Oxetanones

F. HOFFMANN-LA ROCHE AG.

PROCESS FOR PREPARATION OF NEW OXETANONES WITH ACTION

PANCREYTIC LIPASE AND COMPOSITION INHIBITOR

PHARMACEUTICALS CONTAINING THEM

The present invention relates to novel oxetanones, a process for their preparation, the preparation of pharmaceutical compositions containing such oxetanones, as well as the use of said compounds for the preparation of pharmaceutical compositions.

These oxetanones have the general formula

R,

Q-OCHCH

O

R.

(I) in which

Q represents a group of formula (R₃, R₄) NCO (X)_no-C0 (R₃, R₄) NCO-X¹ -

<img file="PT96887B_D0001.tif" />

<img file="PT96887B_D0002.tif" />

or

<img file="PT96887B_D0003.tif" />

<img file="PT96887B_D0004.tif" />

where Rg and R₄ each represents a hydrogen atom or a C1-4 alkyl group.₄ or, taken together with the nitrogen atom to which they are attached, form a trigonal to hexagonal nucleus, optionally containing an oxygen or sulfur atom at a position other than the position relative to the nitrogen atom; X represents an alkylene group of up to 6 carbon atoms, optionally interrupted by an oxygen or sulfur atom or a sulfinyl or south group. and optionally comprising as a substituent a hydroxy, mercapto, aryl, aryloxy, arylthio, arylC_1-4aryl C-alkoxy_1-4aryl (C1-4 alkyl) thio, aryl (C1-4 alkylidene)₄cycloalkylidene Cg_₇ or C1-6 alkylidene or one or two C1-6 alkyl groups, ^TheC 1-6 alkyl or (C 1-6) alkylthio may be two C 1-6 alkyl groups, C 1-6 alkoxy or C 1-6 alkylthio on the same carbon atom or on two adjacent carbon atoms form a possibly monounsaturated trigonal to heptagonal nucleus and an optionally present hydroxy or mercapto group or an unsaturated carbon atom may be present. optionally present to be in a position other than position x with respect to any oxygen or sulfur atom presently present or to a sulfinyl or sulfonyl group also present; or X represents a group of the formula = CHN (R, Rg) or -CHN (R, Rg) CHg where R is R_Q each represents a hydrogen atom or a C1-4 alkyl group.₄, al kil (C ^ _₄) - (CO or OCO) -, aryl, aryl (CO or OCO) -, aryl. -C4 alkyl₄ or aryl (C1-6 alkyl)₄) - (CO or OCO) -; X 'represents an alkylene group of up to 6 carbon atoms having a substituent selected from C1-4 alkoxy groups.₄aryl, aryloxy, arylthio, arylC 1-4 alkyl, aryl alkoxy_1-4 or aryl (C 1 -C 6) alkylthio or one or two

-3?-

<img file="PT96887B_D0005.tif" />

â € ƒâ € ƒâ € ƒ5 substituents selected from alkyl groups wherein two C1 -C6 alkyl groups attached to adjacent carbon atoms form a trigonal to heptagonal nucleus; en represents zero or the integer 1; and

R4 and R6 each represent an alkyl group of up to carbon atoms having 1 to 3 substituents selected from halogen atoms or alkyl, alkenyl, alkynyl or alkadienyl groups having chains of up to 20 carbon atoms interrupted by a group 1 4-arylene which optionally comprises as substituent an ari group. lo at position W and an aryl alkyl group C₄_₄wherein the chain represented by R ^ may be interrupted by an oxygen or sulfur atom or by a sulfinyl or sulfonyl group at a position other than that of an unsaturated carbon atom; or wherein R 4 is aryl-NH- or aryl-alkyl (C 1)₁_₄) -OCONH-.

Alkyl, alkenyl and alkadienyl groups may be straight or branched chain. The methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, undecyl and heptadecyl groups are examples of alkyl groups.

The designations aryl and arylene correspond to phenyl and respectively phenylene or phenyl and respectively phenylene having up to 5 halogen atoms or up to 3 C1-4 alkyl groups as substituents.₄C1 -C4 alkoxy₄ or nitro.

Preferred oxetanones of formula I are those wherein 2 represents a group of formula Qp R4 and R6 each represent an alkyl, alkenyl or alkadienyl group having a chain of up to 20 carbon atoms which may optionally disrupt.

<img file="PT96887B_D0006.tif" />

by a 1,4-phenyl group, optionally bearing a phenyl group at the W position and optionally bearing a phenyl C 1-6 alkyl group as a substituent.₄wherein the group represented by Rg may be interrupted by an oxygen or sulfur atom at a position other than position tf. for an unsaturated carbon atom; X represents an alkylene group having up to 6 carbon atoms, optionally interrupted by an oxygen or sulfur atom and optionally having a substituent selected from hydroxy, mercapto, phenyl, phenoxy, phenylthio, phenyl C1-6 alkyl groups.₄, phenyl alkoxy Cg_₄, phenyl (C6) alkyl₄) -thio, phenyl alkylidene C6₄C6 cycloalkylidene or C6 alkylidene or one or two substituents selected from alkyl groups ^çC1-6 alkoxy or C1-6 alkylthio, where two C1-6 alkyl, C1-6 alkoxy or C1-6 alkylthio groups attached to the same carbon atom may form a trigonal to heptagonal nucleus and may be a hydroxy or mercapto group, even presently occupying a position other than that of an optionally present oxygen or sulfur atom; or X represents a group of formula = CHN (R, Rq); R 1 and R 4 each represent a hydrogen atom or an al group. alkyl alkyl (Cg_₄) - (CO or OCO) -, phenyl or phenyl- (CO or OCO) -; en, Rg and R₄ have the meanings defined above.

Even more preferred are oxetanones of formula I wherein Q represents a group of formula Qg; Rg and Rg each represent an alkyl, alkenyl, alkynyl or al group. up to 20 carbon atoms, optionally with an aryl group at position W as the substituent, wherein the group represented by Rg may be interrupted by a sulfur atom at a position other than position with respect to an unsaturated carbon atom or Rg represents a substituent. aniline group,

-5 alkyl having up to 18 carbon atoms and bearing as the substituent. having a halogen atom or a phenyl-C1 -C4 alkyl-OCONH- group; R6 and R4 each represent a hydrogen atom or a C1-4 alkyl group.₄ or R 6 and R 4, taken together with the nitrogen atom to which they are attached, form a saturated hexagonal nucleus containing an oxygen or sulfur atom at a position other than position relative to the nitrogen atom; n represents zero or the integer 1; X represents an alkylene group having up to 6 carbon atoms optionally interrupted by an oxygen or sulfur atom or a sulfinyl group and optionally having one or two substituents selected from C1-6 alkyl or C1-6 alkoxy groups, wherein two alkyl or alkoxy groups attached to the same carbon atom or two adjacent carbon atoms form a trigonal nucleus to optionally monounsaturated heptago or X represents a group of formula = CHN (R, Rq) or -CHN ( R, Rg) CHg-; and R and R 6 each represent a hydrogen atom or a C 1-6 alkanoyl or benzyloxycarbonyl group.

Even more preferred are oxetanones of formula I wherein Q is a group of formula Q₂; R1 and R2 each represent a C1-4 alkyl group._2Q; Rg and R₄each represents a hydrogen atom and X represents an alkylene group of up to 6 carbon atoms having a substituent selected from C1-4 alkoxy groups.₄ or one or two substituents selected from C1-6 alkyl groups, wherein two C1-6 alkyl groups, attached to adjacent carbon atoms, form a trigonal to heptagonal nucleus.

Also preferred are oxetanones of formula I wherein Q represents a group of formula Qg; Rg represents a hydrogen atom and R₁ and Rg each represent one

<img file="PT96887B_D0007.tif" />

*&gt;

C1-4 alkyl group_2g, especially a hexyl or undecyl group.

Among the oxetanones of formula I in which Q represents a group of formula are especially preferred those in which it represents a methyl, ethyl, propyl, hexyl, 2-butenyl, 3-methyl-2-butenyl, 2-propynyl group. methylthio, penylthio, 5-chloropentyl, benzyl, phenylthio, benzylthio, pentafluorobenzyl, anilino or benzyloxycarbonylamino; represents an undecyl, heptadecyl or 8,11-heptadecadienyl group; Rg and R4 each represent a hydrogen atom or a methyl or isopropyl group or Rg and R4₄together with the nitrogen atom form a morpholino or thiomorpholino group; n represents zero or 1; and X represents a group - (CH₂)₁__g-, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopentylidene, t-butylmethyldene., dimethylvinylidene, cyclopentylidene, cyclohexylidene, phenethylidene, phenylpropylidene, 1,2-cyclohexylene-cyclohexylene -1,6-ylene, acetamidomethylene, benzyloxycarbonylaminomethylene, 1-benzyloxycarbonylamino-1,2-ethylene, methyloxymethylene, methylenethiomethylene, methylenesulfinylmethylene, ethylenethioethylene, ethylenesulfinylethylene, methoxymethylene or ethylene- or propylenedioxymethylene.

Among the oxetanones of formula I wherein Q is a group Q₂ Especially preferred are those wherein R2 represents a hexyl group; R₂ represents an undecyl group and X 'represents an ethylene, 1- methoxy-1,2-ethylene or 1,2-cyclohexylene group.

Examples of these compounds are as follows:

(S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetyl] methyl] dodecyl (S) -2-isopropylmalonate ((or R) -2-carbamoylvalerate ( S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dp, decyl, 7 ', (PS) (S) -2-isopropylmalonamate S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] -9,12-octadecadienyl, (S) -1-[[(2S) (S) -2-isopropylmalonamate , 3S or 2R, 3R) -4-oxo-3-penylthio-2-oxetanyl] methyl] dodecyl, [S: R (2: 1)] -2-isopropylmalonamate [S (R) , 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl, (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-carbamoylcyclopentanecarboxylate, (S) -1 - [[1-benzylmalonamate] (2S, 3S) -3-hexyl-4-oxo-2-oxetyl] methyl] dodecyl,

(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,

5-Oxo-L-proline (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester and particularly (S or R) -2-isopropylmalonamate of (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl, (S) -1 - [[(2S, (All Z, s) -1 - [[(2S, 3S) 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (1: 1 epimer), (S or R) -2-isopropylmalonamate ) -3-ethyl-4-oxo-2-oxetanyl] methyl-9,12-octadecadienyl, (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-carbamoyl-4-methylvalerate (1: 1 epimers), (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (S) -1 - [[carbamoylcyclohexanecarboxylate, (2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (1: 1 epimer),

<img file="PT96887B_D0008.tif" />

(S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-ethylmalonamate (1: 1 epimers), (RS) -2- (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl butylmalonamate (1: 1 epimers),

(S) -1 - [[((2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl 1-carbamoylcyclohexanecarboxylate, [S: R or R: S (2: 1)] (S) -1 - [[(2S, 3S or 2R, 3R) -4-Oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl 2-isopropylmalonamate, and (S or R) -2-isopropylmalonamate (S) -1 - [[(2R, 3R) -3-Benzyl-4-oxo-2-oxetanyl] methyl] dodecyl.

The oxetanones of formula I contain at least 3 asymmetric carbon atoms and may thus be present as optically active enantiomers, of their mixtures, for example racemates, or as diastereomers.

Oxetanones of general formula I may be prepared in a known manner consisting of:

a) esterify an alcohol of general formula

<img file="PT96887B_D0009.tif" />

(Ha) with an acid of formula Qa-OH in which

Qa represents a group of formula Q1 or Qg defined above, or

b) subjecting to cyclization reaction an acid of general formula

-9 • a (Q-0, R₂) CHCH₂CH (OH) CH (R)_x) -COOH (Ilb) or

c) converting the carboxy group to the group represented by T from an acid of general formula

<img file="PT96887B_D0010.tif" />

(IIc) in which

T represents a group of formula

HOCO (X) -CO- (T_no) η 1

HOCO-X'- (T₂) in an amide group of formula (R₃, R₄) NCO-, and

d) optionally separating the mixture of epimers of formula I into the individual epimers.

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

Cyclization of (b) may be carried out in a solvent such as methylene chloride, dimethylformamide (DMF) or acetonitrile using molecular sieves, for example in the presence of 2- (1H-ben hexafluorophosphate zotriazol-1-yl) -1,1,3-tetramethyluronium (HBTU) and a base such as triethylamine at room temperature or up to 50 ° C.

_ζ-ιο · - '' τΛίΠΛί

The amidation of point (c) may be carried out using an ammonia solution or an amine of formula (Rg, R₄) NH, for example in acetonitrile in the presence of HBTU at room temperature or up to 40 ° C.

Optional separation of a mixture of epimers of formula I may be carried out by silica gel chromatography using ethyl acetate / hexane / methylene chloride as eluent.

The alcohols of formula II are known, for example from European Patent Application 0185359 A₂or may be prepared analogously to known alcohols of formula IIa or as described in Examples Aal, MeOaT.

The starting compounds of formula IIb and IIc may be prepared conventionally starting from the corresponding alcohols of formula IIa as described below in Examples J and K (for acids of formula IIb) and K, L and N (for acids of formula IIc).

Example A

(a) To a solution of 720 g of 30% sodium methylate, 465 g of methyl acetoacetate and then 458 g of ethyl bromide were added under a nitrogen atmosphere. Then, the reaction mixture was refluxed. After methanol distillation the residue was poured into ice-cold water.

The mixture was then extracted with n-hexane and water. The organic phases were combined and dried. After evaporation of the solvent and distillation 328 g of methyl 2-acetylbutyrate were obtained, PE 77-79 ° C / 15 Torr.

(b) 144.17 g of the methyl ester obtained in step a) was added under an argon atmosphere at a temperature of 0 ° C.

11 and 5 ° C to a suspension of 26.4 g of sodium hydride in 1250 ml of THF. After stirring at 0 ° to 5 ° C for 1.5 hours, the mixture was cooled to -10 ° C. At this temperature 675 ml of 1.56 M butyl lithium in hexane was added. After stirring at -10 ° C for 30 minutes, a solution of 149.3 g of methyl stearate in 250 ml of THF was added dropwise. After stirring at -10 ° C for 1.5 hours. The reaction solution was added under argon to 250 ml of 37% hydrochloric acid and 300 g of ice. The mixture was extracted with hexane and water. The combined organic phases were dried, filtered and evaporated.

The residue was dissolved in 2500 ml of THF, treated with 76.1 g of 1,8-diazobicyclo [5.4.0] undec-7-eno- (1.5-5) (DBU) and subjected to reflux under argon atmosphere. The cooled reaction solution was extracted with 37% hydrochloric acid and then saturated sodium chloride solution. The combined organic phases were dried and evaporated. The product was dissolved in ethyl acetate. The solution was cooled to room temperature and stirred overnight at 25 ° C. The crystallized substance was filtered under suction, washed with ethyl acetate and dried. 122.5 g of 3-ethyl-6-heptadecyl-4-hydroxy-2H-pyran-2-one were obtained, mp 101 ° -102 ° C.

c) 100 g Raney nickel and 2000 ml THF were added to 100 g pyrone obtained in step b). After hydrogenation at 25 ° C for 3 days the catalyst was filtered under suction and washed with THF. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and stirred at 10 ° C for 17 hours. The crystallize was filtered off under suction, washed with cooled ethyl acetate to -10 ° C.

12Vh and dried at 40 ° C for 17 hours. 90.54 g of racemic (2RS, 2RS, 5SR) -2-ethyl-5-heptadecyl-3-hydroxy-valerolactone, mp 101 ° -102 ° C.

d) 138.5 g of benzoic anhydride and then 2.5 ml of 70% perchloric acid were added to a suspension of 191.3 g of the dlactone obtained under (c) in 1250 ml of toluene. After stirring for 2.5 hours, the reaction mixture was extracted in toluene with 1 N sodium hydroxide solution, 20% sodium chloride solution and saturated sodium chloride solution. The organic phases were combined, dried and evaporated. 243.4 g of racemic (2RS, 3RS, 5SR) -3-benzoyloxy-2-ethyl-5-heptadecyl-4-valerolactone, mp 64.5-66 ° C.

e) 243 g of the benzoate obtained in step d) was dissolved in 450 ml of toluene at 40 ° C under argon atmosphere. 1000 ml of methanol and then 2.5 ml of concentrated sulfuric acid were added and the reaction was stirred at 25 ° C for 20 hours. After neutralization of sulfuric acid the solvent was evaporated with triethylamine. After evaporation the residue was dissolved in t-butyl methyl ether and washed with water. The aqueous phase was extracted with t-butyl methyl ether and the organic phases which were dried with sodium sulfate were combined, the drying agent was filtered under suction and washed with t-butyl methyl ether. then evaporating. 257 g of racemic methyl (2RS, 3RS, 5SR) -3-benzoyloxy-2-ethyl-5-hydroxydocosanoate were obtained.

f) Under argon atmosphere, 257 g of the hydroxy ester obtained in step e) were treated in 1250 ml of n-hexane with 152 g of benzyl 2,2,2-trichloroacetimidate. Then 3.2 ml of trifluoromethanesulfonic acid were added. After stirring for 18 hours^y The precipitate was filtered off under suction and washed with n-hexane. The filtrate was extracted with 5% sodium hydrogen carbonate solution and water. The hexane phases were combined, dried, filtered and concentrated. After stirring at -20Â ° C for 20 hours the crystallize was filtered off with suction, washed with n-hexane and separated. The filtrate was evaporated. 239.6 g of racemic methyl (2RS, 3RS, 5SR) -3-benzyloxy-5-benzyloxy-2-ethyl cosanoate were obtained.

g) Under argon, 239.6 g of the benzyl ether from step f) was treated with a solution of 140 g of potassium hydroxide in 1250 ml of a methanol / 95% (v / v) water mixture. v) and stirred for 17 hours at 40 ° C. The mixture was then concentrated at 40 ° C and the suspension was taken up in t-butyl methyl ether and washed sequentially with 10% sodium chloride solution, 1N hydrochloric acid and again with a 10% sodium chloride solution. The organic phase was dried with sodium sulfate, the drying agent was filtered under suction and washed with t-butyl methyl ether. The filtrate was evaporated. 182.1 g of racemic (2RS, 3RS, 5SR) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid were obtained.

h) 33.3 g of (S) - (-) - O (--ethylethylbenzylamine) was added to a solution of 182.1 g of the β-hydroxy acid obtained in step g) in 1250 ml of methyl acetate. The solution was seeded with 50 mg of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid phenethylamine salt and allowed to stand for 20 hours. The crystallized under suction was filtered, washed with cooled methyl acetate to -20 ° C and then dried. This first crystallize was dissolved in hot methyl acetate, cooled to 45 ° C and seeded with 50 mg of (2S, 3S, 5R) -5- benzyloxy-2-ethyl-3-hydroxydocosanoic acid. The solution was allowed to stand at room temperature for 20 hours. The crystallize was filtered off under suction, washed with cooled methyl acetate to -20 ° C and dried. With the second crystallized the same procedure was repeated as for the first crystallized. 39.4 g of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid phenethylamine salt were obtained, mp 92 ° -95 ° C.

i) 39.4 g of the phenethylamine salt obtained in step h) was treated with 400 ml of t-butyl methyl ether and 80 ml of 1N hydrochloric acid and dissolved under stirring. The organic phase was washed with water, dried, filtered and concentrated. 31.4 g of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid, mp 62-63 ° C.

(j) Benzenesulfonyl chloride (17.6 g) at a temperature of 0 ° C under argon was added dropwise to a solution of 24.5 g of the hydroxy acid obtained in step i) in 250 ml of pyridine. After stirring at 0 ° C for 20 hours at adi. 5 ml of water was added dropwise to that solution. The mixture was stirred at room temperature for 1 hour and the pyridine was evaporated. The crystalline slurry was taken up in t-butyl methyl ether and washed sequentially with 2N hydrochloric acid, 5% sodium hydrogen carbonate solution and 10% sodium chloride solution. The organic phase was dried with sodium sulfate and then triturated with activated charcoal. The drying agent and activated charcoal were filtered off under suction and the filtrate was evaporated. 23.4 g of (3S, 4S) -4 - [(R) -2-benzyloxynonadecyl] -3-ethyl-2-oxetanone was obtained.

A solution of 23.4 g of the oxetanone obtained in step j) in 250 ml of tetrahydrofuran was treated with 2.3 g of 10% palladium / charcoal. After hydrogenation for 5 hours the solution was filtered. After washing with tetrahydrofuran the filtrate was evaporated and the residue was dissolved in n-hexane and seeded with (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2- oxetanone. After 18 hours the crystallize was filtered off under suction, washed with hexane and dried. 16.1 g of (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone, mp 66.5 ° -68 ° C, the starting alcohol compound of Example 1.

Example B

a) 50 g of methyl (R) -3-hydroxytetradecanoate, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine were dissolved in 200 ml of methylene chloride and stirred. at room temperature for 30 hours as well as under reflux for 16 hours. Then an additional 2 g of t-butyldimethylchlorosilane is added. After a further 24 hours at reflux, the triethylamine hydrochloride precipitate was filtered off, washed with diethyl ether and the filtrate concentrated. The residue was dissolved in diethyl ether and then washed with water, 0.5M citric acid again, water and saturated sodium chloride solution, dried, concentrated and subsequently released. All volatile material is heated at 5 ° C for 5 hours under high vacuum. 71.8 g of (R) -3 - [(1,1-dimethylethyl) dimethylsilyloxy] tetradecanoic acid were obtained; IR (cm^-1): 1745, 1254, 895, 776.

b) 18.63 g of the product obtained in step a) were dissolved in 100 ml of diethyl ether and treated with 65 ml of a solution of hi. 1M diisobutyl aluminum dichloride in hexane at a temperature of

From -70 ° C to -75 ° C and then stirred at this temperature for 1 hour. Then 2.5 ml of isopropanol, 10 ml of water and 50 ml of a saturated solution of 0.5 M citric acid were added dropwise to a maximum temperature of 10 ° C. The ether phase was separated, the aqueous phase extracted with ether, the ether phases were combined, washed with saturated sodium chloride solution, dried and concentrated. The residue was chromatographed on silica gel with 5: 1 pentane / diethyl ether and 14.47 g of tradecanal (R) -3 - [(1,1-dimethylethyl) dimethylsilyloxy] -te were obtained. (cm^-1): 1728, 1254, 836, 775.

(c) A solution of 2,55 ml of diisopropylamine in 45 ml of tetrahydrofuran at 0 ° C was treated with 22,5 ml of a 1,6 M solution of n-butyllithium in hexane and, After stirring for 15 minutes, it was cooled to -75 ° C. Then a solution of 2.9 g of thiopentylacetic acid in 9 ml of THF was added dropwise. After stirring for 10 minutes the reaction mixture was allowed to return to room temperature, stirred for 5 minutes and cooled back to -75 ° C. At this temperature a solution of 2.4 g of the aldehyde prepared in step b) in 9 ml of tetrahydrofuran was added dropwise. After stirring for 20 minutes, the reaction mixture was poured into saturated ammonium chloride solution and extracted with hexane. The hexane phase was dried and concentrated. 3.89 g of (2R / S, 3R / S, 5R) -5 - [(1,1-dimethylethyl) dimethylsilyloxy] -3-hydroxy-2-pentylthiohexadecanoic acid was obtained as a mixture of 4 diastereomers.

d) A solution of 3.89 g of the product obtained in step c), 3.18 g of 2- (1H-benzo triazol-1-yl) -11,3,3-tetramethyluronium hexafluorophosphate was stirred for 2 hours. (HBTU), 2 g sieves mo / -177

4A leculars and 3 ml triethylamine in a mixture of 130 ml methylene chloride and 6 ml dimethylformamide. The mixture was then filtered, the filtrate concentrated, the residue was dissolved in water / methanol (3: 7) and extracted with hexane. The hexane phase was dried and concentrated. (3R / S, 4R / S) -4 - [(R) -2 - [(1,1-dimethylethyl) -dimethylsilyloxy] -tridecyl] -3-pentyl-thio-2- (3.57 g) was obtained. oxetanone as a mixture of 4 diastereomers.

e) A solution of 4.5 g of the product obtained in step d) in 200 ml of acetonitrile was treated with 15 ml of 40% hydrofluoric acid and stirred for 18 hours. Then a sodium hydrogen carbonate solution was added and the mixture was then extracted with hexane, the hexane phase was dried and concentrated. The residue was chromatographed on silica gel using 1-5% diethyl ether in methylene chloride as eluent. 699.9 mg of 3R, 4R (or 3S, 4S) -4 - [(R) -2-hydroxytriethyldecyl] -3-pentylthio-2-oxethanone, mp 43 ° C, and 691.2 mg of 3S, 4S (or 3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone, mp 71 ° C, compounds inj. alcohols of Examples 5 and 6.

example C

(a) 18 ml of a 1 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran were treated with 1.8 ml of ethyl acetate under argon at -75 ° C, stirred The mixture was treated at 30 ° C for 30 minutes and then treated with (R) -3-benzyloxytetradecanal (4.8 g) in tetrahydrofuran (15 ml) and stirred at -78 ° C. for 30 minutes. A solution of 3.8 ml of concentrated hydrochloric acid in 6 ml of water was added dropwise to the reaction mixture. The obtained solution was extracted with ethyl acetate, the organic phases were combined, washed with 10% sodium hydrogen carbonate solution and water, dried, filtered and concentrated. Ethyl (3R, 5R and 3S, 5R) -5-benzyloxy-3-hydroxyhexadecanoate (1: 1) was obtained.

(b) A solution of 4 ml of diisopropylamine in 12.5 ml of tetrahydrofuran was treated with 17 ml of a 1,6 M solution of n-butyllithium in n-hexane under an argon atmosphere at 0 ° C. After stirring for 15 minutes, 5 g of the product obtained in step a) were added dropwise in 2.5 ml of tetrahydrofuran at -50 ° C. After 10 minutes at -10 ° C, the temperature was reduced to -50 ° C and then a solution of 3.18 g of benzyl bromide in 3.1 was added dropwise. ml of hexamethylphosphoric acid triamide and stirred at m.p. temperature at -50 ° C for 15 minutes. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 ° C and 50 ml of saturated sodium chloride solution was added and then the mixture was extracted with t-butyl methyl ether, dried. extracts, filtered and the solvent was evaporated. The residue was chromatographed on silica gel using a mixture of n-hexane / ethyl acetate (4: 1) as eluent and then dried. Ethyl (2R, 3R, 5R and 2S, 3S, 5R) -5-benzyloxy-2-benzyl-3-hydroxyhexadecanoate was obtained as a 1: 1 mixture of threo diastereomers.

c) A solution of 3.1 g of the product obtained in step b) and 26 ml of 2.5N sodium hydroxide solution in 37.2 ml of ethanol were refluxed for 50 minutes and then neutralized. at room temperature with 26 ml of 2.5N hydrochloric acid. Desti Ethanol was then extracted and the residue was extracted with t-butyl methyl ether and water. The organic phases were combined, dried

<img file="PT96887B_D0011.tif" />

f, and concentrated. A solution of 3 g of residue in 109 ml of methylene chloride was stirred under argon and treated with 2.59 g of HBTU and 2.74 g of molecular sieves. Then 5.5 ml of dimethylformamide and 2.8 ml of triethylamine were added and the reaction mixture was stirred for 1 hour, filtered and concentrated. The residue was taken up in n-hexane and the solution was then extracted with water, dried and concentrated in vacuo. Chromatography on silica gel using methylene chloride as eluent provided a first trans diastereomer, (3S, 4S or 3R, 4R) -3-benzyl-4 - [(R) -2-benzyloxytridecyl] -2-oxetanone, Rf = 0.45 (5-40 m silica gel thin layer chromatography with methylene chloride) and a second trans (3R, 4R 'or 3'S, 4S) -3-benzyl-4 - ((R) -2-) diastereomer benzyloxytridecyl] -2-oxetanone, Rf = 0.50 (5-40 w silica gel thin layer chromatography with methylene chloride).

d) For 1 hour a solution of 646 mg of the second trans diastereomer obtained in step c) was hydrogenated in 65 ml of tetrahydrofuran in the presence of 646 mg of 10% palladium on charcoal. The reaction mixture was filtered and concentrated. One day, trans: (3R, 4R or 3S, 4S) -3-benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, the alcohol which is the starting compound in Example 7 was obtained. .

e) As described in step d), from the first trans diastereomer obtained in step c) the trans diastereomer was obtained: (3S, 4S or 3R, 4R) -3-benzyl-4 - [(R) -2 -hydroxytridecyl] -2-oxetanone, the alcohol which is the starting compound of Example 8.

Example D

A solution of diisopropylamine (3.0 ml) in tetrahydrofuran (50 ml) at 0 ° C was treated with 12.0 ml of diisopropylamine.

<img file="PT96887B_D0012.tif" />

a 1.6M solution of n-butyllithium in hexane and, after stirring, cooled to -75 ° C. Then a solution of 1.26 g Z-glycine in 10 ml tetrahydrofuran was added dropwise. The reaction mixture was then allowed to return to room temperature and cooled again to -75 ° C, and then dropwise added (0.7 g) of (R) -. 3- (t-Butyldimethylsiloxy) -tetradecanal in 5 ml of tetrahydrofuran. The reaction mixture was stirred at -75 ° C for 1 hour and at -40 ° C.

At -50 ° C for 30 minutes, then warmed to 5 ° C, cooled again to -75 ° C, poured into a Potassium hydrogen sulfate solution was extracted with diethyl ether. The ether phase was dried, concentrated and chromatographed on silica gel using methylene / methane chloride as eluent. 540 mg of (2R / S, 3R / S, 5R) - [1- (Benzyloxy) -formamide] -5- (t-butyldimethylsilyl) -3-hydroxyhexadecanoic acid was obtained as a mixture of 4 diastereomers.

In a manner analogous to that described in Example B) d), from benzyl 4 - [(R) -2- (t-butyldimethylsilyloxy) tridecyl] -2-oxo-3-oxetanecarbamate was obtained from the above product. 1: 1 mixture of the two trans-diastereomeric β-lactones, MS: 476 (m⁺"-ç₄H₈·)·.

In a manner analogous to that described in Example B) e), from the above mixture was obtained (3S, 4S or 3R 4 - [(R) -2-hydroxyitridecyl] -2-oxo-3-oxetanecarbamate , 4R) -benzyl, which is the alcohol starting compound of Example 15, mp 122 ° -124 ° C and (3R, 4R) [(R) -2-hydroxy-tridecyl] -2-oxo-3-oxetanecarbamate or 3S, 4S) -benzyl,

Mp 98 ° -99 ° C.

-Ζ1Example E

Similarly to Example B, from thiophenoxyacetic acid and (R) -3 - [(1,1-dimethylethyl) dimethylsilyloxy] tetradecanal by:

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-butyldimethylsilyloxy) tridecyl] -3- (phenylthio) -2-oxetanone (mixture of 4 diastereomers),

IR (cm^_1): 2927, 2855, 1833, 1254, (3S, 4S) -4 - [(R) -2-hydroxyphtidecyl] -3- (phenylthio) -2-oxetone, mp 79 ° C (ether) and (3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone, mp 47 ° C (ether), the starting alcohol compound of Example 16.

Example F

(a) 270 ml of stearyl chloride at a maximum temperature of 150 ° C were added dropwise to a solution of 117 g of acid. of Meldrum and 131 ml of pyridine in 1.5 liter of methylene chloride. After stirring, the reaction mixture was washed with calcium acid.

NaHCO 3, the aqueous phase was extracted with methylene chloride and the methylene chloride phase was dried and concentrated. The residue was taken up in methanol and stirred under reflux. separated crystals, dissolved in methylene chloride and chromatographed on silica gel with methylene chloride. 175 g of 3-oxolic acid * were obtained.

methylate, mp 52 ° -54 ° C.

b) 1.84 mg was added. of acetyl chloride in 1.84 ml of methanol to a solution of 9.1 (1) (R) -2,2'-bis (di

<img file="PT96887B_D0013.tif" />

phenylphosphino) -6,6'-dimethylbiphenyl] ruthenium in 20 ml of methylene chloride. The obtained solution was hydrogenated under a pressure of 35 bar hydrogen at 60 ° C, along with 39.8 g of the ketoester obtained in step a) and 170 ml of methanol. After the addition of methylene chloride the mixture was evaporated to dryness. The chromatography on. silica gel with diethyl ether and recrystallization from n-hexane gave 35.6 g of methyl (R) -3-hydroxyeicosanoate, mp 64-64.5 ° C.

c) Similarly to Example B, from the product obtained in step b), via methyl (R) -3- (t-butyldimethylsilyloxy) eicosanoate, IV (cm): 1745, 1255, 836;

(R) -3- (t-Butyldimethylsilyloxy) eicosal, IR (cm^-1)): 1728, 1463, 1255, 1104, 836, 775;

(2R / S, 3R / S, 5R) -5- (t-Butyldimethylsiloxy) -3-hydroxy-2- (methylthio) -docosanoic acid (the mixture of 4 diastereomers), MS: 533 (M + H)⁺;

4 - [(R) -2- (t-Butyldimethylsilyloxy) -nonadecyl] -3- (methylthio) -2-oxethanone, (a.l: 1 mixture of two trans diastereomers), IR (cm ): 1834, 1463, 1256, 1106, 836; and

4 - [(R) -2- (t-Butyldimethylsilyloxy) -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 compounds of Example 17 were obtained:

(3S, 4R or 3R, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetone, mp 65 ° C (in methylene chloride) (3R, 4S or 3S, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetone, mp 67 ° C (in methylene chloride)

<img file="PT96887B_D0014.tif" />

(3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetone, mp 71 ° C (in ether) and (3s, 4S or 3R, 4R ) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetone, mp 8G ° C (ether).

Example G

Similarly to Example B, starting from (benzylthio) acetic acid and (R) -3 - [(1,1-dimethylethyl) dimethylsilyloxy] tetra decanal by:

(2R / s, 3R / S, 5R) .- 2- (Benzylthio) -5 - [(1,1-dimethylethyl) dimethyl] acid. liloxy] -3-hydroxyhexadecanoic acid (mixture of 4 diastereomers) and - (3R / S, 4R / S) -3- (benzylthio) -4 - [(Rj -2- (t-butyldimethylsilyl) tridecyl] -2-oxetanone ( mixture of 4 diastereomers), FM: 506 (M⁺), the starting alcohols of Examples 19 and 20 were obtained:

(3S, 43 or 3R, 4R) -3- (benzylthio) -4 - [(R) '-2-hydroxytridecyl] -2 - oxetone, mp 65 ° C (ether), (3R, 4R or 3S, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetone, MS: 374 (Μ⁺· -Η₂Ο), and (3R, 4S and 3S, 4R) -3- (benzylthio) -4 - [(R) -2'-hydroxytridecyl] -2-oxetanone (1: 1 diast.), MS: 374 (M⁺"-H₂O).

Example H

a) -104 g of the mother liquor from the first crystallization of Example Ah) was dissolved in water and methylene chloride. The mixture was made difficult to pH 1 by the addition of concentrated hydrochloric acid while cooling with ice, the methylene phase separated and the aqueous phase extracted with methylene chloride and 1%.

-24/&lt;

The methylene chloride phase was washed with water, dried and concentrated. 86.7 g of the enriched (2R, 3R, 5S) -5-benzyloxy-2-ethyl-3-hydroxy-docosanoic acid dissolved in 500 ml of ethyl acetate and treated with 20.6 g of (R) - (+) - of methylbenzylamine under cooling. After the addition of ethyl acetate the mixture was refluxed, filtered and crystallized. The crystals obtained were recrystallized from ethyl acetate and methyl acetate. 70.0 g of (2R, 3R, 5S) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid phenethylamine salt, mp 88-91 ° C.

(b) Analogously to Example A (i), (j), (k) from the previous salt by:

(2R, 3R, 5S) -5-Benzyloxy-2-ethyl-3-hydroxydocasanoic acid, P, F. 61.5 ° -63 ° C, and (3R, 4R) -4 - [(S) -2-benzyloxynonadecyl] -3-ethyl-2-oxetanone, mp 38 ° -40 ° C gave (3R, 4R) -3-ethyl-4 - [(S) -2-hydroxynonedecyl] -2-oxetanone, mp 66 ° -68 ° C.

(c) A solution of 14,2 g of the product obtained and 4,65 g of triphenylphosphine in 250 ml of tetrahydrofuran, with 1,19 ml of formic acid and, at 5 ° C, was treated with a solution of 14,2 g. then with a solution of diethyl azodicarboxylate (5,12 g) in tetrahydrofuran (20 ml). The mixture was then treated with 0.4 ml formic acid, 2.9 g triphenylphosphine and 1.7 ml diethyl azodicarboxylate. The reaction mixture was concentrated and the residue was chromatographed on silica gel with hexaxro / ethyl acetate; 13.1 g of (R) -1 - [[(2R, 3R) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl format was thus obtained.

The product obtained was dissolved in 150 ml of methanol and treated at 15 ° C with 0.114 g of the Î ± -toluenesulfonic acid monohydrate. After stirring the reaction mixture, it was concentrated, the residue was partitioned between methylene chloride and aqueous sodium hydrogen carbonate solution. extracted with methylene chloride. The methylene chloride phase was dried and concentrated and the residue was recrystallized from ethyl acetate. 9.5 g of (3R, 4R) -3-ethyl-4 - [(-R) -2-hydroxynonadecyl] -2-oxanone, mp 80-82 ° C, the starting alcohol compound of Example 21.

Example I

a) 187.5 ml of a solution of n-butyllithium (1.6M in hexane) at -20 ° C were added dropwise to a solution of 42.5 ml of diisopropylamine in 50 ml of tetrahydrofuran. After stirring, the solution was added dropwise at a maximum temperature of -65 ° C to a suspension of 39.9 g of (S) - (-) - 2-hydroxy-1,2-acetate. triphenylene it in 600 ml of tetrahydrofuran. The reaction mixture was then warmed to 0 ° C, stirred, cooled to -70 ° C and treated with a solution of (R) -3 51.2 g. - [(t-butyl) dimethylsilyloxy] eicosanal in 400 ml tetrahydrofuran. After stirring, 500 ml of saturated ammonium chloride solution was added dropwise, and the mixture was cooled to room temperature with stirring. The reaction mixture was concentrated, shared&gt;

It was partitioned between water and ethyl ether and extracted with ether, washed. The ethereal phase with water was concentrated and taken up in 1 liter of methylene chloride, whereupon dried and concentrated. Got it

91.9 g of (S) -2-hydroxy-1,2,2- [3R: 3S (4: 1), 5R] -5- (t-butyldimethylsiloxy) -3-hydroxydocosanoate was found. tri.phenylethyl, IR (cm: 3525, 1719, 1448, 1250, 1159, 838, 697.

-26b) A solution of 90.8 g of the above product in 1 liter of methanol was treated with 22.15 ml of 5.4 M sodium methylate in methanol. After stirring the solution was concentrated and the residue was partitioned between diethyl ether and saturated ammonium chloride solution and extracted with diethyl ether. The ether phase was dried, concentrated and chromatographed on silica gel with hexane / ethyl acetate. In this way 42.7 g of (3R, 5R) -5- (t -butyldimethylsilyloxy) -3-hydroxydocosanoate IV (cm): 3521, 3468, 1738, 1254, 1168, 1137, 1105 were obtained.

c) Analogous to Example Be) and Cb), c) The latter compound was converted by methyl (2R, 3R, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxy-2-methyldocosanoate, IV (cm -1): 3522, 1739, 1464, 1254, 1066 and (3R, 4R) -4 - [(R) -2- (t-butyldimethylsilyloxy) -nonadecyl] -3-methyl-2-oxetanone, IR (cm^-1); 1830, 1464, 1254, 1129, 1071, in (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-methyl-2-oxetanone, mp 82.5-84 ° C (in acetate hexane / hexane), the alcohol starting compound of Example 22.

Example J

a) Treated with 20 ml of tetrahydrofuran, 1.1 g of (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, 1.6 g of triphenylphosphine 0.825 g of salicylamine and 3 g of molecular sieves (4%) and cooled to 0 ° C. Then 1.4 g of di-t-butyl azodicarboxylate was added. After resuming at room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol / water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane / ethyl acetate (4: 1). 0.727 g of 0 - [[(S) —1—

<img file="PT96887B_D0015.tif" />

- [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] benzamide, MS: 474 (M + H)⁺.

b) 972 mg of the product obtained above were dissolved in 12 ml of methanol and treated with 0.2 g of potassium carbonate. After stirring the reaction mixture was concentrated and the residue was partitioned between methanol / water (7: 3) and hexane and extracted with hexane. The hexane phase was dried and concentrated. This gave 854 mg of (2S, 3S, 5S) -5- (O-carbamoylphenoxy) -2-hexyl-3-hydroxyhexadecanoate methyl, MS: 369, (M⁺· - (O-carbamoylphenoxy)).

c) 850 mg of the product obtained above were dissolved in 12 m -1 methanol / water (98: 2), treated with 800 mg of radium on 5% aluminum oxide and hydrogenated at 100 ° C. At a pressure of 100 bar hydrogen. The reaction mixture was filtered, concentrated and chromatographed on silica gel with hexane / ethyl acetate (1: 1). In this way 213 mg of methyl (25.35.55) -5 - [[((cis) -2-carbamoylcyclohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoate (10 diastereomer) -, MS: 367 [M⁺ ·-H₂NCOCgH₁₀* + H₂O)], 204 mg of a mixed fraction and 142 mg of (25.35.55) -5 - [[((cis) -2-carbamoylcyclohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoate of methyl (2nd diastereomer), MS: 367, [M⁺·- (H₂ncoc₆H₁₀»+ H₂O)].

d) 210 mg of the above-obtained diastereomer were dissolved in 10 ml of acetone and treated with 3 ml of 1N potassium hydroxide. After stirring the reaction mixture was poured into potassium hydrogen sulfate solution and extracted with ether. The ether phase was dried and evaporated. 277 mg of (25.35.55) -5 - [[((cis) -2-carbamoylcyclohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoic acid (10 diastereomer), the acid starting compound, was obtained. Example 23a).

<img file="PT96887B_D0016.tif" />

f

e) In the manner described in d), from the 20th diastereomer obtained in c), (2S, 3S, 5S) -5 - [[(cis) τ-2-carbamoylcyclohexyl] -oxy] -2-hexyl-3-hydroxyhexadecanoic acid (2nd diastereomer), the acidic starting compound in Example 23b).

Example k

a) Analogously to Example Hc) from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and formic acid via the form of (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] decyl, IR (cm ¹): 1826, 1725, 1177, 1122 gave (3S, 4S) -3-hexyl-4 - [(S) -2-hydroxytridecyl] -2-oxetanone, mp 63 ° -64 ° C (with hexane ).

(b) Under argon, at 100 ° C, 1.8 g of the previously prepared hydroxy-b-lactone, 1.3 g of pyridinium ptoluenesulfonate and 2 g of molecular sieves (4Ά) were stirred in 10 ml of methyl 3,3-dimethoxypropionate, then the reaction mixture was filtered and the residue was concentrated by chromatography on silica gel with ether / methylene chloride. Off te mode was obtained:

1. (E) -3 - [[(S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] 'acrylate methyl, IR (cm): 1827,

1714, 1643, 1622, 1192? and

2. (R / S) -3 - [[(S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl].-Oxy] - 826 mg Methyl 3-methoxypropionate (1: 1 mixture of epimers); IR (cm^-1): 1824, 1743, 1438, 1117.

c) 235 mg of the product obtained in b) 2 was suspended. in 25 ml 0.02N sodium hydroxide and the reaction mixture was diluted with acetone. After stirring for 24 hours the mixture was acidified with 5% potassium hydrogen sulfate and extracted with diethyl ether.

The ether phase was dried, concentrated and the residue was chromatographed on silica gel with methylene chloride / methanol. This gave 60 mg of (2S, 3S, 5S) -2-hexyl-3-hydroxy-5 - [(R / S) - + acid

-1-methoxy-2- (methoxycarbonyl) ethoxy] hexadecanoic MS: 337 (M - (H₂O + -O- (CHgO) -CH₂-COOCH₃)).

(d) In an autoclave, a solution of 58 mg of the compound obtained above in 4 ml of condensed ammonia was heated at 50 ° C. The ammonia gas was then released and the mixture was then treated with potassium hydrogen sulfate solution and extracted with methylene chloride. The methylene chloride phase was dried and concentrated. 42.5 mg of aci were obtained. of (2S, 3S, 5S) -5 - [(R / S) -2-carbamoyl-1-methoxyethoxy] -2-hexyl-3-hydroxyhexadecanoic acid, the acid starting compound of Example 24.

Example L A solution of 200 mg of the product obtained in Example Kb) 1 was hydrogenated. in 10 ml tetrahydrofuran using 200 mg of 10% palladium on charcoal. The mixture was then filtered, the filtrate concentrated and the residue was chromatographed on silica gel with diethyl ether in 1% methylene chloride. Obtained

3 - [[(S) -2-E [(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy] propionate 99 mg, MS : .285 (M⁺· - (C ^^ H₂₃«)) .

A 544 mg suspension thereof was treated with 49 ml 0.02 N sodium hydroxide with acetonitrile. The resulting solution was acidified with aqueous potassium hydrogen sulfate solution, the reaction mixture was extracted with diethyl ether, the ether phase was dried and concentrated. It was chromatographed on silica gel with 2% diethyl ether in methylene chloride and then chromatographed.

<img file="PT96887B_D0017.tif" />

with 5% methanol in methylene chloride to give 43.7 mg of 3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] acid] methyl] dodecyl] oxy] propionic, IR (cm -1): 1823, 1715, 1466, 1105, the starting compound is acidic in Example 25.

Example M

Similarly to Example Cb) and c) methyl (3R, 5R) -5- (t-butyldimethylsiloxy) -3-hydroxydocosanoate (Example Ib) was reacted with propargyl bromide to give (2R, 3R , 5R) -5- (t-butyldimethylsilyloxy) -3-hydroxy-2- (2-propynyl) -docosanoate, IR (cm b: 3310, 2120, 1740, 1255, the latter being saponified to give (2R, 3R, 5R) -5- (t-Butyldimethylsilyloxy) -3-hydroxy-2- (2-propynyl) -docosanoic acid, IR (cm -1): 3315, 2120, 1715, 1255 and this acid was cyclized to give (3R, 4R) -4 - [(R) -2- (t-butyl. Dimethylsiloxy) -nonadecyl] -3- (2-propynyl) - 2-oxetanone, IR (cm): 3315, 2130, 1830, 1255.

Upon splitting of the protecting group analogously to that described in Example Be), (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (2-propynyl).-2-oxetanone, mp 62 ° C. -63 ° C (in ethyl acetate), the starting material alcohol in example 60.

Example N

Similarly to Example 1, from (3S, 4S) -3-hexyZL-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and monobenzyl malonate gave (S) -1 - [[ Benzyl (2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecylmalonate, IR (cm S: 1824, 1734, 1149, 1125.

A solution of 430 mg of this product in 15 ml of tetrahydrofuran was treated with 100 mg of palladium on charcoal and then hydrogenated. The reaction mixture was filtered and the filtrate concentrated. 361 mg of · 31 (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl hydrogen dioecyl ester (IV) was obtained (cm^-3·): 1824, 1745, the acid starting compound of Example 26.

Example 0

A solution of 1.96 g of the alcohol of Example M was hydrogenated in 50 ml of ethyl acetate using 0.25 g of 10% palladium on charcoal, then the reaction mixture was filtered and chromatographed. the residue on silica gel with ethyl acetate / hexane. From this fear, 1.44 g of (3R, 4R) -4 - [[(R) -2-hydroxynonadecyl] -3-propyl-2-oxetanone, mp 84 ° -85 ° C (em. ethyl acetate / hexane), the alcohol-starting compound of Example 61.

Example P

a) From (R) '- 3- (t-butyldimethylsilyloxy) -tetradecanal (Example Bb)) in the same manner as d (Example Ca), b), c) through (3R and 3S, 5R) Ethyl 5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoate (mixture of epimers); and (R and S) -2 - [(1R and IS, 3R) -3- (t-butyldimethylsiloxy) -1-hydroxytetra decyl] -5-methyl-4-hexenoate (1: 1 threo diastereomers), (3R, 4R and 3S, 4S) -4 - [(R) -2- (t-butyldimethylsilyloxy) tridecyl] -3- (3-methyl-2-butenyl) -2-oxetanone (trans-diastereomers) 1: 1).

(b) A solution of 1.87 g of the product obtained in (a) in 50 ml of aeethonitrile was treated with 6.2 ml of 40% hydrofluoric acid. After stirring a sodium hydrogen carbonate solution was added and then the mixture was extracted with methylene chloride, the methylene chloride phase was dried and concentrated. The residue was chromatographed on silica gel with ethyl acetate / methylene chloride / n-hexane (1: 4.5: 4.5). Chromatography gave the starting compounds alcohols for Examples 62-65:

- a trans diastereomer, (3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3- (3-methyl-2-butenyl) -2-oxetanone, Rf value = 0.31; and a trans diastereomer, (3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3- (3-methyl-2-butenyl) -2-oxetanone, Rf value = 0.26 (chroma Thin-layer silica gel^- 5-40 µm. with ethyl acetate) methylene chloride / hexane (1: 4.5: 4.5).

Example Q

From ethyl (3R, 5R and 3S, 5R) -5-benzyloxy-3-hydroxyhexadecancate (1: 1) (Example Ca)), analogously to Example Cb) ae), by ( Ethyl 2R, 3R, 5R and 2S, 3S, 5R) -5-benzyl-2- (5-chloropentyl) -3-hydroxyhexadecanoate (threo diastereomers);

a -12 trans diastereomer, (3S, 4S or -3R, 4R) -4 - [(R) -2- (benzyl x) tridecyl] -3- (5-chloropentyl) -2-oxetanone, Rf value = 0.47;

and a trans diastereomer, (3R, 4R or 3S, 4S) -4 - [(R) -2- (benzyloxy) tridecyl] -3- (5-chloropentyl) -2-xetanone, Rf value = 0 28 (thin layer silica gel eromatography of 5 -40% with methylene chloride) afforded the starting compounds alcohols for Examples 66-69:

(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.

Example R

From (R) -3- (t-butyldimethylsilyloxy) -tetradecanal (Example Bb), analogously to Example Cb) · c) through (R and 3, E) -2 - [(1R and IS 1,3R) -3- (t-Butyldimethylsilyloxy) -tetradecyl] -4-hexanoate (threo (1: 1) diastereomers) and (3R, 4R and 3S, 4S) -3 - [(E) -2-butenyl '] -4 - [(R) -2- (t-Butyldimethylsilyloxy) tridecyl] -2-oxetanone (trans (1: 1) diastereomers), the starting alcohols of Examples 70-73 were obtained:

A trans diastereomer (3S, 4S or 3R, 4R) -3 - [(E) -2-butenyl] -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 on silica gel with ethyl acetate / methylene chloride / n-hexane (1: 2: 2).

Example S

From ethyl ((3R, 5R and 3S, 5R) -5-benzyloxy-3-hydroxyhexano decanoate (1: 1) (Example Ca)), analogously to Example Cb) and c) by (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) were obtained. The starting alcohol compounds of Examples 74-77 are:

A 1st trans diastereomer, (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxyitridecyl] -4- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanone, Rf = = 0.43 and a 2nd trans diastereomer, (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3- (2,3,4,5,6 pentafluorobenzyl) -2-oxetanone^-Rf value = = 0.39 [chromatography and thin layer chromatography on silica gel with ethyl acetate / methylene chloride / n-hexane (1: 4.5: 4.5)].

<img file="PT96887B_D0018.tif" />

Example Τ

(a) A solution of 0,5 ml of diisopropylamine in 15 ml of tetrahydrofuran at 0 ° C was treated with 2,0 ml of a 1,6 M solution of n-butyllithium in hexane and After stirring, it was cooled to -75 ° C. Then a solution of 765 mg of N-benzyl-N-phenylglycine methyl ester in 3 ml of tetrahydrofuran was added. After stirring, a solution of 700 mg of (R) -3- (t-butyldimethylsilyloxy) tetradecanal (Example Bb)) in 5 ml of tetrahydrofuran was added dropwise. After stirring at -75 ° C the reaction mixture was poured into aqueous potassium hydrogen sulfate solution and extracted with diethyl ether. The ether phase was dried, concentrated, partitioned between hexane and methanol / water (7: 3), the hexane phase was dried and concentrated, the residue was chromatographed on silica gel with pentane / diethyl ether (5: 1). 96.3 mg of methyl (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoate, diastereomer A, MS: 540 (M + C +). (R) - and 142.8 mg of methyl (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecaate, diastereomer B, MS: 540 (Μ⁺· -Ο₄·Θ ·), and 313.4'g of a mixture of the two previous diastereomers.

b) 134 mg of diastereomer B was suspended in 3 ml of 0.1 N sodium hydroxide and treated with sufficient acetonitrile to give one. clear solution. After stirring the mixture was poured into aqueous potassium hydrogen sulfate, extracted with diethyl ether and dried and concentrated to ether. After chromatography on silica gel with methylene chloride / methanol (9: 1), 108 mg of (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3- hydroxyhexadecanoic, diastereomer B, MS: 526 (M + and C ^H H ·).

35c) Similarly, from diastereomer A of step a) (5R) -2- (N-benzylanilino) -5- (t-butyldimethylsiloxy) -3-hydroxyhexadecanoic acid, diastereomer A, MS: 526 (M⁺"-Ç₄Hg ·).

d) 1.1 g of diastereomer B obtained in step b), 1.1 g of HBTU, 0.5 g of triethylamine and 2 g of 4A molecular sieves in 50 ml of acetonitrile were stirred. After filtration and concentration, the product was chromatographed on silica gel with methylene chloride. 1.04 g of (3R, 4R or 3S, 4S) -3- (N-benzylanilino) -4 - [(R) -2- (t-butyldimethylsilyl) tridecyl] -2-oxetanone, the diastereomer B, MS: 566 (M + H)⁺.

e) Similarly, from diastereomer A obtained in step c) gave (3S, 4S or 3R, 4R) -3- (N-benzylanilino) -4 - [(R) -2- (t-butyl. dimethylsiloxy). ) '- trid'ecyl] -2-oxetanone, o'diasteromer A, MS: 566 (M + H)⁺.

f) 1.0 g of diastereomer B obtained in step d) and 0.8 g of 10% palladium on carbon were hydrogenated in 30 ml of tetrahydrofuran. The mixture was then filtered and concentrated. 834'mg of (3R, 4R or 3S, 4S) -3-anilino-4 - [(R) -2- (t-butyldimethyl siloxy) -tridecyl] -2-oxetanone, diastereomer B, MS: 475 (M⁺·).

g) analogously, from diastereomer A obtained in step e) gave (3S, 4S or 3R, 4R) -3-anilino-4 - [(R) -2- (t-butyldimethylsilyl) tridecyl] -2 -oxetanone, diastereomer A, MS: 475 (M⁺·).

h) The products obtained in steps f) and g) were individually converted analogously to Example Be) into '(3R, 4R or 3S, 4S) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, diastereomer B, mp 104 ° C and respectively (3S, 4S or 3R, 4R) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxethanna, diastereomer A Mp 60 ° -62 ° C, the starting alcohols of Example 79.

/ -36z

Acids of formula Q-OH are known or may be prepared in an analogous manner to known acids, for example by saponification of a corresponding lower alkyl ester in a solvent such as acetone. or methanol with an alkali metal hydroxide such as potassium hydroxide in an alcohol such as ethanol or methanol. Thus, the acidic starting compounds of Examples 2d) and 2e) given below may be prepared as follows:

A solution of ethyl 2-propylmalonamidate (3.8 g) in acetone (30 mL) was treated with 1 N potassium hydroxide (22 mL) in ethanol and stirred for 4 hours, then concentrated with sodium hydrogen carbonate solution and extracted with ethyl acetate. The aqueous phase was acidified to pH 2 at 0 ° C with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried, concentrated and the residue was recrystallized from ethyl acetate / diethyl ether. lico. 1.96 g of 2-propylmalonic acid monoamide, mp 137 ° C were obtained.

In an analogous manner, 2-phenethylmalonamic acid, mp 141.5 ° C, which is the acidic starting compound in Examples 58 and 59, was prepared from ethyl 2-phenethylmalonate.

(+) And (-) - 2-Isopropyl acid monoamide was prepared. (the initial amide compound of Example 11) as follows:

5.5 g of rac-2-isopropylammonic acid monoamide and 12.0 g of quinidine were dissolved in boiling water (100 ml) and seeded with some crystals of (S) -ammonium acid monoamide quinidine salt. (+) - 2-isopropylmalonic and then crystallized. The crystallization was filtered off under suction, washed with water and ether.

-37_: It was diethylated and dried. Thus, 8.3 g of (S) - (+) - 2-isopropylmalonic acid monoamide guinidine salt were obtained. This salt was dissolved in 10% hydrochloric acid and kept at 5 ° C by separating crystals which were suction filtered, washed with water, dried and recrystallized from water with the addition of a few drops. of 1N hydrochloric acid. Thus 720 mg of (S) - (+) -2-isopropyl acid_ç 20 ° C lonetic, mp 174 ° C, [α] = +45.6 ° C^U (ethanol, c = 1).

589

The mother liquor resulting from the crystallization of the quinidine salt was acidified with 10% hydrochloric acid, kept at 5 ° C, separated by suction filtered crystals, washed with water, dried and recrystallized. again in water with a few drops of 1N hydrochloric acid added. Thus, 850 mg of (R) - (-) - 2-isopropylmalonic acid monoamide, mp 176^UC [α] D = -45.6 ° (ethanol, c = 1).

589

The acid starting compound of Example 42 was prepared as follows:

(a) 20.6 g of thiomorpholine was added dropwise to a solution of 13.6 g of methyl malonate monochloride in 100 ml of methylene chloride. After stirring, the mixture was diluted with methylene chloride (200 ml), washed with water in a separatory funnel, then dried, filtered and evaporated. The residue was purified by chromatography on silica gel with methylene chloride and then methylene chloride / acetone (1: 1). 17.6 g of methyl tetrahydro-4-oxo-4H-1,4-thiazine-4-propionate were obtained.

(b) 85 ml of a solution of 1 N potassium hydroxide were added dropwise to a solution of 17.3 g of the ester obtained in step (a) in 170 ml of acetone. After stirring and filtration, it was evaporated

<img file="PT96887B_D0019.tif" />

The mixture was triturated and the residue was triturated in acetone (200 ml) and then filtered. The filter-retained cake was washed with acetone and dried. An aqueous solution of the resulting potassium salt was chromatographed with water on a cation exchange column. The eluate was concentrated to dryness and the residue was triturated with diethyl ether and filtered. 13 g of tetrahydroxy acid were obtained.

<img file="PT96887B_D0020.tif" />

mo follows:

(a) 33 ml of a solution of 1 N potassium hydroxide in a solution of 5.6 g of methyl 1-carbamoyl cyclopentanecarboxylate in 66 ml of acetone were added dropwise. After stirring, the mixture was treated with acetone (250 ml) and the filtered potassium salt separated, then washed with acetone and dried.

(b) A solution of 5,79 g of the potassium salt obtained in 35 ml of water was acidified to pH 1 with 4 ml of concentrated hydrochloric acid at 0 ° C. The precipitate was filtered off, washed with water and then with diethyl ether. After drying, 3.5 g of 1-carbamoyliciciopentanecarboxylic acid were obtained.

The acid starting compound of Example 46 was prepared as follows:

A solution of 10.4 g of monomethyl methoximalonate in 70 ml of methylene chloride at -10 ° C was added dropwise to 26 ml of 25% aqueous ammonia. After stirring the mixture was evaporated and the residue was dissolved with water and chromatographed on a water cation exchange column. The eluant was concentrated, the residue triturated with diethyl ether and filtered. The precipitate was washed with water and dried.

8.9 g of methoxymalmonic acid, mp 128 ° -130 ° C, were obtained.

The acid starting compound of Example 49 was prepared as follows:

A solution of 1.79 g of carbamoyl methyl thioacetic acid in 42 ml of water was treated with 3.71 g of the monoperoxyphthalic acid magnesium salt hexahydrate. After stirring the mixture was filtered and the filtrate which was acidified with 2 ml concentrated hydrochloric acid was concentrated. After filtration, the filtrate was percolated on a cation exchange column, eluted with water and the eluate evaporated to dryness. The residue was suspended in acetone and filtered. It was washed with acetone and dried. 1.65 g of racemic [(carbamoylmethyl) sulfinyl] acetic acid, mp 137-138 ° C, were obtained.

Lower alkyl esters corresponding to the acids of formula Q-OH are known or may be prepared analogously to known esters, for example as described below, from a monoester of formula H- (X)_no-COOR wherein R represents a lower alkyl group through a monoester of a dicarboxylic acid of the formula HOCO- (X) -COOR. Thus the starting acid of Example 2 (f) was prepared as follows:

a) 48 ml of a n-butyl solution were added dropwise. 1.6 M lithium in hexane at 15 ° C to 11 ml diisopropyl.

6 æm 5 g of 4A molecular sieves in 75 ml of tetrahydrofuran. After 15 minutes the reaction mixture was cooled to -78 ° C and a solution of 9.5 g of ethyl 1,3-dioxolane-2-carboxylate in 50 ml of tetrahydrofuran.

After stirring for 20 minutes, carbon dioxide was introduced at a temperature below -70 ° C. After saturation, the mixture was stirred at -75 ° C for 20 minutes and then allowed to return to room temperature. After carbon dioxide volatilization, the reaction mixture was concentrated, the residue was treated with saturated sodium hydrogencarbonate solution and ethyl acetate, the ethyl acetate phase was discarded and the aqueous phase was acidified to 0 ° C. pH 2 with potassium hydrogen sulfate and extracted with ethyl acetate. The ethyl acetate phase was dried and concentrated.

(b) 0.93 ml of isobutylchloroformate in 5 ml of tetrahydrofuran was added dropwise at 0 ° C to a solution of 1,08 g of the product obtained in step a), 1, 1 ml triethylamine and 3 g 4A molecular sieves in 30 ml tetrahydrofuran. After stirring for 40 minutes, ammonia gas was introduced for 10 minutes and then the reaction mixture was stirred overnight, after which it was filtered, concentrated and the residue was chromatographed on silica gel with sodium chloride. methylene / methanol (95: 5). This afforded 420 mg of ethyl 2-carbamoyl-1,3-dioxolane-2-carboxylate, mp 99 ° -100 ° C.

c) A solution of 190 mg of the product obtained in step b) in 10 ml of methanol was treated with 1 ml of 2N potassium hydroxide in methanol and stirred at room temperature for 90 minutes. Then a solution of 280 mg of potassium hydrogen sulfate in 1 ml of water was added, the reaction mixture was filtered under suction and the filtrate was evaporated. Thus, 2-carbamoyl-1,3-dioxolane-2-carboxylic acid was obtained.

Similarly, from ethyl m-dioxane-2-carboxylate, 2-carbamoyl-m-dioxane-2-carboxylic acid (the acid starting compound of Example 3m) was obtained.

-4lV_

Acids of general formula (Rg, R₄) NCO (X)_no-COOH wherein X represents a group -CHN (R, Rg) may be prepared from the corresponding dicarboxylic acid monoesters of the formula HOCO-X-COOR by the corresponding succinimide and amide ester correspondent of general formula H₂NCO-X-COOR, for example as described below for the acid starting compound of Example 9.

a) 4.54 g of dicyclohexylcarbodiimide acid, 4.16 g of monoethyl acetaminomalonate and 2.53 g of N-hydroxysuccinimide were added to 54 ml of tetrahydrofuran at 0 ° C. After stirring for 1 hour, the mixture was allowed to return to room temperature and stirred overnight. It was then cooled to 0 ° C and filtered. The filtrate was treated with 20 ml of 25% aqueous ammonia solution, allowed to stand at room temperature during the day and at 4 ° C overnight. The solution was then evaporated and the residual aqueous solution was treated with sodium hydrogen carbonate. The aqueous phase was separated, the organic phase was washed with a saturated sodium chloride solution, then dried and concentrated. The residue was filtered into hexane containing ethyl acetate. Crystals were obtained which were washed with diethyl ether and then dried. Thus 1.2 g of the [D, L] -N-acetyl-2-carbamoyl glycine ether ester, mp 126 ° -128 ° C.

(b) 5.8 ml of 1 N potassium hydroxide solution was added dropwise to a suspension of 1.09 g of the amide ester obtained in step a) in 7 ml of acetone. After stirring for 3 hours the mixture was concentrated and the residue was dissolved in aqueous sodium hydrogen carbonate solution. The solution was extracted with ethyl acetate, the aqueous phase was acidified to pH3 with cooling hydrochloric acid and then percolated through an ion exchanger. The eluate was concentrated to dryness and the residue triturated with acetone. 500 mg of [D, L] -N-acetyl-2-carbamoyl glycine, mp 120 ° C (decomposition) were obtained.

The acid starting compounds of formula (Rg, R₄) -NCO (X)_no-COOH wherein at least one of R5 and R4 is not hydrogen, may be prepared by reacting the corresponding acid ester of formula - (X)_no-C (0) -0-R with an amine of formula HN (Rg, R₄).

Thus, the acid starting compound of Example 10d) was prepared as follows:

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

Oxetanones of formula I have important pharmacological properties. In particular, they inhibit pancreas lipase and can thus be used for the control and prevention of obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

Inhibition of pancreas lipase by the oxetanones of formula I can be demonstrated experimentally by titrating the oleic acid released by cleavage of triolein by porcine pancreatic lipase. To an emulsion containing 1mM taurode soxylate, 9mM taurocholate, 0.1mM cholestrol, 1mM egg licitin, 15mg / ml BSA, 2mM Tris-HCP, 100mM sodium chloride, 1mM calcium chloride and triolein as substrate A compound of formula I dissolved in ethanol or dimethyl was added. sulfoxide (10% of the emulsion volume) and the reaction was started by

Addition of 1 to 3 µg porcine pancreatic lipase. The pH was maintained at 8 during the reaction by the addition of sodium hydroxide solution. The CI was calculated from the consumption of the determined sodium hydroxide solution over 10 minutes. C14 is the concentration at which Lipase activity is inhibited to half of its maximum value. The following table contains the ICj-θ values ​​determined for the compounds (f and formula I.

<td>Example</td><td>la, 11a</td><td>lb, llb</td><td>2b, 12b</td><td>2d</td><td>2e</td><td>2f</td><td>2gl.13a</td><td>2g2</td>

<td>^CI50</td><td> 0,032</td><td> 0,025</td><td> 0,063</td><td> 0,12</td><td> 0,051</td><td> 0,47</td><td> 0,052</td><td> 0,013</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Example</td><td>3c</td><td>3d</td><td>3e</td><td>3f</td><td>3g</td><td>3am</td><td>3i</td><td>3j</td>

<td>^CI50</td><td> 0,39</td><td> 0,90</td><td> 1,41</td><td> 0,083</td><td> 0,294</td><td> 2,1</td><td> 0,42</td><td> 0,16</td>

<td>Example</td><td>3k</td><td> 31</td><td>4th</td><td>6b, 14c</td><td>7b</td><td>10th</td><td>10b</td><td>10c</td>

<td>^CI50</td><td> 0,12</td><td> 0,78</td><td> 0,16</td><td> 0,056</td><td> 0,079</td><td> 0,083</td><td> 0,042</td><td> 0,1</td>

<td colspan="9"></td>

<td>Example</td><td>10d</td><td>10</td><td>10 37</td><td> 43</td><td> 45</td><td> 51</td><td>78c</td><td>78d</td>

<td>^CI50</td><td> 0,47</td><td> 0,027</td><td> 0,32 0,034</td><td> 0,12</td><td> 0,047</td><td> 0,36</td><td> 0,28</td><td> 0,051</td>

Acute toxicity (after single oral administration to murine gains) was greater than 5000mg / kg for the products of Examples 3d, 3h, 3i, 31, 4a and 10a, b, and, f.

<img file="PT96887B_D0021.tif" />

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

For the preparation of pharmaceutical compositions, the products according to this invention may be processed with pharmaceutically inert organic or inorganic carriers. Lactose, maize starch or its derivatives, talc, stearic acid or salts thereof may be used, for example, as tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, liquid or semi-solid polyols; however, depending on the nature of the active ingredient, carriers are generally not required for soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose.

In addition, the pharmaceutical compositions may contain preservatives, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for osmotic pressure variation, buffering agents, coating agents or agents. antioxidants. They may also contain other substances with therapeutic validity.

As mentioned above, drugs containing an oxetanone of formula X are also the subject of the present invention as well as a process for the preparation of such compounds.

These medicaments comprise incorporating in an dosage form an oxetanone of formula I and, if appropriate, one or more substances with therapeutic properties. As noted, the compounds of formula I may be used for the control or prevention of disease, especially for the control or prophylaxis of obesity, hyperlipemia, atherosclerosis and arteriosclerosis. The dose may vary between wide limits and will, of course, be chosen according to the individual requirements of each particular case. In general, for oral administration, the daily dose is about 0.1 mg to 100 mg / kg body weight.

Oxetanones of formula I may also be added to industrially produced foods and may be considered as fats, oils, butters, margarines, chocolates and other made-up foods. These industrially produced foods which may contain from about 0.1 to 5% by weight of an oxetanone of formula I, as well as their preparation, are also an object of the present invention.

The following examples illustrate the present invention in greater detail, but are not to be construed as limiting its scope in any sense. All temperatures are given in degrees Celsius.

Example 1

A solution of 574 mg of (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone, triphenylphosphine 525 mg, 2-acid monamide 290 mg isopropylmalonic acid and 2 g of molecular sieves (4%) in 10 ml of tetrahydrofuran with stirring at 0 ° C with 0,4 ml of diisopropyl azodicarboxylate. After stirring at that temperature for 30 minutes and at room temperature for 1 hour, the reaction mixture was filtered, the molecular sieves were washed with diethyl ether and the solvent was evaporated. The residue was dissolved in hexane and extracted with methanol / water (7: 3). The diethyl ether hexane phase was diluted, dried and evaporated. The residue was chromatographed on silica gel with methylene chloride / diethyl ether (9: 1). Obtained:

a) 239 mg of (S) - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (R or S) -2-isopropylmalonamate, mp 115 ° C; and

b) 266 mg of (S) - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (S or R) -2-isopropylmalonamate, mp 118 ° C.

Example 2

Similarly to Example 1, from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and Î ± monoamide. 2-isopropylmalonic acid gave:

a) (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (R or S) -2-isopropylmalonate, mp 136 ° C; and

(b) (S) R - (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -2-isopropyl, mp 82 ° C;

c) from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and isopropylidenomalonic acid monoamide gave (S) 2-carbamoyl-3-methylcrotonate ) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl mp 108 ° -111 ° C;

d) from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-propylmalonic acid monoamide gave (RS) -

<img file="PT96887B_D0022.tif" />

(S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (2: 1 epimers) mp 92 -94 ° C Ç;

e) from (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone and 2-propylmalonic acid monoamide gave (RS) -2-carbamoylvalerate of (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl epimers 1: 1), mp 78 ° -80 ° C;

f) from (3S, 4S) -ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxethane and 2-carbamoyl-1,3-dioxolane-2-carboxylic acid gave 2 (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] -octadecyl-carbamoyl-1,3-dioxolane-2-carboxylate, mp 95 ° C.

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

1. (All Z, S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl (R or S) -2-isopropylmalonamate, mp 87 ° -88 ° C (in diethyl 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 cm¹.

Example 3

In a manner analogous to the procedure described in Example 1, the following ester amides were obtained by reacting (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone with following amides:

a) with 4-carbamoylbutyric acid, 4-carbamoylbutyric acid (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, mp 67 - 68 ° C.

<img file="PT96887B_D0023.tif" />

b) with 3-carbamoylpropionic acid, 3-carbamoylpropionic acid (S) -1 - [[((2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, mp 50 0.5 ° -51 ° C;

c) with 2-carbamoyl acetic acid, 2-carbamoyl acetic acid (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester, mp 86.5 ° -87 ° C;

(d) with oxalic acid monoamide, (S) -1 - [[(2S,

3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl, mp 77 ° -78 ° C;

e) with methylcarbamoylacetic acid, (S) -1 - [[(23,3S) -3-hexyl-4-oxo-2-oxetanyl] methyl dodecyl N-methylmalonamate, mp 63 ° -67 ° C;

f) with racemic 2-carbamoyl-4-methylvaleric acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2 (RS) -2-carbamoyl-4-methylvalerate acid oxo-tanyl] methyl] dodecyl (1: 1 epimer), mp 102 ° -104 ° C;

g) with 1-carbamoylcyclohexanecarboxylic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 1-carbamoylcyclohexanecarboxylate, Mp 50-52 ° C;

h) with 2,2-dimethylmalonamidic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 2,2-dimethylmalonamate, [α] D = 23.8 ° C (CHCl 3, C = 0.9%);

(i) with racemic 2-methylmalonamidic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] - (RS) -2-methylmalanomate dodecyl (1: 1 epimers), mp 107 ° -108 ° C;

j) with racemic 2-ethylmalonamidic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] - (RS) -2-ethylmalone dodecyl (1: 1 epimers), mp 87 ° -90 ° C;

k) with racemic 2-butylmalonamidic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] - (RS) -2-butylmaranoic acid dodecyl (1: 1 epimers), mp 96 ° -98 ° C;

(l) with 2,2-diethylmalonamidic acid, (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 2,2-diethylmalonate, [α] D = -21.1 ° C, (CHCl 3, C = 1%);

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

Example 4

Similarly to the procedure described in Example 1, from (3S, 4S) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone;

and

a) From 1-carbamoylcyclohexanecarboxylic acid gave (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl 1-carbamoylcyclohexanecarboxylic acid Mp 78 ° -79 ° C; and

b) 2-carbamoyl-m-dioxane-2-carboxylic acid afforded (S) -1 - [[(2S, 3S) -3-ethyl-4-2-carbamoyl-m-dioxane-2-carboxylate -oxo-2-oxetanyl] methyl] octadecyl, mp 79 ° C.

Example 5

Similarly to the procedure described in Example 1, from (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone and 2-isopropylmalonic acid amide obtained - if:

(a) (R) or (S) -2-isopropylmalonamate from (S) -1 - [[(2R, 3R or 2S, 3S) Ζ +

-4-οχο-3 pentylthio-2-oxetanyl] methyl] dodecyl, MS: 354 [M '- (2-isopropylmalonic acid amide)]; IR (cm): 3397, 2924, 1829, 1731, 1657, 1120; and

b) (S) R - (S) -1 - [[(2R, 3R or 2S, 3S) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl (S or R) -2-isopropyl, mp 77 -78 ° C (diethyl ether).

Example 6

Similarly to the procedure described in Example 1, from (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxytridecyl-3-pentylthio-2-oxetanone and 2-isopropylmalonic acid amide were obtained. if:

a) (S) -1 - [[(2S, 3S or 2R, 3R) -4-Oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl (R or S) -2-isopropylmalonamate, mp 133 ° C ° C (ethyl acetate); and

b) [S: R or R: S (2) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-phenylthio-2-oxetanyl] (2: 1) -2-isopropylmalonamate] methyl] dodecyl, mp 102-104 ° C (ethyl acetate).

Example 7

Similarly to Example 1, 3-benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-isopropylmalonic acid monoamide gave a mixture of epimers which were separated by gel chromatography. of silica with ethyl acetate / hexane / methylene chloride (1: 2: 2) in:

a) (S -) -1 - [[(2R, 3R) -3-Benzyl-4-oxo-2-oxetanyl] methyl] dodecyl (R or S) -2-isopropylmalonamate, mp 85 ° -87 ° C ° C (methylene chloride); and

b) (S) -1 - [[(2R, 3R) -3-Benzyl-4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -2-isopropylmalonamate, mp 108 ° -110 ° C (methylene chloride).

Example 8

Similarly to Example 1, from 3-benzyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-isopropylmalonic acid monoamide, a mixture of epimers was obtained which was separated by gel chromatography. of silica with ethyl acetate / hexane / methylene chloride (1: 2: 2) in:

a) (S) -1 - [[((2S, 3S) -3-Benzyl-4-oxo-2-oxetanyl] methyl] dodecyl (R or S) -2-isopropylmalonamate, mp 107 ° -108 ° C (methylene chloride); and

b) (S) -1 - [[(2S, 3S) -3-Benzyl-4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -2-isopropylmalonamate, mp 148 ° -149 ° C (methylene chloride).

Example 9

1.03 g of di-t-butyl azodicarboxylate was added to a suspension cooled to -10 ° C of 1.06 g of (3S, 4S) -3-hexyl-4 - [(R ) -2-hydroxytridecyl] -2-oxetanone, (D, L) -N-acetyl-2-carbamoylglycine 480 mg, triphenylphosphine 1.1 g and 1.2 g of 4S molecular sieves in 12 ml of tetrahydrofuran. hydrofuran. After stirring at 0 ° C for 1 hour and at room temperature overnight, the reaction mixture was transformed in a manner analogous to that described in Example 1. Obtained:

a) 190 mg of (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (R or S) -2-acetamidomalonamate, mp 125 ° -126 ° C; and

(b) 100 mg of (S) -1 - [[((2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-acetamidomalonamate, (1: epimers: 1), P.

Mp 110 ° -116 ° C, [edp ° = -8 ° (c = 0.5, CHCl₃)

Example 10

Similar to the procedure described in Example 1, the following ester amides were obtained, but using the following amides:

(a) from oxalic acid monoamide, (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl oxamate, mp 99 ° 100 ° Ç;

(b) from 2-carbamoylacetic acid, (S) —1—

- [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl, mp 90.5-91.5 ° C;

c) from methylcarbamoylacetic acid, (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl N-methylmalonamate, P.

84-85 ° C;

d) from dimethylcarbamoylacetic acid, (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octyl N, N-dimethylmalanomate, mp 66 ° -67 ° C;

e) from the racemic 2-ethylmalonamidic acid, (RS) -2-methyl]. (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl malonamate (1: 1 epimers), mp 91.5 ° -92 ° C ;

f) from 3-carbamoylpropionic acid, (S) -1 - [[((2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl succinamate, PF 74, 5th

<img file="PT96887B_D0024.tif" />

-75.7 ° C.

Example 11

Similar to the procedure described in Example 1, but using (S) - (+) - or (+) - 2-isopropyl-malonic acid monoamide, we obtained:

a) (S) - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (R) -2-isopropylmalonamate, mp 115 ° C; and

b) (S) - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (S) -2-isopropylmalonamate, mp 118 ° C.

Example 12

Similarly to Examples 1, 2 a), b) and 11, from. (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and (+) - and (S) - (+) -2-isopropylmalonic acid monoamide, obtained if:

a) (r) -2-isopropylmalonamate-oxetanyl] methyl] dodecyl, P

b) (S) -2-Isopropylmalonamate-oxetanyl] methyl] dodecyl, P of (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2F. 136 ° C; and, respectively, of (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2F. 82 ° C;

(c) from (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone and 2-propylmalonic acid monoamide after separation by silica gel chromatography with methylene / acetonitrile (85:15);

1. (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (R or S) -2-carbamoylvalerate, mp 113 ° C (in methanol / Water); and

2. (S or R) -2-carbamoylvalerate of

<img file="PT96887B_D0025.tif" />

(S) -1 - [[(2S, 3S) -3-Hexyl-4oxo-2-oxetanyl] methyl] dodecyl, mp 85 ° C.

Example 13

Similarly to Examples 1, 2g) and 11, from (3S, 4S) -3-ethyl-4 - [(R, 10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone and (+) θ (S) - (+) - 2-isopropylmalonic acid monoamide, obtained:

a) (all Z, S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl (R) -2-isopropylmalonamate, mp 87 ° -88 ° C (in diethyl ether); and

b) (all Z, S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] -9,12-octadecadienyl (S) -2-isopropylmalonamate, mp 109 ° C (in aqueous methanol).

Example 14

Similarly to Examples 1, 6 and 11, from (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxytridecyl] -3-pentylthio-2-oxetanone and (+) and (S) - (+) - 2-isopropylmalonamide, obtained:

a) (S) -1 - [[(2S, 3S or 2R, 3R) -4-Oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl (R) -2-isopropylmalonamate, mp 133 ° C (ethyl acetate);

b) (S) —1 - [[(2S, 3S or 2R, 3R) - (S) -2-isopropylmalonamate, (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetanyl] methyl] dodecyl, mp 93 ° C (diethyl ether / hexane); and ' . χ ζ

-55c) [S: R (2: 1)] - (S) -1 - [[(2S, 3S or 2R, 3R) -4-oxo-3-pentylthio-2-oxetan.yl] 2-isopropylmalonamate methyl dodecyl, mp 102-104 ° C (ethyl acetate).

Example 15

Similarly to Examples 1 and 11, from (3S, 4S or 3R, 4R) -benzyl 4 - [(R) -2-hydroxytridecyl] -2-oxo-3-oxetanecarbamate and (S) - acid monoamide (+) -2-Isopropylmalonic, (S) -1 - [[(2S, 3S or 2R, 3R) -3- [1- (benzyloxy) -formamido] - (S) -2-isopropylmalonate 4-oxo-2-oxetanyl] methyl dodecyl, P.

F-133 ° C (in diethyl ether / hexane).

Example 16

Similarly to Examples 1 and 11:

a) from (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, mp 88 ° C (ether );

b) from (3S, 4S) -4 - [(R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone and 2-isopropylmalonic acid monoamide gave (RS) -2- (S) -1 - [[(2S, 3S) -4-Oxo-3- (phenylthio) -2-oxetanyl] methyl] dodecyl isopropyl malonamate (1: 1 epimers), mp 109 ° C (ether); and

c) from (3R, 4R) -4 - ((R) -2-hydroxytridecyl] -3- (phenylthio) -2-oxetanone and 2-isopropylmalonic acid monoamide gave the same products as (a) ) and (S) -1 - [[((2R, 3R) -4-oxo-3- (phenylthio) -2-oxetanyl] methyl] dodecyl 2-isopropylmalonamate

<img file="PT96887B_D0026.tif" />

(R: S = 7: 1), mp 85 ° C (ether).

Example 17

Similarly to Examples 1 and 11, from the following (S) - (+) - 2-isopropylmalonic acid monoamide and the following alcohols the following esters were obtained:

a) from (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, (S) -2-isopropylmalonamate 1 - - [[(2S, 3S or 2R, 3R) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl, mp 133 ° C (in ether);

b) from (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, (S) -2-isopropylmalonamate (s) 1 - [[(2R, 3R or 2S, 3S) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl, mp 103 ° (in ether);

c) from (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, (S) -2-isopropylmalonamate 1 - [[(2R13 S or 2S, 3R) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octa decyl, mp 96 ° C (in ether / hexane); and

d) from (3R, 4S or 3S, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone, (S) -2-isopropylmalonamate 1 - - [[(2S, 3R or 2R, 3S) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octa decyl. Mp 120 ° C (in ether / hexane).

Example 18

Similarly to Examples 1 and 11, from (R) - (-) - 2-isopropylmalonic acid monoamine and from:

a) (3S, 4S or 3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2 /₅7·

V,

- '' ··· '-j

oxetanone, (S) -1 - [[(2S, 3S or 2R, 3R) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] - (R) -2-isopropylmalonamate was obtained. octadecyl, mp 96 ° C (ether);

b) (3R, 4R or 3S, 4S) -4 - [(R) -2-hydroxynonadecyl] -3- (methylthio) -2-oxetanone gave (S) -1 (R) -2-isopropylmalonamate - [[(2R, 3R or 2S, 3S) -3- (methylthio) -4-oxo-2-oxetanyl] methyl] octadecyl, mp 87 ° C (in ether / hexane).

Example 19

Similarly to Examples 1 and 11, from the following (S) - (+) - 2-isopropylmalonic acid monoamide and the following alcohols, the following esters were obtained:

a) from (3S, 4S or 3R, 4R) -3- (benzylthio) -4 - [(R) -2-hydroxy-tridecyl] -2-oxetanone, (S) -2-isopropylmalonamate from (S ) -1 - [[(2S, 3S or 2R, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl, P.

Mp 84 ° C (in pentane),

b) from (3R, 4R or 3S, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxy tridecyl] -2-oxetanone, (S) (S) -2-isopropylmalonamate -1 - [[(2R, 3R or 2S, 3S) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl,

Mp 65 ° C (in ether / pentane); and

c) from (3S, 4R and 3R, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxyitridecyl] -2-oxetanone:

1. (S) -1 - [[((2S, 3R or 2R, 3S) -3-Benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl (S) -2-isopropylmalonamate, mp 69 ° C^çC (in pentane); and

2. (S) -1 - [[(2R, 3S or 2S, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl (S) -2-isopropylmalonamate, mp 106 ° Ç

<img file="PT96887B_D0027.tif" />

(in hexane).

Example 20

Similarly to Examples 1 and 11, from the (R) - (-) - 2-isopropylmalonic acid monoamine and the following alcohols, the following esters were obtained:

a) from (3S, 4S or 3R, 4R) -3- (benzylthio) -4 - [(R) -2-hydroxy tridecyl] -2-oxetanone, (S) (R) -2-isopropylmalonamate - 1 - [[(2S, 3S or 2R, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl, P.

Mp 130 ° C in ether / pentane);

b) from (3R, 4R or 3S, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxytridecyl] -2-oxetanone, (S) - (R) -2-isopropylmalonamate 1 - [[(2R, 3R or 2S, 3S) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl, mp 119 ° C (in hexane / pentane); and

c) from (3S, 4R and 3R, 4S) -3- (benzylthio) -4 - [(R) -2-hydroxyitridecyl] -2-oxetanone:

1. (S) -1 - [[(2S, 3R or 2R, 3S) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl (R) -2-isopropylmalonamate, mp 132 ° C (in ether / pentane); and

2. (S) -1 - [[(2R, 3S or 2S, 3R) -3- (benzylthio) -4-oxo-2-oxetanyl] methyl] dodecyl (R) -2-isopropylmalonamate, mp 102 ° C (in ether / pentane).

Example 21

Similarly to Examples 1 and 11, reacting (3R,

4R) -3-ethyl-4 - [(R) -2-hydroxynonadecyl] -2-oxetanone

-s / a) with (S) - (+) - 2-isopropylmalonic acid monoamide gave (S) -1 - [[(2R, 3R) -3-ethyl (S) -2-isopropylmalonate -4-oxo-2-oxetanyl] methyl] octadecyl, mp 116 ° C^O-118 ° C (methylene chloride); and

b) 1-carbamoyl.hexohexanecarboxylic acid afforded (S) -1 - [[(2R, 3R) -3-ethyl-4-oxo-2-oxetanyl] methyl 1-carbamoylcyclohexanecarboxylate ] -octadecyl, mp 71 ° -74 ° C.

Example 22

Similarly to Examples 1 and 11:

a) from (S) - (+) - 2-isopropylmalonic acid monoamide and from (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-methyl-2-oxetanone (S) -1 - [[((2R, 3R) -3-Methyl-4-oxo-2-oxetanyl] methyl] octadecyl (S) -2-isopropylmalonamate, mp 124 ° -126 ° C (in acetate - ethyl / hexane); and

b) from racemic 2-t-butylmalonic acid monoamide and (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-methyl-2-oxetanone gave (RS) -2 S - -1 - [[(2R, 3R) -3-Methyl-4-oxo-2-oxetanyl] methyl octadecyl t-butylmalonamate (1: 1 epimers), mp 51 ° -54 ° C (ethyl acetate / hexane).

Example 23

A solution of 277 mg of (2S, 3S, 5S) -5 - [[(cis) -2-carbamoylcyclohexyl] oxy] -2-hexyl-3-hydroxyhexanoic acid (Example Jd) in 24 ml methylene chloride and 3 ml dimethylformamide with 2 g molecular sieves (48), 240 mg HBTU and 240 mg triethylamine. After stirring were added

300 mg HBTU and 300 mg triethylamine. The mixture was then filtered and the filtrate concentrated. The residue was taken up in methanol / water (7: 3) and hexane and extracted with hexane. The hexane phase was diluted with methylene chloride, then dried and concentrated and the residue was recrystallized from diethyl ether / hexane. Thus were obtained:

a) 96 mg of (IR or S, 2S or R) -2 - [[((2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyloxy] cyclohexanecarboxamide ( Diastereomer (cis), mp 102 ° C (in ether / hexane); and

b) analogously from the (2S, 3S, 5S) -5 - [[((cis) -2-carbamoylcyclohexyl] oxy] -2-hexyl-3-hydroxyhexadecanoic acid (diastereomeric acid) of Example Je ) was obtained (IS or R, 2R or S) -2 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] -oxy] -cyclohexanecarboxamide (20C diastereomer), mp 94 ° C (in diethyl 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) 10 ml methylene chloride / acetonitrile (1: 1) with 1 g molecular sieves (4S), 0.1 ml triethylamine and 50 mg HBTU. After stirring, the reaction mixture was filtered and concentrated and the residue partitioned between hexane and methanol / water (1: 1); The aqueous methanolic phase was extracted with hexane, the hexane phase was dried and concentrated; The residue was then chromatographed on silica gel with 5% methanol in methylene chloride. In this way 21 mg of (R / S) -3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl were obtained. ] -oxy] -3-methoxypropionyl

<img file="PT96887B_D0028.tif" />

namide (3: 1 epimers)_z Mp 54 ° C.

Example 25

Ammonia gas was introduced into a 40 mg solution of 3 - [[(S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl] oxy acid ] -propionic acid (Example L) in 2.5 ml acetonitrile until the solution was saturated and then 50 mg HBTU was added. The mixture was then filtered and evaporated, the residue was chromatographed on silica gel with 5% methanol in methylene chloride. 32.5 mg of (3S, 4S) -4 - [(S) -2- (2-carbamoylethoxy) tridecyl] -3-hexyl-2-oxetanone, mp 35 ° C.

Example 26

A solution of (S) -1 - [[((2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl hydrogen malonate (33.5 mg) was treated with 2 ml acetonitrile with 60 mg HBTU and 75 mg isopropylamine. After stirring, the reaction mixture was filtered, the filtrate concentrated and the residue was 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-isopropylmalonamate, mp 59 ° C.

The following compounds are prepared analogously to Example 1.

Example 27: (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-oxetanyl] methyl] dodecyl 5-carbamoyl valerate, mp 50 ° -51 ° C.

Example 28: (S) -1 - [[(2S, 3S) -3-Hexyl] 6-carbamoylhexanoate

-62ΐ »

-4-oxo-2-oxetanyl] methyl] dodecyl. Mp 52 ° -53 ° C.

Example 29: (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 7-carbamoyl heptanoate. Mp 40 ° -43 ° C.

Example 30: (S) - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 9-carbamoylnonanoate. Mp 29 ° -30 ° C.

Example 31: (S) -1 - [[((2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] .octadecyl 4-carbamoylbutyrate. Mp 74 ° -75 ° C.

Example 32: (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl adipamate. Mp 63.5 ° -64.5 ° C.

Example 33: (S) -1 - [[((2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl 6-carbamoylhexanoate. Mp 71.5 ° -72.5 ° C.

Example 34: (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-oxetanyl] methyl] dodecyl (R or S) -2-t-butylmalonamate. Mp 53 ° -54 ° C.

Example 35: (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -2-t-butylmalonamate. [ο &lt;] ^ θ = -16.4 ° (c = = 0.8, CHCl₃)

Example 36: (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-oxetanyl] methyl] octadecyl (R or S) -2-t-butylmalonamate. Mp 48 ° -49 ° C.

Example 37: (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (S or R) -2-t-butylmalonamate. MP 81-82 ° C.

Example 38: (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (S) -3- [1- (benzyloxy) formamido] succinate. Mp 72 ° -73 ° C.

Example 39: (S) - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl cis-6-carbamoyl-3-cyclohexene-1-carboxylate. Mp 55 ° -59 ° C.

/

Example 63: (S) - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl cis-2-carbamoylcyclohexanecarboxylate. Mp 76 ° 77 ° C.

Example 41: (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl p-oxo-4-morpholinopropionate. Mp 49 ° -51 ° C.

Example 42: (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl tetrahydro-β-OXO-4H-1,4-thiazine-4-propionate -dodecyl. Mp 59 ° -61 ° C.

Example 43: (S) -1 - [[(2S, 1-Carbamoylcyclopentanecarboxylate)

3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl. Mp 62 ° -63 ° C.

Example 44: (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 1-carbamoylcyclopentacarboxylate. Mp 40 ° -41 ° C.

Example 45: (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-oxetanyl] methyl] dodecyl (RS) -2-benzylmalonamate. Mp 86 ° -92 ° C.

Example 46: (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-methoxymalonamate. Mp 65 ° -67 ° C.

Example 47: (S) -1 - [[((2S, 3S) -3-Hexyl] -4-oxo-2-oxetanyl] methyl] dodecyl [(carbamoyl) -thio] -acetate. Mp 58 ° -60 ° C.

Example 48: (S) -1 - [[(2S, 3S) -3-Aethyl-4-oxo-2-oxetanyl] methyl] octadecyl [(carbamoylmethyl) -thio] -acetate. Mp 83-84 ° C.

Example 49: (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl [(RS) - (carbamoylmethyl) sulfinyl] acetate (1: 1 epimer) , P.

Mp 55-59 ° C.

Example 50: (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (RS) - (carbamoylmethyl) thio] acetate S-oxide. Mp 80 ° 82 ° C.

Example 51: (S) -1 - [(2-Carbamethylethyl) thio] propionate [[(2S

-643S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl. Mp 73 ° -74 ° C.

Example 52: (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl 3 - [(RS) - (2-carbamoylethyl) sulfinyl] propionate. Mp 48 ° -51 ° C.

Example 53: (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (carbamoylmethoxy) acetate. Mp 52 ° -53 ° C.

Example 54: (S) -1 - [[((2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (carbamoylmethoxy) acetate. Mp 75 ° -76 ° C.

Example 55: (RS) -2- [1- (Benzyloxy) formamido] malonamate (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanylmethyl] dodecyl (epimers 1 : 1), MP 94 ° -95 ° C

Example 56: (S) -1 - [[((2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (RS) -2-isobutylmalonamate (1: 1 epimer), PF

96-99 ° C.

Example 57a) (S) -1 - [[((2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (RS) -2-benzylmalonamate (1: 1 epimer), mp 96 ° -103 ° C.

Example 57b; (S) -1 - [[(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl] octadecyl (R or S) -2-benzylmalonamate. Mp 118 ° -120 ° C.

Example 58: (S) -1 - [[((2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] dodecyl (RS) -2-phenethylmalonamate (1: 1 epimer), mp 92 ° -93 ° C.

Example 59: (S) -1 - [[((2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] methyl-octadecyl (RS) -2-phenethylmalonamate (epimers), mp 97 ° -98 ° Ç.

Example 60

Analogous to Examples 1 and 11, from monoami f

(S) - (+) - 2-Isopropylmalonic Acid and (3R, 4R) -4 - [(R) -2-Hydroxynonadecyl] -3- (2-propynyl) -2-oxetanone (Example Μ ), (S -) -1 - [[((2R, 3R) -4-Oxo-3- (2-propynyl) -2-oxetanyl] methyl] octadecyl (S) -2-isopropylmalonamate was obtained, Mp 92 ° -95 ° C (in ethyl acetate / hexane).

Example 61

Similarly to Examples 1 and 11, from (S) - (+) - 2-isopropylmalonic acid monoamide and (3R, 4R) -4 - [(R) -2-hydroxynonadecyl] -3-propyl-2 -oxetanone (Example 0) gave (S) -1 - [[(2R, 3R) -4-oxo-3-propyl-2-oxetanyl] methyl] octadecyl (S) -2-isopropylmalonamate, Mp 90 ° -93 ° C (in ethyl acetate / hexane).

The following compounds are prepared analogously to those described in Examples 1 and 11:

Example 62: (S) -1 - [[(2S, 3S) -3- (3-Methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl (R or S) -2-isopropylmalonamate . Mp 100 ° -102 ° C.

Example 63: (S) -1 - [[(2S, 3S) -3- (3-Methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -2-isopropylmalonamate Mp 120 ° -121 ° C.

Example 64: (S) -1 - [[((2R, 3R) -3- (3-Methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl (R or S) -2-isopropylmalonamate Mp 60 ° -62 ° C.

Example 65: (S) -1 - [[(2R, 3R) -3- (3-Methyl-2-butenyl) -4-oxo-2-oxetanyl] methyl] dodecyl (S or R) -2-isopropylmalonamate Mp 76-78 ° C.

<img file="PT96887B_D0029.tif" />

Example 66: (S) -1 - [[(2S, 3S or 2R, (S) -2-isopropylmalonamate),

3R) -3- (5-chlorophenyl) -4-oxo-2-oxetanyl] methyl] dodecyl, δ. Mp 66 ° -72 ° C.

Example 67: (S) -1 - [[(2S, 3S or 2R, (R) -2-isopropylmalonamate),

3R) -3- (5-chlorophenyl) -4-oxo-2-oxetanyl] methyl] dodecyl, mp

130 ° C.

Example 68: (S) -1 - [[(2R, 3R or 2S (S) -2-isopropylmalonamate),

3S) -3- (5-chlorophenyl) -4-oxo-2-oxetanyl] methyl] dodecyl, mp 44 ° 50 ° C.

Example 69: (S) -1 - [[(2R, 3R or 2S (R) -2-isopropylmalonamate),

3S) -3- (5-chlorophenyl) -4-oxo-2-oxetanyl] methyl] dodecyl, mp 85 ° 87 ° C.

Example 70: (S) -1- (2S, 3S or 2R, 3R) - [[3 - [(α-2-butenyl] -4-oxo-2-oxetanyl] (R or S) -2-isopropylmalonamate methyl] dodecyl, mp 105-107 ° C.

Example 71: (S) -1- (2S, 3S or 2R, 3R) - ([S - R) -2-isopropylmalonamate] - [[3 - [(E) -2-butenyl] -4-oxo-2-oxetanyl ] methyl] dodecyl, mp 96 ° -98 ° C.

Example 72: (S) -1- (2R, 3R or 2S, 3S) (S) -2-Isopropylmalonamate - [[3 - [(E) -2-Butenyl-4-oxo-2-oxetanyl] methyl] dodecyl, mp 89 ° -90 ° C.

Example 73: (S) -1- (2R, 3R or 2S, 3S) (R) -2-Isopropylmalonamate - [[3 - [(E) -2-Butenyl-4-oxo-2-oxetanyl] methyl] dodecyl, mp 60 ° 63 ° C.

Example 74: (S) -1 - [[(2R, 3R or 2S (R) -2-isopropylmalonamate),

3S) -3- (2,3,4,5,6-pentafluorobenzyl) -2-oxetanyl] methyl] dodecyl,

Mp 107 ° -109 ° C.

* Ί

Example 75: (S) -1 - [[(2R, 3R or 2S (S) -2-isopropylmalonamate),

3S) -3- (3,4,5,6-pentafluorobenzyl) -2-oxetanyl] methyl] dodecyl, P.

Mp 115-118 ° C.

Example 76: (S) -1 - [[(2S, 3S or 2R, 3R) -3- (2,3,4,5-pentafluorobenzyl) -2-oxetanyl] methyl] (R) -2-isopropylmalonamate dodecyl, P.

88 ° -90 ° C, and

Example 77: (S) -1 - [[(2S, 3S or 2R (S) -2-isopropylmalonamate),

3R) -3- (2,3,4,5-pentafluorobenzyl) -2-oxetanyl] methyl] dodecyl, P.

Mp 52-55 ° C.

Example 78

Analogous to Examples 1 and 2, but using (R) - or (S) -2-pyrrolidone-5-carboxylic acid instead of 2-isopropylmalonic acid monoamide afforded:

a) 5-Oxo-D-proline (S) -1 - [[(2S, 3S) -3-Hexyl-4-oxo-2-oxetanyl] methyl] decyl ester NMR (CDCl3): 0.88 (m, 6H); 1.26 (m, 2H); 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] decyl ester, mp 51 ° -52 ° C ° C.

c) 5-oxo-D-proline (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester, mp 55 ° C (ether diethyl) and

d) 5-oxo-L-proline (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] oc tadecyl ester, mp 57 ° -58 ° C ° C.

Example 79

Similarly to Examples 1 and 11, from (S) - (+) - 2-isopropylmalonic acid monoamine, and:

a) from 3R, 4R (or 3S, 4S) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, diastereomer B (Example T) gave (S) -2-isopropylmalonamate from (S) -1 - [[(2R, 3R or 2S, 3S) -3-anilino-4-oxo-2-oxetanyl] methyl] dodecyl (diastereomer B), mp 92 ° C; and

b) from (3S, 4S or 3R, 4R) -3-anilino-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, diastereomer A (Example T) gave (S) —2 (S) -1 - [[(2S, 3S or 2R, 3R) -3-Anilino-4-oxo-2-oxetanyl] methyl] dodecyl -isopropylmalonamate (diastereomer A), mp 77 ° C.

The following pharmaceutical compositions were prepared in known manner.

Example A

Soft Gelatin Capsules:

Amounts per capsule

An oxetanone of formula I 50 mg

Medium Chain Triglyceride 450 µl

Example B

Hard Gelatin Capsules:

<td>An oxetanone of formula I</td><td> 20,0</td><td>mg</td>

<td>Crystallized Lactose</td><td> 37,0</td><td>mg</td>

<td>Microcrystalline cellulose :</td><td> 20,0</td><td>mg</td>

<td>Polyvinylpolypyrrolidone</td><td> 8,5</td><td>mg</td>

<td>Sodium salt of starch carboxymethyl ether</td><td> 8,5</td><td>mg</td>

Baby powder

4.5 mg

Example B (cont.) /

-69S

Amounts per capsule

Magnesium stearate

Capsule Filling Weight

4.5 mg

100.0 mg

Example C

Tablets:

<td>An oxetanone of formula I</td><td>30.0 mg</td>

<td>Anhydrous lactose</td><td>118.8 mg</td>

<td>Microcrystalline cellulose</td><td>30.0 mg</td>

<td>Polyvinylpyrrolidone</td><td>10.0 mg</td>

<td>Carboxymethylcellulose polymer</td><td>10.0 mg</td>

<td>Magnesium stearate</td><td>1.2 mg</td>

<td>Weight per pill</td><td>200.0 mg</td>

Example D:

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

<td>An oxetanone of formula I</td><td>60.0 mg</td>

<td>Lactose Powder</td><td>70.0 mg</td>

<td>Hydroxypropyl methylcellulose</td><td>52.5 mg</td>

<td>Polyvinylpyrrolidone</td><td>7.5 mg</td>

<td>Baby powder</td><td>8.0 mg</td>

<td>Magnesium stearate</td><td>1.0 mg</td>

<td>Colloidal Salicylic Acid</td><td>1.0 mg</td>

<td>Core Weight</td><td>200.0 mg</td>

<td>Hydroxypropyl methylcellulose</td><td>2.5 mg</td>

Baby powder

1.25 mg /

-s

<td colspan="2"> 4</td>

<td>Titanium dioxide Coating Film Weight</td><td>1.25 mg 5.0 mg</td>

<td>Example E:</td><td></td>

<td>An oxetanone of formula I</td><td>200.0 mg</td>

<td>Ethylvaniline</td><td>10.0 mg</td>

<td>Aspartame</td><td>30.0 mg</td>

<td>Skimmed powdered milk</td><td>4,760.0 mg</td>

Total

000.0 mg