SA91110250B1 - Oxetanones - Google Patents

Abstract

Novel oxetanones are synthesized that are pancreas lipase-inhibiting enzyme having the formula: where R2, R1, and Q have the meanings given in the description, starting with the corresponding β-hydroxycarboxylic acids.

Description

OXETANONES FULL DESCRIPTION BACKGROUND OF THE INVENTION 2 The present invention relates to novel oxetanones, a method for their manufacture, and pharmaceutical preparations containing these oxetanones, as well as the use of these oxetanones in the manufacture of pharmaceutical preparations. 0 the general description of the invention; These octanones have the formula: 0 ' 4 0=m a I 9 be a group of the formula: (R3 RHNCO(X)y-CO- Ql (R3,RHNCO-X'- 02 nN N C—N (er 1 0 1 3 3 1 and 82 form two alkyls having as many carbons as OMA carbons substituted with one to three halogen atoms or “alkyl or alkynyl” groups alkenyl or alkadienyl having up to Yo JY carbon atom optionally interrupted by ¢4-arylene de gene vo optionally substituted by an aryl group in the © position and optionally substituted by a -alkyl group b ,©871-0; Cum an oxygen atom or a sulfur atom can intersect an RI group or by means of a sulphinyl group an aryl group "e" in a position other than position 0 to an unsaturated carbon atom; or A18 be an aryl- group NH--

’ or R45 R3 aaryl-Cpy -alkyl-OCONH-- form hydrogen or alkyl group | contains 1-;carbon atoms; Or in association with atom 17 connected to it so that together they form a saturated ring having ¥ to 1 members that optionally contains an atom 0 or 8 in a position other than the position NY a « being the number 1 or zero. X is an alkylene group containing up to I carbons; which is optionally interrupted by atom 0 or atom 5 or by sulphinyl ie seas 1 or sulphonyl optionally replaced by hydroxy groups or aryl-Cy4 - J aryl-Cy,4 -alkyl J arylthio J aryloxy J aryl J (mercapto alkoxy or J aryl-Ci4 alkyliden 4 aryl-C,,4 -alkylthio - cycloalkylidene gene: or Cig —alkylidene group or by one group or 0 two Crg-alkyl groups or Cpg-alkoxy or Cg-alkylthio or where te sane can be sala-j© or Cjg-alkoxy or Crg-alkylthio on the same carbon atom or on two adjacent © atoms of a ring containing “ to 1 optionally monosubstituted members or an optionally present hydroxy or mercapto group or must be an optionally present unsubstituted © atom in a position other than the “©” attached to an optionally present 0 or 5 atom or an optionally present [sulphiny] or sulphonyl group ; or a group with the formula: =CHN(R,R") a «-CHN(R,R")CHp- R's R Cua | form hydrogen «aryl «C4 -alkyl(CO or (OCO)- “C4 -alkyl z aryl-Cy4 -alkyl(CO or OCO)- i aryl-C;4 -alkyl “aryl(CO or OCO)- and not to have an alkylene group containing a number of The carbon atoms separate into SION | It can be substituted by -alkoxXy group bur, aryl, aryloxy, arylthio, aryl-Ciy -alkylthio Jf aryl-Cy4 -alkoxy J aryl-C, -alkyl group, or by one or more -Cig groups alkyl where two Cig alkyl groups attached to adjacent © atoms can form a ring of it? to 1 member. 0 can

: : : The present invention describes compounds having the following formula: Q-OCHCH, > =0 | : 7 © being a group of the formula: (R3 RHNCO(X)-CO- Ql (R3,RHNCO-X'- q2 ; “alkyl or alkadienyl having up to J 5,30 carbon interrupted optionally interrupted by a © group (1,4-27160; Adie optionally by an aryl group in the © position and optionally substituted by ov. Via an aryl-Cryg -alkyl group, where an oxygen atom or a sulfur atom can intersect the RD group, or via a sulphinyl or sulphonyl group in a position other than the © position to an unsaturated carbon atom; or R1 The aryl-NH-- group or the -alkyl-OCONH--b,©-ionized group” 183 R45 form two alkyl J hydrogens containing 1- carbon atoms, or in combination with 1 atom connected to it so that they form ve together a saturated ring having YF to 1 members optionally containing an atom 0 or 5 in a position unlike the © position of atom 17. “The number is 1 or 0. X is an alkylene group containing on a number of up to + carbon atoms” which are optionally interrupted by a © atom or a 5 atom or by a sulphinyl or sulphonyl group optionally substituted by hydroxy groups or r 11 o aryl-Ci4 - sl aryl-Ci4 -alkyl J arylthio Ar aryloxy si aryl i.e. mercapto

Cs - 4 aryl-Ci4 —alkyliden J aryl-C,, -alkylthio or alkoxy or by one group or Cp —alkylidene ic sana slcycloalkylidene or where it can be Crg-alkylthio or Cig-alkoxy Or Cyg-alkyl two groups on the same carbon atom -alkylthio or “<” alkyl-er or Cpg-alkyl two groups 0 optionally monosubstituted members 1 or two adjacent © atoms A ring containing on ? to optionally present or must be a non-mercapto © atom or a hydroxy or substituted group optionally present in a position other than position 08 and attached to an optionally present or unsubstituted atom 0 or 5 that is a sulphonyl or sulphinyl group Optionally or a combination of 1 all of the formula: 0 − «-CHN(R,R")CH3- a =CHN(R, R") aryl ben -alkyl(CO or (OCO)- ben -alkyl and 18 form hydrogens R cua and aryl-Cy 4 -alkyl(CO or OCO)- Jl aryl-C;.4-alkyl caryl(CO or OCO)- 1 atoms containing a number of Carbon atoms separated into alkylene form a group © aryl-C, J arylthio or aryloxy or aryl J Ci4-alkoxy can be replaced by a group of 10 or by a group or aryl-Coy alkylthio or aryl-Cy -alkoxy sf b -alkyl bonded to Crg-alkyl atoms where two Crg-alkyl groups can form two members. 17 contiguous ring ?to © straight chain <3 alkadienyl, alkenyl and z-alkyl groups can be branched “propyl “ethyl” methyl ralkyl groups. Examples are Jv., undecyl hexyl “pentyl “isobutyl” butyl “isopropyl” and alkenyl groups. Examples of alkadienyl 5 alkenyl groups represent .heptadecyl analogues respectively. alkadienyl le «phenyl or phenylene «Juli, »phenyl and “sticky” on “Aryl” denote substituted by a number of halogen atoms up to © atoms or phenylene respectively; And ve nitro Cry alkoxy «Cig -alkyl groups up to ?" groups on fluorine, chlorine, bromine and iodine. 'Halogen' indicates

Among the preferred compounds of formula I are those that form Q led: group 01; 11 R25 are alkenyl alkyl or alkadienyl groups in which to 337 carbon optionally interrupted by a 1,4-phenylene ¢ group optionally substituted with a phenyl group in the © position and optionally substituted by a “phenyl-C4 -alkyl” group 0 where a © atom or an 8 atom can intersect R' in a position unlike the a position of an unsaturated © atom; 32 The alkylene group contains up to 1 carbon atom, optionally interrupted by atom 0 or atom 8, and is optionally substituted by a hydroxy group or a mercapto or phenyl i.e. phenoxy or phenylthio i see -alkyl b0 - collide sl - b -ds Cs - sl phenyl-Cy,4 -alkylidene J phenyl-C;4 —alkylthio J alkoxy ; cycloalkylidene 0 or Cig -alkylidene or with one or both groups — Cis alkyl or -alkoxy Br or Cum «Cyg -alkylthio» Two groups - Crs - alkyl or Cy -alkoxy or alkylthio© attached to the same carbon atom can form a ring containing 1 to “ members, and the hydroxy group or mercapto must be in a position other than the a position, with a 0 or 5 atom optionally present, or X, the group “=CHN(R,RO) ve, and the first hydrogen is - BR -alkyl-(CO) BR or (000)- R phenyl R R4,R3,n 4 phenyl-(CO or OCO)-- have the meanings given above. Among the other preferred compounds according to the formula (J) in which © is a '0' group; it is possible to mention compounds in which l18 and 18 have two alkyl, alkenyl, alkynyl or alkadienyl groups each containing 01 A carbon atom optionally substituted by an aryl group © position 0 where 18 can intersect an 8 atom in a position unlike position 0 or an unsaturated C atom; Rf is a canilino or alkyl containing up to 18 A carbon atom (C) substituted by a halogen atom or a -alkyl-OCONH-- b-ab group with an R's R' band forms two hydrogens or a Cry -alkyl group or forms with a [1] atom to which it is attached a saturated ring It includes 1 members and contains an atom 0 or 5 in a position unlike the position » of the 0 atom Sn NO ve the number 1 or yellow as 1 the alkylene group contains up to 1 y and the substituent is sulphinyl or 5 or interrupted by an O group optionally interrupted by an oS atom of atoms, and where “Cig-alkoxy or optionally Cig-alkyl by one or two groups attached to the same © atom or Cig-alkoxy or Cig -alkyl lie gaan Optionally monosubstituted members or M1 can form two adjacent © atoms of a ring containing “ to - form hydrogens; RT; Ry -©1101051870112- or =CHN(RR') form a group of 0 -benzyloxycarbonyl i alkanoyl (C,) and 11 Q octanones represented by the formula 1 are also preferred in which © forms a group of be X's form Hydrogen Ry and 18 Crop -alkyl independent diay ois RY, containing a number of carbon atoms preferably to 6 carbon atoms alkylene group: (Crg-alkyl or with one or two groups Crug -alkoXy replacing it with a cas < 0 group attached to adjacent carbon atoms forming a © ring: -alkyl where two groups can form 1 JY members of R 5 in which the © group is 0; T preferably Also the octanones with the formula or hexyl, especially “Cig -alkyl”, each one being independently R75 hydrogen and an 8 .undecyl 0, are particularly preferred among the octanones of formula 1, in which © is hexyl sl propyl ethyl 5 methyl R is those compounds in which Q' ic gana or methylthio or 2-propynyl 4 3-methyl-2-butenyl J 2-butenyl Jf or benzylthio R phenylthio sf benzyl J 5-chloropentyl pentylthio is R' where ¢benzyloxycarbonylamino 4 anilino J pentafluorobenzyl r. ol 6S R', rR' and 8,11-heptadecadienyl J heptadecyl si undecyl : form an N group or in association with an isopropyl or methyl atom | hydrogen” - the group is X or yellow 1 the number is “thiomorpholino sf morpholino 0 or isopropylidene 4 propylidene J ethylidene a -(CH,) 4 or isopentylidene or pentylidene 4 isobutylidene J butylidene vo or cyclopentylidene or dimethylvinylidene or t-butylmethylene or phenylpropylidene or phenethylidene or cyclohexylidene

A acetamidomethylene ie cyclohex-3-en-1,6-ylene 1 ,2-cyclohexylene 1-benzyloxycarbonylamino- i benzyloxycarbonylaminomethylene ie s methylenethiomethylene ie methyleneoxymethylene J 1,2-ethylene ethylene- J ethylenethioethylene ie methylenesulphinylmethylene or ethylene or methoxymethylene or sulphinylethylene 0 |propylenedioxymethylene 0 |

Q2 is preferred especially among the octanones represented by formula 1 in which the © group is X's undecyl be rR' hexyl R' be in those compounds in which 1,2-cyclohexylene is 1-methoxy- 1,2-ethylene «ethylene The following are examples of such compounds: 1 (5)-1-[[(2S,35)-3-hexyl-4-ox0-2-0xetanyl Jmethyl]Jdodecyl (S)-2- 1sopropyl- malonamate, (5)-1-[[(28,3S)-3-hexyl-4-oxo0-2-oxetanyl Jmethyl]dodecyl (S or R)-2- carbamoylvalerate, (all Z,S)-1 -[[(285,35)-3-ethyl-4-0x0-2-0xetanyl jmethyl]-9,12- vo octadecadienyl (S)—2-isopropylmalonamate, (S)-1-[[(28S,3S or 2R,3R)-4-0x0-3-pentylhtio-2-oxetanyl[methyl]dodecyl (S) —2-isopropylmalonamate, (S)-1-[[(28,3S or 2R,3R)-4-0x0- 3-pentylhtio-2- oxetanyl Jmethyl]dodecyl [S:R (2:1)]-2-isopropylmalonamate, Ye (S)-1-[[(2S,3S)-3-ethyl-4-0x0-2- oxetanyl Jmethyl Joctadecyl (S or R)-2- t-butylmalonamate, 0 (S)-1-[[(2S,35)-3-ethyl-4-ox0-2-oxetanyl JmethylJoctadecyl 1- : carbamoylcyclo-pentanecarboxylate, ( S)-1-[[(285,3S)-3-hexyl-4-0x0-2-0xetanyl JmethylJdodecyl (RS)]-2- Yo : benzyl-malonamate, (S)-1-[[(285,3S) )-3-hexyl-4-0x0-2-oxetanyl jmethyl Jdodecyl 3-[(2- carbamoylethyl) thio]propionate, 5-oxo-D-proline (S)-1-[[(2S,3S)-3- ethyl-4-0x0-2 oxetanyljmethyljoctadecyl ester, v. 5-oxo-L-proline (S)-1-[[(2S,3S)-3-ethyl-4-0x0-2- oxetanylJmethyl]octadecyl ester and especially (8)-1-[[(285,3S) -3-hexyl-4-0x0-2-oxetanyl jmethyl dodecyl (S or R)-2- isopropyl-malonamate, vo

9 8 -hexyl-4-oxo-2-oxetanylJmethyl]dodecyl (RS)-2- 5-1-3 Carbamoylvalerate (epimers 1:1), (all Z,S)-1-[[( 2S,35)-3 -ethyl-4-0x0-2-oxetanylJmethyl]-9,12- octadecadienyl (S or R)-2-isopropylmalonamate, |(S)-1-[[(2S,3S) )-3 -hexyl-4-ox0-2-oxetanyl methyl [dodecyl (RS)-2- ° Carbamoyl-4-methylvalerate (epimers 1:1), (S)-1-[[(2S, 35)-3 -hexyl-4-ox0-2-oxetanylJmethyl]dodecyl 1- Carbamoylcyclohexanecarboxylate, (S)-1-[[(28,39)-3 -hexyl-4-oxo0-2-oxetanylJmethyl] dodecyl (RS)-2- methyl- malonamate (epimers 1:1), (S)-1-[[(2S,3S)-3 -hexyl-4-oxo-2-oxetanylJmethyl]dodecyl (RS )-2- ethyl- malonamate (epimers 1:1), (S)-1-[[(2S,35)-3 -hexyl-4-o0x0-2-oxetanylJmethyl]dodecyl (RS)-2 - butylmalonamate (epimers 1:1), (S)-1-[[(2S,35)-3 -ethyl-4-oxo-2-oxetanylJmethyl]octadecyl-1- Vo carbamoylcyclohexanecarboxylate, (S)-1-[(2S,3S or 2R,3R)-4-0x0-3 -pentylthio-2-oxetanylJmethyl]dodecyl [S:R or R:S(2:1)]-2-isopropylmalonamate and (S)-1-[[(2R,3R)-3 -benzyl-4-oxo-2-oxetanylJmethyl]dodecyl (S or R)-2- 1sopropylmalonamate.

Y. Compounds of the formula ] contain at least three asymmetric carbon atoms and can exist accordingly as optically active enantiomers or as their “mixtures” for example as a mixture of enantiomers ( Racemates or homologues + optical mixtures. Diastereomers Compounds of formula I can be synthesized in a manner known to those of ordinary skill in this technical field by { esterifying an alcohol of formula: 0 0= = b 1c R2 Ila with an acid of formula (QOH) in which “0 is a group of formula Q or 0; or +=(conversion of an acid of formula 115 to cyclization

Ve (Q-O,R2)CHCH,CH(OH)CH(R1)-COOH IIb or in group 1 in a carboxy acid c) converting group

T-OCHCH, Ne=o0

RY z | R? 81

IIc where '1 is a group having the form

HOCO(X)n-CO- 11 ; (HOCO-X'- 12 or 'ny XX R4' is known only as RI cua (R3,RHYNCO- (amide) to the del group here which has formula 1 to the immers epimers d) as desired; separate a mixture of the individual epimers separately. room temperature or during tetrahydrofuran, THF Jw ether, for example, in celsius to -2” sina. Cooling, for example, of about “methylene chloride” by performing the ring-locking process (B) in a solvent such as Sa Vo using Desiccant pellets or sieve particles acetonitrile or dimethylformamid 2-(1H-benzotrizol-1-yl)- 1,1,3,3- like in the presence of molecular sieve

Jie d tetramethyluronium hexafluorophosphate, (HBTU) C. "00 at room temperature or at a temperature of up to triethylamine (C) using amide (amidation) solution 7 group induction can be performed

HBTU and in the presence of acetonitrile in (R’ RYNH formula) 41 amide or ammonia at room temperature or at a temperature of up to 40”C.

11 By means of Se oI, a selective separation process can be performed for a mixture of ethyl epimers using silica gel over silica gel chromatography: -eluting agent as a flushing agent methylene chloride | hexane [acetate] in European Patent Application No. Oe dla formula alcohols are defined or may be prepared by analogy with known alcohols according to formula 118 or as 0 18578094 described in Examples A to I C to R. Substances may be prepared acidic elemental represented by the formula 110 and 11; in a manner known in e.g. starting with the alcohols corresponding to formula 118 as described herein in this description 0 se and k; to; n (in relation to the full IIb) of the invention in examples j and k (in relation to acids ') Tle acids 1. Example a under ethyl bromide and then 578 g methyl acetoacetate annihilation was added ( I heated a mixture of .9670 sodium methylate nitrogen to 17/g of Sle solution. The substance was poured into methanol and after distillation. at reflux the reaction at boiling point under condensation and water. The remaining n-hexane was collected on water-ice mixture.The reaction was extracted by 1 organic layers and dried.After evaporation of the solvent and after distillation, 78”g of

Torr Yo 1; boiling point 77-74*C/at 2-acetylbutyrate methyl pressure at 0-0C; 44.17 g of argon b) was added under gas in sodium hydride “©8” obtained from A to a suspension consisting of 77.4 g of A and after stirring at 0-C for an hour and a half; refrigerated A mixture of THF JodYo. > Ralume 1.96 C. Added at this temperature 1758 ml_ of “01- reaction at lysate for 1.- stirring or after stirring at aay hexane in butyllithium after THF Geo. In methyl stearate, a solution of 49.7 g caddy was added slowly. : argon an hour and a half.” The reaction mixture was added under “sad gas” 01- stirring when the reaction mixture was extracted mB ate. ys 9677 hydrochloric to 10*”ml vo acid and water. The collected organic layers were dried. Filtered and then evaporated by hexane

Ren dad was dissolved in Maou 111 and treated with 1,1 ligm of diazabicyclo [5.4.0] undec -7ene (1.5-5) (DBU) -1.8 and the mixture was heated at boiling point under condensation under argon gas. The cold reaction solution was extracted by hydrochloric AES 9077 and then by a saturated solution of chloride 8001010. The combined organic layers were collected and evaporated. The resulting substance was dissolved in ethyl acetate. The solution was cooled to room temperature and stirred at YO C overnight. The crystalline material was filtered under reduced pressure; Washed with ethyl acetate and dried. And thus dias at 77,#80 g of 3-ethyl-6-heptadecyl-4-hydroxy-2H-pyran-2-one ._ melting point 017-01C. cipal (— 0.100 g of Raney-nickel and 1000 mL of THF to 100 g of pyrone obtained in (b). After the hydrogenation reaction was carried out at °Yo C For 7 all the catalyst was filtered under low pressure and washed with THF. » It was washed with ethyl acetate Vo at -01*C and dried at 0?*C for 11 hours. Thus, 100 g of rac-(2RS,2RS,55R)-2 was obtained. ethyl-5-heptadecyl-3-hydroxy- evalerolactone melting point 001-011 C. z (a) added 78.5 benzoic anhydride aa and JaV¥,0 from 7170 perchloric acid to a suspension consisting of 11,291 g of d-lactone obtained in c) in dal You of toluene | After stirring for two and a half hours, the reaction mixture in toluene was extracted by a solution of sodium hydroxide IN In a solution of 9600 sodium chloride and then with a saturated sodium chloride solution. organic layers collected; dried and steamed. Thus, he obtained 4.4 "g of rac-(2RS,3RS,55R)-3-benzoyloxy-2-ethyl-5- cheptadecyl-d- valerolactone melting point 4.5*1-75* diode. : vo e) cud 7.7 g of benzoate obtained in (d) in Jato: from toluene at 5560 C under le “©8©80. After that 1000 mL was added of concentrated methanol and Ja¥,0 sulphuric asa. The reaction mixture was stirred or agitated at ©?* at rest for 1" hour.

Vy solvent evaporation. The triethylamine was dissolved by sulfuric after neutralization with t-acid and washed with water. The aqueous layer was extracted by t-butyl methyl ether remaining in sodium sulphate. The organic layers were collected and dried over butyl methyl ether, then t-butyl methyl evaporated. The diluted agent was filtered under reduced pressure; and washed with methyl rac-(2RS,3RS,5SR)-3-benzoyloxy-2-m, thus obtaining 07 "g of -ethyl-5-hydroxydocosanoate obtained in (e) in the hydroxyester of aaYoV argon and) treated under benzyl gas 2,2,2-trichloro- from saYoY with n-hexane from You after trifluoromethanesulphonic acid was added, 7 ml of 0 : n= h. The formed precipitate was filtered under reduced pressure and washed by A stirring for 0. Layers were collected. 968 sodium bicarbonate. The filtrate was extracted by a solution of (hexane C) for 1 h. Filtered *00<- and dried; filtered. It was concentrated after stirring at hexane and left. The n-hexane filtrate evaporated the crystalline material at low pressure and washed with methyl (rac(ZRS,3RS,5SR)-3-benzoyloxy-5-, thus obtaining 9.7 " g of benzyloxy-2-ethyldocosanoate m argon of the compound prepared in (f) under benzyl ether gas g) 4.7 "g of 1 ml 7*0 in potassium hydroxide was treated with a solution It consisted of 4600 gm of EAS 11 C for a period of ote 9645 water by volume (7/7).The mixture was stirred at [methanol, then t-butyl methyl ether, then the reaction mixture was concentrated at 550 C and the suspension was taken in, then IN acid hydrochloride 9600 sodium chloride washed successively with © solution again. The organic layer was dried with % sodium chloride by means of a solution. The desiccant was filtered under reduced pressure; and washed with sodium sulphate over 1,871 g of dias (thereby mad) as t-butyl methyl ether -1ac(2RS,3RS,55R)-3-benzoyloxy-2-ethyl-3-hydroxydocosanoic acid to a solution formed From (S)-(-)-a-methylbenzylamine 0h added 7.7g of methyl ml of 17510 beta hydroxy acid prepared in (g); in aa) AY) of the compound phenethylamine salt, then taste the solution by adding .mg of acetate salt

1 and left 1ac(28S,3S,5R)-5-benzoyloxy-2-ethyl-3-hydroxy docosanoic acid methyl for 7 hours. The crystalline material was filtered under reduced pressure; It was washed with 0 methyl acetate for 0 degrees Celsius, then dried. The first crystalline substance was dissolved in *71- at phenethylamine acetate incorporation of salt 0°C and then inoculated with the addition of hot oto; cooled to “(28,38,5R)-5-benzoyloxy-2-ethyl -3-hydroxydocosanoic acid For compound 0 Leave the solution at room temperature for 7 hours. The crystalline material was filtered under pressure, and dried. OY 0 — cooled at methyl acetate washed by Low 0 repeated the same previous steps used in the first crystalline material also with the second crystalline material (25,35,510)-5-phenethylamine, thus obtaining 9,4 g of salt; g of salt and dissolved with stirring. hydrochloric IN acid from Joh t-butyl methyl ether was filtered and then concentrated, thus obtaining dia. The organic layer was washed by water; (28,38,5R)-5 -benzoyloxy-2- ethyl-3-hydroxydocosanoic from 60.1 mg 1. Melting point 17-77* decantation. 420 mg/l 1 argon Je) was added drop by drop at zero percentage acid. Ga to a solution composed of 1,9? g benzenesulphonyl chloride 0 After stirring at pyridine to 7500 l obtained in (i) in B-hydroxyacid for 0 “hours, #ml of water was added to the solution drop by drop. Stir the solution at an Aggie of 0 vy. t-butyl The crystal mass of pyridine was kept at room temperature for one hour. incense (7 caliber); hydrochloric solution and washed sequentially with methyl ether acid. The organic layer was dried %). Sodium chloride and sodium bicarbonate %o active charcoal solution were treated with activated vegetable charcoal, Ssodium sulphate. The dried material and charcoal were filtered under At low pressure, the filtrate evaporated, thus obtaining ve -(35,45)-4-[(R)-2-benzyloxynonadecyl]-3-ethyl-2-oxetanone? g of

1 Yo obtained in (J) in oxetanone k) a solution consisting of 77.4 g of hydrogenated Ake was treated after a procedure of 9600 PAC (ml | 111 By ?, more than: for # hours » The hydrogenated solution was filtered under reduced pressure. Hydrogenation washing, then baiting by adding n-hexane and evaporation of the filtrate. The residue was dissolved in THE by -1-4/RT0©-3-(35,45)._ [(R)-2-hydroxynonadecyl]-2-oxetanone 0 was filtered and dried. Thus, hexane is under reduced pressure; Washed by crystalline dela)A after (3S,45)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2- from aa) was obtained at .1C; The alcoholic precursor in example 1-5 melting point coxetanone z example b g of Ye umethyl (R)-3-hydroxytetradecanoate dg 0 cad ( v. 4-dimethylaminopyridine from aat,) « t-butyldimethylchlorosilane and methylene chloride nitrate 0001 stirred in triethylamine from aaY4, ¢ as well as at boiling point under condensation dell the mixture at room temperature for a period after heating t-butyldimethylchlorosilane was added to the ligation of & dela 1 for the duration of the mixture at boiling point for ; The precipitate formed with ys was filtered out and the filtrate was concentrated. The remaining ether was dissolved and triethylamine hydrochloride was washed, then once 0.0 M citric acid for celal 801 and washed sequentially with ether in dried; I concentrated and liberated accordingly another sodium chloride with water and a saturated solution of, thus obtaining an eld of any volatile substances at 00 °C under very low pressure for a period of (6(-3-])1,1-a, except for 8 , Al-Ajm Mutasma Manan [Adh 1 Nolt 1st Amsn (1 Nahta’a)

YY Ade 164l (Veo (cml) (IR) Infrared Spectrum cacid

Ge was treated with 1 #ml Bother Lm 001 b) Anib 4.17 g of product in (1) at a temperature of hexane in diisobutylaluminium hydride 1 Molar solution: C to - 75 * Celsius, then stirred at this temperature for one hour.Then *71- ranges from

CItric molar 19 of 18002008001 10 mL water and 10#*mL acid solution JaY,0 were added > and C ether was extracted. A layer of 501 droplets was separated by a droplet at a temperature not exceeding 20 degrees, dried and concentrated. The brine collected by ether was washed with the aqueous layer of ether.

1 Using the remaining SL by chromatographic separation on a sald gel, I separated (8(-3-])1,1- from pV 4.47, thus obtaining (V:0) with a ratio of ether | pentane 1 infrared spectrum “dimethylethyl)dimethylsilyloxy] tetradecanal Alala. ) a solution of 63786 0 in n-butyllithium MoLab 0.1 Ja¥Y,0 0 C solution was treated with and after stirring for 11 minutes; Cool to -75*C, then add a solution consisting of drop by drop after stirring for 10 minutes. Leave THF Jed in pentylthioaceic acid, g of the reaction solution at room temperature and stir for # minutes, then cool again to - 75 AH: aldehyde drop by drop of a solution consisting of 7.4 gm of the canal. And at this temperature 0. Pour AEE after stirring the reaction solution for THF Jad obtained in (b) in dried Jhexane and extracted by ammonium chloride on a saturated solution of (2R/S,3R /S,5R)-5-[(1,1-) and thus concentrated 895.1 g of hexane (dimethylethyl)dimethylsilyloxy]-3-hydroxy-2-pentylt hiohexadecanoic diastereomers in the form of a mixture of § isomers stereoisomer acid vo stirred for 2 hours a solution composed of 7.85 g of the product obtained in (C); (2 2-(1H-benzotriazol-1-yl)-1,1,3,3- (HBTU) g of sieve particles g tetramethyluroniumhexafluoro phosphate

Jal Ve in a mixture consisting of triethylamine Ja¥ 5 angstrom molecular sieve, then the mixture was filtered; filtration. The remaining substance was dissolved in and concentrated, thus obtaining 0.57 g of hexane. The hexane layer was dried by (3R/S,4R/S)-4-[(R)-2- [(1,1 -dimethyl-ethyl)dimethylsilyloxy] tridecyl]-: in the form of a mixture of; Stereoisomers. 3-pentylthio-2-oxetanone by acetonitrile Ja¥ “+ from product in (d) in pnt, 0 e) A solution of vo sodium was treated and stirred for 81 hours. Then a solution of 9640 hydrofluoric acid (J)© was added

VY

And concentrated hexane The hexane layer was dried, then the mixture was extracted using methylene bicarbonate in ether. The residue was separated chromatography on silica gel using: 3R,4R (or 3S,45)-4- with a ratio of)—% 0 Thus, he obtained 1949.4 mg of 24-melting point chloride [(R)-2-hydroxy tridecyl]-3-pentylthio-2-oxetanone 35,4S (or 3R,4R)-4-[(R)- 2-hydroxytridecyl]-3- and 191.7 mg of alcoholic 48© in ald C; Substances OV) Melting point cpentylthio-2-oxetanone (6 »5). Examples No. — Example 1 molar lithium bis (trimethylsilyl)amide a) A solution of 8.0 ml of ; Celsius and stirred oVo—at argon under ethyl acetate Jo),A by THF in 0 minutes and then treated accordingly with 0.8 g of Ye solution at this temperature for a period of time. And stirred at -/7* for THF in 101 ml of (R)-3-benzyl-oxy tetradecanal acid JV A for half an hour. A solution consisting of ethyl acetate and water was added drop by drop to the reaction mixture. Extract the resulting solution by concentrated Jat in hydrochloric and water; dried; 9 sodium bicarbonate combined organic layers were washed by vo (3R,5R and 3S,5R)- 5-benzyloxy-3- and concentrated. Thus, he obtained cad. (1:1) hydroxyhexadecanoate by THF lm 17,* and diisopropylamine from Jat b) treated with a solution consisting of: at argon molar) at 0-16 * 806 under gas 0,6 (n-BuLi) is more than a solution of

THF Ja¥,0 from the product in (a) in pao (Adin) 0 add zero percentage. After stirring the water the temperature was reduced to 0) vm point by point at — 0 00 C. And after 10 minutes, at 0.08 mg of benzyl bromide, after adding a drop by drop of a solution consisting of 000 p071c1210©171005. Invert the mixture at -; 59°C acid triamide from Ja¥,) for 10 minutes. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 2. The reaction mixture was cooled to 0°C and 0*mL of a saturated solution of lela? ve «t-butyl methyl ether to it. The reaction mixture was extracted with sodium chloride. The extracts were dried; I filtered and evaporated the solvent. The remaining material was treated by chromatography on gel 11

Ya

The remaining material was dried with a ratio of 4:0 to ethyl acetate n-hexane silica by (2R3R,5R and 28,35,5R)-5-benzyloxy-2-benzyl-3- was obtained

JY stereoisomers with a threo ratio in the form of hydroxyexa-decanoate min. A solution consisting of 1, “g of product 001 c) heated to boiling under condensation for -ethanol from JaTV,Y in (ke Y,0) sodium hydroxide in (b) and 77 ml © hydrochloric solution. This solution was accordingly treated at room temperature with 77 ml t-butyl methyl ether acid and the residue was extracted with ethanol (©,7N). Incense and water. The collected organic layers were dried and concentrated. A solution consisting of “g of the substance” was stirred, then it was treated with argon under methylene chloride gas, remaining in ml and 4 liters of sieve particles. Accordingly add *#,#ml of HBTU 9 stoning from 0 in 1 hour; filter and concentrate sad Jeli and stir mixed triethylamine JeY,A and DMF residue in normal hexane; Extract the reaction solution with water; The cial was dried and concentrated under reduced pressure. Chromatographic separation on silica gel using (35,45 or 3R,4R)-3-stereosymmetric trans first compound gave methylene chloride: Rf value ascending coefficient cbenzyl-4-[(R)-2-benzyloxytridecyl ]-2-oxetanone 0 on silica gel thin-layer chromatography 5,; trans thin layer chromatography and then obtained the second compound, methylene chloride μm | using 46-5 (BR,4R or 35,45(-3- benzyl-4-[(R)-2-benzyloxytridecyl]-2 - Stereoisomer: (Thin layer chromatography on silica gel 1.90 Rf ascent coefficient .0xetanone ! .methylene chloride *- e; microns using vy. stereo or optical Silda trans d) Hydrogenate a solution of 71476 mg of the second compound

Pd/C for one hour in the presence of 147 g of THF Ja10 obtained from (C) in the stereoisomer or trans reaction mixture was filtered and concentrated. Thus, he got a boat. : (BR,AR or 385,45)-3-benzyl-4-[(R)-2-hydroxytridecyl]-2- optically 7. The alcoholic precursor in an example coxetanone ve

Jail trans e) As described in (d), the same steps were carried out on the first compound, spatially or optically isomer trans, obtained from (c). Thus, he got a boat

or optically (35,4S or 3R4R)-3-benzyl-4-[(R)-2-hydroxytridecyl]-2- coxetanone) | the alcoholic precursor in Example A Example D was treated at 0°C Composed of “diisopropylamine in 0 mL THF made by Jad Yo from a solution of n-butyllithium (0M) in hexane and after stirring the solution was cooled to -75*C. Then I add drop by drop a solution consisting of (a2), YT of Z-glycine in 10 mL THF . The reaction mixture, Bul, was left at room temperature and cooled again to -75*C. I add drop by drop at -75* a solution consisting of A, .g of (R)-3-(t-butyldimethyl siloxy)tetradecanal in THF Jeo invert Lilia oy. The reaction is at -75 H C for an hour one and at Pfam °C to — 000 °C for half an hour then to 20 °C and cool again to -75* °C. Then the reaction mixture was poured on a dilute solution of potassium hydrogen sulphate and extracted with .ether. The ether layer was dried, concentrated and separated by chromatography on silica gel using methylene chloride | to cut it off. Juan ly; #4 mg of (2R/S,3R/S,5R)-2-[1- (benzyloxy)formamido]-5-(t-butyl dimethyl 1» siloxy)-3- hydroxy hexadecanoic acid in the form of a mixture of; Stereoisomers. Similar to (b); (d) From the above output. 4-[(R)-2~(t-butyldimethyl siloxy)tridecyl]-2-oxo-3-oxetanecarbamate | was obtained on heath with a 1:1 mixture of ctransdiastereomeric .beta.-lactones 0 Mass spectrum (MS): 476 (M+e-C4Hge) and similar to b) and e) from the above mixture obtained (3S,4S or 3R,4R)-benzyl 2-0<0- 3-0<7©01276027030218-[2-377070<7-70106071-(18)]-4; The alcoholic starting material in the example Vo melting point (3R,4R or 3S,45)-benzyl-4- 5 Asia 074-177 dan (([(R)-2-hydroxytridecyl]-2-oxo-3- oxetanecarbamate ro _fusion -9A 4C.

1 — Example (R)-3-[(1,1- and thiophenoxyacetic acid) by analogy with example (b); and from each of the following obtained: dimethylethyl)dimethylsilyloxy]tetradecanal ( 2R/S, 3R/S, S5R)-5- (t-butyldimethylsiloxy)- 3-hydroxy-2- (I (a mixture of; stereoisomers) and (phenylthio)hexadecanoic 801 0 (3R/S,4R /S)-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-3-(phenyl infra Cada (Le) (mixed_of thioisomers)-2- 16 oxetanone acetate (YAco (YAYY (1-NlH): (IR) red .(38,48)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2 -oxetanone ‎(3R 4R)-4-[(R)-2-hydroxytridecyl]-3- 5 (ether) endometrium V4 Melting point 0 prefix sald (ether) _fusion 547 °C dan «( phenylthio)-2-oxetanone

AT alcoholic for example and stearoyl C; 077 ml of *001 a) was added drop by drop at a temperature not exceeding 1

Ja YY and Meldrum to a solution of 71111g_ of acid 16 reaction mixture by Jue after stirring 0,* .methylene chloride in pyridine methylene by Addl (;N); The hydrochloric acid layer was re-extracted and concentrated. The remaining material was taken in methylene chloride and the chloride layer was dried. The separated crystals were filtered out; It was dissolved in ea pil with boiling under condensation. after methanol. methylene was separated by chromatography on silica gel using methylene chloride is “methyl 3-oxoeicosanoate from axVVo, thus obtaining chloride melting point 4-057 ** C. b) acetyl chloride pase), Af was added at 4 JeV,A of methanol to a solution of 0 ve of aaa.) of [(R)-2,2'-bis(diphenylphosphino)-6,6'-dimethyldiphenyl] . ruthenium diacetate in 10 mL methylene chloride. Hydrogenate the resulting solution with hydrogen at 35 bar pressure at OT C in the presence of 1.8 g methylene produced in (a) and 761 mL of 8001) 006. After Addition of ketoester from the evaporation of the mixture to the degree of dryness.The chromatographic separation process was carried out on “chloride” to give 8.1 “gm of n-hexane, and the resulting substance crystallized from ether to silica gel using the melting point of 08,018 °C. . amethyl (R)-3-hydroxyeicosanoate

R)3-(t- got 2 in (b) on co dhe pe c) with similarity 0m. (00-1 AH): (IR) infrared radiation ula butyldimethylsiloxy)eicosanoate Your blood decomposed into infrared spectrum 1 (R)-3-(t-butyldimethylsiloxy) eicosanoate, which he said. (VEY khaate (cml) (IR) (2R/S,3R/S,5R)-5-(t-butyldimethylsiloxy)-3 -hydroxy-2-(methyl ve 577 (MS) (mixed from; optical homologues); (a mixture of two trans-oxetanone compounds AYE (em l) (IR) infrared spectrum 0:1 6 and AY 4- [(R)- 2-(t) -butyldimethylsiloxy) nonadecyl]-3- (methylthio)-2- spectrum (VY) (a mixture of two optical or stereoisomer-18 compounds in a ratio of OXetanone

AFT OTT OY eT Come ETF (AVE (cml) (IR) Infrared

AY The following alcohols are starting materials for Example 7 )354 or 3R,45)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2- “(methylene chloride) Melting point 210°C (from coxetanone .345 or 3S,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2- “(methylene chloride) (from 4:5 °1Y melting point coxetanone (BR, 4R or 385,4S5)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2- Yo and “(ether) C (from 71 pH coxetanone yy (35,4S) or 3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2- (from ether coxetanone 0 1,10) ]-3-(18) (benzylthio)-acetic acid From cs by analogy with an example it was obtained: ethyl)dimethylsilyloxy]tetradecanal M0 (2R/S, 3R/S, 5R)- 2- (benzylthio)-5- [(1,1dimethyl ethyl) dimethyl- (mixture of; optical or silyloxy isoforms] -3-hydroxyhexadecanoic acid stereo); (3R/S,4R/S)-3 -(benzylthio)-4-[(R)-2-(t-butyldimethylsiloxy) tridecyl]- 500 (MS) (admixture of; optical or stereoisomers); mass spectrum 2-oxetanone 0 «(M™)

Yeo 19 The following alcohols are the starting materials for the two examples (35,4S or 3R,4R)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2- «(ether) Melting point 210 °C oxetanone (BR,4R or 385,48)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2- 0 f M'eH,0) ¥V¢ (MS) Mass spectrum coxetanone (3R,4S or 3S,4R)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]-2-

YVE (MS) (1:1 optical or stereoisomers); Mass spectrum oxetanone (11 p.) (Metze H Jha Y.) Dissolve 10 g of the mother liquor in the first crystallization process in Example A (H) in water and f (f pH=1 1) make the reaction medium methylene chloride anethylene chloride acidic at pH concentrated with cooling in ice The HCl layer was separated by adding methylene acid and the methylene chloride layer was washed and the aqueous layer was extracted by (2R,3R,58)- 5- with water, dried and concentrated, thus obtaining 7.7 / g of chloride » ethyl 00, where it was dissolved in benzyloxy-2-ethyl-3-hydroxy-docosanoic acid after 2,8) ae a-methylbenzylamine And he was treated with 7.07 gm of acetate

YY

Heat the reaction mixture to boiling point with condensation; filter and crystallize The ethyl acetate was re-added, thus obtaining methyl acetate 5 ethyl acetate. The crystals formed were crystallized by (2R,3R,5S)-5-benzyloxy-2-ethyl-3-phenethylamine in a 0-degree salt lag. Melting 11-48* Diode; chydroxydocosanoic acid _b) By analogy with the examples of a (iii “k) of the above salt obtained: 0m degree “(2R,3R,55)-5-benzyloxy-2- ethyl-3-hydroxydocosanoic acid C; f IY -71,© fusion i>» «(3R,4R)-4-[(S)-2-benzyloxynonadecyl]-3-ethyl-2-oxetanone homeostatic; tt =YA fusion i>» «(3R4R)-3- othyl-4-[(S)-2-hydroxynonadecyl]-2-oxetanone ve

Asia STAT Melting of pA, obtained as ml _ nm_mg0;,9 a solution of mle c) in (111 ml at **C by ,ml of triphenylphospine diethyl from a200Y Then, with a solution of formic acid, Jar acid, this mixture was treated again with [THF Lm01 in azodicarboxylate 0 diethyl azodi- laamyl, triphenylphospine, and g formic acid, the concentration of the reaction mixture The remaining substance was treated chromatography on a .carboxylate gel to hydrate it._ thus obtaining 1.71 g of acetate / hexane using ISL -(R)-1-[[(2R,3R)-3-ethyl-4-0x0- 2-0xetanyl Jmethyl Joctadecyl formate in °C by 2V0 and treated at methanol dolor. The resulting product was dissolved in Y. After stirring, the reaction mixture was concentrated. p-toluenesulphonic acid, 54 g of acid aqueous sodium Jl and a solution of methylene chloride, the remaining material was divided between methylene, dried a layer of 1026071606 chloride, and extracted by bicarbonate: thus obtaining ethyl acetate from 488d sald and concentrated and crystallized chloride «3R,4R] -3-ethyl- 4-[(R)-2-hydroxynonadecyl]-2-oxetanone from ade vo .71 C; The alcoholic precursor in the example SAY = A melting point

Y¢ ie 1.6M) n-butyllithium from SaVAY,0 solution in diisopropylamine v= add drop by drop at {after THF 10 mL in diisopropylamine to solution #7. ml of hexane in: “stirring.” The solution was added drop by drop at a temperature not exceeding #10°C to a suspension of * (5)-(-)-2- hydroxy-1,2,2-triphenylethyl-acetate of »a¥%,4 component 0.

Vom and then the reaction mixture was warmed to 0 °C; move It was cooled to THF ml (R)-3-[(t-butyl)dimethyl in a dwelling then treated with a solution consisting of 000 dgm of Ja0 and after stirring was added drop by drop in Jato 1117. silyloxy]eicosanal The reaction mixture was warmed to room temperature. ammonium chloride saturated solution of ether was extracted by ether s and stirred. The reaction solution was concentrated and then partitioned between the water © «methylene chloride with water and concentrated; And I took in one liter of ether a layer of (8) -2-hydroxy-1,2,2- was washed, dried and concentrated. Thus, he obtained 11.4 g of triphenylethyl [3R:3S (4:1),5R]-5-(t-butyldimethylsiloxy)-3- hydroxy-

EEA AVIA YoYo (cml) (JR) Infrared Spectrum «docosanoate

LAY AYA YYed 8 Vo methanol fraction 1 of the compound obtained above in pad 0A b) A solution of after stirring; methanol (*4, M) in sodium methylate JaYY,Yo was treated with ammonium And a saturated solution of ether The solution was concentrated and the remaining material was divided between the Cuda ether layer and then the ether was treated and extracted by chloride, thus obtaining ethyl acetate / hexane chromatography on silica gel by © «(3R LARA 7 g of ,5R)-5-(t-butyldimethylsiloxy)-3-hydroxydocosanoate

AVIA Accomplished FETA (YoY) (cml) (JR) Infrared Spectrum

NYeo bm fa c) similar to example b (e) and example c (b c) converted the latter compound to (2R,3R,5R)-5- (t-butyldimethylsiloxy)- 3-hydroxy- 2-methyl- vo

ETE Blood Ed (cml) (IR) Infrared Spectrum “docosanoate (3R,4R)-4-[(R)-2-(t-butyldimethylsiloxy)- About Lady 0111 14

Yo:(cmrl) (IR) infrared spectrum [onodecyl]-3-methyl-2-oxetanone

GRARMA[R)-2- kart-lahn to aYer mc *AE=AY, 0 melting point chydroxynonodecyl]-3-methyl- 2-oxetanone

YY alcoholic precursor used in ex ¢(hexane / EtOAc C (from ex 0 (3S,48)-3-hexyl-4-[(R)-2-hydroxytridecyl]- M011a) A mixture of salicylamide “.87 g of © ctriphenylphosphine 0.1 g of 0.1 2-oxetanone ha was treated and the mixture was cooled at Lm01 g Particle Sieve Angstrom by 71A511-01. After the solution was heated to azodicarboxylate at 0.4 mg C. Then water and methanol at room temperature were added and stirred to concentrate and the remaining material was divided between 0 and concentrated hexane. The hexane layer was dried and extracted by #06). 0: ) ethyl / hexane, and the residue was separated by chromatography on silica gel using 0-[[(S)-1-[[(2S,35)-3-hexyl- from an+,VYV, thus obtaining . (1:£) acetate 66 (MS) Mass spectrum “4-0x0-2-oxetanylJmethyl[dodecyljoxy]benzamide (MFHT 0) and methanol was treated with 11% in del b) 777 mg of the obtained compound was dissolved after Stirring concentrated the reaction mixture and the substance potassium carbonate 01.7 g was fractionated by hexane dried and extracted by hexane (Y:Y) water / methanol remaining between: (25,35,55)- 5-(0- at 54+ mg of Juan kalzo_tzekro hexane dik Mass: Cab «carbamoylphenoxy)-2-hexyl-3- hydroxyhexadecanoate 0 . M"e-(0-carbamoylphenoxy) ¥14 (MS): (MS) Water fmethanol for 11 c) + 05 mg_ of the compound obtained above was dissolved in aluminum oxide hydrogenated on 965 rhodium 0010 mg and treated by (14:7) filtration of the reaction mixture; By hydrogen at a pressure of 001 at ethyl acetate / hexane, it was concentrated and then chromatographically treated on silica gel using vo methyl (25,35,55)-5-]](619)-2, thus obtaining “11 mg of: 1 (isomer carbamoylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoate

: first photodiode) Mass spectrum: (MS) 767[(1,711:0), 11000 (((M"e-(H), 0 mg of mixed molecule and 1;7 mg of methyl (25,35,58) )-5-[[(cis)- ‎ carbamoylcyclohexyl]oxy]- 2-hexyl-3-hydroxyhexadecanoate (second photoisomer).[M"@-(H, NCOCH0# +H,0)] 767 (MS) m d) The axle of the first photoisomer obtained above was dissolved in 10 ml of 06 and treated with “ml potassium hydroxide (1 N). After stirring, the reaction mixture was poured over potassium hydrogen sulphate solution and extracted With ether the ether layer was dried and evaporated, thus obtaining ana¥VV -5-(25,35,55) [[(cis)-2- carbamoylcyclohexyl] oxy]-2-hexyl-3-hydroxyhexadecanoic 861:1 (the first optical isomer) the acidic initiator in example ?(iv .e) as described in (d) the second optical Slade in (c) obtained (28,38,55)-5-[ [(cis)-2-carbamoyl ~~ cyclohexyl] oxy]-2- hexyl-3- hydroxyhexadecanoate acid (second isotope); the acidic initiator in example (YY vo z z in your example a) Similar to example H(C) obtained from (35,45)-3-hexyl-4-[(R)-2- hydroxytridecyl]-2-oxetanone | and formic acid by means of -(1-1 [25,35-(5) «3-hexyl-4-oxo-2-oxetanylJmethyl]dodecyl formate 177 OY O\VYo OAT (cml) (IR) and (3S, 48)-3-hexyl-4- da jn ([(S)-2-hydroxytridecyl]-2-oxetanone fusion UY 514 C (from (hexane b) inverted at oY er Celsius under argon gas mixture consisting of 8 g of hydroxy-B- lactone prepared wel, g pyridinium p-toluenesulphonate and g particles: vo sieve (; angstrom) in 10 mL methyl 3,3-dimethoxypropionate and the reaction mixture was then filtered off. The residue was concentrated and chromatographically treated on silica gel using “Atad / methylene chloride”, thus obtaining:

7l .1 “mg of methyl (E)-3-[[(S)-1-[[(2S,3S)-3-hexyl-4-0x0-2- “coxetanyljmethyl]dodecyl]oxy ]-3-acrylate IR AVY E OAYY (em) THICK VAY 71.71 mg of (R/S)-3-[[(S)- 1-[[(28,3S)-3-hexyl-4- oxo0-2-oxetanyl] ‎V:V) methyl] dodecyl] oxy]-3-methoxypropionate 0 mixture_ of imamers); IR spectrum ANY EFA AVEY AYE (cml) (TR) c) Suspended 775 mg of the resulting compound in B-7 in NaOH deo (.07 N) and the reaction mixture was diluted with acetone after stirring for ; An hour the mixture was made acidic by: a solution of potassium hydrogen sulphate 960, then extracted with ether, 1 | ether layer was dried, concentrated, and the remaining substance was treated chromatography on silica gel using methanol / methylene chloride, thus obtaining 10 mg of -2-(25,35,55) hexyl- 3-hydroxy- 5-[(R/S)- 1-methoxy- 2-(methoxycarbonyl)ethoxy] chexadecanoic acid Mass spectrum (M"e- (H, O+--O--(CH; O)-- Y¥v (MS) CH, --COOCH3)). 3) Heat at 200°C in an autoclave a solution of mg of the previous compound in Jat condensed ammonia 000060560. The ammonia gas was left to evaporate and the reaction mixture was treated with dbus solution & potassium hydrogen sulphate: and extracted by means of methylene chloride. A layer of methylene chloride was dried. Thus, Juan focused on 7.5 mg of -8/8(9-2)]-23,38,587-5) «carbamoyl-1-methoxyethoxy]-2-hexyl-3-hydroxyhexadecanoic acid + the acidic precursor In example (YE) an example of hydrogenating a solution consisting of 1007 mg of the resulting compound in example (K) in 10 ml 1117 © using 100 mg of 0/120 (9600). Then the mixture was filtered, the filtrate was concentrated, and the filtrate was separated. ve left on silica gel using 961 of ether in methylene chloride, thus obtaining 19 mg of methyl 3-[[(S)-1-[[(25,3S)-3-hexyl-4-0x0- 2-

Ya

01 »- YAS (MS) [1GT] prophylaxis?; The mass spectrum of dodecyl[oxy]propionate (C11 Hp; .SIGMA))). sodium hydroxide 4-component suspension was treated; * mg of this compound in 4 ml aqueous The resulting solution was made acidic by 0.07 N acetonitrile and ether was dried The reaction mixture was extracted by 0 28810770 hydrogen sulphate 0 967 and concentrated. Chromatographic separation on silica gel using ether gave layer 1061106 in methanol and then using 965 of methylene chloride in ether A 3-[1 (5)-1-11 (25,35)- 3-hexyl-4-oxo0-2-oxetanyl], a chloride stereoisomer:(cm™) (IR) ©071h0<m0061071[0006©:71[0<77] acid

Yo acidic initiator in example VETT #01 non-lacquer eg m methyl (3R,5R)-5-(t-c (b and c) react J with similarity to propargyl (example Z). (b)) with butyldimethylsiloxy)-3-hydroxydocosanoate methyl (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3- to give bromide 1. (IR) infrared (aha hydroxy-2) -(2-propynyl)docosanoate last to give Cd Gua A Yes AVEC 7070 901 (em) (2R,3R,5R)- 5-(t-butyldimethylsiloxy)- 3-hydroxy- 2- )2- 01 (cml) (IR) Infrared spectrum 0100701710000088001© acid Z ‎(BRAR)-4-[(R)-2-(t- bad) Then this acid was orbited 1785 2170 ا 0 spectrum «butyldimethylsiloxy)nonadecyl]-3-(2-propynyl)-2-oxetanone

AYoo AY. YAY. (one): Mak (IR) infrared radiation, similar to example B (e), got protecting group after splitting the protecting group ' «(3R,4R)-4-[(R)-2- hydroxynonadecyl]-3-(2-propynyl)-2-oxetanone on the alcoholic precursor in example “(ethyl acetate) C (from *”-717 melting point vo.(01)

Example n Similar to example dean (1) of 3-hexyl-4-[(R)}-2-hydroxy (35,48) tridecyl]-2-oxetanone and monobenzyl malonate on (S) -1-[[(28,38)-3- wh chexyl-4- 0x0-2-oxetanylJmethyl}jdodecylmalonate Gad 0 red AAYE (em) (IR) El Tekla IYO A solution of ;17 mg of this compound in THF JaYo was treated with 100 mg of 0/00 and then hydrogenated. The reaction mixture was filtered and the filtrate was concentrated thus obtaining 11 mg “(S)-1-[ [(28,38)-3-hexyl-4-ox0-2-0xetanyl Jmethyl]dodecyl hydrogen malonate : Infrared Spectrum (cml) (IR) 1874 1/45 Acidic Starting Material for Example TT An example of hydrogenating a solution consisting of 976.10 g of the resulting alcohol in an example M in #0 ml ethyl 46 by 75.1 g 00/0 .9600, then the reaction mixture was filtered and the remaining material was treated chromatography on silica gel by hexane [ethyl acetate and thus 6 obtained ;;, g of (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-propyl-2- coXetanone Melting point 44-85C ( from “(hexane / ethyl acetate alcoholic precursor in example SY |) from (R)-3-(t-butyl dimethylsiloxy)tetradecanal (example b (b)) similar to © method used in example c dd) b; = (3R and 3S,5R)-5-(t- butyldimethylsiloxy)-3-hydroxyhexadecanoat (a mixture of epimers) and ethyl (R and S)-2-[(1R and 1S, 3R)- 3-(t-butyl dimethylsiloxy)-1- hydroxy- tetradecyl]-5-methyl-4-hexenoate (threo homologues):1(« (BR,4R and 3S,4S) -4-[(R)-2-(t-butyl dimethyl siloxy)tridecyl]-3-(3- methyl-2-butenyl)-2-oxetanone vo (stereoisomers 1:1 trans).

Ye with acetonitrile Jao 0 of the resulting compound in (1( in pa), AY b) treated with a solution of sodium 9640._after_stirring a hydrofluoric solution was added | The chloride layer was dried in ml of acid. | methylene chloride [ethyl acetate using ©:15-77 The chromatographic separation gave the alcoholic starting material for the examples (35,49(4-1(8)-2- the first is the optical or stereotrans jad value The ascending coefficient chydroxytridecyl]-3-(3-methyl-2-butenyl)-2-oxeranone : and 00.71 (RE)z (BR4R)-4-[(R)-2- second is trans Photometric or stereo lad Ve ascent coefficient value chydroxytridecyl]- 3-(3-methyl-2-butenyl)-2-oxeranone using os Set —0 (Thin Layer Chromatography on Silica Gel 176 (RE) ). 16 (2R,3R,5R and eg — () by (1:1) (3-hydroxyhexadecanoate 2S,3S,5R)-5- benzyl-2- (5-chloropentyl)- 3-hydroxyhexadecanoate «(threo (stereoisomers (3S,4S or 3R,4R)-4-[(R)-2-(benzyl- s : first trans stereoisomer (Rf) dad .oxy)tridecyl climb coefficient] -3-(5-chloropentyl)-2-oxetanone 0 or, bY (BR,4R or 35,4S)-4-[(R)-2-(benzyloxy): s the second trans isotropic:

YA (Rf) ascending coefficient dad .tridecyl]-3-(5-chloropentyl)-2-oxetanone methylene (thin layer chromatography on silica gel 0—?μm using

PAT The alcoholic precursor used in the examples is chloride ve (3R,4R or 35,4S)-3-(5-chloropentyl)-4-[(R)-2-hydroxytridecyl]-2-oxetanone

Sun (3S,4S or 3R,4R)-3-(5-chloropentyl)-4-[(R)-2-hydroxytridecyl]-2- .oxetanone example t with similarity to JE JA (B c) obtained from R)-3-(t-butyl- dimethylsiloxy)tetradecanal 0 (example b (b)) obtained (R and S,E)-2-[(1R and 1S, 3R)-3-(t-butyldimethylsiloxy)tetradecyl]-4-hexenoate (threo 1:0 stereoisomers); and (BR,4R and 3S,45)-3-[(E)-2- butenyl]-4-[(R)-2-(t-butyl dimethyl- Lad sald (trans del jp) 1:1(siloxy)tridecyl]-2-oxetanone : 0 Alcoholic in examples 1 -no: first trans homomer (3S,4S and 3R,4R)-3-[(E)-2-butenyl]-4- [(R)-2- hydroxytridecyl]-2-oxetanone The value of the ascent coefficient is 0.5975 (Rf) and the second trans isomorph is (3R,4R and 38,4S)-3-[(E)-2-butenyl]-4- dad [( R)-2- hydroxytridecyl]-2-oxetanone ascending coefficient it (Rf) ve (Thin layer chromatography on silica gel using methylene / ethyl acetate. (Y:¥:1) «n-hexane] /chloride eg x with similarity to Jha c (b; —( obtained from (3R,5R and 3S,5R)-5-benzyloxy- (1:1) 3-hydroxyhexadecanoate (example — a)) on (2R,3R and 28,3S,5R)- © (benzyloxy)- 3-hydroxy- 2- (2,3,4,5,6- pentafluorobenzyl 0 -5 hexadecanoate) (stereosymmetries (threo and (BR,4R and 3S,4S)-4-[(R)-2-(benzyloxy)tridecyl]-3- (2,3,4,5,6- pentafluorobenzyl)-2 oxetanone (photoisomers ¢(trans the alcoholic precursor in Examples 4 ll-la: Yo the first trans isoform is and 3R4R)-4-[(R)- 38,48)-2 . hydroxytridecyl]-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanone EY (Rf) climb coefficient value, 0, vy 2- (3RAR and 35,45(-4-[08) - It is the SGI trans stereoisomer coefficient value of hydroxytridecyl]-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanone ethyl (thin layer chromatography on silica gel using 1.74). (RE) Rise 2 .(£,0:¢,0:1) n-hexane | methylene chloride / acetate Examples at zero * THF lm #1 in diisopropylamine A) A solution of *,0 ml of (Ralume 016) hexane in n-butyllithium (1.6M) was treated with " ml of a solution and after stirring, the reaction mixture was cooled at -75 * C. A solution consisting of 66 mg of THF was added after stirring in ml of N-benzyl-N-phenylglycine / (Example B) b)) in (R)-3-(t-butyldimethylsiloxy)tetradecanal mg of vv aqueous after stirring at -75 * H *C pour the reaction mixture on a solution of THF diluted concentrated ether layer dried ether and extracted with potassium hydrogen sulphate and concentrated hexane (7:) water; a layer of methanol / s hexane was dried and partitioned between (1:0) in the ratio of ether / pentane. The remainder was treated by chromatography on silica gel using methyl (SR)-2-(N-benzyl anilino)-5-(t- on ¥,237” of dias thus vo as isoform le .butyldimethyl-siloxy)-3-hydroxyhexadecanoate methyl ( (M'C, Hye), ©40 :015(a)© Mass spectrum of (N-benzyl- anilino)-5-(t-butyldimethylsiloxy)- 3-hydroxyhexa- (M'e-C;, ot. (MS) photosynthesis (b). mass spectrum alin. In the form of “decanoate from a mixture of two of the above two optical isomers. aa VY, E (© and 11 © of the isotope (b) in “ml 148011 1,1N treated aaa VE b) commented to be a clear solution. After stirring, the mixture was poured acetonitrile with a sufficient amount of ether and extracted by means of aqueous potassium hydrogen sulphate on a solution of © chromatography on silica gel Adee and concentrated. After conducting ether, the tA (pa) layer was dried in a ratio of (1:9) and thus methanol / methylene chloride was obtained using vo (5R)-2-(N-benzylanilino)-5-(t- butyldimethylsiloxy)- 3-hydroxy- | from

YY

(M'e-C, 0X1 (MS)

Hye). (5R)-2-(N-benzylanilino)- 5-(t- c) By analogy, he obtained from the (1) isomer (a). butyldimethylsiloxy)-3-hydroxyhexadecanoic acid (01). HPLCTON-" oY (MS) Mass Spectrum 0 mg1,* HBTU b (b) 1, g of Identical Seal nm_mg 1,1 QB (a .acetonitrile #ml 0 f" g of sieve particles (; angstroms) (in triethylamine using Sh). After filtration and concentration, the result was treated by chromatography on a gel 3R,4R (or 38,48(-3-07- from aa), + 4) and thus He obtained methylene chloride J .benzylanilino)-4-[(R)-2-(t-buty] dimethylsiloxy)tridecyl]-2-oxetanone 0 (MHH)T 011 (MS) isomorphic (b). Mass spectrum 35,45 (or 3R,4R)-3-(N- e) by similarity obtained from the optical isomer (a) from c on -2-[1 ben 106 AH 111 slowly six 1 butt-)-2-(6)] -4-(manufactured 1g oxetanone (MFHT 011 (MS) mass spectrum of) stereoisomer “0 ml in (9600) 0/50 mg 0.8 and hydrogenated 1 g of stereoisomer (B) from d (5 ve 3RAR (or) the reaction mixture was then filtered and concentrated thus obtaining 4 "mg of [THF 3S,4S)-3- anilino)-4-[(R)-2-(t- butyl dimethyl siloxy) tridecyl]-2- . 11 (H 4700 (MS) isomeroid B; mass spectrum coxetanone 35,45 (or 3R,4R)-3-g) the similarity obtained from the isomer A of (a) on the isomer canilino )-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxetanone 0-0 z (Me) 475 (MS) mass spectrum of photodiodes 3141+ each separately to joy h) Similar to example b e the products from aliadl «(or 3S,4S)-3- anilino)-4-[(R)-2-hydroxytridecyl]-2-oxetanone were converted to a homeopathy; And in the order, 50014 optical B »; Melting point 3R,4R (or 3S,4S)-3-anilino)-4-[(R)-2-hydroxytridecyl]-2-oxetanone Yo °C; The alcoholic precursor in the ONY example, the melting point of the optical isomer, 0 »

Ya

Ye

A Blea Z The acids represented by formula 08-017 are known or can be prepared by methods corresponding lower alkyl to known acid preparation methods; Like a saponification procedure for

Jie alkali metal hydroxide by methanol i.e. acetone in a solvent such as ester preparation (Say .methanol or ethanol Jie in alcohol potassium hydroxide acid starting materials in examples ¥ (9) and (e) mentioned here as follows: 0” 0 ml in ethyl 2-propylmalonamidate was treated with a solution consisting of 7.8 g of H; then concentrated sad and stirred ethanol in 1 KOH water for 71 l. By 0086 ethyl acetate was made and extracted by sodium bicarbonate and taken in a solution at 0 °C by 1 acidic aqueous layer and pH 011 adjusted at ; ethyl acetate layer clue .ethyl acetate and extracted by hydrochloric aes a 0 was dried, concentrated, and the remaining substance was crystallized by brine by means of 2-propylmalonic acetate (aes from paa), 47 “atta. Thus, [ethyl acetate] was obtained

Asa 50117 Melting point acid 2) £1.0 lead)! 4a » 2-phenethylmalonamic acid 2- ethyl malonamic acid was prepared; Which is the acidic prefix in Examples 09-04, similarly from vo .phenethylmalonamate (material (+) and (-)-2- isopropylmalonic acid monoamide). Prepare (Sa) as follows: 11. The amide prefix in For example, 7 gm of rac-2-isopropylmalonic acid monoamide gm of quinidine salt of was dissolved in 100 ml boiling water and flavored with a small amount of quinidine 0 crystals, then crystallized. The crystals were filtered at (S)-(+) -2-isopropylmalonic acid monoamide quinidine Low pressure Washed with water and 6161 and then dried, thus obtaining 0.000 g of This salt was dissolved in salt of (S)-(+)-2-isopopylmalonic acid monoamide and the separated crystals were filtered Agia 0 was left at (%) +) hydrochloric acid at low pressure and washed with water; It was dried and then recrystallized again from water with the addition of ve (5)-(1)- a few drops of 1N hydrochloric acid, thus obtaining 17 / mg of

Yo Celsius; Modulus 5174 _melting _ point “2-isopropylmalonic acid monoamide [a] 53020 = +45.6° (ethanol, c=1). Specific photocyclization: quinidine acid resulting from the salt crystallization process, mother liquor, was made into the mother liquor and left at ** the urethra. The separated crystals (%) +) were filtered by hydrochloric (aes) under reduced pressure; washed with water; dried and recrystallized again from water with the addition of 0M 5 + mg of 0, thus obtaining . (1) hydrochloric aes Few drops of reflux YY fusion Aa ((R)-(-)-2-isopropylmalonic acid monoamide

[0]ss0”" = -45.6.degree. (ethanol, c=1). Optical specific deviation coefficient: The acidic starting material for Example 7 can be prepared as follows: − methyl VF, to a solution of thiomorpholine From pate a) add 0 diluted “cull” after 001 ml methylene chloride in malonate monochloride with water in a jue separation funnel 0 ml “methylene chloride” of the reaction mixture by filtration and evaporation. The remaining material by ida separating funnel methylene chromatography, then using methylene chloride on silica gel, then using methylene, thus obtaining 11/7 g of (0:1) in the ratio of acetone / chloride v.tetrahydro--oxo -4H-1,4-thiazine-4-propionate drop by drop to (1) potassium hydroxide from a solution of Joho Canal b) a solution of 1,9/7 g of the ester prepared in (1) in/06 A 1 ml 8061006. After stirring: then acetone from dof + and filtration, the reaction mixture was evaporated and the residue was treated with and dried. Chromatography was carried out on filtered acetone. The layer was washed ov. An aqueous solution of potassium salt The product produced by water on a cation exchanger separation column to the degree of dryness, and the eluate concentrate was treated with tetrahydro-B-oxo- cation exchanger column. YY 14 Melting point “4H-1,4-thiazine-4-propionic” The acidic starting material for example £8 can be prepared as follows: Yo drop by drop to a solution of 1 potassium hydroxide add “mL of solution (I

Je in methyl 1-carbamoylcyclopentanecarboxylate of a20,7 composed of

The .acetone after stirring alse the reaction mixture by JaVo.9061006 and the separated potassium salt was filtered out then the acetone Jue was dried. b) Taking a solution consisting of 0.79 g of potassium salt obtained in 5© “ml cele and making it acidic at pH = 1 by means of concentrated hydrochloric acid at its ovarian zero. The precipitate was filtered and washed with water, then jue with diethyl ether. Thus, after drying, aa¥,0 was obtained from -carbamoylcyclopentane carboxylic acid 1. The acid starting material for Example 47 can be prepared as follows: I add drop by drop at -001* Celsius solution consisting of 4.00 g of monomethyl methoxymalonate in 0 ml methylene chloride to JaYT of aqueous ammonia solution (%YO) after stirring the mixture was evaporated and the remaining substance was dissolved in water and a process was performed Chromatographic separation on a cation exchanger using water. The effluent was concentrated and the residue was treated with diethyl ether and filtered; Jue the precipitate with water and dry it. Thus, he obtained 8.,94 g of cmethoxymalonamic acid - melting point AY IVA Celsius. The Vo acid starting material for Example 59 could be prepared as follows: A solution consisting of pa), Va of carbamoylmethylthioacetic acid in mL water was treated with 1 No,?g of monooperoxyphthalic acid magnesium salt 1 7016 . After stirring, the reaction mixture was filtered and the filtrate was concentrated and made acidic by “ml hydrochloric acid.” After the filtration process, the filtrate was collected on a cation exchanger and separated by using water as a liquid flush and the water was evaporated to dryness. The residue was suspended in acetone and filtered. 6 was washed and dried; obtained 0.16 g of rac- 40 86006 [Istam01n (1-01C00 2:6)]; melting point 50/-117 C. Lower alkyl esters and corresponding to acids represented by formula 08-1 They are known esters or can be prepared by methods analogous to the preparation of known vo© esters.For example and as described here and starting with the monoester of formula R" Ju Cua H-(X)y-COOR" on the set of dad gg Jower- alkyl dicarboxylic acid monoester represented by the formula HOCO-(X)-COOR" vv (q) as follows: YJB The initial acid n-butyllithium can be prepared from a solution of JefA a) I add drop by drop at 210 °C and #*g_ of diisopropylamine molecules into 11 mL of hexane in ¥en

VA= Cool the reaction mixture to pH 1 and then sieve THF (; Angstrom) in #/ml of ethyl 1,3-dioxolane-2-C and add drop by drop to a solution of 23.0 of © 01 min. A second gas was added after stirring for THF ely l*0 carboxylate oVo—refined. after saturation; The mixture was stirred at OV carbon dioxide at a temperature below Sle C for 10 minutes and then warmed to room temperature. After volatilization of the reaction mixture was concentrated and the remaining substance was treated with a saturated solution of eos,

Lal and made the layer ethyl acetate and Alta 206121. Eliminate the layer of bicarbonate ve and then potassium hydrogen sulphate by ¥ = pH acidic at a pH and concentrated. b) Added to a solution consisting of 1 g of the product of THE Jee in isobutylchloroformate.

THF Ja: from sieve particles (; angstroms) (in pals triethylamine Ja), 1) a(ve) for 10 minutes and then ammonia gas ; min; ammonia gas 0 was added after stirring for .

Anal Mixed heart interaction throughout the night. Then, the filtrate was filtered and concentrated, and the substance methanol / methylene chloride was separated by chromatography on silica gel using i ethyl 2-carbamoyl-1,3-dioxolane-2-, thus obtaining 0147 mg of (0:40) C. 0001-4 melting point carboxylate 00 methanol c) a solution of 190 mg of product in (b) was treated in 10 mL of 7N 16011 solution in 0060801; The mixture was stirred at a temperature of Jo) by potassium hydrogen in the room for 100 minutes. Then a solution consisting of 7880 mg of

Cy water. The reaction mixture was filtered under reduced pressure; The filtrate Ja) evaporated in 56 .2-carbamoyl-1,3-dioxolane-2-carboxylic acid on Jas ve all sald) 2-carbamoyl-m-dioxane-2-carboxylic acid obtained .ethyl m-dioxane-2-carboxylate (m)) isomorphic with ¥ acidic JCal

Ya

Acids represented by the formula: (R3,RHNCO(X),-COOH dicarboxylic acid monoester) can be prepared from =CHN(R,RO) on the X group, where the _opposite and succinimide are denoted by HOCO- X-COOR "the corresponding represented by the formula" the corresponding corresponding by the format "1121400-200014; for example as amide ester H0

A is described here for the preparation of the acidic starting material in the example of monoethyl 4.17 g dicyclohexylcarbodiimide a) 4.54 g of

THF to 4 #ml N-hydroxysuccinimide from aaY,0Y and acetaminomalonate at 0°C. After stirring for one hour, the mixture was left to warm at room temperature J, and the mixture continued to be stirred overnight. Cool again to 0°C and filter. The filtrate was left at room temperature ((%Y0) by + “ml of aqueous ammonia solution” overnight. Then the solution was evaporated and the aqueous solution was treated in a dish for one day, then at a resting place*; the layer was separated aqueous; the remaining sodium bicarbonate organic layer was washed by the organic layer was washed by ASL the sodium bicarbonate layer was separated by hexane then dried and concentrated the residue was filtered in sodium chloride ve saturated solution and then Dried and thus, ether crystals obtained were washed with ethyl acetate containing grade “[D,L]-N-acetyl-2- carbamoylglycine ether ester obtained on 110 g of C. 177-178 Melting : potassium hydroxide of Je A of (Se b) add drop by drop of the solution obtained in (a) in amide ester of pa), 0% to a suspension composed of (serpentine 1 (© Concentrate the mixture and the remaining substance was dissolved in the cleat solution after stirring for a period of acetone for 100 ml and made ethyl acetate The solution was extracted by 20110118 sodium bicarbonate with hydrochloric (aes) by ¥ = pH layer The aqueous solution is acidic at pH. The effluent was concentrated to the point of Jon exchanger cooling and then collected over an ion exchanger [D,L]I-N- on .. epigastric (disintegration of AVY. Fusion Ax cacetyl-2-carbamoylglycine -(decomposition

Yq It is possible to prepare acidic starting materials represented by the formula: (R3,RHNCO(X),-COOH acid ester or 184 different from hydrogen, by reacting R3 where at least one is represented by the formula amine the corresponding representative In the form "00-0)0(0-16)-(100)0] with

HNR3RY 0 (d) as follows: 01 Preparation of the acidic starting material in example (Kay Sad in 10ml of monomethyl malonate a solution of “g dela) A was stirred for a while Concentrated the solution and then filtered through an exchanger (9640). 0

Gaggia 77-177 Melting point “dimethylcarbamoylacetic acid” from The compounds represented in formula 1 are considered to have valuable pharmaceutical properties, especially as they inhibit, and therefore can be used for pancreas lipase oul sill (spall) yeast (enzyme) to break down sclerosis chyperlipemia Increased fats in the blood obesity To control or prevent obesity and atherosclerosis 58) in mammals, whether atherosclerosis 0 humans or others. Oxetanones Understand how to inhibit pancreatic lipolysis by compounds (Kay oleic) And oleic acid titrimetrically by measuring the Glee 1 heterojunction represented by the formula: pancreatic lipase degradation by triolein yeast released from a 40 M Gl moiety on pig sia emulsion added to the emulsion © 0.1 molar cholesterol ctaurocholate Ysa (lt «taurodeoxycholate (BSA) mL of [ane 0 (egg lecithin molar_egg-fat) ctaurocholate Ysa (lt «taurodeoxycholate (BSA)] mL of [ane 0 (egg lecithin molar_egg-fat) ctaurocholate 1 molar J sodium chloride molar yolk 001 Tris 1101 Molar LY 1 in the form of a liquid suspension to the compound represented by the formula triolein calcium chloride reaction fay by volume of emulsion). The lipase ace is adjusted by adding __ from *-1 micrograms of yeast, calculating sodium hydroxide during the reaction by adding solution A at pH

The lethal concentration of .969 animals (1050) of the amount of sodium hydroxide consumed calculated during 10 minutes. The lethal concentration hall (1050) is the concentration that sie inhibits lipase activity to half of its maximum value. The following table contains the measured JE half (IC50) values for the compounds represented by Formula 1. Example 11 | dad; YY | D "ee" and "zao | YY ah ab jay example av l aab; lap 0 b | —V; aj sa »aa amay ° acute toxicity After administering a single dose to the rat (single) that is greater than mg/kg of the compounds in examples (IT) 2 from (NE 1 and 10 () (b); ( = ( ) 3) Ahad oxetanones can be used with the formula 1 As medicines, for example, in the form of pharmaceutical preparations. These pharmaceutical preparations can be taken orally in the form of 801618 tablets, coated tablets, dragees, hard or soft gelatine capsules; solutions. Emulsions or suspensions.suspensions

For the manufacture of these pharmaceutical preparations, the compounds of this invention can be combined with organic carriers or inorganic alls inorganic pharmacologically inert. For example, lactose or maize starch or their derivatives or talc can be used. talc or stearic acid or 01 its salts or as carriers for tablets; For coated tablets, bagged tablets or hard gelatin capsules. One of the holders suitable for soft gelatin capsules; For example (Jal vegetable oils vegetable oils waxes cowaxes fats 1218; polyalcohols liquid or semi-solid; and in general Ald do not use carriers in the case of capsules: gelatinous deel, depending on the nature of the main active ingredient 80876 , Lcingredient 0 from Jol all suitable for the manufacture of solutions and syrups, for example; water, alcohols andl sucrose ©880003:05; invert sugar and glucose.glucose in addition to alld can Pharmaceutical preparations should contain preserving agents, “solubilizers,” stabilizing agents, yeah, materials like J se “wetting agents, emulsifying agents, sweetening agents, sweetening agents, colored materials. Je «coloring agents flavorful flavoring agents salts for varying the cosmotic pressure: oA pH buffers coating agents 5 anti-oxidants Lad ( Sa antioxidants that they contain other substances, y., of pharmacological ded. As mentioned before, drugs containing oxetanone represented by the formula [1] are the object of this invention, in addition to the methods of manufacturing these drugs, Al, which include mixing oxetanone Jad in form 1 and if desired; With one or more other compounds of pharmaceutical value in an acceptable form for administration. Also, as already mentioned, the compounds represented by formula 1 can be used to control or prevent diseases; Especially in controlling or preventing obesity, cobesity, increased blood lipids, chyperlipemia, atherosclerosis, and atherosclerosis65 in mammals, whether humans or others. The dose given can change

£Y

OB over a large extent; Of course, it is determined according to the individual requirements of each particular case. Generally, 0 to 100 mg/kg of pan weight) the daily dose given orally ranges from the body is assumed to be correct. Represented in formula 1 to the food oxetanone of Lad can be added “margarine” like fat; oils; | Vegetable margarine Lelia producer foodstuffs 0 has an effect on obesity. such items as chocolate and sweets; Especially food sweets 01 that may contain oxystanone or formula 1 in an amount ranging from 965 to 965 by weight, as well as its manufacturing process are also among the objectives of this invention. Limitations of this Jia The following examples illustrate this invention in more detail. The detail is that it -degrees Celsius is the invention in any way. All temperatures are given in a gradient of 0 1 eg (35.45)-3- of p2eOVE treated at 0 °C with stirring, a solution consisting of aae0Yo -4-Attah [(R) )-2- hydroxynonadecyl]- 2-oxetanone 2-isopropylmalonic acid monoamide from aasY4: “riphenylphosphine) der,t by THF | 01 μg of sieve particles (; angstroms) in he after stirring at 0°C for 1*min and at .01150070071 azodicarboxylate at room temperature for 1 h; The reaction mixture was filtered, the sieve particles were washed, and then extracted by hexane and solvent evaporation. The residue was dissolved in b ether, dried, and evaporated. The b ether hexane layer was diluted with L(V: VY) water in a ratio of methanol/[methylene chloride]. The residue was separated by chromatography on silica gel using ©. He thus obtained: (1:4) day ether (5)-[[(2S,35)-3-ethyl-4-0x0-2-oxetanyl methyl] octadecyl 774 mg from (iC; and ©0111 Melting point (R or S)-2-isopropylmalonamate º (S)-[[(2S,3S)-3-ethyl-4-ox0-2-oxetanyl [methyl] b) 11 mg of

Ase *111 melting point coctadecyl (5 or R)-2-isopropylmalonamate >

For example 0 by analogy with example) ¢ obtained from (38,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]- 2-oxetanone and 2-isopropylmalonic acid monoamide) On : a) (5)-1-[[(2S,3S)-3-hexyl-4-ox0-2-oxetanylJmethyl]dodecyl (R or S)- (2-isopropylmalonamate 0 melting point AY C; and b) (S)-1 -[[(2S,3S)-3-hexyl-4-ox0-2-oxetanyljmethyl]dodecyl (R or S)- 2-isopropylmalonamate melting point PAY c) From (35,45)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone 1sopropylidenemalonic acid monoamide / obtained -3-1167/1-(3 3 ) 3-1- “4-0x0-2-oxetanylJmethyl]ldodecyl 2-carbamoyl-3-methyl crotonate 0 Aa Melting 111-018C; (a) From (35,45)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone 2-5 propylmalonic acid monoamide obtained (S)-1-[ 1(25,3S)-3- hexyl-4-ox0-2- oxetanylJmethylldodecyl (RS)-2-carbamoylvalerate (del p da 0 (V1)ve isomers 24-0C fusion;e) From (3S,48S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone and 2-propylmalonic acid monoamide obtained (S)-1-[[(2S) ,35)-3-ethyl-4-0ox0- 2-oxetanyl]methyl]octadecyl(RS)-2-carbamoylvalerate | (stereoisomers (V0) | melting point PA VA C; © f) From ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone (35,45) and 2-carbamoyl-1,3-dioxolan-2-carboxylic acid obtained (S)-1 -[[(2S,3S)-3- ethyl-4-0x0-2- oxetanyl]methyl]octadecyl 2-carbamoyl-1,3-dioxolane- 2-carboxylate Melting point 240 °C; 0 (obtained From (3S,4S)-3-ethyl-4-[(R,10Z,13Z)-2-hydroxy-10,13- ' 2-isopropylmalonic acid monoamide s nonadecadienyl]-2-oxetanone vo on:

£4 (all Z,S)-1-[[(2S,35)-3-ethyl-4-0x0-2- oxetanyl]methyl]-9,12-1 coctadecadienyl (R or S) -2-isopropylmalonalate and (ether (from 436 (all Z,S)-1-[[(2S,3S)-3-ethyl-4-0x0-2- oxetanyl]methyl]-9,12- Infrared spectrum coctadecadienyl (S or R)-2-isopropylmalonalate 0 mg TEV AVITAL. FYAY (cml) (IR)

Y example, by reactance 1, similar to example 49) ester amides obtained amides a= (3S,4S)-3-hexyl-4-[(R)-2- hydroxytridecyl]-2- oxetanone / the following: > 0 4-carbamoylbutyric acid (S)-1- obtained 4-carbamoylbutyric acid a) with dan ([[(2S,3S)-3-hexyl-4-0x0-2 -oxetanyl methyl] dodecyl ester C; TASTY fusion 3-carbamoylpropionic obtained 3-carbamoylpropionic acid b) by “acid (S)-1-[[(2S,3S)-3-hexyl -4-0x0-2-oxetanyl] methyl]dodecyl ester D. melting point 0.0= 001 C; dn 2-carbamoylacetic acid 2-carbamoylacetic acid c) was obtained by dan «(S)- 1-[[(2S,3S)-3-hexyl-4-0x0-2-oxetanyl Jmethyl]dodecyl ester C;PAV—AT,0 z fusion (S)-1-[[(2S,3S) )- 3-hexyl-4- was obtained by oxalic acid monoamide d) by © dy gia OVA=YY Melting point c0x0-2-0xetanyl jmethyl]dodecyloxamate (S)-1-[[(2S,3S9) )-3- methylcarbamoylacetic acid e) was obtained by ia» chexyl-4-oxo-2-oxetanyl] methyl] dodecyl N-methylmalonamate ) Melting 17-77 C; (S)-1- was obtained on rac-2-carbamoyl-4-methylvaleric acid f) by vo[[(2S,3S)-3-hexyl-4-0x0-2-0xetanyl]methyl]dodecyl (RS)-2

e carbamoyl-4-methylvalerate (stereoisomers (Vi) melting point “VY 04 dimer” g by 1-carbamoylcyclohexane carboxylic acid obtained -1-(5) 3-hexyl-4 - oxo0-2- oxetanyl] methyl] dodecyl -(25,35]] (1-carbamoylcyclohexanecarboxylate 0 melting point .507-85 C; h by 2,2-dimethylmalonamidic acid obtained -3-(25) ,35)]]-1-(5)a chexyl-4-0x0-2-oxetanylJmetyl]dodecyl 2,2- dimethylmalonamate SARC: (0.9%=¢ [on™ = -23.8° (CHCl) ;/i) by rac-2-methylmalonamidic acid obtained (S)-1-[[(28,3S)-3- hexyl-4-oxo-2-oxetanylJmetyl]dodecyl (RS)- 2-methyl malonamate 0 (imiters of (V0) melting point ©0018-0117 melting point; j) by rac-2-ethylmalonamidic acid obtained -3-(25,35)]]-1-( 5) hexyl-4-oxo-2-oxetanylJmetyl]dodecyl ~~ (RS)-2-ethyl malonamate (1:1 immers); melting point =A 000C; 1s K) by rac -2-butylmalonamidic acid obtained -3-(25,35]]-1-(5) ‎(RS)-2-butyl | malonamate ~~ the brightest factor[ the number of selection*1601-4-0:0 -2-0 (0:1 epimers), melting point 48-97*C; (J by 2,2-diethylmalonamidic acid obtained (S)-1-[[(28,38)-3- chexyl-4-oxo-2-oxetanyljmetyl]dodecyl 2,2-diethyl malonamate specific photocyclic coefficient: [a]p?=-21.1°%(CHCl; c=1%), m) by 2-carbamoyl-m-dioxane-2- carboxylic acid obtained -1 -(5) [[(2S,3S)-3-hexyl-4- oxo-2-oxetanyllmetyl]dodecyl 2-carbamoyl-m- cdioxane-2-carboxylate (melting point) 20 dimers. Example £z Yo with analogy to Example 1 of (35,45)-3-ethyl-4-[(R)-2-hydroxynonadcyl]-2-oxetanone and

£1 (S)-1-[[(28,35)-3- obtained l-carbamoylcyclohexanecarboxylic acid a) ethyl- 4-0x0- 2-oxetanyl] methyl] octadecyl 1- 7C; and 4-177 pH ccarbamoylcyclohexanecarboxylate (S)-1- on Joa 2-carbamoyl-m-dioxane-2-carboxylic acid B [[(28S,3S)-3-ethyl-4- oxo0-2-oxetanylmethyl]octadecyl-2-carbamoyl-m- 0 °C. OVA Melting point «di oxane-2-carboxylate ° 2 eg (BR4R or 35,45(-4-])0 (2- from das 1 by analogy with an example)' (2-isopropylmalonic acid and hydroxytridecyl]-3- pentylthio-2-oxetanone : on: amide 0 (S)-1-[[(2R) ,3R or 28,3S)-4-oxo0-3-pentylthio-2-oxetanyl] methyl] (I [M'e- Yot :(MS) Mass spectrum: «dodecyl (R or S)-2-isopropylmalonamate : (cm=1) (IR) Cala 2-isopropylmalonic acid amide] and 11701 TOV (IVY (VAY) bond (S)-1-[[(2R,3R or 28,3S)-4 -0xo0-3-pentylthio-2-oxetanyl] methyl] b) 1s celsius OVYA-YY Melting point “dodecyl (S or R)-2-isopropylmalonamate (diethyl ether) 1 eg ( BRA4R or 3548)-4-[(R)-2- obtained from 1 by analogy with example 2-isopropylmalonic acid and hydroxytridecyl]-3- pentylthio-2-oxetanone +06 on: amide (S )-1-[[(28,3S or 2R,3R)-4-oxo0-3-pentylthio-2-oxetanyl] methyl] (I Diode VYY fusion 4a «dodecyl (R or S)-2 isopropylmalonamate) and «(ethyl acetate) (S)-1-[[(2S,3S or 2R,3R)-4-0x0-3-pentylthio-2- oxetanyl] methyl] (= vo -1011 melting point «dodecyl -[S:R or R:S(2:1)]-2-isopropylmalonamate (ethyl acetate) 04

Z like no similarity with example 1 obtained from 3-benzyl-4-[(R)-2-hydroxytridecyl]-2- oxetanone | R 2-isopropylmalonic acid monoamide on an epimeric mixture where chromatography separated on silica gel using hexane ethyl acetate /

(Y:Y:)) methylene chloride ° to give: (S)-1-[[(2R,3R)-3-benzyl-4-oxo0-2-oxetanylJmethyl]dodecyl (R or (I 4s) «S)-2-isopropylmalonamate _fusion methylene ) 4s °AV-Ae

(chloride f/b)(S)-1-[[(2R,3R)-3-benzyl-4-oxo0-2-oxetanyl methyl]dodecyl (Sor 4a jy(R)-2-isopropylmalonamate 0 Melting VV eV A C ) methylene chloride . Example A Similar to example 1 obtained from 3-benzyl-4-[(R)-2-hydroxytridecyl]- 2- oxetanone 0 and 2-isopropylmalonic acid monoamide was applied to an emery mixture, where it was separated by chromatography on silica gel by hexane | ethyl acetate / methylene chloride in a ratio of 1:7:1 to give: (a) S)-1-[[(28,38)-3-benzyl-4-oxo0-2-oxetanyl methyl dodecyl (R or S)- 018-0117 lea 4a jn 2-isopropylmalonamate C ) methylene (chloride 0 and b) (S)-1-[[(2S,3S)-3-benzyl-4-oxo-2-oxetanylJmethyl]dodecyl (S or 4a 0 (R)-2-isopropylmalonamate Fusion 1049-1478 methylene (chloride eg + Yo added ¥ aa) of di-t-butyl azodicarboxylate into a suspension cooled at 501 chloride of 1 an), from (3S5,45)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2- coxetanone 00mg of ([D,L]-N-acetyl-2 - carbamoylglycine 1 mg

£A after THF 11 sieve particles (; angstroms) (in 0.7 mg and triphenylphospine) were stirred (dal) for one hour at zero degrees Celsius and overnight at a temperature, thus obtaining: 1 at Reaction mixture Same steps as for example (S)-1-[[(28,38)-3-hexyl-4-oxo0-2-oxetanyl[methyl] dodecyl of 001 mg (i and -977) 11 * Melting point ((R or S)-2-acetamidomalonamate E0 (S)-1-[[(25,35)-3-hexyl-4-oxo0-2-oxetanylJmethyl] b) 100 mg of “VV melting point (VY ey) “dodecyl (RS)-2-acetamidomalonamate [a]p” = -8.degree.(c=0.5, CHCL3) °C; optical specific cycling coefficient: 7 : 01 Example: amides But using the following 1 similarly to the example of ester amides he obtained Ve (S)-1-[[(28, 3S)-3-ethyl-4-ox0- on oxalic acid monoamide obtained from (i) melting point *001-44 (2-oxetanyl]methyl]octadecyl oxamate (S)-1-[[(2S,3S)-3-ethyl-4 - to 2-carbamoylacetic acid b) obtained from acid -4+,0 fusion 4s ox0-2-oxetanyl]methyl]octadecyl malonamate

Gugie®d),0 ys (S)-1-[[(28,3S)-3-ethyl-4- methylcarbamoylacetic acid c) obtained from fusion 4550 coxo-2-oxetanyl|methyl] octadecyl N-methylmalonamate dy gia 60-84 (S)-1-[[(25,35)-3-ethyl-4- dimethylcarbamoylacetic acid obtained from (2 ia coxo0-2-oxetanyl|methyl]octadecyl -N,N-dimethyl malonamate v0 melting point 17-75*C; (S)-1-[[(28,3S)-3-ethyl- on rac-2-ethylmalonamidic acid e) was obtained from (Ipimers 4-0x0-2-oxetanyl]methyl]octadecyl (RS)-2- methylmalonamate M. p. 17-91.5*C; (V2) (S)-1- [[(2S,35) )-3-ethyl-4- to 3-carbamoylpropionic acid obtained from (5 vo -74,5 fusion ds cox0-2-oxetanyl|methyl]octadecyl succinamate, which has no affinity.

11 Example (S)-(+)- or (+)-2-isopropylmalonic acid But using 1 in analogy with an example he obtained: monoamide (S)-[[(28,35)- 3-ethyl-4-ox0-2-oxetanylJmethylJoctadecyl (6)-2- { C; and oY Yo melting point cisopropylmalonamate E0 (S)-[[(28,38)-3-ethyl-4- 0xo-2-oxetanylJmethylJoctadecyl (58(-2- b) 0xo-2-oxetanylJmethylJoctadecyl )58(-2- b) 5118 C. Melting point disopropylmalonamate 1 ex. (38,4S)-3-hexyl-4-[(R)-2- obtained from 11, (SY ¢(f)?1 by analogy with the examples (+) and (S)-(+)- 2-isopropylmalonic [hydroxytridecyl]-2- oxetanone 0 on: acid monoamide (S)-1-[[(2S,3S)-3-hexyl-4-ox0-2-oxetanyl]methyl]octadecyl (R)-2- ) C; and, respectively, YY melting point disopropylmalonamate (S)-1-[[(28,3S)-3-hexyl-4-0x0-2-oxetanylJmethyl]octadecyl (S)-2-b | SAY cisopropylmalonamate melting point 0 and (3S,48)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone) (— after chromatography on silica gel 2- Propylmalonic acid monoamide obtained: (V0:A0) in the ratio of acetonitrile / methylene chloride using (98(2-1-[1])28,39(-3 - TADAO*0-2 -0<e-4- 1 pud 1000671 (R or S)- ( ) water ; / methanol C ) of IVY melting point <2-carbamoylvalerate 0 (S)-1 -[[( 28,3S)-3-hexyl-4-ox0-2-oxetanyl]methyl]dodecyl (SorR)- (¥ C. 0A0 melting point 2-carbamoylvalerate 1 Example © (3S,48)- 3-ethyl-4-[(R,10Z,13Z)-2- from 11, (JY 0) in analogy with examples (S)-(+)-2-, (3) and hydroxy-10 ,13-nonadecadienyl]-2-oxetanone 0 Obtained: isopropylmalonic acid monoamide

(all Z,S)-1-[[(2S,3S)-3-ethyl-4-0x0-2-e*absorbent-1[-9,12-a) | C PAA-AY fusion da yn coctadecadienyl (R)-2-isopropylmalonalate and “(ether (from) (all Z,S)-1-[[(2S,3S)-3-ethyl) -4-0x0-2-oxetanyl[methyl]-9,12- b) aqueous (from 50019 melting point coctadecadienyl (S)-2-isopropylmalonalate 0 (aqueous methanol)

Ve example (35,48 or 3RAR)-4-[(R)-2- obtained from 1 6 111 similar to the examples (S)-(+)-2- iso- and -( ), and hydroxytridecyl]-3-pentylthio-2-oxetanone oo at: propylmalonamide 0 (S)-1-[[(28,3S or 2R,3R)-4-ox0-3-pentylthio-2-oxetanyl ] methyl] (i ethyl ) C YY _Melting point “dodecyl (R)-2-isopropylmalonamate “(acetate (S)-1-[[ (2S,3S or 2R,3R)-4-oxo0-3) - pentylthio- 2-oxetanyl] methyl] b) diethyl ) fusion 597 moiety ix 2 “dodecyl-(S)-2-isopropylmalonamate 0 and “(hexane [ ether (S)-1-[[] (2S,3S or 2R,3R)-4-0x0-3-pentylthio- 2-oxetanyl] methyl] (—:0.2-1117 fusion 4a «dodecyl [S:R(2:1)]-2 -isopropylmalonamate (ethyl acetate) 1C .example 0 (3S,4S or 3R,4R)-benzyl 4-[(R)-2- obtained from 1 11 by analogy with examples (S) -(+)-2-isopropyl- and hydroxytridecyl]-2-oxo-3-oxetanecarbamate (S)-1-[[(28,3S or 2R,3R)-3-[1- on malonic acid monomide 0 (benzyloxy)formamido]-4- oxo-2-oxetanylmethyl]dodecyl- (S)-2- (hexane /ether) .Celsius 5077. Melting point Jisopropylmalonamate Yo oY: Z 01 as and 111 by analogy with examples and (3R, 4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone) of (I (S)-1 [[2R,3R)- obtained (S)-(+)-2-isopropylmalonic acid monomide 4-ox0-3-(phenylthio)-2-oxetanylJmethyl]dodecyl ~~ (S)-2- isopropyl 0 « (ether) °C AA °C Melting point ¢malonamate f (35,45)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone)b) from He obtained 2-isopropylmalonic acid monoamide (S)- 1-[[ (2S,35)-4- oxo-2- oxetanyl] methyl] dodecyl (RS)-2-, (ether) (epimerate 1) :0); Melting point 4 (+2) C isopropylmalonamate 0 (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone c) obtained from the same compounds as in 2-isopropylmalonic acid monoamide (S)-1-[[(2R,3R)-4-0x0-3-(phenylthio)-2-oxetanyl] methyl] dodecyl- ; (i.(ether) °C Melting point A0 °C;) 0:7 = S:R) 2-isopropylmalonamate 7 m Example (S)-(+)-2-isopropylmalonic acid obtained from 111 By analogy with the following examples: The following esters on alcohols and monoamide alcohols (35,48 or 3R4R)-4-[(R)-2-hydroxynonadecyl]-3-a)) were obtained from (S)-1-[[(2S,3S or 2R,3R)-3-(methyl on (methylthio)-2-oxetanone «thio]-4-ox0-2-oxetanylJmethyl]octadecyl ~~ (S) -2-isopropylmaloamate rv. (ether C (from 507 melting point (3R4R or 35,48)-4-[(R)-2-hydroxynonadecyl]-3-b) obtained from (S)-1-[[( 2R,3R or 28,3S)-3- (methylthio) on (methylthio)-2- oxetanone degree «-4-ox0- 2-oxetanyl] methyl] octadecyl (S)-2-isopropylmaloamate «(ether C (from 5001” fusion vo: (3S,4R or 3R,45)-4-[(R)-2-hydroxynonadecyl]-3-c) obtained from (S)-1 -[[(2R,3S or on-frame6«()-3-(25,31‎ (methylthio)-2- oxetanone oY «thi0)-4-0x0-2-oxetanylJmethyl]octadecyl (S)-2- isopropylmaloamate and “(hexane/ether) fusion 43550247 (from da (BR,4S or 3S,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2- (2 (S) )-1-[[(2S,3R or 2R,35)-3-(methylthio)-4-0x0-2- on oxetanone

Seay 4a coxetanyl]methyl]octadecyl (S)-2-isopropylmaloamate (hexane / ether) .(C) from 0 z 08 Jee (R)-(-)-2-isopropylmalonic acid | The two examples ee are similar to j smonoamide 0 (3S,4S or 3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2- { (S)-1-[[(28) ,3S or 2R,3R)-3-(methylthio)-4-0x0- 2- obtained the oxetanone 2A melting point coxetanylmethyl]octadecyl (R)-2-isopropylmaloamate and “(ether) (from 45h (BR, 4R or 38S,4S)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2- («= ve (S)-1-[[(2R,3R or 28, 3S)-3-(methylthio)-4-ox0- 2-oxetanone

PAV coxetanyl[methyl]octadecyl (R)-2-isopropylmaloamate (hexane / ether) has a melting point of 1 as (S)- (+)-2-isopropylmalonic acid from 11 and 11. 1 with the following aly 5 examples: The following esters obtained alcohols and monoamide alcohols (35,45 or 3R,4R)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]- obtained from ( )5(-1-1125,35 or 2R,3R)-3-(benzylthio)-4-0x0-2- at 2-oxetanone * 8 4 melting point coxetanyl[methyl]octadecyl (S)-2-isopropylmaloamate «(pentane homologue (from vo (3R,4R or 38,485)-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]- b) obtained from (S )-I-[[(2R,3R or 28S,3S)-3-(benzylthio)-4-0x0-2- on 2-oxetanone oy melting point coxetanyljmethyl] dodecyl (S)-2-isopropylmaloamate and «(pentane / ether C (from (3S,4R and 3R,4S)-3-(benzylthio)-4-[(R)-2-hydroxy- c) obtained from: tridecyl ]-2-oxetanone (S)-1-[[(28,3R or 2R,38S)-3-(benzylthio)-4-0x0-2- oxetanyl] methyl] ( 0 lea (of 54 lea) 4a «dodecyl- (S)-2-isopropylmaloamate and «(pentane (5)-1-[[(2R,38 or 28,3R)-3-(benzylthio)-4-0x0-2-oxetanyl] methyl] (¥) (from Lge © 0016 presently 4a dodecyl- (S)-2-isopropylmaloamate 1 (hexane 0).

Ye d mal (R)-(-)-2-isopropylmalonic acid from 11 01 similar to the following examples: the following esters obtained alcohols and monoamide alcohols (35,45 or 3R,4R )-3-(benzylthio)-4-[(R)-2-hydroxytridecyl]- obtained from (i )5-1-1)25,35 or 2R,3R)-3-(benzylthio)-4- oxo0-2-on 2-oxetanone 0 melting point coxetanyl|methyljoctadecyl (R)-2-isopropylmalonamate «(pentane / ether (from VV (3R,4R or 38,4S)-3-(benzylthio) )-4-[(R)-2-hydroxytridecyl]- b) obtained from (S)-1-[[(2R,3R or 28,3S)-3-(benzylthio)-4-oxo0-2- The fusion 2-oxetanone da coxetanyl[methyl]dodecyl- (R)-2-isopropylmaloamate 0 and “(pentane / hexan) 14 (3S,4R or 3R,4S)-3 (benzylthio)-4-[(R)-2-hydroxy- : obtained from (— to: tridecyl]-2- oxetanone (S)-1-{[(2S,3R or 2R,35)- 3-(benzylthio)-4-0x0-2- oxetanyl] methyl] )1 ether C (of VYY) Melting point “dodecyl-(R)-2-isopropylmaloamate 0” and “(pentane of (S) -1-[[(2R,3S or 28,3R)-3-(benzylthio)-4-oxo0-2- oxetanyl] methyl] (¥ / ether C (from ©0011) Melting point «dodecyl-( R)-2-isopropylmaloamate -(pentane 1 mal (3R,4R)-3-ethyl-4-[(R)-2-hydroxy-) with 1 VV reactance similar to the two examples: nonadecyl]- 2-oxetanone (S)-1- obtained (S)-(+)-2-isopropylmalonic acid monoamede a) with [[(2R,3R)-3-ethyl-4-0x0-2-oxetanyl Imethyl]octadecyl-(S)-2-isopropyl- and “(methylene chloride) 0118 = VV1 melting point ¢malonamate A (S)-1-[[(2R,3R)- 3- He obtained 1-carbamoylcyclohexanecarboxylic acid b) 0 ethyl-4- oxo-2- oxetanyl] methyl] octadecyl -1-carbamoylcyclohexane- 7 e. 4-171 melting point ccarboxylate

YY mal 11 0 similar to examples (3R,4R)-4- 5 (S)-(+)-2-iso propylmalonic acid monoamide obtained from (I 1s (S)-1-[[ (2R,3R)- on [(R)-2-hydroxynonadecyl]-3-methyl-2-oxetanone 3-methyl- 4-oxo- 2-oxetanyl] methyl] octadecyl (S)-2-isopropyl- and “(hexane [ethyl acetate) C (from 2VYI=VYE melting point) malonamate (3R,4R)-4-[(R)-2- 5 rac-2-t-butylmalonic acid monoamide b) obtained from (S)-1-[[(2R,3R)-3- hydroxynonadecyl]-3-methyl-2-oxetanone 0 methyl-4-ox0-2-oxetanyl Jmethyl]octadecyl (RS) -2-t- butylmalonamate .(hexane / ethyl acetate) 20 4-51 melting point (V3) (Example YY immers | (2S,3S,5S8)-5-[ [(cis)-2- carbamoyl- a solution consisting of 7.7/7 mg of (e.g. (d)) in cyclohexylloxy]-2-hexyl-3-hydroxyhexadecanoic acid (re)g sieve particles (Aas; DMF Jo, methylene chloride; ml ull ay triethylamine and 40 7 mg HBTU angstroms were added); 460 mg of co filtrate the reaction mixture; Hexane (Y:V) dui ell / methanol The filtrate. The remaining material was partitioned between methylene chloride by means of hexane. The hexane layer was diluted and extracted by means of: hexane [ether], dried and concentrated. The residue of (IR or 5,25 or R)-2-[[(S)-1- [[(2S,3S)-3-hexyl-4-0X0-2-a) crystallized 176 mg of 0 (stereoisomer oxetanyl]methyl[dodecyl]oxy]cyclohexanecarboxamide and “(hexane / ether) C (from ©0117) Melting point (cis I) (28,38,58)-5-[ [(cis)-2-carbamoy] cyclohexylJoxy]-2- b) similarly obtained (second isomer; acid in example (e)) hexyl-3-hydroxyhexadecanoic acid (1S or R,2R or S) -2-[[(S)-1- [[(2S,3S)-3-hexyl-4-ox0-2-oxetanyl] on 0 (cis (second stereoisome methyl]ldodecyl]oxy]cyclohexanecarboxamide .(hexane / ether) Melting point 4 4*C (from

Ye Jb (28,38,58)-5-[(R/S)-2-carbamoyl- 1- of antY,0 was treated with a solution of lm01k(d)) in Ji)methoxyethoxy] -2-hexyl-3-hydroxydecanoic acid o

Ade molecules aa) dad (Y:Y)acetonitrile / methylene chloride filter “ull after HBTU of _mg*001 and triethylamine 0.1 lm (? angstrom) with a ratio of cla [ methanol s hexane The reaction mixture was concentrated and the residue was fractionated between: hexane The aqueous layer of chexane was dried with z (0) methanol; layer extracted and centered; Accordingly, the residue was separated by chromatography on silica gel using 765 of © (R/S)-3-, thus obtaining 11 mg of “methylene chloride in methanol [[(S)-1- [[(2S,3S) )-3-hexyl-4-0x0-2- oxetanyl[methyl]dodecyl]oxy]-3- Melting point 20 °C. ¢():Y (imiters of methoxypropionamide z Yo as 3- [[(S)-1-[[(25,35)-3- from pats pushing chloride gas into a solution of Yo in J (eg hexyl-4-oxo-2-oxetanyl) Imethyl]dodecyl]oxy] propionic acid until the solution is completely saturated with ammonia, then add 00 mg of acetonitrile JaYo

.HBTU and then the reaction mixture was filtered and evaporated. The residue was separated by chromatography on silica gel using 65% of methanol in methylene chloride, thus obtaining 7.9 mg of carbamoylethoxy]-3-hexyl-2-2)-2-(4-1). 5-(353,45) coxetanone Melting Point © * Residue. As +7 a solution consisting of 77.5 mg of (S)-1-[[(28S,3S)-3-hexyl-4-0x0-2- oxetanylJmethyl]dodecyl hydrogen malonate (example n) was treated in ml acetonitrile by 10 mg of HBTU and #lamgm 712701076a150000. After “ull” the mixture was filtered. The reaction was concentrated and the residue was separated by chromatography on silica gel using hexane ethyl acetate [methylene chloride 0%] (V:Y:Y) thus obtaining Cae from (S)-1-[[(2S,3S)-3-hexyl-4-ox0-2- oxetanyl] methyl]dodecyl- N- Disopropylmalonamate Melting point 209 Ay sie The following compounds were synthesized in a manner similar to example: 1 Z Example YY 1-[[(28,3S)- 3-hexyl- 4-oxo-2- oxetanyllmethyl ]dodecyl- 5- 1 -(5) ccarbamoylvalerate Melting point “©1-© 0 eliminator. Example YA 1-[[(2S,3S)- 3-hexyl-4- oxo-2 -oxetanyl] methyl]dodecyl- 6- -(5) «carbamoyl hexanoate º Melting point 07-57 C. Ya de. z (S) -1-[[(2S,3S)- 3- hexyl-4-oxo- 2-oxetanyl] methyl] dodecyl- 7- “carbamoyl heptanoate Melting point 40-047 C. re Jo 1-[[(28,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- 9- -(8) 0 carbamoyl nonanoate 0 Melting point 7 01-9 C.

AAS

(S)- 1-[[(2S,3S)-3- ethyl-4-oxo- 2-oxetanyl] methyl] octadecyl- 4- 7 e. 5-17 4 Melting point “carbamoyl butyrate:

TY Ex. (S)- 1-[[(2S,3S)-3- ethyl-4- -2-m′oxetanyl] methyl] octadecyl 0 octacid. 21¢,0-1Y, 0 melting point cadipamate

YY Example (S)-1- [[(2S,3S)- 3-ethyl-4- oxo-2- oxetanyl] methyl] octadecyl-6- Melting point 77.8-171.5 AH Celsius. carbamoylhexanoate º re ge. y (S)-1-[[(28,3S)-3-hexyl-4-oxo0-oxetanyl jmethyljdodecyl (R or S)-2-t- melting point 4-507© butyl malonamate ro Example ‎ (S)-1-[[(2S,3S)-3-hexyl-4-ox0-2-oxetanyl (6)-APO000| GTA or R)-2- [a]p®® = -16.4° (c=0.8, esl : optical cycling coefficient ct-butylmalonamate 0 .CHCl5)

Joe (S)-1-[[(28,3S)-3-ethyl-4-ox0-2-oxetanyl jmethylJoctadecyl (R or S)-2-

Adie; Melting point 4-48 ?;* t-butylmalonamate©! As 0 (S)-1-[[(2S,3S)-3-ethyl-4-ox0-2-oxetanyl methyl Joctadecyl (S or R)-2-2 C. 87-1 melting point ct-butylmalonamate

TA Example (S)-1-[[(2S,3S)-3-hexyl-4-0x0-2-oxetanyl methyl] ~~ dodecyl-(S)-3-[1- celsius). ‎ 57-177 Melting point «(benzyloxy)formamido] succinamate ro oA: ra Jo. (S)-1-[[(28,35)-3-hexyl-4-oxo0-2-oxetanyl jmethyl] dodecyl- cis-6- melting point 204-00 decant. ccarbamoyl-3-cyclohexene-1- carboxylate 50 ex (5)-1- [[(2S,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- -2-mN 0 Melting point 77-/ * ccarbamoylcyclohexanecarboxylate 41 ex. **©0- 44 Melting point cmorpholinopropionate º : 47 Example 1 (S)-1-[[(2S,3S)-3-Hexyl-4-0x0-2-oxetanyl A[ Jdodecyl-] tetrahydro- C. oN =o Melting point “(B-0x0-4H -1,4-thiazine-4-propionate, 4 eg (S)- 1-[[(2S,3S) - 3-ethyl-4- oxo-2-oxetanyl] methyl] octadecyl 1- endometriosis 7-771 Melting point ccarbamoylceyclopentanecarboxylate 0 Example (S)-1- [[(2S,25)-3 - hexyl-4-0x0-2- oxetanyl] methyl] dodecyl- 1- C. 51-40 Melting point ccarbamoylcyclopentanecarboxylate 46 Example (S)-1-[[ (2S,35)-3- hexyl-4-oxo- 2-oxetanyl] methyl] dodecyl- (RS)-2- 0C. - ]])25,35(- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- (RS)-2- (0:1 immers); Melting point 17-75 C. methoxymalonomate 49 ; ex. (S)-1 -[[(2S,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- 10 C. —0A Melting point ¢[(carbamoyl) thiolacetate

04 £A Example (S)-1- [[(2S,3S)-3- ethyl-4- oxo-2- oxetanyl] methyl] octadecyl Melting point 4-87 58°C. (([( carbamoyl methyl)thio]acetate £9 Ex (S)-1- ]])25,35(- 3-hexyl-4- -2-m oxetanyl] methyl] dodecyl- [(RS) - 0 204-00 Melting point (Vi) ((carbamoylmethyl)sulphinyl]acetate epimers. or example (S)-1- [])25,35(- 3-ethyl- 4-0xo- 2-oxetanyl] methyl] octadecyl- [(RS)- : 80-87 C. Melting point ((carbamoylmethyl)thio]acetate S-oxide 0 51 Ex. (S)-1 -[[(2S,35)-3- hexyl-4- oxo-2-oxetanyl] methyl] dodecyl- 3- [(2- HOME. OV E-VY melting point ccarbamoylethyl)thio]propionate of Example (S)-1-[[(2S,35)-3-hexyl-4-oxo0-2-oxetanyl] methyl]dodecyl- 3-[(RS)- M -48 M. (V2) (epimers of (2-carbamoylethyl)sulphinylpropionate C.20) or z-methyl (S)-1- [[(2S,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- C. fo —0Y Melting point «(carbamoylmethoxy)acetate 0 ot Example: (S)-1- ]])25,39(-3- ethyl- 4-oxo- 2- oxetanyl] methyl] octadecyl C. 77-175 melting point “(carbamoylmethoxy)acetate z oo as (S)-1-[[(2S,3S)-3-hexyl-4-0x0 -2-oxetanyl] methyl]dodecyl- (RS)-2-[1- C 15-44 C. Melting point (V1) ((benzyloxy)formamido]malonamate epimers C.

+ 506 Ex. (5)-1- [[(2S,35)-3- ethyl-4- ox0-2- oxetanyl] methyl] octadecyl (RS)- melting point 249-97 demerit. (Vi ) (2-isobutylmalonamate fo irimers as (5)-1- [[(2S,3S)- 3-ethyl-4- oxo-2-oxetanyl] methyl] octadecyl- (RS)- 0 homologue 2) 0 VAT melting point (V2) (epimers of 2- benzylmalonamate ov eg (5)-1-[[(2S,35)-3-ethyl-4-oxo-2-oxetanyl methyl Joctadecyl- (R or S)- putty. © 0001-1187 Melting point (2-benzylmalonamate / 54 as 1 (5)-1- [])25,35)- 3-hexyl- 4 -oxo0- 2-oxetanyl] methyl] dodecyl- (RS)-2- (0:1 epimers); melting point 47-57 C. phenethylmalonamate 54 as (S)-1- ]])25, 35(- 3-ethyl- 4-oxo0- 2-oxetanyl] methyl] dodecyl- (RS)-2- 1c (0:1 apimer); melting point 18-417°C. phenethylmalonamate 01 eg (S )-(+)-2-isopropylmalonic acid obtained from 101o with the ideal model (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3- (2-propynyl)-2- s monoamide (S)-1-[[(2R,3R)-4-0x0-3-(2- propynyl)-2-on (» JU)oxetanone + i>oxetanyl] methyl] octadecyl- (S) Similar Ideal (BR, 4R)-4- [(R)-2-hydroxynonadecyl]- 3-propyl- 2-5 monoamide > (S)-1-[[(2R,3R)-4-0x0-3-propyl -2- oxetanyl] p) on JU) oxetanone

24¥-4. Fusion 4a “methyl]octadecyl (S)-2-isopropylmalonamate (hexane / ethyl acetate) (from 435:11f1) The following compounds are synthesized in a manner similar to an ideal TY example (S)- 1- [[(2S,3S)- 3-(3-methyl- 2-butenyl)- 4-ox0-2-oxetanyl] methyl] 0 C. 017-001 Melting Point “dodecyl (R or S) )-2-isopropylmalonamate 1 Jo. (S)-1- [[(2S.3S)- 3-(3-methyl- 2-butenyl)- 4-ox0-2- oxetanyl] methyl] 171-171 Melting point “dodecyl- (S or R)-2-isopropylmalonamate º 0 +5 e.g. (S)-1- [[(2R, 3R)-3- (3-methyl- 2-butenyl) - 4-oxo- 2- oxetanyl] 7-100 Melting point amethyl]dodecyl- (R or S)-2-isopropylmalonamate : homologue. 10 Example - (S)-1- [[(2R) , 3R)-3-(3-methyl-2-butenyl)-4-oxo-2-oxetanyl] methyl]

Ag sie YAY Melting point “dodecyl- (S or R)-2-isopropylmalonamate 11 Example (S)-1- [[(2S, 3S or 2R, 3R)-3- (5-chloropentyl)- 4-0*0-2-oxetanyl] 77-7176 Melting point amethyl]dodecyl- (S)-2-isopropylmalonamate 0 °C. 9 as (S)-1-[[(2S, 38 or 2R,3R)-3-(5-chloropentyl)-4-oxo0-2- oxetanyl] : C. VY Melting point methyl] dodecyl (R)-2-isopropylmalonamate

Yo

TA Example (S)-1-[[2R, 3R or 2S, 3S)3- (5-chloropentyl)-4- oxo0-2- fusion 4a coxetanyllmethyl]dodecyl- (S)-2-isopropylmalonamate C. 0-4 34 as : (S)-1- [[(2R, 3R or 28, 3S)-3- (5-chloropentyl)- 4-oxo-2- fusion ds, coxetanyl ]methyl]dodecyl- (R)-2-isopropylmalonamate C. 87-0 (8)-1-(2S, 3S or IR, 3R)-[[3- [(E)-2- butenyl]- 4 -oxo- < 0 4”, “2-oxetanyl Jmethyl] dodecyl (R or S)-2-isopropylmalonamate C.*01 7-015 Fusion as (S)-1- (2S, 35) or 2R, 3R)[[3- [(E)-2-butenyl]- 4-oxo- is» 2-oxetanyl Jmethyl] dodecy-1 (S or R)-2-isopropylmalonamate D. fusion 14-47 e.g. ?No (8)-1-(2R,3R or 28,35)-[[3-[(E)-2-butenyl]-4-ox0-2- oxetanyl] methyl] degree Melting point 0-484 *C. dodecyl- (S)-2-isopropylmalonamate vr Je. 0 (S)-1-(2R,3R or 28,35)-[[3-[(E)-2-butenyl]-4-oxo-2- oxetanyl] methyl] C. OAY-T 0 Melting point cdodecyl- (R)-2-isopropylmalonamate ve eg (S)-1-[[(2R,3R or 25,35)-3-(2,3,4,5,6-penta fluorobenzyl) )-2-oxetanyl] 508-107 fusion 4a pn amethyl]dodecyl- (R)-2-isopropylmalonamate vo C.

For example vo (S)-I-[[(2R,3R or 285,35)-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanyl] cmethyl]dodecyl- (S)-2-isopropylmalonamate Melting point 111-1101°C. : both (S)-1-[[(2S,3S or 2R,3R)-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanyl—AA leat)! 4a 0 amethyl]dodecyl-(R)-2-isopropylmalonamate .24 homocysteine. 1 Example YY (S)-1-[[(2R,3R or 2S,35)-3-(2,3,4,5,6-pentafluorobenzyl)-2-oxetanyl] 0 | ! Ada methyl]dodecyl- (S)-2-isopropylmalonamate Melting 0-200C. YA Ji is similar to exemplary 1 and 7a but by using (R)- or (S)-2-pyrrolidone-5- carboxylic acid 0 instead of 2-isopropylmalonic acid monoamide it was obtained: 5 -oxo-D-proline (S)-1-[[(2S,3S)-3-hexyl-4-0x0-2-oxetanyl methyl] (i«dodecyl ester : | H-NMR (CDCI3) : 0.88(m,6H); 1.26(m,26H); 1.55-1.9(m,4H); 1.95- 2.55(m,6H); 3.21(m,1H); 4.25(m,1H); 4.31 (m,1H); 5.14(m,1H); 0 5.80(s,1H) (ppm) « b 5-oxo-L-proline (S)-1-[[(2S,3S)- 3-hexyl-4-0x0-2-oxetanyl]methyl] «dodecyl ester melting point dys 20Y-0) 5-ox0- D-proline- (S)-1- [[(2S,3S) )- 3-ethyl- 4-oxo-2-oxetanyl] (— amethyl] octadecyl ester VO “(diethyl ether) and 5-oxo-L-proline- (S)-1 -[[(2S,3S)-3-ethyl-4-0x0-2-oxetanylJmethyl] (a coctadecyl ester, melting point 20A-0YC.

56> as both ideally modeled MV 1 of (S)-(+)-2-isopropylmalonic acid monoamide and a) 3R,4R (or 3S,4S)-3-anilino-4-[ (R)-2-hydroxytridecyl]-2-oxetanone 0 stereoisomer b Js v) obtained -3-)2§,38 (S)-1-[[(2R,3R or anilino-4-oxo0-2-oxetanyljmethyl}jdodecyl-(S)-2-isopropylmalonamate (stereoisomer b); melting point 17C; and b) from (or 3R,4R)-3-anilino- 4-[(R)-2-hydroxytridecyl]-2- 35,45 A©07©]8000; _stereoisomer a (example t) or 25,35)]]-1-(5) 2R,3R)-3-anilino-4-oxo0-2-oxetanyl]methyl]dodecyl- (S )-2-isopropyl- 0 malonamate (stereoisomer of melting point YY C. Pharmaceutical preparations are made of the following compositions in a manner known to those with ordinary skill in this technical field: Example: Gi yo gelatin capsules Soft: soft gelatine capsules Amount per capsule Oxetanone has the formula FOOLY (I) 0 Medium-chain triglyceride 7 ml Example B F It has the formula 0 (I) mg Lactose crystals, 0 mg Microcrystalline cellulose mg Polyvinylpyrrolidone 0 | : 2 mg carboxymentyl ether of starch Sodium salt of mg Talc©, mg

Magnesium stearate: “0 mg Magnesium stearate mg I per capsule Lindl weight Example JF: 1861618 mg tablets (I) 0006 HA0 has the formula 0 anal YALA Lactose anhydrous anal vs Microcrystalline cellulose mg 0 ‎ Polyvinylpyrrolidone mg 0 Polymer of carboxymethylcellulose aaa), Y Magnesium stearate 0

NT tablet weight Example duff Tablets with controlled release of the active substance and long retention in the stomach: 0 mg (I) of the formula oxetanone º PEOVER Lactose powder eo 5 mg Hydroxypropylmethylcellulose ©, Polyvinylpyrrolidone aaah, + Talc 0 mg/mg Magnesium stearate 0 mg Colloidal silicic lacquer 0 mg 6 Nucleus weight 6 mg Hydroxypropylmethylcellulose anal, Yo Talc axa), Yo Titanium dioxide 0 mg Weight of the film coating 0

Example E: Reconstitutable powder Reconstitutable powder 6 mg (I) has the formula oxetanone mg Ethylvanillin (N-L-o-Aspartyl-L- : Aspartame |.

PEON phenylalanine 1-methyl ester) 0 mg Sprayed skinned milk powder 0 mg Total Weight

Claims (1)

Claims 1 - 01 oxetanones have the formula: 0 >” Bogen = =0 R? Rt I Y where © is a group with the formula: (R3 RHNCO(X),-CO- Ql v (R3,RYNCO-X'- Q? ¢ rr oo j il 0 Q3 Q and R25 RI 1 form an alkyl with 81 carbon atoms substituted by one v to three halogens or alkynyl alkenyl i calkyl groups Or alkadienyl A having a number of carbon atoms up to *01 carbon atom interrupted 4 optionally 4-arylene de gana optionally substituted by a baryl group of © mode and optionally substituted 01° by a -caryl group (Cyg)-alkyl where !18 atom 0 or atom 8 can be interrupted or interrupted by “1” a sulphinyl or sulphonyl group in a position other than position 0 of an unsaturated carbon atom; VY or RI being a group aryl-NH- or caryl-C,_4-alkyl-OCONH- group R3 and 1084 form hydrogen or (Cp y)-alkyl or form association with the attached N atom Logs ¢\ A saturated ring of Y to 1 members optionally contains a 0 atom or an S atom in a position other than the \o position of 0 for the Al atom: 8 be a number equal to 1 or zero X 7 be an alkylene group contain a number of carbon atoms up to IN carbon; 'A' and optionally interrupted by atom O or atom 58; Or it is interrupted by a sulphonyl sulphinyl group 4 optionally substituted by a group | hydroxy or aryl sf mercapto or aryloxy or TA or aryl- (Cpg)-alkoxy or aryl-(C,)-alkyl or arylthio Ye or (Cyp)-cycloalkylidene a aryl-(Cy_)-alkylidene J aryl-(C, _,)-alkylthio Y) or (Croralkyl | one or both groups Lables J (Cp o)-alkylidene YY or (Crgralkyl Ue gene) where it can form (Cp g)-alkylthio | (C ,.¢)-alkoxy Yr on the same carbon atom or on two carbons (Cpg-alkylthio 4 (Cyg)-alkoxy Yt mono-unsaturated 3- to optionally unsaturated 1 members adjacent 7-ring to Yo An optionally present or mercapto group and a hydroxy group or a 7-membered ring YA group An arbitrary unsaturated © atom must be in the opposite position » with respect to the 9-membered sulphonyl or csulphinyl atom or 8-membered atom Optionally present or with respect to the © TA group is a group with the formula: Xf optionally 1 -CHN(R,RO)CH,- Moat-R 7 aryl a «(Cy4)-alkyl(CO) or OCO)- of 1 tola(er) sf and 20 form hydrogen; R 8 and aryl-(Cy_4)-alkyl(CO or OCO)- ie aryl-(C,_4)-alkyl 4 caryl (CO or OCO)- YY contains up to 6 carbon atoms that alkylene de gana can be 1 vy aryl-(Cy_4)-alkyl J arylthio 4 aryloxy 4 aryl J (C,)-alkoxy with a re group or with one or both caryl(Cpg)-alkylthio § aryl(C,)-alkoxy or ro groups two adjacent carbon atoms so that they form (Crg)alkyl where two (Cp g)-alkyl groups are connected Dr .3- to 7-membered ring to pursuant to claim (1); Where © is a T group of the formula oxetanones Y = 01 oxystanones of the formula !01;1 have up to 300 alkadienyl, alkenyl, or alkyl carbons forming R25 RI v opal groups in phenyl optionally substituted with a 1,4-phenylene group optionally interrupted by a group of © atom or a 5 atom in Rl interrupted by Cus phenyl-(Cpy)-alkyl and optionally substituted by a group of put in the opposite position » for an atom 0 unsaturated 1 carbon; It is optionally interrupted by atom 0 or SIN containing an even alkylene that forms an X v group or a phenoxy J phenyl J mercapto 5 atom 8 optionally substituted by hydroxy groups A phenyl-(C,4)- J phenyl-(C ;4)-alkoxy s phenyl-(C, ,)-alkyl 4 phenylthio 9 alkylthio | Ve any s-al-ol-(6)-1 sane or (Cs)-cycloalkylidene a-e) alkylidene or interrupted by one group or (Cpg)-alkoxy sf (Cpg)-alkyl Ue sane or Cum (( Cypg)-alkylthio VY Two groups (Cpgralkoxy si (Cpg)alkyl or (Cpg)-alkylthio) attached to the same carbon atom can form a saturated to 7-membered ring \¢ -3 hydroxy group or mercapto is optionally present and the JS of them must be in the opposite position » For atom 0 or atom 5 optionally present or X 5 the ROS group is 16 =CHN(RR?) Two hydrogens R (Crg)alkyl R (Cra) phenyl 4 alkyl-(CO OR OCO)- Vv or R45 R3 ens phenyl-(CO or OCO)- VA have the same meanings given in the claim (1). They form alkynyl sf alkenyl Ji calkyl or alkadienyl groups having a number of carbon atoms up to *1 carbon atom optionally substituted by Aaryl position 0; Cus 0 can interrupt !18 atom 8 in opposite position for mode » for an unsaturated © atom; or RI : anilino or alkyl group having up to 5,37 carbons substituted with a halogen atom or “phenyl-(C,_4)-alkyl-OCONH- (de sons 7 A 3p and 84 forming a hydrogen or (Cy y)-alkyl group or both with a1 atoms attached to them 1 forming a ring of “saturated members containing atom 0 or 85 in a position other than the OL position 1 | for N53 1 « be a number equal to 1 or yellow X VY be an alkylene group containing a number of carbon atoms up to (OS SON vr optionally interrupted by a © atom or 5; or interrupted by a sulphinyl group and optionally substituted with one or both (Cpg)alkyl groups or un (Cpg)alkoxy groups can form two (g)-alkyl Vo groups (©) or . (Cpg)-alkoxy attached to the same © or two carbon atoms A ring of © 1 WY 4 optionally mono-substituted members «optionally mono-unsaturated or X Vv is -CHN(R,ROCH,- J =CHN(R,R?) i.e. sana and VA and 20 form hydrogen; .benzyloxycarbonyl sl (C,.s)-alkanoyl ve or methyl (8 Rl wherein o(¥) according Protective element oxetanones oxetanones -0 or 3-methyl-2-buyenyl ol 2-butenyl 4 hexyl J propyl or ethyl Y or benzyl 4 S-chloropentyl or pentylthio ie methylthio or 2-propynyl 3 or anilino or pentafluorobenzyl or benzylthio or phenylthio t 8,11- 4 heptadecyl or undecyl be 112. “benzyloxycarbonylamino ° or isopropyl or methyl two hydrogens or R44 R3 <heptadecadienyl 1 form n cthiomorpholino or morpholino it forms an N group in association with a v propylidene atom ie ethylidene J (CHy)ig forming an X or yellow group 1 A number equal to A “pentylidene” isobutylidene “butylidene or isopropylidene or q: or cyclopentylidene i.e. t-butylmethylene dimethylvinylidene available in my blood Ve 1,2- or phenylpropylidene or phenethylidene or 1 cyclohexylidene or acetamidomethylene or cyclohex-3-en-1,6-ylene sl «cyclohexylene vy 1-benzyloxycarbonylamino-1,2-ethylene ie benzyloxycarbonylaminomethylene 7 methylenesulphinyl ie methylenethiomethylene ie methyleneoxymethylene ‎ Vt or ethylenesulphinylethylene J ethylenethioethylene J methylene vo .propylenedioxymethylene 4 ethylene- si methoxymethylene i has formula 1 according to claim (1) where the © oxetanones are oxetanones -#* 0 being X's and 184 being hydrogen R3(Cppg)-alkyl form R? RD “Q? group ¥ carbon SIA can contain a number of carbon atoms up to alkylene group 1 where (Cpg-alkyl or one group or two (Cp g)-alkoxy groups; replaced by a group of 0 attached to adjacent carbon atoms a ring composed of (Cp alkyl) can form two groups of 0 members. 1 to 1 is 182 chexyl be RI of claim (0)¢ in which the oxetanones are +1 oxetanones. 1,2-cyclohexylene sl 1-methoxy-1,2-ctylene aa ethylene in which X's undecyl 7 is Cus(1) of protectant Wh 1; of the formula oxetanones are oxystanones 7-1 or hexyl rock (Cpp)-alkyl forming R25 group 03; 183 forming hydrogen and for 18 Y -undecyl v vA of the following group: (V) according to the claimant Oxetanones Oxystanones —A 1 (S)-1- [[(2S,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- (S)-2- Y «<isopropylmalonamate 3 (S)-1- [[(2S,35)-3-hexyl-4-oxo-2-oxetanyljmethyl]dodecyl (S or R)-2- ¢ «carbamoylvalerate ° (all Z,S)-1-[[(2S,3S)- 3-ethyl-4-0x0-2- oxetanyl[methyl]-9,12-octadecadienyl 1 «(S)-2-isopropylmalonamate 7 (5(-1-1125,35 or 2R,3R)-4-0x0-3 -pentylthio-2- oxetanyl]methyl]dodecyl (S)-2- A «<isopropylmalonamate 4 : (S)-1-[[(2S,3S or 2R,3R)-4-0x0-3-pentyl thio-2 -oxetanylJmethyl]dodecy] 1¢[S:R(2:1)]-2-isopropylmalonamate 11 (S)-1-[[(28S,35)-3-ethyl-4-ox0-2-oxetanyl methyljoctadecyl (S) or R)-2-t- VY «butylmalonamate VY 8 1-[[(28,3S)-3-ethyl-4-0x0-2-oxetanyl [LGTA] octadecyl 1-carbamoyl- 6 «cyclopentanecarboxylate Vo (8) )-1-[[(2S,3S)-3-hexyl-4-ox0-2-oxetanyl jmethyljdodecyl (RS)- 2- Vi benzylmalonamate VY(S)-1-[[(28,35)-3-hexyl -4-ox0-2-0xetanyl]methyl]dodecyl 3-[(2- VA «carbamoylethyl)thio]propionate V4 5-oxo-D-proline (S)-1-[[(28S,3S)-3-ethyl -4-ox0-2-oxetanyl]methyljoctadecyl Y. and “ester 71 5-oxo-L-proline [off*3-0121-4-00-2-0-(1)25,35]]- 1-(6)methyl]octadecyl YY .ester YY: according to the claimant (¥) of the following group: 1-4-oxetanones (S)-1-[[(2S,3S)-3-hexyl -4-oxo0-2-oxetanylJmethyl]dodecyl (S or R)-2- Y «<isopropylmalonamate v For (S)-1-[[(25,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- (RS)-2- £ carbamoylvalerate ° (0:1 epimer) (all Z,S)-1-[[(25,3S)-3-ethyl-4- oxo-2-oxetanyl|methyl}-9,12-octadecadienyl (S 1 «or R)- 2-isopropylmalonamate 7 (S)-1-[[(2S,3S)-3-hexyl-4-ox0-2-oxetanyl methyl] dodecyl (RS)-2-carbamoyl- A 4-methylvalerate 9 (¢(V:)(S)-1-[[(2S,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- 1- 01 “carbamoylcyclohexanecarboxylate 11 (S)-1- [[(28.3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl (RS)-2- VY methylmalonamate \y (imiters «(V:) (S)-1- [[(2S,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl (RS)-2- VE ethylmalonamate Vo (¢(V:) (S)-1- [[(2S,3S)- 3-hexyl- 4-oxo- 2-oxetanyl] methyl] dodecyl- (RS)-2- V1 butylmalonamate 7 (¢(V) :) (S)-1- []25,39( 3-ethyl- 4-oxo- 2-oxetanyl] methyl] octadecyl- 1- VA “carbamoylcyclohexanecarboxylate 1 (S)-1- [[ (2S,3S or 2R,3R)-4- oxo-3- pentylthio-2- oxetanyl] methyl] dodecyl Ye ¢[S:R or R:S(2:1)]-2- isopropyl malonamate 71 y !and (S)-1-[[(2R,3R)-3-benzyl-4-oxo0-2-oxetanylJmethyl] dodecyl (S or R)-2- YY .isopropylmalonamate YY 1-01 oxetanones of claim (1) for use as pharmaceutically active substances. 1-11 method of making oxetanones according to claim (1); characterized by: z Y |( esterifying an alcohol has the formula: 0 HOCHCH, Ne=0 R? 81 iE] r with an acid of formula 011-08; where 08 is a group of the form Ql or 03; or ¢ b) cyclizing an acid of formula IIb (Q-0,R?)CHCH,CH(OH)CH(R!)-COOH Ib . 1 or v c) the conversion of the carboxy group in group 1 into an acid with the formula: 0 T-OCHCH, Ne = 0 R? 1 IIc ; 4 where 7 is a group with the formula HOCO(X),-CO- 11 9 6 or 72 (HOCO-X'- 11) to the (R3,RHYNCO- amide) group and 1" >< d) as desired; separating a mixture of epimers of formula 10 1 into individual epimers 1-17 - a drug containing oxetanone According to any of the elements (1-11) and an inert carrier 7 therapeutically. «obesity dieu increased fat in chyperlipemia all atherosclerosis v and arteriosclerosis.