JPS6178787A - Cholesterol-synthetic trans-6-(2- (substituted pyrrole-1-yl)alkyl)-pyran-2-one inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a blood cholesterol lowering agent (hypo-ch
olesterolemic agent) and hypolipidemic agent
) and relates to commercially available compounds and pharmaceutical compositions. More specifically, the present invention provides the enzyme 3-hydro d
Certain trans-6-C2-(ffi-converted picopyrrol-yl)alkylcupilan-2-ones, which are potent inhibitors of 3-methylglutaryleucoenzyme A reductase (aMG-coA reductase), and their derivatives The present invention relates to ring-opening acids containing such compounds, pharmaceutical compositions containing such compounds, and methods of reducing serum cholesterol levels using such pharmaceutical compositions.

High levels of blood cholesterol and blood thimble are conditions in the early stages of arteriosclerosis.

It is well known that inhibitors of HMG-OoA ductase are effective in lowering plasma cholesterol levels in humans, particularly low-density riboprotein member cholesterol (LDL).
, L. Goldstein: lN e w -1 and
Jour, al of Medicinal (19
81) 305, A 9. See pages 515-517]. It is now believed that lowering LDL-0 levels can prevent coronary heart disease ([Journal of the American
an Medical As5ocationJ (
1984) 25LA3, pp. 351-374].

Furthermore, it is known that certain derivatives of mevalonic acid (3,5-dihydroxy-6-methylpentanoic acid) and the corresponding ring-closed lactone form of 7paronolactone inhibit cholesterol biosynthesis (F, M, Singer et al.: 1Proc, soc.

ff1xper, B1oyu, Mad, Ko (1959)
102, 270 Sada and F. H. Fulcher: “
Arch, Biochem, B10phys, J(19
71) 146.422 Sada].

U.S. Patent No. 3,983,140, No. 4.049.49
No. 5 and No. 4.137.322 Mei 711fI4,
Discloses the fermentative production of a natural product called compactin, which has an inhibitory effect on cholesterol biosynthesis.

Compactin has been shown to have a complex structure that includes a mevalonolactone moiety [Brown et al.
“J, Ohem, l3oc, Perkin IJ
(1976) p. 1165].

US Pat. No. 4,255,444 discloses several synthetic derivatives of mevalonolactone that have antilipidemic activity.

U.S. Patent Nos. 4.19F3,425 and 4,262
, No. 0.13 discloses aralkyl derivatives of mevalonolactone that are useful in the treatment of hyperlipidemia.

U.S. Patent No. 4,375,475, 4(8)-
Discloses certain substituted 4-hydroxytetrahydrobyran-2-ones that are inhibitors of cholesterol biosynthesis in their trans stereoisomeric form.

According to the present invention, NF inhibiting the enzyme 5-hydroxy-6-methylgeltaryleucoenzyme (i(MG-00A reductase))
Certain trans-6-C2-(ifvirol-1-yl)alkyllevvilan-2-ones and the corresponding ring-opened hybyroxy acids derived therefrom are provided, which are potent inhibitors of cholesterol biosynthesis because of their aerobic properties. Ru.

Sometimes, even in its broadest compound context, the invention provides compounds of structural formula (1).

In the above formula, ・X is 1OH, etc. -cH2cH2- 4 or -aH (aH5-OH2-. phenyl substituted by alkyl of 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkanoyloxy of 2 to 8 carbon atoms, 2-, 3
- or 4-pyridinyl, 2-, 3- or 4-pyridinyl-N-O, where R5 is alkyl of 1 to 4 carbons; ), , R2 and R
3 is independently hydrogen, chlorine, bromine, cyano, trifluoromethyl, phenyl, alkyl of 1 to 4 carbon atoms, 2
Carbalkoxy of ~8 carbon atoms, -aH2oR6
(wherein R6 is hydrogen or alkanoyl of 1 to 6 carbon atoms), -(!H20cONHR7 (wherein R7
is alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted with chlorine, bromine or alkyl of 1 to 4 carbon atoms). a ring to which R2 and R3 are represented by the carbon atom to which they are attached (wherein n is 3 or 4), where RQ is hydrogen, alkyl of 1 to 6 carbon atoms,
phenyl or benzyl) or in which R9 and Rlo are hydrogen, alkyl of 1 to 4 carbon atoms or benzyl.

R4 is alkyl, cyclopropyl, cyclobutyl or trifluoromethyl of 1 to 4 carbon:g atoms.

In addition, the corresponding dihydroquinic acid anastomosis of the formula (LD (in the formula, X s R1 , "2 ' R3 and R4 are the aforementioned abbreviations) corresponding to the open ring form of the lactone ring of the compound of formula (1) and its Pharmaceutically acceptable salts, in which all of the compounds are in the trans racemic form of the tetrahydropyran moiety, are also included within the scope of this invention.

In another aspect of the present invention, firstly, a 4-[(pyrrol-1-yl)-alkyl] aldehyde of Takeguchi (wherein X, Rj, R2, R5 and R4 are as defined above); The compound is reacted with an alkali metal salt of the dianion of methyl acetohepatate to form a compound of structural formula (IV), where X % R1, R2, R5 and R4 are as previously described, followed by @(
b) Compound v11m is reduced with trialkylborane and sodium borohydride and (c) oxidized with alkaline hydrogen peroxide to form the acid compound of Nibacterium and finally Kfd) in an inert bath if necessary. The acid compound of formula (■) can be cyclized to obtain the lactone compound of formula (1) by heating the compound of formula (■), or alternatively, if necessary, the acid compound of formula A method is provided for preparing a compound of formula (I) as described above by converting it into a salt.

In another aspect, the present invention provides a blood lipid-lowering or blood cholesterol-lowering agent comprising a blood lipid-lowering or blood cholesterol-lowering effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition useful as a pharmaceutical composition is provided.

In another aspect, the invention provides a method of inhibiting cholesterol biosynthesis in a patient in need of treatment by administering the pharmaceutical composition of the invention as described above.

In terms of a first preferred subcompound, the invention provides:
X is -C! Compounds of formula (1) are provided, in which H20H2-, R1 is as previously described, R2 and R3 are independently hydrogen, chlorine or bromine, and R4 is as previously described.

In terms of a second preferred subcompound, the invention provides:
X is -og2ci-+2-, R1 is phenyl or fluorine, chlorine, hydroxy, trifluoromethyl, 1-
is phenyl substituted with alkyl of 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkanoyloxy of 2 to 8 carbon atoms or R1 is 2-26-
or 4-pyridinyl, 2-13- or 4-pyridinyl-N-oxide or (wherein R5 is alkyl of 1 to 4 carbon atoms and Ha4- is chloride, bromide or iodide) Certain aforementioned compounds of formula (1) are provided. In this aspect of the invention R2> and R3 are preferably independently hydrogen, chlorine or bromine and R4 is alkyl of 1 to 4 carbon atoms or trifluoromethyl.

In terms of a third preferred subcompound, the invention provides:
X is -oa2oa2-, Rj is phenyl or fluorine, chlorine, hydroxy, trifluoromethyl% 1-4
phenyl substituted by alkoxy of 5 carbon atoms or alkanoyloxy of 2 to 8 carbon atoms]
, R2 and R5 are independently hydrogen, chlorine or bromine) and R4 is isopropyl or trifluoromethyl.

In terms of a fourth preferred subcompound, the invention provides:
X is 10H20H2-) and R1 is phenyl or fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4I@ carbon atoms or alkanoyl of 2 to 8 carbon atoms 7enyl substituted by oxy or R1 is 1-naphthyl,
or 2-su7tyl, the compound of formula (1) described above is provided. In this preferred aspect of the invention, R2 and R5 are independently hydrogen, chlorine, bromine, cyanide, trifluoromethyl, phenyl, alkyl of 1 to 4 carbon atoms, 2 to 8 carbon atoms. Carbalkoxy% -0
H20R6 (wherein R6 is hydrogen or alkanoyl of 1 to 6 carbon atoms), -0H200ONKita7 (wherein R7 is alkyl of 1 to 6 carbon atoms, phenyl or chlorine, bromine or 1 to 4 carbon atoms) phenyl substituted with an alkyl carbon atom). In this aspect of the invention, R2 and R5 also represent a ring in which they are denoted by a bond in which n is 3 or 4 and denoted by K, in which R8 is hydrogen, 1 to 4 carbon atoms. atomic alkyl, phenyl or benzyl) thereby forming a ring denoted by where R9 and R10 are hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl. In this aspect of the invention R4 is preferably alkyl of 1 to 4 carbon atoms, cyclopropyl, cyclobutyl or trifluoromethyl.

In terms of a fifth preferred subcompound, the invention provides:
X is -0H20H2- and R1 is phenyl or fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or carbon of 2 to 8 carbon atoms There is provided a compound of formula (I) as defined above which is phenyl substituted by an atom alkanoyloxy.

R2 and R3 are preferably independently hydrogen, chlorine, bromine,
phenyl or carbalkoxy of 2 to 8 carbon atoms. In this aspect of the invention, R2 and R3
also, when taken together with the carbon atoms to which they are attached, a ring denoted by (wherein R8 is hydrogen or alkyl of 1 to 4111i1 carbon atoms) or (wherein R8 is hydrogen or alkyl of 1 to 4111i1 carbon atoms) R
9 and R10 can form a ring denoted by hydrogen or alkyl of 1 to 4 carbon atoms. In this aspect of the invention, R4 is preferably
4 carbons; g atom alkyl or trifluoromethyl.

In terms of a sixth preferred subcompound, the invention provides:
X is 10H20H2-, and R1 is phenyl or fluoro, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or
A compound of formula (1) as described above is provided which is phenyl substituted with alkanoyloxy of 8 carbon atoms. R2
and R5 are preferably independently carbalkoxy of 2 to 8 carbon atoms or when taken together with the carbon atom to which they are attached, where R8 is hydrogen or 1 to 8 carbon atoms; alkyl of 4 carbon atoms).

In this aspect of the invention R4 is preferably inpropyl or trifluoromethyl.

The term "alkyl" as used throughout this specification and claims refers to a branched or unbranched saturated hydrocarbon group derived by the removal of a single hydrogen atom from an alkane. .

The term "alkoxy" refers to an alkyl group, as described above, attached to the remainder of the parent molecule by an oxygen atom.

The term "alkanoyloxy" refers to an alkyl group, as described above, attached to the remainder of the parent molecule by a carbonyl group and then an oxygen atom.

The term "6carbalkoxy" refers to an alkyl group, as described above, attached to the remainder of the parent molecule by an oxygen atom and then a carbonyl group.

The term "1 norbornenyl" refers to a group derived by removal of a hydrogen atom (other than at the bridgehead carbon atom) from bicyclo(2,2,0hept-2-ene).

Specific examples of compounds contemplated as falling within the scope of this invention include the following compounds.

trans-6-C2-[2-7 chlorobutyl-5-(4-
fluorophenyl)-1H-virol-1-yl]ethyl]tetrahydro-4-hydroxy7-2H-bilan-2
-one, trans-6-C2-C2-cyclohexyl-5-(4
-fluorophenyl)-1H-birow#-1-yl]ethyl]tetrahydro-4-hydroquik-bilan-2-one, tra/suutet2hydro4-hydroxy-6-[:2
-(2-nonal-5-]dinyl~IH-virol-1-
yl)ethylcou2H-bilan-2-one1 trans-6-C2-C2-<4-chlorophenyl)-
5-methy/I/-I H-pillow/L/-1-yl]
ethyl]tetrahydro-4-hydroxy-2H-bilan-2-one, trans-tetrahydro-4-hydroxy~6-[2-
C2-(4-methoxyphenyl)-5-methyl-1■-
Virol-1-yl]ethyl]-2H-pyran-2-one, trans-6-C2-C2-(C1,1'-hy()dinyl]-4-yl)-5-methyl-1H-virol- 1-
yl)ethylcotetrahydro-4-hydroxy-2H-
Bilan-2-one, trans-tetrahydro-4-hydroxy-6-C2-
C2-Methyl-5-[3-(trifluoromethyl)phenyl3-1H-virol-1-yl]ethyl]-2H-
Bi'lan-2-one, trans-6-(2-C2-(2
,5-dimethylphenyl)-s-(i-methylethyl)
-1H-virol-1-yl]ethyl'Jfdoorhydro-4-hydroxy-2day-bilan-2-one, trans-6-C2-C2-(2,6-cymethoxyphenyl)-
5-(1-methylethyl)-1H-virol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-bilan-2-one, trans-tetrahydro-4-hydroxy-6-C2-C2-methyl-5- (2-naphthalenyl)-1H-virol-1-yl]ethyl]-2H-vilan-2-one, trans-6-[2-(2-(ncrohequinyl)-5-toIJfluoromethyl-1H-pyrrole-1 -yl)ethylcotetrahydro-4-hydroxy-2H-bilan-2
-one, trans-6-(2-[2-(4-fluorophenyl)
-3,4-dimethyl-5-(1-methylethyl)-1
H-Virrol-1-y, L]ethyl]tetrahydro-4
-Hydroxy-2H-bilan-2-one, trans-2-(4-fluorophenyl)-5-(1-
methylethyl)-1-C2-(tetrahydro-4-hydroxy/-6-oquino2H-hyran-2-yl)ethyl]-IH-virol-6,5-dicarboxylic acid, trans-2-(4-fluorophenyl) ) --N5. N
3. N4. N4-Tetramethyl-5-(1-methylethyl)-1-[2-(tetrahydro-4-hydroxy-6
-oxo-2H-kl”ran-2-yl)ethylk1
H-pyrrole-6,4-dicarbonitrile, trans-6-C2-C3,4-dichloro-2-(3-
fluorophenyl) -5-(1-methylethyl)-1
H-Virrol-1-yl]ethyl]tetrahydro-4-
Hydroxy-2H-bilan-2-one, trans-2-(4-fluorophenyl)-5-(1-
methylethyl)-1-[:2-(tetrahydro)-4-
Hydroxy-6-oquino2H-pyran-2-yl)ethyl-1H-virol-3,4-dicarbonitrile, trans-6-C2-C3,4-diacetyl-2-(4
-fluorophenyl)-5-(1-methylethyl)-i
H-Virrol-i-yl]ethyl]tetrahydro 4-
Hydroxy-2H-bilan-2-one, tra/sudiethyl/l/2-(4-fluorophenyl)-1-[2-(tetrahydro)-4-hydroxy-6
-Oquino2H-bilan-2-yl)ethyl]-5-(
trifluoromethyl)-1H-virol-3,4-dicarboxineto, trans-bis(1-methylethyl)
2-(it-fluorophenyl)-5-(1-methylethyl)-1-C2-(tetrahydrofa)-4-hydroxy-6-oxo-2H-bilan-2-yl)ethyl)-
1H-virol-5,a-di:hrubo〆xylate, trans-6-C2-C3,4-diethyl-2-(4-
Fluorophenyl)-5-(1-methylethyl)-1H
-Virrol-1-yl]ethyl]tet2hydro4-hydroxy-2H-vilan-2-one, trans-6-(2-(:2-(4-fluorophenyl)-3,4-bis(hydroxymethyl) )-5-(1-
methylethyl)-1H-virol-1-yl]ether]
Tetrahydro 4-hydroxy-2H-bilan-2-one, trans-1-methylethyl 4-chloro-2-(4-fluorophenyl)'-5-(1-methylethyl)-1-
(2-(tetrahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1m-pyrrole-5-fj ruboxylate, trans-6-C2-C4-<4-fluorophenyl)
-6-(1-methylethyl)-1H-furoC5,4-c
[Virrol-5(3H)-yl]ethyl]tetrahydro-4-hydroxy-2H-vilan-2-one, trans-6-[2-(2-(4-7fluorophenyl))
-5-(1-methylethyl)-3,4-bisCCI:
(phenylamino)carbonyl[oxy]methyl]-1
H-pyrrol-1-yl]ethyl]tetrahydro-4-
Hydroxy-2H-bilano-2-one, trans-1-methylethyl 4-chloro-5-(4-fluorophenyl)-2-(1-1thylethyl)-1-(
2-(tetrahydro)-4-hydroxy-6-oxo-
2H-pyran-2-yl)ethyl)-1H-pyrrole-
6-carboxylate, trans-ethyl 5-(4-7/L/olophenyl)-
1-1:2-(tetrahydro)-4-hydroxy-6-
oxo-2H-pyran-2-yl)ethyl)-2-(trifluoromethyl)-ia-pyrrole-5-carboxylate, trans-ethyl 5-(4-fluoro7enyl-2-
(1-Methylethyl)-4-;yUNIR-1-(2-(
Tetrahydro-4-hydroxy-6-4xo-2a-pyran-2-yl)ethyl]-IH-virol-3-carboxylate, trans-6-(2-(1-(4-fluorophenyl)-4, 5,6,7-tetrahydro-5
-Methyl-2H-(findol-2-yl]ethyl]
Tet2hydro-4-hydroxy-2H-pyran-2-one, trans-4-(4-fluorophenyl)-2-methyl-6-(1-methylethyl)-5-[2-(tetrahydro-4- Hydroxy-6-oxo-2H-pyran-2-
yl)ethyl]pyrroloC3,4-c]bi0-ru 1
．． ! l (2H,5H)-dione, trans-6-(2
-[:1=(4-fluoropheny/L/)-5,s-dihydro-6-[1-methylethyl)pyrrolo(3,4-c
[Virrol-2(4H)-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, trans-6-(2-[:1-'(4-fluorophenyl)-5,5-dihydro- 5-Methyl-3-(1-methylethyl)pyrrolo[3,4-c,]]pyrrole-24
H) -yl]ethyl]tetrahydro4-hydroxy-2H-pyran-2-one, trans-6-C2-C5
-chloro-5-(4-fluorophenyl)-2-(1-
methylethyl)-4-722-1H-pyrrole-1-
yl]ethyl]tetrahuman c1-4-hydroxy-2H
-pyran-2-one, trans-6-(2-(2-(4-fluorophenyl)
-5-(1-methylethyl) -3,4-diphenyl-
11i-Virrol-1-yl]ethyl]tetrahydro-
4-Hydroxy-2H-pyran-2-one.

Particularly preferred compounds according to the invention are as indicated by the arrows.

trans-6-C2-(3,4-dichloro-2-(4-
Fluorophenyl)-5-(1-methylethyl)-1a
-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-bin-2,-one, trans-6-(2-C3,4-dibromo-2-(4-
Fluorophenyl)-5-(1-methylethyl)-11
1-Virrol-1-yl]ethyl]tetrahydro-4-
Hydroxy-2H-bilan-2-one, trans-6-(:2-[:2-(4-fluoro7enyl)-5-(t!j7
Co methyl; +-IH-virol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-bilane-
2-one, trans-dimethe/I/2-(4-7fluorophenyl)-5-(1-methylethyl)-1-C2-(
Tetrahydro-4-hydroxy-6-oxo-2H-bilan-2-yl)ethyl]-1H-pyrrole-6,4-
Dicarboxylate, trans-6-[2-[2-(4
-Fluorophenyl-5-methyl-1H-virol-
1-yl]ethyl]tetrahydro-4-hydroxy7-2
H-bilan-2-one, trans-6-(2-(2-(4-fluorophenyl)
-5-(1-methylethyl)-1+(-virol-i-
yl]ethyl]tetrahydro 4-hydroxy-2H-
Bilan-2-one, trans-6-C2-C2-cyclopropyl-5-(4-fluorophenyl)-1H-virol-1-yl]ethyl]tetonhydro 4-hydroxy-2H-bilan-2-one, trans -6-C2-C2-C1,1-:)methylethyl)-5-(4-fluorophenyl-IH-hyro-1-yl]ethyl]tetrahydro-4-hydroxy-
2H-bilan-2-one, trans-tetrahydro-4
-Hydroxy-6-C2-C2-(2-methoxyphenyl)-5-trifluoromethyl# -I H-biC2-/
1z-1-yl]ethyl)-2H-2-one, trans-tetrahydro-4-hydroxy-6-C2-
C2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-virol-1-yl]ethyl]-2H-
Vilan-2-one, trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-virol-1-yl]ethyl]-2H-
Viran-2-one, trans-6-(2-(2-bicycloC2,2,1]heb-5-en-2-yl-5-methy/I/-IH-virol-1-1)ethyl]tetrahydro 4-Hydroxy-2H-bilan-2-one, trans-6-(2-(
2-(4-Fluorophenyl)-s-(i~methylphenyl)-1H-virol-1-yl]furovir]tetrahydro-4-hydroxy-2H-bilan-2-.

Compounds of the invention where R2 and R3 are hydrogen are prepared by the methods outlined in Reaction Sequence 1 or Reaction Sequence 2. As shown in reaction sequence 1, thiazolium salt (■)
and a suitably substituted vinyl ketone (
Vll) to produce diketone ■ (
Ang, Chem, Int, E! dJ Volume 15 639-7
12 (1976)].

Reaction of the diketone (1) with an omega-aminoalkyl nitrile (a compound with the Roman numeral (1), where X is methylene, ethylene or 1-methylethylene) in acetic acid produces a dimethyl pyrrol nitrile.

Treatment of virol nitrile with diisobutylaluminum hydride in an inert solvent such as dichloromethane produces the corresponding virol aldehyde (X[).

Reaction of pyrrolaldehyde (Xff) with the dilithium or lithium sodium salt of methyl acetoacetate produces 7-(substituted pyrrolyl)-5-hydroxy/-3-oquinohepkunoate (Xlll). Heptanoate (Xlff) is dissolved in a polar solvent such as tetrahtomifuran, through which a small amount of air is introduced. A slight excess of a trialkylporane, such as tributylborane, is added to the mixture, which is then preferably heated between about 0°C and -78°C.
Cool to a temperature of °C, then add sodium borohydride.

After stirring the mixture for about 1-2 hours, the mixture is acidified with basic hydrogen peroxide. This reaction results in 7-(Okimata pyrrolyl)-3,5-dihydroxyheptane a(xrv>
generate. In this case, the product has the desired N,R* configuration primarily at the 3- and 5-position carbon atoms to which the hydroxy group is attached.

The acid can be converted to the corresponding pharmaceutically acceptable salt by conventional methods, or alternatively it can be dissolved in an inert agent such as refluxing toluene with azeotropic removal of water. 6-(2-(
Substituted virol-1-yl)alkyl]ben-2-4
(1). This cyclization reaction can produce a vlJ substance enriched with 85-90% of the desired active trans configuration of the 4-hydroxy group with respect to the 6-(substituted pyrrolyl)alkyl group on the bilan-2-one lactone ring. understood.

Reaction Sequence 1 cVD (v OH The diketone diagram can be prepared by reacting the known al7-arhaloketone (XV) with the known beta-ketoester (XVI), followed by hydrolysis and decarboxylation in conventional manner, as shown in FIG. The diketone (1) is reacted with ammonium acetate in acetic acid to form the cyclized 2,5-disubstituted virol (X).

If R1 and/or R4 are sterically bulky groups, Ike's preferred alternative to this step is to convert the diketone diagram to an omega-hydroxyalkylamine [compound (■), or methylene, ethylene, 1-methyl ethylene] to produce N-(omega-hydroxyalkyl)-2,5-disubstituted virol (XIX).

2,5-Dicaptomethylated pearl (XW) is a compound of sodium hydride, 1,1-dimethoxy-omega-bromoalkane [compound* (XXI), where X is methylene, ethylene, 1-methylethylene or vinyl]. ], then omega-(substituted virol) aldehyde (XX) by successive reactions with acid
Convert to 7 /L/ 7'human' (XX) is
Next, the formula (1
) is used in the production of compounds.

2.5-Disubstituted pyrrole (XVII) can be prepared by reaction with acrylonitrile (if X is ethylene) or (if X is other than ethylene) by formula CXD
By starting with the compound of C), the corresponding (2,5-di-alylrunnitrile) can be converted to [1]. In this latter case, the formula (XI
The hydroxy 1° functional group of the compound of formula
Produce a nitrile of Xl[). The compound of formula (XXI[) is then used for the preparation of the compound of the invention 2fJ) by the method described in the reaction sequence 1iC7K described above.

Reaction Sequence 2 The starting materials and intermediates conveniently used in Reaction Sequences 1 and 2 above can be prepared by the general method outlined in Reaction Sequence 6. For example, vinylone ketone (■) as shown in Reaction/[#3 can be produced by either of the two exemplified methods. In one method, a known acid chloride (XXm) is dissolved in dichloromethane in the presence of anhydrous aluminum chloride.
It reacts with trimethylsilylethene (XXIV).

In another method of producing vinyl ketones (■), which is preferred when R+ is an aromatic substituent such as phenyl or substituted phenyl, known methylarylketones (XXV) are converted into (dimethylamine ethyl) Converted to an aryl ketone (XXVT) and then to a vinyl lactone (■) by deamination.

Reaction Sequence 6 ArOCH-OH2 (I) The compound of the present invention of formula (1) in which the groups R2 and R3 are groups other than hydrogen or halokane can be synthesized by the method detailed in Reaction No. 1, Sequences 4 to 8. I can do it.

By applying the method detailed in Reaction Pressure 4,
Compounds of the invention in which both R2 and R3 are halogen can be prepared by halogenating the un-R-substituted compound with N-halosuccinimide in a step process that includes prior protection of the 4-hydroxy group of the lactone ring. can be manufactured.

Thus, for example, the 2,5-disubstituted pyrrol-1-yl compound (XXW) is converted into the tertiary butyldimethylsilyl ether (XXVl[)K, which is compatible with ore. The protected compound is then chlorinated with N-chlorosuccinimide in a polar bath such as dimethylformamide to form the silylated 3,4-dichloro compound CXXK). The protected silyl ether group is then removed by reaction with a buffered fluoride reagent such as tetrabutylammonium fluoride in a mixed l1rl:acid/tetrahuman C27 run solvent system and removed by filtration to form the dichloro compound (XX
X) is generated.

Reaction order 4 Reaction order 5 (Xl) Dimethylformamide (XX
XI) Instead of K in this way, as detailed in Reaction Sequence 5, (2,5-:)1-hpyrrole-1-ylnoalkyl nitrile ■ [see Reaction Sequence 1] is reacted with N in dimethylformamide. -2,5-disubstituted-3, halogenated by using halosuccinimide
4-Dihalovirol (XXN) is obtained. [Eiguchi et al.:
“J, Het, chem, J Volume 19, 977 Sada (1
982) 30 These compounds can then be converted to the compounds of the invention by the method detailed in Reaction Sequence 1.

A third method is described by R. Huisgen et al. "Ang, Ghem.

Engineering, Fl! d, J3, p. 166 (1964).
using the chemical advantages of onic compounds). In this operating method detailed in Reaction Sequence 6, N-
An alkyl-N-acylamino acid is treated with #R8 hydrate and a substituted acetylenic compound to produce pyrrole. For example, reaction sequence 6 is alpha/S loester (XXX
XII) with 2-(1-(2-aminoethyl, 1)-1,3-dioxalan in triethylamine to give N-alkyl-alpha-amino esters (XXXI)
Show how to get . Amine esters (XXXI[[) are acylated with acid chloride and then hydrolyzed in base to form N-acyl-N-alkyl amino acids
v> is generated.

This latter compound is converted into the desired substituted acetylenic compound CX
XXV) to form a substituted virol compound <XXX■
Generate ノ. Acidic hydrolysis of compound * CXXXVI) gives the analogous aldehyde compound (XXXV[) of compound CM) of reaction sequence 1. Compounds of formula (XXxvM) are conveniently used in sequential steps in the method detailed in Reaction Sequence 1 to produce compounds of the invention.

Suitable substituents for the acetylenic compound in this method of producing compounds of the invention include carbalkoxy, phenyl, alkanoyl, alkyl and cyano groups. Disubstituted acetylene compound and N
The reaction with -acyl-N-alkyl amino acids <xxxrv> generally proceeds smoothly. For example, dicarpomethoxyacetylene reacts smoothly at 25°C. However, if only one active group is attached to acetylene, the reaction mixture generally has to be heated to 70-110° C. in order to obtain high yields of virol compounds.

Reaction Sequence 6 (XXXVt) When the groups R2 and Et3 are carbomethoxy, various other pyrroles can be derived from the compound of general formula (XXXVI). Some of these transformations are detailed in Reaction Sequences 7 and 8.

For example, as shown in reaction sequence 7, one compound (, ¥X
XM) with a reducing agent such as lithium aluminum hydride to give bis(hydroxymethyA/)pyrrole. This one then further West et al.: “J, Org.
If using the procedure of Ohem, J 38, 2675 (1973), triethyl 7 run and trifluoro I! 11: Dimethyl compound (XX)m by &12
can be reduced to

Instead of K (by reacting a compound of formula (XXXM) with a Grignard reagent or an alkyllithium reagent in a conventional manner, as shown in Reaction Sequence 8, followed by reduction and standard treatment), the higher dialkyl Birol (
XXXIX) can be obtained.

Reaction of the diester (XXXV) or the corresponding diacid (obtained by conventional hydrolysis) with a secondary amine gives the bis(dialkylamide) (XL).

Alternatively, reaction of compound (XXXM) with a primary amino followed by thermal cyclization in conventional manner affords virolosacinimide (XLI), which can be reduced if necessary with lithium aluminum hydride. It can be reduced to (XLII) by a reagent.

[ Anderson et al.: F.J., M.
ea, Oham, J vol. 22, p. 977 (1979)
Please refer to

The acid (XIJ) derived by conventional hydrolysis of the compound of formula (XXXM) is also bis(amitonpyrrole (
It is also possible to convert XLiV) and then dehydrate it to form bis(α-/I/(XL\)). If necessary, it can be added to the bis by reacting with a conventional Grignard reagent (IJ O).
Pyrrole to bis(alkanoyl)pyrrole (XLM)
can be induced.

Reaction Sequence 8 (XLVI) The ring-opened dihydroxy acid of structural formula (n) described above is
It is an intermediate in the synthesis of lactone compounds by the reaction methods described above or can be prepared from lactone compounds by conventional hydrolysis of lactone compounds of formula (1).

In the ring-opened dihydroxy acid form, the compounds of the invention react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases.

The term "pharmaceutically acceptable metal cation" contemplates positively charged metal ions derived from sodium, potassium, calcium, magnesium, aluminum, iron, zinc, and the like.

The term "pharmaceutically acceptable amine cation" contemplates positively charged ions derived from ammonia and organic nitrogenous bases of sufficient strength to form such cations.

Bases useful for the formation of pharmaceutically acceptable non-toxic base addition salts of compounds of the invention form classes readily understood by those skilled in the art.

The free acid form of the compound can be regenerated from the salt, if necessary, by contacting the salt with an aqueous solution of an acid such as hydrochloric acid.

Although base addition salts differ from the free acid form of the compounds of the present invention in physical properties such as melting point and solubility in polar solvents, they are considered equivalent to the free acid form for purposes of the present invention. It is regarded.

Compounds of the invention can exist in unsolvated as well as solvated forms. Generally, solvent phase forms with pharmaceutically acceptable common agents such as water, ethanol, etc. are equivalent to unsolvated forms for purposes of this invention.

The compounds of the present invention are useful as blood cholesterol lowering or dust lipid lowering agents because of their ability to inhibit the synthesis of cholesterol by inhibiting the enzyme 6-hydroxy6-methylglumeryleucoenzymutase (HMG-00A reductase). be.

H of the compounds of the invention that inhibit cholesterol biosynthesis
Q-force was determined by two methods.

The first method (referred to as aS Niscreen) is based on R. E.

FArchiv. by Duggan et al. Biochem. B
iopkxya. Ko (1972) 1 5 2 volumes, 21
-Use the operating method described in 27 members. In this method, foods containing 5% cholestyramine are added to
Standard laboratory rat HM by giving rats for days
The level of G-OoA enzyme activity is increased and the rats are then sacrificed.

Rat liver is homogenized and the incorporation of cholesterol-140-acetate into non-saponifiable lipids by the rat liver homogenate is measured. The micromolar concentration of compound required for 50% inhibition of sterol synthesis over a period of 1 hour is determined and expressed as the 050 value.

The second method (referred to as COR screen) is described by T. Kita et al. in rJ. olin. Engineering best. J (1
980) Using the operating method described in Volume 6, pp. 1094-1100. In this method,
Converted to 14q-mevalonate in the presence of a purified enzyme preparation of HMG-CoA reductase 14
0-) Measure the amount of IMG-CQAQ. The micromolar concentration of compound required for a 50-fold inhibition of cholesterol synthesis is determined and recorded as IOsoli.

The activity of some representative examples of compounds of the invention is
Compactin was compared with that of Compactin, a compound of the prior art, shown in the table. In particular, R2 and R
Compounds of the invention in which 3 is a substituent other than hydrogen have an activity comparable to that of the natural product compactin.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

Solid carriers are diluents, flavoring agents, solubilizing agents, lubricants, suspending agents,! 13 or one or more substances that can act as tablet disintegrants. It may also be an encapsulating substance.

In powders, the carrier is a finely divided solid that is mixed with the finely divided active compound. In tablets, f! The compound is mixed with a carrier having the necessary binding properties in appropriate proportions and compressed into the desired shape and size.

In preparing a suppository formulation, a low melting point wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the =a acid component is uniformly dispersed therein by stirring or other means. The molten homogeneous mixture is then molded into regular size molds and allowed to cool and solidify.

Powders and tablets suitably contain from 5 to about 70% active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, tar, turmeric, lactose, pectin, dextrin, starch, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

The term "formulation" refers to the formulation of the active compound with an encapsulating material as a carrier, in which the active ingredient (with or without other carriers) is surrounded by the carrier, thereby giving a capsule in which the active ingredient is associated with the carrier. It is intended to encompass the following. Similarly, cachet is also included. Tablets, powders, cachets, and capsules can be conveniently used as solid use forms suitable for oral administration.

Liquid form preparations include solutions, suspensions and emulsions. For example, water or water for parenteral injection -
A propylene glycol solution can be mentioned. Liquid preparations can also be formulated as solutions in aqueous polyethylene glycol. Water bath solutions for oral use are prepared by dissolving the active ingredient in water and adding, if desired, a suitable coloring agent,
It can be manufactured by adding flavoring agents, stabilizing agents and birthing agents. Aqueous suspension '144 liquid for oral use is
Finely divided active ingredients such as natural or synthetic rubber,
It can be manufactured by dispersing with resin, methylcellulose, sodium carboxymethylcellulose and other known suspending agents.

Preferably, the pharmaceutical formulation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing uniform quantities of the active ingredient. The unit dosage form can be a packaged preparation containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, capsule, or tablet itself, or it can be the appropriate number of any of these packaged forms.

In therapeutic use as a blood lipid-lowering or blood cholesterol-lowering agent, the compounds utilized in the pharmaceutical methods of the invention are administered to a patient at a usage level of 40 to 600 R'i per day. . For a normal human adult weighing about 70k), this is about 0.0kg/ki'u) of body weight per day.
This corresponds to the usage amount of 5 to aOJIfI.

However, the amount used may vary depending on the needs of the patient, the extent of the disease being treated and the compound used.

Determination of the optimum amount to use for a particular situation is within the skill of those skilled in the art.

The following examples illustrate specific methods of making compounds of the invention. These examples are illustrative and do not limit the scope of the invention, which is defined by the following claims.

Example 1 trans-6-C2-C2-(4-7 fluorophenyl)
-5-(1-methylether)-1H-virol-1-yl]ethyl]f'to5humanx-4-hydroxy-2H-
Production process of pyran-2-one A: Production of 1-(4-fluorophenyl)-5-methyl-1#4-hexanedione "The method described in org, syn, , 0o11.J, Vol. 1-(4-fluorophenyl)-2-propen-1-one (43f.

286.7 mmol) and 31.7 mmol of isobutyraldehyde.
2m (,544 mmol), triethylamine 287!
(200 mmol) and 14.5 t (57,7 mmol) of 2-(2-hydroxyethyl)-6-methyl-4-benzylthiazolium chloride and the mixture is stirred at 70 C under nitrogen for 12 h I&J5. .

After this time one mixture was cooled to room temperature and the cooled mixture was mixed with ether (500 m) and water (ioorIL).
t). The aqueous layer was further extracted with 300 mA of ether, the ether baths were combined and sequentially 200 mA of water.
, 2 times each with 200 m of 2M hydrochloric acid and 100 rnt of salt water.
and finally dried over anhydrous magnesium sulfate.

The ether was removed and the residue was distilled (boiling point 115-1
20°C, 0.2 mmHg) and 1-(4-fluorophenyl)-5-methyl-1,4-hechitinedione 36
．． 7r (165 mmol, 58°) is obtained. This solidifies when left alone.

Other process A: Production of 1-(4-fluorophenyl)-5-methyA/-i, 4-hexanedione "Tst, Let, ters J (1979) 199
Isopropyl vinyl ketone (1,971,20 mmol), prepared from isobutyryl chloride and vinyltrimethylsilane by the method detailed on page 5, was
-fluorobenzaldehyde (2,4f, 20 mmol), triethylamine 2m (14 mmol) and 2-
(2-Hydroxyethyl)-3-methyl-4-benzylthiazolium chloride 1. Or (4,0 mmol)
Mix with. The mixture is stirred and heated under nitrogen for 5 hours. After cooling to room temperature, the mixture is partitioned between ether (200 m) and water (50 m). Water layer ether 200-
and combine the ether solutions. 21 te combined,
/L/solution was sequentially diluted with 5Q of water and 50Q of 2M hydrochloric acid.
Wash twice and with salt water for 50 minutes. Dry the ethereal solution over anhydrous magnesium sulfate.

After removal of the ether, the remaining liquid was used as eluent at 20:1 (
Flash chromatography on silica gel using hexane-ethyl acetate (valley f/valley t). This operation yields pure 1-(4-fluoropheny/L/)-5-methyl-1,4-hexanedione 1591 with a melting point of 47-49°C.

Step 8B: 2-C2-[:2-(4-fluoro7enyl)-5-(1-methylethyl)-5-methy/L/-1H-virol-1-yl]]-1-
Preparation of cyanethane 1-(4-fluorophenyl)-5 in glacial acetic acid 250-
-Methyl-1,4-hexanedione (36,5F, 16
4 mmol), 6-7 minopropionitrile 11/2
A solution of 7maht (251?, 180.4 mmol) and p-toluenesulfonic acid (0,1?) is stirred and heated to reflux under nitrogen for 6 hours. After cooling to room temperature,
The mixture is poured into 500 ml of ice water and the resulting aqueous suspension is extracted twice with 60 ml of ether. The combined ether extracts were successively washed twice with 200 g of water, three times with 200 g of sodium bicarbonate water bath and 200 g of brine.
and then dried over anhydrous sodium sulfate.

Remove the ether and use the remaining liquid as eluent I
Flash chromatography on silica gel using hechitin-ethyl acetate at CI: 1 (volume/t) gave 2-C2-[2-(4-fluorophenyl) as an oil.
-s-(i-methylethyl)-1H-virol-1-yl]-1-cyanoethane 54.8f is obtained. This solidifies when left alone.

Recrystallization from Improvil ether gives an analytical material with a melting point of 78-80'C.

Elemental analysis value for 016H177N 2: Calculated value 7
4.97 kettle 6.69% 10.93 related fu experimental value 75.
18% Section 6.64 ICJ, 95% Process C: 5-C2
-C2-(4-fluoro7enyl)-5-(1-methylethyl)-1H-virol-1-yl]-1-Bronognal Preparation of dichloromethane at ambient temperature under nitrogen 300rnt
2-(:2-[:2-(4-fluorophenyl)-
Diisobutylaluminum in dichloromethane was added to a stirred solution of 5-(1-methylethyl)-jH-virol-1-yl]-1-cyanethane (34,8 F, 135.8 mmol) over 30 minutes. (DiBAL's f,
156.2- of 0M bath solution is added dropwise.

The resulting mixture was stirred for 3 hours and then further stirred for 1. OM
Add 20fILt of DIBAL solution. The mixture was stirred at room temperature overnight, then an excess of...
e) is decomposed by careful addition of methanol.

When gas evolution has stopped, add 1 ice cube to the solution with vigorous stirring.
Carefully pour in 500 g of 2M hydrochloric acid.

The resulting emulsion was extracted twice with 500 liters of ether and the combined ether extracts were sequentially extracted with water at 100 rP.
lt% sodium bicarbonate water bath solution 100 rILt each
Wash twice and with brine IQOm and then dry over anhydrous magnesium sulfate.

The ether was removed and the residue was eluted with 10:1
Pure 3-(2-[:2-(4-fluorophenyl)-5
-(1-methylethyl)-1H-virol-1-yl]
]-1-propanal is obtained.

Step D = Preparation of methyl 7-[2-[2-(4-fluorophenyl-)-5-(1-methylethyl)-1H-virol-1-yl]]-5-hydroxy-3-oxo-heptanoate Nitrogen Hexane washed sodium hydride in anhydrous tetrahydrofuran cooled to 0° C. under 2.
Methyl acetoacetate a9m in anhydrous tetrahydro7ran 150fnt to a stirred suspension of 17F (9α6 mmol)
(82.4 mmol) is added dropwise over 30 minutes. When gas evolution ceases, 693 g of a 2.1 M solution of n-butyllithium in hexane is added dropwise.

The resulting bath liquid was stirred for 30 minutes and the 5-C2-C2-(4-fluorophenyl)-5-(1-methylethyl)-1H-virol-1 in 150 g of anhydrous tetrahydrofuran was stirred for 30 minutes. -il))-1-proAnal 19.4 f
(74.9 mmol) is added dropwise over 30 minutes. The solution was stirred for a further 1 hour and added 1 aomt of a saturated ammonium chloride water bath followed by 100 m g of 2M hydrochloric acid.
The reaction mixture is quenched by the addition of .

The resulting mixture was mixed with ether # (50M) and water (1oo
k). Separate the aqueous layer and 50% ether
Extract with 0-. Combine the ether extracts and add 50 ml of brine
m and then dried over anhydrous magnesium sulfate. The ether was removed and the residue was eluted with 5
Methyl 7-(2-(2-(4-fluorophenyl)-
5-(1-methylethyl)-1H-virol-1-yl]]-5-hydroxy=3-oxo-heptanoate 1
Obtain 9.9F (64%).

Step E Nidoran-6-C2-C2-(4-fluorophenyl)-5-(1-methylethyl)-1H-virol-1-yl]ethyl]tetrahydro-4-human-2H-bilan-2- Preparation of methyl 7-C2-C2-(4-fluorophenyl)-5-(1-methylethyl)-1H-virol-1-yl]]-5-hydroxy-3-oquine-hebutano at room temperature under nitrogen violet. Sixty syringes of air are introduced into a solution of 1M bath solution of tributylborane in tetrahydrofuran containing 19.9 F (53 mmol) of the ester. The bath solution was then allowed to stand in the oven for 18 hours and then cooled to -78°C.

Then +nl sodium hydride (2,27F, 60 mmol) is added in one portion. The mixture is stirred at -78°C for 60 minutes and at 0°C for 90 minutes. 10 - water and 10 - methanol
Carefully add the mixture of m1 (gas evolution). 60 mg of 3M sodium hydroxide solution and 30% H2O2 solution/
f! Add c301nt to the mixture simultaneously from a separate addition funnel. The vigorously stirred mixture is kept at 0° C. for 60 minutes and then at room temperature for 2 hours.

The mixture is then partitioned between 300° of water and 300° of ether. The ether Ifj was extracted with 10% sodium hydroxide bath 501Rt and the aqueous layers were combined, acidified with #hydrochloric acid and ethyl acetate/l15o.

- Extract twice. The ethyl acetate extracts are combined, washed twice with brine and dried over anhydrous magnesium sulfate. Remove ethyl acetate and make oily acid 12°5? is obtained, which is dissolved in 500 m of toluene and heated to remove water azeotropically. After cooling the bath to room temperature and removing the toluene, the residue was flash chromatographed on Nori gel using 2:1 (vol/vol) hexane-ethyl acetate as eluent to give a colorless solution. A solid 112 is obtained. Recrystallized from diimpropyl ether with melting point of 1.
04-105C trans-6-(2-C2-(4-fluorophenyl)-5-(1-methylethyl)-1H-
Virol-1-yl]ethyltetrahydro-4-hydroxy-2H-vilan-2-one 9.5 F (52%)
get.

Elemental analysis value for C32oH24FN03: Calculated value:
7G, 42% 7.00% 4.06% experimental value 70
．． 26% 7.33% 5.99%Example 2 trans-6-(2-(2-(4-fluorophenyl)
-5-Methyl-1H-virol-1-yl]ethyl]te, 1-(4-fluorophenyl)-2-propene of Production Example 1 aA of trahydro-4-hydroxy-2H-bilan-2-one The procedure of Example 1 is used using -1-one and ingtyraldehyde, dualdehyde and 3-buten-2-one. Thereafter, the procedure of step B- is carried out to trans-6-[2-LC2-(4-fluorophenyl)-5-methyl-IH-pyro)v-
1-yl]ethyl]tetrahydro-4-hydroxy-2
H-bilan-2-one is obtained.

cl 81 (elemental analysis value for 2QFN03: O
H N calculated value 6
a12% 6, 35% 4.41% experimental value 6a39%
6.18% 4.25%Example 3 trans-6-(2-(2-cyclopropyl-5-(4
-fluorophenyl)-1H-virol-11l)ethylcotetrahydro-4-hydroxy-2H-bilan-2
4-fluorobenzaldehyde and 1-cyclopropyl-one in Step A of Preparation Example 1 of Using the procedure of Example 1 using the 2-pro-1-one, the procedure of steps B-E is then followed to obtain the trans-6-[2-[2-
7 cloprobiAI-5-(4-fluorophenyl)-1H-virol-1-yl]ethyl]natrahydro-4-hydroxy-2H-vilan-2-one is produced.

Elemental analysis value for 020H22FNOS: O
H N calculated value 6
9. 9 6% 6.46% 4.08% Experimental value 70
．． 02% 6.54% 4.01%Example 4 Trans-6-C2'-C2-(1.
1-dimethylethyl)-5-(4-fluorophenyl)
-1H-pyrrol-1-yl]ethyl]tetrahydro-
In place of 1-(4-fluorophenyl)-2-proben-1-one and isobutyraldehyde in Step A of Production Example 1 of 4-hydroxy-2H-bilan-2-one, equimolar amounts of 4-fluorobenzaldehyde and t The procedure of Example 1 is used using -butylvinyl ketone. After that, the operating method of iB-E was performed to obtain a melting point of 177-17.
trans-6-(2-C2-(
1.1-dimethylethyl)-5-(4-7/L/olophenyl)-1H-virol-1-yl]ethyl]tetrahydro-4-hydroxyl 2H-hyran-2-one is produced.

Elemental analysis value for 0.2jH26FNo31c: OHN Calculated value 70.17% 7.29% 590 Experimental value
70.22% 7.50% 580% Example 5 Trans-6-[2-(5-phenyl-2-methyl)-
1H-Virrol-1-yl]ethyl]tetrahydro 4
-Equimolar amounts of benzaldehyde and 3-butene (in place of 1-(4-fluorophenyl)-2-propen-1-one and isobutyraldehyde in Step A of Production Example 1 of -Hydroxy-2H-bilan-2-one) The procedure of Example 1 is adapted using -2-one. Thereafter, the operating method of step B- was carried out to obtain trans-6-(:2-(5-phenyl-2-methyl)-1H-
Virrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-vilan-2-one is produced.

Elemental analysis value for 019H25NO4K: OHN Calculated value 6928% 7.04% 4.25% Experimental value
6&93% 7.00% 4.10%Example 6 trans-tetrahydro 4-hydroxy-6-(2-
(2-(2-methoxyphenyl)-5-methyl-1H-
Virol-1-yl]ethyl]-2I(-bilane-2-
The procedure of Example 1 is used, with the exception of flK equimolar amounts of 2-methoxybenzaldehyde and methyl vinyl ketone of 4-2 fluorobenzaldehyde and impropyl vinyl ketone in other step A of Preparation of Example 1. Subsequent process B-Fl
trans-tetrahydro-4-hydroxy-6-C2-C with a melting point of 112.5~115℃ using the operating method of
2-(2-methoxyphenyl)-5-methyl-1H-virol-1-yl]ethyl]-2H-vilan-2-one is produced.

Elemental analysis value for 0NIH23NO4: Calculated value 6λ
28% 7.04% 4.25% Experimental value 69.04%
122% 4.17%Example 7 trans-tetrahydro4-hydroxy-6-[2-
(2-(4-methoxyphenyl)-5-methyl-1H-
Production example of virol-1-yl]ethyl-2H-vilan-2-one The procedure of Example 1 is used using -methoxybenzaldehyde and 3-buten-2-one. Then, using the operating method of step B-■, the melting point is 95 to 9.
trans-tetrahydro-4-hydroxy-6- at 5°C
[2-(2-(4-methoxyphenyl)-5-methyl-
1H-Virrol-1-yl]ethyl]-2H-pyran-
2-one is generated.

Elemental analysis value for a19H2gNo4: OHN Calculated value 6228% 7.04% 4.25% Experimental value
6a93% 7. O0% 4.10%Example 8 trans-6-[2-(2-cyclohexyl-5-methyl-1H-virol-1-y/l/)ethylcotetrahydro-4-hydroxy-2H-bilan-2 In place of 1-(4-fluorophenyl]-2-propen-1-one and imbutyraldehyde in Step A of Preparation Example 1 of -one, equimolar amounts of cyclohexanecarboxaldehyde and 6-buten-2-one were added. Using the procedure of Example 1, the procedure of Example 1 is then used to prepare trans-6-[2-(2-7chlorohexyl-5-methyl) having a melting point of 129-130°C. -1a-Hirol-1-i/L/
) ethyl]tetrahydro-4-hydroxy-2H-bilan-2-one.

Gengo analysis value for 018H27NO3: OHN Calculated value 70.79% a5M% 4.59% Experimental value
71.11% &71% 4.47%Example 9 trans-tetrahydro-4-hydroxy-6-C2-
C2-Methyl-5-C3-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]ethyl) -2H
-1-(4-fluorophenyl)-2-pro in Step A of Production Example 1 of Bilan-2-one is equivalent to 3-(trifluoromethyl)benzaldehyde in place of cy-1-one and isobutyraldehyde. and 3-buten-2-one using the procedure of Example 1. Thereafter, trans-tetrahydro-
4-hydroxy-6-(2-(2-methyl-5-C5-
C trifluoromethyl/I/)phenyl]-1H-bilow/I/-1-yl]ethyl)-2H-:'9-2
- Promote onwo generation.

Elemental analysis value for Cl9H2073NO5: OHN Calculated value 62.12% 5.49% 5.81% Experimental value
62.22% 5.61% 573% Example 10 trans-6-C2-C2-((1,1'-bi7unyl)-4-yl)-5-methyl-1H-pyrrol-1-yl] Equivalent moles of 1-(4-fluorophenyl)-2-propen-1-one and imbutyraldehyde of A) The procedure of Example 1 is repeated once using 1 portion of 4-phenylbenzaldehyde and 6-buten-2-one. Thereafter, trans-6 with a melting point of 104-107°C was prepared using the procedure in step E-.
-(2-C2-((1,1'-biphenylcu-4-yl)-5-methyl-1H-virol-1-yl]ethyl)
Tetrahydro 4-hydroxy-2H-bilan-2-one is produced.

C24H25NO! Elemental analysis value for S; OHN Calculated value 76.77% 6.71% 3.73% Experimental value 76.66% 6.66% 571% Example 11 Trans-tetrahydro-4-hydroxy-6-[2-
(1-(4-fluorophenyl)-2-propen-1-one of Step aA of Production Example 1 of 2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-ylk-2H-bilan-2-one) and imbutyraldehyde) with equimolar caps of 1-captaldehyde and 3-butene-2
- Use the procedure of Example 1 with one turn. Then, using the operating method of step B-B, melting point 167-168
trans-tetrahydro-4-hydroxy-6-(
2-[2-methyl-5-(1-naphthalenyl)-1H-
Virrol-1-yl]ethyl]-2H-bilacy-2-one is produced.

Example 12 Trans-tetrahuman 0-4-hydroboxy6-C2-
C2-methy/I/-5-(2-su7talenyl)-1H-
Process a of Production Example 1 of virol-1-yl]ethyl]-2H-bilan-2-one A's 1-(4-fluorophenyl)-2-
Instead of propen-1-one and isobutyraldehyde, equimolar amounts of 2-nat aldehyde and 5-butene-
2-on 1A! The operating method of Example 1 is conveniently used. After that, using the operating method of steps B-H, the melting point is 45-5GC.
trans-tetrahydro-4-hydrocy6-[2
-(2-Methyl-5-(2-naphthalenylN)-1H-virol-1-yl]ethyl]-2H-vilan-2-one is produced.

Elemental analysis value for 022H25NO5: G
HN Calculated value 75.62% 6.65% 4.00% Experimental value 75.12% 688% 197% Example 15 Trans-6-[2-(bicycloC2,2,1)hept-5-ene-2- Ilu-5-methyl-1H-virol-
1-yl)ethyl]-tetrahydro-4-hydroxy-
1-(4
- fluoropheninol-2-propen-1-one and equimolar amounts of bicycloC2 instead of imbutyraldehyde;
,2,1]hept-5-ene-2-carboxaldehyde (mixture of diastereomers) and 3-butene-2
Using the procedure of Example 1 with -on. One of the endo and exo isomers was then used in the norbornene ring with a melting point of 125-126°C using the procedure in step E-.
:1 mixture as trans-6-C2-CbicycloC2
,2,1) hept-5-en-2-yl-5-methyl-
1H-virol-1-yl)ethyl]tetrahydro 4
-Hydroxy-2H-bilan-2-one is produced.

c19s25No5 K versus i elemental analysis value: Calculated value 7
2.35% 7.99 width 4.44% experimental value 72.1
1% a02% 4.52%9'1j14°trans-6-42-[2-(diphenylmethyl)-5
-Methyl/I/ -I H-Virrol-1-yl]ethyl]tet2human o-4-hydroxy7-2g-bilane-2-
The 1-(4-fluorophenyl)-2-polymer of Step iA of Preparation Example 1 of 1-(4-fluorophenyl)-2-one was prepared by adding equimolar amounts of diphenylacetaldehyde and 5-buten-2-one instead of 1-one and isobutyraldehyde. and use the N1 operating method.

Then using the operating method of step B-z, melting point 129-1
52'C trans-6-(2-[2-(diphenylmethyl)-5-methyl-1H-virol-1-yl]ethyl]tetrahydro-4-hydro-?cy2H-pyran-2-one is produced.

Elemental analysis value for 025H27NO5: CHN Calculation Direct 7107% 6.99 56
0% laughter experience 1st shift 76.85φ 7.14no
&4545φ 15 trans-6-(2-[2-(4-fluorophenyl)
-5-(1-methylethyl)-1H-virol-1-yl]propyl]tetrahydro-4-hydroxy-2H-
The procedure of Example 1 is used, substituting 2-aminopropatol for the ethanolamine in step B of the preparation of bilan-2-one. Thereafter, using the procedure of step 0-E, trans-6-[2-(2
-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-1l]propyl]tetrahydro-4-hydroxy-2H-pyran-2-one is produced.

Elemental analysis value for 02jH2dFNO3: Calculated value 7
0.17% 7.29% 3.90% Experimental value 70.0
6% 7.36% 5.82%Example 16 Trans-tetrahydro 4-hydroxy-6-C2'
-C2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl) -2
1-(4-
The procedure of Example 1 is used using equimolar amounts of 2-methoxybenzaldehyde and 3-buten-2-one in place of fluorophenyl)-2-propen-1-one and isobutyraldehyde. Then using the procedure in step B-, trans-tetrahydroc1-4-hydroxy-6-[2-(2-(2-methoxyphenyl)-5-
(1-Methylethyl)-1H-pyrrol-1-yl]ethyl]-2H-bilan-2-one is produced.

Elemental analysis value for 021H27NO5: OHN Calculated value 7056% 7.61% 592% Experimental value 7
Q, 43% 7.66% 573%Example 17 Method 1 Step A: 6-C2-C2-<4-fluorophene,/
I/)-5-(1-methylethyl)-1H-pyrrole-
Preparation of 1-yl]ethyl]tetrahydro-4-tert-butyldimethylsilyloxy-trans-2H-pyran-2-one 6-C2-C2-(4-fluorophenyl)-5-( 1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro4-hydroxy-trans-2a-pyran-2-,t
F, 1.5 mmol) and tertiary-butyldimethylchlororane (0.27f, 1.8 mmol) in a solution of
Imidazole ((1L61 - 14.5 mmol) is added in one portion. The solution is stirred at room temperature overnight and then partitioned between hexane (100 m) and water (50 m). The aqueous layer is extracted twice with 50 m each of hexane. The combined hexane extracts were added to a2o (2x25d) and brine (25m
) and then dried (MgSO4). The title compound [17
Obtain F (100%). 90 MH; x NMR (OD
Ot5) δQ, 10(s, 6H), 0.90(e
, 9H), 1.31] (d, J=Hg 6B), j
, 4~'1.8 (m.

4B), 2.48 (m, 2H), 2.95Cm,
1H), 3.9-4.3 (m, 3B), 5.85 (a.

Ja+=2gg LH), 6.02(d, J=2Hz,
1H), 6.8-7.5 (m, 4H).

Step B: 6-(2-(2-(4-fluoro7enyl)
-3,4-dichloro-5-(1-methylethyl)-1
H-pyrrol-1-yl]ethyl]tetrahydro-4-
1 of human 1c2xy-trans-2H-pyran-2-one
6-(2-(2-(4-fluorophenyl)-5-(1
-methylethyl)-1H-pyrrol-1-yl]ether]-tetrahydroc1-4-tert-butyldimethylsilyloxy-trans-2H-pyran-2-one (1,49
f, % N-chlorosuccinimide (0,87F + 6.48 mmol) is added in one portion to a stirred solution of 3.24 mmol. The solution was stirred at 0° C. for 1 hour and then warmed to room temperature under VC for 3 hours.

Dilute it with water (50m) and ether (2X
1000 m). Add ether extract to 1 part hexane
00- diluted and water (50 m), 10% aqueous NaH
OO3 (50 mg), 10% aqueous NaH803 (50
m), washed with salt water (50mj) and then dried (Mg■4)
do. The crude product remaining after one filtration and concentration was dissolved in tetrahydrofuran (15fILt) and glacial acetic acid (0,
75d, 13 mmol) and tetragutylammonium fluoride (IM THF fi$9.72-)
Process with. The solution was stirred for 5 hours and diluted with ethyl acetate (100
m) and saturated aqueous NaHOO5 (2X50 m)
), washed with salt water (25fnt) and then dried (Mg804
)do. The residue remaining after filtration and concentration is flash chromatographed on a 7-force gel using 2:1 hexane-ethyl acetate as eluent. This gives pure lactone CL5C1 (35%). Recrystallization from ether solution gives colorless crystals with a melting point of 129 DEG -131 DEG C.

Elemental analysis value for C20”22FO42N03: OH
N Calculation 4tL 57.98 Section 5.35 Hide 538chi Experimental Value 5a24% 5.24% Engineering 39% Engineering R (KBr)
v 3559.2990.1711.1518.122
5.1160.1055.851%816('IK-'
. 20QMHz NMR (CDO25) δ1,44
(a, J=7Hz, 6H), t8 (m, 4H),
2.12 (d, J=3Hz, 1H.

-○H], 2!55 (m, 2H), s, 1a (M, 1H
), 4.0 (M, 2) 1), 4.50CM.

IH), 4.45 (M, IH), 7.0-7.4 (M,
4H).

Method 2 Step A: 2-(4-fluorophenyl)-5-(1-
methylethyl)-3,4-dichloro-1H-pyrrole+
1-Pro/+? Preparation of Nitrile Dry dimethylformamide 50, cooled at 0 °C under nitrogen.
N-chlorosuccinimide (105r, 786 .5 mmol) at once. After stirring for 60 min at 0°C and 90 min at 25°C, additional N-chlorosuccinimide 89 (60
mmol). The solution was stirred for a further 60 minutes, then poured into ether (6t) and dissolved in H2O (3X500r
nt), 10% aqueous NaH8O3 (300 ml), a
2o(sa.

-), washed with brine and then dried (MgSO4). 7-layer chromatography on silica gel using 10:1 hexane-ethyl acetate as eluent gave an oil. This oil solidifies on standing. Recrystallized from isopropyl ether-hexane, melting point 80-82
C. colorless crystals 96f are obtained.

Elemental analysis value for 016H150t27N2: Q
HN Calculated value 5z09% 4.65% &61% Experimental value 5
901% 4.56% &59% Engineering R (KBr) 29
33.2249.1520.1490.1344.13
15.1218.848.524c+a-1゜100M
Hz NMR (ODGt5) δ1.42 (cl.

:r=7az, 6H), 2.33 (t a J=
7Hz, 2H)-3,0(8pt et r J2
7Tiz *IH), 4.05(t, J=7Hz, 2H
) x 70-74 (M, 4H).

The product of this step was used in the method described above in Example 1, Step C to produce 6-[2-(2-(4-fluorophenyl)-
3,4-dichloro-5-(1-methylethyl)-1H-
Pyrrol-1-yl]ethyl]tetrahydro-4-hydroxyate 2H-pyran-2-one is obtained.

Example 18 6-[2-(2-(4-fluorophenyl)-3,4-
dibromo-5-(1-methylethyl)-ta-virol-1-yl]ethyl]tetrahydro-4-hydroxy-
By using N-promosuccinimide in place of N-chlorosuccinimide in Step B of Method 1 of Production Example 17 of trans-2u-bilan-2-one, the melting point was 143.
A corresponding amount of the title compound is obtained.

Elemental analysis value for 02oH22FBr2NO5: CH
, HBr F Calculated value 47-7.4%4.41%2.78' stone 51.
76% & 77% experimental value 47.52%4.34%2.8
4%31.75%3.72%EngR(KBr) 3350
．． 2966.1711.1510.1484.1225
．． 1072.847.82 Qcm-1゜200MH2
NMR (ODO65) σ1.4° (d, J==7Hz,
6H), 1.5-1.8 (m, 41t), 1
．． 94(brs, 11(,-〇H), 2.58(m
, 2H), δ13 (m, IH), 4.0 (m e
2 H), 4.31 (m, IH), 4.47 (m+
IH), 7.0-7.3 (m, 4H).

Example 19 Step A: Ethyl-2-(1-(1-okine-2.2.2
- trifluoroethyl)-4-okine-4-(4-
Production of fluorophenyl)-butyrate Drying DM? A solution of ethyl 1,1.1-tri'fluoroacetoacetate (14.6 m, 0.1 mol) in hexane-washed sodium chloride (0, 106 moles) 0
Add dropwise to WIj suspension at 0°C. FJ, Org in 1 dry DMF f 01) d when gas generation is completed.

α-promo 4′-7tv a, prepared as described in Ohem, J 29, 3459 (1964).
A bath of acetophenone (1 mol a) is added dropwise over 30 minutes. The mixture is gradually warmed to 25° C. overnight. It is then quenched by the addition of 6N HCl to s Hz0
(1t) and ether (2x50otnt)
) to extract. The combined ether extracts were heated to Hz0 (2X
100 mg) and brine (100 d) and then trap dried (MgSO4). Flash chromatography on silica gel using eluent and 1, C5:1 hexane-ethyl acetate affords the title compound 72. Engineering R (Film) 3380.1768.1744.1
688.1601.1511.1416.1293.1
263.1268.121mu1160.1100%10
04.841cgL-'. 20Q MHz NMR (
CDC, 15) δ1.29(t, J=7Hz.

6H), 5.75℃m, 2H), 4.26 (q,
J=7Hz, 2H), 4.55 (dd, ,T
=4.7.

9.6 Hz lj H), 7.21 (m, 2H), δ
02 (m, 2H).

Step B: Preparation of 2-(4-fluorophenyl)-5-trifluoromethyl-IH-virol-1-propanenitrile Ethyl in 5:5:1 acetic acid-water and sulfur ra11o-
2-(1-(1-oxo-2,2,2-)lifluoroethyl))-4-okine-4-(4-fluorophenyl)
-A solution of butyrate (5f, 15.6 mmol) is stirred and heated under reflux for 4 hours.

The cooled solution is carefully poured into 400 ml of saturated aqueous bicarbonate and then extracted with ether (2×300 m).

The combined ether extracts were diluted with saturated aqueous bicarbonate (2 x 50 m
), washed with brine (50 m) and then dried (Mgso4). The crude diketone remaining after filtration and leakage was dissolved in 2 ml of glacial acetic acid.
0rnt and add 6-aminopro/sulfonitrile 7-malate 2P (18 mmol). The solution is stirred and heated under reflux for 5 hours. The cooled bath liquid was poured into 200 ml of saturated aqueous bicarbonate and diluted with ether (2×200
−) to extract. The combined ether extracts were heated to Hz0 (2x
so mt ) and brine (50 mt) and dried briefly (Mgso4). iF'! and flash chromatography of the residue remaining after concentration to yield the title compound 1.2F (27%).

Engineering R (ODO25) 2258.1611.1570.1
478.1657.1172.1106.1064.8
44"-'o 200MHvs NMR (CD025
) δ2.51 (t, J=7.3Hz, 2H
), 4.3 (t, J=7H2,2H), 6.16(
d,, T=5.8Hz, IH), 6.67 (d
, J=18Hz, IH), 7.1~7.5 (
m, 4H). Mass spectrum/L/M/e 282
．． 263.242.229.173゜6-C2-C2-
trifluoromethyl]-5-(4-fluorophenyl)
2-(4-fluorophenyl)-3 in Step O of Production Example 1 of -1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-trans-2H-bilan-2-one
,4-dichloro-5-(1-methylethyl)-B-pyrrole-1-propanenitrile (7) JK: 2-(4-
fluorophenyl)-5-trifluoromethyl-1H-
using pyrrole-1-propanenitrile and step C
Using the procedure %D and E, corresponding amounts of the title compound are obtained as an oil.

Elemental analysis value for 018H1774NO5: OHN Calculated value 5a22 section 4.61% 577% Experimental value 5
&88% 5.07% 4.03% Engineering R (Film)
3440.2927.1728.156.1477, 1
342,1266.1230.1160.1101.1
060.845.7132on-1゜200MHz N
MR (ODO4) δ1.3-2.1 (m, 4H)
, 2.34 (brs, IH, -0H), 2.55 (m
, 2H), 3.9-4.3 (m, 3H), 4.52 (
m, IH), 6.11 ((L, J=5.8Hz
, IEl), 6.61 (ad, J=08.
3.8Hz.

1H), 7.0-7.4 (m, 4H).

Example 20 (to) -N-(4-fluorobenzoyl) -N -[
Preparation of 2-(2-ethyl)-1,3-dioxolanyl]valine Methyl-2-bromo-3-methylbutyrate (4,6F, 256 mmol), 2-(1- A solution of (2-aminoethyl)-1,3-dioquinrane (2,95P, 25 mmol) and triethylamine (55M, 25 mmol) is stirred and heated for 20 hours. The cooled solution is poured into ether (50M) and extracted with 10t (2M) (2X50-). The aqueous layer is made alkaline with 25% water 1 NaOH and extracted with ethyl acetate (2×100 mg). The combined ethyl acetate extracts were washed with brine and dried (MgSO4
)do. Filtration and concentration give 3rg of the title compound as a liquid.

90 MHz NMR (○DOjg)'α93 (d
, J=7Hz, 6H), 1.70(brs,
IH, -NH), 1.86 (m, 2H), 2.60 (m
, 3H), 2.94 (d, , T=6Hz, 1H), 3.
68 (s, 5kl), 3.86 (m, 4H), 4.
89(t,,T=4Hz.

iH).

(To) Methyl-N-(4-fluorobenzoyl)-N-
Production of (2-(2-ethyl)-1,3-dioquinranyl)valine Dichloromethane (cH2ct2) cooled to 0°C 20
Methyl-N-C2-(2-ethy/L/)-1 in rnt
,3-dioxolanyl]valine (3f, 13 mmol)
and 4-fluorobenzoyl chloride (1,65m, 14 mmol) in aa2az210 +rlt to a stirred solution of triethylamine (i6m, 26 mmol)
Add the solution. The solution was incubated at 0 °C for 60 min and at room temperature for 60 min.
Stir for a minute. Then pour it into ether and water,
Saturated aqueous bicarbonate, washed with brine and then dried (MgSO4
)do. Flash chromatography on silica gel using 1:1 hexane-ethyl acetate as eluent affords the title compound 3f.

90 MHz NMR (ODO45) δ0.90 (br
d, J=71 (Z, 6H), 1.8~2.5 (m
, 3H), 3.45(br, +l, I=6.8Hz
, 1H), 172 (s.

3H), 5. BO (m, 6H), 4.80 (m,
1H), 6.7-7.5 (m, 4M).

±-N-(4-fluorobenzoyl)-N-[2-
Preparation of (2-ethyl/I/)-1,3-dioxolanyl]valine The methyl ester prepared as described above (iF, 2.83 mmol and NaOH ( 0,4?, 10 mmol) is stirred and heated under reflux for 3 hours. The cooled solution is diluted with water and extracted with ether. The aqueous layer is diluted with 6M f(C
Acidify with 6 and extract with ethyl acetate (2X). The combined ethyl acetate extracts were washed with brine and dried (Mg
soa) Acid 0.96F by Pi4 and concentration
(2.8 mmol is obtained.

90 MHz NMR (CDC6,5) δα85 (m,
6H), 1.8 (m, 2H), 2.5 (m, IH), 5
．． 3-3.9 (m, 7H), 4.6 (m, IH), 6
．． 8-7.4 (m, 4H).

Dimethyl-1-[:2-(2-ethyl)-1,3-dioxolanyl)-2-(4-fluorophenyl)-5-
Preparation of (1-methylethyl)-1H-virol-3,4-dicarboxylate Dimethylacetylene dicarboxylate (1,3-110,6 mmol) was dissolved in acetic anhydride 10- 2 of N-(4-fluorobenzoyl)-N-[2-(2-ethyl)-1,3-dioxolanyl]valine (1,1N', 5.28 mmol)
Add to solution at 5°C. Carbon dioxide production begins immediately. The solution was stirred for an additional 2 hours, concentrated to remove excess acetylene and solvent, and then passed through silica gel.
treat This gives virol 21 as a solid. This product has an inpropyl ether-hexane melting point of 143-146°C.

(, element x analysis ii for 22H24PNO4:O
H N calculated value 62
．． 55% 6.20% Engineering 61% Experiment 1fL 62.8
4% 6.26% 560% Engineering R (KBr) 1719,
1449.1241.1209.1178, 945cI
L-' o 200MHz NMR (CDC4) δ 1
35 ((L, , T=7Hg, 6H), 1, 8
0 (m. 2H), 5 18 (septet, J=7
Hz, IH)% i56(a, 5H), i7~
4.0 (m, 6H), 3.83 (s, 3H), 4
．． 64 (t, !=4Hz, IH), 7-7, 3
(m, 4H).

Dimethyl-1-(1-(3-okinopropyl))-2-
(4-fluorophenyl)-5-(1-methylethyl)
-1H-Virrole-3.4-'; Preparation of carboxylate dimethyl-1-(2
-(2-ethyl)-1,3-dioquinranyl)-2
-(4-fluorophenyl)-5-(1-methylethyl)-1H-virol-3,4-dicarboxylate (0
．． A solution of 5F, 1.18 mmol/L/) and p-toluenesulfonic acid (0.23F, 1.2 mmol) is stirred and heated under reflux for 48 hours.

The cooled solution was concentrated, diluted with ether (2oomg), saturated aqueous bicarbonate (2X50 rd), brine (
50 m) and dried (MgEpO4). Seven batch chromatography on silica gel using 4:1 hexane-ethyl acetate as eluent yields the pure aldehyde cL4f.

9 0 MHz NMR (CDC15) δ 1.35
(d, !=7Hz, 6H)%z6 1(t,
J=7Hz, 2H), 3.18(septat, J=7
Hz, IH), i53(s.

3EI), 3.81 (s, 5H), 4.03 (
t, J=7Hz, 2H), 6.9-7.3(M
, 4H), 9, 45 (s+, IEri.

Dimethyl-2-(4-fluorophenyl)-5-1(1
-Methylethyl)-1-(2-(tetrahydro-4-hydroxy-6-oxo-2H-bilan-2-yl)ethyl]-1H-pyrro/l/-3, Step C of Production Example 1 of 4-dicarboxylate 2-(4-fluorophenyl)- in
flK of 5-(1-methylethyl)-1H-virol-1-propanal dimethyl-1-(1-(3-ochynepropyl))-2-(4-fluorophenyl)-5-(1
-methylethyl)-1H-virol-3,4-dicarboxylate and step 0. Following procedures D and E, corresponding amounts of the title compound, melting point 167-170C, are obtained.

C24H2Bf” Yuan Cumulative Analysis 11i for NO7K :O
HN Calculated value 62.47% 6.12% 6.04 Yield test 1
Straight 62.32 Width 5.87% 2.99
Engagement R (KJ3r) 2450.2980, 1719, 1
499.1225.1174.1074.811cm-
'. 200MH2NMR (CDO43) δ1.34
(d, J=7H2, 6H), 1.57 (m, 4H),
2.40 (d, J=3H2, IH), 2.56 (m.

2H)% 3.16(septet,,,T=7klz
, IH), 3.55 (s, 3H), 183 (s.

5H), 4.0 (m, 2H), 4.26 (m+ IH)
, 4.44 (m, IH), 7.1-7.3 (m
.

4H).

Claims (1)

[Claims] 1) A compound having the structural formula ▲A mathematical formula, a chemical formula, a table, etc.▼(I) or a corresponding lactone ring-opened dihydroxy acid derived therefrom or a pharmaceutically acceptable salt thereof. In the formula, X is -CH_2-, -CH_2CH_2- or -
CH(CH_3)CH_2-, and R_1 is 1-naphthyl, 2-naphthyl, cyclohexyl, norbornenyl, phenyl, fluorine, chlorine, hydroxy, trifluoromethyl, alkyl of 1 to 4 carbon atoms, phenyl, 2-, 5- or 4-pyridinyl, 2-, 3- or 4-pyridinyl-N-oxide or ▲ mathematical formula, chemical formula, substituted by alkoxy of carbon atoms or alkanoyloxy of 2 to 8 carbon atoms;
There are tables etc.▼ (wherein R_5 is alkyl of 1 to 4 carbon atoms and Hal^- is chloride, bromide or iodide), and R_2 and R_3 are independently hydrogen, chlorine, bromine, cyano, trifluoromethyl, phenyl, alkyl of 1 to 4 carbon atoms, carbalkoxy of 2 to 8 carbon atoms, -CH_2OR_6, where R_6 is hydrogen, alkanoyl of 1 to 6 carbon atoms , -CH_2OCON
HR_7 (wherein R_7 is alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted with chlorine, bromine or alkyl of 1 to 4 carbon atoms) or the carbon to which these are attached When combined with atoms, R_2 and R_3 are ▲a ring represented by a mathematical formula, a chemical formula, a table, etc.▼ (in which n is 3 or 4), ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ There are rings represented by ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_8 is hydrogen, alkyl of 1 to 6 carbon atoms,
phenyl or benzyl) or ▲ mathematical formula, chemical formula, table, etc. ▼ where R_9 and R_1_0 are hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl. and R_4 is alkyl of 1 to 4 carbon atoms, cyclopropyl, cyclobutyl or trifluoromethyl. 2) X is -CH_2CH_2-, R_1 is as defined in claim 1, R_2 and R_3 are independently hydrogen, chlorine or bromine, and R_4 is as defined in claim 1; A compound according to claim 1, which is as defined in claim 1. 3) X is -CH_2CH_2-, and R_1 is phenyl, fluorine, chlorine, hydroxy, trifluoromethyl, 1
Phenyl, 2-, 3- or 4-pyridinyl, 2-, 3- substituted by alkyl of ~4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkanoyloxy of 2 to 8 carbon atoms or 4-pyridinyl-N-oxide or ▲ has a mathematical formula, chemical formula, table, etc. ▼ where R_5 is alkyl of 1 to 4 carbon atoms and Hal^- is chloride, bromide or iodide. , R_2 and R_3 are independently hydrogen, chlorine, bromine and R_4 is alkyl of 1 to 4 carbon atoms or trifluoromethyl. 4) X is -CH_2CH_2- and R_1 is phenyl or phenyl substituted by fluorine, chlorine, hydroxy, trifluoromethyl, alkoxy of 1 to 4 carbon atoms or alkanoyloxy of 2 to 8 carbon atoms; and R_2 and R_3 are independently hydrogen, chlorine or bromine and R_4 is isopropyl or trifluoromethyl. 5) X is -CH_2CH_2- and R_1 is phenyl, fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or phenyl, 1-naphthyl, 2-naphthyl substituted by alkanoyloxy, where R_2 and R_3 are independently hydrogen, chlorine, bromine, cyano, trifluoromethyl, phenyl, alkyl of 1 to 4 carbon atoms, 2 Carboalkoxy of ~8 carbon atoms, -CH_2OR_6 (wherein R_6 is hydrogen or 1-
alkanoyl of 6 carbon atoms), -CH_2O
CONHR_7 (wherein R_7 is alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted by chlorine, bromine or alkyl of 1 to 4 carbon atoms)
or R_2 and R_3 together with the carbon atoms to which they are bonded, then R_2 and R_3 are represented by ▲a mathematical formula, a chemical formula, a table, etc.▼ (where n is 3 or 4). ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Rings represented by ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_8 is hydrogen, alkyl of 1 to 4 carbon atoms,
phenyl or benzyl) or ▲ mathematical formula, chemical formula, table, etc. ▼ where R_9 and R_1_0 are hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl. and R_4 is alkyl of 1 to 4 carbon atoms, cyclopropyl, cyclobutyl or trifluoromethyl. 6) X is -CH_2CH_2- and R_1 is phenyl or fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or phenyl substituted by alkanoyloxy, and R_2 and R_3 are independently hydrogen, chlorine, bromine, phenyl, carbalkoxy of 2 to 8 carbon atoms, or R_2 and R_
If 3 is combined with the bonded carbon atom, R
_2 and R_3 are ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, n is 3 or 4) A ring represented by ▲ There are ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_8 is hydrogen or 1 to 4 (wherein R_9 and R_1_0 are hydrogen or alkyl of 1 to 4 carbon atoms) 2. A compound according to claim 1, wherein R_4 is alkyl of 1 to 4 carbon atoms or trifluoromethyl. 7) X is -CH_2CH_2- and R_1 is phenyl or fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or phenyl substituted by alkanoyloxy, and R_2 and R_3 are independently carboalkoxy of 2 to 8 carbon atoms or together with the carbon atom to which they are attached, ▲ formula, Chemical formulas, tables, etc. ▼ where R_8 is hydrogen or alkyl of 1 to 4 carbon atoms, and R_4 is isopropyl or trifluoromethyl. Compounds described. 8) trans-6-[2-[3,4-dichloro-2-(
4-fluorophenyl)-5-(1-methylethyl)-
1H-pyrrol-1-yl]ethyl]tetrahydro-4
-Hydroxy-2H-pyran-2-one, trans-6-[2-[3,4-dibromo-2-(4-
Fluorophenyl)-5-(1-methylethyl)-1H
-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, trans-6-[2-[2-(4-fluorophenyl)-5-(trifluoromethyl)-1H- Pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, trans-dimethyl2-(4-fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro -4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarboxylate, trans-6-[2-[2-(4-
Fluorophenyl-5-methyl-1H-pyrrol-1-yl]
ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl] ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, trans-6-[2-[
2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrole-
1-yl]ethyl]tetrahydro-4-hydroxy-2
H-pyran-2-one, trans-6-[2-[2-(
1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, trans-tetrahydro-4-hydroxy-6 -[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-2
-one, trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-(
1-methylethyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)
-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, trans-6-[2-(2-bicyclo[2,2,1]hep-5-en-2-yl-5- Methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-
2H-pyran-2-one and trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylphenyl)-1H-pyrrol-1-yl]propyl]tetrahydro-4-hydroxy- A compound according to claim 1 selected from the group consisting of 2H-pyran-2-one. 9) (a) Introduction Formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, X, R_1, R_2, R_3 and R_4 are as described below) substitution )-alkyl] aldehyde compound is reacted with an alkali metal salt of the dianion of methyl acetoacetate to obtain the structural formula (IV) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (IV) (wherein X, R_1, R_2, R_3 and R_4 (as described below), followed by (b) reduction of compound (IV) with trialkylborane and sodium borohydride, and (c) oxidation with alkaline hydrogen peroxide to form the compound of formula (V). ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Forming the oxide of formula (V) and finally (d) cyclizing the acid compound of formula (V) by heating in an inert solvent if necessary to form the formula Structural formula ▲ Numerical formula, chemical formula, table, etc. comprising a step of obtaining the lactone compound of (I) or, if necessary, converting the acid compound of formula (V) into a pharmaceutically acceptable salt. ▼ [In the formula, X is -CH_2-, -CH_2CH_2- or -CH(CH_3)CH_2-, and R_1 is 1-
naphthyl, 2-naphthyl, cyclohexyl, norbornenyl, phenyl, fluorine, chlorine, hydroxy, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or Phenyl, 2-, 3- substituted by alkanoyloxy
or 4-pyridinyl, 2-, 3- or 4-pyridinyl-N-oxide or ▲mathematical formula, chemical formula, table, etc.▼ (wherein R_5 is alkyl of 1 to 4 carbon atoms and Hal^- is chloride, bromide or iodide) and R_2 and R_3 are independently hydrogen, chlorine, bromine, cyano, trifluoromethyl, phenyl, alkyl of 1 to 4 carbon atoms, Carbalkoxy, -CH_2OR_6 (in the formula R
_6 is hydrogen, alkanoyl of 1 to 6 carbon atoms), -CH_2OCONHR_7 (wherein R_7 is 1 to 6
phenyl substituted by alkyl, phenyl, chlorine, bromine or alkyl of 1 to 4 carbon atoms) or together with the carbon atoms to which they are attached R_2 and R_3 are rings represented by ▲ which have mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, n is 3 or 4), ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Rings represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_8 is hydrogen, alkyl of 1 to 6 carbon atoms,
phenyl or benzyl) or ▲ mathematical formula, chemical formula, table, etc. ▼ where R_9 and R_1_0 are hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl. and R_4 is alkyl, cyclopropyl, cyclobutyl or trifluoromethyl of 1 to 4 carbon atoms] or the corresponding lactone ring-opened dihydroxy acid derived therefrom or a pharmaceutically acceptable salt thereof. Manufacturing method. 10) A pharmaceutical composition useful as a blood cholesterol lowering agent comprising a blood cholesterol lowering effective amount of the compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 11) A method of treating a patient in need of treatment by inhibiting cholesterol biosynthesis by administering the pharmaceutical composition according to claim 10.