One object of the present invention is a compound of the formula I wherein X is O or NH ; R1 is lower alkyl, cycloalkyl, heterocycloalkyl or aryl, wherein the aryl ring is unsubstituted or substituted by benzyloxy; R2 is H, lower alkyl or aryl; R3 is lower alkyl,-SCH3, acetyl, wherein Ra is H or lower alkyl, Rb is lower alkyl, heteroaryl, -OC (CH3) 3 or aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by lower alkyl or aryl, heterocycloalkyl, wherein the heterocycloalkyl ring is unsubstituted or substituted by-COOC (CH3) 3 ; (CH=CR') o-aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, alkoxy, hydroxyl, benzyloxy, halogen, acetyl,- (CH2) 2NHS02Ph,

-NHCO (CH2) 2NHCOOC (CH3) 3,-(CH2) 2NHCOC6H30CH3C1, or for the non aromatic part of fused ring system also by oxo, o is 0 or 1 ; R'is H or lower alkyl, aryloxy, wherein the aryl ring is unsubstituted or substituted by lower alkyl or alkoxy, or (CH=CH) q-heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by lower alkyl, acetyl, alkoxy, halogen, -COOC (CH3) 3 or by halogen substituted benzyl; or for the non aromatic part of fused ring system also by oxo; q is 0 or 1; R4 is H, lower alkyl,-(CH2) 2SCH3,-NHCOCH3,-NHSO2p-Cl-Ph, amino, - NHCOOC (CH3) 3, hydroxyl, aryl, benzyl or halogen substituted benzyl; R5, R5 are independently from each other H, lower alkyl or aryl; R6, R6 are independently from each other H, lower alkyl or-SCH3; m is 1, 2 or 3 ; n is 0 or 1; and p is 0, 1, 2 or 3 ; and pharmaceutically acceptable salts thereof, with the exception that the compound is not 3-acetyl-4-hydroxy-5-isobutyl-1, 5-dihydro- pyrrol-2-one or 3-acetyl-5-benzyl-4-hydroxy-1, 5-dihydro-5H-furan-2-one.

Compounds of 3-acetyl-4-hydroxy-5-isobutyl-1, 5-dihydro-pyrrol-2-one and 3- acetyl-5-benzyl-4-hydroxy-1, 5-dihydro-5H-furan-2-one are disclosed in EP 0841063 Al.

The said compounds are claimed in said European Patent Application to be effective in preventing and treating cytopenia caused by cancer chemotherapy, radiation therapy, and the like.

Unless otherwise stated, the following terms used in this Application have the definitions given below. It must be noted that, as used in the description and the claims, the singular forms"a", "an"and"the"include plural referents unless the context clearly dictates otherwise.

"Alkyl"means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl"refers to an alkyl group of one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like or those which are specifically exemplified herein.

"Alkoxy"means a moiety of the formula-ORZ, wherein RZ is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like or those which are specifically exemplified herein.

"Aryl"means a mono-, bi-or tricyclic aromatic radical consisting of one or more fused rings, in which at least one ring is aromatic in nature. The aryl group can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently hydroxy, cyano, alkyl, alkoxy, thiol, thioalkyl, halo, haloalkyl, nitro, amino, monoalkylamino, phenyloxy, benyloxy, acetyl, (CH2) ZNHSOZPh, --NHCO (CH2) 2NHCOOC (C. H3) 3,- (CH2) 2NHCOC6H30CH3CIor for the non aromatic part fused ring system also by oxo, unless otherwise specifically indicated. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 10, 11-dihydro-5H-dibenzo [a, d] cyclohepten- 5yl, optionally substituted 9H-fluoren-9-yl, optionally substituted indan-1-yl and the like or those which are specifically exemplified herein.

"Aryloxy"means a moiety of the formula-ORY, wherein Ry is an aryl moiety as defined herein. Examples of aryloxy moieties include, but are not limited to, optionally substituted phenoxy and optionally substituted naphthoxy.

"Cycloalkyl"means a monovalent or divalent saturated carbocyclic moiety consisting of mono-or bicyclic rings. Cycloalkyl can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, amino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentenyl, optionally substituted cyclohexyl, optionally substituted cyclohexylen, optionally substituted cycloheptyl, and the like or those which are specifically exemplified herein.

"Halogen"refers to a substituent fluoro, chloro, bromo, or iodo.

"Heteroaryl"means a monocyclic, bicyclic or tricyclic radical of 5 to 12 ring atoms having at least one aromatic ring and furthermore containing one, two, or three ring

heteroatoms selected from N, O, or S, the remaining ring atoms being C. Heteroaryl can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, alkoxycarbonyl, amino, acetyl,-NHCOOC (CH3) 3 or halogen substituted benzyl, or for the non aromatic part of cyclic ring also by oxo, unless otherwise specifically indicated. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyrazinyl, optionally substituted pyridinyl, optionally substituted pyrimdinyl, optionally substituted indonyl, optionally substituted isoquinolinyl, optionally substituted carbazol-9-yl, optionally substituted furanyl, optionally substituted benzofuranyl, optionally substituted benzo [1, 2,3] thiadiazolyl, optionally substituted benzo [b] thiophenyl, optionally substituted 9H-thioxanthenyl, optionally substituted thieno [2,3-c] pyridinyl and the like or those which are specifically exemplified herein.

"Heterocycloalkyl"means a monovalent saturated moiety, consisting of one, two or three rings, incorporating one, two, or three heteroatoms (chosen from nitrogen, oxygen or sulfur). Heterocycloalkyl can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, or carbonylamino, unless otherwise specifically indicated. Examples of heterocyclic moieties include, but are not limited to, optionally substituted tetrahydro- furanyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, and the like or those which are specifically exemplified herein.

"Pharmaceutically acceptable salts"of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e. g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide; or addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid,

ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2- naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p- toluenesulfonic acid, trimethylacetic acid, and the like.

"LDA"means lithiumdiisopropylamide.

"DCC"means dicyclohexyl carbodiimide.

"EDC"means N- (3-dimetylaminopropyl)-N'-ethyl carbodiimide hydrochloride.

"DMAP"means 4-dimethylamino pyridine.

"BOC"means t-butyloxycarbonyl.

It has been found that the compounds of general formula I are p-secretase inhibitors and the related compounds may be useful in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in later life.

Pathologically AD is characterized by the deposition in the brain of amyloid in extracellular plaques and intracellular neurofibrillary tangles. The amyloid plaques are mainly composed of amyloid peptides (Abeta peptides) which originate from the p- Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified of which the most abundant are proteins of 695,751 and 770 amino acids length. They all arise from a single gene through differential splicing. The Abeta peptides are derived from the same domain of the APP but differ at their N-and C-termini, the main species are of 40 and 42 amino-acid length.

Abeta peptides are produced from APP through the sequential action of 2 proteolytic enzymes termed (3-and y-secretase. ß-Secretase cleaves first in the extracellular domain of APP just outside of the trans-membrane domain (TM) to produce a C-terminal fragment of APP containing the TM-and cytoplasmatic domain (CTFß). CTFß is the substrate for y-secretase which cleaves at several adjacent positions within the TM to produce the Ap peptides and the cytoplasmic fragment. The p- Secretase is a typical aspartyl protease.

It is hypothesized that inhibiting the production of A-beta will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with A-beta production.

Compounds that inhibit beta-or gamma-secretase activity, either directly or indirectly, could control the production of A-beta.

Thus, the compounds of this invention will be useful in treating AD by blocking the activity of ß-secretase and reducing or preventing the formation of the A-beta peptides.

Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, relating to the p-secretase inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of Alzheimer's disease.

A further object of the invention are all forms of enantiomers, racemates or diastereomeric mixtures of compounds of formula I.

In one embodiment the invention provides the compounds of the general formula la wherein Rl is lower alkyl, cycloalkyl, heterocycloalkyl or aryl, wherein the aryl ring is unsubstituted or substituted by benzyloxy; R2 is H, lower alkyl or aryl; R3 is lower alkyl,-SCH3, acetyl, wherein Ra is H or lower alkyl, Rb is lower alkyl, heteroaryl, -OC (CH3) 3 or aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by lower alkyl or aryl,

heterocycloalkyl, wherein the heterocycloalkyl ring is unsubstituted or substituted by-COOC (CH3) 3 ; (CH=CR') o-aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, alkoxy, hydroxyl, benzyloxy, halogen, acetyl,- (CH2) 2NHS02Ph, -NHCO (CH2) 2NHCOOC (CH3) 3,-(CH2) 2NHCOC6H30CH3C1, or for the non aromatic part of fused ring system also by oxo, o is 0 or 1; R'is H or lower alkyl, aryloxy, wherein the aryl ring is unsubstituted substituted by lower alkyl or alkoxy, or (CH=CH) q-heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by lower alkyl, acetyl, alkoxy, halogen, -COOC (CH3) 3 or by halogen substituted benzyl; or for the non aromatic part of fused ring system also by oxo; q is 0 or 1 ; is H, lower alkyl,-(CH2) 2SCH3,-NHCOCH3,-NHSO2p-Cl-Ph, amino, -NHCOOC (CH3) 3, hydroxyl, aryl, benzyl or halogen substituted benzyl; R5, R5 are independently from each other H, lower alkyl or aryl; R6, R6 are independently from each other H, lower alkyl or-SCH3; m is 1,2 or 3; n is 0 or 1; and p is 0, 1, 2 or 3 ; and pharmaceutically acceptable salts thereof, with the exception that the compound is not 3-acetyl-5-benzyl-4-hydroxy-1, 5-dihydro- 5H-furan-2-one.

In another embodiment the present invention provides the compound of formula Ia, wherein R'is lower alkyl, cycloalkyl, heterocycloalkyl, or aryl, wherein the aryl ring is unsubstituted or substituted by benzyloxy; R2 is H, lower alkyl or aryl;

R3 is lower alkyl,-SCH3, acetyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by lower alkyl or aryl, heterocycloalkyl, (CH=CR') o-aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, alkoxy, hydroxyl, benzyloxy, halogen, acetyl,- (CH2) 2NHS02Ph, -NHCO (CH2) 2NHCOOC (CH3) 3 or-(CH2) 2NHCOC6H60CH3Cl, o is 0 or 1; R'is H or lower alkyl, aryloxy, wherein the aryl ring is unsubstituted or substituted by lower alkyl or alkoxy, or (CH=CH) q-heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by lower alkyl, acetyl, alkoxy, halogen, or by halogen substituted benzyl; q is 0 or 1 ; R4 is H, lower alkyl,-(CH2)2SCH3, -NHSO2p-Cl-Ph, amino, -NHCOOC (CH3) 3, hydroxyl, aryl, benzyl or halogen substituted benzyl; R5, R5 are independently from each other H, lower alkyl or aryl; R6, R6 are independently from each other H, lower alkyl or-SCH3; m is 1, 2 or 3 ; n is 0 or 1; and p is 0,1, 2 or 3; and pharmaceutically acceptable salts thereof, with the exception that the compound is not 3-acetyl-5-benzyl-4-hydroxy-1, 5-dihydro- 5H-furan-2-one.

In still another embodiment the present invention provides the compound of formula la, wherein Rl is methyl, cyclohexyl, phenyl, morpholin-4-yl or 4-benzyloxy-phenyl; R2 is H, methyl or phenyl;

R3 is methyl,-SCH3, acetyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by methyl, tert-butyl or phenyl, tetrahydro-furan-2-yl, pyrrolidine-2-yl, 1-tert-butyloxycarbonylpyrrolidine-2-yl, piperidine-2-yl, 1-tert-butyloxycarbonyl piperidine-2-yl, (CH=CR') o-aryl, wherein the aryl ring is unsubstituted or substituted by methyl, tert-butyl, methoxy, hydroxyl, benzyloxy, chloro, fluoro, acetyl,- (CH2) 2NHS02Ph, -NHCO (CH2) 2NHCOOC (CH3) 3, or- (CH2) 2NHCO-3-chloro-2-methoxybenzene, o is 0 or 1; R'is H or methyl, aryloxy, wherein the aryl ring is unsubstituted or substituted by methyl or methoxy, or (CH=CH) q-heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by methyl, acetyl, methoxy, chloro, or by chloro or fluoro substituted benzyl; q is 0 or 1; is H, methyl, ethyl,- (CH2) 2SCH3,-NHSO2p-Cl-Phenyl, amino, -NHCOOC (CH3) 3, hydroxyl, phenyl, benzyl or chloro substituted benzyl; RS, R5 are independently from each other H, methyl or phenyl; R6, R6 are independently from each other H, methyl or-SCH3; m is 1,2 or 3; n is 0 or 1 ; and p is 0, 1, 2 or 3 ; and pharmaceutically acceptable salts thereof, with the exception that the compound is not 3-acetyl-5-benzyl-4-hydroxy-1, 5-dihydro- 5H-furan-2-one.

In yet another embodiment the present invention provides the compound of formula la, wherein Rl is methyl, cyclohexyl, phenyl, morpholin-4-yl or 4-benzyloxy-phenyl;

R2 is H, methyl or phenyl; R3 is methyl,-SCH3, acetyl, cyclopropanyl, 2,2, 3,3-tetramethyl-cyclopropanyl, 2- phenyl-cyclopropanyl, cyclopent-2-enyl, cyclohexanyl, 4-tert-butyl-cyclohexanyl, tetrahydro-furan-2-yl, pyrrolidine-2-yl, 1-tert-butyloxycarbonylpyrrolidine-2-yl piperidine-2-yl, 1-tert-butyloxycarbonylpiperidine-2-yl, phenyl, 2-toluenyl, 3-toluenyl, 4-tert-butyl-phenyl, 4-fluro-phenyl, 4-chloro- phenyl, 4-hydroxy-phenyl, 4-benzyloxy-phenyl, 2-methoxy-phenyl, 3-methoxy- phenyl, 4-methoxy-phenyl,-CH=C-phenyl, 2,4-dimethoxy-phenyl, 2, 5-dimethoxy- phenyl, 3,4-dimethoxy-phenyl, 3, 5-dimethoxy-phenyl, 4,5-dimethoxy-phenyl, 4- methoxy-2-methyl-phenyl, 4-methoxy-3-methyl-phenyl,-phenyl-4- (CH2) ZNHSOZPh, -phenyl-4-NHCO (CH2) 2NHCOOC (CH3) 3, -phenyl-4-(CH2I)2NHCO-3-chloro-2-methoxybenzene, naphthlen-2-yl, 6- methoxy-naphthalen-2-yl, 2-acetyl-naphthalen-1-yl, 10, 11-dihydro-5H- dibenzo [a, d] cyclohepten-5-yl, 9H-fluoren-9-yl, phenoxy, 3-dimethyl-phenoxy, 2,3-dimethyl-phenoxy, 2-methoxy-phenoxy, 3- methoxy-phenoxy, naphthalene-1-yloxy, -CH=CH-pyridin-3-yl, indol-l-yl, lH-indol-3-yl, 1-methyl-lH-indol-3-yl, 4- fluoro-benzyl-lH-indol-3-yl, 1-(4-chloro-benzyl)-5-methoxy-2-methyl-1H-indol- 3-yl, 1- (4-chloro-benzoyl)-5-methoxy-2-methyl-lH-indol-3-yl, 2-acetyl-1, 2- dihydro-isoquinolin-1-yl, 1, 2,3, 4-tetrahydro-isoquinoline-2-yl, (3, 4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester)-3-yl, 2-methyl-benzofuran-3-yl, 5- chloro-benzofuran-3-yl, benzo [b] thiophen-3-yl, or 9H-thioxanthen-9-yl, R4 is H, methyl, ethyl,-(CH2) 2SCH3,-NHSO2p-Cl-Phenyl, amino, -NHCOOC (CH3) 3, hydroxyl, phenyl, benzyl or chloro substituted benzyl; R5,R5' are independently from each other H, methyl or phenyl; R6, R6 are independently from each other H, methyl or-SCH3 ; m is 1, 2 or 3 ; n is 0 or 1; and p is 0, 1, 2 or 3 ; and pharmaceutically acceptable salts thereof,

with the exception that the compound is not 3-acetyl-5-benzyl-4-hydroxy-1, 5-dihydro- 5H-furan-2-one Still in another embodiment the present invention provides the compound of general formula Ib wherein R'is lower alkyl, cycloalkyl, heterocycloalkyl or aryl, wherein the aryl ring is unsubstituted or substituted by benzyloxy ; Ruz ils H, lower alkyl or aryl; R3 is lower alkyl,-SCH3, acetyl, wherein Ra is H or lower alkyl, Rb is lower alkyl, heteroaryl, -OC (CH3) 3 or aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by lower alkyl or aryl, heterocycloalkyl, wherein the heterocycloalkyl ring is unsubstituted or substituted by-COOC (CH3) 3 ; (CH=CR') o-aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, alkoxy, hydroxyl, benzyloxy, halogen, acetyl,- (CH2) 2NHS02Ph, -NHCO (CH2) 2NHCOOC (CH3) 3, or-(CH2) 2NHCOC6H60CH3C1, or for the non aromatic part of fused ring system also by oxo, o is 0 or 1; R'is H or lower alkyl, aryloxy, wherein the aryl ring is unsubstituted or substituted by lower alkyl or alkoxy, or

(CH=CH) q-heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by lower alkyl, acetyl, alkoxy, halogen, -COOC (CH3) 3 or by halogen substituted benzyl; or for the non aromatic part of fused ring system also by oxo, q is 0 or 1; R4 is H, lower alkyl,-(CH2) 2SCH3,-NHCOCH3,-NHSO2p-Cl-Ph, amino, - NHCOOC (CH3) 3, hydroxyl, aryl, benzyl or halogen substituted benzyl; R5, R5 are independently from each other H, lower alkyl or aryl; R6, R6 are independently from each other H, lower alkyl or-SCH3; m is 1, 2 or 3 ; n is 0 or 1; and p is 0,1, 2 or 3; and pharmaceutically acceptable salts thereof, with the exception that the compound is not 3-acetyl-4-hydroxy-5-isobutyl-1, 5-dihydro- pyrrol-2-one.

Still yet in another embodiment the present invention provides the compound of formula Ib, wherein Rl is aryl; R2 is H; R3 is-SCH3, wherein Ra is H or lower alkyl, Rb is lower alkyl, heteroaryl, -OC (CH3) 3 or aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by lower alkyl, heterocycloalkyl, wherein the heterocycloalkyl ring is unsubstituted or substituted by-COOC (CH3) 3 ;

aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, alkoxy, benzyloxy or for the non aromatic part of fused ring system also by oxo" aryloxy, wherein the aryl ring is unsubstituted or substituted by alkoxy, or heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by lower alkyl,-COOC (CH3) 3 or by halogen substituted benzyl, or for the non aromatic part of fused ring system also by oxo; R4 is H, lower alkyl,-NHCOCH3, amino, -NHCOOC (CH3) 3, aryl or benzyl; R 5R5 are H; R6, R" are H ; m is 2; n is 0 or 1 ; and p is 0, 1, 2 or 3 ; and pharmaceutically acceptable salts thereof.

Yet in another embodiment the present invention provides the compound of formula Ib wherein Ru ils phenyl; R2 is H; R3 is-SCH3, wherein Ra is H or methyl, Rb is methyl, lH-pyrrol-3-yl,-OC (CH3) 3 or aryl, wherein the aryl ring is unsubstituted or substituted by methyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by methyl, heterocycloalkyl, wherein the heterocycloalkyl ring is unsubstituted or substituted by-COOC (CH3) 3 ; aryl, wherein the aryl ring is unsubstituted or substituted by methyl, tert-butyl, methoxy, benzyloxy or for the non aromatic part of fused ring system also by oxo,

aryloxy, wherein the aryl ring is substituted by methoxy, or heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by methy,- COOC (CH3) 3 or by 4-fluoro-benzyl-1-yl, or for the non aromatic part of fused ring system also by oxo; R4 is H, methyl,-NHCOCH3, amino, -NHCOOC (CH3) 3, phenyl or benzyl; RUZ are H; R6,R6' are H; m is 2; n is 0 or 1; and p is 0, 1, 2 or 3 ; and pharmaceutically acceptable salts thereof.

Still yet in another embodiment the present invention provides the compound of formula Ib, wherein R1 is phenyl; R2 is H ; R3 is-SCH3,-NHCOCH3,-NHCO-phenyl,-NHCO- (4-methyl-phenyl),-NHCO- (2, 5- dihydro-lH-pyrrol-3-yl), NHCOOC (CH3) 3, cyclopropanyl, 1-methyl-cyclopropanyl, cyclohexanyl, 1-tert-butyloxycarbonylpyrrolidine-2-yl, 1-tert-butyloxycarbonylpiperidine-2-yl, tetrahydro-furan-2-yl, phenyl, toluenyl, 4-tert-butyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-benzoxy-phenyl, 3, 4-dimethoxy-phenyl, naphthalene-2-yl, 6-methoxy- naphthalen-2-yl, 3-oxo-indan-1-yl, 2-methyl-phenoxyl, 1, 2, 5-trimethyl-lH-pyrrole-3-yl, 5-methyl-pyrazine-2-yl, 5-methyl-2, 4-dioxo-lH- pyriminine-1-yl, 3-methyl-furan-2-yl, indol-l-yl, lH-indol-3-yl, (4-fluoro-benzyl)- lH-indol-3-yl, isoquinoline-3-yl, 3, 4-dihdyro-1H-isoquinoline-2-carboyxlic acid

ter-butyl ester, thieno [2,3-c] pyridine-7-yl, benzo [1, 2,3] thiadiazole-5-yl, 2,3- dihydro-benzofuran-7-yl, 2-benzo [b] thiophen-3-yl, or carbazol-9-yl, R4 is H, methyl, -NHCOCH3, amino, -NHCOOC (CH3) 3, phenyl or benzyl; R5,R5 are H; R6,R6' are H; m is 2; n is 0 or 1 ; and p is 0, 1, 2 or 3 ; and pharmaceutically acceptable salts thereof.

Representative compounds of formula I in accordance with the present invention are shown in Table 1 below.

Table 1 Ex X R1- (CR6R6') m-R2- (CHR4) n (CR5R5') P-R3 Al O CH3-CH (CH3) CH2- H-CH2CH (CH3)- CH3 A2 O CH3-CH (CH3) CH2- H-CH2CH2-SCH3 A3 O CH3-CH (CH3) CH2- H-CH2CH2CH (CH3)- CH3 A4 O CH3-CH (CH3) CH2- H-CH (CH3) CH2--COCH3 A5 O CH3-CH (CH3) CH2- H- H3 A6 O CH3-CH (CH3) CH2- H--y rac'--/ A7 O CH3-CH (CH3) CH2- H- A8 O CH3-CH (CH3) CH2- C kk"3 F c"t A9 O CH3-CH (CH3) CH2- H- rac A10 O CH3-CH (CH3) CH2- H-CH2- JJ All O CH3-CH (CH3) CH2- H-CH2CH2CH2- J. J A12 0 CH3-CH (CH3) CH2- H- Phot A13 O CH3-CH (CH3) CH2- H-CH2- A14 O CH3-CH (CH3) CH2- H-CH2- A15 O CH3-CH (CH3) CH2- H-CH2- A16 O CH3-CH (CH3) CH2-H-CH2-ACH, CH A17 O CH3-CH (CH3) CH2- H-CHZ-°" /' OGH A18 O CH3-CH (CH3) CH2-H-CH2-CH309 CHO\ ^/OCH, A19 O CH3-CH (CH3) CH2- H,-CHZ- A20 O CH3-CH (CH3) CH2- H-CH (CH3)- A21 0 CH3-CH (CH3) CH2- H-CH (CH2CH3)- J A22 O CH3-CH (CH3) CH2-H-CH (CH3)-, a3, OCH, I A23 O CH3-CH (CH3) CH2- H-CH2CH2- . A24 O CH3-CH (CH3) CH2- H-CH2CH2-CH, J A25 O CH3-CH (CH3) CH2-H-CH2CH2-- y A26 O CH3-CH (CH3) CH2- H-CH2CH2- OCH, A27 O CH3-CH (CH3) CH2- Ou cH, o I A28 O CH3-CH (CH3) CH2- H-CH (CH3) CH2- A29 O CH3-CH (CH3) CH2-H-CH (CH3) CH2-C) S H3 . A30 O CH3-CH (CH3) CH2- H-CH2CH (CH3)- A31 0 CH3-CH (CH3) CH2- H _ RVP A32 O CH3-CH (CH3) CH2- H-CH2- CH, o A33 O CH3-CH (CH3) CH2- H-CH2- i A34 O CH3-CH (CH3) CH2- H-CH (CH3)- A35 O CH3-CH (CH3) CH2- H-CH2CH2CH2- J A36 O CH3-CH (CH3) CH2-H-CH2CH2CH2-JAOCH3 OCH3 A37 O CH3-CH (CH3) CH2- H-CH (CH3) CH2-fN A38 O CH3-CH (CH3) CH2- H-CH (CH3) Chez- A39 O CH3-CH (CH3) CH2-H-CH2-4 b A40 O CH3-CH (CH3) CH2- H-CH2CH2- H A41 O CH3-CH (CH3) CH2-H-CH2-J> A42 O CH3-CH (CH3) CH2- H-CH2- O N rac A43 O CH3-CH (CH3) CH2- H-CH (C6H5)- A44 O CH3-CH (CH3) CH2- H-CH (C6H5) CH2- A45 O CH3-CH (CH3) CH2- H-CH2- A46 O CH3-CH (CH3) CH2- H-CH2- i B1 O CH3-CH (SCH3) CH2- H-CH2CH2--SCH3 B2 O CH3-CH (SCH3) CHZ- H- B3 O CH3-CH (SCH3) CH2-H,. cH, CH3CH3 B4 O CH3-CH (SCH3) H--0. B5 O CH3-CH (SCH3) CH2- H- B6 O CH3-CH (SCH3) CH2- H- "' C H IB7 O CH3-CH (SCH3) CH2- H-CH2- B8 O CH3-CH (SCH3) CH2- H-CH2CH2CH2- B9 O CH3-CH (SCH3) CH2- H-CH2- B10 O CH3-CH (SCH3) CH2- H-N2-fY Orme B11 O CH3-CH (SCH3) CH2-H-CH2-O- zizi /v \ocH, B12 O CH3-CH (SCH3) CH2- : OCH, ocH, B13 0 CH3-CH (SCH3) CH2- H-CH2-OCH, OCH3 ..... OCH, B14 0 CH3-CH (SCH3) CH2- H-CH2- B15 O CH3-CH (SCH3) CH2- H-CH (CH3)- B16 0 CH3-CH (SCH3) CH2- H-CH (CH2CH3)- B17 0 CH3-CH (SCH3) CH2- H-CH (CH3)-, fYT° IB18 O CH3-CH (SCH3) CH2- H-CH2CH2- cH, B19 0 CH3-CH (SCH3) CH2- H-CH2CH2- J B20 O CH3-CH (SCH3) CH2- H-CH2CH2- B21 O CH3-CH (SCH3) CH2- H-CH2CH2- ocH, B22 O CH3-CH (SCH3) CH2- H-CH2CH2-I ocH, CH, o B23 O CH3-CH (SCH3) CH2- H-CH (CH3) CH2- Y' :'H B24 O CH3-CH (SCH3) CH2- H-CH2CH (CH3)- -' B25 O CH3-CH (SCH3) CH2- H R R RVR B26 O CH3-CH (SCH3) CH2- H-CH2- CH30 B27 O CH3-CH (SCH3) CH2- H-CH2-"0 H, C CH, CH, B28 O CH3-CH (SCH3) CH2- H-CH (CH3)- B29 O CH3-CH (SCH3) CH2- H-CH (CH2CH3)- B30 O CH3-CH (SCH3) CH2- H-CH2- B31 O CH3-CH (SCH3) CH2- H-CH2CH2CH2- B32 O CH3-CH (SCH3) CH2-H-CH2CH2CH2-vOCH OCH3 B33 O CH3-CH (SCH3) CH2- H-CH2-" H B34 O CH3-CH (SCH3) CH2- H-CH2CH2- b B35 O CH3-CH (SCH3) CH2- H-CH2- razz rac B36 O CH3-CH (SCH3) CH2- H-CH (C6H5)- B37 O CH3-CH (SCH3) CH2- H-CH2CH (C6H5)- B38 O CH3-CH (SCH3) CH2- H-CH2- B39 O CH3-CH (SCH3) CH2- H-CH2- Cl O cydohexyl-CH2-H C2 O cyclohexyl-CH2-H-CH2- C3 O cyclohexyl-CH2-H-CH2CH2- C4 O cyclohexyl-CH2-H-CH2CH2CH2- C5 O cyclohexyl-CH2-H-CH (NHSO2-4-Cl- Phenyl) CH2CH2- C6 O cyclohexyl-CH2-H-CH2CH2CH2CH2- C7 O cyclohexyl-CH2-H-CH (CH3) CH2- C8 O cyclohexyl-CH2-H-CH (CH3) CH2- H ' a C9 O cyclohexyl-CHr H-CH (CH3) CHZ- bu C10 O cyclohexyl-CH2-H-CH (CH3) CH2- Y NHBoc N O H C11 O cydohexyl-CH2-H-CH (CH3) CH ; 2- Y C12 O cydohexyl-CH2-H-CH (CH3) CH2- U C13 O cyclohexyl-CH2-H-CHNHBOCCH2- 0 C14 O cydohexyl-CH2-H-CHNHCOCH2- 'OH C15 O cyclohexy :-CH2-H-CH (NH2) CH2-nOH 'OH C16 0 cyclohexyl-CH2-H-CH2- CHO C17 O cyclohexyl-CH2-H-CH2-" b C18 O cyclohexyl-CH2-H-CH2-c", C19 O cyclohexyl-CH2-H-CH2- b C20 O cyclohexyl-CH2-H-CH2-H, C b 'OCH, C21 O cyclohexyl-CHZ-H-CHZ-", ° bzw CH, C22 O cyclohexyl-CH2-H-CH2- C23 O cyclohexyl-CH2-H-CH2CH2- - N H C24 O cyclohexyl-CH2-H-CH2-"3° rv C25 O cyclohexyl-CH2-H-CH2- C26 O cyclohexyl-CH2-H-CH2- C27 O cyclohexyl-CH2-H-CH2CH (C6H5)--C6H5 C28 O cyclohexyl-CH2-H-CH (C6H5) CH2--C6H5 C29 O cydohexyl-CH2-H-CH (C6H5) Chez- 'F C30 O cyclohexyl-CH2-H-CH (CH2C6H5) CH2--C6H5 C31 0 cydohexyl-CH2-H-CH (CH2C6H5-4- Cl) CH2- C32 O cydohexyl-CH2-H-CH2- t3 C33 O cydohexyl-CH2-H-CH2- D 1 O C6H5--CHZ-H- D2 O C6H5--CH2-H-CH (CH3) CH2- H3 SCH 3 D3 CHz-H-CH2- CHO- D4 O C6H5--CH2-H-CH2CH2CH2- D5 O C6H5--CH2-H-CH2- O C6H5--CH2-H-CH (C6H5) Chez- D7 O C6Hs--CH2-H-CH2-Q < E1 O C6H5--CH2CH2-H-CH2CH2--SCH3 E2 O C6H5--CH2CH2-H-CH (CH3)--CH3 CH2CH (CH3)- E3 C6H5--CH2CH2-H-CH (CH3)--CH3 CH2CH2CH2- E4 O C6H5--CH2CH2-H E5 O C6H5--CH2CH2-H E6 O C6H5--CH2CH2-H-CH2- E7 O C6H5--CH2CH2-H-CH2CH2CH2- E8 O C6H5--CH2CH2-H-CH2- E9 O C6H5--CH2CH2-H-CH2- CH, E10 O C6H5--CH2CH2-H-CH (CH3)- Ell O C6H5--CH2CH2-H-CH (CH2CH3)- E12 O C6H5--CH2CH2-H-CH2-ocr,, I OCH3 E13 O C6H5--CH2CH2-H-CH2-, ;)"OCH3 OCH, E14 O CsHs--CH2CH2-H-CH2- 'I ocH, E15 O C6H5--CH2CH2-H-CH2CH2- E16 O C6H5--CH2CH2-H- RVR E17 O C6H5-CH2CH2-H-CH2CH (CH3)- E18 O C6H5--CH2CH2-H-CH (OH) CHZ-'I E19 O C6H5--CH2CH2-H-CH2CH2-s¢D, CH3 '- E20 O C6H5--CH2CH2-H-CH2- CH30 E21 O C6H5--CH2CH2-H-CH2CH2-Yy"' y E22 O C6H5--CH2CH2-H-CH2CH2- OCH E23 O C6H5--CH2CH2-H-CH2CH2-OCH, OCH, OCH3 E24 O C6H5--CH2CH2--CH (CH3) Chez- kc E25 O C6H5--CH2CH2-H-CH (CH3) Chez- E26 O C6H5--CH2CH2-H-CH2CH2CH2- E27 O C6Hs--CH2CH2-H-CH2CH2CH2-JAOCH3 laOCH3 OCH3 E28 O C6H5--CH2CH2-H-CH2-oJa3 W E39 O C6H5--CH2CH2-H-CH (CH3)-) a3OCH, I E30 O C6H5-CH2CH2-H-CH2-0% oX H E31 O C6Hs-CH, H C H H \ E32 O C6Hs--CH2CH2-H-CH2-43 rev E33 O C6Hs--CH2CH2-H-CH2CH2-@ " E34 O C6H5--CH2CH2-H-CH2- E35 O C6H5--CH2CH2-H-CH2CH (C6H5)- E36 O C6H5--CH2CH2-H-CH2- i E37 O C6H5--CH2CH2-H-CH2- E38 O C6H5--CH2CH2-H-CH2- r E39 O C6H5--CH2CH2-H-CH (NHBOC)- CH3 E40 O C6H5--CH2CH2-H-CH (NH2)-CH3 E41 O C6H5--CH2CH2-H-CH (NHBOC) CH2- E42 O C6H5--CH2CH2-H-CH (NH2) CH2 NHBOC E43 O C6Hs--CH2CH2-H nOX i E44 O C6H5--CH2CH2-H i E45 O C6H5--CH2CH2-H NHBOC 0-, c E46 O C6H5--CH2CH2-H-CH (NH2) CHZ- i i E47 O C6H5--CH2CH2-H oc U E48 O C6Hs--CH2CH2-> N E49 O C6H5--CH2CH2-H rOC rac - E50 O C6H5--CH2CH2-H rac - E51 O CgHs--CH2CH2-H- rac E52 O C6H5--CH2CH2-H ""6 F1 O C6H5--CH2CH2CH2-H F2 O C6H5--CH2CH2CH2-H-CH2CH2CH2- F3 O C6H5--CH2CH2CH2-H (CH3) CH2-AH3 Fls H Ha CH F4 O C6Hs-.-CH2CH2CH2-H-CH2-CHX CHO F5 O C6H5--CH2CH2CH2-H-CH2- F6 O C6Hs--CH2CH2CH2-H-CH2CH (C6H5)- F7 O C6H5--CH2CH2CH2-H-CH2- G1 O CN--CH2CH2CH2-H-CH2CH2--SCH3 G2 O -CH2CH2CH2-H--y G3 O O--CH2CH2CH2-H tcHH3H3 CHCH, . HCH3 G4 0-CH2CH2CH2-H L/ G5 O -CHZCHZCHZ-H- G6 O CN--CH2CH2CH2-H-CH2- G7 O-CH2CH2CH2-H-CH>CH2CH2- G8 0-CH2CH2CH2-H-CH2- G9 O--CH2CH2CH2-H-CH (CH3)- G 10 O-CH2CH2CH2-H-CH2-JSOCH, 'i 'v'OCH G 11 O CCN--CH2CH2CH2-H-CH2-CH, Ons OCH G12 O CN--CH2CH2CH2-H-CH2-CH30 OCH3 n G13 O Y-\-CH2CH2CH2-H-CH2-. ocH, G14 O--CH2CH2CH2-H-CH2CH2-mOCH, OCH, G15 O CCN-CH2CH2CH2-H-CH2CH (CH3)- G 16 O 0-CH2CH2CH2-H-CH2CH2- Cl30- G17 O CCh--CH2CH2CH2-H-CH2CH2-oCH, G18 O CCN--CH2CH2CH2-H-CH2CH2-s3z0CH, G19 O -CHZCHZCHZ-. H-CHZ-.. Cho G20 O q-\-CH2CH2CH2-H-CH2-Yi G2 1 O CCN--CH2CH2CH2-H-CH2-CHX CH30 G22 O cOe-CH2CH2CH2-H-CH2-o 4 G23 O CCN--CH2CH2CH2-H-CH2CH2CH2-o G24 O-CH2CH2CH2-H-CH2- G25 0-CH2CH2CH2-H-CH2- RIZ G26 O _-CH2CH2CH2-H-CH2- b G27 0-CH2CH2CH2-H-CH2CH2- G28 0-CH2CH2CH2-H-CH2- 6 G29 0-CH2CH2CH2-H-CH2CH (C6H5)- G30 O -CH2CH2CH2-H-CH2-jT \/T ? H1 O 4-benzyl--CH2CH2-H-CH2CH2CH2- oxyphenyl 11 O C6H5--CH2CH2-CH3 I2 O C6H5--CH2CH2-CH3-CH2CH2CH2- I3 O C6H5-CH2CH2-CH3-CH (CH3) CH2- H3 HO ' 3 14 O C6H5--CH2CH2-CH3-CH2- Cho 15 O C6H5--CH2CH2-CH3-CH2- b I6 O C6H5--CH2CH2-CH3-CH2CH (C6H5)- 17 O C6H5--CH2CH2-CH3-CH2- Jl O C6Hs--CH2CH2-C6H5- J2 O C6H5--CH2CH2-C6H5-CH2- CHO-' J3 O C6H5--CH2CH2-CgHs-CH2- 0 J4 O C6H5--CH2CH2-C6H5-CH2CH (C6H5)- J5 O C6H5--CH2CH2-C6H5-CH2- Je3 Kl NH C6H5--CH2CH2-H-CH2CH2--SCH3 K2 NH C6H5--CH2CH2-H K3 NH C6H5--CH2CH2-H Hz K4 NH C6H5--CH2CH2-H < K5 NH C6H5--CH2CH2-H-CH2CH2CH2- K6 NH C6H5--CH2CH2-H K7 NH C6H5--CH2CH2-H N CH K8 NH C6H5--CH2CH2-H "6 K9 NH C6H5--CH2CH2-H s K10 NH C6H5--CH2CH2-H Hic K11 NH C6H5--CH2CH2-H K12 NH C6H5--CH2CH2-H- Con CM, CFI K13 NH C6H5--CH2CH2-H-CH2- I Itlil K14 NH C6H5--CH2CH2-H-CH2-3 K15 NH C6H5--CH2CH2-H-CH2- b K16 NH C6H5--CH2CH2-H-CH2-CH3 . IN y NH 0 K17 NH C6H5--CH2CH2-H-CH (CH3)- OCH. K18 NH C6H5--CH2CH2-H-CH (CH3)-) zizi K19 NH C6H5--CH2CH2-H-CH2CH2-CH, K20 NH C6H5--CH2CH2-H-CH2CH2-A3OCH, K21 NH C6H5--CH2CH2-H-CH2CH2- H, cor K22 NH C6H5--CH2CH2-H-CH2CH2- C6H5- K23 NH C6Hs--CH2CH2-H-CH (CH3) CH2-t l kAc". K24 NH C6H5--CH2CH2-H-CH2- cl, o K25 NH C6H5--CH2CH2-H-CH2CH2CH2- K26 NH C6H5--CH2CH2-H-CH2CH2CH2-OCH3 LOCH3 K27 NH C6H5--CH2CH2-H-CH2--NHCOCH3 K28 NH C6H5--CH2CH2-H-CHNHCOCH3-SCH3 - CH2CH2- K29 NH C6H3--CH2CH2-H-CH2-N<3 /N K30 NH C6H5--CH2CH2-H-CH2-rV 0 o K31 NH C6H5--CH2CH2-H-CH2-@ 0 H K32 NH C6H5--CH2CH2-H-CH (CH3)-oNrOusCH, CH3 H3 K33 NH C6H5--CH2CH2-H-CH (CH2C6H5)-Y WHcH3 If K34 NH C6H5--CH2CH2-H- ' L% K35 NH C6H5--CH2CH2-H N HH, rac K36 NH C6Hs-CH2CH2-H X N CH K37 NH C6H5--CH2CH2-H-CH (NHBOC) Chez- K38 NH C6H5--CH2CH2-H-CH (NH2) CH2- YL K39 NH C6H5--CH2CH2-H-CH2- b K40 NH C6H5--CH2CH2--CH2- b K41 NH C6H5--CH2CH2-H-CH2- K42 NH C6H5--CH2CH2-H-CH2CH2- K43 NH C6H5--CH2CH2-H-CH2- K44 NH C6H5--CH2CH2-H-CH2CH (C6H5)--C6H5 K45 NH C6H5--CH2CH2-H-CH (C6H5) CH2--C6H5 K46 NH C6Hs--CH2CH2-H-CH2-b Still yet in another embodiment the present invention provides the compound of formula I, which is

Rac-4-hydroxy-5-isobutyl-3- [ (9H-thioxanthen-9-yl) -acetyl]-5H-furan-2-one ; 3- [3- (4-tert-Butyl-phenyl) -2 (R, S) -methyl-propionyl]-5 (R, S)-cyclohexylmethyl-4- hydroxy-5H-furan-2-one; 5-Chloro-N- (2- {4- [3- (5 (R, S)-cydohexylmethyl-4-hydroxy-2-oxo-2, 5-dihydro-furan-3- yl) -2 (R, S)-methyl-3-oxo-propyl]-phenyl}-ethyl)-2-methoxy-benzamide ; Rac-5-cyclohexylmethyl-4-hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5H-furan-2-one ; <BR> <BR> <BR> <BR> <BR> <BR> Rac-5-cyclohexylmethyl-3-{ [1- (4-fluoro-benzyl)-lH-indol-3-yl]-acetyl}-4-hydroxy-5H- furan-2-one; Rac-5-cyclohexylmethyl-3- [ (9H-fluoren-9-yl)-acetyl]-4-hydroxy-5H-furan-2-one ; Rac-3- (carbazol-9-yl-acetyl)-5-cyclohexylmethyl-4-hydroxy-5H-furan -2-one ; 5 (R, S)-Benzyl-3- [3- (4-tert-butyl-phenyl)-2 (R, S)-methyl-propionyl]-4-hydroxy-5H- furan-2-one, Rac-4-hydroxy-3- [ (2-methoxy-phenoxy)-acetyl]-5-phenethyl-5H-furan-2-one ; Rac-4-hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5-phenethyl-5H-furan-2-one ; Rac-3- (3, 3-diphenyl-propionyl)-4-hydroxy-5-phenethyl-5H-furan-2-one ; Rac-4-hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5- (3-phenyl-propyl) -5H-furan-2-one; Rac-3- [ (9H-fluoren-9-yl)-acetyl]-4-hydroxy-5-methyl-5-phenethyl-5H- furan-2-one ; 4-Hydroxy-3 (R, S) - [2- (6-methoxy-naphthalen-2-yl) -propionyl]-5 (R, S)-phenethyl-1, 5- dihydro-pyrrol-2-one; [1- (4-Benzyloxy-benzyl)-2- (4-hydroxy-2-oxo-5 (R, S)-phenethyl-2, 5-dihydro-1H-pyrrol- 3-yl) -2 (R, S) -oxo-ethyl]-carbamic acid tert-butyl ester; Rac-4-hydroxy-3- (indol-1-yl-acetyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one; or Rac-3-(carbazol-9-yl-acetyl)-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one.

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the process described below, which process comprises acylation of a compound of formula II

wherein X is O or NH; R'is lower alkyl, cycloalkyl, heterocycloalkyl or aryl, wherein the aryl ring is unsubstituted or substituted by benzyloxy; R2 is H, lower alkyl or aryl; R6, R6 are independently from each other H, lower alkyl or-SCH3; m is 1, 2 or 3 ; with a carboxylic acid of formula III HOOC-(CHR4)n-(CR5R5')p-R3 (III) wherein R3 is lower alkyl,-SCH3, acetyl, wherein Ra is H or lower alkyl, Rb is lower alkyl, heteroaryl, -OC (CH3) 3 or aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, cycloalkyl, wherein the cycloalkyl ring is unsubstituted or substituted by lower alkyl or aryl, heterocycloalkyl, wherein the heterocycloalkyl ring is unsubstituted or substituted by-COOC (CH3) 3 ; (CH=CR') o-aryl, wherein the aryl ring is unsubstituted or substituted by lower alkyl, alkoxy, hydroxyl, benzyloxy, halogen, acetyl, -(CH2)2NHSO2Ph, -NHCO (CH2) 2NHCOOC (CH3) 3,-(CH2) 2NHCOC6H30CH3C1, or for the non aromatic part of fused ring system also by oxo, o is 0 or 1 ; R'is H or lower alkyl,

aryloxy, wherein the aryl ring is unsubstituted or substituted by lower alkyl or alkoxy, or (CH=CH) q-heteroaryl, wherein the heteroaryl ring is unsubstituted or substituted by lower alkyl, acetyl, alkoxy, halogen, -COOC (CH3) 3 or by halogen substituted benzyl; or for the non aromatic part of fused ring system also by oxo; q is 0 or 1 ; R4 is H, lower alkyl,- (CH2) 2SCH3,-NHCOCH3,-NHSO2p-Cl-Ph, amino, - NHCOOC (CH3) 3, hydroxyl, aryl, benzyl or halogen substituted benzyl; R5, 5R are independently from each other H, lower alkyl or aryl; n is 0 or 1; and p is 0, 1, 2 or 3 ; to produce a compound of formula I

wherein X, Ru, R, R3, R4, R5, Rs, R6, R6, m, n and p, are as defined above, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

The compounds of formula la may be prepared in accordance with the following scheme 1: Scheme 1

Aldehydes or ketones IV may be reacted with 3 (E)-methoxy-acrylic acid methyl ester V (Miyata, Okiko; Schmidt, Richard R.; Angewandte Chemie (1982), 94 (8), 651-2) in solvents like diethyl ether or THF in the presence of a base like lithiumdiisopropylamide (LDA) at a temperature in the range of-100°C to-50°C, or at - 80°C to give the tetronic acid derivatives VI.

Cleavage of the methoxy group in VI may be accomplished with a strong mineral acid such as HI, HBr or HC1 preferably HBr in water and acetic acid at a temperature in the range of 20°C to 100°C, or at 40°C to give the tetronic acid IIa.

Acylation of IIa followed by Fries rearrangement (Nomura, Keiichi; Hori, Kozo; Arai, Mikio; Yoshii, Eiichi; Chem. Pharm. Bull. (1986), 34 (12), 5188-90) maybe effected with a carboxylic acid and a dehydrating agent such as dicyclohexyl carbodiimide (DCC) or N- (3-dimetylaminopropyl)-N'-ethyl carbodiimide hydrochloride (EDC), preferably EDC and a base like an alkylamine, preferably NEt3 in a solvent like CH2C12 or THF, preferably THF in the presence of 10 to 50 mole%, preferably 30 mole% of 4- dimethylamino pyridine (DMAP) at a temperature in the range of 0°C to 35°C, preferably at 25°C to give the acylated tetronic acid Ia.

The compounds of formula Ib may be prepared in accordance with the following scheme 2: Scheme 2

The tetramic acid IIb may be prepared according to the method described by Jouin, P; Castro, B; J. Chem. Soc. Perkin Trans. I, 1987,1177.

Acylation of IIb followed by Fries rearrangement (Nomura, Keiichi; Hori, Kozo; Arai, Mikio; Yoshii, Eiichi; Chem. Pharm. Bull. (1986), 34 (12), 5188-90) maybe effected with a carboxylic acid and a dehydrating agent such as DCC or EDC, preferably EDC and a base like an alkylamine, preferable NEt3 in a solvent like CH2Cl2 or THF, preferably THF in the presence of 10 to 50 mole%, preferably 30 mole% of DMAP at temperatures between 0°C to 35°C, preferably 25°C to give the acylated tetramic acid Ib.

A more detailed description for preparing a compound of formula I can be found in Examples A1-A46, B1-B39, C1-C33, D1-D7, E1-E52, F1-F7, G1-G30, HI, 11-17, Jl-J5 and K1-K46.

The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention inhibit the p-secretase.

Cellular screening methods for inhibitors of A-beta production, testing methods for the in vivo suppression of A-beta production, and assays with membranes or cellular

extracts for the detection of secretase activity are known in the art and have been disclosed in numerous publications, including WO 98/22493, US 5,703, 129, US 5,593, 846 and GB 2,395, 124; all hereby incorporated by reference. ß-Secretase has been described in several publications including EP 855,444, WO 00/17,369, WO 00/58,479, WO 00/47,618, WO 01/00, 663 and WO 01/00, 665.

For example, inhibition of ß-secretase of the pharmaceutical compounds may be demonstrated by their ability, e. g. , to inhibit the cleavage of a fluorescent peptide substrate (e. g. in an assay like e. g. the FRET Assay as described inter alia by Grueninger- Leitch et al. ) or to displace, e. g. , a peptidic p-secretase inhibitor at the active binding site of ß-secretase, e. g. as demonstrated in accordance with the following test method.

Competitive Radioligand Binding Assay (RLBA) 96 well microplates (Optiplate Packard) are coated with purified BACE protein (see e. g. GB 2,385, 124: Examples 1 and 2) using a concentration of 1 pLg/ml in 30 mM sodium citrate buffer adjusted to pH 5.5. The coating is achieved by incubation of 100 pl/well for 1-3 days at 4 °C. The plate is then washed with 2 x 300 pl/well of 10 mM citrate pH 4.1.

To each well 100 ul binding buffer (30 mM citrate, 100 mM NaCl, 0.1% BSA, pH 4.1) is dispensed. The test compound is added in 5 VLI from a DMSO stock solution or appropriate dilutions. To this the tracer (tritiated Compound A, see e. g. GB 2,385, 124: Example 4) is added in 10 pl/well from a 10 uCi/ml stock solution in binding buffer.

After incubation for 1.5-2 hours in a humid chamber at ambient temperature the plate is washed with 2 x 300ul/well water and flipped on a dry towel. Following the addition of 50well MicroScint20 (Packard) the plate is sealed and vibrated for 5 seconds. The bound radioactivity is counted on a Topcount (Packard). Total binding is typically between 2000 and 10000 cpm/well depending mainly on the purity and concentration of the BACE protein. Non-specific binding as assessed by competition with > 1 µM peptidic inhibitor (Bachem # H-4848) is typically between 30 and 300 cpm/well. The IC-50 values are calculated by Microsoft Excel FIT.

Some exemplary IC50 inhibition data for the p-secretase inhibition are given in Table 2 below: Table 2 Example No. ICsOinvitro (llM) Example No. ICsOinvitro (llM) C12 12 G29 85 C9 13 C33 11 C19 15 17 31 D2 33 J4 41 E7 57 K38 16 F5 14 K46 36

In another embodiment, the present invention provides the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to the p-secretase inhibition. In still another embodiment the present invention provides the use of compounds of formula I and their pharmaceutically acceptable salts in the manufacture of medicaments for the prevention or treatment of CNS disease. In yet another embodiment the present invention provides the use of compounds of formula I and their pharmaceutically acceptable salts in the manufacture of medicaments for the prevention or treatment of Alzheimer's disease.

The compounds of formula I and the pharmaceutically acceptable salts of the compound of formula I can be used as medicaments, e. g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e. g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e. g. in the form of suppositories, parenterally, e. g. in the form of injection solutions.

The compound of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.

Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

In accordance with the invention compounds of formula I as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the inhibition of the p-secretase, such as of Alzheimer's disease.

The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

Tablet Formulation (Wet Granulation) Item Ingredients mg/tablet 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1111 Total 167 167 167 831 Manufacturing Procedure 1. Mix items 1, 2,3 and 4 and granulate with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through suitable milling equipment.

4. Add item 5 and mix for three minutes; compress on a suitable press.

Capsule Formulation Item Ingredients mg/capsule 5 mg 25 mg 100 mg 500 mg

1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148--- 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing Procedure 1. Mix items 1,2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

Example Al (RS) -4-Hydroxy-5-isobutyl-3- (3-methyl-butyryl)-5H-furan-2-one a) 5-Isobutyl-4-methoxv-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to - 100°C a solution of 5.47 g of 3 (E)-methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 3-methyl butyraldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HC1 (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, various ratios) to give the 5-isobutyl-4-methoxy-5H-furan-2-one in 30-40% yield.

MS: 171.2 (M+H) + b) 4-Hydroxy-5-isobutyl-5H-furan-2-one A mixture of the 5-isobutyl-4-methoxy-5H-furan-2-one (10 mmole) and 15 ml of aqueous HC1 (37%) was stirred at 40°C until completion of the reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give the 4-hydroxy- 5-isobutyl-5H-furan-2-one in 60-90% yield.

MS: 100.1 (M-C4H8) c) (RS)-4-Hydroxy-5-isobutyl-3-(3-methyl-butyryl)-5H-furan-2-on e To as suspension of the 4-hydroxy-5-isobutyl-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C 3-methyl-butyric acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HC1 (2 N), the aqueous solution was saturated with NaCl, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H2O, gradient) to give the (RS)-4-hydroxy-5- isobutyl-3- (3-methyl-butyryl)-5H-furan-2-one in 10-60% yield.

MS m/e (%): 239.2 (M-H)- Example A2 4-Hydroxy-5-isobutyl-3- (3-methylsulfanyl-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3-methylsulfanyl-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 256.9 (M-H)- Example A3 4-Hydroxy-5-isobutyl-3- (4-methyl-pentanoyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 4-methyl-pentanoic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 253.2 (M-H)- Example A4 1- (4-Hydroxy-5-isobutyl-2-oxo-2, 5-dihydro-furan-3-yl)-2-methyl-pentane-1, 4-dione The title compound was obtained in comparable yields according to the procedures described for example Al using 2-methyl-4oxo-pentanoic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 268.3 (M-H)- Example A5 4-Hydroxy-5-isobutyl-3- (2,2, 3, 3-tetramethyl-cyclopropanecarbonyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2,2, 3, 3,-tetramethyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 279.0 (M-H)- Example A6 4-Hydroxy-5-isobutyl-3- (tetrahydro-furan-2-carbonyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Al using tetrahydro-furan-2-carboxylic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 252.9 (M-H)- Example A7 3-Cyclohexanecarbonyl-4-hydroxy-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using cyclohexanecarboxylic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 265.2 (M-H)- Example A8 3-(4 (4-tert-Biityl-cyclohexanecarbonyl)-4-hydroxy-5-isobutyl-5H- furan-2=orie The title compound was obtained in comparable yields according to the procedures described for example Al using 4-tert-butyl-cyclohexanecarboxylic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 321.1 (M-H)- Example A9 3- (Cyclopent-2-enyl-acetyl)-4-hydroxy-5-isobutyl-5H-furan-2-on e The title compound was obtained in comparable yields according to the procedures described for example Al using cyclopent-2-enecarboxylic acid (prepared according to Palaty, Jan; Abbott, Frank S. ; Journal of Medicinal Chemistry (1995), 38 (17), 3398-406) instead of 3-methyl-butyric acid in step c).

MS: 263.1 (M-H)- Example A10 3- (2-Cyclohexyl-acetyl)-4-hydroxy-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using cyclohexyl-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 281.1 (M+H) + Example Al 1 3- (4-Cyclohexyl-butyryl)-4-hydroxy-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using cyclohexyl-butyric acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 307.0 (M-H)- Example A12 4-Hydroxy-5-isobutyl-3- (2-phenoxy-benzoyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2-phenoxy-benzoic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 351.2 (M-H)- Example A13 4-Hydroxy-5-isobutyl-3-phenylacetyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using phenyl-acetic acid (commercially available) instead of 3- methyl-butyric acid in step c).

MS: 275.1 (M+H) + Example A14 4-Hydroxy-5-isobutyl-3-o-tolylacetyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using o-tolyl-acetic acid (commercially available) instead of 3- methyl-butyric acid in step c).

MS: 287.2 (M-H)- Example A15 3- [ (4-Chloro-phenyl)-acetyl]-4-hydroxy-5-isobutyl-5H-furan-2-on e

The title compound was obtained in comparable yields according to the procedures described for example Al using (4-chloro-phenyl) -acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 307.2 (M-H)- Example A16 4-Hydroxy-5-isobutyl-3- [2- (4-methoxy-3-methyl-phenyl)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using (4-methoxy-3-methyl-phenyl) -acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 317.1 (M-H)- Example A17 3- [2- (3, 5-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5-isobutyl-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example Al using (3,5-dimethoxy-phenyl)-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 352.3 (M+NH4) + Example A18 3- [2-(2, 5-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5-isobutyl-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example Al using (2, 5-dimethoxy-phenyl)-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 335.2 (M+H) + Example A19 3- [2- (2, 4-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5-isobutyl-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example Al using (3,4-dimethoxy-phenyl)-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 335.2 (M+H) t Example A20 3- (2-phenyl-propionyl-4-hydroxy-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2-phenyl-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 287.0 (M-H)- Example A21 4-Hydroxy-5-isobutyl-3- (2-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2-phenyl-butyric acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 303.2 (M+H) + Example A22 4-Hydroxy-5-isobutyl-3- [2-(6-methoxy-naphthalen-2-yl)-propionyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2- (6-methoxy-naphthalen-2-yl)-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 369.2 (M+H) + Example A23 4-Hydroxy-5-isobutyl-3- (3-phenyl-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3-phenyl-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 287.0 (M+H)- Example A24 4-Hydroxy-5-isobutyl-3- (3-m-tolyl-propionyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Al using 3-m-tolyl-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 320.4 (M+NH4) + Example A25 4-Hydroxy-5-isobutyl-3- [3- (3-methoxy-phenyl)-propionyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3- (3-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 336.2 (M+NH4) + Example A26 4-Hydioxy-5-isobutyl-3- [3- (4-methoxy-phenyl)-propionyl]-5H-furan-2-oiie The title compound was obtained in comparable yields according to the procedures described for example Al using 3- (4-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 336.2 (M+NH4) + Example A27 3- [3- (2, 5-Dimethoxy-phenyl)-propionyl]-4-hydroxy-5-isobutyl-5H-furan -2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3- (2, 5-dimethoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 349.4 (M+H) + Example A28 3- [3- (4-Chloro-phenyl)-2-methyl-propionyl]-4-hydroxy-5-isobutyl-5 H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3- (4-chloro-phenyl)-2-methyl-propionic acid (prepared according to Ferorelli, S.; Loiodice, F. ; Tortorella, V.; Amoroso, R.; Bettoni, G.; Conte-

Camerino, D.; De Luca, A.; Farmaco (1997), 52 (6-7), 367-374. ) instead of 3-methyl- butyric acid in step c).

MS: 354.3 (M+NH4) + Example A29 3- [3- (4-tert-Butyl-phenyl)-2-methyl-propionyl]-4-hydroxy-5-isobut yl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3- (4-tert-Butyl-phenyl)-2-methyl-propionic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav ; Roubal, Zdenek; Nemecek, Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1), 183-93) instead of 3-methyl- butyric acid in step c).

MS: 376.5 (M+NH4) + Example A30 4-Hydroxy-5-isobutyl-3- (3-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3-phenyl-butyric acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 320.4 (M+NH4) + Example A31 4-Hydroxy-5-isobutyl-3-((R)- (R) -2-phenyl-cyclopropanecarbonyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using (R)- (R)-2-phenyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 318.3 (M+NH4) + Example A32 4-Hydroxy-5-isobutyl-3- [2- (2-methoxy-phenoxy)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2- (2-methoxy-phenoxy)-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 319.1 (M-H)- Example A33 4-Hydroxy-5-isobutyl-3- [2- (naphthalen-1-yloxy)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2-(naphthalen-1-yloxy)-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 339.0 (M-H)- Example A34 4-Hydroxy-5-isobutyl-3- (2-phenoxy-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2-phenoxy-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 322.4 (M+NH4) + Example A35 4-Hydroxy-5-isobutyl-3- (4-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 4-phenyl-butyric acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 301.2 (M-H)- Example A36 3- [4- (3, 4-Dimethoxy-phenyl) -butyryl]-4-hydroxy-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 4- (3, 4-dimethoxy-phenyl)-butyric acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 380.3 (M+NH4) + Example A37 4-Hydroxy-5-isobutyl-3- ( (Z)-2-methyl-5-pyridin-3-yl-pent-4-enoyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Al using (Z) -2-methyl-5-pyridin-3-yl-pent-4-enoic acid (prepared according to Ziegler, Frederick E.; Sobolov, Susan B. Journal of the American Chemical Society (1990), 112 (7), 2749-58) instead of 3-methyl-butyric acid in step c).

MS: 328.1 (M-H)- Example A38 4-Hydroxy-5-isobutyl-3- ( (Z)-2-methyl-5-phenyl-hex-4-enoyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using (Z) -2-methyl-5-phenyl-hex-4-enoic acid (prepared according to Ziegler, Frederick E.; Sobolov, Susan B. Journal of the American Chemical Society (1990), 112 (7), 2749-58) instead of 3-methyl-butyric acid in step c).

MS: 341.1 (M-H)- Example A39 ., 4-Hydroxy-3- (2-lH-indol-3-yl-acetyl)-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 2-lH-indol-3-yl-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 314.2 (M+H) + Example A40 4-Hydroxy-3- (3-lH-indol-3-yl-propionyl)-5-isobutyl-5H-furan-2-one The title was obtained in comparable yields according to the procedures described for example Al using 3-lH-indol-3-yl-propionic acid (commercially available) instead of 3- methyl-butyric acid in step c).

MS: 345.3 (M+NH4) + Example A41 4-Hydroxy-5-isobutyl-3- (2-naphthalen-2-yl-acetyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Al using 2-naphthalen-2-yl-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 342.2 (M+NH4) + Example A42 3- [2- (2-Acetyl-1, 2-dihydro-isoquinolin-1-yl)-acetyl]-4-hydroxy-5-isobutyl-5H- furan-2- one The title compound was obtained in comparable yields according to the procedures described for example Al using 2- (2-Acetyl-1, 2-dihydro-isoquinolin-1-yl)-acetic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 368.0 (M-H)- Example A43 3-Diphenylacetyl-4-hydroxy-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using diphenylacetic acid (commercially available) instead of 3- methyl-butyric acid in step c).

MS: 368.3 (M+NH4) + Example A44 3- (3, 3-Diphenyl-propionyl)-4-hydroxy-5-isobutyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using 3,3-Diphenyl-propionic acid (commercially available) instead of 3-methyl-butyric acid in step c).

MS: 363.1 (M-H)- Example A45 4-Hydroxy-5-isobutyl-3- [ (9H-thioxanthen-9-yl)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using (9H-thioxanthen-9-yl) -acetic acid (prepared according to Jilek, Jiri O. ; Holubek, Jiri; Svatek, Emil; Ryska, Miroslav; Pomykacek, Josef ; Protiva,

Miroslav. Collection of Czechoslovak Chemical Communications (1979), 44 (7), 2124- 38) instead of 3-methyl-butyric acid in step c).

MS: 312.4 (M+NH4) + Example A46 3- [ (10, 11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-acetyl]-4-hydroxy-5-isobutyl-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Al using (10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-acetic acid (prepared according to Tucker, Thomas J. ; Lumma, William C.; Lewis, S. Dale; Gardell, Stephen J. ; Lucas, Bobby J. ; Sisko, Jack T.; Lynch, Joseph J. ; Lyle, Elizabeth A.; Baskin, Elizabeth P.; Woltmann, Richard F. ; Appleby, Sandra D.; Chen, I-Wu ; Dancheck, Kimberley B.; Naylor-Olsen, Adel M.; Krueger, Julie A.; Cooper, Carolyn M.; Vacca, Joseph P. Journal of Medicinal Chemistry (1997), 40 (22), 3687-3693) instead of 3- methyl-butyric acid in step c).

MS: 308.4 (M+NH4) + Example Bl 4-Hydroxy-3- (3-methylsulfanyl-propionyl) -5- (2-methylsulfanyl-propyl)-5H-furan-2- one a) 4-Methoxy-5-(2-methvl-sulfanyl-propyl)-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E)-methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 3- methylsulfanyl-butyraldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HC1 (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, various ratios) to give the 4-methoxy-5- (2-methyl-sulfanyl- propyl) -5H-furan-2-one in 30-40% yield.

MS: 202.3 (M) t

b) 4-Hydroxy-5- (2-methylsulfanyl-propyl)-5H-furan-2-one A mixture of the 4-methoxy-5- (2-methyl-sulfanyl-propyl)-5H-furan-2-one (10 mmole) and 15 ml of aqueous HC1 (37%) was stirred at 40°C until completion of the reaction.

The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give the 4-hydroxy-5- (2-methylsulfanyl-propyl)-5H-furan-2-one in 60-90% yield.

MS: 188.0 (M) + c) 4-Hydroxy-3- (3-methylsulfanyl-propionyl)-5- (2-methylsulfanyl-propyl)-5H-furan-2- one To as suspension of the the 4-hydroxy-5-(2-methylsulfanyl-propyl)-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C 3-methylsulfanyl-propionic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HC1 (2 N), the aqueous solution was saturated with NaCl, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H20, gradient) to give the 4-hydroxy-3- (3-methylsulfanyl-propionyl) -5- (2-methylsulfanyl- propyl) -5H-furan-2-one in 10-60% yield.

MS: 289.0 (M-H)- Example B2 3-Cyclopropanecarbonyl-4-hydroxy-5- (2-methylsulfanyl-propyl) -5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using cyclopropanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 255.0 (M-H)- Example B3 4-Hydroxy-5- (2-methylsulfanyl-propyl) -3- (2,2, 3,3-tetramethyl-cyclopropanecarbonyl)- 5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example B1 using 2,2, 3,3-tetramethyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 311.0 (M-H)- Example B4 <BR> <BR> <BR> <BR> <BR> <BR> 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- (tetrahydro-furan-2-carbonyl)-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example B1 using tetrahydro-furan-2-carboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 285.0 (M-H)- Example B5 3-Cyclohexanecarbonyl-4-hydroxy-5- (2-methylsulfanyl-propyl) -5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using cyclohexanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 297.2 (M-H)- Example B6 3- (4-tert-Butyl-cyclohexanecarbonyl)-4-hydroxy-5- (2-methylsulfanyl-propyl) -5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B 1 using 4-tert-butyl-cyclohexanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 353.2 (M-H)- Example B7 3- (2-Cyclohexyl-acetyl) -4-hydroxy-5- (2-methylsulfanyl-propyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-cyclohexyl-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 311.0 (M-H)- Example B8 3- (4-Cyclohexyl-butyryl)-4-hydroxy-5- (2-methylsulfanyl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 4-Cyclohexyl-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 339.1 (M-H)- Example B9 4-H. ydroxy-5- (2-methylsulfanyl-propyl)-3-phenylacetyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using phenylacetic acid (commercially available) instead of 3- methylsulfanyl-propionic acid in step c).

MS: 305.0 (M-H)- Example B10 4-Hydroxy-3- [2- (4-methoxy-3-methyl-phenyl)-acetyl]-5- (2-methylsulfanyl-propyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2- (4-methoxy-3-methyl-phenyl)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 349.2 (M-H)- Example B 11 3- [2- (3, 5-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5- (2-methylsulfanyl-propyl) -5H- furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example B1 using 2- (3, 5-dimethoxy-phenyl) -acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 365.1 (M-H)- Example B12 3- [2- (2, 4-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5- (2-methylsulfanyl-propyl) -5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Bl using 2- (2, 4-dimethoxy-phenyl)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 365.1 (M-H)- Example B 13 3- [2- (2, 5-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5- (2-methylsulfanyl-propyl) -5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2, 5-Dimethoxy-phenyl)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 365.1 (M-H)- Example B14 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- (2-naphthalen-2-yl-acetyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2,2, 3,3-tetramethyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 355.1 (M-H)- Example B 15 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- (2-phenyl-propionyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Bl using 2-phenyl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 319.1 (M-H)- Example B 16 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- (2-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-phenyl-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 333.0 (M-H)- Example B17 4-Hydroxy-3- [2- (6-methoxy-naphthalen-2-yl)-propionyl]-5- (2-methylsulfanyl-propyl)- 5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2- (6-methoxy-naphthalen-2-yl)-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 399.2 (M-H)- Example B18 4-Hydroxy-5- (2-methylsulfanyl-propyl) -3- (3-phenyl-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 3-phenyl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 319.1 (M-H)- Example B19 4-Hydroxy-5- (2-methylsulfanyl-propyl) -3- (3-m-tolyl-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 3-m-tolyl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 333.1 (M-H)- Example B20 4-Hydroxy-3- [3- (3-methoxy-phenyl) -propionyl]-5- (2-methylsulfanyl-propyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Bl using 3- (3-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 349.2 (M-H)- Example B21 4-Hydroxy-3- [3- (4-methoxy-phenyl)-propionyl]-5- (2-methylsulfanyl-propyl) -5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 3- (4-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 349.2 (M-H)- Example B22 3- [3-(2, 5-Dimethoxy-phenyl)-propionyl]-4-hydroxy-5- (2-methylsulfanyl-propyl) -5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Bl using 2, 5-dimethoxy-phenic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 379.1 (M-H)- Example B23 3- [3- (4-tert-Butyl-phenyl)-2-methyl-propionyl]-4-hydroxy-5- (2-methylsulfanyl- propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 3- (4-tert-Butyl-phenyl)-2-methyl-propionic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav; Roubal, Zdenek; Nemecek,

Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1), 183-93) instead of 3- methylsulfanyl-propionic acid in step c).

MS: 389.2 (M-H)- Example B24 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- (3-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 3-phenyl-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 333.0 (M-H)- Example B25 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- ( (R)- (R)-2-phenyl-cyclopropanecarbonyl)- 5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-((R)-(R)-2-phenyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 331.0 (M-H)- Example B26 4-Hydroxy-3- [2- (2-methoxy-phenoxy)-acetyl]-5- (2-methylsulfanyl-propyl)-5H-furan- 2-one The title compound was obtained in comparable yields according to the procedures described for example Bl using 2-(2-methoxy-phenoxy)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 351.1 (M-H)- Example B27 3- [2- (2, 3-Dimethyl-phenoxy)-acetyl]-4-hydroxy-5-(2-methylsulfanyl-pr opyl)-5H- furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Bl using 2- (2, 3-dimethyl-phenoxy)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 349. 2 (M-H)- Example B28 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- (2-phenoxy-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-phenoxy-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 335.0 (M-H)- Example B29 4-Hydroxy-5- (2-inethylsulfariyl-propyl)-3- (2-phenoxy-butyryl)-5H-furari-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-phenoxy-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 349.2 (M-H)- Example B30 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- [2- (naphthalen-1-yloxy)-acetyl]-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-(naphthalen-1-yloxy)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 371.1 (M-H)- Example B31 4-Hydroxy-5- (2-methylsulfanyl-propyl) -3- (4-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 4-phenyl-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 333.1 (M-H)- Example B32 3- [4- (3, 4-Dimethoxy-phenyl)-butyryl]-4-hydroxy-5-(2-methylsulfanyl-p ropyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 4- (3, 4-dimethoxy-phenyl)-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 393.0 (M-H)- Example B33 4-Hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5-(2-methylsulfanyl-propyl)-5H-furan -2-one The title compound was obtained in comparable yields according to the procedures described for example B using (lH-indol-3-yl)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 344.0 (M-H)- Example B34 <BR> <BR> <BR> <BR> <BR> 4-Hydroxy-3- (3-lH-indol-3-yl-propionyl)-5- (2-methylsulfanyl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Bl using 3-lH-indol-3-yl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 358.0 (M-H)- Example B35 3- [2- (2-Acetyl-1, 2-dihydro-isoquinolin-1-yl)-acetyl]-4-hydroxy-5-(2-methylsul fanyl- propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Bl using 2- (2-acetyl-1, 2-dihydro-isoquinolin-1-yl)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 400.2 (M-H)-

Example B36 3-Diphenylacetyl-4-hydroxy-5- (2-methylsulfanyl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using diphenylacetic acid (commercially available) instead of 3- methylsulfanyl-propionic acid in step c).

MS: 341.1 (M-H)- Example B37 <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- (3, 3-Diphenyl-propionyl)-4-hydroxy-5- (2-methylsulfanyl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 3,3-diphenyl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step c).

MS : 394. 9 (M-H)- Example B38 4-Hydroxy-5- (2-methylsulfanyl-propyl)-3- (2-9H-thioxanthen-9-yl-acetyl)-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-9H-thioxanthen-9-yl-acetic acid (prepared according to Jilek, Jiri O. ; Holubek, Jiri; Svatek, Emil; Ryska, Miroslav; Pomykacek, Josef; Protiva, Miroslav. Collection of Czechoslovak Chemical Communications (1979), 44 (7), 2124- 2138) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 425.2 (M-H)- Example B39 3- (2-10, 11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-yl-acetyl) -4-hydroxy-5- (2- methylsulfanyl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example B1 using 2-10, 11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-yl- acetic acid (prepared according to Tucker, Thomas J.; Lumma, William C.; Lewis, S.

Dale; Gardell, Stephen J. ; Lucas, Bobby J. ; Sisko, Jack T.; Lynch, Joseph J. ; Lyle, Elizabeth A.; Baskin, Elizabeth P.; Woltmann, Richard F.; Appleby, Sandra D.; Chen, I-Wu ;

Dancheck, Kimberley B.; Naylor-Olsen, Adel M.; Krueger, Julie A.; Cooper, Carolyn M.; Vacca, Joseph P. Journal of Medicinal Chemistry (1997), 40 (22), 3687-3693) instead of 3-methylsulfanyl-propionic acid in step c).

MS: 421.2 (M-H)- Example Cl 3-Cyclohexanecarbonyl-5-cyclohexylmethyl-4-hydroxy-5H-furan- 2-one a) 5-Cyclohexylmethvl-4-methoxy-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E) -methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the cyclohexyl- acetaldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HCl (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n- heptane/AcOEt, various ratios) to give the 5-cyclohexylmethyl-4-methoxy-5H-furan-2- one in 30-40% yield.

MS: 114.0 (M-C7Hl2) + b) 5-Cydohexvlmethyl-4-hvdroxy-5H-furan-2-one A mixture of the 5-cyclohexylmethyl-4-methoxy-5H-furan-2-one (10 mmole) and 15 ml of aqueous HCl (37%) was stirred at 40°C until completion of the reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 5- cyclohexylmethyl-4-hydroxy-5H-furan-2-one in 60-90% yield.

MS: 197.2 (M+H) + c) 3-Cyclohexanecarbonyl-5-cyclolmethyl-4-hydroxy-5H-furan-2-on e To as suspension of the 5-cyclohexylmethyl-4-hydroxy-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was

added at 22°C cyclohexanecarboxylic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HC1 (2 N), the aqueous solution was saturated with NaCI, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H2O, gradient) to give the 3- cyclohexanecarbonyl-5-cyclohexylmethyl-4-hydroxy-5H-furan-2- one in 10-60% yield.

MS: 305.1 (M-H)- Example C2 3-Cyclohexylacetyl-5-cyclohexylmethyl-4-hydroxy-5H-furan-2-o ne The title compound was obtained in comparable yields according to the procedures described for example Cl using cyclohexylacetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS : 319. 2 (M-H)- Example C3 5-Cyclohexylmethyl-3- (3-cyclohexyl-propionyl)-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 3-cyclohexyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 333.3 (M-H)- Example C4 3- (4-Cyclohexyl-butyryl)-5-cyclohexylmethyl-4-hydroxy-5H-furan -2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 4-cyclohexyl-butyricc acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 347.3 (M-H)- Example C5 4-Chloro-N- [3-cyclohexyl-1- (5-cyclohexylmethyl-4-hydroxy-2-oxo-2, 5-dihydro-furan- 3-carbonyl)-propyl]-benzenesulfonamide The title compound was obtained in comparable yields according to the procedures described for example Cl using (Prepared from the commercially available amine and the corresponding sulfochloride) instead of cyclohexanecarboxylic acid in step c).

MS: 536.3 (M-H)- Example C6 5-Cyclohexylmethyl-3- (5-cyclohexyl-pentanoyl)-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 5-cyclohexyl-pentanoic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 361.3 (M-H)- Example C7 5-Cyclohexylmethyl-4-hydroxy-3- (2-methyl-3-phenyl-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 2-methyl-3-phenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 341.1 (M-H)- Example C8 3- [3- (4-tert-Butyl-phenyl)-2-methyl-propionyl]-5-cyclohexylmethyl -4-hydroxy-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using (4-tert-butyl-phenyl) -2-methyl-propionic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav; Roubal, Zdenek; Nemecek, Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1), 183-93) instead of cydohexanecarboxylic acid in step c).

MS: 397.2 (M-H)- Example C9

3- [3- (4-Benzyloxy-phenyl)-2-methyl-propionyl]-5-cyclohexylmethyl- 4-hydroxy-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 3- (4-benzyloxy-phenyl)-2-methyl-propionic acid (prepared according to Hitchcock, Janice M.; Sorenson, Stephen M.; Dudley, Mark W. ; Peet, Norton P; WO 9419349 Al (1994) ) instead of cyclohexanecarboxylic acid in step c).

MS: 447.2 (M-H)- Example C10 (2- {4- [3- (5-Cyclohexylmethyl-4-hydroxy-2-oxo-2, 5-dihydro-furan-3-yl) -2-methyl-3- oxo-propyl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester The title compound was prepared from the corresponding BOC-protected precursor by deprotection using CF3COOH and was obtained in comparable yields according to the. procedures described for example Cl using (prepared from the aniline (Biagi, Giuliana; Dell'omodarme, Giuliana; Giorgi, Irene; Livi, Oreste; Scartoni, Valerio ; Farmaco (1992), 47 (1), 91-8) and the corresponding acid) instead of cyclohexanecarboxylic acid in step c).

MS: 527.3 (M-H)- Example Cll <BR> <BR> <BR> N- (2- {4- [3- (5-Cyclohexylmethyl-4-hydroxy-2-oxo-2, 5-dihydro-furan-3-yl)-2-methyl-3-<BR> <BR> oxo-propyl]-phenyl}-ethyl)-benzenesulfonamide The title compound was obtained in comparable yields according to the procedures described for example Cl using (prepared from the amine (Bosies, Elmar; Heerdt, Ruth; Kuhnle, Hans Frieder; Schmidt, Felix H.; Stach, Kurt; U. S.

4,113, 871 (1980), 13 pp) and the corresponding sulfochloride) ) instead of cyclohexanecarboxylic acid in step c).

MS: 524.2 (M-H)- Example C12

5-Chloro-N- (2- {4- [3- (5-cyclohexylmethyl-4-hydroxy-2-oxo-2, 5-dihydro-furan-3-yl) -2- methyl-3-oxo-propyl]-phenyl}-ethyl)-2-methoxy-benzamide The title compound was prepared from the corresponding BOC-protected precursor by deprotection using CF3COOH and was obtained in comparable yields according to the procedures described for example Cl using (prepared according to Bosies, Elmar; Heerdt, Ruth; Kuhnle, Hans Frieder; Schmidt, Felix H.; Stach, Kurt; U. S.

4,113, 871 (1980), 13 pp. ) instead of cyclohexanecarboxylic acid in step c).

MS: 552.1 (M-H)- Example C13 [1- (4-Benzyloxy-benzyl)-2- (5-cyclohexylmethyl-4-hydroxy-2-oxo-2, 5-dihydro-furan-3- yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example Cl using (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 567.6 (M+NH4) + Example C14 [2- (5-Cyclohexylmethyl-4-hydroxy-2-oxo-2, 5-dihydro-furan-3-yl)-1- (4-hydroxy- benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example Cl using (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 458.4 (M-H)- Example C15 3- [2-Amino-3- (4-hydroxy-phenyl)-propionyl]-5-cyclohexylmethyl-4-hydroxy-5 H- furan-2-one; compound with trifluoro-acetic acid

The title compound was prepared from the corresponding BOC-protected precursor (Example C14) by deprotection using CF3COOH.

MS: 360.2 (M+H) + Example C16 5-Cyclohexylmethyl-4-hydroxy-3- [ (2-methoxy-phenoxy)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using (2-methoxy-phenoxy) -acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 359.0 (M-H)- Example C17 5-Cyclohexylmethyl-4-hydroxy-3- [ (1 H-indol-3-yl)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using (lH-indol-3-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 352.2 (M-H)- Example C18 5-Cyclohexylmethyl-4-hydroxy-3- [ (1-methyl-lH-indol-3-yl)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using (1-methyl-1H-indol-3-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 366.0 (M-H)- Example C19 <BR> <BR> <BR> <BR> <BR> <BR> 5-Cyclohexylmethyl-3-{ [1- (4-fluoro-benzyl)-lH-indol-3-yl]-acetyl}-4-hydroxy-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 1-(4-fluoro-benzyl)-lH-indol-3-yl]-acetic acid (commercially available) instead of cydohexanecarboxylic acid in step c).

MS: 462.3 (M-H)- Example C20 <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3-{ [1- (4-Chloro-benzyl)-5-methoxy-2-methyl-lH-indol-3-yl]-acetyl}- 5-<BR> <BR> <BR> <BR> <BR> <BR> <BR> cyclohexylmethyl-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 1- (4-Chloro-benzyl)-5-methoxy-2-methyl-lH-indol-3- yl] -acetic acid (prepared by alkylation of the indole with the corresponding p- chlorophenly methyl bromide) instead of cyclohexanecarboxylic acid in step c).

MS: 520.3 (M-H)- Example C21 <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3-{ [1-(4-Chloro-benzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]-acet yl}-5-<BR> <BR> <BR> <BR> <BR> <BR> <BR> cyclohexylmethyl-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 1- (4-Chloro-benzoyl)-5-methoxy-2-methyl-lH-indol-3- yl] -acetic acid (prepared by acylation of the indole with the corresponding acid chloride) instead of cyclohexanecarboxylic acid in step c).

MS: 534.2 (M-H)- Example C22 5-Cyclohexylmethyl-4-hydroxy-3- (indol-1-yl-acetyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using indol-1-yl-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 352.2 (M-H)- Example C23 5-Cyclohexylmethyl-4-hydroxy-3- (3-lH-indol-3-yl-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 3-lH-indol-3-yl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 366.1 (M-H)- Example C24 5-Cyclohexylmethyl-4-hydroxy-3- [ (2-methyl-benzofuran-3-yl)-acetyl]-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 2-methyl-benzofuran-3-yl) -acetyic acid (prepared according to Wu, Jing et al. ; WO 9828268 (1998), 889 pp. ) instead of cyclohexanecarboxylic acid in step c).

MS: 367.2 (M-H)- Example C25 3- [ (5-Chloro-benzofuran-3-yl)-acetyl]-5-cyclohexylmethyl-4-hydr oxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 5-Chloro-benzofuran-3-yl)-acetic acid (prepared according to Aeggi, Knut A.; Renner, Ulrich; CH504429 (1971), 7 pp. ) instead of cyclohexanecarboxylic acid in step c).

MS: 387.2 (M-H)- Example C26 3- (Benzo [b] thiophen-3-yl-acetyl)-5-cyclohexylmethyl-4-hydroxy-5H-furan- 2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using Benzo [b] thiophen-3-yl-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS : 369.1 (M-H)- Example C27 5-Cyclohexylmethyl-3- (3,3-diphenyl-propionyl)-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 3,3-diphenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 403.3 (M-H)-

Example C28 5-Cyclohexylmethyl-3- (2, 3-diphenyl-propionyl)-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 2,3-diphenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 403.3 (M-H)- Example C29 5-Cyclohexylmethyl-3- [3- (4-fluoro-phenyl)-2-phenyl-propionyl]-4-hydroxy-5H-furan- 2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 3- (4-fluoro-phenyl)-2-phenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 421.1 (M-H)- Example C30 3- (2-Benzyl-3-phenyl-propionyl)-5-cyclohexylmethyl-4-hydroxy-5 H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 2-benzyl-3-phenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 417.2 (M-H)- Example C31 3- [2- (4-Chloro-benzyl)-3- (4-chloro-phenyl)-propionyl]-5-cyclohexylmethyl-4-hydroxy- 5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using 2- (4-chloro-benzyl)-3- (4-chloro-phenyl)-propionic acid (prepared according to Iizuka, Kinji; Kamijo, Tetsuhide; Kubota, Tetsuhiro; Akahane, Kenji; Umeyama, Hideaki; Kiso, Yoshiaki. EP252727 Al (1988), 21 pp. ) instead of cyclohexanecarboxylic acid in step c).

MS: 485.2 (M-H)-

Example C32 5-Cyclohexylmethyl-3- [ (9H-fluoren-9-yl)-acetyl]-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using (9H-fluoren-9-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 401.4 (M-H)- Example C33 3- (Carbazol-9-yl-acetyl)-5-cyclohexylmethyl-4-hydroxy-5H-furan -2-one The title compound was obtained in comparable yields according to the procedures described for example Cl using Carbazol-9-yl-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS : 402. 3 (M-H)- 'H-NMR (300 MHz, internal standard TMS, J values in Hz, d6-DMSO): 8.13 (d, J = 7.1, 2H), 7.26 (s, br. 4H), 7.20-7. 10 (m, 2H), 5.49 (s, br. 2H), 4.33 (dd, J = 9.8 and 2.8, 1H), 3.0 (s, br., 1H), 1.90-0. 80 (m, 13H) Example D1 5-Benzyl-3-cyclohexanecarbonyl-4-hydroxy-5H-furan-2-one a) 5-Benzyl-4-methoxy-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E)-methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the phenyl- acetaldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HC1 (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n- heptane/AcOEt, various ratios) to give the 5-benzyl-4-methoxy-5H-furan-2-one in 30- 40% yield.

MS: 205.2 (M+H) +

b) 5-Benzyl-4-hydroxy-5H-furan-2-one A mixture of the 5-benzyl-4-methoxy-5H-furan-2-one (10 mmole) and 15 ml of aqueous HC1 (37%) was stirred at 40°C until completion of the reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 5-benzyl-4- hydroxy-5H-furan-2-one in 60-90% yield.

MS : 190.1 (M) + 5-Benzyl-3-crclohexanecarbonyl-4-hydroxy-5H-furan-2-one To as suspension of the 5-benzyl-4-hydroxy-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C cyclohexanecarboxylic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HC1 (2 N), the aqueous solution was saturated with NaCI, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H20, gradient) to give the 5-Benzyl-3- cyclohexanecarbonyl-4-hydroxy-5H-furan-2-one in 10-60% yield.

MS: 299.2 (M-H)- Example D2 5-Benzyl-3- [3- (4-tert-butyl-phenyl)-2-methyl-propionyl]-4-hydroxy-5H-furan -2-one The title compound was obtained in comparable yields according to the procedures described for example D1 using 3- (4-tert-butyl-phenyl)-2-methyl-propionic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav; Roubal, Zdenek; Nemecek, Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1), 183-93) instead of cyclohexanecarboxylic acid in step c).

MS: 391.1 (M-H)- Example D3 5-Benzyl-4-hydroxy-3- [ (2-methoxy-phenoxy)-acetyl]-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Dl using (2-methoxy-phenoxy)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 353.1 (M-H)- Example D4 5-Benzyl-3- (4-cyclohexyl-butyryl)-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Dl using 4-cyclohexyl-butyric acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 341.1 (M-H)- Example D5 5-Benzyl-4-hydroxy-3- [(lH-indol-3-yl) : acetyl]-5H-furan-2-one The title compound compound was obtained in comparable yields according to the procedures described for example Dl using (lH-indol-3-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 346.1 (M-H)- Example D6 5-Benzyl-3- (3,3-diphenyl-propionyl)-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example D1 using 3,3-diphenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 397.2 (M-H)- Example D7 5-Benzyl-3- [ (9H-fluoren-9-yl)-acetyl]-4-hydroxy-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Dl using (9H-fluoren-9-yl) -acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 395.1 (M-H)- Example El Rac-4-Hydroxy-3- (3-methyl-sulfanyl-propionyl)-5-phenethyl-5H-furan-2-one a) 4-Hydroxc-5-phenethyl-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E)-methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 3-phenyl- propionaldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HC1 (37%) and the layers were separated.

The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n- heptane/AcOEt, various ratios) to give the 4-hydroxy-5-phenethyl-5H-furan-2-one in 30-40% yield.

MS: 218.0 (M) + b) 4-Hydroxy-5-phenethyl-5H-furan-2-one A mixture of the 4-hydroxy-5-phenethyl-5H-furan-2-one (10 mmole) and 15 ml of aqueous HC1 (37%) was stirred at 40°C until completion of the reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 4-hydroxy-5- phenethyl-5H-furan-2-one in 60-90% yield.

MS: 202.9 (M-H)- c) Rac-4-Hydroxy-3- (3-methyl-sulfanyl-propionyl)-5-phenethyl-5H-furan-2-one To as suspension of the 4-hydroxy-5-phenethyl-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C 3-methyl-sulfanyl-propionic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HC1 (2 N), the aqueous solution was saturated with NaCl, the organic layer was separated, washed with brine dried and evaporated. The

residue was purified on preparative HPLC (RP-18, CH3CN/H20, gradient) to give the Rac-4-hydroxy-3- (3-methyl-sulfanyl-propionyl)-5-phenethyl-5H-furan-2-one in 10- 60% yield.

MS: 305.0 (M-H)- Example E2 Rac-3- (2 (R, S), 4-dimethyl-pentanoyl)-4-hydroxy-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using 2 (R, S), 4-dimethyl-pentanoic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 315.2 (M-H)- Example E3 Rac-4-hydroxy-3- (2 (R, S)-methyl-hexanoyl)-5-phenethyl-5H-fuian-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2 (R, S), 4-dimethyl-pentanoic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 315.2 (M-H)- Example E4 Rac-3-cyclopropane-carbonyl-4-hydroxy-5-phenethyl-5H-furan-2 -one The title compound was obtained in comparable yields according to the procedures described for example E1 using 3-cyclopropane-carboxylic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 271.2 (M-H)- Example E5 Rac-3-cyclohexane-carbonyl-4-hydroxy-5-pheriethyl-5H-furan-2 -one The title compound was obtained in comparable yields according to the procedures described for example E1 using cyclohexane-carboxylic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 210.1 (M-C8H8) Example E6 Rac-3- (2-cyclohexyl-acetyl)-4-hydroxy-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-cyclohexyl-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 327.2 (M-H)- Example E7 Rac-3- (4-cyclohexyl-butyryl)-4-hydroxy-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 4-cyclohexyl-butyric acid (commercially available) instead of 3=iriethyl=sulfanyl-propionic acid in step c).

MS: 355.2 (M-H)- Example E8 Rac-4-hydroxy-5-phenethyl-3-phenylacetyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using phenylacetic acid (commercially available) instead of 3- methyl-sulfanyl-propionic acid in step c).

MS: 321.1 (M-H)- Example E9 Rac-4-hydroxy-5-phenethyl-3- (2-o-tolyl-acetyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-o-tolyl-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 335.1 (M-H)- Example E10 Rac-4-hydroxy-5-phenethyl-3- (2 (R, S)-phenyl-propionyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example E1 using 2 (R, S) -phenyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 335.0 (M-H)- Example E11 Rac-4-hydroxy-5-phenethyl-3- (2 (R, S)-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2 (R, S) -phenyl-butyric acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 349.2 (M-H)- Example E12 <BR> <BR> <BR> <BR> Rac-3- [2- (2, 5-dimethoxy-phenyl)-acetyl]-4-hydrbxy-5-phehethyl-5H-furan-2 -ohe The title compound was obtained in comparable yields according to the procedures described for example El using 2- (2, 5-dimethoxy-phenic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 381.2 (M-H)- Example E13 Rac-3- [2- (2, 4-dimethoxy-phenyl)-acetyl]-4-hydroxy-5-phenethyl-5H-furan-2 -one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2- (2, 4-dimethoxy-phenyl) -acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 381.1 (M-H)- Example E14 Rac-3- [2- (3, 5-dimethoxy-phenyl)-acetyl]-4-hydroxy-5-phenethyl-5H-furan-2 -one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2- (3, 5-dimethoxy-phenyl)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 381.1 (M-H)- Example E15 Rac-4-hydroxy-5-phenethyl-3- (3-phenyl-propionyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using 3-phenyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 335.1 (M-H)- Example E16 <BR> <BR> <BR> <BR> <BR> 4-Hydroxy-5-phenethyl-3- ( (R)- (R)-2-phenyl-cyclopropanecarbonyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using (R)- (R)-2-phenyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).- MS: 347.2 (M-H)- Example E 17 Rac-4-hydroxy-5-phenethyl-3- (3 (R, S)-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 3 (R, S) -phenyl-butyric acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 349.2 (M-H)- Example E 18 Rac-4-hydroxy-3- (2 (R, S)-hydroxy-3-phenyl-propionyl)-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2 (R, S)-hydroxy-3-phenyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 351.1 (M-H)- Example E19 Rac-4-hydroxy-5-phenethyl-3- (3-m-tolyl-propionyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example E1 using 3-m-tolyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 349.3 (M-H)- Example E20 Rac-4-hydroxy-3- [2- (2-methoxy-phenoxy)-acetyl]-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2- (2-methoxy-phenoxy)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 369. 2 (M+H) t Example E21 Rac-4-hydroxy-3- (3imethoxy-phenyl)-propionyl]-5-phenethyl-5H-furan-2-onè- The title compound was obtained in comparable yields according to the procedures described for example El using 3- (3-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 365.1 (M-H)- Example E22 Rac-4-hydroxy-3- [3- (4-methoxy-phenyl)-propionyl]-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using 3- (4-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 365.0 (M-H)- Example E23 Rac-3- [3-(2, 5-dimethoxy-phenyl)-propionyl]-4-hydroxy-5-phenethyl-5H-fura n-2-one The title compound was obtained in comparable yields according to the procedures described for example El using 3- (2, 5-dimethoxy-phenyl) -propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 395.2 (M-H)- Example E24 Rac-3- [3- (4-tert-butyl-phenyl)-2 (R, S)-methyl-propionyl]-4-hydroxy-5-phenethyl-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 3- (4-tert-butyl-phenyl)-2 (R, S) -methyl-propionic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav; Roubal, Zdenek; Nemecek, Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1) ; 183-93) instead of 3-methyl- sulfanyl-propionic acid in step c).

MS: 405.4 (M-H)- Example E25 Rac-3- [3- (4-chloro-phenyl)-2 (R, S)-methyl-propionyl]-4-hydroxy-5-phenethyl-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using 3- (4-chloro-phenyl)-2 (R, S) -methyl-propionic acid (prepared according to Ferorelli, S.; Loiodice, F. ; Tortorella, V.; Amoroso, R.; Bettoni, G.; Conte-Camerino, D.; De Luca, A.; Farmaco (1997), 52 (6-7), 367-374) instead of 3- methyl-sulfanyl-propionic acid in step c).

MS: 383.1 (M-H)- Example E26 4-Hydroxy-5-phenethyl-3- (4-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using 4-phenyl-butyric acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 349.3 (M-H)- Example E27 3- [4- (3, 4-Dimethoxy-phenyl)-butyryl]-4-hydroxy-5-phenethyl-5H-furan- 2-one

The title compound was obtained in comparable yields according to the procedures described for example El using 4- (3, 4-Dimethoxy-phenyl)-butyric acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 409.2 (M-H)- Example E28 4-Hydroxy-3- (2-naphthalen-2-yl-acetyl)-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-naphthalen-2-yl-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 371.1 (M-H)- Example E29 Rac-4-hydroxy-3- [2 (R, S)-(6-methoxy-naphthalen-2-yl)-propionyl]-5-phenethyl-5H furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2 (R, S)- (6-methoxy-naphthalen-2-yl)-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 415.2 (M-H)- Example E30 3- [ (2-Acetyl-naphthalen-1-yl)-acetyl]-4-hydroxy-5-phenethyl-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using (2-Acetyl-naphthalen-1-yl)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 415.2 (M-H)- Example E31 3- [2-(2-Acetyl-1, 2-dihydro-isoquinolin-l-yl)-acetyl]-4-hydroxy-5-phenethyl-5H -furan- 2-one

The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-(2-Acetyl-1, 2-dihydro-isoquinolin-1-yl)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 416.1 (M-H)- Example E32 4-Hydroxy-3- (2-lH-indol-3-yl-acetyl)-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example El using 2-lH-indol-3-yl-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 360.0 (M-H)- Example E33 Rac-4-hydróxy-3-(3-lH-indol-3-yl-propionyl)-5-phènethyl-5H -furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 3-lH-indol-3-yl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 374.2 (M-H)- Example E34 Rac-4-hydroxy-3- [2- (naphthalen-1-yloxy)-acetyl]-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-(naphthalen-1-yloxy)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 387.1 (M-H)- Example E35 Rac-3- (3, 3-diphenyl-propionyl)-4-hydroxy-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 3,3-diphenyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 411.2 (M-H)- Example E36 Rac-3- (2-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl-acetyl)-4-hydroxy-5- phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl-acetic acid (prepared according to Tucker, Thomas J.; Lumma, William C.; Lewis, S. Dale; Gardell, Stephen J.; Lucas, Bobby J. ; Sisko, Jack T.; Lynch, Joseph J.; Lyle, Elizabeth A.; Baskin, Elizabeth P.; Woltmann, Richard F. ; Appleby, Sandra D.; Chen, I-Wu ; Dancheck, Kimberley B.; Naylor-Olsen, Adel M.; Krueger, Julie A.; Cooper, Carolyn M.; Vacca, Joseph P. Journal of Medicinal Chemistry (1997), 40 (22), 3687-3693) instead of 3- methyl-sulfanyl-propionic acid in step c).

MS: 437.3 (M-H)- Example E37 Rac-4-hydroxy-5-phenethyl-3- (2-9H-thioxanthen-9-yl-acetyl) -5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-9H-thioxanthen-9-yl-acetic acid (prepared according to Jilek, Jiri O. ; Holubek, Jiri; Svatek, Emil; Ryska, Miroslav; Pomykacek, Josef; Protiva, Miroslav. Collection of Czechoslovak Chemical Communications (1979), 44 (7), 2124- 38) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 441.6 (M-H)- Example E38 Rac-3- (2-9H-fluoren-9-yl-acetyl)-4-hydroxy-5-phenethyl-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example E1 using 2-9H-fluoren-9-yl-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 409.2 (M-H)- Example E39 Rac- [2- (4-hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-furan-3-yl)-1 (R, S)-methyl-2-oxo- ethyl] -carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example E1 using (commercially available) instead of 3-methyl- sulfanyl-propionic acid in step c).

MS: 374.2 (M-H)- Example E40 Rac-3- (2 (R, S)-amino-propionyl)-4-hydroxy-5-phenethyl-5H-furan-2-one The title compound was prepared from the corresponding BOC-protected precursor (Example E40) by deprotection using CF3COOH.

MS : 27. 6. 1 (M+H) t Example E41 [1 (R) -Benzyl-2- (4-hydroxy-2-oxo-5 (R, S) -phenethyl-2, 5-di-hydro-furan-3-yl)-2-oxo- ethyl] -carbamic acid tert-butylester The title compound was obtained in comparable yields according to the procedures described for example El using (commercially available) instead of 3-methyl- sulfanyl-propionic acid in step c).

MS: 450.1 (M-H)- Example E42 3- (2 (R)-Amino-3-phenyl-propionyl)-4-hydroxy-5 (R, S)-phenethyl-5H-furan-2-one The title compound was prepared from the corresponding BOC-protected precursor (Example E42) by deprotection using CF3COOH.

MS: 352.2 (M+H) + Example E43

Rac- [1 (R, S)- (4-benzyloxy-benzyl)-2- (4-hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-furan- 3-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example El using (commercially available) instead of 3- methyl-sulfanyl-propionic acid in step c).

MS: 556.2 (M-H)- Example E44 [1 (S)- (4-Benzyloxy-benzyl)-2- (4-hydroxy-2-oxo-5 (R, S) -phenethyl-2, 5-dihydro-furan-3- yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example E1 using (commercially available) instead of 3- methyl-sulfanyl-propionic acid in step c).

MS: 458.2 (M+H-C5H902) + Example E45 <BR> <BR> [1 (R) - (4-Benzyloxy-benzyl)-2- (4-hydroxy-2-oxo-5 (R, S) -phenethyl-2, 5-dihydro-furan- 3-yl) -2-oxo-ethyl] -carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example E1 using (commercially available) instead of 3- methyl-sulfanyl-propionic acid in step c).

MS: 458.2 (M+H-csH9o2) Example E46 Rac-3- [2 (R, S)-amino-3- (4-benzyloxy-phenyl)-propionyl]-4-hydroxy-5-phenethyl-5H- furan-2-one

The title compound compound was prepared from the corresponding BOC-protected precursor (Example E44) by deprotection using CF3COOH.

MS: 458.3 (M+H) + Example E47 2- (4-Hydroxy-2-oxo-5 (R, S)-phenethyl-2, 5-dihydro-furan-3-carbonyl)-pyrrolidine-1 (S) - carboxylic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example El using (commercially available) instead of 3-methyl- sulfanyl-propionic acid in step c).

MS: 400.3 (M-H)- Example E48 4-Hydroxy-5 (R, S) -phenethyl-3- (pyrrolidine-2 (S)-carbonyl)-5H-furan-2-one The title compound was prepared from the corresponding BOC-protected precursor (Example E48) by deprotection using CF3COOH.

MS: 302.1 (M+H) + Example E49 Rac-2 (R, S)- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-furan-3-carbonyl) -piperidine- 1-carboxylic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example E1 using (commercially available) instead of 3-methyl- sulfanyl-propionic acid in step c).

MS: 414.2 (M-H)- Example E50 Rac-4-hydroxy-5-phenethyl-3 (R, S)- (piperidine-2-carbonyl)-5H-furan-2-one The title compound was prepared from the corresponding BOC-protected precursor (Example E50) by deprotection using CF3COOH.

MS: 316.1 (M+H) + Example E51 Rac-3 (R, S)- (4-hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-furan-3-carbonyl) -3,4-dihydro- 1H-iso-quinoline-2-carboxylic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example E1 using (commercially available) instead of 3-methyl- sulfanyl-propionic acid in step c).

MS: 462.2 (M-H)- Example E52 Rac-4-hydroxy-5-phenethyl-3 (R, S)- (1, 2,3, 4-tetrahydro-isoquinoline-3-carbonyl)-5H- furan-2-one The title compound was prepared from the corresponding BOC-protected precursor (Example E52) by deprotection using CF3COOH.

MS: 364.1 (M+H) + Example F1 3-4-Cyclohexanecarbonyl-4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one a) 4-Methoxv-5- (3-phenyl-propvl)-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E) -methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 4-phenyl- butyraldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HC1 (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n- heptane/AcOEt, various ratios) to give the 4-methoxy-5- (3-phenyl-propyl)-5H-furan-2- one in 30-40% yield.

MS: 250.3 (M+NH4) + b) 4-Hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one A mixture of the the 4-methoxy-5- (3-phenyl-propyl)-5H-furan-2-one (10 mmole) and 15 ml of aqueous HCl (37%) was stirred at 40°C until completion of the reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 4-hydroxy-5- (3- phenyl-propyl) -5H-furan-2-one in 60-90% yield.

MS: 218.1 (M) t c) 3-4-Cyclohexanecarbonyl-4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one To as suspension of the 4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C cyclohexanecarboxylic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HCl (2 N), the aqueous solution was saturated with NaCl, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H2O, gradient) to give the 3- 4-Cyclohexanecarbonyl-4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one in 10-60% yield.

MS: 327.2 (M-H)- Example F2 3- (4-Cyclohexyl-butyryl)-4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example F1 using 4-cyclohexyl-butyric acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 369.1 (M-H)- Example F3 3- [3- (4-tert-Butyl-phenyl)-2-methyl-propionyl]-4-hydroxy-5- (3-phenyl-propyl) -5H- furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Fl using 3- (4-tert-Butyl-phenyl)-2-methyl-propionic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav; Roubal, Zdenek; Nemecek, Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1), 183-93) instead of cyclohexanecarboxylic acid in step c).

MS: 419.1 (M-H)- Example F4 4-Hydroxy-3- [ (2-methoxy-phenoxy)-acetyl]-5- (3-phenyl-propyl) -5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Fl using (2-methoxy-phenoxy)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 381.1 (M-H)- Example F5 4-Hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5- (3-phenyl-propyl) -5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example F1 using (lH-indol-3-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 374.2 (M-H)- Example F6 3- (3, 3-Diphenyl-propionyl)-4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example F1 using 3,3-Diphenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 425.2 (M-H)- Example F7 3- [ (9H-Fluoren-9-yl)-acetyl]-4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example F1 using (9H-Fluoren-9-yl) -acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 423.2 (M-H)- Example G1 4-Hydroxy-3- (3-methylsulfanyl-propionyl)-5- (3-morpholin-4-yl-propyl)-5H-furan-2- one a) 4-Methoxv-5-(3-morpholin-4-yl-propyl)-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E) -methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 4- morpholin-4-yl-butyraldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6. 5 ml of aqueous HCl (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, various ratios) to give the 4-methoxy-5- (3-morpholin-4-yl- propyl) -5H-furan-2-one in 30-40% yield.

MS: 242.3 (M+H) + b) 4-Hydroxy-5-(3-phenyl-propyl)-5H-furan-2-one A mixture of the 4-methoxy-5- (3-morpholin-4-yl-propyl)-5H-furan-2-one (10 mmole) and 15 ml of aqueous HCl (37%) was stirred at 40°C until completion of the reaction.

The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one in 60-90% yield.

MS: 226.0 (M-H)- <BR> <BR> <BR> <BR> <BR> <BR> c) 4-Hydroxy-3- (3-methylsulfanyl-propionyl)-5- (3-morpholin-4-yl-propyl)-5H-furan- 2-one

To as suspension of the 4-hydroxy-5- (3-phenyl-propyl)-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C 3-methyl-sulfanyl-propionic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HC1 (2 N), the aqueous solution was saturated with NaCl, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H20, gradient) to give the 4- hydroxy-3- (3-methylsulfanyl-propionyl) -5- (3-morpholin-4-yl-propyl)-5H-furan-2-one in 10-60% yield.

MS: 328.1 (M-H)- Example G2 3-Cyclopropanecarbonyl-4-hydroxy-5- (3-morpholin-4-yl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using cyclopropanecarboxylic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 294.2 (M-H)- Example G3 4-Hydroxy-5- (3-morpholin-4-yl-propyl)-3- (2, 2,3, 3-tetramethyl-cyclopropanecarbonyl) - 5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2,2, 3, 3-tetramethyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 350.3 (M-H)- Example G4 4-Hydroxy-5- (3-morpholin-4-yl-propyl) -3- (tetrahydro-furan-2-carbonyl)-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example G1 using tetrahydro-furan-2-carboxylic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 324.1 (M-H)-

Example G5 3-Cyclohexanecarbonyl-4-hydroxy-5- (3-morpholin-4-yl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Gl using cyclohexanecarboxylic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 338.2 (M+H) + Example G6 3- (2-Cyclohexyl-acetyl)-4-hydroxy-5- (3-morpholin-4-yl-propyl) -5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-cyclohexyl-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS : 350. 3 (M-H)- Example G7 3- (4-Cyclohexyl-butyryl)-4-hydroxy-5- (3-morpholin-4-yl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 4-cyclohexyl-butyric acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 378.2 (M-H)- Example G8 4-Hydroxy-5- (3-morpholin-4-yl-propyl) -3-phenylacetyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Gl using phenylacetic acid (commercially available) instead of 3- methyl-sulfanyl-propionic acid in step c).

MS: 344.2 (M-H)- Example G9 4-Hydroxy-5- (3-morpholin-4-yl-propyl)-3- (2-phenyl-propionyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-phenyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 358.1 (M-H)- Example G10 3- [2- (3,5-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5- (3-morpholin-4-yl-propyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2- (3, 5-Dimethoxy-phenyl) -acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 404.4 (M-H)- Example Gll 3- [2- (2, 5-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5- (3-morpholin-4-yl-propyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2- (2, 5-dimethoxy-phenyl) -acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 404.3 (M-H)- Example G12 3- [2- (2, 4-Dimethoxy-phenyl)-acetyl]-4-hydroxy-5- (3-morpholin-4-yl-propyl) -5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2- (2, 4-dimethoxy-phenyl) -acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 404.2 (M-H)- Example G13 4-Hydroxy-3- [2- (4-methoxy-2-methyl-phenyl)-acetyl]-5- (3-morpholin-4-yl-propyl) - 5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example G1 using 2- (4-methoxy-2-methyl-phenyl)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 390.3 (M+H) + Example G14 4-Hydroxy-3- [3- (4-methoxy-phenyl)-propionyl]-5- (3-morpholin-4-yl-propyl) -5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Gl using 3- (4-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 388.2 (M-H)- Example G15 4-Hydroxy-5- (3-morpholin-4-yl-propyl)-3- (3-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 3-phenyl-butyric acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 372.2 (M-H)- Example G16 3- [3- (2, 5-Dimethoxy-phenyl)-propionyl]-4-hydroxy-5- (3-morpholin-4-yl-propyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2,5-dimethoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 418.2 (M-H)- Example G 17 4-Hydroxy-5- (3-morpholin-4-yl-propyl) -3- (3-m-tolyl-propionyl)-5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example G1 using 3-m-tolyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 372.2 (M-H)- Example G18 4-Hydroxy-3- [3- (3-methoxy-phenyl) -propionyl]-5- (3-morpholin-4-yl-propyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 3- (3-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 388.1 (M-H)- Example G19 4-Hydroxy-3- [2- (3-methoxy-phenoxy)-acetyl]-5- (3-morpholin-4-yl-propyl)-5H-furan- 2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2- (3-methoxy-phenoxy)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 390.3 (M-H)- Example G20 4-Hydroxy-5- (3-morpholin-4-yl-propyl)-3- (2-m-tolyloxy-acetyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-m-tolyloxy-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 376.4 (M+H) + Example G21 4-Hydroxy-3- [2- (2-methoxy-phenoxy)-acetyl]-5- (3-morpholin-4-yl-propyl) -5H-furan- 2-one

The title compound was obtained in comparable yields according to the procedures described for example G1 using 2- (2-methoxy-phenoxy)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 392.2 (M+H) + Example G22 3- [2- (2, 3-Dimethyl-phenoxy)-acetyl]-4-hydroxy-5- (3-morpholin-4-yl-propyl)-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2- (2, 3-Dimethyl-phenoxy) -acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 390.3 (M+H) + Example G23 4-Hydroxy-5- (3-morpholin-4-yl-propyl)-3- (4-phenyl-butyryl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 4-phenyl-butyric acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 372.2 (M-H)- Example G24 4-Hydroxy-5- (3-morpholin-4-yl-propyl)-3- (2-naphthalen-2-yl-acetyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-naphthalen-2-yl-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 396.3 (M+H) + Example G25 4-Hydroxy-5- (3-morpholin-4-yl-propyl) -3- [2- (naphthalen-1-yloxy)-acetyl]-5H-furan- 2-one

The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-(naphthalen-1-yloxy)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 410.3 (M-H)- Example G26 4-Hydroxy-3- (2-lH-indol-3-yl-acetyl)-5- (3-morpholin-4-yl-propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-lH-indol-3-yl-acetic acid instead of 3-methyl-sulfanyl- propionic acid in step c).

MS: 385.3 (M+H) + Example G27 4-Hydroxy-3- (3-lH-indol-3-yl-propionyl)-5- (3-morpholin-4-yl-propyl)-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example G1 using 3-lH-indol-3-yl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 399.4 (M+H) + Example G28 3- [2- (2-Acetyl-1, 2-dihydro-isoquinolin-1-yl)-acetyl]-4-hydroxy-5- (3-morpholin-4-yl- propyl)-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-(2-acetyl-1, 2-dihydro-isoquinolin-1-yl)-acetic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 414.4 (M+H) + Example G29 3- (3, 3-Diphenyl-propionyl)-4-hydroxy-5- (3-morpholin-4-yl-propyl) -5H-furan-2-one

The title compound was obtained in comparable yields according to the procedures described for example Gl using 3, 3-diphenyl-propionic acid (commercially available) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 436.4 (M+H) + Example G30 4-Hydroxy-5- (3-morpholin-4-yl-propyl)-3- (2-9H-thioxanthen-9-yl-acetyl) -5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example G1 using 2-9H-thioxanthen-9-yl-acetic acid (prepared according to Jilek, Jiri O. ; Holubek, Jiri; Svatek, Emil; Ryska, Miroslav; Pomykacek, Josef; Protiva, Miroslav. Collection of Czechoslovak Chemical Communications (1979), 44 (7), 2124- 2138) instead of 3-methyl-sulfanyl-propionic acid in step c).

MS: 466. 3 (M+H) t Example H1 5- [2- (4-Benzyloxy-phenyl)-ethyl]-3- (4-cyclohexyl-butyryl) -4-hydroxy-5H-furan-2-one a) 5-r2-(4-Benzyloxy-phenyl) ethyll-4-methoxy-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E)-methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 3- (4- benzyloxy-phenyl)-propionaldehyde in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HC1 (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, various ratios) to give the 5- [2- (4- benzyloxy-phenyl) ethyl]-4-methoxy-5H-furan-2-one in 30-40% yield.

MS: 325.2 (M+H) + b) 5-12-(4-Benzyloxv-phenyl)-ethyll-4-hydroxy-5H-furan-2-one A mixture of the 5- [2- (4-benzyloxy-phenyl) ethyl]-4-methoxy-5H-furan-2-one (10 mmole) and 15 ml of aqueous HC1 (37%) was stirred at 40°C until completion of the

reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 5- [2- (4-benzyloxy-phenyl)-ethyl]-4-hydroxy-5H-furan-2-one in 60-90% yield.

MS: 310.2 (M) t <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> c) 5- [2- (4-Benzyloxy-phenyl)-ethyll-3- (4-cyclohexyl-butvryl)-4-hydroxy-5H-furan-2- one To as suspension ofthe 5- [2- (4-benzyloxy-phenyl)-ethyl]-4-hydroxy-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C 4-cyclohexyl-butyric acid (0.22 mmole) (commercil available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HCl (2 N), the aqueous solution was saturated with NaCI, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H20, gradient) to give the 5- [2- (4-benzyloxy-phenyl)-ethyl]-3- (4-cyclohexyl-butyryl)-4-hydroxy-5H-furan-2-one in 10-60% yield.

MS: 463.2 (M+H) + Example I1 3-Cyclohexanecarbonyl-4-hydroxy-5-methyl-5-phenethyl-5H-fura n-2-one a) 4-Methoxy-5-methyl-5-phenethvl-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E) -methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 4-phenyl- butan-2-one in 4.5 ml of THF within 2 min and stirring was continued at-100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice-water, the pH was adjusted to 4 with 6.5 ml of aqueous HCl (37%) and the layers were separated. The aqueous layer was extracted twice with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n- heptane/AcOEt, various ratios) to give 4-methoxy-5-methyl-5-phenethyl-5H-furan-2- one in 30-40% yield.

MS: 233.2 (M+H) +

b) 4-Hydroxy-5-methyl-5-phenethyl-5H-furan-2-one A mixture of the the 4-methoxy-5-methyl-5-phenethyl-5H-furan-2-one (10 mmole) and 15 ml of aqueous HCl (37%) was stirred at 40°C until completion of the reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 4-hydroxy-5- methyl-5-phenethyl-5H-furan-2-one in 60-90% yield.

MS: 218.2 (M) + c) 3-Cyclohexanecarbonyl-4-hydroxy-5-methyl-5-phenethyl-5H-fura n-2-one To as suspension of the 4-hydroxy-5-methyl-5-phenethyl-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C cyclohexanecarboxylic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HCl (2 N), the aqueous solution was saturated with NaCI, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H2O, gradient) to give the 3- cyclohexanecarbonyl-4-hydroxy-5-methyl-5-phenethyl-5H-furan- 2-one in 10-60% yield.

MS: 327.2 (M-H)- Example I2 3- (4-Cyclohexyl-butyryl)-4-hydroxy-5-methyl-5-phenethyl-5H-fur an-2-one The title compound was obtained in comparable yields according to the procedures described for example Fl using 4-cyclohexyl-butyric acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 369.2 (M-H)- Example I3 3- [3- (4-tert-Butyl-phenyl)-2-methyl-propionyl]-4-hydroxy-5-methyl -5-phenethyl-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Fl using 3- (4-tert-Butyl-phenyl)-2-methyl-propionic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav; Roubal, Zdenek; Nemecek,

Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1), 183-93) instead of cyclohexanecarboxylic acid in step c).

MS: 419.2 (M-H)- Example 14 4-Hydroxy-3- [ (2-methoxy-phenoxy)-acetyl]-5-methyl-5-phenethyl-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example F1 using (2-methoxy-phenoxy) -acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 381.2 (M-H)- Example 15 4-Hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5-methyl-5-phenethyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example F1 using (lH-indol-3-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 374.2 (M-H)- Example 16 3- (3, 3-Diphenyl-propionyl)-4-hydroxy-5-methyl-5-phenethyl-5H-fura n-2-one The title compound was obtained in comparable yields according to the procedures described for example F1 using 3,3-diphenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 425.3 (M-H)- Example 17 3- [ (9H-Fluoren-9-yl)-acetyl]-4-hydroxy-5-methyl-5-phenethyl-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example F1 using (9H-fluoren-9-yl) -acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 423.2 (M-H)-

Example J1 3-Cyclohexanecarbonyl-4-hydroxy-5-phenethyl-5-phenyl-5H-fura n-2-one a) 4-Methoxy-5-phenethyl-5-phenyl-5H-furan-2-one To as solution of 20 ml of LDA (2M in THF) and 130 ml of THF was added at-95°C to- 100°C a solution of 5.47 g of 3 (E)-methoxy-acrylic acid methyl ester in 4.5 ml of THF within 1 min, stirring was continued at the same temperature for 5 min, which was followed by the addition of a pre-cooled (-78°C) solution of 33 mmole of the 1,3- diphenyl-propan-l-one in 4.5 ml of THF within 2 min and stirring was continued at- 100°C for 30 min and at-78°C for 1 h. The cold solution was poured onto 130 ml of ice- water, the pH was adjusted to 4 with 6.5 ml of aqueous HC1 (37%) and the layers were separated. The aqueous layer was extracted twice with dichlorbmethane, the organic layers were washed with brine, dried and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, various ratios) to give 4-methoxy-5-phenethyl-5-phenyl- 5H-furan-2-one in 30-40% yield.

MS: 294.2 (M) t b) 4-Hydroxy-5-phenethyl-5-phenyl-5H-furan-2-one A mixture of the the 4-methoxy-5-phenethyl-5-phenyl-5H-furan-2-one (10 mmole) and 15 ml of aqueous HC1 (37%) was stirred at 40°C until completion of the reaction. The suspension was filtered and the residue washed with ice-cold water and dried. An oily reaction mixture was extracted with dichloromethane, the organic layers were washed with brine, dried and evaporated. The residue was either triturated with AcOEt/hexane or chromatographed with dichloromethane/MeOH (various ratios) to give 4-hydroxy-5- phenethyl-5-phenyl-5H-furan-2-one in 60-90% yield.

MS: 176.0 (M-C8Hg) c) 3-Cyclohexanecarbonyl-4-hydroxy-5-phenethyl-5-phenyl-5H-fura n-2-one To as suspension of the 4-hydroxy-5-phenethyl-5-phenyl-5H-furan-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C cyclohexanecarboxylic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HC1 (2 N), the aqueous solution was saturated with NaCI, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H2O, gradient) to give the 3- cyclohexanecarbonyl-4-hydroxy-5-phenethyl-5-phenyl-5H-furan- 2-one in 10-60% yield.

MS: 389.1 (M-H)- Example J2 4-Hydroxy-3- [ (2-methoxy-phenoxy)-acetyl]-5-phenethyl-5-phenyl-5H-furan-2- one The title compound was obtained in comparable yields according to the procedures described for example J1 using (2-methoxy-phenoxy)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 443.1 (M-H)- Example J3 4-Hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5-phenethyl-5-phenyl-5H-furan-2-one The title was obtained in comparable yields according to the procedures described for example J1 using (lH-indol-3-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 436.1 (M-H)- Example J4 3- (3, 3-Diphenyl-propionyl) -4-hydroxy-5-phenethyl-5-phenyl-5H-furan-2-one The title compound was obtained in comparable yields according to the procedures described for example J1 using 3,3-diphenyl-propionic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 384.2 (M-C8H8) Example J5 3- [ (9H-Fluoren-9-yl)-acetyl]-4-hydroxy-5-phenethyl-5-phenyl-5H- furan-2-one The title compound was obtained in comparable yields according to the procedures described for example Fl using (9H-Fluoren-9-yl)-acetic acid (commercially available) instead of cyclohexanecarboxylic acid in step c).

MS: 485.2 (M-H)- Example Kl 4-Hydroxy-3- (3-methylsulfanyl-propionyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one

a) Rac-f (2s2-dimethyl-4, 6-dioxo-F 1F3l dioxan-5-ylidene)-hydroxy-methyll-3-phenyl- propylT-carbamic acid ter-but ester To a solution of 4.00 g of rac-homophenylalanine in 80 ml of dichloromethane was subsequently added at 22°C 2.17 g of Meldrum's acid and 4.02 g of DMAP followed by a solution of 3.16 g of DCC in 20 ml of dichloromethane over 5 min and stirring was continued for 16 h. The suspension was filtered, the filtrate washed with aqueous HCl and water, dried and evaporated. The residue was triturated with 60 ml of methanol over 15 min, the suspension was diluted with 60 ml of diethylether, filtered and the residue was washed with MeOH/diethylether (1: 1,20 ml) and dried to give 3.54 g of rac-{1- [(2, 2- dimethyl-4,6-dioxo- [1, 3] dioxan-5-ylidene)-hydroxy-methyl]-3-phenyl-propyl}- carbamic acid tert-butyl ester as a white solid.

MS: 423.2 (M+NH4) +. b) Rac-3-hydroxy-5-oxo-2-phenethyl-2, 5-dihydro-pyrrole-l-carboxylic acid ter-butyl ester A suspension of 3.40 g of rac-{1- [(2, 2-dimethyl-4,6-dioxo- [1, 3] dioxan-5-ylidene)- hydroxy-methyl]-3-phenyl-propyl}-carbamic acid tert-butyl ester and 40 ml of methanol was heated to reflux temperature for 1 h and evaporated to give 2.53 g of rac-3-hydroxy- 5-oxo-2-phenethyl-2, 5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester as a colourless foam.

MS: 304.1 (M+H) + c) Rac-4-hydroxy-5-phenethyl-l, 5-dihydro-pyrrol-2-one A solution of 1.58 g of rac-3-hydroxy-5-oxo-2-phenethyl-2, 5-dihydro-pyrrole-1- carboxylic acid tert-butyl ester in 32 ml of dichloromethane was treated at 22°C with 2.0 ml of trifluoroacetic acid and stirring was continued for 16 h. The solution was evaporated to dryness, the residue dissolved in 8 ml of diethylether and stirring was continued until the crystallization set in. The suspension was diluted with 8 ml of n- heptane, stirred for 15 min and filtered. The residue was washed with n-heptane and dried to give 0.85 g of rac-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one as a white solid.

MS: 204.2 (M+H) +

To as suspension ofthe rac-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one (0.2 mmole), NEt3 (0.68 mmole), DMAP (0.066 mmole) and EDC (0.44 mmole) in 2 ml of THF was added at 22°C 3-methylsulfanyl-propionic acid (0.22 mmole) (commercially available) and stirring was continued until completion of the reaction. The pH of the reaction mixture was adjusted to 3 using aqueous HCl (2 N), the aqueous solution was saturated with NaCl, the organic layer was separated, washed with brine dried and evaporated. The residue was purified on preparative HPLC (RP-18, CH3CN/H20, gradient) to give the 4-hydroxy-3- (3-methylsulfanyl-propionyl)-5-phenethyl-1, 5- dihydro-pyrrol-2-one in 20-60% yield.

MS: 304.1 (M-H)- Example K2 3-Cyclopropanecarbonyl-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using cyclopropanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 270. 3 (M-H)- Example K3 <BR> <BR> <BR> <BR> <BR> <BR> <BR> 4-Hydroxy-3-(1-methyl-cyclopropanecarbonyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 1-methyl-cyclopropanecarboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 283.3 (M-H)- Example K4 4-Hydroxy-5-phenethyl-3-(tetrahydro-furan-2-carbonyl)-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using tetrahydro-furan-2-carboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 302.2 (M+H) + Example K5

3- (4-Cyclohexyl-butyryl)-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 4-cyclohexyl-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 356.2 (M+H) + Example K6 4-Hydroxy-5-phenethyl-3- (thieno [2,3-c] pyridine-7-carbonyl)-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using thieno [2,3-c] pyridine-7-carboxylic acid (prepared according to Bass, R. J.; Popp, F. D.; Kant, J. Journal of Heterocyclic Chemistry (1984), 21 (4), 1119-20) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 365.1 (M+H) + Example K7 <BR> <BR> <BR> <BR> <BR> <BR> 4-Hydroxy-3-(5-methyl-pyrazine-2-carbonyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 5-methyl-pyrazine-2-carboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 324.1 (M+H) + Example K8 4-Hydroxy-3- (isoquinoline-3-carbonyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using isoquinoline-3-carboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 358.1 (M+H) + Example K9 3- (Benzo [1, 2,3] thiadiazole-5-carbonyl)-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2- one

The title compound was obtained in comparable yields according to the procedures described for example K1 using benzo [1, 2,3] thiadiazole-5-carboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 364.1 (M-H)- Example K10 4-Hydroxy-3- (3-methyl-furan-2-carbonyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 3-methyl-furan-2-carboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 319.2 (M-H)- Example Kl l <BR> <BR> <BR> <BR> <BR> <BR> 3-(2, 3-Dihydro-benzofuran-7-carbonyl)-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2- one The title compound was obtained in comparable yields according to the procedures described for example K1 using 2, 3-dihydro-benzofuran-7-carboxylic acid (prepared according to Voelter, Wolfgang; El-Abadelah, Mustafa M.; Sabri, Salim S.; Khanfar, Monther A. Zeitschrift fuer Naturforschung, B: Chemical Sciences (1999), 54 (11), 1469-1473) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 348.2 (M-H)- Example K12 4-Hydroxy-5-phenethyl-3- (1, 2, 5-trimethyl-lH-pyrrole-3-carbonyl)-l, 5-dihydro-pyrrol- 2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 1, 2, 5-trimethyl-lH-pyrrole-3-carboxylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 337.2 (M-H)- Example K13 4-Hydroxy-5-phenethyl-3-phenylacetyl-1, 5-dihydro-pyrrol-2-one

The title compound was obtained in comparable yields according to the procedures described for example Kl using phenyl-acetic acid (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 320.1 (M-H)- Example K14 4-Hydroxy-3- (2-naphthalen-2-yl-acetyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using 2-naphthalen-2-yl-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 370.2 (M-H)- Example K15 4-Hydroxy-3- [2- (3-oxo-indan-1-yl)-acetyl]-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 2- (3-oxo-indan-1-yl)-acetic acid (prepared according to Thompson, Hugh W.; Brunskull, Andrew P. J.; Lalancette, Roger A. Acta Crystallographica, Section C: Crystal Structure Communications (1998), C54 (6), 829- 831) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 374.2 (M-H)- Example K16 1- [2-(4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrol-3-yl)-2-oxo-ethyl]-5- methyl-1H-pyrimidine-2, 4-dione The title compound was obtained in comparable yields according to the procedures described for example K1 using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 368.1 (M-H)- Example K17 4-Hydroxy-5-phenethyl-3- (2-phenyl-propionyl)-1, 5-dihydro-pyrrol-2-one

The title compound was obtained in comparable yields according to the procedures described for example Kl using 2-phenyl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 336.2 (M+H) + Example K18 4-Hydroxy-3- [2- (6-methoxy-naphthalen-2-yl)-propionyl]-5-phenethyl-1, 5-dihydro- pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using 2- (6-methoxy-naphthalen-2-yl)-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 414.2 (M-H)- Example K19 4-Hydroxy-5-phenethyl-3- (3-m-tolyl-propionyl)-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using 3-m-tolyl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 348.2 (M-H)- Example K20 4-Hydroxy-3- [3-(3-methoxy-phenyl)-propionyl]-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 3- (3-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 364.2 (M-H)- Example K21 4-Hydroxy-3- [3- (2-methoxy-phenyl)-propionyl]-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 3- (2-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 364.2 (M-H)- Example K22 4-Hydroxy-3- [3- (4-methoxy-phenyl)-propionyl]-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using 3- (4-methoxy-phenyl)-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 364.2 (M-H)- Example K23 3- [3- (4-tert-Butyl-phenyl) -2-methyl-propionyl]-4-hydroxy-5-phenethyl-1, 5-dihydro- pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 3- (4-tert-butyl-phenyl)-2-methyl-propibnic acid (prepared according to Kuchar, Miroslav; Rejholec, Vaclav; Roubal, Zdenek; Nemecek, Oldrich; Collect. Czech. Chem. Commun. (1979), 44 (1), 183-193) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 406.4 (M+H) + Example K24 4-Hydroxy-3- [ (2-methoxy-phenoxy)-acetyl]-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using (2-methoxy-phenoxy)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 368.2 (M+H) + Example K25 4-Hydroxy-5-phenethyl-3- (4-phenyl-butyryl)-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using 4-phenyl-butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 348.2 (M-H)-

Example K26 3- [4- (3, 4-Dimethoxy-phenyl)-butyryl]-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2- one The title compound was obtained in comparable yields according to the procedures described for example K1 using 4- (3, 4-dimethoxy-phenyl) -butyric acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 408.3 (M-H)- Example K27 N- [2- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrol-3-yl)-2-oxo-ethyl]- acetamide The title compound was obtained in comparable yields according to the procedures described for example K1 using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 301.1 (M-H)- Example K28 N- [1- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrole-3-carbonyl)-3- methylsulfanyl-propyl]-acetamide The title compound was obtained in comparable yields according to the procedures described for example K1 using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 377.2 (M+H) t Example K29 N- [2- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrol-3-yl)-2-oxo-ethyl]-N- methyl-benzamide

The title compound was obtained in comparable yields according to the procedures described for example Kl using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 379.2 (M+H) + Example K30 N- [2- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrol-3-yl)-2-oxo-ethyl]-4- methyl-benzamide The title compound was obtained in comparable yields according to the procedures described for example Kl using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 379.2 (M+H) + Example K31 N- [2- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrol-3-yl)-2-oxo-ethyl]- nicotinamide The title compound was obtained in comparable yields according to the procedures described for example Kl using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 364.2 (M-H)- Example K32 [2- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrol-3-yl)-l-methyl-2-oxo-ethyl]- carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example K1 using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 375.3 (M+H) + Example K33 [1-Benzyl-2- (4-hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-1 H-pyrrol-3-yl)-2-oxo-ethyl]- carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example Kl using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 451.2 (M+H) + Example K34 2- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrole-3-carbonyl)-pyrrolidine-1- carboxylic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example Kl using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 401.4 (M+H) + Example K35 2- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrole-3-carbonyl)-piperidine-1- carboxylic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example K1 using (commercially available) instead of 3- methylsulfanyl-propionic acid in step d).

MS: 415.3 (M+H) + Example K36 3- (4-Hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrole-3-carbonyl)-3, 4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was obtained in comparable yields according to the procedures described for example K1 using (commercially available) instead of 3-

methylsulfanyl-propionic acid in step d).

MS: 463.3 (M+H) + Example K37 <BR> <BR> [1- (4-Benzyloxy-benzyl)-2- (4-hydroxy-2-oxo-5-phenethyl-2, 5-dihydro-lH-pyrrol-3-yl)- 2-oxo-ethyl] -carbamic acid tert-butyl ester The title compound was obtained in comparable yields according to the procedures described for example K1 using (commercially available) instead of 3-

methylsulfanyl-propionic acid in step d).

MS: 574.3 (M+NH4) + Example K38 3- [2-Amino-3- (4-benzyloxy-phenyl)-propionyl]-4-hydroxy-5-phenethyl-1, 5-dihydro- pyrrol-2-one; compound with trifluoro-acetic acid The title compound compound was prepared from the corresponding BOC-protected precursor (Example K37) by deprotection using CF3COOH.

MS: 457.2 (M+H) + Example K39 4-Hydroxy-3- [ (lH-indol-3-yl)-acetyl]-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using-[(lH-indol-3-yl)-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 361.1 (M+H) + Example K40

3-{[1-(4-Fluoro-benzyl)-1H-indol-3-yl]-acetyl}-4-hydroxy-5-p henethyl-1, 5-dihydro- pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 1-(4-Fluoro-benzyl)-lH-indol-3-yl]-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 469.2 (M+H) + Example K41 4-Hydroxy-3- (indol-1-yl-acetyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using indol-1-yl-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 361.2 (M+H) + Example K42 4-Hydroxy-3-(3-lH-indol-3-yl-propionyl)-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using 3-lH-indol-3-yl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 373.1 (M-H)- Example K43 3- (2-Benzo [b] thiophen-3-yl-acetyl)-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example K1 using 2-benzo [b] thiophen-3-yl-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 378.2 (M+H) + Example K44 3- (3, 3-Diphenyl-propionyl)-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one

The title compound was obtained in comparable yields according to the procedures described for example Kl using 3,3-diphenyl-propionylic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 412.2 (M+H) + Example K45 3-(2, 3-Diphenyl-propionyl)-4-hydroxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using 2,3-Diphenyl-propionic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 412.3 (M+H) + Example K46 3- (Carbazol-9-yl-acetyl)-4-hydioxy-5-phenethyl-1, 5-dihydro-pyrrol-2-one The title compound was obtained in comparable yields according to the procedures described for example Kl using carbazol-9-yl-acetic acid (commercially available) instead of 3-methylsulfanyl-propionic acid in step d).

MS: 411.3 (M+H) + H-NMR (300 MHz, internal standard TMS, J values in Hz, d6-DMSO): 9.20 (s, br., 1H), 8.15 (d, J = 7.7, 2H), 7.50-7. 10 (m, 11H), 5.69 (s, 2H), 4.00 (J = 7.6 and 4, 1H), 2.95 (s, br. 1H), 2.80-2. 65 (m, 2H), 2.20-2. 00 (m 1H), 1.95-1. 80 (m, 1H)