NO177055B - Analogous Process for the Preparation of Therapeutically Active 2-Oxetanones - Google Patents

Abstract

Novel oxetanones inhibiting pancreatic lipase, of the formula <IMAGE> in which Q, R<1> and R<2> have the meaning given in the description, are disclosed, which are prepared starting from the corresponding beta -hydroxycarboxylic acids.

Description

The present invention relates to an analogue method for the production of therapeutically active new oxetanones.

These oxetanones have the formula I

• where Q is a group with the formula

R<1> is (C 1 -C 8 )alkyl optionally substituted with halogen;

straight or branched (C 2 -C 6 )alkenyl; (C 2 -C 4 )-alkynyl; -SO; benzyl optionally substituted with 1-5 halo atoms on the benzene ring; -NHC(=0)OR' or anilino, where

A = (C-1-C4) alkyl, phenyl or benzyl

R<1> = benzyl

R 2 is (C 6 -C 18 )alkyl, (C 6 -C 18 )alkenyl or alkadienyl,

R<3> and R<4> are hydrogen or C1-C4 alkyl, or together with the N atom to which they are attached they form morpholine or thiomorpholine,

n is the number l or 0,

X is an alkylene group interrupted by an O or S atom or by a sulfinyl or sulfonyl group, containing up to 8 C atoms, or

X is branched or unbranched (C 1 -C 8 )alkylene optionally substituted with phenyl or (C 1 -C 8 ) alkoxy;

(C 2 -C 4 )alkenylene; =CHNHC(=O)CH 3 ; <=>CHNHC(=0)CH2C6<H>5<;>

-CHNH(C(=O)OR')CH2-; or

and

X' is (C-L-4) alkylene optionally substituted with (C 1 -C 4 ) alkoxy; or

Preferred oxetanones of formula I are compounds, where R<1> is methyl, ethyl, propylhexyl, 2-butenyl, 3-methyl-2-butenyl, 2-propynyl, methylthio, pentylthio, 5-chloropentyl, benzyl, phenylthio, benzylthio , pentafluorobenzyl, anilino or benzyloxycarbonylamino, R<2> is undecyl, heptadecyl or 8,11-heptadecadienyl, R<3> and R<4> are hydrogen, methyl or isopropyl, or together with the N atom they form a morpholino or thiomorpholino group, n is the number 1 or 0, and X is the group (C<H>2)1.8, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopentylidene, t-butylmethylene, dimethylvinylidene, cyclopentylidene, cyclohexylidene, phenethylidene, phenylpropylidene, 1,2-cyclohexylene, cyclohex-3,4-en-1,6-ylene, acetamidomethylene, benzyloxycarbonylaminomethylene, 1-benzyloxycarbonylamino-1,2-ethylene, methyleneoxymethylene, methylenethiomethylene, methylenesulfinylmethylene, ethylenethioethylene, ethylenesulfinylethylene, methoxymethylene or ethylene- or propylenedioxymethylene.

Further preferred oxetanones of formula I are compounds where R<1> is hexyl, R<2> is undecyl and X' is ethylene, 1-methoxy-1,2-ethylene or 1,2-cyclohexylene.

Equally preferred are the oxetanones of formula I, where Q is a group Q<3>; R<3> is hydrogen, R<1> is hexyl, and R2 is undecyl.

Examples of such compounds are the following: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(S)-2-isopropyl malonate,

(S)[(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-isopropylmalonate, (S) -l-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, (S)-l-[[(2S, 3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl-[S:R (2:1)]-2-isopropylmalonate,

(S)-l-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octa-decyl-(S or R)-2-t-butylmalonate, (S)-l- [[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octa-decyl-1-carbamoylcyclopentanecarboxylate, (S)-1-[[(2S,3S)-3-hexyl-4- oxo-2-oxetanyl]methyl]do-decyl-(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-oxe-tanyl]methyl]octadecyl ester,

5-oxo-L-proline-(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetany]methyl]octadecyl ester,

(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(S or R)-2-isopropylmalonate, (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-isopropylmalonate,

(S)[(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-carbamoylcyclohexanecarboxylate, (S)[(2S,3S)-3-hexyl- 4-oxo-2-oxetanyl]methyl]dodecyl-(RS)-2-methylmalonamate (epimers 1:1), (S)[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]do-decyl-(RS)-2-ethylmalonamate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(RS)-2-butylmalonamate (epimers 1:1), (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octa-decy1-1- carbamoylcyclohexanecarboxy1ate, (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl-[S:R or R:S (2:1)] -2-isopropyl malonate,

(S)-1-[[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl-(S or R)-2-isopropylmalonate.

The oxetanones of formula I can be prepared in a manner known per se by

a) esterifies an alcohol of formula IIa

with an acid of formula Q<a->OH, where Q<a> is a group with

formula Q<1> or Q<3>, or

b) cyclizes an acid of formula IIb

(Q-0, R 2 ) CHCH 2 CH (OH) CH (R 1 ) -COOH IIb

or

c) in an acid of formula lic

where T is a group of formula

HOCO(X)n-CO-T<r-> or HOCO-X<1->T2

converts the carboxy group in the group T to an amide group (R<3>,R<4>)NCO-, and d) separates, if desired, an epimer mixture of formula I into the individual epimers.

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

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

The facultative separation of an epimer mixture of formula I can be carried out e.g. by chromatography over silica gel with ethyl acetate/hexane/methylene chloride as eluent.

The alcohols of formula IIa are known, e.g. from the European patent application no. 0 185 359 A2, or can be prepared analogously to the known alcohols of formula Ila or as described in Examples A to I, M and 0 to T.

The starting acids of formula IIb and Ic can be prepared in a manner known per se, e.g. starting from corresponding alcohols of formula Ila as described below in examples J and K (for the acids Ilb) respectively. K, 1 and N (for the acids lic).

Example A

a) Under nitrogen, 465 g of acetoacetic acid methyl ester and then 458 g of ethyl bromide are added to 720 g of a 30% sodium methylate solution in 1200 ml of methanol. The reaction mixture is then refluxed. After distilling off the methanol, the residue is poured into ice water. Then extract with n-hexane and water. The organic phases are combined and dried. After evaporation of the solvent and distillation, 328 g of 2-acetylbutyric acid methyl ester are obtained, m.p. 77-79 c/ 15 torr. b) Under argon, 144.17 g of the methyl ester from a) are added at 0-5°C to a suspension of 26.4 g of sodium hydride in 1250 ml of THF. After stirring for 1.5 hours at 0-5°C, cool to -10°C. At this temperature, 675 ml of 1.56 M butyl lithium in hexane are added. After stirring for 30 minutes at -10°C, a solution of 149.3 g of stearic acid methyl ester in 250 ml of THF is added dropwise. After stirring for 1.5 hours at -10°C, the reaction solution is added under argon to 250 ml of 37% hydrochloric acid and 300 g of ice. It is extracted with hexane and water. The combined organic phases are dried, filtered and evaporated.

The residue is dissolved in 2500 ml of THF, 76.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) is added and boiled under argon with reflux. The cooled reaction mixture is extracted with 37% hydrochloric acid and then with saturated sodium chloride solution. The combined organic phases are dried and evaporated. The product is dissolved in acetic acid ethyl ester. The solution is cooled to room temperature and stirred overnight at 25°C. The crystallisate is filtered, washed with ethyl acetate and dried. 122.5 g of 3-ethyl-6-heptadecyl-4-hydroxy-2H-pyran-2-one are obtained, m.p. 101-102°C.

c) 100 g of Raney nickel and 2000 ml of THF are added to 100 g of the pyrone from b). After 3 days of hydration at 25°

the catalyst is filtered off and washed with THF. The filtrate is evaporated to dryness. The residue is dissolved in acetic acid ethyl ester and stirred at 10° for 17 hours. The crystallisate is filtered off, washed with -10° cold acetic acid ethyl ester and dried for 17 hours at 40°C. 90.54 g of rac-(2RS,3RS,5SR)-2-ethyl-5-heptadecyl-3-hydroxy-6-valerio-lactone are obtained, m.p. 101-102°C.

d) To a suspension of 191.3 g of the 6-lactone from c) in 1250 ml of toluene, 138.5 g of benzoic anhydride is added and

then 2.5 ml perchloric acid 70%. After stirring for 2.5 hours, the reaction mixture is extracted in toluene with 1N caustic soda in a 20% sodium chloride solution and then with saturated sodium chloride solution. The organic phases are combined, dried and evaporated. 243.4 g of rac-(2RS,3RS,5SR)-3-benzoyloxy-2-ethyl-5-heptadecyl-5-valeriolactone are obtained, m.p. 64.5-66°C.

e) Under argon, 243 g of the benzoate from d) are dissolved in 450 ml of toluene at 40°C. 1000 ml of methanol are added and

then 2.5 ml of concentrated sulfuric acid, and the reaction mixture is stirred for 20 hours at 25°C. After neutralizing the sulfuric acid with triethylamine, the solvent is evaporated. The residue is dissolved in t-butyl methyl ether and washed with water. The aqueous phase is extracted with t-butyl methyl ether, and the organic phases are combined and dried over sodium sulfate, the drying agent is filtered and washed with t-butyl methyl ether and then evaporated. 257 g of rac-(2RS,3RS,5SR)-3-benzoyloxy-2-ethyl-5-hydroxy-docosanoic acid methyl ester are obtained.

f) Under argon, 152 g of benzyl-2,2,2-trichloroacetimidate are added to 257 g of the hydroxy ester from e) in 1250 ml of n-hexane. 3.2 ml of trifluoromethanesulfonic acid are then added. After stirring for 18 hours, the fines are filtered and washed with n-hexane. The filtrate is extracted with 5% sodium bicarbonate solution and water. The combined hexane phases are dried, filtered and concentrated. After stirring for 20 hours at -20°C, the crystallisate is filtered, washed with n-hexane and discarded. The filtrate is evaporated. 239.6 g of rac-(2RS,3RS,5SR)-3-benzoyloxy-5-benzyloxy-2-ethyldocosanic acid methyl ester are obtained.

g) Under argon, add to 239.6 g of the benzyl ether from f) a solution of 140 g of potassium hydroxide in 1250 ml of 95%

(v/v) methanol/water, and it is stirred for 17 hours at 40°C. The solution is then concentrated at 40°C, the suspension is taken up in t-butyl methyl ether, and it is washed successively 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 and washed with t-butyl methyl ether. The filtrate is concentrated. 182.1 g of rac-(2RS,3RS,5SR)-5-benzyloxy-2-ethyl-3-hydroxy-docosanic acid are obtained.

h) To a solution of 182.1 g of the B-hydroxy acid from g)

33.3 g are added dropwise to 1250 ml of acetic acid methyl ester

(S)-(-)-α-methylbenzylamine. The solution is inoculated with 50 mg of the phenethylamine salt of (2S,3S,5R)-5-benzyloxy-2-ethyl-3-hydroxycocosanoic acid and allowed to stand for 20 hours. The crystallisate is filtered off, washed with -20°C cold acetic acid methyl ester and then dried. This 1st crystallisate is dissolved in hot acetic acid methyl ester, cooled to 45°C and seeded with 50 mg of the phenethylamine salt of (2S,3S,5R)-5-benzyloxy-2-ethyl-3-hydroxycocosanoic acid. The solution was left for 20 hours at room temperature. The crystallisate is filtered off, washed with -20°C cold acetic acid methyl ester and dried. The same procedure as with the 1st crystallisate is repeated with the 2nd crystallisate. 39.4 g of the phenethylamine salt of (2S,3S,5R)-5-benzyloxy-2-ethyl-3-hydroxycocosanoic acid are obtained,

m.p. 92-95°C.

i) 39.4 g of the phenethylamine salt from h) are added to 400 ml 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 concentrated. 31.4 g of (2S,3S,5R)-5-benzyloxy-2-ethyl-3-hydroxy-docosanic acid are obtained, m.p. 62-63.5°C.

j) Under argon, 17.6 g of benzene sulphochloride are added dropwise to a solution of 24.5 g of the B-hydroxy acid from i) in 250 ml of pyridine at 0°C. After 20 hours of stirring at 0°C, 5 ml of water is added dropwise to the solution. It is stirred for 1 hour at room temperature. The pyridine is evaporated. The crystal slurry is taken up in t-butyl methyl ether and washed

successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and 10% sodium chloride solution. The organic phase is dried over sodium sulphate and then stirred with activated charcoal. Desiccant and activated carbon are filtered off and the filtrate is evaporated. 23.4 g of (3S,4S)-4-[(R)-2-benzyl-oxynonadecy1]-3-ethyl-2-oxethanone are obtained.

k) A solution of 23.4 g of the oxetanone from j) in 250 ml of THF is added to 2.3 g of Pd/C 10%. After 5 hours of hydration, the hydrator solution is filtered off. After washing with THF, the filtrate is evaporated, the residue is dissolved in n-hexane and grafted with (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxethanone. After 18 hours, the crystallisate is filtered off, washed with hexane and dried. 16.1 g of (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxethanone are obtained, m.p. 66.5-68°C, the starting alcohol from example 1.

Example B

a) 50 g of (R)-3-hydroxytetradecanoic acid methyl ester, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and

Dissolve 29.4 g of triethylamine in 200 ml of methylene chloride and re-

stirred for 30 hours at room temperature and for 16 hours under reflux. A further 2 g of t-butyldimethylchlorosilane are then added. After a further 24 hours under reflux, the precipitated triethylamine hydrochloride salt is filtered off, washed with ether and the filtrate concentrated. The residue is dissolved in ether and washed successively with water, 0.5M citric acid, again with water and saturated sodium chloride solution, dried, concentrated and then freed at 50°C in high vacuum for 5 hours from volatile material. 71.8 g of (R)-3-(t-butyldimethylsiloxy)tetradecanoic acid methyl ester are obtained, IR (cm"<1>): 1745, 1254, 895, 776.

b) 18.63 g of the product from a), dissolved in 100 ml ether, is added at a temperature of -70°C to -75°C 65 ml IM

diisobutylaluminum hydride solution in hexane and then stirred for 1 hour at this temperature. 2.5 ml isopropanol, 10 ml water and 50 ml 0.5M citric acid solution are then added dropwise at a maximum of 10°C. 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) and 14.47 g of (R)-3-(t-butyldimethylsiloxy)tetradecanal is obtained, IR (cm"<1>): 1728, 1254, 836, 775.

c) A solution of 2.55 ml of diisopropylamine in 45 ml of THF is added at 0°C to 22.5 ml of a solution of 1.6M n-butyllithium in hexane, stirred for 15 minutes and cooled to -75°C. A solution of 2.92 g of pentylthioacetic acid in 9 ml of THF is then added dropwise. After stirring for 10 minutes, the reaction mixture is allowed to warm to room temperature, stirred for 5 minutes and cooled again to -75°C. At this temperature, a solution of 2.4 g of the aldehyde from b) in 9 ml of THF is added dropwise. After stirring for 20 minutes, the reaction mixture is poured onto saturated ammonium chloride solution and extracted with hexane. The hexane phase is dried and concentrated. 3.89 g of (2R/S,3R/S,5R)-5-(t-butyldimethylsiloxy)-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 hexafluorophosphate (HBTU), 2 g 4Å molecular sieve and 3 ml of triethylamine in a mixture of 130 ml of methylene chloride and 6 ml of DMF are stirred for 2 hours. It is then filtered, the filtrate is concentrated, the residue is dissolved in water/methanol (3:7) and extracted with hexane. The hexane phase is dried and evaporated. 3.57 g of (3R/S,4R/S)-4-[(R)-2-(t-butyldimethylsiloxy]tridecyl]-3-pentyl 10-2-oxetanone is obtained as a mixture of 4 diastereomers. e) A solution of 4.59 g of the product from d) in 200 ml of acetonitrile is added to 15 ml of 40% hydrofluoric acid and stirred for 18 hours. Sodium bicarbonate solution is added, 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. 699.9 mg (3R,4R

or 3S,4S)-4-[(R)-2-hydroxytridecyl]-3-pentylthio-2-oxetanone, m.p. 43°C and 691.2 mg of (3S,4S or 3R,4R)-4-[(R)-2-hydroxytridecyl]-3-pentylthio-2-oxethanone, m.p. 71°C, the starting alcohols for Examples 5 and 6.

Example C

a) 18 ml of an IM solution of lithium-bis(trimethylsilyl)-amide in THF is added under argon at -75°C 1.8 ml of acetic acid ethyl ester, stirred for 30 minutes at this temperature and then 4.8 g (R) are added -3-benzyloxytetradecanal in 15 ml of THF and stirred for half an hour at -78°C. A solution of 3.8 ml of concentrated hydrochloric acid in 6 ml of water is added dropwise to the reaction mixture. The obtained solution

extracted with ethyl acetate, the combined organic phases are washed with 10% sodium bicarbonate and water, dried, filtered and concentrated. Ethyl (3R,5R and 3S,5R)-5-benzyloxy-3-hydroxyhexadecanoate is obtained

(1:1).

b) A solution of 4 ml of diisopropylamine in 12.5 ml of THF is added under argon at 0°C 17 ml of a 1.6M solution of

n-BuLi in n-hexane. After 15 minutes of stirring, 5 g of the product from a) is added dropwise in 2.5 ml of THF at -50°C. After 10 minutes at -10°C, the temperature is lowered to -50° and after the dropwise addition of a solution of 3.18 g of benzyl bromide in 3.1 ml of hexamethylphosphoric acid triamide at -50°C, the mixture is stirred for 15 minutes. The cooling bath is then removed and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is cooled to 0°C and 50 ml of saturated sodium chloride solution is added, 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/acetic ester (4:1). The residue Ethyl-(2R,3R,5R and 2S,3S,5R)-5-benzyloxy-2-benzyl-3-hydroxyhexadecanoate is obtained as 1:1 threo-diastereomers.

c) A solution of 3.1 g of the product from b) and 26 ml of 2.5N caustic soda in 37.2 ml of ethanol is heated for 50 minutes

with reflux and then neutralized at room temperature with 26 ml of 2.5N hydrochloric acid. The ethanol is distilled off, then 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 2.59 g of HBTU and 2.74 g of molecular sieve are added. 5.5 ml of DMF and 2.8 ml of triethylamine are then added and the reaction mixture is stirred for 1 hour, filtered and concentrated. The residue is taken up in n-hexane, then the solution is extracted with water, dried and concentrated in vacuo. Chromatography on silica gel with methylene chloride gives a 1st trans diastereomer, (3S,4S or 3R,4R)-3-benzyl-4-[(R)-2-benzyloxytridecyl]-2-oxetanone, Rf value: 0.45 (thin layer chromatography over silica gel 5-40 µl with methylene chloride) and a 2nd trans diastereomer, (3R,4R or 3S,4S)-3-benzyl-4-[(R)-2-benzyl-oxytride-

cyl]-2-oxetanone, Rf value: 0.50 (thin layer chromatography over silica gel 5-40 µl with methylene chloride). d) A solution of 646 mg of the 2nd trans diastereomer from c) in 65 ml of THF is hydrated in the presence of 646 mg of Pd/C 10% for 1 hour. The reaction mixture is filtered and concentrated. A trans-diastereomer is obtained: (3R,4R)-3-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, the starting alcohol in example 7. e) As described under d) one obtains from the 1 .trans diastereomer from c) the trans diastereomer: (3S,4S)-3-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, the starting alcohol in example 8.

Example D

A solution of 3.0 ml of diisopropylamine in 50 ml of THF is added at 0°C to 12.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, is cooled to -75°C. A solution of 1.26 g of Z-glycine in 10 THF is then added dropwise. The reaction mixture is then allowed to warm to room temperature and cooled again to -75°C. Now 0.70 g of (R)-3-(t-butyldimethylsiloxy)-tetradecanal in 5 ml of THF is added dropwise at -75°C. The reaction mixture is stirred for 1 hour at -75°C, for 1/2 hour at -40°C to -50°C, then warmed to 5°C, cooled again to -75°C and poured onto dilute potassium hydrogen sulfate solution and extracted with ether . The ether phase is dried, concentrated and chromatographed with methylene chloride/methanol on silica gel. 540 mg of (2R/S,3R/S,5R)-2-[1-(benzyloxy)form-amido]-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic acid is obtained as a mixture of 4 diastereomers.

Analogous to Bd), the above-mentioned product yields benzyl-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxo-3-oxetanecarbamate as a 1:1 mixture of the two trans-di-

astereomeric 6-lactones, MS: 476 (M+»-C4H9«) .

Analogous to Be), one obtains from the mixture listed above (3S,4S or 3R,4R)-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxo-3-oxetane carbamate, the starting alcohol 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.

Example E

Analogous to example B, from thiophenoxyacetic acid and (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanal 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)tri-decyl]-3-(phenylthio)-2-oxetanone (mixture of 4 diastereomers), IR (cm "<1>): 2927, 2855, 1833, 1254,

obtained (3S,4S)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone, m.p. 79°C (ether) and (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxethanone, m.p. 47°C (ether), the starting alcohols for example 16.

Example F

a) To a solution of 117 g of Meldrum's acid and 131 ml of pyridine in 1.5 l of methylene chloride, 270 ml of stearic acid chloride are added dropwise at a maximum of 15°C. After stirring, the reaction mixture is washed with 4N hydrochloric acid, the aqueous phase is subsequently extracted with methylene chloride, the methylene chloride phase is dried and concentrated. The residue is taken up in methanol and stirred at reflux. After cooling, the precipitated crystals are filtered off, dissolved in methylene chloride and chromato-

is graphed on silica gel with methylene chloride. 175 g of methyl 3-oxoeicanoate are obtained, m.p. 52-54°C. b) 1.84 mg of acetyl chloride in 1, 84 ml of methanol. The resulting solution is hydrogenated together with 39.8 g of the keto ester from a) and 170 ml of methanol at 35 bar hydrogen and 60°C. After adding methylene chloride, evaporate to dryness. Chromatography on silica gel with ether and recrystallization from n-hexane yields 35.7 g of (R)-3-hydroxyeicosane acid methyl ester, m.p. 64-64.5°C. c) Analogous to example B, the product is obtained from

b) via

methyl-(R)-3-(t-butyldimethylsiloxy)eicosanoate, IR (cm"<1>): 1745, 1255, 836,

(R)-3-(t-butyldimethylsiloxy)eicosanal, IR (cm"<1>): 1728, 1463, 1255, 1104, 836, 775,

(2R/S,3R/S,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2-(methylthio)-docosanic acid (mixture of 4 diastereomers), MS: 533 (M + H)<+>,

4-[(R)-2-(t-butyldimethylsiloxy)nonadecyl]-3-(methylthio)-2-oxetanone (1:1 mixture of two trans diastereomers), IR (cm"<1>): 1834, 1463, 1256, 1106, 836 and

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 starting alcohols from Example 17:

(3S,4R or 3R,4S)-4-[(R)-2-hydroxynonadecyl]-3-

(methylthio)-2-oxetanone, m.p. 65°C (from methylene chloride),

(3R,4S or 3S,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxetanone, m.p. 67°C (from methylene 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-(methylthio)-2-oxethanone, m.p. 80°C (from ether).

Example G

Analogously to example B, one obtains from (benzylthio)-acetic acid and (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanal 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-oxethanone (mixture of 4 diastereomers), MS: 506 ( M<+>)

the following starting alcohols for example 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-oxetanone, MS: 374 (M<+>« -H 2 O) and

(3R,4S and 3S,4R)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxetanone (1:1 diastereomer), MS: 374 (M<+>»- H2O).

Example H

a) 104 g of mother liquor from the 1st crystallization in example Ah) is dissolved in water and methylene chloride. Acidified under ice-cooling by the addition of concentrated HC1 to pH 1, the methylene chloride phase is separated, the aqueous phase is extracted with methylene chloride, the methylene chloride phase is washed with water, dried and concentrated. 86.7 g of enriched (2R,3R,5S)-5-benzyloxy-2-ethyl-3-hydroxycocosanoic acid is obtained, which is dissolved in 500 ml of ethyl acetate and 20.6 g of (R)-(+)-cc-methyl is added -benzylamine under cooling. After the addition of ethyl acetate, the mixture is heated to the reflux temperature, filtered and crystallized. The crystals obtained are recrystallized from ethyl and methyl acetate. 70.0 g of the phenethylamine salt of (2R,3R,5S)-5-benzyloxy-2-ethyl-3-hydroxy-docosanic acid is obtained, m.p. 88-91"C. b) Analogous to example Ai)j)k), the above-mentioned salt was obtained via

(2R,3R,5S)-5-benzyloxy-2-ethyl-3-hydroxycocosanoic acid, m.p. 61.5-63"C and

(3R,4R)-4-[(S)-2-benzyloxynonadecyl]-3-ethyl-2-oxetanone, m.p. 38-40°C

obtained (3R,4R)-3-ethyl-4-[(S)-2-hydroxynonadecyl]-2-oxetanone, m.p. 66-68°C.

c) A solution of 14.2 g of the product obtained and 8.65 g of triphenylphosphine in 250 ml of THF is added at +5°C

1.19 ml of formic acid and then a solution of 5.12 g of diethyl azodicarboxylate in 20 ml of THF. 0.4 ml of formic acid, 2.9 g of triphenylphosphine and 1.7 ml of diethyl azodicarboxylate are then added again. The reaction mixture is concentrated and the residue is chromatographed on silica gel with hexane/ethyl acetate; thereby obtaining 13.1 g of (R)-1-[[(2R,3R)-3-

ethyl 4-oxo-2-oxetanyl]methyl]octadecyl formate.

The product obtained is dissolved in 150 ml of methanol and 0.114 g of p-toluenesulfonic acid monohydrate is added at 15°C. After stirring, the reaction mixture is concentrated, the residue is distributed between methylene chloride and aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride phase is dried, concentrated and the residue is recrystallized from ethyl acetate. 9 is obtained .5 g (3R,4R)-3-ethyl-4-[(R)-2-hydroxynona-decyl]-2-oxetanone, m.p. 80-82°C, the starting alcohol from example 21.

Example I

a) To a solution of 42.5 ml of diisopropylamine in 500 ml of THF, 187.5 ml of n-butyllithium solution (1.6M in hexane) is added dropwise at -20°C. After stirring, the solution is added dropwise at max. -65°C to a suspension of 39.9 g of (S)-(-)-2-hydroxy-1,2,2-triphenylethyl acetate in 600 ml of THF. The reaction mixture is then heated to 0°C, stirred, cooled to -70°C and a solution of 51.2 g of (R)-3-[(t-butyl)dimethylsilyloxy]eicosanal in 400 ml of THF is added.

After stirring, 500 ml of saturated ammonium chloride solution is added dropwise at -70°C, then heated to room temperature and stirred. The reaction mixture is concentrated, distributed between water and ether and extracted with ether, the ether phase is washed with water, concentrated, taken up in methylene chloride, dried and concentrated. 91.9 g of (S)-2-hydroxy-1,2,2-triphenylethyl-[3R:3S(4:1),5R]-5-(t-butyldimethylsiloxy)-3-hydroxycocosanoate, IR (cm "<1>): 3525, 1719, 1448, 1250, 1159, 838, 697.

b) A solution of 90.8 g of the product obtained above in methanol is added to 22.15 ml of 5.4 M sodium methylate in

methanol. After stirring, the solution is concentrated, the residue is distributed between ether and saturated ammonium chloride solution and extracted with ether. The ether phase is dried, concentrated and

chromatographed with hexane/ethyl acetate on silica gel. 42.7 g of methyl-(3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxycocosanoate are obtained, IR (cm"<1>): 3521, 3468, 1738, 1254, 1168, 1137, 1105. c ) Analogous to examples Be) and Cb), c) the latter compound is converted via methyl-(2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2-methyldocosanoate, IR (cm"<1 >): 3522, 1739, 1464, 1254, 1066 and (3R,4R)-4-[(R)-2-(t-Butyldimethylsiloxy)nodecyl]-3-methyl-2-oxethanone, IR (cm" <1>): 1830, 1464, 1254, 1129, 1071 to (3R,4R)-4-[(R)-2-hydroxy-oxynonadecyl]-3-methyl-2-oxethanone, mp 82.5-84 "C (from EtOAc/hexane), the starting alcohol of Example 22.

Example J

a) 1.1 g (3S,4S)-3-hexyl-4<->[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g triphenylphosphine, 0.825 g salicylamide and 3 g molecular sieve (4Å) 20 ml of THF are added and cooled to 0°C. 1.4 g of azodicarboxylic acid di-t-butyl ester is added. After heating to room temperature and stirring, the reaction mixture is concentrated and the residue is distributed between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase is dried, concentrated and the residue is chloronatographed with hexane/acetic ester (4:1) on silica gel.

0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]benzamide are obtained, MS: 474 (M + H) <+>.

b) Dissolve 972 mg of the product obtained above in 12 ml of methanol and add 0.2 g of potassium carbonate. After stirring

the reaction mixture is concentrated and the residue is distributed between methanol/water (7:3) and hexane and extracted with hexane. The hexane phase is dried and concentrated. 854 mg of methyl-(2S,3S,5S)-5-(o-carbamoylphenoxy)-2-hexyl-3-hydroxyhexadecanoate are obtained, MS: 369 (M<+>«-(o-carbamoylphenoxy)).

c) Dissolve 850 mg of the product obtained above in 12 ml of methanol/water (98:2), add 800 mg of 5% rhodium on

aluminum oxide and hydrogenated at 100°C and 100 bar hydrogen. The reaction mixture is filtered, concentrated and chromatographed on silica gel with hexane/acetic acid (1:1). 213 mg of methyl-(2S,3S,5S)-5-[[(cis)-2-carbamoyl-cyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoate (1st diastereomer) are obtained, MS: 367 [M+# -(H2NCOC6H10«+H2O) ]; 240 mg of mixture fraction and 142 mg of methyl-(2S,3S,5S)-5-[[(cis)-2-carbamoylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoate (2nd diastereomer), MS: 367 [ M<+>»~

(H2NCOC6H10«+H2O) ] .

d) Dissolve 210 mg of the 1st diastereomer obtained above in 10 ml of acetone, add 3 ml of 1N potassium hydroxide. After stirring, the reaction batch is poured onto potassium hydrogen sulphate solution and extracted with ether. The ether phase is dried and evaporated. 277 mg of (2S,3S,5S)-5-[[(cis)-2-carbamoylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoic acid (1st diastereomer), the starting acid in example 23a), is obtained. e) As described under d), the 2nd diastereomer is obtained from c) (2S,3S,5S)-5-[[(cis)-2-carbamoylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoic acid ( 2. diastereomer), the starting acid in example 23b).

Example K

a) Analogous to example Hc) from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and formic acid via

(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl formate, IR (cm"<1>): 1826, 1725, 1177, 1122, obtained (3S,4S)-3-hexyl-4-[(S)-2-hydroxytridecyl]-2-oxetanone, mp 63-64°C (from hexane).

b) 1.8 g of the hydroxy-B-lactone prepared above, 1*3 9 pyridinium p-toluenesulfonate and 2 g of molecular sieve (4Å) are stirred in 10 ml of 3,3-dimethoxypropionic acid methyl ester at 100°C under argon, then filtered off the reaction mixture, the residue is concentrated and chromatographed with ether/methylene chloride on silica gel.

1. 213 mg methyl-(E)-3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]acrylate, IR

(cm"<1>): 1827, 1714, 1643, 1622, 1192, and 2. 826 mg methyl-(R/S)-3-[[(S)-1-[[(2S,3S)-3 -hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-3-methoxypropionate (1:1 epimer mixture), IR (cm"<1>): 1824, 1743, 1438, 1117. c) 235 mg of the product from b)2. is suspended in 25 ml of 0.02N NaOH and the reaction mixture is diluted with acetone.

After stirring for 24 hours, acidify with a 5% potassium hydrogen sulphate solution and extract with ether. The ether phase is dried, concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol. 60 mg of (2S,3S,5S)-2-hexyl-3-hydroxy-5-[(R/S)-1-methoxy-2-(methoxycarbonyl)ethoxy]hexadecanoic acid are obtained, MS: 337 (M< +>«-(H20+«0-(CH30)-CH2-COOCH3). d) A solution of 58 mg of the above compound in 4 ml of condensed ammonia is heated in an autoclave at 50"C. The ammonia gas is then allowed to escape, potassium- hydrogen sulfate solution and extract with methylene chloride. The methylene chloride phase is dried and concentrated. 42.5 mg of (2S,3S,5S)-5-[(R/S)-2-carbamoyl-1-methoxyethoxy]-2-hexyl-3-hydroxyhexadecanoic acid is obtained , the starting acid from example 24.

Example L

A solution of 200 mg of the product from example Kb)l. in 10 ml of THF is hydrated with 200 mg of Pd/C (10%). It is then filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with 1% ether in methylene chloride. 99 mg of methyl-3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionate are obtained, MS: 285 (M< +>«-(<c>ii<H>23<#>))-

A suspension of 544 mg of this compound in 49 ml of 0.02N sodium hydroxide is added to 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 methylene chloride and then with 5% methanol in methylene chloride gives 43.7 mg of 3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2- oxetanyl]methyl]dodecyl]oxy]propionic acid, IR (cm"<1>): 1823, 1715, 1466, 1105, the starting acid of Example 25.

Example M

Analogous to example Cb) and c), methyl-(3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxycocosanoate (example Ib) is reacted with proparyl bromide to methyl-(2R,3R,5R)-5-(t- butyldimethylsiloxy)-3-hydroxy-2-(2-propynyl)docosanoate, IR (cm"1) : 3310, 2120, 1740, 1255, and the latter is saponified to (2R,3R,5R)-5-(t- butyldimethylsiloxy)-3-hydroxy-2-(2-propynyl)docosanoic acid, IR (cm"<1>): 3315, 2120, 1715, 1255 and is cyclized to (3R,4R)-4-[(R)-2- (t-butyldimethylsiloxy)-nonadecyl]-3-(2-propynyl)-2-oxetanone, IR (cm"<1>): 3315, 2130, 1830, 1255.

After removal of the protecting group analogously to example Be), (3R,4R)-4-[(R)-2-hydroxynona-decyl]-3-(2-propynyl)-2-oxetanone is obtained, m.p. 62-63°C (from acetic acid), the starting alcohol in example 60.

Example N

Analogous to example 1, benzyl-(S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecylmalonate, IR (cm"<1>): 1824, 1734, 1149, 1125.

A solution of 430 mg of this product in 15 ml of THF is added to 100 mg of Pd/C and then hydrated. The reaction mixture is filtered and the filtrate is concentrated. 361 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl hydrogen malonate are obtained, IR (cm"1) : 1824, 1745, the starting acid in example 2 6.

Example O

A solution of 1.96 g of the alcohol product from example M in 50 ml of ethyl acetate is hydrated with 0.25 g of 10% Pd/C, then the reaction mixture is filtered and the residue is chromatographed on silica gel with ethyl acetate/hexane. 1.44 g is obtained

(3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-propyl-2-oxetanone, m.p. 84-85°C (from ethyl acetate/hexane), the starting alcohol in Example 61.

Example P

a) From (R)-3-(t-butyldimethylsiloxy)tetradecanal (example Bb) one obtains analogously to example Ca)b)c) via

ethyl-(3R and 3S,5R)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate (epimer mixture),

ethyl-(R and S)-2-[(1R and IS,3R)-3-(t-butyldimethylsiloxy)-1-hydroxytetradecyl]-5-methyl-4-hexenoate (1:1 threo-diastereomers),

(3R,4R and 3S,4S)-4-[(R)-2-(t-butyldimethylsiloxy)tri-decyl]-3-(3-methyl-2-butenyl)-2-oxethanone (1:1 trans- diastereomers are) .

b) 6.2 ml of 40% hydrofluoric acid is added to a solution of 1.87 g of the product from a) in 50 ml of acetonitrile. After stirring, sodium bicarbonate solution is added, then extracted with methylene chloride and the methylene chloride phase is dried and concentrated. The residue is chromatographed on silica gel with 1 ethyl acetate/4.5 methylene chloride/4.5 n-hexane. Chromatography affords the starting alcohols for Examples 62-65: a 1st trans diastereomer, (3S,4S)-4-[(R)-2-hydroxy-tridecyl]-3-(3-methyl-2-butenyl)-2- oxetanone, Rf value: 0.31 and

a 2nd trans diastereomer, (3R,4R)-4-[(R)-2-hydroxy-tridecyl]-3-(3-methyl-2-butenyl)-2-oxethanone, Rf value: 0.26 (thin-layer chromatography over silica gel 5-40 p. with 1 acetate/4.5 methylene chloride/4.5 n-hexane) .

Example Q

From ethyl-(3R,5R and 3S,5R)-5-benzyloxy-3-hydroxyhexadecanoate (1:1) (example Ca) one obtains analogously to example Cb) to e) via ethyl-(2R,3R,5R and 2S,3S,5R)-5-benzyl-2-(5-chloropentyl)-3-hydroxyhexadecanoate (threodiastereomers),

a 1. trans diastereomer, (3S,4S or 3R,4R)-4-[(R)-2-(benzyloxy)tridecyl]-3-(5-chloropentyl)-2-oxetanone, Rf value: 0, 47,

and a 2nd trans diastereomer, (3R,4R or 3S,4S)-4-[(R)-2-(benzyloxy)tridecyl]-3-(5-chloropentyl)-2-oxetanone, Rf value: 0 ,28 (thin-layer chromatography over silica gel 5-40 µl with methylene chloride), the starting alcohols for examples 66-69: (3R,4R or 3S,4S)-3-(5-chloropentyl)-4-[(R)-2-hydr -oxytridecyl]-2-oxetanone, and

(3S,4S or 3R,4R)-3-(5-chloropentyl)-4-[(R)-2-hydroxytridecyl]-2-oxethanone.

Example R

From (R)-3-(t-butyldimethylsiloxy)tetradecanal (example Bb) one obtains analogously to example Cb) and c) via ethyl-(R and S,E)-2-[(1R and IS,3R)-3 -(t-butyldimethylsiloxy)-tetradecyl]-4-hexenoate (1,1-threo-diastereomers) and

(3R,4R and 3S,4S)-3-[(E)-2-butenyl]-4-[(R)-2-(t-butyldimethylsiloxy) tridecyl]-2-oxetanone (1:1 trans- diastereomers) the starting alcohols of Examples 70-73: a 1st trans diastereomer, (3S,4S or 3R,4R)-3-[(E)-2-buteny1]-4-[(R)-2-hydroxytridecyl]- 2-oxetanone, Rf value: 0.475 and

a 2nd trans diastereomer, (3R,4R or 3S,4S)-3-[(E)-2-butenyl]-4-[(R)-2-hydroxytridecyl]-2-oxetanone, Rf value: 0 ,44 (chromatography and thin-layer chromatography in over silica gel with 1 acetic acid/2 methylene chloride/2 n-hexane.

Example S

From ethyl-(3R,5R and 3S,5R)-5-benzyloxy-3-hydroxyhexadecanoate (1:1) (example Ca) one obtains analogously to example Cb) and c) via ethyl-(2R,3R and 2S ,3S,5R)-5-(benzyloxy)-3-hydroxy-2-(2,3,4,5,6-pentafluorobenzyl)hexadecanoate (threo-diastereomers) and

(3R,4R and 3S,4S)-4-[(R)-2-(benzyloxy)tridecyl]-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanone (trans-diastereomers) the starting alcohols from Examples 74-77: a 1st trans diastereomer, (3S,4S or 3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(2,3,4,5,6-pentafluorobenzyl) -2-oxetanone, Rf value: 0.43 and

a 2nd trans diastereomer, (3R,4R or 3S,4S)-4-[(R)-2-hydroxytridecyl]-3-(2,3,4,5,6-pentafluoro-

benzyl)-2-oxetanone, Rf value: 0.39 (chromatography and thin layer chromatography on silica gel with 1 acetate/4.5 methylene chloride/4.5 n-hexane).

Example T

a) A solution of 0.5 ml of diisopropylamine in 15 ml of THF is added at 0°C to 2.0 ml of a solution of 1.6M n-butyllithium in hexane and cooled after stirring to -75°C. A solution of 765 mg of N-benzyl-N-phenyl-glycine methyl ester in 3 ml of THF is then added. After stirring, a solution of 700 mg of (R)-3-(t-butyldimethylsiloxy)tetradecanal (Example Bb) in 5 ml of THF is added dropwise. After stirring at -75°C, the reaction mixture is poured onto aqueous potassium hydrogen sulphate and extracted with ether. The ether phase is dried, concentrated, distributed between hexane and methanol/water (7:3), the hexane phase is dried and concentrated and the residue is chromatographed with pentane/ether (5:1). One obtains

96.3 mg methyl-(5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer A, MS: 540 (M<+>»-C4Hg») and 142 .8 mg methyl-(5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer B, MS: 540 (M<+>«-C4H9«) and 313.4 mg of a mixture of the two above-mentioned diastereomers.

b) 134 mg of diastereomer B is suspended in 3 ml of 0.1N NaOH and enough acetonitrile is added that a

clear solution. After stirring, it is poured onto aqueous potassium hydrogen sulphate and extracted with ether, the ether phase is dried and concentrated. After chromatography on silica gel with methylene chloride/methanol (9:1), 108 mg of (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic acid, diastereomer B, MS is obtained: 526 (M+«-C4H9«) .

c) Analogously, diastereomer A is obtained from a) (5R)-2-(N-benzylanilino)5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic acid, diastereomer A, MS: 526 (M+»-C4H9#). 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 4Å are stirred in 50 ml of acetonitrile. After filtration and concentration, the product is chromatographed on silica gel with methylene chloride. 1.04 g of (3R,4R or 3S,4S)-3-(N-benzylanilino)-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxethanone, diastereomer B, MS is obtained: 566 (M+H)<+>. e) Analogously, diastereomer A is obtained from c) (3S,4S or 3R,4R)-3-(N-benzylanilino)-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2- oxetanone, diastereomer A, MS: 566 (M+H)<+. >f) 1.0 g of diastereomer B from d) and 0.8 g of Pd/C (10%) are hydrated in 30 ml of THF. It is then filtered and concentrated.

834 mg of (3R,4R or 3S,4S)-3-anilino-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxethanone, diastereomer B, MS: 475 (M<+> "). g) Analogously, diastereomer A is obtained from e) (3S,4S or 3R,4R)-3-anilino-4-[(R)-2-(t-butyldimethylsiloxy)-tridecyl]-2-oxetanone, diastereomer A, MS: 475 (M<+>»). h) Products f) and g) are converted separately analogously to Be) to (3R,4R or 3S,4S)-3-anilino-4-[(R)-2-hydroxytridecyl]-2-oxetanone, diastereomer B, m.p. 104°C or

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

The acids of formula Q<a->OH are known or can be prepared analogously to known acids, e.g. by saponification of a corresponding lower alkyl ester in a solvent, such as acetone or methanol, with an alkali metal hydroxide, such as potassium hydroxide, in an alcohol, such as ethanol or methanol. In this way, the starting acids can be prepared for

subsequent examples 2d) and 2e) as follows:

A solution of 3.8 g of 2-propylmalonamic acid ethyl ester in

30 ml of acetone is added to 22 ml of IN KOH in ethanol and stirred in

4 hours later it is concentrated, taken up in sodium bicarbonate solution and extracted with ethyl acetate. The aqueous phase is acidified at 0°C with hydrochloric acid to pH 2 and extracted with ethyl acetate. The acetate phase is washed with brine, dried, concentrated and the residue recrystallized from ethyl acetate/ether. 1.96 g of 2-propylmalonic acid monoamide is obtained, m.p. 13 70 C.

Analogously, 2-phenethylmalonamic acid, mp. 141.5°C, the starting acid for example 58-59.

The (+) and (-) 2-isopropylmalonic acid monoamide (the starting amide in example 11) can be prepared as described in the following: 5.5 g of rac-2-isopropylmalonic acid monoamide and 12.0 g of quinidine are dissolved in 100 ml of boiling water, inoculated with some crystals of the quinidine salt of (S)-(+)-2-isopropylmalonic acid monoamide and is then crystallized. The crystallisate is filtered, washed with water and ether and dried; 8.3 g of quinidine salt of (S)-(+)-2-isopropylmalonic acid monoamide are obtained.

This salt is dissolved in 10% hydrochloric acid, and it is allowed to stand at 5°C, the precipitated crystals are filtered, washed with water, dried and recrystallized once more from water while adding a few drops of IN hydrochloric acid. This gives 720 mg of (S)-(+)-2-isopropylmalonic acid monoamide, m.p. 174°C, [ot]<2>5°89 = +45.6° (ethanol, c=1) .

The mother liquor resulting from the crystallization of the quinidine salt is acidified with 10% hydrochloric acid and allowed to stand at 5°C, the precipitated crystals are filtered, washed with water, dried and recrystallized again from water with the addition of a few drops of IN hydrochloric acid. 850 mg of (R)-(-)-2-isopropylmalonic acid monoamide is obtained, m.p. 176°C, [α]<2>5°89 =-45.6°

(ethanol, c=1).

The starting acid, for example 42, can be prepared as follows: a) 20.6 g of thiomorpholine is added dropwise to a solution of 13.6 g of malonic acid methyl ester monochloride in 100 ml of methylene chloride. After stirring, the mixture is diluted with 200 ml of methylene chloride, washed in a separatory funnel with water, then dried, filtered and evaporated. The residue is purified by chromatography on silica gel with methylene chloride and then with methylene chloride/acetone (1:1). 17.6 g of methyl-tetrahydro-6-oxo-4H-1,4-thiazine-4-propionate are obtained.

b) To a solution of 17.3 g of the ester from a) in 170 ml of acetone, add dropwise 85 ml of IN potassium hydroxide. After

stirring and filtering is evaporated, the residue is stirred into 200 ml of acetone and then filtered. The filter cake is washed with acetone and dried. An aqueous solution of the resulting potassium salt is chromatographed on a cation exchange column with water. The eluate is evaporated to dryness, the residue is treated with ether and filtered. 13 g of tetrahydro-S-oxo-4H-1,4-thiazine-4-propionic acid are obtained, m.p. 119-120°C.

The starting acids, for example 44, are prepared as follows: a) To a solution of 5.6 g of methyl-1-carbamoylcyclopentanecarboxylate in 66 ml of acetone, 33 ml of 1N potassium hydroxide is added dropwise. After stirring, 250 ml of acetone is added to the mixture, the precipitated potassium salt is filtered off and then washed with acetone and dried. b) A solution of 5.79 g of potassium salt in 35 ml of water is acidified at 0°C with 4 ml of concentrated hydrochloric acid to pH 1. The precipitate is filtered off, washed with water and then with diethyl ether. After drying, 3.5 g of 1-carbamoyl-cyclopentanecarboxylic acid is obtained.

The starting acid, for example 46, can be prepared as follows: A solution of 10.4 g of methoxymalonic acid monomethyl ester in 70 ml of methylene chloride is added dropwise at -10 °C to 26 ml of 25% aqueous ammonia. After stirring, the mixture is evaporated, the residue is dissolved in water and chromatographed on a cation exchanger with water. The eluate is concentrated, the residue is treated with diethyl ether and filtered off. The precipitate is washed with ether and dried. 8.9 g of methoxymalonamide acid are obtained, m.p. 128-130°C.

The starting acid for example 49 can be prepared as follows: A solution of 1.79 g of carbamoylmethylthioacetic acid in 42 ml of water is added to 3.71 g of monoperoxyphthalic acid magnesium salt hexahydrate. After stirring, it is filtered off, the filtrate is concentrated and acidified with 2 ml of concentrated 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 slurried with acetone and filtered off. Wash with acetone and dry. 1.65 g of rac-[(carbamoylmethyl)sulfinyl]acetic acid is obtained, m.p. 137-138°C.

The lower alkyl esters corresponding to the acids of formula Q<a->OH are known or can be prepared in analogy with the known esters, e.g. as described in the following starting from the monoester with the formula H-(X)n-COOR", where R" is lower alkyl, over the dicarboxylic acid monoester with the formula HOCO-(X)n-COOR". Thus, the starting acid can be prepared, for example 2f) as follows: a) To 11 ml of diisopropylamine and 5 g of 4Å molecular sieve in 75 ml of THF, 48 ml of a 1.6M n-butyllithium solution in hexane is added dropwise at -15° C. After 15 minutes, the reaction mixture is cooled to -78° C and added dropwise to a solution of 9.5 g of ethyl 1,3-dioxolane-2-carboxylate in 50 ml of THF. After 20 minutes of stirring, CO 2 is introduced at a temperature below -70° C. After saturation, stir for 20 minutes at -75"C and then heated to room temperature. After evaporation of the CO2 gas, the reaction mixture is concentrated, the residue is added to saturated bicarbonate solution and vinegar, the vinegar phase is discarded, the water phase is acidified with potassium hydrogen sulfate to pH 2 and extracted with vinegar. The acetic ester phase is dried and concentrated.

b) To a solution of 1.08 g of the product from a), 1.1 ml of triethylamine and 3 g of molecular sieve 4Å in 30 ml of THF are added

dropwise at 0°C 0.93 ml chloroformate isobutyl ester in 5 ml THF. After 40 minutes of stirring, ammonia gas is introduced for 10 minutes and the reaction mixture is then stirred overnight. After this, it is filtered, the filtrate is concentrated, and the residue is chromatographed on silica gel with methylene chloride/methanol (95:5). 420 mg of ethyl 2-carbamoyl-1,3-dioxolane-2-carboxylate are obtained, m.p. 99-100"C.

c) A solution of 190 mg of the product from b) in 10 ml of methanol is added to 1 ml of 2N KOH in methanol and stirred for 90

minutes at room temperature. A solution of 280 mg of potassium hydrogen sulphate in 1 ml of water is then added, the reaction mixture is filtered, and the filtrate is evaporated. 2-carbamoyl-1,3-dioxolane-2-carboxylic acid is obtained.

Analogously, 2-carbamoyl-m-dioxane-2-carboxylic acid (the starting acid of example 3m) is obtained from ethyl m-dioxane-2-carboxylate.

The acids with the formula (R<3>,R<4>)NCO(X)n-COOH, where X is a group =CHN(R,R°), can be prepared starting from the corresponding dicarboxylic acid monoester with the formula HOCO-X- COOR" over a corresponding succinimide and the corresponding amide ester of formula H2NCO-X-COOR", e.g. as described below for the starting acid in example 9.

a) To 54 ml of THF are added at 0°C 4.54 g of dicyclohexylcarbodiimide, 4.16 g of acetamino-monoethylmalonate and

2.53 g of N-hydroxysuccinimide. After stirring for 1 hour, the solution is allowed to warm to room temperature and stirred overnight. The solution is then cooled to 0"C and filtered. 20 ml of a 25% aqueous ammonia solution is added to the filtrate,

and it can stand all day at room temperature and overnight at 4°C. The solution is then evaporated, sodium bicarbonate is added to the remaining aqueous solution. The aqueous phase is separated, the organic phase is washed with saturated 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. 1.2 g of [D,L]-N-acetyl-2-carbamoylglycine ethyl ester is obtained, m.p. 126-128°C.

b) To a suspension of 1.09 g of the amide ester from a) in 7 ml of acetone, add dropwise a solution of 5.8 ml of IN

kalilut. After stirring for 3 hours, the mixture is concentrated, and the residue is dissolved in aqueous sodium bicarbonate solution. The solution is extracted with ethyl acetate, the aqueous phase is acidified under cooling with hydrochloric acid to pH 3 and then percolated over an ion exchanger. The eluate is concentrated to dryness, and the residue is treated with acetone. 500 mg of [D,L]-N-acetyl-2-carbamoylglycine is obtained, m.p. 120°C (decomposition).

The starting acid with the formula (R<3>,R<4>)NCO(X)n-COOH, where at least one of R<3> and R<4> is different from H, can be prepared by reacting the corresponding acid ester with formula HOC(O)-(X)n-C(O)O-R" with an amine HN(R<3>,R<4>).

One can prepare the starting acid, for example 10d) as

following:

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

The oxetanones of formula I have valuable pharmacological properties. They particularly inhibit pancreatic lipase and can therefore be used to combat or prevent obesity, hyperlipaemia, atherosclerosis and arteriosclerosis.

The inhibition of pancreatic lipase by the oxetanones of formula I can be shown experimentally, by titrimetrically determining the oleic acid released by the cleavage of triolein by porcine pancreatic lipase. To an emulsion containing 1 mM taurodeoxycholate, 9 mM taurocholate, 0.1 mM cholesterol, 1 mM Eilezithin, 15 mg/ml BSA, 2 mM tris-HCl, 100 mM sodium chloride, 1 mM calcium chloride and the substrate triolein, one adds the compound of formula I dissolved in ethanol or dimethylsulfoxide (10% of the emulsion volume) and starts the reaction by adding 1-3 µg of porcine pancreatic lipase. The pH value is maintained during the reaction by adding caustic soda at 8. The IC50 value is calculated from the consumption of caustic soda obtained during 10 minutes. The IC50 value is the concentration at which the lipase activity is inhibited by 50%. The following table contains the IC50 values in µg/ml obtained for the compounds of formula I.

The acute toxicity (after a single oral administration to mice) amounts to more than 5000 mg/kg for the products of examples 3d, 3h, 3i, 31, 4a and 10a, b, e and f.

The oxetanones of formula I can be used as medicine, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, lacquer tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.

For the production of pharmaceutical preparations, the products of the invention can be administered with pharmaceutically inert,

inorganic or organic carriers. Such carriers can be used for tablets, varnish tablets, dragées and hard gelatin capsules, e.g. lactose, corn starch or derivatives thereof, talc, stearic acid or its salts. Soft gelatin capsules are suitable as carriers, e.g. vegetable oils, waxes, fats, semi-fats and liquid polyols; however, depending on the nature of the active ingredient, no carrier is necessary in soft gelatin capsules. For the production of solutions and

syrups are suitable that carry e.g. water, polyols, sucrose, invert sugar and glucose.

The pharmaceutical preparations may also contain preservatives, solvents, stabilizers, humectants, emulsifiers, sweeteners, dyes, flavorings, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They may also contain therapeutically valuable substances.

As mentioned, the compounds of formula I can be used in combating or preventing diseases and thus in particular in combating or preventing obesity, hyperlipemia, atherosclerosis and arteriosclerosis. The dosage can vary within wide limits and must of course be adapted in each individual case to the individual circumstances. In general, with oral administration, a daily dose of approx. 0.1 mg to 100 mg/kg body weight may be appropriate.

The following examples shall illustrate the present invention in more detail. All temperatures are given in degrees Celsius.

Example 1

To a solution of 574 mg of (3S,4S)-3-ethyl-4-[(R)-2-hydroxy-nonadecyl]-2-oxetanone, 525 mg of triphenylphosphine, 290 mg of 2-isopropylmalonic acid monoamide and 2 g of molecular sieve (4Å) in 10 ml of THF, 0.4 ml of azodicarboxylic acid diisopropyl ester is added while stirring at 0°. After stirring for 30 minutes at 0° and one hour at room temperature, 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 evaporated. The residue is chromatographed with methylene chloride/ether (9:1) on silica gel. One obtains a) 239 mg of (S)-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-octadecyl-(R or S)-2-isopropyl malonate, m.p. 115° and b) 266 mg of (S)-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-octadecyl-(S or R)-2-isopropylmalonate, m.p. 118°.

Example 2

Analogous to example 1, one obtains from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2-isopropylmalonic acid monoamide

a) (S)-1-[[(2S,3S)-3-hexyl-4-oxo)-2-oxetanyl]methyl]-dodecyl-(R or S)-2-isopropylmalonate, m.p. 136° and b) (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl-(S or R)-2-isopropylmalonate, m.p. 82°; c) from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and isopropylidenemalonic acid monoamide one obtains (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 one obtains (S)-1-[[(2S,3S)-3- hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(RS)-2-carbamoylvalerate (epimers 1:1), m.p. 92-94°; e) from (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone and 2-propylmalonic acid monoamide one obtains (S)-1-[[(2S,3S)-3- ethyl 4-oxo-2-oxetanyl]methyl]octadecyl-(RS)-2-carbamoyl valerate (epimers 1:1), m.p. 78-80°; f) from (3S,4S)-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone and 2-carbamoyl-1,3-dioxolane-2-carboxylic acid one obtains

(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-2-carbamoyl-1,3-dioxolane-2-carboxylate, m.p. 95°;

g) of (3S,4S)-3-ethyl-4-[(R,10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone and 2-isopropylmalonic acid monoamide

was obtained

1. (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl-(R or S)-2-isopropyl malonate,

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-isopropyl malonate, IR: 3393, 1840, 1716, 1647, 1185 cm"<1>.

Example 3

Analogous to example 1, the reaction of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone with the following amides yields the following ester amides: a) with 4-carbamoylbutyric acid, 4- carbamoylbutyric acid-(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 67-68°, b) with 3-carbamoylpropionic acid 3-carbamoylpropionic acid (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl ester is obtained, m.p. 50.5-51°, c) with 2-carbamoylacetic acid gives 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 gives (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyloxamate, m.p. 77-78°, e) with methylcarbamoylacetic acid yields (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-N-methylmalonate, m.p. 63-67°, f) with rac-2-carbamoyl-4-methylvaleric acid yields (S)-1- [[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(RS )-2-carbamoyl-4-methylvalerate (epimers 1:1), m.p. 102-104°, g) with 1-carbamoylcyclohexanecarboxylic acid yields (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-1-carbamoylcyclohexanecarboxylate, m.p. 50-52°, h) with 2,2-dimethylmalonamic acid yields (S)-1-[[(2S,3S)-3-hexy1-4-oxo-2-oxetanyl]methyl]dodecyl-2,2-dimethyl- malonamate, [a]<2>D° = -23.8° (CHC13, c = 0.9%), i) with rac-2-methylmalonamic acid yields (S)-1-[[(2S,3S)- 3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(RS)-2-methylmalon-amate (epimers 1:1), m.p. 107-108°, j) with rac-2-ethylmalonamic acid yields (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(RS)-2- ethyl malonate (epimers 1:1), m.p. 87-90°, k) with rac-2-butylmalonamic acid yields (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(RS)-2- butyl malonate (epimer 1:1), m.p. 96-98°, 1) with 2,2-diethylmalonamic acid yields (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-2,2-diethyl- malonamate, [a]2D° =-21.1° (CHC13, c = 1%),

m) with 2-carbamoyl-m-dioxane-2-carboxylic acid yields (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-2-carbamoyl-m -dioxane-2-carboxylate, m.p. 51°.

Example 4

Analogous to example 1, from (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone and

a) from 1-carbamoylcyclohexanecarboxylic acid obtained (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl-1-carbamoylcyclohexanecarboxylate, m.p. 78-79° and b) from 2-carbamoyl-m-dioxane-2-carboxylic acid obtained (S)-1- [[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl- 2-carbamoyl-m-dioxane-2-carboxylate, m.p. 79°.

Example 5

Analogously to example 1, one obtains from ((3R,4R or 3S,4S)-4-[(R)-2-hydroxytridecyl]-3-pentylthio-2-oxethanone and 2-isopropylamino acid amide

a) (S)-1-[[(2R,3R or 2S,3S)-4-oxo-3-pentylthio-2-oxe-tanyl]methyl]dodecyl-(R or S)-2-isopropylmalonate, MS: 354 [M<+>«-(2-isopropylmalonic acid amide)]; IR (cm"<1>): 3397, 2924, 1829, 1731, 1657, 1120 and b) (S)-1-[[(2R,3R or 2S,3S)-4-oxo-3-pentylthio-2 -oxe-tanyl] methyl] dodecyl-(S or R)-2-isopropylmalonamate, m.p.

77-78° (diethyl ether).

Example 6

Analogous to example 1, one obtains from (3S,4S or 3R,4R)-4-[(R)-2-hydroxytridecyl]-3-pentylthio-2-oxethanone and 2-isopropylmalonic acid amide a) (S)-1-[[ (2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxe-tanyl]methyl]dodecyl-(R or S)-2-isopropylmalonate, m.p.

133° (ethyl acetate) and

b) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxe-tanyl]methyl]dodecyl-[S:R or R:S (2:1 )]-2-isopropyl malonate, m.p. 102-104° (ethyl acetate).

Example 7

Analogous to example 1, an epimer mixture is obtained from (3R,4R)-3-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2-isopropylmalonic acid monoamide, which is separated by chromatography on silica gel with ethyl acetate /hexane/methylene chloride (1:2:2) to a) (S)-1-[[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl- (R or S )-2-isopropyl malonate, m.p. 85-87° (methylene chloride) and b) (S)t(2R/3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl-(S or R)-2-isopropylmalonate, m.p. 108-110° (methylene chloride) .

Example 8

Analogous to example 1, an epimer mixture is obtained from (3S,4S)-3-benzyl-4-t(R)-2-hydroxytridecyl]-2-oxetanone and 2-isopropylmalonic acid monoamide, which by chromatography on silica gel with ethyl acetate/hexane/methylene chloride (1:2:2) are separated into

a) (S)-1-t(2S,3S)-3-benzyl-4-oxo-2-oxetanyl]methyl]-dodecyl-(R or S)-2-isopropylmalonate, m.p. 107-108°

(methylene chloride) and

b) (S)-1-t[(2S,3S)-3-benzyl-4-oxo-2-oxetanyl]methyl]-dodecyl-(S or R)-2-isopropylmalonate, m.p. 148-149°

(methylene chloride).

Example 9

To a -10°C cooled suspension of 1.06 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxethanone, 480 mg of [D,L]-N- acetyl-2-carbamoylglycine, 1.1 g of triphenylphosphine and 1.2 g of molecular sieve (4Å) in 12 ml of THF is added to 1.03 g of azodicarboxylic acid di-t-butyl ester. After stirring for 1 hour at 0°C and overnight at room temperature, the reaction mixture is processed as described in example 1. One obtains a) 190 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2 -oxetanyl]-methyl]dodecyl-(R or S)-2-acetamidomalonate, m.p. 125-126° and b) 100 mg (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-(RS)-2-acetamidomalonate (epimer 1 :1),

m.p. 110-116°, [α]<2>D<5> = -8° (c = 0.5, CHCl 3 ).

Example 10

Analogously to example 1, however, using the following amides, the following ester amides are obtained: a) from oxalic acid monoamide, (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyloxamate is obtained, m.p. . 99-100°, b) from carbamoylacetic acid yields (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecylmalonate, m.p. 90.5-91.5°, c) from methylcarbamoylacetic acid yields (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl-N-methylmalonate, m.p. 84-85°, d) from dimethylcarbamoylacetic acid yields (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl-N,N-dimethyl-malonate, m.p. 66-67°, e) from rac-2-methylmalonamic acid yields (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl-(RS)-2- methylmalon-amate (epimers 1:1), m.p. 91.5-92°, f) from 3-carbamoylpropionic acid yields (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl-succinamate, m.p.

74.5-75.7°.

Example 11

Analogous to example 1, however using (S)-(+)-respectively. (±)-2-isopropylmalonic acid monoamide, one obtains a) (S)-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octa-decyl-(R)-2-isopropylmalonate, m.p. 115° and b) (S)-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octa-decyl-(S)-2-isopropylmalonate, m.p. 118°.

Example 12

Analogously to examples 1, 2a) b) and 11, one obtains from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and (±)- respectively. (S)-(+)-2-isopropylmalonic acid monoamide

a) (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(R)-2-isopropylmalonate, m.p. 136° or b) (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. 82°; c) from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2-propylmalonic acid monoamide is obtained after chromatographic separation on silica gel with methylene chloride/acetonitrile (85:15) 1 (S)-1-[[(2S,3S)-3-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 -carbamoyl valerate, m.p. 85°.

Example 13

Analogously to examples 1, 2g) and 11, one obtains from (3S,4S)-3-ethyl-4-[(R,10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone and (± ) - respectively (S)-(+)-2-isopropylmalonic acid monoamide

a) (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl-(R)-2-isopropylmalonate, m.p. 87-88°

(from ether) and

b) (all Z,S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl-(S)-2-isopropylmalonate, m.p. 109°

(from aqueous methanol).

Example 14

Analogously to examples 1, 6 and 11, one obtains from (3S,4S or 3R,4R)-4-[(R)-2-hydroxytridecyl]-3-pentylthio-2-oxetanone and (±)- respectively. (S)-(+)-2-isopropylmalonic acid amide

a) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxe-tanyl]methyl]dodecyl-(R)-2-isopropylmalonate, m.p. 133°

(ethyl acetate),

b) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxe-tanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. 93°

(diethyl ether/hexane) and

c) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxe-tanyl]methyl]dodecyl-[S:R (2:1)]-2 -isopropyl malonate, m.p.

102-104° (ethyl acetate).

Example 15

Analogous to examples 1 and 11, from (3S,4S or 3R,4R)-benzyl-4-[(R)-2-hydroxytridecyl]-2-oxo-3-oxetane-carbamate and (S)-(+) -2-isopropylmalonic acid monoamide obtained

(S)-1-[[(2S,3S or 2R,3R)-3-[1-(benzyloxy)formamido]-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. 133° (from ether/hexane).

Example 16

It was analogous to examples 1 and 11

a) of (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone and (S)-(+)-2-isopropylmalonic acid monoamide obtained

(S)-1-[[(2R,3R)-4-oxo-3-(phenylthio)-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. 88° (ether), b) from (3S,4S)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone and 2-isopropylmalonic acid monoamide obtained (S)-1-[[( 2S,3S)-4-oxo-3-(phenylthio)-2-oxetanyl]methyl]dodecyl-(RS)-2-isopropylmalonate (1:1 epimer), m.p. 109° (ether), c) of (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone and 2-isopropylmalonic acid monoamide obtained the same

product as under a) and (S)-1-[[(2R,3R)-4-oxo-3-(phenylthio)-2-oxetanyl]methyl]dodecyl-2-isopropylmalonate (R:S = 7:1) , m.p. 85° (ether).

Example 17

Analogous to examples 1 and 11, the following esters were prepared from (S)-(+)-2-isopropylmalonic acid monoamide and from the following alcohols: a) from (3S,4S or 3R,4R)-4-[(R)-2- hydroxynonadecyl]-3-(methylthio)-2-oxetanone was obtained by (S)-1-[[(2S,3S or 2R,3R)-3-(methylthio)-4-oxo-2-oxetanyl]methyl]octadecyl- (S)-2-isopropyl malonate, m.p. 133° (from ether), b) from (3R,4R or 3S,4S)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxethanone one obtained (S)-1-[ [(2R,3R or 2S,3S)-3-(methylthio)-4-oxo-2-oxetanyl]methyl]octadecyl-(S)-2-isopropylmalonate, m.p. 103° (from ether),

c) from (3S,4R or 3R,4S)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxethanone one obtained (S)-1-[[(2R,3S or

2S,3R)-3-(methylthio)-4-oxo-2-oxetanyl]methyl]octadecyl-(S)-2-isopropylmalonate, m.p. 96° (from ether/hexane),

d) from (3R,4S or 3S,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxethanone one obtained (S)-1-[[(2S,3R or

2R,3S)-3-(methylthio)-4-oxo-2-oxetanyl]methyl]octadecyl-(S)-2- isopropyl malonate, m.p. 120° (from ether/hexane).

Example 18

Analogous to examples 1 and 11, from (R)-(-)-2-isopropylmalonic acid monoamide and a) from (3S,4S or 3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio )-2-oxetanone obtained (S)-1-[[(2S,3S or 2R,3R)-3-(methylthio)-4-oxo-2-oxetanyl]methyl]octadecyl-(R)-2-isopropylmalonamate, m.p. 96° (from ether), b) from (3R,4R or 3S,4S)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxethanone obtained (S)-1-[[ (2R,3R or 2S,3S)-3-(methylthio)-4-oxo-2-oxetanyl]methyl]octadecyl-(R)-2-isopropylmalonate, m.p. 87° (from ether/hexane).

Example 19

Analogous to examples 1 and 11, the following esters were prepared from (S)-(+)-2-isopropylmalonic acid monoamide and from the following alcohols: a) from (3S,4S or 3R,4R)-3-(benzylthio)-4-[ (R)-2-hydroxytridecyl]-2-oxetanone gave (S)-1-[[(2S,3S or

2R,3R)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-

isopropyl malonate, m.p. 84° (from pentane),

b) from (3R,4R or 3S,4S)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxethanone one obtained (S)-1-[[(2R,3R or

2S,3S)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. 65° (from ether/pentane),

c) from (3S,4R or 3R,4S)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxethanone was obtained

1. (S)-1-[[(2S,3R or 2R,3S)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. 69°

(from pentane) and

2. (S)-1-[[(2R,3S or 2S,3R)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. 106°

(from hexane).

Example 20

Analogously to examples 1 and 11, the following esters were obtained from (R)-(-)-2-isopropylmalonic acid monoamide and the following alcohols: a) of (3S,4S or 3R,4R)-3-(benzylthio)-4-[ (R)-2-hydroxytridecyl]-2-oxetanone gave (S)-1-[[(2S,3S or 2R,3R)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl] dodecyl-(R)-2-isopropylmalonate, m.p. 130° (from ether/pentane), b) from (3R,4R or 3S,4S)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-oxethanone one obtained (S) -1-[[(2R,3R or 2S,3S)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(R)-2-isopropylmalonate, m.p. 119° (from hexane/pentane), c) from (3S,4R and 3R,4S)-3-(benzylthio)-4-[(R)-2-hydroxy-tridecyl]-2-oxethanone 1 was obtained. ( S)-1-[[(2S,3R or 2R,3S)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(R)-2-isopropylmalonate, m.p. 132°

(from ether/pentane),

2. (S)-1-[[(2R,3S or 2S,3R)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl-(R)-2-isopropylmalonate, m.p. 102°

(from ether/pentane).

Example 21

Analogous to examples 1 and 11, by reaction of (3R,4R)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone a) with (S)-(+)-2-isopropylmalonic acid monoamide obtained (S)-1-[[(2R,3R)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl-(S)-2-isopropylmalonate, m.p. 116-118° (methylene chloride), b) with 1-carbamoylcyclohexanecarboxylic acid obtained (S)-1-[[(2R,3R)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl-1-carbamoylcyclohexanecarboxylate, m.p. . 71-74°.

Example 22

It was analogous to examples 1 and 11

a) from (S)-(+)-2-isopropylmalonic acid monoamide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-methyl-2-oxetanone obtained (S)-1-[[( 2R,3R)-3-methyl-4-oxo-2-oxetanyl]methyl]octadecyl-(S)-2-isopropylmalonoamate, m.p. 124-126° (from acetic ester/hexane), b) from rac-2-t-butylmalonic acid monoamide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-methyl-2-oxethanone obtained (S )-1-[[(2R,3R)-3-methyl-4-oxo-2-oxetanyl]methyl]octadecyl-(RS)-2-t-butylmalonamate (epimers 1:1), m.p. 51-54° (acetic ester/- hexane).

Example 23

A solution of 277 mg of (2S,3S,5S)-5-[[(cis)-2-carbamoylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoic acid (Example Jd) in 24 ml of methylene chloride and 3 ml of DMF is added 2 g molecular sieve (4Å), 240 mg HBTU and 240 ml triethylamine. After stirring, 300 mg of HBTU and 300 mg of triethylamine are added. It is then filtered and the filtrate is concentrated. The residue is distributed between methanol/water (7:3) and hexane and extracted with hexane. The hexane phase is diluted with methylene chloride, dried and concentrated and the residue is recrystallized from ether/hexane. This yields a) 96 mg of (IR or S,2S or R)-2-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ]oxy]cyclohexanecarboxamide (1st cis-diastereomer), m.p. 102° (from ether/-hexane); b) analogously, from (2S,3S,5S)-5-[[(cis)-2-carbamoyl-cyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoic acid (2.

diastereomeric acid) in example Je) obtained (IS or R,2R or S)-2-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl ]dodecyl]oxy]cyclohexanecarboxamide (2nd cis-diastereomer), m.p. 94° (from ether/hexane).

Example 24

A solution 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 methylene chloride/acetonitrile (1:1) 1 g molecular sieve (4Å), 0.1 ml triethylamine and 50 mg HBTU are added. After stirring, the reaction mixture is filtered, concentrated and the residue distributed between hexane and methanol/water (1:1); the aqueous methanolic phase is extracted with hexane, the hexane phase is dried and concentrated; then the residue is chromatographed on silica gel with 5% methanol in methylene chloride. This gives 21 mg of (R/S)-3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-3- methoxypropionamide (epimers 3:1), m.p. 54°.

Example 25

In a solution of 40 mg of 3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionic acid (Example L) in 2, 5 ml of acetonitrile is blown in with ammonia gas to saturation and then 50 mg of HBTU is added. It is then filtered and evaporated and the residue is chromatographed with 5% methanol in methylene chloride. 32.5 mg of (3S,4S)-4-[(S)-2-(2-carbamoylethoxy)tridecyl]-3-hexyl-2-oxetanone are obtained, 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 added to 60 mg of HBTU and 75 mg of isopropylamine. After stirring, the reaction mixture is filtered off, the filtrate is concentrated and the residue is chromatographed on silica gel with hexane/methylene chloride/ethyl acetate (2:2:1). 31.1 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl-N-isopropylmalonate are obtained, m.p. 59°.

In an analogous manner to that described in example 1, the following compounds were prepared: Example 27: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-5-carbamoyl valerianate , m.p. 50-51°, 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-carbamoyl nonanoate, 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-4-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-2-oxetanyl]-methyl]dodecyl-(R or S)-2 -t-butylmalonate, mp 53-54°, Example 35: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-(S or R )-2-t-butyl malonate, [ct]2D° = -16.4° (c = 0.8, CHCl 3 ),

Example 36: (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-(R or S)-2-t-butylmalonate, m.p. 48-49°,

Example 37: (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-(S or R)-2-t-butylmalonate, m.p. 81-82°,

Example 38: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-(S)-3-[1-(benzyloxy)formamido]succinamate, m.p. 72-73°,

Example 39: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]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-carbamoylcyclohexanecarboxylate, m.p. 76-77°,

Example 41: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-6-oxo-4-morpholine propionate, m.p. 49-51°, Example 42: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-tetrahydro-6-oxo-4H-1,4 -thiazir-4-propionate, m.p. 59-61°,

Example 43: (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-1-carbamoylcyclopentanecarboxylate, m.p. 62-63°,

Example 44: (S)-1-[[(2S,2S)-3-hexyl-4-oxo-4-oxetanyl]-methyl]dodecyl-1-carbamoylcyclopentanecarboxylate, m.p. 40-41°,

Example 45: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-(RS)-2-benzylmalonomate (epimer 1:1), m.p. 86-92°,

Example 46: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-(RS)-2-methoxymalonate (epimer 1:1), m.p.

65-67°,

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-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-[(carbamoylmethyl)thio]acetate, m.p. 83-84°, Example 49: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-[(RS)-(carbamoylmethyl)sulfinyl]acetate (epimers 1:1), m.p. 55-59°,

Example 50: (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-[(RS)-(carbamoylmethyl)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°,

Example 52: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-3-[(RS)-(2-carbamoylethyl)sulfinyl]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-isobutylmalonate (epimer 1:1), m.p. 96-99°,

Example 57a) : (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-(RS)-2-benzylmalonamate (epimers 1:1), m.p. . 96-103°,

Example 57b^ : (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-(R or S)-2-benzylmalonate, m.p. 118-120°,

Example 58: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]-methyl]dodecyl-(RS)-2-phenethylmalonate (epimer 1:1), m.p. 92-93°,

Example 59: (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]-methyl]octadecyl-(RS)-2-phenethylmalonate (epimer 1:1), m.p. 97-98°.

Example 60

Analogous to examples 1 and 11, from (S)-(+)-2-isopropylmalonic acid monoamide and (3R,4R)-4-[(R)-2-hydroxynonadec-yl]-3-(2-propynyl)-2 -oxetanone (Example M) obtained (S)-1-[[(2R,3R)-4-oxo-3-(2-propynyl)-2-oxetanyl]methyl]octadecyl-(S)-2-isopropylmalonate, m.p. . 92-95°C (from acetic acid/hexane).

Example 61

Analogous to examples 1 and 11, (S)-(+)-2-isopropylmalonic acid monoamide and (3R,4R)-4-[(R)-2-hydroxynona-decyl]-3-propyl-2-oxetanone (example 0) obtained (S)-1-t[(2R,3R)-4-oxo-3-propyl-2-oxetanyl]methyl]octadecyl-(S)-2-isopropylmalonate, m.p. 90-93° (from acetic acid/hexane).

In an analogous manner to that described in examples 1 and 11, the following compounds were prepared: Example 62: (S)-1-[[(2S,3S)-3-(3-methyl-2-butenyl)-4-oxo-2 -oxetanyl]methyl]dodecyl-(R or S)-2-isopropylmalonate, 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-isopropyl malonate , m.p. 120-121°,

Example 64: (S)-1-[[(2R,3R)-3-(3-methyl-2-butenyl)-4-oxo-2-oxetanyl]methyl]dodecyl-(R or S)-2-isopropyl malonate , 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-isopropylmalonate , m.p. 76-78°,

Example 66: (S)-1-[[(2S,3S or 2R,3R)-3-(5-chloropentyl)-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. . 66-72°,

Example 67: (S)-1-[[(2S,3S or 2R,3R)-3-(5-chloropentyl)-4-oxo-2-oxetanyl]methyl]dodecyl-(R)-2-isopropylmalonate, m.p. . 130°,

Example 68: (S)-1-[[(2R,3R or 2S,3S)-3-(5-chloropentyl)-4-oxo-2-oxetanyl]methyl]dodecyl-(S)-2-isopropylmalonate, m.p. . 44-50°,

Example 69: (S)-1-[[(2R,3R or 2S,3S)-3-(5-chloropentyl)-4-oxo-2-oxetanyl]methyl]dodecyl-(R)-2-isopropylmalonate, 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-isopropyl malonate, 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- isopropyl malonate, m.p. 96-98°,

Example 72: (S)-2-(2R,3R or 2S,3S)-[[3-[(E)-2-butenyl]-4-oxo-2-oxetany]methyl]dodecyl-(S)-2 -isopropyIma1onamate, 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 -isopropyl malonate, 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 -isopropyl malonate, 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 -isopropyl malonate, 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 -isopropyl malonate, m.p. 88-90°,

Example 77: (S)-1-[[(2S,3S or 2R,3R)-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanyl]methyl]dodecyl-(S)-2 -isopropyl malonate, m.p. 52-55°.

Example 78

Analogously to examples 1 and 2, however, using (R)-or (S)-2-pyrrolidone-5-carboxylic acid instead of 2-isopropylmalonic acid monoamide, one obtains

a) 5-oxo-D-proline-(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, <1>H-NMR (CDC13) : 0.88 (m, 6H); 1.26 (m, 26H); 1.55-1.9 (m, 4H); 1.95-2.55 (m, 6H); 3.21 (m, 1H); 4.25 (m,1H); 4.31 (m,1H); 5.14 (m, 1H); 5.80 (S,1H) ppm. , b) 5-oxo-L-proline-(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 51-52°, c) 5-oxo-D-proline-(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxet-nyl]methyl]octadecyl ester, m.p. 55° (diethyl ether), d) 5-oxo-L-proline-(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester, m.p. 57-58°.

Example 79

Analogous to examples 1 and 11, from (S)-(+)-2-isoprop-ylmalonic acid and a) from (3R,4R or 3S,4S)-3-anilino-4-[(R)-2-hydroxytri -decyl]-2-oxetanone, diastereomer B (Example T) obtained (S)-1-[[(2R,3R or 2S,3S)-3-anilino-4-oxo-2-oxetanyl]methyl]-dodecyl- (S)-2-isopropyl malonate (diastereomer B), m.p.

92°, and

b) of (3S,4S or 3R,4R)-3-anilino-4-[(R)-2-hydroxytridecyl]-2-oxetanone, diastereomer A (Example T) obtained (S)-1-[[ (2S,3S or 2R,3R)-3-anilino-4-oxo-2-oxetanyl]methyl]-dodecyl-(S)-2-isopropylmalonate (diastereomer A), m.p.

77°.

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

Example A

Soft gelatin capsules:

Quantity per capsule

Example B

Hard gelatin capsules:

Example C Tablets:

Example D

Tablets with controlled active ingredient release and increased retention time in the stomach:

Example E

Claims (6)

1. Analogy method in the preparation of therapeutic active oxetanones of formula I where Q is a group of the formula R<1> is (C 1 -C 8 )alkyl optionally substituted with halogen; straight or branched (C 2 -C 6 )alkenyl; (C 2 -C 4 )-alkynyl; -SO; benzyl optionally substituted with 1-5 halogen atoms on the benzene ring; -NHC(=0)OR' or anilino, where A = (C-L-C8)alkyl, phenyl or benzyl R<1> = benzyl R 2 is (C 6 -C 18 )alkyl, (C 6 -C 18 )alkenyl or alkadienyl, R<3> and R<4> are hydrogen or C1-C4alkyl/ or they form together with the N atom to which they are attached, morpholine or thiomorpholine, n is the number 1 or 0, X is an alkylene group interrupted by an O or S atom or by a sulfinyl or sulfonyl group, containing up to 8 C atoms, or X is branched or unbranched (C 1 -C 8 )alkylene optionally substituted with phenyl or (C 1 -C 4 ) alkoxy; (c2~c4)alkenylene; =CHNHC(=O)CH 3 ; <=>CHNHC(=O)CH2C6<H>5; -CHNH(C(=O)OR')CH2-; or and X' is (C-1-C4)alkylene optionally substituted with (C 1 -C 4 ) alkoxy; or characterized in that one a) esterifies an alcohol with formula with an acid of formula Q<a->OH, where Q<a> is a group of formula Q<1> or Q<3>, or b) cyclizes an acid of formula (Q-0,R2)CHCH2CH(OH)CH(R<1>)-COOH Ilb or c) in an acid of formula where T is a group of formula HOCO(X)n-CO- T<1 >or HOCO-X<»->T2 converts the carboxy group in the group T into an amide group (R<3>,R<4>)NCO-, and d) separates, if desired, a epimer mixture with formula I in the individual epimers. 2. Method according to claim 1, where R<1> is methyl, ethyl, propyl hexyl, 2-butenyl, 3-methyl-2-butenyl, 2-propynyl, methylthio, pentylthio, 5-chloropentyl, benzyl, phenylthio, benzylthio, pentafluorobenzyl, anilino or benzyloxycarbonylamino, R<2> is undecyl, heptadecyl or 8,11-heptadecadienyl, R<3> and R<4> are hydrogen, methyl or isopropyl, or together with the N atom they form a morpholino or thiomorpholino group , n is the number 1 or 0, and X is the group (CH2) 1. 8, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopentylidene, t-butylmethylene, dimethylvinylidene, cyclopentylidene, cyclohexylidene, phenethylidene, phenylpropylidene, 1,2 -cyclohexylene, cyclohex-3,4-en-1,6-ylene, acetamidomethylene, benzyloxycarbonylaminomethylene, 1-benzyloxycarbonylamino-1,2-ethylene, methyleneoxymethylene, methylenethiomethylene, methylenesulfinylmethylene, ethylenethioethylene, ethylenesulfinylethylene, methoxymethylene or ethylene or propylenedioxymethylene, characterized by that the corresponding output is used gs materials. 3. Process according to claim 1, where R<1> is hexyl, R<2> is undecyl and X<1> is ethylene, 1-methoxy-1,2-ethylene or 1,2-cyclohexylene, characterized in that it is used corresponding starting materials. 4. Method according to claim 1, where Q is a group Q<3>; R<3> is hydrogen, R<1> is hexyl, and R2 is undecyl, characterized in that corresponding starting materials are used. 5. Process according to claim 1 in the preparation of: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(S)-2-isopropylmalonate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(S or R)-2-carbamoyl valerate, (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-isopropylmalonate, (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]octa - decyl-(S or R)-2-t-butylmalonamate, (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octa- decyl-l-carbamoylcyclopentanecarboxylate, (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(RS)-2-benzylmalonamate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-3-[(2-carbamoylethyl)thio]propionate, 5-oxo-D-proline-(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxe- tanyl ]methyl]octadecyl ester, 5-oxo-L-proline-(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxe- tanyl]methyl]octadecyl ester, characterized in that similarly substituted starting materials are used. 6. Process according to claim 1 in the preparation of: (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(S or R)-2-isopropylmalonate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(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]do- decyl-(RS)-2-carbamoyl-4-methylvalerate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl -1-carbamoylcyclohexanecarboxylate, (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(RS)-2-methylmalonate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(RS)-2-ethylmalonamate (epimers 1:1), (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]do- decyl-(RS)-2-butylmalonamate (epimers 1:1), (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octa- decyl-l-carbamoylcyclohexanecarboxylate, (S)-l-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2- oxetanyl]methyl]dodecyl-[S:R or R:S (2:1)]-2-isopropylmalonate, (S)-1-t[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]do- decyl-(S or R)-2-isopropyl malonate, characterized by using correspondingly substituted starting materials.