stirring. The organic phase is washed with water, dried, filtered and concen-trated. There are obtained 31.4 g of (2S,3S,5R)-5-benzyloxy-2-ethyl-3-hydroxy-docosanoic acid, m.p. 62-63.5oC.
j ) 17.6 g of benzenesulphonyl chloride are added dropwise at OoC under argon to a solution of 24.5 g of the ~3-hydroxyacid from i) in 250 ml of pyridine.
After stirring at OoC for 20 hears 5 ml of water are added dropwise to the solution. The mixture is stirred at room temperature far 1 hour. The pyridine is evaporated. The crystal slurry is taken up in t-butyl methyl ether and washed in sequence with 2N hydrochloric acid, 5%O sodium bicarbonate solution and 10% sodium chloxide solution. The organic phase is dried over sodium sulphate and thereafter triturated with active charcoal. The drying agent and active charcoal are filtered off under suction and the filtrate is evaporated.
3o There are obtained 23.4 g of (3S,4S)-4-[(R)-2-benzyloxynanadecyl]-3-ethyl-2-oxetanone.
k) A solution of 23.4 g of the oxetanone from j) in 250 ml of THF is treated with 2.3 g of 10% Pd/C. After hydrogenation fox 5 hours the hydrogenation solution is suction filtered. After washing with THF the filtrate is evaporated, the residue is dissolved in n-hexane and seeded with (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanane. After 18 hours the crystallizate is filtered off -11- _ under suction, washed with hexane and dried. There are obtained 16.1 g of (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone, m.p. 66.5-68oC, the alcohol starting material of Example 1.
Example B
a) 50 g of methyl (R)-3-hydroxytetradecanoate, 35 g of t-butyldimethylchloro-silane, 6.1 g of 4-dimethylarninopyridine and 29.4 g of triethylamine are dissolved in 200 ml of methylene chloride and stirred at room temperature for 30 hours as well as under reflux for 16 hours. Thereupon, a further 2 g of t-butyldimethylchlorosilane are added. After a further 24 hours under reflux the 1o precipitated triethylamine hydrochloride salt is filtered off, washed with ether and the filtrate is concentrated. The residue is dissolved in ether and washed in sequence with water, 0.5M citric and, again with water and saturated sodium chloride solution, dried, concentrated and subsequently freed from volatile material at 5oC in a high vacuum for 5 hours. There are obtained 71.8 g of (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanoic acid, IR
(cm-1): 1745,1254, 895, 776.
b) 18.63 g of the product from a) dissolved in 100 ml of ether are treated with 65 ml of 1M diisobutylalurninium hydride solution in hexane at a temperature of -70oC to -75oC and then stirred at this temperature for 1 hour. Thereupon, 2.5 ml of isopropanol, 10 ml of water and 50 ml of 0.5M citric acid solution are added dropwise at a max. of lOoC. The ether phase is separated, the aqueous 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) arid there are obtained 14.47 g of (R)-3-[(1,1~
dimethylethyl)dimethylsilyloxy]tetradecanal, IR (em-1):1728,1254, 836, 775.
c) A solution of 2.55 ml of diisopropylamine in 45 ml of THF is treated at OoC with 22.5 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring for 15 minutes, cooled to -75oC. Then, a solution of 2.9 g of pentylthio-acetic acid in 9 ml of THF is added dropwise. After stirring for 10 minutes the reaction mixture is left to warm to room temperature, stirred for 5 minutes and again cooled to -75oC. At this temperature there is added dropwise a solution of 2.4 g of the aldehyde from b) in 9 ml of THF. After stirring for 20 minutes the reaction mixture is poured into saturated ammonium chloride solution and extracted with hexane. The hexane phase is dried and concen-trated. There are obtained 3.89 g of (2R/S,3R/S,SR)-5-[(1,1-dimethylethyl)dimethylsilyloxy]-3-hydroxy-2-pentylthiohexadecanoic acid as a mixture of 4 diastereomers.
d) A solution of 3.89 g of the product from c), 3.18 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophospliate (HBTU), 2 g of 4.~
molecular sieve and 3 rnl of triethylamine is stirred fox 2 hours in a mixture of 130 ml of metliylene chloride and 6 ml of UMF. Thereupon, the mixture is filtered, the filtxate is concentrated, the residue is dissolved in water/methanol (3:7) and extracted with hexane. The hexane phase is dried and concentrated.
There axe obtained 3.57 g of (3R/S,4R/S)-4-[(R)-2-[(1,1-1o dimethylethyl)dimethylsilyloxy]tridecyl]-3-pentylthio-2-oxetanone as a mixture of 4 diastereomers.
e) A solution of 4.5 g of the product from d) in 200 ml of acetonitrile is treated with 15 ml of 40°~o hydrofluoric acid and stirred for 18 hours.
Thereupon, sodium bicarbonate solution is added, the mixture is then extracted with hexane and the hexane phase is dried and concentrated. The residue is chromatographed on silica gel with 1-5% ether in methylene chloride. There are obtained 699.9 mg of 3R,4R (or 3S,4S)-4-[(R)-2-hydroxytri-decyl]-3-pentylthio-2-oxetanone, m.p. 43oC, and 691.2 mg of 3S,4S (or 3R,4R)-4-[(R)-2-hydroxytridecyl]-3-pentylthio-2-oxetanone, m.p. 7loC, the alcohol 2o starting materials of Examples 5 and 6.
Example C
a) 18 ml of a 1M solution of lithium bis(trimethylsilyl)arnide in THF are treated with 1.8 ml of ethyl acetate under argon at -75oC, stirred at this temperature for 30 minutes and subseuently treated with 4.8 g of (R)-3-benzyl-oxytetradecanal in 15 ml of THF and stirred at -78oC for half an hour. A
solution of 3.8 ml of cone. hydrochloric acid in 6 ml of water is added dropwise to the reaction mixture. The solution obtained is extracted with ethyl acetate, the combined organic phases are washed with 10% sodium bicarbonate and water, dried, filtered and concentrated. Thzre is obtained ethyl (3R,5R and 3S,5R)-5-benzyloxy-3-hydroxyhexadecanoate (1:1).
b) A solution of 4 ml of diisopropylamine in 12.5 ml of THF is treated with 17 ml of a 1.6M solution of n-BuLi in n-hexane under argon at OoC. After stirring for 15 minutes 5 g of the product from a) in 2.5 ml of THF are added dropwise at -50oC. After 10 minutes at -lOoC the temperature is lowered to -50oC and, after the dropwise addition of a solution of 3.18 g of benzyl bromide in 3.1 ml of hexamethylphosphoric acid triamide, the mixture is stirred at -50oC for 15 minutes. Thereafter, the cooling bath is removed and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is cooled to OoC and 50 ml of saturated sodium chloride solution are added thereto, the mixture is extracted with t-butyl methyl ether, the extracts are dried, filtered and the solvent is evaporated. The residue is chromatographed on silica gel with n-hexane/ethyl acetate (4:I). 1'he residue is dried. There is obtained ethyl (2R,3R,5R and 2S,3S,5R)-5-benzylaxy-2-benzyl-3-hydroxyhexa-decanoate as 1:I thxeo diastereomers.
1o 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 heated at reflex for 50 minutes and subsequently neutralized at room temperature with 26 ml of 2.5N hydrochloric acid. The ethanol is distilled off, whereupon 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 treated with 2.59 g of I-IBTU and 2.74 g of molecular sieve. Subsequently, 5.5 ml of DMF and 2.8 ml of triethylamine are added and the reaction mixture is stirred for I hour, filtered and concentrated. The residue is taken up in n-hexane, the solution is thereupon extracted with 2o water, dried and concentrated in a vacuum. Chromatography on silica gel with methylene chloride gives a Ist traps diastereomer (3S,4S or 3R,4R)-3-benzyl-4-[(R)-2-benzylaxytridecyl]-2-oxetanane, Rf value: 0.45 (thin-layer chromato-graphy over silica gel 5-40 m with methylene chloride) and a 2nd traps 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 ~.
with methylene chloride).
d) A solution of 646 mg of the 2nd traps diastereamer from c) in 65 ml of TI-iF is hydrogenated for 1 hour in the presence of 646 mg of 10% Pd/C. The reaction mixture is filtered and concentrated. There is obtained a traps diastereomer: (3R,4R or 3S,4S)-3-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxekanone, the alcohol starting material in Example 7.
e) As described under d), from the Ist traps diastereomer from c) there is obtained the traps diastereom~r: (3S,4S or 3R,4R)-3-benzyl-4-[(R)-2-hydroxy-tridecyl]-2-axetanone, the alcohol starting mateial in Example 8.
Exam~Ie D

~0~~~~'~

A solution of 3.0 ml of diisopropylamine in 50 ml of TI-IF is treated at OoC
with 12.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, cooled to -75oC. A solution of 1.26 g of Z-glycine in 10 ml of TlE-~ is then added dropwise. Then, the reaction mixture is left to warm to room temperature and again cooled to -75oC. 0.7 g of (R)-3-(t-butyldimethylsiloxy)tetradecanal in 5 ml of THF is now added dropwise at -75oC. The reaction mixhare is stirred at -75oC
for 1 hour and at -40o to -50oC for 1 /2 hour, then warmed to 5oC, again cooled to -75oC, poured into dilute potassium hydrogen sulphate solution and extracted with ether. The ether phase is dried, concentrated and chromato-1o graphed on silica gel with methylene chloride/methanol. There are obtained 540 mg of (2R/S,3R/S,SR)-2-[1-(benzyloxy)formarnido]-5-(t-butyldimethyl-siloxy)-3-hydroxyhexadecanoic acid as a mixture of 4 diastereomers.
In analogy to B)d), from the above product there is obtained benzyl 4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxo-3-oxetanecarbamate as a 1:1 mixture of the two traps-diastereomexic ~3-lactones, MS: 476 (M+A-C4H9p).
In analogy to B)e), from the above mixture there are obtained (3S,4S or 3R,4R)-benzyl 4-[(R)-2-hydroxytridecyl]-2-oxo-3-oxetanecarbamate, the alcohol starting material in Example 15, m.p. 122-124°C, and (3R,4R or 3S,4S)-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxo-3-oxetanecarbamate, m.p. 98-99°C.
2p Example E
In analogy to Example B, from thiophenoxyacetic acid and (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanal there is obtained, via a) (2R/S,3R/S,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2 (phenylthio)hexadecanoic acid (mixture of 4 diastereomers) and 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, (3S,4S)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone rn.p. 79°C
(ether), and (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone, rn.p.
47°C (ether), the alcohol starting material of Example 16.
Example E

a) 270 ml of stearoyl chloride are added dropwise at a maximum of 150oC to a solution of 117 g of Meldrum acid and 131 ml of pyridine in 1.51 of methylene chloride. After stirring the reaction mixture is washed with 41x1 hydrochloric acid, the aqueous phase is back-extracted with methylene chloride and the methylene chloride please is dried and concentrated. The residue is taken up in methanol and stirred unde reflux. After cooling the separated cryskals are filkered off, dissolved in methylene chloride and chromatographed on silica gel with mekhylene chloride. There are obtained 175 g of methyl 3-oxoeicasanoate, m.p. 52-54aC.
1o b) 1.84 mg of acetyl chloride in 1.84 ml of methanol are added to a solution of 9.1 mg of [(R)-2,2'-bis(diphenylphasphino)-6,6'-dimethylbi-phenyl]ruthenium diacetate in 20 ml of methylene chloride. The solution obtained is hydrogenated at 35 bar of hydrogen and 60oC together with 39.8 g of the ketoester from a) and 170 ml of methanol. After the addition of methylene 15 chloride the mixture is evaporated to dryness. Chromatography on silica gel with ether and recrystallization from n-hexane yields 35.6 g of methyl (R)-3-hydroxyeicosanoate, m.p. 64-64.5oC.
c) Analogously to Example B, from the product of b) there are obtained, via methyl (R)-3-(t-butyldimethylsiloxy)eicosanoate, IR (cm-1): 1745, 1255, 836, z0 (R)-3-(t-butyldimethylsiloxy)eicosanal, IR (crn-1): 1728, 1463, 1255, 1104, 836, 775, (2R/S,3R/S,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2-(methylthio)docosanoic acid (mixture of 4 diastereomers), MS: 533 (M+H)+, 4-[(R)-2-(t-butyldimethylsilaxy)nonadecyl]-3-(methylthio)-2-oxetanone, 25 (1:1 mixture of two traps diastereomers), IR (cm-1): 1834,1463, 2256,1106, 836, and 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, the following alcohol starting materials of Example 17:
30 (3S,4R or 3R,4S)-4-[(R)-2-Hydroxynanadecyl]-3-(methylthio)-2-oxetanone, m.p. 65°C (from methylene chloride) -16- ~~3~~~'~
(3R,4S or 3S,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxetanone, m.p. 67°C (from rnethylene chloride) (3R,4R or 3S,4S)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxetanone, m.p. 71°C (from ether) and (3S,4S or 3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthia)-2-oxetanone, m.p. 80°C (from ether).
Example G
Analogously to Example B, from (benzylthio)-acetic acid and (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tEtradecanal there is obtained, to via (2R/S,3R/S,5R)-2-(benzylthio)-5-[(1,1-dimethylethyl)dimethylsilyloxy]-3-hydroxyhexadecanoic acid (mixture of 4 diastereomers) and (3R/S,4R/S)-3-(benzylthio)-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxetanone (mixture of 4 diastereomers), MS: 506 (M+), the following alcohol starting materials of Examples 19 and 20:
(3S,4S or 3R,4R)-3-(Benzylthio)-4-((R)-2-hydroxytridecyl]-2-oxetanone, m.p.
65°C (ether), (3R,4R or 3S,4S)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-axetanone, MS:
374 (M+~-H20), and (3R,4S and 3S,4R)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxetanone (1:1 diast.), MS: 374 (M+~-H20).
Example H
a) 104 g of the mother liquor from the 1st crystallization in Example Ah) are dissolved in water and methylene chloride. The mixture is acidified to pH 1 by z5 the addition of cone. HCl while cooling with ice, the methylene chloride phase is separated, the aqueous phase is extracted with rnethylene chloride and the methylene chloride phase is washed with water, dried and concentrated. 'There are obtained 86.7 g of enriched (2R,3R,5S)-5-benzyloxy-2-ethyl-3-hydroxy-docosanoic acid which are dissolved in 500 ml of ethyl acetate and txeated with 20.6 g of (R)-(+)-a-methylbenzylamine while cooling. After the addition of 2~3~~G'~

ethyl acetate the mixture is heated to reflex, filtered and crystallized-out.
The crystals obtained are recrystallized from ethyl acetate and methyl acetate.
There are obtained 70.0 g of the phenethylamine salt of (2R,3R,5S)-5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid, m.p. 88-91°C.
b) Analogously to Example Ai),j),k), from the above salt there is obtained, via (2R,3R,5S)-5-benyzloxy-2-ethyl-3-hydroxydocosanoic acid m.p. 61.5-63°C, and (3R,4R)-4-[(S)-2-benzyloxynonadecyl]-3-ethyl-2-oxetanone, m.p. 38-40°C, (3R,4R)-3-ethyl-4-[(S)-2-hydroxynonadecyl]-2-oxetanone, rn.p. 66-68°C.
c) A solution of 14.2 g of the product obtained and 8.65 g of triphenyl-phospine in 250 ml of THF is treated at +5oC with 1.19 ml of formic acid and then with a solution of 5.12 g of diethyl azodicarboxylate in 20 ml of THF.
The mixture is then again treated with 0.4 ml of formic acid, 2.9 g of triphenyl-phosphine and 1.7 ml of diethyl azodicarboxylate. The xeaction mixture is concentrated and the residue is chromatographed on silica gel with hexane/ethyl acetate; there are thus obtained 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 treated at l5oC with 0.114 g of p-toluenesulphonic acid monohydrate. 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. There are obtained 9.5 g of (3R,4R)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone, m.p. 80-82oC, the alcohol starting material in Example 21.
Example I
a) 187.5 ml of n-butyllithium solution (1.61vi in hexane) are added dropwise at -20oC to a solution of 42.5 ml of diisopropylamine in 500 ml of THF. After stirring the solution is added dropwise at a maximum of -65oC to a suspension of 39.9 g of (S)-(-)-2-hydroxy-1,2,2-triphenylethyl-acetate in 600 ml of THF.
Then, the reaction mixture is warmed to OoC, stirred, cooled to -70oC and treated with a solution of 51.2 g of (R)-3-[(t-butyl)dimethyisilyloxy]eicosanal in 400 ml of THF. After stirring 500 ml of saturated ammonium chloride solution are added dropwise, the mixture is then warmed to roam temperature and stirred. The reaction mixture is concentrated, partitioned between water and ether and extracted with ether, the ether phase is washed with water, concentrated, taken up in 1 1 of methylene chloride, dried and concentrated.
There are obkained 91.9 g of (S)-2-hydroxy-1,2,2-triphenylethyl [3R:3S(4:1),5R]-5-(t-bukyldimetlvylsiloxy)-3-hydroxydacosanoate, IR (cm-1): 3525, 1719, 1448, 1250, 1159, 838, 697.
b) A solution of 90.8 g of the produet obtained above in 1 1 of methanol is x0 treated 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 with hexane/ ethyl acetate. There axe thus obtained 42.7 g of methyl (3R,5R)-5-(t-butyldimethyl-siloxy)-3-hydroxydocosanoate, IR (cm-1): 3521, 3468,1738,1254,1168, 1137, 1105.
c) Analogously to Example Be) and Cb), c), the latter compound is converted, via methyl (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2-methyldocosanoate, IR (cnn-1): 3522, 1739, 1464, 1254,1066, and (3R,4R)-4-[(R)-(t-butyldimethylsiloxy)nonodecyl]-3-methyl-2-oxetanone, IR (cnrl): 1830, 1464, z0 1254, 1129, 1071, into (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-methyl-2-oxetanone, m.p. 82.5-84°C (from EtOAc/hexane), the alcohol starting material in Exarnpie 22.
Exam le a) 1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4~) are treated with 20 ml of THF and cooled to OoC. Thereupon, 1.4 g of di-t-butyl azadicarboxylate are 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 chr~matagraphed on silica gel with hexane/ethyl acetate (4:1). There are thus obtained 0.727 g of o-[((S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]axy]benzamide, MS: 474 (M+H)+.
b) 972 mg of the product obtained above are dissolved in 12 ml of methanol and treated 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. There are thus obtained 854 mg of methyl (2S,3S,5S)-5-(o-carbamoylphenoxy)-2-hexyl-3-hydroxyhexadecanoate, MS: 369 (M+~-(o-carbamoylphenaxy)).
c) 850 mg of the product obtained above are dissolved in 12 ml of rnethanol/water (98:2) treated,with 800 mg of 5 percent rhodium on aluminium oxide and hydrogenated at '100oC and 100 bar of hydrogen. The reaction mixture is filtered, concentrated and chromatographed on silica gel 1o with hexane/ ethyl acetate (1:1). There are thus obtained 213 mg of methyl (2S,3S,5S)-5-[[(cis)-2-carbamoylcydohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoate (1st. diast.), MS: 367 [M+~-(H2NCOC6HIpe+H20)], 204 mg of a mixed fraction and 142 rng of methyl (2S,3S,5S)-5-[[(cis)-2-carbamoylcyclohexyl]oxy]-2-hexyl-hydroxyhexadecanaate (2nd.diast.), MS: 367 [M+~-(H2NCOC6I-I10~+H20)].
d) 210 rng of the 1st diastereomer obtained above are dissolved in 10 ml of acetone and treated with 3 ml of 1N potassium hydroxide. After stirring the reaction mixture is poured into potassium hydrogen sulphate solution and extracted with ether. The ether phase is dried and evaporated. There are obtained 277 mg of (2S,3S,5S)-5-[[(cis)-2-carbamaylcyclohexyl]oxy]-2-hexyl-3-2o hydroxyhexadecanoic acid (1st. diast.), the acid starting material in Example 23a).
e) As described in d), from the 2nd diastereomer from c) there is obtained (2S,3S,5S)-5-[[(cis)-2-carbamaylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoic arid (2nd. diast.), the acid starting material in Example 23b).
Example K
a) Analogously to Example Hc), from (3S,4S)-3-hexyl-4-[(R)-2-hydroxy-tridecyl]-2-oxetarzone and formic acid there is obtained, via (S)-1-[[(2S,3S)-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl formate, IR (cxn-1): 1826, 1725, 1177, 1122, (3S,4S)-3-hexyl-4-[(S)-2-hydroxytridecyl]-2-oxetanone m.p. 63-64°C (from hexane).
b) 1.8 g of the hydroxy-b-lactone prepared above, 1.3 g of pyridinium p-toluenesulphonate and 2 g of molecular sieve (4~) in 10 ml of methyl 3,3-dimethoxypropionate are stirred at 100oC under argon, the reaction mixture is 2~~~~~~
-zo-then filtered, the xesidue is concentrated and chromatographed on silica gel with ether/ methylene chloxide. There are thus obtained 1. 213 mg of methyl (E)-3-[((S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]a~.-rylate, IR (crn-1): 1827,1714,1643,1622,1192, and 2. 826 rng of methyl (R/S)-3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-3-methoxypropionate (1:1 epimer mixture), IR
(crn-1): 1824,1743,1438,1117.
c) 235 mg of the product of b)2. are suspended in 25 ml of 0.02N NaOH and the reaction mixture is diluted with acetone. After stirring for 24 hours the 1o mixture is acidified with 5 percent potassium hydrogen sulphate solution and extracted with ether. The ether phase is dried and concentrated and the residue is chromatographed on silica gel with methylene chloride/ methanol. There are thus obtained 60 mg of (2S,3S,5S)-2-hexyl-3-hydroxy-5-[(R/S)-1-rnethoxy-2-(methoxycarbonyl)ethoxy]hexadecanoic acid, MS: 337 (M~' ~-(H20+-O-(CH30)-CH2-COOCH3)).
d) A solution of 58 mg of the above compound in 4 ml of condensed ammonia is heated at 50oC in an autoclave. Subsequently, the ammonia gas is allowed to escape and the mixture is then treated with potassium hydrogen sulphate solution and extracted with rnethylene chloride. The methylene 2o chloride phase is dried and concentrated. 'There are obtained 42.5 mg of (2S,3S,5S)-5-((R/ S)-2-carbarnoyl-1-rnethoxyethoxy]-2-hexyl-3-hydroxyhexa-decanoic acid, the acid starting material of Example 24.
Example 1L
A solution of 200 mg of the product of Example IGb)1. in 10 mI of THF is hydrogenated using 200 mg of Pd/C (10%). Then, the mixture is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with 1% ether in methylene chloride. There are obtained 99 mg of methyl 3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionate, MS: 285 (M+~_(C11H23')).
A suspension of 544 mg of this compound in 49 ml of 0.02N sodium hydroxide is treated with acetonitrile, 'The resulting solution is acidified with aqueous potassium hydrogen sulphate, the reaction mixture is extracted with ether and the ether phase is dried and concentrated. Chromatography on silica gel with 2% ether in rnethylene chloride and then 5% methanol in methylene chloride yields 43.7 mg of 3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-axetanyl]methyl]dodecyl]oxy]propionic acid, L1? (cm-1): 1823,1715,1466,1105, the acid starting material in Example 25.
Example 1VI
Analogously to Example Cb) and c), methyl (3R,5R)-5-(t-butyldimethyl-silaxy)-3-hydroxydacosanoate (Example Ib) is reacted with propargyl bromide to give methyl (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydraxy-2-(2-propynyl)docosanoate, IR (cm-1): 3310, 2120, 1740, 1255, the latter is saporu'fied to give (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2-(2-propinyl)docosanoic aad, IR (cm°1): 3315, 2120, 1715, 1255, and this acid is cyclized to give (3R,4R)-4-[(R)-2-(t-butyldimethylsilaxy)nonadecyl]-3-(2-propynyl)-2-oxetanone, IR (cm-1): 3315, 2130, 1830,1255 .
After cleavage of the protecting group analogously to Example Ee) there is abtained (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(2-propynyl)-2-oxetanone, m.p.
'15 62-63°C (~ram ethyl acetate), the alcohol starting material in Example 60.
Example N
Analogously to Example 1, from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and monobenzyl malonate there is obtained benzyl (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecylmalonate, IR (cxn-1): 1824, 1734, 1149, 1125.
A solution of 430 mg of this product in 15 ml of TPIF is treated with 100 mg of Pd/C and then hydrogenated. The reaction mixture is filtered and the filtrate is concentrated. There are obtained 361 mg of (S)-1-[[(2S,3S)-3-hexyl-4-axo-2-axetanyl]methyl]dodecyl hydrogen malonate, IR (cm-1): 1824, 1745, the aad starting material of Example 26.
Examt~le O
A solution of 1.96 g of the alcohol product of Example IvI in 50 ml of ethyl acetate is hydrogenated using 0.25 g of 10 percent Pd/C; the reaction mixture as then filtered and the residue is chramatographed on silica gel with ethyl acetate/ hexane. There are thus obtained 1.44 g of (3R,4R)-4-((R)-2-hydroxy-nonadecyl]-3-propyl-2-oxetanone, an.p. 84-85°C (from ethyl acetate/hexane), the alcohol starting material in Example 61.

~03~~~'~
_~- _ Example P
a) Prom (R)-3-(t-butyldimethylsiloxy)tetradecanal (Example Bb) there is obtained analogously to Example Ca),b),c), via ethyl (3R and 3S,5R)-S-(t-butyl-dimethylsiloxy)-3-hydroxyhexadecanoate (epimer mixture) and ethyl (R and S)-2-[(1R and 1S,3R)-3-(t-butyldimethylsiloxy)-1-hydroxy-tetradecyl]-5-methyl-4-hexenoate (1:1 threo diastereomers), (3R,4R and 3S,4S)-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-3-(3-methyl-2-butenyl)-2-oxetanone (1:1 trans diastereomers).
b) A solution of 1.87 g of the product of a) in 50 ml of acetonitriie is treated with 6.2 ml of 40% hydrofluoric acid. After stirring sodium bicarbonate solution is added, the mixture is then extracted with methylene chloride and the methylene chloride phase is dried and concentrated. The residue is chromatographed on silica gel with ethyl acetate/methylene chloride/n-hexane (1:4.5:4.5). The chromatography gives the alcohol starting materials for Examples 62-65:
A 1st traps diastereomer, (3S,4S)-4-((R)-2-hydroxytridecyl]-3-(3-methyl-2-butenyl)-2-oxetanone, Rf-value: 0.31, and a 2nd traps diastereomer, (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(3-methyl-2-bukenyl)-2-oxetanone Rf value: 0.26 (thin-layer chromatography over silica gel 5-40 a with ethyl acetate/ methylene chloride/hexane (1:4.5:4.5).
Example Q
From ethyl (3R,5R and 3S,SR)-5-benzyloxy-3-hydroxyhexadecanoate (1:1) (Example Ca) there are 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), a 1st traps diastereomer, (3S,4S or 3R,4R)-4-[(R)-2-(benzyloxy)tridecyl]-3-(S-chloropentyl)-2-oxetanone, Rf value: 0.47, and a 2nd traps diastereomer, (3R,4R or 3S,4S)-4-[(R)-2-(benzyloxy)tridecyl]-3-(5-chloropentyl)-2-oxetanone, Rf value: 0.28 (thin-layer chromatography over 3o silica gel 5-40 ~ with rnethylene chloride), the alcohol starting materials for Examples 66-69:

2~~~~~~
(3R,4R or 3S,4S)-3-(5-chloropentyl)-4-((R)-2-hydroxytridecyl]-2-oxetanone and (3S,4S or 3R,4R)-3-(5-chloropentyl)-4-[(R)-2-hydroxytridecyl]-2-oxetanone.
Exazn~le R.
From (R)-3-(t-butyldimethylsiloxy)tetradecanal (Example Bb) there are obtained 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 diastereo-rners) and (3R,4R and 3S,4S)-3-((E)-2-butenyl]-4-((R)-2-(t-butyldimethyl-1o siloxy)tridecyl]-2-oxetanone (1:1 traps diastereomers), the alcohol starting materials for Examples 70-73:
A 1st traps diastereomer, (3S,4S or 3R,4R)-3-[(E)-2-butenyl]-4-[(R)-2-hydroxytridecyl]-2-oxetanone, Rf value: 0.475 and a 2nd traps diastereomer, (3R,4R or 3S,4S)-3-((E)-2-butenyl]-4-[(R)-2-15 hydroxytridecyl]-2-oxetanone, Rf value: 0.44 (chromatography and thin-layer chromatography over silica gel with ethyl acetate/methylene chloride/n hexane (1:2:2).
Example S
From ethyl (3R,5R and 3S,5R)-5-benzyloxy-3-hydroxyhexadecanoate (1:1) 2o (Example Ca) there are 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-pentafluoro-benzyl)hexadecanoate (threo diastereomers) and (3R,4R and 3S,4S)-4-[(R)-2-(banzyloxy)tridecyl]-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanone (traps diastereomers), the alcohol staxting 25 materials of Examples 74-77:
A 1st traps diastereomer, (3S,4S or 3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanone, Rf value: 0.43, and a 2nd traps diastereorner, (3R,4R or 3S,4S)-4-[(R)-2-hydroxytridecyl]-3 (2,3,4,5,6-pentafluorobenzyl)-2-oxetanone, Rf value: 0.39 (chromatography and 3o thin-layer chromatography on siliea gel with ethyl acetate/methylene chloride/n-hexane (1:4.5:4.5)).

Example T
a) A solution of 0.5 ml of diisopropylamine in 15 ml of THF is treated at OoC
with 2.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, cooled to -75oC. Then, a solution of 765 mg of N-benzyl-N-phenylglycine methyl ester in 3 ml of TFIF is added. After stirring a solution of 700 mg of (R)-3-(t-butyldimethylsiloxy)tetxadecanal (Example Bb) in 5 rnl of THF is added dropwise. After stirring at -75oC the reaction mixture is poured into aqueous potassium hydrogen sulphate and extracted with ether. The ether phase is dried, concentrated, partitioned between hexane and methanol/water (7:3), the 1o hexane phase is dried and concentrated and the residue is chromatographed on silica gel with pentane/ether (5:1). There are obtained 96.3 mg of methyl (5R)-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer A, MS: 540 (M+ ~-C,IHHg ~ ), and 142.8 mg of methyl (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereo-mer B, MS: 540 (M+~-C4Hg ~ ), and 313.4 g of a mixture of the above two diastereomers.
b) 134 mg of diastereomer B are suspended in 3 ml of 0.1N NaOH and treated with sufficient acetonitrile to farm a clear solution. After stirring the mixture is poured into aqueous potassium hydrogen sulphate and extracted with ether and the ether phase is dried and concentrated. After chromato-graphy on silica gel with methylene chloride/methanol (9:1) there are obtained 108 mg of (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexa-decanoic acid, diastereomer 8, MS: 526 (M+~-C4Hg~).
c) Analogously, from diastereomer A from a) there is obtained (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic acid, diastereomer A, MS: 526 (M+~-C4Hg~).
d) 1.1 g of diastereomer B from b), 1.1 g of HBTU, 0.5 g of triethylamine and 2 g of molecular sieve 4~ are stirred in 50 ml of ac~torutrile. After filtration and concentration the product is chromatographed on silica gel with methylene chloride. There are thus obtained 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)+.
e) Analogously, from diastereomer A from c) there is obtained 3S,4S (or 3R,4R)-3-(N-benzylanilino)-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxetanone, diastereorner A, MS: 566 (M+H)+.

~~~~~6'~
-~- _ f) 1.0 g of diastereomer 8 from d) and 0.8 g of Pd/C (10%) are hydrogenated in 30 ml of THP. Thereupon, the mixture is filtered and concentrated. There are thus obtained 834 yng of 3R,4R (or 3S,4S)-3-anilino-4-((R)-2-(t-butyldi-methylsiloxy)tridecyl]-2-oxetanone, diasteromer B, MS: 475 (M+~).
g) Analogously, from diastereomer A from e) there is obtained 3S,4S (or 3R,4R)-3-anilino-4-[(R)-2-(t-butyldinaethylsiloxy)tridecyl]-2-oxetanone, diastereomer A, MS: 475 (M~~ ~ ).
h) The products of f) arid g) are converted individually analogously to Example Be) into 3R,4R (or 3S,4S)-3-anilino-4-[(R)-2-hydroxytridecyl]-2 to oxetanone, diastereomer B, m.p. 104°C, and, respectively 3S,4S (or 3R,4R)-3-anilino-4-[(R)-2-hydroxytridecyl]-2-oxetanone, diastereomer A, m.p. 60-62°C, the alcohol starting materials for Example 79.
The acids of the formula Qa-OH axe known or can be prepared in analogy to the known acids, e.g. by saponifying 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. Thus, the acid starting materials of Examples 2d) and 2e) hereinafter can be prepared as follows:
A solution of 3.8 g of ethyl 2-propylmalonamidate in 30 ml of acetone is 2o treated with 22 ml of 1N KOH in ethanol and stirred fox 4 hours, then concentrated, taken up in sodium bicarbonate solution and extracted with ethyl acetate. The aqueous phase is acidified to pH 2 at OoC with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with brine, dried, concentrated and the residue is recrystallized from ethyl acetate/ether. There are obtained 1.96 g of 2-propylmalonic acid monoamide, rn.p. 137oC.
The 2-phenethylmalonamic acid, m.p. 141.5oC, the acid starting material for Examples 58-59, is prepared analogously from ethyl 2-phenethyl-malonamate.
3o The (+) and (-)-2-isopropylmalonic acid monoamide (the amide starting material of Example 11) can be prepared as described hereinafter:
5.5 g of rac-2-isopropylmalonic aad monoamide and 12.0 g of quinidine are dissolved in 100 ml of boiling water, seeded with a few crystals of the quinidine salt of (S)-(+)-2-isopropylmalonic acid monoamide and then crystallized out. The crystallizate is filtered off under suction, washed with water and ether and dried; there are thus obtained 8.3 g of the quinidine salt of (S)-(+)-2-isopopylmalonic acid monoamide. This salt is dissolved in 10 percent hydrochloric acid and left at 5oC, the separated crystals are filtered off under suction, washed with water, dried and recrystallized again from water with the addition of a few drops of 1N hydrochloric acid. There are thus obtained 720 mg of (S)-(+)-2-isopropylmalonic acid monoamide, m.p. 174°C, (a] a =
+45.6° (ethanol, c = 1).
The mother liquor resulting in the crystallization of the quinidine salt is made acid with 10% hydrochloric acid and left at SoC, the separated crystals are filtered off under suction, washed with water, dried and again xecrystallized from water with the addition of a few drops of 1N hydrochloric acid. There are thus obtained 850 rng of (R)-(-)-2-isopropylmalonic aad rnonoamide, m.p.
176°C, [a]~= -45.6° (ethanol, c =1).
The acid starting material for Example 42 can be prepared as follows:
a) 20.6 g of thiomorpholine are added dropwise to a solution of 13.6 g of methyl rnalonate monochloride in 100 rnl of methylene chloride. After stirring the mixture is diluted with 200 ml of methylene chloride, washed with 2o water in a separating funnel, then dried, filtered and evaporated. The residue is purified by chromatography on siliea gel with rnethylene chloride and then methylene chloxide/acetone (1:1). There are obtained 17.6 g of methyl tetra-hydro-(3-oxo-4H-1,4-thiazine-4-propionate.
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 rnl of acetone: After stirring and filtering the mixture is evaporated and the residue is triturated 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 with water on a ration exchanger column. The 2luate is concentrated to dryness and the residue is triturated with ether and filtered off. There are obtained 13 g of tetrahydro-(3-oxo-4H-1,4-thiazine-4-propionic acid, m.p. 119-120oC.
The acid starting material fox Example 44 is prepared as follows:
a) 33 ml of 1N potassium hydroxide solution are added dropwise to a solution of 5.6 g of methyl 1-carbamoylcyclopentanecarboxylate in 66 ml of ~~3~9~'~
-27_ acetone. Afker stirring the mixture is treated with 250 ml of acetone and the separated potassium salt is filtered off and then washed with acetone and dried.
b) A solution of the 5.79 g of potassium salt obtained in 35 ml of water is acidified to pI-I 1 with 4 ml of cone. hydrochloric acid at OoC. The precipitate is filtered o.ff and washed with water and then with diethyl ether. 3.5 g of 1-carbamoylcydopentanecarboxylic acid axe obtained after drying, The acid starting material for Example 46 can be prepared as follows:
A solution of 10.4 g of monomethyl methoxymalonate in 70 ml of 1o methylene chloride is added dropwise at -lOoC to 26 ml of 25 percent aqueous ammonia. After stirring the mixture is evaporated and the residue is dissolved in water and chromatographed on a canon exchanger with water. The eluate is concentrated and the residue is triturated with diethyl ether and filtered off.
The precipitate is washed with water and dried. There are obtained 8.9 g of 15 methoxymalonamic acid, m.p. 128-130oC.
The acid starting material for Example 49 can be prepared as follows:
A solution of 1.79 g of carbamoylmethylthioacetic acid in 42 ml of water is treated with 3.71 g of monoperoxyphthalic acid magnesium salt hexahydrate.
After stirring the mixture is filtered and the filtrate is concentrated and 20 acidified with 2 ml of cone. hydrochloric acid. After filtration the filtrate is percolated over a cation exchanger, eluted with water and the eluate is evaporated to dryness. The residue is suspended in acetone and filtered off.
It is washed with acetone and dried. There are obtained 1.65 g of rac-((carbamoylmethyl)sulphinyl]acetic acid, m.p. 137-138oC.
25 The lower alkyl esters corresponding to the ands of formula Qa-OH are known or can be prepared in analogy to the known esters, e.g. as described hereinafter starting from the monoestex of the formula H-(X)h-COOR", wherein R" is lower-alkyl, via the dicarboxylic acid monoester of the formula HOCO-(X)n-COOR". Thus, the starting acid of Example 2f) can be prepared as 3o follows:
a) 48 ml of a 1.6M n-butyllithium solution in hexane are added dropwise at -l5oC to 11 ml of diisopropylamine and 5 g of 4~ molecular sieve in 75 ml of THF. After 15 minutes the reaction mixture is cooled to -78oC and a solution of 9.5 g of ethyl 1,3-dioxolane-2-carboxylate in 50 ml of TIFF is added dropwise.

After stirring for 20 minutes C02 is introduced at a temperature below -70oC.
After saturation the mixture is stirred at -75oC for 20 minutes and then warmed to room temperature. After volatizadon of the C02 gas the reaction mixture is concentrated, the residue is treated with saturated bicarbonate solution and ethyl acetate, the ethyl acetate phase is discarded, the aqueous phase is acidified to pH 2 with potassium hydrogen sulphate and extracted with ethyl acetate. The ethyl acetate phase is dried and concentrated.
b) 0.93 ml of isobutyl chloroformate in 5 ml of THF is added dropwise at OoC
to a solution of 1.08 g of the product from a), 1.1 ml of triethylamine and 3 g of molec~.llar sieve 4th in 30 ml of TI-IF. After stirring for 40 minutes ammonia gas is introduced for 10 minutes and the reaction mixture is subsequently stirred overnight. Thereupon, it is filtered, the filtrate is concentrated and the residue is chromatagraphed on silica gel with methylene chloride/methanol (95:5). There are thus obtained X20 mg of ethyl 2-carbamoyl-1,3-dioxolane-2-carboxylate, m.p. 99-100oC.
c) A solution of 190 mg of the product from b) in 10 ml of methanol is treated with 1 rnl of 2N ICON in methanol and stixred at room temperature for 90 minutes. Thereupon, a solution of 280 mg of potassium hydrogen sulphate in 1 ml of water is added, the reaction mixture is suetion filtered and the filtrate is evaporated. There is thus obtained 2-carbamoyl-1,3-dioxolane-2-carboxylic acid.
2-Carbamoyl-m-dioxane-2-carboxylic acid (the acid starting material for Example 3m) is obtained analogously from ethyl m-dioxane-2-carboxylate.
The acids of the formula (R3,R4)NCO(X)n-COON in which X is a group =CHN(R,Ro) can be prepared starting from the corresponding dicarboxylic acid monoester of the formula HOCO-X-COOK" via a corresponding succinimide and the corresponding amide ester of the formula H2NC0-X-COOK", e.g. as described hereinafter for the acid starting material of Example 9.
a) 4.54 g of dicyclohexylcarbodiimide; 4.16 g of rnonoethyl acetamino-malonate and 2.53 g of N-hydroxysuccinimide are added to 54 ml of THF at OaC. After stirring for 1 hour the mixture is left to warm to room temperature and is stirred overnight. 'Then, it is cooled to OoC and filtered. The filtrate is treated with 20 ml of 25% aqueous ammonia solution, left to stand at room temperature over the day and at 4oC overnight. Then, the solution is evaporated and the residual aqueous solution is treated with sodium bicar-2~~~~'~
_29_ bonate. The aqueous phase is separated, the organic phase is washed with sahirated sodium chloride solution, then dried and concentrated. The residue is filtered in hexane containing ethyl acetate. The crystals obtained are washed with ether and then dried. There are obtained 1.2 g of [D,L]-N-acetyl-2-carba-moylglycxne ether ester, m.p. 126-128aC.
b) A solution of 5.8 ml of 1N potassium hydroxide is added dxapwise 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 to aqueous phase is acidified to pH 3 with hydrochloric acid while cooling and then percolated over an ion exchanger. The eluate is concentrated to dryness and the residue is triturated v,~ih acetone. There are obtained 500 mg of [D,L]-N-acetyl-2-carbamoylglycine, m.p. 120oC (decomposition).
Acid starting materials of the formula (R3,R4)NCO(X)n-COON in which at least one of R3 and R4 is different from H can be prepared by reacting the corresponding acid ester of the formula HOC(O)-(X)n-C(O)O-R" with an amine HN (R3,R4).
Thus, the acid starting material of Example 10d) can be prepared as follows:
A solution of 3 g of rnonomethyl malonate in 15 ml of 40% aqueous dimetlhylamine is concentrated after stirring for 18 hours, filtered through a strongly acidic cation exchanger, concentrated to dryness and crystallized from chloroform. Concentration of the mother liquor and crystallization from ether yield 1.3 g of dimethylcarbamoylacetic acid, m.p. 72-76oC.
The oxetanones of formula I have valuable pharmacological properties.
In particular, they inhibit pancreas lipase and can accordingly be used in the control or prevention of obesity, hyperlipernia, atherosclerosis and arterioscle-rosin.
The inhibition of pancreas lipase by the axetanones of formula I can be demonstrated experimentally by measuring titrimetrically the oleic acid liberated in the cleavage of triolein by hog panereas lipase. To an emulsion which contains 1 rnlvl of taurodeoxycholate, 9 mM of taurocholate, 0.1 mM of cholesterol, 1 mM of egg lecithin, 15 mg/ml of ESA, 2 mM of Tris HCI, 100 rnIdl of sodium chloride, 1 mM of calcium chloride and triolein as the substrate is added the compound of formula I dissolved in ethanol or dimethyl sulphoxide (10°l° of the emulsion volume) and the reaction is started by the addition of 1-3 ~,g of hog pancreas lipase. The pH is held at 8 during the reaction by the addition of sodium hydroxide solution. The IC50 is calculated from the consumption of sodium hydroxide solution determined during minutes. The IC50 is that concentration at which the lipase activity is inhibited to half of the maximum. The following Table contains the IC50 values determined for the compounds of formula I.
Example1a,11a1b,11b2b,12b 2d 2e 2f 2g1.'13a2g2 IC50 0.0320.025 0.063 0.12 0.0510.47 0.052 0.013 Example3c 3d 3e 3f 3g 3h 3i 3j ~~

IC50 0.39 0.90 1.41 0.0830.294 2.1 0.42 0.16 Example3k 31 4a 6b,14c 7b 10a 10b 10c IC50 0.12 0.78 0.16 0.056 0.079 0.0830.042 0.1 Example10d 10e 10f 37 43 45 51 78c 78d ICSp 0.47 0.027 0.32 0.034 0.120.047 0.36 0.28 0.051 The acute to~daty (after single oral administration to mice) amounts to more than 5000 rng/kg for the products of Examples 3d, 3h, 3i, 31, 4a and 10a, b, a and f.
The oxetanones of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets; dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.

z~~~~~~

For thE~ manufacture of pharmaceutical preparations the products in accordance with the invention can be processed with pharmaceutically inert, inorganic ox organic carriers. Lactose, maize starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as such carriexs far tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers far soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; depending on the nature of the active ingredient no carriers axe, however, generally required in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are, for example, water, ~o polyols, sacchaxose, invert sugar and glucose.
Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain 15 still other therapeutically valuable substances.
As mentioned earlier, medicaments containing an oxetanone of formula I are likewise an object of the present invention, as is a process for the manufacture of such medicaments which comprises bringing an oxetanone of formula I and, if desired, one or more other therapeutically valuable 2o substances into a galenical administration form. As mentioned; the compounds of formula I can be used in the control or prevention of illnesses, especially in the control or prevention of obesity, hyperlipemia, atherosclerosis and arteriosclerosis. The dosage can vary within wide limits and will, or course, be filled to the individual requirements in each particular case. In 25 general, in the case of oral administration a daily dosage of about 0.1 mg to 100 mg/kg body weight should be appropriate.
'The oxetanones of formula I can also be added to industrially-produced foodstuffs, whereby fats, oils, butter, margarine, chocolate and other confectionery goods especially come into consideration. Such industrially-3o produced foodstuffs, which can contain about 0.1 to 5 wt.% of an oxetanone or formula I, and their manufacture are likewise objects of the present invention.
The following Examples illustxate the present invention in more detail, but they axe not intended to limit its scope in any manner. All temperatures are given in degrees Celsius.
35 Example 1 ~~~~r ~~~

A solution of 574 mg of (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone, 525 mg of triphenylphosphine, 290 mg of 2-isopropylmalonic acid monoamide and 2 g of molecular sieve (4.~.) in 10 ml of THF are treated which skirring at Oo with 0.4 ml of diisoprapyl azodicarboxylate. After stirring at Oo for 30 minutes and at room temperature for 1 hour the reaction mixture is filtered, the molecular sieve is washed with ether and the solvent is evaporated. The residue is dissolved in hexane and extracted with methanol/water (7:3). The hexane phase is diluted with ether, dried and evaported. The residue is chromatographed on silica gel with methylene chloride/ether (9:1). There are obtained a) 239 mg of (S)-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (R or S)-isopropylmalonamate, m.p. 115°, and b) 266 mg of (S)-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (S or R)-isopropylmalonamate, m.p. 118°.
Example 2 Analogously to Example 1, from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2-isopropylmaloruc acid monoamide there are obtained a) (Sr1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, m.p. 136°, and b) (S~1-[[(2S,3S~3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, m.p. 82°;
c) from (3S,4S)-3-hexyl-4-((R)-2-hydroxytridecyl]-2-oxetanone and isopropylidenemalonic acid monoamide them is obtained (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 2-carbamoyl-3-methylcrotonate, m.p.
108-111 °;
d) from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2-propylmalonic acid monoamide there is obtained (S)-1-[[{2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-carbarnoylvalerate (epimers 1:1), m.p. 92-94°;
e) from (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone and 2-propylmalonic acid monoamide there is obtained (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (RS)-2-carbamoylvalerate (epimers 1:1), m.p. 78-80°;

-33- ~~~~~~3~
f) from (3S,4S)-ethyl-4-((R)-2-hydroxynonadecyl]-2-oxetanone and 2-carbamoyl-1,3-dioxolan-2-carboxylic acid there is obtained (S)-1-([(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]oetadecyl 2-carbamoyl-1,3-dioxolane-2-carboxylate, m.p. 95°;
g) from (3S,4S)-3-ethyl-4-[(R,10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2 oxetanone and 2-isopropylmalonic acid monoamide there are obtained 1. (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxekanyl]methyl]-9,12-octadecadienyl (R
or S)-2-isopropylmalonamate, m.p. 87-88° (from ether) and 2. (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 czW 1.
Exam le 3 The following ester amides are obtained analogously to Example 1 by reacting (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone with the following amides:
a) with 4-carbamoylbutyric acid the 4-carbatnoylbutyric acid (S)-1-[((2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 67-68°, b) with 3-carbamoylpropionic and the 3-carbamoylpropionic acid (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 50.5-51°, c) with 2-carbamoylacetic acid the 2-carbamoylacetic acid (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 86.5-87°, d) with oxalic acid monoamide the (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyi oxamate, m.p. 77-78°, e) with methylcarbamoylacetic acid the (S)-1-[I(2S,3S)3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl N-methylmalonamate, m.p. 63-67°, f) with rac-2-carbamoyl-4-methylvaleric acid the (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-carbamoyl-4-methylvalerate (epimere 1:1), m.p. 102-104°, g) with 1-carbamoylcyclohexanecarboxylic acid the (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 1-carbamoyltyclohexanecarboxylate, m.p. 50-52°, -h) with 2,2-dimethylmalonamidic acid the (S)-1-[[(2S,3S)3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 2,2-dimethylmalonarnate, (a]p = -23.8° (CHC13, c = 0.9%), i) with roc-2-methylmalanamidic acid the (S)-1-[[(2S,3S)3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-methylmalonamate (epimers 1:1), m.p.
107-108°, j) with roc-2-ethylmalonamidic acid the (S)-1-[[(2S,3S)3-hexyl-4-oxo-2-oxetanyl]methyl]dadecyl (RS)-2-ethylmalanamate (epirners 1:1), m.p. 87-90°, lc) with roc-2-butylmalonamidic acid the (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-to oxetanyl]methyl]dodecyl (RS)-2-butylmalonamate (epimers 1:1), m.p. 96-98°, 1) with 2,2-diethylmalonamidic acid the (S)-1-[[(2S,3S)-3-hexyl-4-axo-2-oxetanyl]methyl]dodecyl 2,2-diethylmalonamate, [a]p =-21.1° (CHCl3, c =1%), m) with 2-carbamoyl-m-diaxane-2-carboxylic acid the (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 2-carbamoyl-m-dioxane-2-carboxylate, m.p.
51°.
15 Example 4 Analogously to Example 1, from (3S,4S)-3-ethyl4-[(R)-2-hydroxynonadecyl]-2-axetanane and a) 1-carbamoylcyclohexanecarboxylic aad there is obtained (S)-1-[[(2S,3S)-3-ethyl-4-axo-2-oxetanyl]methyl]octadecyl 1-carbamoylcyclahexanecarboxylate, 2o m.p. 7&79°, and b) 2-carbamoyl-m-dioxane-2-earbaxylic acid there is obtained (S)-1-[((2S,3S)-3-ethyl-4-oxa-2-oxetanyl]methyl]octadecyl 2-carbamoyl-m-dioxane-2-carbaxylate, m.p. 79°.
Example 5 25 Analogously to Example 1, from (3R,4R or 3S,4S)-4((R)-2-hydroxytridecyl]-3-pentylthio-2-axetanane and 2-isopropylmalonic acid amide there are obtained a) (S)-1-([(2R,3R ar 2S,3S)-4-oxo-3-pentylthio2-oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, MS: 354 [Mv ~-(2-isopropylmalonic acid amide)]; IR
30 (cm 1): 3397, 2924,1829,1731,1657,1120, and ~~~~a9~'~

b) (S)-1-[[(2R,3R or 2S,3S)-4-oxo-3-pentylthio2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylrnalonamate, m.p. T7-78° (diethyl ether).
Example 6 Analogously to Example 1, from (3S,4S or 3R,4R)-4[(R)-2-hydroxytridecyl]-3-pentylthio-2-oxetanone and 2-isopropylmalonic acid amide there are obtained a) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, m.p. 133° (ethyl acetate), and b) (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).
Example 7 Analogously to Example 1, from 3-benzyl-4-[(R)-2-hydroxytridecyl]-~2-oxetanone and 2-isopropylmalonic acid monoamide there is obtained an epimer rnixure which is separated by chromatography on silica gel with ethyl t5 acetate/hexane/ methylene chloride (1:2:2) into a) (S~1-[[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, m.p. 85-87° (rnethylene chloride), and b) (S)-1-[[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonarnate, m.p. 108-110° (methylene chloride).
Example 8 Analogously to Example 1, from 3-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2-isopropylmalonic acid monoamide there is obtained an epimer mixture which is separated by chromatography on silica gel with ethyl acetate/ hexane/methylene chloride (1:2:2) into a) (S~1-[[(2S,3S)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, m.p. 107-108° (methylene chloride); and b) (S)-1-[[(2S,3S)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, m.p. 148-14g° (methylene chloride).
Example 9 ~~~ >~~
-1.03 g of di-t-butyl azodicarboxylate are added to a suspension, cooled to -IOoC, of 1.06 g of (3S,4S)-3-hexyl-4-[(R}-2-hydroxytxidecyl]-2-oxetanone, 480 mg of [D,L]-N-acetyl-2-carbamoylglycine, 1.1 g of triphenylphospine and 1.2 g of molecular sieve 4~ in 12 rnl of THF. After stirring at OoC for 1 hour and at room temperature overnight the reaction mixture is worked-up analogously to that described in Example 1. There are obtained a) 190 mg of (S}-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)-2-acetamidomalonamate, m.p. 125-126°, and b) 100 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-acetamidomalonamate (epimers 1:1), m.p. 110-116°, [a]p = -8° (c = 0.5, CHC13) Example 10 The following ester amides are obtained analogously to Example 1, but using the following amides:
a) from oxalic and monoamide the (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl oxamate, m.p. 99-100°, b) from 2-carbamoylacetic acid the (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl malonamate, m.p. 90.5-91.5°, c) from methylcarbamoylacedc acid the (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl N-methylmalonamate, m.p. 84-85°, 2o d) from dimethylcarbamoylacetic acid the (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl N,N-dimethylmalonamate, m.p. 66-67°, e) from rac-2-ethylmalonamidic acid (S)-1-[[(2S,3S-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (RS)-2-methylmalonamate (epimers 1:1), m.p. 91.5-92°, z5 f) from 3-carbamoylpropioruc acid the (J)-1-[[(2S,3S)3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl succinamate, m.p. 74.5-75.7°.
Example 11 Analogously to Example 1, but using (S)-(t)- or (~-2-isopropylmalonic acid monoamide, there are obtained a) (S)-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (R)-2-isopropylmalonamate, rn.p. 115°, and b) (S)-[((2S,3S)-3-ethyl-4-axo-2-oxetanyl]methyl]octadecyl (S)-2-isopropylmalonarnate, m.p. 118°.
Example 12 Analogously to Examples 1,2a),b) and 11, from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and (t)- and (S)-(+)-2-isopropylmalonic acid rnanoamide there are obtained a) (S)-1-[((2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (R)-2-1o isopropylmalonamate, m.p. 136°, and respectively, b) (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 82°, c) from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2-propylmalonic acid monoamide, after separation by chromatography on silica gel with methylene chloride/ acetonitrile (85:15), 1. (S)-1-([(2S,3S)r3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)-2-carbamoylvalerate, m.p. 113° (from methanol/water), and 2. (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-carbamoylvalerate, m.p. 85°.
2o Example 13 Analogously to Examples 1, 2g) and 11, from (3S,4S)-3-ethyl-4-[(R,10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone and (~)- and (S)-(+)-2-isapropylmalonic and monoamide there are obtained a) (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (R)-2-isopropylmalonamate, m.p. 87-88° (fxom ether), and 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).
Example 14 Analogously to Examples 1, 6 and 11, from (3S,4S or 3R,4R)-4-((R)-2-hydroxytridecyl]-3-pentylthio-2-oxetanone and (+_)- and (S)-(+)-2-isopropylmalanarnide there are obtained a) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 133° (ethyl acetate), b) (S)-1-([(2S,3S or 2R (S)-2-isopropylmalonamate, rn.p. 93° (diethyl ether/hexane) and c) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl [S:R
(2:1)]-2-isopropylmalonamate, m.p. 102-104° (ethyl acetate).
1o Example 15 Analogously to Examples 1 and 11, from (3S,4S or 3R,4R)-benzyl 4-[(R)-2-hydroxytridecyl]-2-oxo-3-oxetanecarbamate and (S)-(+)-2-isopropylmalonic acid monoamide there is obtained (S)-1-([(2S,3S or 2R,3R)-3-[1-(benzyloxy)formarnido]-4-oxo-2-oxetanyl)methyl]dodecyl (S)-2-15 isopropylmalonamate, m.p. 133° (from ether/hexane).
Example 16 Analogously to Examples 1 and 11, a) from (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone and (S)-(+)-2-Isopropylmalonic acid monoamide there is obtained (S)-1-[[(2R,3R)-4-20 oxo-3-(phenylthio)-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 88° (ether), b) from (3S,4S)~-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-~-oxetanone and 2-isopropylmalonic acid monoarnide there is obtained (S)-1-[[(2S,3S)-4-oxo-3-(phenylthio)-2-oxetanyl]methyl]dodecyl (RS)-2-isopropylmalonamate (1:1 25 epimers), m.p. 109° (ether), and c) from (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone and 2-isopropylmalonic acid monoamide there are obtained the same products as in a) and (S)-1-([(2R,3R)-4-oxo-3-(phenylthio)-2-oxetanyl]methyl]dodecyl 2-isopropylmalonamate (R:S = 7:1), m.p. 85° (ether).
30 Exam,~le 17 1~~~.~~~

Analogously to Examples 1 and 11, .from (S)-(+)-2-isopropylmalonic acid monoamide and the following alcohols there are obtained the following esters:
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, m.p. 133° (from ether), 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-isopropylmalonarnate, m.p. 103° (from ether), c) from (3S,4R cr 3R,4S)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-l0 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), and 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-2-15 oxetanyl]methyl]octadecyl (S)-2-isopropylmalonarnate, m.p. 120°
(from ether/hexane).
Example 18 Analogusly to Examples 1 and 11, from (R)-(-)-2-isopropylmalonic acid monoamide and 2o a) (3S,4S or 3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxetanone there is obtained (S)-1-[[(2S,3S or 2R,3R)-3-(methylthio)-4-oxo-2-oxetanyl]methyl]octadecyl (R)-2-isopropylmalonarnate, m.p. 96° (from ether), b) (3R,4R or 3S,4S)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxetanone there is obtained (S)-1-[[(2R,3R or 2S,3S)-3-(methylthio)-4-oxo-2-25 oxetanyl]methyl]octadecyl (R)-2-isopropylmalonamate, m.p. 87° (from ether/hexane).
Example 19 In analogy to Examples 1 and 11, from (S)-(+)-2-isopropylmalonic acid monoamide and the following alcohols there are obtained the following esters:

2~ ~ ~~~~~

a) From (3S,4S or 3R,4R)-3-(benzylthio)-4-[(R)-2-hydroxytxidecyl]-2-oxetanone the (S)-1-[[(2S,3S or 2R,3R)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 84° (from pentane), b) from (3R,4R or 3S,4S)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxetanone the (S)-1-[[(2R,3R or 25,35)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonamate, m.p. 65° (from ether/pentane) and c) from (3S,4R and 3R,4S)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxetanone the (S)-1-[[(2S,3R or ZR,3S)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 69° (from pentane), and 2. the (S)-1-[[(2R,3S or 25,3R)-3,~(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 106° (from hexane).
Example 20 In analogy to Examples 1 and 11, from (R)-(-)-2-isopropylmalonic acid monoamide and the following alcohols there are obtained the follawing esters:
a) Frorn (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, m.p. 130° (from ether/pentane), 2o b) from (3R,4R or 3S,4S)-3-(Benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxetanone the (S)-1-j[(2R,3R or 2S,3S)-3-(benzylthio)-4-oxa-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 119° (from hexan/pentane), and c) from (3S,4R and 3R,4S)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxetanone 1. the (S)-1-[[(2S,3R or 2R,3S)-3-(benzylthia)-4-oxo-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 132° (from ether/pentane), and 2. the (S)-1-[[(2R,3S or 2S,3R)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 102° (from ether/pentane).
Example 21 _41_ Analogously to Examples 1 and 11, by reacting (3R,4R)-3-ethyl-4-[(R)-2-hydraxynonadecyl]-2-oxetanone a) with (S)-(+)-2-Isopropylmalonic acid monoamide there is obtained (S)-1-[[(2R,3R)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 116-118° (methylene chloride), and b) wikh 1-carbamoylcyclohexanecarboxylic acid there is obtained (S)-1-[[(2R,3R)-3-ethyl-4-oxo-2-oxetanyl]methyl]actadecyl 1-carbamoylcyclohexanecarboxylate, m.p. 71-74°.
Example 22 to In analogy to Examples 1 and 11, a) from (S)-(+)-2-isopropylmalonic and monoarnide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-methyl-2-oxetanone there is obtained (S)-1-[[(2R,3R)-3-rnethyl-4-oxo-2-oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p.
124-126° (from ethyl acetate/hexane), and 15 b) from rac-2-t-butylmalonic acid monoamide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-methyl-2-oxetanane there is obtained (S)-1-[[(2R,3R)-3-methyl-4-oxo-2-oxetanyl]methyl]octadecyl (RS)-2-t-butylmalonamate (epimers 1:1), m.p. 51-54° (ethyl acetate/hexane).
Example 23 2o A solution of 277 mg of (2S,3S,5S)-5-[j(cis)-2-carbamoylcycloh.exyl]oxy]-2-hexyl-3-hydroxyhexadecanoic acid (Example Jd) in 24 ml of methylene chloride and 3 ml of DMF is treated with 2 g of molecular sieve (4~), 240 mg of HBTU
and 240 mg of triethylamine. After stirring 300 rng of HBTU and 300 mg of triethylamine are added thereto. The mixture is then filtered and the filtrate is 25 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. There are thus obtained a) 96 mg of (1R or S,2S or R)-2-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo--2-30 oxetanyl]methyl]dodecyl]oxy]cyclohexanecarboxamide (1st cis diastereomer), m.p. 102° (from ether/hexane), and b) analogously from (2S,3S,5S)-5-[[(cis)-2-carbamoylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoic acid (2nd diast. acid) in Example Je) there is obtained (1S
or R,2R or S)-2-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]cyclohexanecarboxamide (2nd cis diastereomer), rn.p. 94° (from ether/hexane).
Example 24 A solukion of 42.5 mg of (2S,3S,5S)-5-[(R/S)-2-carbamoyl-1-methoxyethoxy]-2-hexyl-3-hydroxydecanoic acid (Example Kd) in 10 ml of mekhylene chloride/acetonitrile (1:1) is txeated with 1 g of molecular sieve (4th), 0.1 ml of triethylamine and 50 mg of HBTU. After stirring the reaction mixture is filtered and 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; the residue is subsequently chromatographed on silica gel with 5 percent methanol in methylene chloride. There are thus obtained 21 mg of (R/S)-3-[[(S)-1-[[(2S,3S)-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-3-methoxypropionamide (epimers 3:1 ), m.p. 54°.
Example 25 Ammonia gas is blown into a solution of 40 mg of 3-[[(S)-1-[[(2S,3S)-3-2o hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionic acid (Example L) in 2.5 ml of acetonitrile until the solution is saturated and subsequently 50 mg of HBTU
are added. Then, the mixture is filtered and evaporated and the residue is chromatographed on silica gel with 5 percent methanol in methylene chloride.
There are obtained 32.5 mg of (3S,4S)-4-[(S)-2-(2-carbamoylethoxy)tridecyl]-3-hexyl-2-oxetanone, m.p. 35°.
Example 26 A solution of 33 5 mg of (S)-1-([(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl hydrogen malonate (Example N) in 2 ml of acetonitrile is treated with 60 mg of HBTU and 25 mg of isopropylamine. After stirring the reaction mixture is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with hexan~/methylene chloride/ethyl acetate (2:2:1). There are obtained 31.1 mg of (S)-1-[[(2S,3S)-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl N-isopropylmalonamate, m.p. 59°.

The following compounds are manufactured in an analogous manner to Example 1:
Example 27: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 5-carbamoylvalerate, m.p. 50-510.
Example 28: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl~dodecyl 6-carbamoylhexanoate, m.p. 52-53°, Example 29~ (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 7-carbamoylheptanoate, m.p. 40-43°, Example 30: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 9-carbamoylnonanoate, m.p. 29-30°, Example 31: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 4-carbamoylbutyrate, m.p. 74-75°, Example 32: (S)-1-[(2S,3S)-3-Ethyl-~f-oxo-2-oxetanyl]methyl]octadecyl adipamate, m.p. 63.5-64.5°, Example 33: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 6-carbamoylhexanoate, m.p. 71.5-72.5°, Example 34: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-oxetanyl]methyl]dodecyl (R or S)-2-t-butylmalonamate, m.p. 53-54°, Example 35: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl] methyl]dodecyl (S or R)-2-t-butylmalonamate, [cc]p = -16.4° (c = 0.8, ~H~13), Example 36: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (R or S)-2-t-butylmalonamate, m.p. 48-49°, Example 37: (S)-1-[[(2S,3S)-3-Ethyl-~4-oxo-2-oxetanyl]methyl]octadecyl (S or R)-2-t-butylmalonamate, m.p. 81-82°, Example 38: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-3-[2~~(benzyloxy)formamido]succinamate, m.p. 72-73°, Example 39: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]met)nyl]dodecyl cis-6-carbamoyl-3-cyclohexene--1-carboxylate, m.p. 55-59°, -Example 40: (S~-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl cis-2-earbamoylcydohexanecarboxylate, m.p. 76-77°, Example 41: (S)-1-[[(2S,3S)-3-Hexyl-~4-axo-2-oxetanyl]methyl]dodecyl (3-oxo-4-morpholinopropionate, m.p. 49-51°, Exam lp a 42:" (S)-1-[[(2S,3S)-3-I-Iexyl-4-oxa-2-oxetanyl]methyl]dodecyl tetrahydro-(i-oxo-4hl-1,4-thiazine-4-propionate, m.p. 59-61°, Example 43: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 1-carbam.oylcydopentanecarboxylate, m.p. 62-63a, Examt~le 44: (S)-1-[[(2S,2S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 1-1o carbamoylcyclopentanecarboxylate, m.p. 40-41°, Example 45: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-benzylmalonomate (epimers 1;1), m.p. 86-92°, Example 46: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-methoxyrnalonamate (epimers 1;1), m.p. 65-67°, z5 Example 47: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl [(carbamoyl)thio]acetate, m.p. 58-60°, Example 48: (S)-1-[[(2S,3S)-3-Aethyl-4-oxo-2-oxetanyl]methyl]octadecyl [(caxbaanoylrnethyl)thio]acetate, m.p. 83-84°C, Example 49: (S)-1-[((2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl [(RS)-20 (carbamoylmethyl)sulphinyl]acetate (epimers 1:1), m.p. 55-59°, Example 50: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl [(RS)-(earbamoylmethyl)thio]acetate S-oxide, m.p. 80-82°, Example 51: (S)-1-[[(2S,3S~3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 3-[(2-carbamoylethyl)thio]propionate, m.p. 73-74°, 25 Example 52: (S)-1-[[(2S,3S~3-Hexyl-4-oxo-2~-oxetanyl]methyl]dodecyl 3 [(RS)-(2-carbamoylethyl)sulphinyl]propionate (epimers 1:1), m.p. 48-51°, Example 53: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (carbamoylmethoxy)acetate, m.p. 52-53°, ?~'~~~~'~

Example 54: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (carbamoylmethoxy)acetate, m.p. 75-76°, Example 55: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-[1-(benzyloxy)formamido]malonamate (epimers 1:1), m.p. 94-95°, Example 56: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (RS)-2-isabutylmalonamate (epimers '1:1), m.p. 96-99°, Example 57a): (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]axiethyl]octadecyl (RS)-2-benzylmalonamate (epimers 1:1), rn.p. 96-103°, Example 57b): (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (R
'l0 or S)-2-benzylmalonarnate, m.p. 118-120°, Example 58: (S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-phenethylmalonamate (epirners 1:1), m.p. 92-93°, Example 59: (S)-1-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (RS)-2-phenethylmalonamate (epimers 1:1), m.p. 97-98°.
Example 60 Analogously to Examples 1 and 11, from (S)-(+)-2-isopropylrnalonic acid monoamide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(2-propynyl)-2-oxetanone (Example IvI) there is obtained (S)-1-[[(2R,3R)-4-oxo-3-(2-propynyl)-oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 92-95°C (from ethyl acetate/ hexane).
Example G1 Analogously to Examples 1 and 11, from (S)-(+)-2-isopropylmaloruc acid monoamide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-propyl-2-oxetanone (Example O) then is obtained (S)-1-[[(2R,3R)-4-~xo-3-propyl-2-oxetanyl]methyl]octadecyl (S)-2-isopropylrnalonamate, m.p. 90-93° (from ethyl acetate/hexane).
The following compounds are manufactured in an analogous manner to Example 1 and 11:
Example 62: (S)-1-[[(2S,3S)-3-(3-Methyl-2-butenyl)-4-oxo-2-3o oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, m.p. 100-102°, -Example 63: (S)-1-([(2S,3S)-3-(3-Methyl-2-butenyl)-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, m.p. 120-121°, Exarn~le 64: (S)-1-[[(2R,3R)-3-(3-Methyl-2-butenyl)-4-oxo-2 oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, m.p. 60-62°, Example 65: (S)-1-[[(2R,3R)-3-(3-Methyl-2-butenyl)-4-oxo-2 oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, m.p. 76-78°, Exarziple 66: (S)-1-[[(2S,3S or 2R,3R)-3-(5-Chloropentyl)-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 66-72°, Example 67: (S)-1-(((2S,3S or 2R,3R)-3-(5-Chloropentyl)-4-oxo-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 130°, Example 68: (S)-1-[[(2R,3R or 2S,3S)-3-(5-Chloropentyl)-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 44-50°, Exam 1__p a 69: (S)-1-[((2R,3R or 2S,3S)-3-(5-Chloropentyl)-4-oxo-2-axetanyl]methyl]dodecyl (R)-2-isapropylmalonamate, m.p. 85-87°, Example 70: (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°, Example 71: (S)-1-(2S,3S or 2R,3R)-[[3-((E)-2-Butenyl]-4-oxo-2 oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, m.p. 96-98°, Example 72: (S)-1-(2R,3R or 2S,3S~([3-[(E)-2-Butenyl]-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 89-90°, Example 73: (S)-1-(2R,3R or 2S,3S~[[3-[(E)-2-Butenyl]-4-oxo-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 60-63°, Example 74: (S)-1-[[(2R,3R or 2S,3S)-3-(2,3,4,5,6-Pentafluorobenzyl)-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 107-109°, Example 75: (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°, Example 76: (S)-1-[[(2S,3S or 2R,3R)-3-(2,3,4,5,6-Pentafluorobenzyl)-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 88-90°, and Example 77: (S)-1-(((2S,3S or 2R,3R)-3-(2,3,4,5,6-Pentafluorobenzyl)-2-oxetanyl]methyl]doderyl (S)-2-isoprapylmalonamate, m.p. 52-55°.
Example 78 Analagously to Examples 1 and 2, but using (R)- or (S)-2-pyrrolidane-5-carboxylic acid in place of 2-isopropylmalonic acid manoarnide there are obtained a) 5-oxo-D-proline (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, 1H-1VMR (CDC13): 0.88 (m,6H); 1.26 (m,26H); 1.55-1.9 (m,4H); 1.95-2.55 (m,6H); 3.21 (m,lH); 4.25 (m,lH); 4.31 (m,lH); 5.14 (m,lH); 5.80 (s,lH) ppm, 1o b) 5-oxo-L-proline (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-axetanyl]methyl]dodecyl ester, m.p. 51-52°, c) 5-oxo-D-praline (S)-1~[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester, m.p. 55° (diethyl ether), and d) 5-axo-L-praline (S)-1-[[(2S,3S)-3-ethyl-4-axo-2-oxetanyl]methyl]octadecyl ester, m.p. 57-58°.
Example 79 Analogously to Examples 1 and 11, from (S)-(+)-2-isopropylmalonic acid monoamide and a) 3R,4R (ar 3S,4S)-3-anilino-4-[(R)-2-hydroxytridecyl]-2-oxetanone, diastereomer B (Example T) there is obtained (S)-1-[[(2R,3R or 2S,3S)-3-anilino-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate (diastereomer B), m.p. 92°, and b) from 3S,4S (or 3R,4R)-3-anilino-4-[(R)-2-hydroxytridecyl]-2-axetanone, diastereomer A (Example T) thexe is obtained (S)-1-[((2S,3S or 2R,3R)-3-z5 aniline-4-oxo-2-oxetanyl)methyl]dodecyl (S)-2-isopropylrnalonamate (diastereomer A), m.p. 77°.
Pharmaceutical preparations of the following composition are manufactured in a manner known per se:
Example A
3o Soft gelatine capsules:

Amount per capsule An oxetanone of formula I 50 mg Medium-chain triglyceride 450 yl Example B
I-Iard geltaine capsules:
An oxetanone of formula I 20.0 mg Lactose tryst. 37.0 rng Mieracrystalline cellulose 20.0 mg Polyvinylpolypyrrolidone 8.5 mg 1o Sodium salt of the carboxymentyl ether of starch 8.5 mg Talc 4.5 mg Magnesium stearate 1._ 5 m~
Capsule fill weight 100.0 mg Example C
Tablets An oxetanone of formula I 30.0 g Lactose anhydrous 118.8 Microcrystalline cellulose 30.0 Polyvinylpyrrolidone 10.0 2o Polymer of carboxymethylcellulose 10.0 Magnesium stearate 1.2 Tablet weight 200.0 mg -4~-Example D
Tablets with controlled release of the active ingredient and increased residence time in the skomach:

An oxetanone of formula I 60.0 mg Lactose powd. 70.0 mg Hydroxypropylmethylcellulose 52.5 mg Polyvinylpyrrolidone 7.5 mg Talc 8.0 mg Magnesium stearate 1.0 mg Colloidal silicic acid 1.0 mg Nucleus weight 200.0 mg Hydroxypropylmethylcellulose 2.5 mg Talc .1.25 mg Titanium dioxide 1.25 mg Weight of the film coating 5.0 mg Exarn_ple EE
Reconstitutable powder:
An oxetanone of formula Z 200.0 mg Ethylvanillin 10,0 mg 2o Aspartame 30.0 mg Sprayed skinned milk powder 4,760.0 mg Total 5,000.0 mg

Claims (14)

1. Oxetanones of the formula Q is a group of the formula (R3,R4)NCO(X)n-CO- ~~Q1 (R3,R4)NCO-X'- ~~~Q2 or and R1 and R2 are alkyl with up to 18 C atoms substituted by 1 to 3 halogen atoms or alkyl, alkenyl, alkynyl or alkadienyl groups with up to 20 C
atoms optionally interrupted by a 1,4-arylene group, optionally substituted by an aryl group in the .omega.-position and optionally substituted by an aryl-C1-4-alkyl group, whereby R1 can be interrupted by an O or S
atom or by a sulphinyl or sulphonyl group in a position other than the .alpha.-position to an unsaturated C atom, or R1 is an aryl-NH- or aryl-C1-4-alkyl-OCONH- group, wherein aryl and arylene denote phenyl or phenylene substituted by up to 5 halogen atoms or up to 3 C1-4-alkyl, C1-4-alkoxy or nitro groups.
R3 and R4 are hydrogen or C1-4-alkyl or together with the N atom to which they are attached form a saturated 3- to 6-membered ring optionally containing an O
or S atom in a position other than the .alpha.-position to the N atom, n is the number 1 or 0, X is an alkylene group, which contains up to 6 C atoms, which is optionally interrupted by an O or S atom or by a sulphinyl or sulphonyl group and which is optionally substituted 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 ar C1-6-alkylidene group or by one or two C1-6-alkyl, C1-6-alkoxy or C1-6-alkylthio groups, whereby two Cl-6-alkyl, C1-6-alkoxy or C1-6-alkylthio groups on the same C atom or on two adjacent C atoms can form an optionally mono-unsaturated 3- to 7-membered ring and an optionally present hydroxy or mercapto group or an optionally present unsaturated C atom must be in a position other than the .alpha.-position to an optionally present O or S atom or to an optionally present sulphinyl or sulphonyl group, or X is a group of the formula =CHN(R,R~) or -CHN(R,R~)CH2-R and R~ are 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)- and X' is an alkylene group containing up to 6 C atoms which can be 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 groups, whereby two C1-6-alkyl groups attached to adjacent C atoms can form a 3- to 7-membered ring.

2. Oxetanones of formula I according to claim 1, wherein Q is a group of the formula Q1, R1 and R2 are alkyl, alkenyl or alkadienyl groups with up to 20 C atoms optionally interrupted by a 1,4-phenylene group, optionally substituted by a phenyl group in the .omega.-position and optionally substituted by a phenyl-C1-alkyl group, whereby R1 can be interrupted by an O or S atom in a position other than the .alpha.-position to an unsaturated C atom, X is an alkylene group, which contains up to 6 C atoms, which is optionally interrupted by an O or S
atom and which is optionally substituted by a hydroxy, mercapto, phenyl, phenoxy, phenylthio, phenyl-C1-4-alkyl; phenyl-C1-4-alkoxy, phenyl-C1-4-alkylthia, phenyl-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, whereby two C1-6-alkyl, C1-6,-alkoxy or C1-6-alkylthio groups attached to the same C atom can form a 3- to 7-membered ring and an optionally present hydroxy or mercapto group must be in a position other than the .alpha.-position to an optionally present O or S atom, or X is a group =CHN(R,R~), R and R~ are hydrogen, C1-4-alkyl, C1-4-alkyl-(CO or OCO)-, phenyl or phenyl-(CO or OCO)-and n, R3 and R4 have the significance given in claim 1.

3. Oxetanones of formula I according to claim 1, wherein Q is a group Q1.
R1 and R2 are alkyl, alkenyl, alkynyl or alkadienyl groups with up to 20 C
atoms optionally substituted by an aryl group in the .omega.-position, whereby can be interrupted by a S atom in a position other than the .alpha.-position to an unsaturated C atom, or R1 is anilino, alkyl with up to 18 C atoms substituted by a halogen atom or a phenyl-C1-4-alkyl-OCONH- group, R3 and R4 are hydrogen or C1-4-alkyl or together with the N atoms to which they are attached form a saturated 6-membered ring containing an O or S atom in a position other than the .alpha.-position to the N atom, n is the number 1 or 0, X is an alkylene group, which contains up to 6 C atoms, which is optionally interrupted by an O or S atom or by a sulphinyl group and which is optionally substituted by one or two C1-6-alkyl or C1-6-alkoxy groups, whereby two C1-6, alkyl or C1-6-alkoxy groups attached to the same C atom or to two adjacent C
atoms can form an optionally mono-unsaturated 3- to 7-membered ring, or X
is a group =CHN(R,R~) or -CHN(R,R~)CH2- and R and R~ are hydrogen, C2-5-alkanoyl or benzyloxycarbonyl.

4. Oxetanones according to claim 3, wherein R1 is methyl, ethyl, propyl, hexyl, 2-butenyl, 3-methyl-2-butenyl, 2-propynyl, methylthio, pentylthio, 5-chloropentyl, benzyl, phenylthio, benzylthio, pentafluorobenzyl, anilino or benzyloxycorbonylamino, R2 is 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 the number 1 or O and X is the group -(CH2)1-8-, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopentylidene, t-butylmethylene, dimethylvinyli-dene, cyclopentylidene, cyclohexylidene, phenethylidene, phenylpropylidene, 1,2-cyclohexylene, cyclohex-3-en-1,6-ylene, acetamidomethylene, benzyloxy-carbonylaminomethylene, 1-benzyloxycorbonylamino-1,2-ethylene, methyleneoxymethylene, methylenethiomethylene, methylenesulphinyl-methylene, ethylenethioethylene, ethylenesulphinylethylene, methoxy-methylene or ethylene- or propylenedioxymethylene.

5. Oxetanones of formula I according to claim 1, wherein Q is a group Q2, R1 and R2 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 group or by one or two C1-6-alkyl groups, whereby two C1-6-alkyl groups attached to adjacent C atoms can form a 3- to 7-membered ring.

6. Oxetanones according to claim 5, wherein R1 is hexyl, R2 is undecyl and X' is ethylene, 1-methoxy-1,2-ethylene or 1,2-cyclohexylene.

7. Oxetanones of formula I according to claim 1, wherein Q is a group Q3, R3 is hydrogen and R1 and R2 are C1-20-alkyl, especially hexyl or undecyl.

8. Oxetanones according to claim 1 from the following group:
(S)-1-([(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropyl-malonamate, (S)-1-([(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-carbamoylvalerate, (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (S)-2-isopropylmalonamate, (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, (S)-1-([(2S,3S) or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl [S:R(2:1)]-2-isopropylmalonamate, (S)-1-[((2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (S or R)-2-t-butylmalonamate (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 1-carbamoyl-cyclopentanecarboxylate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-benzylmalonamate, (S)-1-[((2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 3-[(2-carbamoylethyl)thio]propionate, 5-oxo-D-proline (S)-1-[((2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester and 5-oxo-L-proline (S)-1-[((2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester.

9. Oxetanones according to claim 2 from the following group:
(S)-1-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-carbamoylvalerate (epimers 1:1), (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (S
or R)-2-isopropylmalonamate (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-carbamoyl-4-methylvalerate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 1-carbamoylcyclo-hexanecarboxylate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-methylmalonamate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-ethyl-malonamate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-butyl-malonamate (epimers 1:1), (S)-1-[[2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 1-carbamoylcyclohexanecarboxylate, (S)-1-[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl [S:R
or R:S(2:1)]-2-isopropylmalonamate and (S)-1-[[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate.

10. Oxetanones according to claim 1 for use as pharmaceutically active substances in control of obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

11. A process for the manufacture of the oxetanones of claim 1, which process comprises a) esterifying an alcohol of the formula with an acid of the formula Q a-OH, wherein Q a is a group of the formula Q1 or Q3, or b) cyclizing an and of the formula (Q-O,R2)CHCH2CH(OH)CH(R1)-COOH ~~~IIb or c) converting the carboxy group in the group T in an acid of the formula wherein T is a group of the formula HOCO(X)n -CO- ~~T1 or HOCO-X'- ~~T2, into an amide group (R3, R4)NCO-, and d) if desired, separating a mixture of epimers of formula I into the individual epimers.

12. A medicament containing an oxetanone according to claim 1 and a therapeutically inert carrier material.

13. The use of an oxetanone according to any one of claims 1 to 9 for the manufacture of a medicament for the control or prevention of obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

14. The use of an oxetanone according to any one of claims 1 to 9 for the control or prevention of obesity, hyperlipemia, atherosclerosis and arteriosclerosis.