Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis

Certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and the corresponding ring-opened acids derived therefrom which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase and are thus useful hypolipidemic or hypocholesterolemic agents. Pharmaceutical compositions containing such compounds, and a method of inhibiting the biosynthesis of cholesterol employing such pharmaceutical compositions are also disclosed.

BACKGROUND OF THE INVENTION 
The present invention is related to compounds and pharmaceutical 
compositions useful as hypocholesterolemic and hypolipidemic agents. More 
particularly, this invention concerns certain trans-6-[2-(3- or 
4-carboxamidosubstitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and the 
corresponding ring-opened acids derived therefrom which are potent 
inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase 
(HMG CoA reductase), pharmaceutical compositions containing such 
compounds, and a method of inhibiting the biosynthesis of cholesterol 
employing such pharmaceutical compositions. 
High levels of blood cholesterol and blood lipids are conditions involved 
in the onset of arteriosclerosis. It is well known that inhibitors of 
HMG-CoA reductase are effective in lowering the level of blood plasma 
cholesterol, especially low density lipoprotein cholesterol (LDL-C), in 
man (cf. M. S. Brown and J. L. Goldstein, New England Journal of Medicine, 
305, No. 9, 515-517 (1981). It has now been established that lowering 
LDL-C levels affords protection from coronary heart disease (cf. Journal 
of the American Medical Association, 251, No. 3, 351-374 (1984). 
Moreover, it is known that certain derivatives of mevalonic acid 
(3,5-dihydroxy-3-methylpentanoic acid) and the corresponding ring-closed 
lactone form, mevalonolactone, inhibit the biosynthesis of cholesterol 
(cf. F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102: 370 (1959) 
and F. H. Hulcher, Arch. Biochem. Biophys., 146: 422 (1971)). 
U.S. Pat. Nos. 3,983,140; 4,049,495 and 4,137,322 disclose the fermentative 
production of a natural product, now called compactin, having an 
inhibitory effect on cholesterol biosynthesis. Compactin has been shown to 
have a complex structure which includes a mevalonolactone moiety (Brown et 
al., J. Chem. Soc. Perkin I (1976) 1165. 
U.S. Pat. No. 4,255,444 to Oka et al. discloses several synthetic 
derivatives of mevalonolactone having antilipidemic activity. 
U.S. Pat. Nos. 4,198,425 and 4,262,013 to Mitsue et al. disclose aralkyl 
derivatives of mevalonolactone which are useful in the treatment of 
hyperlipidemia. 
U.S. Pat. no. 4,375,475 to Willard et al. discloses certain substituted 
4-hydroxytetrahydropyran-2-ones which, in the 4(R)-trans-stereoisomeric 
form, are inhibitors of cholesterol biosynthesis. 
Published PCT application No. WO 84/01231 discloses certain indole analogs 
and derivatives of mevalonolactone having utility as hypolipoproteinemic 
and antiatherosclerotic agents. 
SUMMARY OF THE INVENTION 
In accordance with the present invention, there are provided certain 
trans-6-[2-(3- or 4-carboxamido-substituted 
pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and the corresponding ring-opened 
hydroxy-acids derived therefrom which are potent inhibitors of cholesterol 
biosynthesis by virtue of their ability to inhibit the enzyme 
3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). 
In particular, in its broadest aspect the present invention provides 
compounds of structural formula I 
##STR1## 
wherein X is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 
CH.sub.2 -- or --CH.sub.2 CH(CH.sub.3)--. 
R.sub.1 is 1-naphthyl; 2-naphthyl; cyclohexyl; norbornenyl; 2-, 3-, or 
4-pyridinyl; phenyl, phenyl substituted with fluorine, chlorine, bromine, 
hydroxyl; trifluoromethyl; alkyl of from one to four carbon atoms, alkoxy 
of from one to four carbon atoms, or alkanoyloxy of from two to eight 
carbon atoms. 
Either R.sub.2 or R.sub.3 is --CONR.sub.5 R.sub.6 where R.sub.5 and R.sub.6 
are independently hydrogen; alkyl of from one to six carbon atoms; 2-, 3-, 
or 4-pyridinyl; phenyl; phenyl substituted with fluorine, chlorine, 
bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight 
carbon atoms; and the other of R.sub.2 or R.sub.3 is hydrogen; alkyl of 
from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; 
cyclohexyl; phenyl; or phenyl substituted with fluorine, chlorine, 
bromine, hydroxyl; trifluoromethyl; alkyl of from one to four carbon 
atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two 
to eight carbon atoms. 
R.sub.4 is alkyl of from one to six carbon atoms; cyclopropyl; cyclobutyl; 
cyclopentyl; cyclohexyl; or trifluoromethyl. 
Also contemplated as falling within the scope of the present invention are 
the hydroxy acids, and pharmaceutically acceptable salts thereof, derived 
from the opening of the lactone ring of the compounds of structural 
formula I above. 
In another aspect of the present invention, there is provided a method of 
preparing the compounds of structural formula I above which comprises the 
steps of 
(a) first reacting a substituted [(pyrrol-1-yl)alkyl]aldehyde compound of 
the formula 
##STR2## 
with the dilithio or sodio-lithio salt of methyl acetoacetate to form a 
compound of the structure 
##STR3## 
(b) reducing the product of step (a) with a trialkylborane compound such 
as tributylborane in the presence of sodium borohydride in an inert 
solvent; 
(c) oxidizing the product of step (b) with alkaline aqueous hydrogen 
peroxide solution to produce a compound of the formula 
##STR4## 
and (d) cyclizing the product step (c) to a lactone of formula I above by 
heating in an inert solvent such as toluene or, alternatively converting 
the product of step (c) to a pharmaceutically acceptable salt by 
conventional methods. 
In yet another aspect, the present invention provides pharmaceutical 
compositions useful as hypolipidemic or hypocholesterolemic agents 
comprising a hypolipidemic or hypocholesterolemic effective amount of a 
compound in accordance with this invention as set forth above, in 
combination with a pharmaceutically acceptable carrier. 
In another aspect, the present invention provides a method of inhibiting 
cholesterol biosynthesis in a patient in need of such treatment by 
administering an effective amount of a pharmaceutical composition as 
defined above. 
DETAILED DESCRIPTION 
The compounds of the present invention comprise a class of trans-6-[2-(3- 
or 4-carboxamidosubstituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones in 
which the pyran-2-one moiety is attached, through an alkyl chain, to the 
substituted pyrrole nucleus at the nitrogen, or 1-position, of the 
pyrrole. The alkyl group may be methylene, ethylene, propylene, or 
methylethylene. The preferred alkyl chain linking the substituted pyrrole 
nucleus and the 4-hydroxypyran-2-one ring is ethylene. 
The compounds of structural formula I above possess two asymmetric carbon 
centers, one at the 4-hydroxy position of the pyran-2-one ring, and the 
other at the 6-position of the pyran-2-one ring where the alkylpyrrole 
group is attached. This asymmetry gives rise to four possible isomers, two 
of which are the R-cis- and S-cis-isomers and the other two of which are 
the R-trans- and S-trans-isomers. This invention contemplates only the 
trans- form of the compounds of formula I above. 
In the compounds of the present invention, position 2 of the substituted 
pyrrole nucleus is substituted with 1-naphthyl; 2-naphthyl; cyclohexyl; 
norbornenyl; 2-, 3-, or 4-pyridinyl; phenyl, phenyl substituted with 
fluorine, chlorine, bromine, hydroxyl; trifluoromethyl; alkyl of from one 
to four carbon atoms, alkoxy of from one to four carbon atoms, or 
alkanoyloxy of from two to eight carbon atoms. Preferred substituent 
groups at the 2-position of the pyrrole nucleus are phenyl and substituted 
phenyl. 
In the compounds of this invention, position 5 of the pyrrole nucleus is 
substituted with alkyl of from one to six carbon atoms; cyclopropyl; 
cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl. Preferred 
substituents are alkyl or trifluoromethyl with isopropyl being 
particularly preferred. 
The preferred reaction sequence which is used to prepare compounds of the 
present invention involves the cycloaddition of a disubstituted acetylene, 
in which one substituent is carboxamido or N-substituted carboxamido, to 
an appropriately substituted N-acylaminocarboxylic acid to form a 
substituted pyrrole. This addition may occur in either of two ways, 
leading to a substituted pyrrole addition product in which the carboxamido 
substituent resides on either carbon 3 or 4 of the pyrrole nucleus. 
Thus, in compounds of the present invention, the substituent at either 
position 3 or 4 of the pyrrole nucleus is --CONR.sub.5 R.sub.6 where 
R.sub.5 and R.sub.6 are independently hydrogen; alkyl of from one to six 
carbon atoms; 2-, 3-, or 4-pyridinyl; phenyl; phenyl substituted with 
fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of 
from three to eight carbon atoms and the other of the two positions is 
unsubstituted or is substituted with alkyl of from one to six carbon 
atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; or phenyl 
substituted with fluorine, chlorine, bromine, hydroxyl; trifluoromethyl; 
alkyl of from one to four carbon atoms, alkoxy of from one to four carbon 
atoms, or alkanoyloxy of from two to eight carbon atoms. 
Preferred groups for R.sub.5 and R.sub.6 are hydrogen, phenyl, or 
substituted phenyl. In a particularly preferred group of compounds within 
the present invention, R.sub.5 is hydrogen and R.sub.6 is phenyl or 
substituted phenyl. 
The compounds of this invention are prepared by the general reaction scheme 
outlined in Reaction Sequence 1 which takes advantage of the chemistry of 
mesionic compounds of the type described originally by R. Huisgen et al., 
Ang. Chem. Int. Ed., 3: 136 (1964). 
The known, or readily prepared, .alpha.-haloesters of structural formula II 
are reacted with the known 2-[1-(2-aminoalkyl)]-1,3-dioxalane, III, in the 
presence of an acid scavenger such as triethylamine to produce the 
N-alkyl-.alpha.-aminoesters, IV. The aminoesters, IV are 
##STR5## 
acylated with an acid halide and subsequently hydrolyzed in aqueous base 
solution to produce the N-acyl-N-alkyl aminoacids, V. 
The N-acyl-N-alkyl aminoacids, V, are reacted with the appropriately 
substituted carboxamido acetylenic compounds, VI, in the presence of an 
acid anhydride to produce a mixture of the isomeric substituted pyrrole 
compounds VIIa and VIIb. Depending upon the substituents present, this 
cyclo-addition reaction affords differing ratios of the two products. For 
example, in the situation where R.sub.4 is trifluoromethyl, the reaction 
yields roughly equimolar amounts of the two isomeric products. In such 
situations, the two isomeric products are separated by chromatographic 
techniques well known in the art, and subsequently further purified, if 
desired, by recrystallization. On the other hand, in the case where 
R.sub.4 is 1-methylethyl, the cyclo-addition reaction yields predominantly 
one product which can be purified by recrystallization alone. 
Hydrolysis of the acetal function of compounds VIIa and VIIb in aqueous 
acid solution affords the aldehydes VIIIa and VIIIb. The aldehydes, VIII, 
are further converted to compounds of the present invention by the 
processes depicted in Reaction Sequence 2. 
The aldehyde compounds, VIII, are reacted with the dilithium or 
lithio-sodio salt of methyl acetoacetate to produce the corresponding 
7-(substituted-pyrrolyl)-5-hydroxy-3-oxoheptanoates, IX. The heptanoates, 
IX, are dissolved in a polar solvent such as tetrahydrofuran, through 
which a small amount of air has been bubbled. A slight excess of a 
trialkylborane, such as tributylborane, is added to the mixture which is 
then cooled to a temperature of preferably between about 0.degree. C. and 
-78.degree. C. after which sodium borohydride is added. 
The mixture is stirred for about one to two hours and then oxidized by the 
addition of basic aqueous hydrogen peroxide solution. The reaction 
produces the 7-(substituted-pyrrolyl)-3,5-dihydroxyheptanoic acids, 
##STR6## 
X, in which the product contains a predominance of the desired R*,R* 
configuration at carbon atoms three and five which bear the hydroxy 
groups. 
The acids may be converted to a corresponding pharmaceutically acceptable 
salt by conventional means, if desired, or cyclized to the 
trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones, I, by dehydration 
in an inert solvent such as refluxing toluene with azeotropic removal of 
water. This cyclization step has been found to produce material containing 
from 85-90% of the desired trans-configuration of the 4-hydroxy group 
relative to the 6-(substituted-pyrrol-1-yl)alkyl group on the pyran-2-one 
lactone ring. 
The ring-opened hydroxy acids of structural formula II above are 
intermediates in the synthesis of the lactone compounds of formula I and 
may be used in their free acid form or in the form of a pharmaceutically 
acceptable metal or amine salt in the pharmaceutical method of the present 
invention. These acids react to form pharmaceutically acceptable metal and 
amine salts. The term "pharmaceutically acceptable metal salt" 
contemplates salts formed with the sodium, potassium, calcium, magnesium, 
aluminum, iron, and zinc ions. The term "pharmaceutically acceptable amine 
salt" contemplates salts with ammonia and organic nitrogenous bases strong 
enough to form salts with carboxylic acids. Bases useful for the formation 
of pharmaceutically acceptable nontoxic base addition salts of compounds 
of the present invention form a class whose limits are readily understood 
by those skilled in the art. 
The free acid form of compounds of the present invention may be regenerated 
from the salt form, if desired, by contacting the salt with a dilute 
aqueous solution of an acid such as hydrochloric acid. 
The base addition salts may differ from the free acid forms of the 
compounds of this invention in such physical characteristics as solubility 
and melting point, but are otherwise considered equivalent to the free 
acid form for the purposes of this invention. 
The compounds of the present invention may exist in solvated or unsolvated 
form. In general, the solvated forms with pharmaceutically acceptable 
solvents such as water, ethanol and the like, are equivalent to the 
unsolvated forms for the purposes of this invention. 
The compounds of this invention are useful as hypocholesterolemic or 
hypolipidemic agents by virtue of their ability to inhibit the 
biosynthesis of cholesterol through inhibition of the enzyme 
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). 
The ability of compounds of the present invention to inhibit the 
biosynthesis of cholesterol was measured by two methods. A first method 
(designated CSI screen) utilized the procedure described by R. E. Dugan et 
al., Archiv. Biochem. Biophys., (1972), 152, 21-27. In this method, the 
level of HMG-CoA enzyme activity in standard laboratory rats is increased 
by feeding the rats a chow diet containing 5% cholestyramine for four 
days, after which the rats are sacrificed. 
The rat livers are homogenized, and the incorporation of 
cholesterol-.sup.14 C-acetate into nonsaponifiable lipid by the rat liver 
homogenate is measured. The micromolar concentration of compound required 
for 50% inhibition of sterol synthesis over a one-hour period is measured, 
and expressed as an IC.sub.50 value. 
A second method (designated COR screen) employed the procedure detailed by 
T. Kita, et al., J. Clin. Invest., (1980), 66: 1094-1100. In this method, 
the amount of .sup.14 C-HMG-CoA converted to .sup.14 C-mevalonate in the 
presence of a purified enzyme preparation of HMG-CoA reductase was 
measured. The micromolar concentration of compound required for 50% 
inhibition of cholesterol synthesis was measured and recorded as an 
IC.sub.50 value. 
The activity of several representative examples of compounds in accordance 
with the present invention appears in Table 1, and is compared with that 
of the prior art compound, compactin. 
For preparing pharmaceutical compositions from the compounds of this 
invention, inert, pharmaceutically acceptable carriers can be either solid 
or liquid. Solid form preparations include powders, tablets, dispersable 
granules, capsules, cachets, and suppositories. 
A solid carrier can be one or more substances which may also act as 
diluents, flavoring agents, solubilizers, lubricants, suspending agents, 
binders, or tablet disintegrating agents; it can also be an encapsulating 
material. 
In powders, the carrier is a finely divided solid which is in a mixture 
with the finely divided active component. In tablets, the active compound 
is mixed with the carrier having the necessary binding properties in 
suitable proportions and compacted in the shape and size desired. 
For preparing suppositories, a low-melting wax such as a mixture of fatty 
acid glycerides and cocoa butter is first melted, and the active 
ingredient is dispersed therein by, for example, stirring. The molten 
homogeneous mixture is then poured into convenient sized molds and allowed 
to cool and solidify. 
Powders and tablets preferably contain between about 5 to about 70% by 
weight of the active ingredient. Suitable carriers are magnesium 
carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, 
starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a 
low-melting wax, cocoa butter, and the like. 
The term "preparation" is intended to include the formulation of the active 
compound with encapsulating material as a carrier providing a capsule in 
which the active component (with or without other carriers) is 
TABLE 1 
__________________________________________________________________________ 
##STR7## 
IC.sub.50 
(Micromoles/liter) 
Compound 
X R.sub.1 R.sub.2 R.sub.3 R.sub.4 
CSI COR 
__________________________________________________________________________ 
1 CH.sub.2 CH.sub.2 
##STR8## 
##STR9## 
##STR10## CH(CH.sub.3).sub.2 
0.035 0.050 
2 CH.sub.2 CH.sub.2 
##STR11## 
##STR12## 
##STR13## CF.sub.3 
0.40 0.40 
3 CH.sub.2 CH.sub.2 
##STR14## 
##STR15## 
##STR16## CF.sub.3 
0.018 0.020 
Compactin (Prior art) 0.026 0.028 
__________________________________________________________________________ 
surrounded by a carrier, which is thus in association with it. In a similar 
manner, cachets are also included. Tablets, powders, cachets, and capsules 
can be used as solid dosage forms suitable for oral administration. 
Liquid form preparations include solutions suitable for oral or parenteral 
administration, or suspensions and emulsions suitable for oral 
administration. Sterile water solutions of the active component or sterile 
solutions of the active component in solvents comprising water, ethanol, 
or propylene glycol may be mentioned as examples of liquid preparations 
suitable for parenteral administration. 
Sterile solutions may be prepared by dissolving the active component in the 
desired solvent system, and then passing the resulting solution through a 
membrane filter to sterilize it or, alternatively, by dissolving the 
sterile compound in a previously sterilized solvent under sterile 
conditions. 
Aqueous solutions for oral administration can be prepared by dissolving the 
active compound in water and adding suitable flavorants, coloring agents, 
stabilizers, and thickening agents as desired. Aqueous suspensions for 
oral use can be made by dispersing the finely divided active component in 
water together with a viscous material such as natural or synthetic gums, 
resins, methyl cellulose, sodium carboxymethyl cellulose, and other 
suspending agents known to the pharmaceutical formulation art. 
Preferably, the pharmaceutical preparation is in unit dosage form. In such 
form, the preparation is divided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation, the package containing discrete quantities of the 
preparation, for example, packeted tablets, capsules, and powders in vials 
or ampoules. The unit dosage form can also be a capsule, cachet, or tablet 
itself, or it can be the appropriate number of any of these packaged 
forms. 
In therapeutic use as hypolipidemic or hypocholesterolemic agents, the 
compounds utilized in the pharmaceutical method of this invention are 
administered to the patient at dosage levels of from 40 mg to 600 mg per 
day. For a normal human adult of approximately 70 kg or body weight, this 
translates to a dosage of from about 0.5 mg/kg to about 8.0 mg/kg of body 
weight per day. 
The dosages, however, may be varied depending upon the requirements of the 
patient, the severity of the condition being treated, and the compound 
being employed. Determination of optimum dosages for a particular 
situation is within the skill of the art. 
The following examples illustrate particular methods for preparing 
compounds in accordance with this invention. These examples are 
illustrative and are not to be read as limiting the scope of the invention 
as it is defined by the appended claims.

EXAMPLE 1 
Preparation of 
trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4 
-hydroxy-6-oxo2H-pyran-2-yl)ethyl]-pyrrole-3-carboxamide 
Step A: Preparation of 
.alpha.-[[2-(1,3-dioxalan-2-yl)ethyl]amino]-4-fluorobenzeneacetic acid, 
ethyl ester 
A solution of 26 g (220 mmol) of 2-[1-(2-aminoethyl)]-1,3-dioxalane in 50 
ml of acetonitrile was added at room temperature with stirring to a 
solution of 200 mmol of .alpha.-bromo-4-fluorobenzeneacetic acid, ethyl 
ester (J. W. Epstein et al., J. Med. Chem., 24: 481-490 (1981)) and 42 ml 
(300 mmol) of triethylamine in 350 ml of acetonitrile. The resulting 
mixture was stirred at room temperature overnight and then poured into 500 
ml of diethyl ether. The resulting suspension was extracted with 300 ml of 
water and then twice with 300-ml portions of 2M hydrochloric acid. The 
combined extracts were made basic with 25% aqueous sodium hydroxide 
solution and extracted twice with 500-ml portions of ethyl acetate. The 
ethyl acetate extracts were combined, washed successively with water and 
brine, and then dried over anhydrous magnesium sulfate. The drying agent 
was removed by filtration, and the residue concentrated to yield 49.5 g of 
.alpha.-[[2-(1,3-dioxalan-2-yl)ethyl]amino]-4-fluorobenzeneacetic acid, 
ethyl ester. 
The 90 MHz proton magnetic resonance spectrum of the product in 
deuterochloroform exhibited signals at 1.18 (triplet, 3H, J=7 Hz); 1.85 
(multiplet, 2H); 2.20 (broad singlet, 1H); 2.6 (multiplet, 2H); 3.85 
(multiplet, 4H); 4.1 (quartet, 2H, J=7 Hz); 4.22 (singlet, 1H); 4.83 
(triplet, 1H, J=4.5 Hz); and 6.8-7.3 (multiplet, 4H) parts per million 
downfield from tetramethylsilane. 
Step B. Preparation of 
.alpha.-[[2-(1,3-dioxolan-2-yl)ethyl]-(2-methyl-1-oxopropyl)amino]-4-fluor 
obenzeneacetic acid, ethyl ester. 
Thirty grams (100 mmol) of 
.alpha.-[[2-(1,3-dioxalan-2-yl)ethyl]amino]-4-fluorobenzeneacetic acid, 
ethyl ester from Step A were dissolved in 200 ml of dichloromethane 
together with 28.6 ml (205 mmol) of triethylamine and the resulting 
mixture was cooled to 0.degree. C. under dry nitrogen. A solution of 11 ml 
(105 mmol) of isobutyryl chloride in 50 ml of dichloromethane was slowly 
added with stirring. After addition was complete, the mixture was stirred 
for an additional 60 minutes and then poured into 100 ml of diethyl ether. 
The ether solution was washed successively with portions of water, 2M 
hydrochloric acid, sodium bicarbonate solution, and brine, and then dried 
over anhydrous magnesium sulfate. Evaporation of the solvents yielded 35 g 
of 
.alpha.-[[2-(1,3-dioxolan-2-yl)-ethyl]-(2-methyl-1-oxopropyl)amino]-4-fluo 
robenzene-acetic acid, ethyl ester. 
The 90 MHz proton magnetic resonance spectrum of a deuterochloroform 
solution of the product exhibited signals at 1.2 (multiplet, 9H); 1.7 
(multiplet, 2H); 2.85 (multiplet, 1H); 3.35 (multiplet, 2H); 3.80 
(multiplet, 4H); 4.20 (quartet, 2H, J=7 Hz); 4.60 (triplet, 1H, J=4.5 Hz); 
5.81 (singlet, 1H); and 6.8-7.3 (multiplet, 4H) parts per million 
downfield from tetramethylsilane. 
Step C. Preparation of 
.alpha.-[[2-(1,3-dioxolan-2-yl)ethyl]-(2-methyl-1-oxopropyl)amino]-4-fluor 
obenzeneacetic acid 
A solution of 35 g (95.3 mmol) of the ester from Step B and 12 g (300 mmol) 
of sodium hydroxide in 480 ml of 5:1 methanol water was heated under 
reflux and stirred for two hours. The solution was cooled to room 
temperature, concentrated, and diluted by the addition of 500 ml of water. 
The resulting solution was extracted with ether and the aqueous layer was 
acidified with ice-cold 6M hydrochloric acid and then extracted twice with 
300-ml portions of ethyl acetate. 
The combined extracts were washed with brine, dried over anhydrous 
magnesium sulfate, and evaporated to yield 30 g of crude 
.alpha.-[[2-(1,3-dioxolan-2-yl)ethyl]-(2-methyl-1-oxopropyl)amino]-4-fluor 
obenzeneacetic acid which was used without further purification. 
The 90 MHz proton magnetic resonance spectrum of a deuterochloroform 
solution of the product exhibited signals at 1.11 (doublet, 6H, J=7 Hz); 
1.4-1.9 (multiplet, 2H); 2.85 (multiplet, 1H); 3.32 (multiplet, 2H); 3.75 
(multiplet, 4H); 4.52 (triplet, 1H, J=4.5 Hz); 5.73 (singlet, 1H); and 
6.8-7.3 (multiplet, 4H) parts per million downfield from 
tetramethylsilane. 
Step D. Preparation of N,3-diphenylpropynamide 
A solution of 171 mmol of dicyclohexylcarbodiimide in 250 ml of 
dichloromethane was added dropwise over a two hour period at 0.degree. C. 
to a suspension of 171 mmol of propiolic acid, 179.6 mmol of aniline, and 
5 mmol of 4-dimethylaminopyridine in 400 ml of dichloromethane. After 
addition was complete, the mixture was stirred for an additional 30 
minutes and then diluted with diethyl ether. The resulting mixture was 
filtered through silica gel, concentrated, and the residue recrystallized 
to provide 30.5 g of N,3-diphenyl-2-propynamide, mp 
122.degree.-123.degree. C. 
Analyzed for C.sub.15 H.sub.13 NO: Calc.: C, 80.69%; H, 5.87%; N, 6.27%; 
Found: C, 80.54%; H, 5.58%; N, 6.52%. 
The infrared spectrum of a KBr pellet of the compound showed principal 
peaks at 2215, 1630, 1595,1549, 1490, 1445, 1330, 756, and 691 reciprocal 
centimeters. 
Step E. Preparation of 
1-[2-(1,3-dioxalan-2-yl)ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di 
phenyl-1H-pyrrole-3-carboxamide 
A solution of 95 g (280 mmol) of 
.alpha.-[[2-(1,3-dioxolan-2-yl)ethyl]-(2-methyl-1-oxopropyl)amino]-4-fluor 
obenzeneacetic acid, prepared as described in Step C above, and 98 g (439 
mmol) of N,2-diphenylpropenoic carboxamide, prepared as described in Step 
D above, was heated at 90.degree. C. with stirring for four hours, 
(Vigorous gas evolution occurred for two hours.) After this time, the 
mixture was cooled to room temperature and chromatographed twice on silica 
gel, eluting with 4:1 hexane:ethyl acetate to separate the product 
(R.sub.f =0.35) from the starting material (R.sub.f =0.5). 
Recrystallization of the product from isopropyl ether provided 59.5 g 
(119.3 mmol) of 
1-[2-(1,3-dioxalan-2-yl)ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di 
phenyl-1H-pyrrole-3-carboxamide, mp 159.degree.-162.degree. C. 
Analyzed for C.sub.31 H.sub.31 FN.sub.2 O.sub.3 : Calc.: C, 74.68%; H, 
6.27%; N, 5.62%; Found: C, 75.04%; H, 6.12%; N, 5.89%. 
Step F. Preparation of 
5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrro 
le-3-carboxamide 
A solution of 59 g (118.3 mmol) of 
1-[2-(1,3-dioxalan-2-yl)ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di 
phenyl-1H-pyrrole-3-carboxamide, from Step E above, and 0.4 ml of 
concentrated hydrochloric acid in 1200 ml of anhydrous ethanol was heated 
under reflux with stirring for 24 hours. After this time the mixture was 
cooled to room temperature, concentrated, and the residue taken up in 1200 
ml of 3:1 acetone:water and 5 g of p-toluenesulfonic acid was added. This 
mixture was heated under reflux with stirring for two days after which 
time the solution was cooled to room temperature and partitioned between 1 
liter of diethyl ether and 200 ml of brine solution. 
The organic phase was separated, washed successively with sodium 
bicarbonate solution and brine, dried over anhydrous magnesium sulfate and 
concentrated. The oil which resulted was dissolved in the minimum amount 
required of hot isopropyl ether. The crystals which formed upon cooling 
were collected by filtration to yiled 36.8 g of 
5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrro 
le-3-carboxamide. A further crop of 9.8 g of crystals were obtained from 
the mother liquor. 
Analyzed for C.sub.29 H.sub.27 FN.sub.2 O.sub.3 : Calc.: C, 76.63%; H, 
5.99%; N, 6.16%; Found: C, 76.48%; H, 6.20%; N, 6.14%. 
Step G. Preparation of 
2-(4-fluorophenyl)-.delta.-hydroxy-5-(1-methylethyl)-.beta.-oxo-3-phenyl-4 
-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, methyl ester 
A solution of methyl acetoacetate (26.4 ml, 243 mmol) in 250 ml of 
anhydrous tetrahydrofuran was added dropwise to a stirred suspension of 
hexane-washed sodium hydride (6.4 g, 267 mmol) in 200 ml of 
tetrahydrofuran at 0.degree. C. When gas evolution was complete, 97.2 ml 
of 2.5M n-butyl lithium was added dropwise over a period of 60 minutes. 
The resulting solution was stirred for 30 minutes at 0.degree. C. and then 
cooled to -78.degree. C. after which a solution of 36.8 g (80.9 mmol) of 
5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrro 
le-3-carboxamide, from Step F above, in 100 ml of tetrahydrofuran was added 
over a period of thirty minutes. The resulting solution was stirred for 30 
minutes at -78.degree. C. and then warmed to 0.degree. C. where it was 
held for an additional 60 minutes. 
The mixture was then acidified by the dropwise addition of 300 ml of 
ice-cold 3M hydrochloric acid, diluted with ether, washed successively 
with water and brine, dried over anhydrous magnesium sulfate, and 
concentrated. Flash chromatography of the residue yielded 37.9 g of 
2-(4-fluorophenyl)-.delta.-hydroxy-5-(1-methylethyl)-.beta.-oxo-3-phenyl-4 
-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, methyl ester. 
The 90 MHz proton magnetic resonance spectrum of the product exhibited 
signals at 1.50 (doublet, 6H, J=7 Hz); 1.8 (multiplet, 2H); 2.45 (doublet, 
2H, J=7 Hz); 2.8 (broad, 1H); 3.33 (singlet, 2H); 3.5 (multiplet, 1H); 
3.67 (singlet, 3H); 3.8-4.0 (multiplet, 2H); and 6.8-7.3 (multiplet, 14H) 
parts per million downfield from tetramethylsilane. 
Step H. Preparation of 
R*,R*-2-(4-fluorophenyl-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-pheny 
l-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid and 
trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4 
-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide 
Air (60 ml) was bubbled via a syringe through a solution of 
2-(4-fluorophenyl)-.delta.-hydroxy-5-(1-methylethyl)-.beta.-oxo-3-phenyl-4 
-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, methyl ester (48 g, 
84.1 mmol) and 92.5 ml of 1M tributylborane in 100 ml of anhydrous 
tetrahydrofuran. The mixture was stirred overnight at room temperature and 
then cooled to -78.degree. C. Sodium borohydride (3.85 g, 101.8 mmol) was 
added to the cooled mixture in one portion. The mixture was allowed to 
warm slowly to 0.degree. C. over a period of three hours, during which 
there was vigorous gas evolution. 
The dry ice-acetone bath applied to the reaction vessel was replaced by an 
ice bath and 18.3 ml of glacial acetic acid were added dropwise, followed 
by 204 ml of 3M aqueous sodium hydroxide solution and 30.5 ml of 30% 
aqueous hydrogen peroxide solution. 
The mixture was vigorously stirred while being allowed to warm to room 
temperature overnight. The mixture was then partitioned between diethyl 
ether and water and the aqueous layer was separated, acidified, and 
extracted with ethyl acetate. 
The ethyl acetate extract was washed with brine, dried, and evaporated to 
yield crude 
R*,R*-2-(4-fluorophenyl-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-pheny 
l-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid which was used 
without further purification. 
The crude acid was taken up in toluene and lactonized by heating under 
reflux for six hours. This mixture was chromatographed to provide 30 g of 
trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4 
-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide as a foamy 
solid, mp 90.degree.-97.degree. C. 
Analyzed for C.sub.33 H.sub.33 FN.sub.2 O.sub.4 : Calc.: C, 73.31%; H, 
6.15%; N, 5.18%; Found: C, 73.46%; H, 6.31%; N, 5.28%. 
This material was found by HPLC analysis to comprise a 9:1 molar ratio of 
the cis- and trans-isomeric forms of the product. Recrystallization from 
toluene-ethyl acetate yield the essentially pure trans-form, mp 
148.degree.-149.degree. C. 
EXAMPLE 2 
Preparation of 
R*,R*-2-(4-fluoro-phenyl-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-phen 
yl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, sodium salt 
A mixture of 
trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4 
-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (10 g, 18.5 
mmol) and 0.74 g (18.5 mmol) of sodium hydroxide in 90 ml of a 1:2 mixture 
of tetrahydrofuran-water was cooled to 0.degree. C. This mixture was 
allowed to warm slowly to 25.degree. C., after which time it was 
concentrated and the residual solid dried under vacuum. 
The infrared spectrum of the product exhibited principal absorption peaks 
at 3400, 1651, 1598, 1565, 1511, 1438, 1412, 1316, 1224, 1159, 844, 754, 
and 702 reciprocal centimeters. 
The 90 MHz proton magnetic resonance spectrum of a hexadeutero 
dimethylsulfoxide solution of the product exhibited signals at 1.34 
(doublet, J=7 Hz, 6H); 1.5 (multiplet, 4H); 1.80 (doublet of doublets, 
J=15, 8 Hz, 1H); 1.99 (doublet of doublets, J=15, 4 Hz, 1H); 3-4 
(multiplet, 8H); 6.9-7.3 (multiplet, 12H); 7.50 (doublet, J=8 Hz, 2H); and 
9.85 (singlet, 1H) parts per million downfield from tetramethylsilane. 
EXAMPLES 3 AND 4 
Preparation of 
trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H- 
pyran-2-yl)ethyl]-5-(trifluoromethyl)-pyrrole-3-carboxamide and 
trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H- 
pyran-2-yl)ethyl]-2-(trifluoromethyl)pyrrole-3-carboxamide 
Step A. Preparation of 
.alpha.-[[2-(1,3-dioxalan-2-yl)ethyl]amino]-4-fluorobenzeneacetic acid. 
.alpha.-[[2-(1,3-Dioxolan-2-yl)ethyl]amino]-4-fluorobenzeneacetic acid, 
ethyl ester (36.5 g, 122.8 mmol, prepared as described above in Example 1, 
Step A) was dissolved in 1500 ml of a 5:1 mixture of methanol-water 
together with 7.6 g of sodium hydroxide. This mixture was heated under 
reflux for a period of two and one-half hours after which time the 
solvents were removed under vacuum. 
The solid residue was taken up in 325 ml of water and a mixture of 14 ml of 
glacial acetic in 28 ml of water was added with stirring. After stirring 
for a time, an additional 3 ml of glacial acetic acid were added and the 
mixture was chilled for 75 minutes. The solids were collected by 
filtration, washed with water and then ethyl acetate and dried to yield 
.alpha.-[[2-(1,3-dioxalan-2-yl)ethyl]amino]-4-fluorobenzeneacetic acid, mp 
218.degree.-220.degree. C. 
Step B. Preparation of a mixture of 
5-(4-fluorophenyl)-1-(3-oxopropyl)-N,4-diphenyl-2-(trifluoromethyl)-1H-pyr 
role-3-carboxamide and 
2-(4-fluorophenyl)-1-(3-oxopropyl)-N,4-diphenyl-5-(trifluoromethyl)-1H-pyr 
role-3-carboxamide 
.alpha.-[[2-(1,3-Dioxalan-2-yl)ethyl]amino]-4-fluorobenzeneacetic acid 
(6.06 g, 22.5 mmol) was dissolved in 45 ml of trifluoroacetic anhydride 
and 7.47 g (33.8 mmol) of N,3-diphenyl-2-propynamide (prepared as 
described above in Example 1, Step D) was added. The resulting mixture was 
heated under reflux for a period of five and one-half hours. The mixture 
was then cooled, and 1.74 ml of trifluoroacetic acid were added and the 
mixture was stirred overnight. 
The excess trifluoroacetic anhydride was removed under vacuum, and water 
was added, followed by sufficient acetone to give a homogenous solution. 
This solution was stirred at room temperature for three hours. The mixture 
was seeded with N,3-diphenyl-2-propynamide, and a precipitate formed. 
After three hours, this precipitate was removed by filtration. 
The acetone was removed from the filtrate under vacuum and the solid 
residue was taken up in ether, washed successively with two portions of 
water, two portions of sodium bicarbonate solution, and two portions of 
brine and dried over anhydrous magnesium sulfate. The ether was removed 
under vacuum to yield a crude mixture of the two title compounds. 
This mixture was separated by column chromatography on 600 g of silica gel, 
eluting with a 4:1 mixture of hexane-ethyl acetate. 
The first fraction eluted was 
5-(4-fluorophenyl)-1-(3-oxopropyl)-N,4-diphenyl-2-(trifluoromethyl)-1H-pyr 
role-3-carboxamide. 
The 90 MHz proton magnetic resonance spectrum of a deuterochloroform 
solution of this material exhibited signals at 2.73 (triplet, J=7 Hz, 2H); 
4.21 (triplet, J=7 Hz, 2H); 6.7-7.3 (multiplet, 5H); 7.40 (singlet, 5H), 
and 9.43 (singlet, 1H) parts per million downfield from tetramethylsilane. 
The second compound eluted from the column was 
2-(4-fluorophenyl)-1-(3-oxopropyl)-N,4-diphenyl-5-(trifluoromethyl)-1H-pyr 
role-3-carboxamide. 
The 90 MHz proton magnetic resonance spectrum of a deuterochloroform 
solution of this material exhibited signals at 2.67 (triplet, J=7 Hz, 2H); 
4.25 (triplet, J=7 Hz, 2H); 7.0-7.3 (multiplet, 14H); and 9.43 (singlet, 
1H) parts per million downfield from tetramethylsilane. 
Step C. Preparation of 
trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H- 
pyran-2-yl)ethyl]-5-(trifluoromethyl)-pyrrole-3-carboxamide and 
trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H- 
pyran-2-yl)ethyl]-2-(trifluoromethyl)-pyrrole-3-carboxamide 
Employing the general methods detailed in Example 1, Steps G and H, the 
title compounds were prepared from the aldehyde compounds of this example, 
Step B. 
The elemental analyses of the two title compounds were: 
For 
trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H- 
pyran-2-yl)ethyl]-2-(trifluoromethyl)-pyrrole-3-carboxamide: 
Analyzed for C.sub.31 H.sub.26 N.sub.2 O.sub.4 : Calc.: C, 65.72%; H, 
4.63%; N, 4.94%; Found: C, 65.82%; H, 4.91%; N, 4.69%. 
The 
trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H- 
pyran-2-yl)ethyl]-5-(trifluoromethyl)-pyrrole-3-carboxamide was found, upon 
recrystallization from toluene to contain 0.25 mols of toluene as solvent 
of crystallization, mp 106.degree.-111.degree. C. 
Analyzed for C.sub.31 H.sub.26 N.sub.2 O.sub.4.0.25C.sub.7 H.sub.8 : Calc.: 
C, 66.72%; H, 4.79%; N, 4.72%; Found: C, 66.81%; H, 4.86%; N, 4.60%.