AU618106B2 - 3-keto-naphtylethyl substituted pyran-2-ones and equilavent hydroxy acids - Google Patents

Description

6181, f:)o 0991 FORM 10 This document contains thl' amienidiealits ,ilo\ed under Section 83 t2) by the Super- |I visi.g Examiner on Q ~um~cva~~n~a:* COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class S Complete Specification Lodged: Accepted: S* Published: Priority: SRelated Art: Name and Address of Applicant: i? 0 t 00 0) Merck Co., Inc.

126 East Lincoln Avenue Rahway New Jersey UNITED STATES OF AMERICA Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Hales, 2000, Australia Address for Service: Complete Specification for the invention entitled: "3-Keto-Naphtylethyl Substituted Pyran-2-ones and Equivalent Hydroxy Acids".

i~ ~CL~6 :i The following statement is a full description of best method of performing it known to me/us this invention, including the F9 0019 /MW14 1770OIA 00 00 0 0 0 o100 0 o. 0 0540 o TITLE OF THE INVENTION 113-Keto-Naphtylethyl Substituted Pyran-2-ones and Equivalent Hydroxy Acids".

ABSTRACT OF THE DISCLOSURE Compounds of formula and (II): o 0 0 XOH 0 1 00 e I) (II) are HNG-CoA reductase inhibitors.

-~AL

-i F9 0019/MW14 1A- 17700IA 0 01 o0 0 0 0 0 0 o0 o S00 0 0 o 00 00 0 0 0

DO

a o 00 0 0 0 0 0 0 D 00 00 a o d D~i3 i*d 0 d TITLE OF THE INVENTION "3-Keto-Naphtylethyl Substituted Pyran-2-ones and Equivalent Hydroxy Acids".

BACKGROUND OF THE INVENTION 15 Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities i.e. several grams at a time and they are not very palatable.

MEVACOR (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of analogs thereof, produced by microbial, enzymatic and synthetic techniques.

elli

J

L

I

F9 0019 /MWl4 -2 17700IA The naturally occurring compounds and their analogs have the following general structural formulae:

HOU

HCO

2 21

ORH

0 00 00 0 00 P 00 0 0 0 0 00 00 0 00* 00 00 0 0 0 000* 00 0 0 00 0 0 0 00 0 000 wherein: Rl is hydrogen, Cl 1 5 alkyl or Cl 1 5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and R* is 400 0 1 KW CH2 2 0H CH2 CH2 CM

H

3 x F9 0019/MW14 3 17700IA wherein Q is R 3 or R 3 -CH; R 3 is H or OH or Q is

CH

S M is -HR 4

R

4 is hydrogen or hydroxy; X is

CR

5

R

6 0, S, or NH; R 5 and R 6 are H, OH, or

OR

7 where R 7 represents a phosphoryl or acyl moiety;

R

2 is hydrogen or methyl; and a, h, c, and d represent single bonds, one of a, h, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is or O O oo o 5 C= and when d is a double bond, M is =C and 0 0 0

H

provided that when R 5 or R 6 is OH or OR 7 or X is 0, S, or NH, a, b, and c are single bonds.

S* U.S. Patent 4,517,373 discloses hydroxy containing compounds represented by the above general i formula wherein R* is S 9 coalkyl OH Ci C 1 1oalkyl CH 2 H H 3 AND CH- Ho

I

i 0019/MW14 4 17700IA U.S. Patent 4,537,859 and U.S. Patent 4,448,979 also disclose hydroxy-containing compounds represented by the above general formula wherein R* is 0

,A

CH1 o o 0 00 o 0 S0 0 O 60¢ e9 00 0 a 4 T H CH 2 CHO H 3

HO

o

I

C

CH

2

-H

CH

3

H

3 "OH AND j i! i 0000 0 0 o 0 00 6 0 a a a a I t These compounds are prepared by the action of certain microorganisms on the corresponding 20 non-hydroxylated substrates. One such organism described in U.S. 4,537,859 is of the genus Nocardia.

U.K. Patent 2,075,013 discloses hydroxy containing compounds represented by the above general formula wherein R* is:

/CH

R2 -O CH2 /Iv.

Rpi

OH

OH

oQo 12K 0019/14W14 -5 1770OIA wherein Rl is H or Me, and R 2 is H or azyl.

U.S. Patent Application Serial No. 254,525 filed October 6, 1988 discloses 6-substituted compounds of the above general formula wherein R* is: 0 R I H 2

I

'I

0 00 0 00 00 40 00 0 o *0 00 0 0 00 00 00 0 004 00 04 0 0 0004 0 0 00 0 0 0 0 O 00 0 0 wherein R is CH 2 OH, CH 2 O0~ C0 2

R

7 o NS9 20 and Rl, R 4

R

7

R

8 and R 9 are broadly defined organic moieties.

U.S. Patents 4,604,472 and 4,733,003 disclose compounds of the above formula wherein R* is: 0010 ox cH2

CH,

Y 4

R

2 6 wherein X represents a hydrogen atom or a 2-methylbutyryl group, Y represents a hydrogen atom or a methyl group and R 1 and R 2 are the same or different and each represents an oxygen atom or a group of formula =N-OR 3 where R 3 is a hydrogen or alkyl moiety.

SUMMARY OF THE INVENTION According to a first embodiment of this invention, there is provided a compound represented by the following structural formulae (I) or (II): HO O coz R o o o .H

CH

3 00f 0, 0a 3 According to a second embodiment of this invention, there is provided a hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of S the first embodiment and a pharmaceutically acceptable carier.

S 15 According to a third embodiment of this invention, there is provided a hypocholesterolimic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of the first embodiment in combination with a pharmaceutically acceptable nontoxic cptionic polymer capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract and a pharmaceutically acceptable carrier.

According to a fourth embodiment of this invention, there is provided a method of treating hypercholesterolemia comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of the first embodiment.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to HMG-CoA reductase inhibitors of structural formulae and (II) ;i iILA 6A 0O 0 0 H (I) (II) 00 0 Or,0 0 where i n Ris selected from: 0 110 alkyl; substituted C0110 alkyl in which one or more substituent(s) is selected from halogen, hydroxy, C 1 10 alkoxy,

C

1 5 alkoxycarbonyl, C1-5 acyloxy, 0M/632Z F9 0019 /1W14 -7 1770OIA 40 0 0 +0 4 0 *0 4 ~0 0 00 00 4 '*04 0 40 0 0 44 4 0' 4 .0 4 440 (3) (4) (6)

C

3 8 cycloalkyl, phenyl, substituted phenyl in which the substituents are X and Y, Cl- 10 alkylS(O)n in which -a is 0 to 2, C3- 8 cycloalkylS(0)n, phenylS(O)n, substituted phenylS(0)n in which the substituents are X and Y, and (in) oxo;

C

1 10 alkoxy;

C

2 10 alkenyl;

C

3 8 cycloalkyl; substituted C 3 8 cycloalkyl in which one substituent is selected from

C

1 10 alkyl I substituted C 1 10 alkyl in which the substituent is selected from halogen, (ii) hydroxy, (iii) C 1 10 alkoxy, (iir) C 1 5 alkoxycarbonyl,

C

1 5 acyloxy, (vi) phenyl, (vii) substituted phenyl, in which the substituents are X and Y (viii) C 1 10 alkYlS(O )n, (ix)

C

3 8 cycloalkylS (O)n, phenylS(O)n, 0400 F9 0019/NW14 -8 -1770OIA substituted phenylS(0)n in which the substituents are X and Y, and (xii) oxo, Cl- 10 alkylS(O)n,

C

3 8 cycloalkylS(O)n, e) phenylS(0)n, substituted phenylS(0)n in which the substituents are X and Y, 0 halogen, 0(h) hydroxy, 15(i) Cl- 10 alkoxy, 0~15 Cl.

5 alkoxycarbonyl, 0 0(k) Cl 1 5 acyloxy, phenyl, and (in) substituted phenyl in which the substituents are X and Y; .t 4 phenyl; o 04(8) substituted phenyl in which the substituents are X and Y; amino; (10) G 1 5 alkylamino; 4(11) di(Cl 1 5 alkyl)amino; 10(12) phenylamino; (13) substituted phenylamino in which the substituents are X and Y; (14) phenyl C1_10 alkylamino; substituted phenyl C 1 10 alkylamino in which the substituents are X and Y; (16) a member selected from I1 0019 /MW14 9- 1770OIA (a) (b) (c) (d) (e) (17)

R

3

S

(a) (b) (c) piper idinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; and in which R 3 is selected from C1_ 10 alkyl, phenyl, and substit-uted phenyl in which the substituents are X and Y; o Pp P 4 4 Pt P. 00 o 4 o 4 P 44 o 4 4 0 49 44 P P04 P4 40 P 4 p o 4 P440 P 4 P 44 4

PP

44 4 P PP

P.

4 P pop

R

2 is H, CH 3 or CH 2 0H; 15 X and Y are independently selected from: a) OH, b) halogen, c) trifluoromethyl, d) Cl 1 3 alkoxy, 20 e) Clp 3 alkylcarbonyloxy, f) phenylcarbonyloxy, g) Clj 3 alkoxycarbonyl, h) phenyloxycarbonyl, i) hydrogen; 25 j) Cl 1 5 alkyl; Z is selected from N(1) hydrogen;

C

1 5 alkyl; substituted C 1 5 alkyl in which the substituent is selected from phenyl,

I;

H

tSP, C4P0 F9 0019/MW14 10 17700IA dimethylamino, and acetylamino, and 2,3-hydroxypropyl; halogen is C1 or F; a is a single bond or a double bond; and pharmaceutically acceptable salts of the compound (II) in which Z is hydrogen.

Except where specifically defined to the contrary, the terms "alkyl", "alkenyl", "acyl" "aryloxy" and "alkoxy" include both the straight-chain o o oo0o and branched-chain species of the term.

One embodiment of this invention is the O .o class of compounds of formulae and (II) wherein: 0 0

R

1 is selected from: C1- 1 0 alkyl; osu 20 substituted C1_10 alkyl in which one 0 o or more substituent(s) is selected from o halogen, hydroxy, C1- 1 0 alkoxy, C1- 5 alkoxycarbonyl, C1-5 acyloxy, S(f) C3-8 cycloalkyl, phenyl, substituted phenyl in which the substituents are X and Y, and oxo; C3- 8 cycloalkyl; substituted C3- 8 cycloalkyl in which one substituent is selected from F9 0019 /MW14 11 1770OIA 4

I

00 o 0 0 0 Ot 00 @0 0 0 0 0 0 0 00 0 0 0 0 00 00 o 0 0 000 00 00 0 0 0 0 0 0 0 0~ 0 0 00 0 0 0 0 00 00 0 0400 0000

C

1 10 alkyl, substituted CI-1 0 alkyl in which the substituent is selected from Wi halogen, (ii) hydroxy, (iii) C 1 10 alkoxy (iv) Cl.

5 acyloxy, Cl 1 5 alkoxycarbonyl, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y, and (viii) oxo, halogen, hydroxy,

C

1 10 alkoxy,

C

1 5 alkoxycarbony'L, Cl 1 5 acyloxy, phenyl, substituted phenyl in which the substituents are X and Y; phenylamino; substituted phenylamino in which the substituents are X and Y; phenylCl-l 0 alkylamino; and substituted phenyl Cl- 10 alkylamino in which the substituents are X and Y; X and Y are independently selected from:

OH.

F,

trifluoromethyl, (di) Cl-3 alkoxy, hydrogen, Cl 1 5 alkyl.

F9 0019/MW14 12 17700IA In one subclass are the compounds of formulae MI and (II) wherein R, is Gl- 10 alkyl.

Illustrating this subclass are those compounds of formulae and (II) wherein: Ris 2-butyl or 2-methyl-2-butyl; and

R

2 is H or CH 3 Exemplifying this subclass are the following 0~0 compounds: 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6dimethyl-3-oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl- 0 l(S)1ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one; 6(R)-[2-[8(S)-(2,2--dimethylbutyryloxy)-2(S),6dimethyl-3-oxo-l ,2,3,7 8a(R)-hexahydronaphthyl- 000 20 l(S)1ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- 00 0 pyran-2-one; o to(3) )-(2-methylbutyryloxy)-2(S )-methyl-3- S. oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl--l(S)]ethyl>- 4(R)-hydroxy-3 6-tetrahydro-2H-pyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylb-utyryloxy)-2(S)methyl-3-oxo-l 8a(R)-hexahydronaphthyll(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)dimethyl-3--oxo-,2,3,5,6,7,8,8a(R)-octahydronaphthyl-l(S)]ethyl]--4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; F9 0019/MW14 13 17700IA 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)methyl-3-oxo-1,2,3,5,6,7,8,8a(R)-octahydronaphthyl -l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one.

6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6(R)dimethyl-3-oxo-l,2,3,5,6,7,8,8a(R)-octahydronaphthyl-l(S)]ethyl]-4(R)-hydioxy-3,4,5,6-tetrahydro-2H-pyran-2-one; 6(R)-[2-[8(S)-(2-methylbutyryloxy)-)-2( methyl-3-oxo-l,2,3,5,6,7,8,8a(R)-octahydronaphthyl m oo -l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one.

The compounds of formulae and (II) S"0 a wherein R 2 is methyl and a is a double bond, may be prepared from lovastatin or simvastatin or its analogs having a 6-methyl group by one of the a :20 following microbiological procedures: adding the substrate to a growing culture of "o Nocardia autotrophica for a suitable incubation period followed by isolation, and derivatization.

if desired; collecting a culture of the bioconverting microorganism and contacting the collected cells S °with the substrate; or preparing a cell-free, enzyme-containing extract from the cells of the bioconverting microorganism and contacting this extract with the substrate.

Cultivation of the bioconverting microorganism of the genus Nocardia can be carried out by conventional means in a conventional culture medium

-I

F9 0019/MW4 14 17700IA Scontaining nutrients well known for use with such microorganisms. Thus, as is well known, such culture media contain sources of assimilable carbon and of assimilable nitrogen and often inorganic salts.

Examples of sources of assimilable carbon include glucose, sucrose, starch, glycerin, millet jelly, molasses and soybean oil. Examples of sources of assimilable nitrogen include soybean solids (including soybean meal and soybean flour), wheat germ, meat extracts, peptone, corn steep liquor, %O dried yeast and ammonium salts, such as ammonium sulphate. If required, inorganic salts, such as .4o66. sodium chloride, potassium chloride, calcium carbonate or phosphates, may also be included. Also, if desired, other additives capable of promoting the Sproduction of hydroxylation enzymes may be employed in appropriate combinations. The particular cultivation technique is not critical to the process oo 20 of the invention and any techniques conventionally C 920 09 used for the cultivation of microorganisms may equally ooo b employed with the present invention. In general, of course, the techniques employed will be chosen having regard to industrial efficiency. Thus, liquid culture is generally preferred and the deep culture I method is most convenient from the industrial point of view.

Cultivation will normally be carried out under aerobic conditions and at a temperature within the range from 20 to 37 0 more preferably from 260 to 28 0

C.

F9 0019/MWI4 15 17700IA Method is carried out by adding the substrate to the culture medium in the course of cultivation. The precise point during the cultivation at which the starting compound is added will vary depending upon the cultivation equipment, composition of the medium, temperature of the culture medium and other factors, but it is preferably at the time when the hydroxylation capacity of the microorganism begins to increase and this is usually 1 or 2 days after beginning cultivation of the microorganism. The Samount of the substrate added is preferably from 0.01 So to 5.0% by weight of the medium, more preferably from 0.05 to from 0.05 to 0.1% by weight.

*6 After addition of the substrate, cultivation is o€ continued aerobically, normally at a temperature within the ranges proposed above. Cultivation is normally continued for a period of from 1 to 2 days after addition of the substrate.

20 In method cultivation of the micro- 00o20 So0 o organism is first carried out under conditions such o as to achieve its maximum hydroxylation capacity; this capacity usually reaches a maximum between 4 and 5 days after beginning the cultivation, although this period is variable, depending upon the nature and I temperature of the medium, the species of micro- ,q4 organism and other factors. The hydroxylation capacity of the culture can be monitored by taking samples of the culture at suitable intervals, determining the hydroxylation capacity of the samples by contacting them with a substrate under standard conditions and determining the quantity of product obtained and plotting this capacity against time as a iz- -i F9 0019/MW14 16 17700IA !V graph. When the hydroxylation capacity has reached i its maximum point, cultivation is stopped and the microbial cells are collected. This may be achieved by subjecting the culture to centrifugal separation, Sfiltration or similar known separation methods. The whole cells of the cultivating microorganism thus collected, preferably, are then washed with a suitable washing liquid, such as physiological saline or an appropriate buffer solution.

I0 Contact of the collected cells of the micro- (O o organism of the genus Nocardia with the substrate is generally effected in an aqueous medium, for example O 0in a phosphate buffer solution at a pH value of from i 15 5 to 9. The reaction temperature is preferably within 615 the range from 200 to 45 0 more preferably from 250 to 30 0 C. The concentration of the substrate in the reaction medium is preferably within the range from 0.01 to 5.0% by weight. The time allowed for the reaction is preferably from 1 to 5 days, although 0 this may vary depending upon the concentration of the 9 substrate in the reaction mixture, the reaction temperature, the hydroxylation capacity of the microorganism (which may, of course, vary from species to species and will also, as explained above, depend 4 upon the cultivation time) and other factors.

The cell-free, enzyme-containing extract employed in method may be obtained by breaking down the whole cells of the microorganism obtained as described in relation to method by physical or chemical means, for example by grinding or ultrasonic treatment to provide a disintegrated cellular mass or by treatment with a surface active agent or an enzyme I I 0019/MW14 17 17700IA r j i j: i a r o a '9 aD o a 9 a a9 a b 0 a a1 0*1 Va.

a to produce a cellular solution. The resulting cellfree extract is then contacted with the substrate under the same conditions as are described above in relation to method The microorganism useful in the novel process of this invention is of the genus Nocardia.

Of particular importance are the known strains of microorganism, Nocardia autotrophica, subspecies canberrica, ATCC 35203 of the culture MA-6181 and subspecies amethystina ATCC 35204 of the culture MA-6180 of the culture collection of Merck Co., Inc., Rahway, New Jersey. A sample of the culture designated ATCC 35203 and ATCC 35204 is available in the permanent culture collection of the American Type Culture Collection at 12301 Parklawn Drive, Rockville, MD 20852.

After completion of the conversion reaction by any of the above methods, the desired compound can 20 be directly isolated, separated or purified by conventional means. For example, separation and purification can be effected by filtering the reaction mixture, extracting the resulting filtrate with a water-immiscible organic solvent (such as 25 ethyl acetate), distilling the solvent from the extract, subjecting the resulting crude compound to column chromatography, (for example on silica gel or alumina) and eluting the column with an appropriate eluent, especially in an HPLC apparatus.

Where the acyl moiety of formulae or (II) is other than 2-methylbutyryl or 2,2-dimethylbutyryl, the acyl moiety of lovastatin may be hydrolyzed and the hydroxyl group reesterified with F9 0019/MW14 18 17700IA an appropriate alkanoyl halide following the procedure in U.S. Patent 4,444,784. The alkanoyl halide can be formed by standard transformations such as substitution with an alkyl halide or other appropriate electrophile at an acidic C-H site on an available starting material. See for example U.S.

Patents 4,766,145 and allowed pending applications S.N. 205,406 and S.N. 205,407 filed June 10, 1988.

Starting material wherein R 2 is CH 2 0H may be prepared following the procedures in copending S*o application S.N. 254,525 filed October 6, 1988.

The compounds of formulae and (II) may o 0also be prepared following the synthetic methodology in Scheme 1.

i 0 a e o 9 00 ao to$$ i; 0019 /MW14 19 SCHEME 1 1770OIA wCJ- 4 49 4 9 4 4 44 49 49 4 4 40 4 0 4 4 4~0 04 4 4 4 PhSeX

H

2 n-Bu3SnH R,

AIBN

CH,

OH

I'

4 4449 4 4 99 9 9 49 9 0 9 49 4 9 909 449' 9099 To TC 0 0

CH

2 C1 2 /EtN A PC/lOH H CFJSO SimY, PhM 1000s H3 O Pd(OAC) 2

CH

3 CN, 20 0

C

0Toy", 'Al T BU 4

NF

R, H3 HOAC Rl 2CH T A hydroxcy protecting group such as trialkylsilyl.

Rl2= H, CH 3 or CH 2

OT.

F9 0019/MW14 20 17700IA SStarting material is treated with a reagent suitable for protecting the alcohol group at the lactone 4-position. Examples of suitable reagents are t-rialkylsilyl chlorides, dialkylarylsilyl chlorides and dihydropyran.

The diene is treated with a halogenating agent such as phenylselenyl chloride or bromide or phenylsulfinyl chloride, preferably phenylselenyl chloride, in an approximately equimolar ratio in an inert solvent at about -80 0 C, for approximately minutes; illustrative of such inert solvents are 0 ,e methylene chloride, ether and the like. After a standard workup the product residue is dissolved in o 9 15 an ethereal solvent, chilled to about 0°C and oxidized with an agent such as 30% hydrogen peroxide or a peroxy acid such as peroxybenzoic acid to yield a Shalohydrin analog Intermediate is treated with a halide reducing agent such as a trialkyltin hydride or a triaryltin hydride, preferably tri-n-butyltin hydride and a radical initiator such as azobisisobutyro- 0 0o 0 nitrile (AIBN) in an inert solvent such as benzene at a temperature between 70 0 C and 100 0 C preferably about 25 90 0 C for 0.5 to 5 hours preferably 2 hours, to yield compound Compound is treated with pyridinium chlorochromate (PCC) on aluminum oxide in toluene to yield the enone Compound is contacted with trimethylsilyl trifluoromethanesulfonate and an amine to yield the trimethylsilyl ether diene F9 0019/MW14 21 17700IA Compound is treated with palladium acetate in acetonitrile to form dienone Hydroxyl protecting groups are removed by treatment with tetrabutyl ammonium fluoride and acetic acid in tetrahydrofuran to yield product Enone can be converted to compounds of formula wherein a is a single bond by treatment with tetrabutyl ammonium fluoride in acetic acid.

Alternatively the compounds of formulae (I) can be prepared following the synthetic outline of Scheme 2.

0 0 0 0 0 9 o 00 0 0@ i o o 0 0 f00 iA, 0019 /MW14 22 17700IA SCHEME 2 0 it /C\9 m-CPBA EtOAc, 000 'H3

/C\

I(dba) 3 2d,, THF (iPro) 3 P 5500 a o~ 0 0 00 0~ 0 0 a o* 00 0 Coo 00 00 a o 0 0000 o a C 00 0 00 0 0 0 0 00 a 0 C 000 (10)

CH

2 C 12

PCC

(11) 3, pyrazole 0000 0 11 R, 0

R

2 0 (12) F9 0019/MW1 4 23 17700IA Diene starting material is converted to epoxides and by treatment with m-chloroperoxybenzoic acid at about 0°C. The mixture of epoxides is then contacted with tris (dibenzylideneacetone)-dipalladium(0) and triisopropoxy phosphine to yield the mixture of hydroxy dienes (10) and This mixture is then oxidized with PCC attenuated with dimethylpyrazole to yield 5-one compound (12) and product Enone of Scheme 1 can also be formed from hydroxyl protected epoxide or the mixture of S° epoxides and as shown below: 0 0 9 oo f II II 20 R1 O R, OH o l CH (Ph3P)bPd A CCH Ph2P PC12 Ph]Me, 1200C p12' O I Compound can then be employed in Scheme 1 to form product

I_

ir U'll I- 0019/MW14 24 17700IA

'I

o o st 0 4 S *0 D a 0 aa Where the reaction conditions of the above noted chemical transformations would be deleterious to the substituents in the 8-acyloy moiety, the acetoxy group can be employed as a protecting group which after the elaboration elsewhere in the molecule can be removed by hydrolysis to give the 8-hydroxy derivative which then can be acylated according to the general procedures described in U.S. Patent 4,661,483.

Where t'e product formed by the above described synthetic pathways is not the desired form of that compound, then that product may be subjected to one or more further reactions such as hydrolysis, disilylation, salification, esterification, acylation, ammonolysis or lactonizaton by conventional methods.

Preferred metal salts are salts with alkali metals, such as sodium or potassium, salts with alkaline earth metals, such as calcium or magnesium, or salts with other metals such as aluminum, iron, zinc, copper, nickel or cobalt, of which the alkali metal, alkaline earth metal, and aluminum salts are preferred, the sodium, calcium and aluminum salts being most preferred.

Preferred amino acids to form amino acid salts are basic amino acids, such as arginine, lysine, a,B-diaminobutyric acid or ornithine.

Preferred amines to form amine salts include dibenzylamine, ethylenediamine, morpholine, and tris(hydroxymethyl)aminomethane. Also preferrred is ammonia to form the ammonium salt.

Esters are preferably the alkyl esters, such as the methyl, ethyl, propyl, isopropyl, butyl,

I

0019/MW14 25 17700IA 0 0 o a a 9 o 0 a a on 0 0 0 t* 4

B

o 0 isobutyl, or pentyl esters, of which the methyl ester is preferred. However, other esters such as phenyldimethylamino-Cl_5alkyl, or acetylamino- Cl_5alkyl may be employed if desired.

Metal salts of the carboxylic acids of formula (II) may be obtained by contacting a hydroxide or carbonate with the carboxylic acid of formula The aqueous solvent employed is preferably water, or it may be a mixture of water with an organic solvent, preferably an alcohol (such as methanol or ethanol), a ketone (such as acetone), an aliphatic hydrocarbon (such as hexane) or an ester (such as ethyl acetate). It is preferred to use a 15 mixture of a hydrophilic organic solvent with water.

Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating or cooling.

Amine salts of the carboxylic acids of 20 formula (II) may be obtained by contacting an amine in an aqueous solvent with the carboxylic acid of formula Suitable aqueous solvents include water and mixtures of water with alcohols (such as methanol or ethanol), ethers (such as diethyl ether 25 and tetrahydrofuran), nitriles (such as acetonitrile) or ketones (such as acetone); it is preferred to use aqueous acetone as the solvent for this reaction.

The reaction is preferably carried out at a temperature of ambient or below, more preferably a temperature of from 50 to 10 0 C. The reaction immediately goes to completion. Alternatively, a metal salt of the carboxylic acid of formula (II) (which may have been obtained as described above) can 1 440 44.4r i--Ii 0019/MW14 26 17700IA :i *i

I

S.a i a a *ot *s a 0 t &a 8) a .aa a oa a 00 a Lt be dissolved in an aqueous solvent, after which a mineral acid salt (for example the hydrochloride) of the desired amine is added, employing the same reaction conditions as when the amine itself is reacted with the carboxylic acid of formula (II) and the desired product is then obtained by metathesis.

Amino acid salts of the carboxylic acids of formula (II) may be obtained by contacting an amino acid in aqueous solution with the carboxylic acid of formula Suitable aqueous solvents include water and mixtures of water with alcohols (such as methanol or ethanol) or ethers (such as tetrahydrofuran).

15 Esters, preferably alkyl esters, of the carboxylic acids of formula (II) may be obtained by contacting the carboxylic acid of formula (II) with an appropriate alcohol, preferably in the presence of an acid catalyst, for example a mineral acid (such as hydrochloric acid or sulphuric acid), a Lewis acid (for example boron trifluoride) or an acidic ion exchange resin. The solvent employed for this reaction is not critical, provided that it does not adversely affect the reaction; suitable solvents 25 include the alcohol itself, benzene, chloroform, ethers and the like. Alternatively, the desired product may be obtained by contacting the carboxylic acid of formula (II) with a diazoalkane, in which the alkane moiety may be substituted or unsubstituted.

This reaction is usually effected by contacting the acid with an ethereal solution of the diazoalkane.

As a further alternative, the ester may be obtained by contacting a metal salt of the carboxylic acid of

-A

p.ri-*h -r~U -r F9 0019/MW14 27 17700IA 4 90 9p 0* 99 9 900 *o 91 *9 0t 9 9 9 9999s 9 9 019 9999 formula (II) with a halide, preferably an alkyl halide, in a suitable solvent; preferred solvents include dimethylformamide, tetrahydrofuran, dimethylsulfoxide and acetone. Finally, esters may also be obtained from the lactone of formula by reaction with an appropriate alkoxide in an absolute alkanol. All of the reactions for producing esters are preferably effected at about ambient temperature, but, if required by the nature of the reaction system, the reactions may be conducted with heating or cooling.

Lactones of the carboxylic acids of formula may be obtained by lactonizing the carboxylic 15 acids of formula (II) under ordinary conditions known to one skilled in the art.

The intrinsic HMG-CoA reductase inhibition activity of the claimed compounds is measured in the in vitro protocol published in J. Med. Chem., 28, p.

20 347-358 (1985).

Representative of the intrinsic HMG-CoA reductase inhibitory activities of the claimed compounds is the relative potency of (2,2-dimethylbutyryloxy)-2(S),6-dimethyl-3-oxo-l,2,3,- 25 7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one which exhibited an

IC

5 0 value of 2 ng/ml when compared to an IC 5 0 value of 4.2 ng/ml for simvastatin. Compound (2,2-dimethylbutyryloxy)-2(S), 6(R)-dimethyl-3-oxo- 1,2,3,5,6,7,8,8a(R)-octahydro-naphthyl-l(S)]ethyl]- 4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; exhibited an IC 5 0 of IY F9 0019/MW14 28 17700IA The compounds of this invention are useful as antihypercholesterolemic agents for the treatment of arteriosclerosis, hyperlipidemia, familial hypercholesterolemia and the like diseases in humans.

They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients but daily dosage for adults is within a range of from about 2 mg to 2000 mg (preferably 10 to 100 mg) which may be given in two to four divided doses. Higher doses may be favorably o .15 employed as required.

The compounds of this invention may also be Scoadministered with pharmaceutically acceptable nontoxic cationic polymers capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract. Examples of such polymers include cholestyramine, colestipol and poly[methyl-(3-tri- 0 methylaminopropyl)imino-trimethylene dihalide]. The t relative amounts of the compounds of this invention and these polymers is between 1:100 and 1:15,000.

Included within the scope of this invention is the method of treating arteriosclerosis, familial hypercholesterolemia or hyperlipidemia which comprises administering to a subject in need of such treatment a nontoxic, therapeutically-effective amount of the compounds of formulae or (II) or pharmaceutical compositions thereof.

F9 0019/MW14 -29 1 7700IA The following examples illustrate the preparation of the compounds of the formulae and (II) and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

EXAM~PLE 1 Preparation of 6(R)-[2-[8(S)-(2,2-dimethy.butyryloxy)-2(S) ,6-dimethyl-3-oxo-l ,2,3,7,8 ,8a(R)- 4 hexahydronaphthyl-1(S)]ethyl]-4(R)--hydroxy-3,4,5,6- 0040 tet rahydro-2H-pyran-2-one Utilizing the general procedure for the 000 bioconversion of sodium salt of 7-El,2,6,7,8,8a(R)- 0* hexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethylbutyryloxy)-l(S)-naphthyl]-3(R) heptanoic acid as described in co-pending patent application Serial No. 254,525, filed October 6, 1'98 8 the above titled compound was isolated as a minor product.

7 A 0019/MW14 30 17700IA The following media are utilized in the bioconversion reactions described below: Medium A Grams per liter distilled water Yeast extract Malt extract 10.0 Nutrient broth Dextrose pH 7.4 Medium sterilized for 20 min. at 121°C r ii o 0 0 *0 00 o 0s 00 00 00 0~ *000 00 0 0 O 04 tt1 Medium B Dextrose 10.0 Polypeptone Meat extract Corn steep liquor pH Medium sterilized for 20 min. at 121°C Grams per liter distilled water I. Culture Conditions and Bioconversion A lyophilized tube of Nocardia autotrophica subsp. canberrica ATCC 35204 (MA-6180) was used to inoculate 18 x 175 agar slants (Medium A) which were incubated at 27 0 C for 7 days. The slant culture was washed with 5 ml of sterile medium B and transferred to a 250 ml flask containing 50 ml of sterile medium B. This first stage seed was grown at 27°C on a 220 rpm shaker and, after 24 hours, 2 ml was transferred to another flask of sterile medium B.

3 1 FTr.

F9 0019/MW14 31 17700IA o a a 99 o a a> 0 0 9 a o 4 4 9i 0 0 R f« f ~o o fl a 4 1 0 Grown under the above conditions, the second seed was used to start the bioconversion culture: ml of the seed culture was placed in 400 ml of sterile medium B in a 2L flask. After the culture had grown for 24 hours, 80 mg of the sodium salt of 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)- (2,2-dimethylbutyryloxy)-l(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid was added to each flask. The incubation was continued for 28 hours or until no 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)- (2,2-dimethylbutyryloxy)-l(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid could be detected by HPLC. The whole broth was clarified by centrifugationfollowed 15 by filtration through Whatman No. 2 filter paper.

II. HPLC Methods Aliquots of whole broth could be analyzed for 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl- 20 8(S)-(2,2-dimethylbutyryloxy)-l(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid derivatives by HPLC.

Filtered broth could be injected directly (10 to or after dilution with methanol. The compounds were separated on reverse phase columns utilizing a gradient from 35 to 45 percent aqueous acetonitrile at flow rates ranging between 1 and 3 ml/min.

Addition of glacial acetic acid or H 3 P0 4 (0.1 ml/L mobile phase) was required for the separation of the free acids. Derivatives of 7-[1,2,6,7,8,8a(R)hexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethylheptanoic acid were detected by monitoring the absorbance at 238 nm, as well as the absorbance ratio of 238 nm/228 nm. The desired products, 6(R)-[2-[8(S)-(2-alkylacyloxy)-2(S),6-dimethyl-3- 4

I

i ''i

J

0019/MW14 32 17700IA oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]- 4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, were detected by monitoring the absorbance at 293 nm.

III. 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6dimethyl-3-oxo-l,2,3,7,8,8a(R)-hexahydronaphthyll(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2Hpyran-2-one Following the general procedure described above, the pH of the whole broth from the bioconversion of twenty kilograms of the sodium salt of o 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)- (2,2-dimethylbutyryloxy)-l(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (12,700 liters) was adjusted to 4.0 with 2N sulfuric acid and was then extracted with ethyl acetate (2x4500 The whole broth extraction was followed by an extraction of the ethyl acetate solution into 1N sodium bicarbonate (20% by volume) 20 and the aqueous extract was then washed with ethyl acetate. To the aqueous extract was then added methylisobutylketone (MIBK, 570 and the pH of the aqueous phase adjusted to 3.1 using 7.2N sulfuric acid. The MIBK extract of the acidified aqueous phase was then separated from the aqueous phase which was then extracted with a second time MIBK (570 1,z The MIBK extracts were combined, filtered through diatomaceous earth, azeotropically dried and concentrated in vacuo to 870 liters. The MIBK solution was heated to 95 0 C, and then treated with trifluoroacetic acid (0.9 in MIBK (23

L

F9 0019/MW14 33 17700IA After about 15 minutes, the mixture was cooled to 0 C and washed successively with 1N sodium bicarbonate (0.5 volumes) and water (2x0.5 volumes).

The organic phase was concentrated in vacuo and the residue dissolved in acetonitrile, which was then diluted to 30% acetonitrile using 0.02M phosphate buffer at pH= 7 Aliquots which contain approximately 700 gm. of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-6-hydroxymethyl-2(S)-methyl-l,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetra- 0 hydro-2H-pyran-2-one were chromatographed over an go SP-207 (300 1, brominated copolymer of styrene and o 15 divinylbenzene, Mitsubishi Co.) column. Elution with oO acetonitrile/buffer 37%, 47%, and acetonitrile/water gave the above titled product and the 6-hydroxymethyl compound as a i mixture. The desired product may be further purified 1 20 by removing most of the' 6-hydroxymethyl compound by crystallization by dissolving the mixture in a isopropyl acetate (IPAC) or methyl-t-butyl ether I' (MTBE) and then adding the solution to a non-polar Ssolvent (n-heptane, cyclohexane or petroleum ether).

IV. Isolation of 6(R)-[2-[8(S)-(2,2-dimethyl- Sbutyryloxy)-2(S),6-dimethyl-3-oxo-1,2,3,7,8,8a(R)hexahydronaphthyl-l(S)]ethyl]-4(R)-hydroxy-3,4,5,6tetrahydro-2H-pyran-2-one The crystallization mother liquors from Step III were concentrated to an oil and then dissolved in toluene:methanol:acetonitrile V:V:V) to a final volume of 100 ml. This solution was charged to j F9 0019/MW14 34 17700IA a 10 liter column of Sephadex LH-20 (Pharmacia Inc.) equilibrated with hexane:toluene:methanol (3:1:1, V:V:V) and eluted with this solvent at a flow rate of 100 ml/min.

The desired compound eluted between 11 and 14 column volumes and the rich cut eluant was concentrated to a solid. The product was further purified by preparative reverse phase hplc on a C 18 column (21.4 mm ID x 30 cm) eluted with a linear gradient starting 10 minutes after injection from acetonitrile in water to 75% acetonitrile in water "over 40 minutes at a flow rate of 10 ml/ min. The fractions containing the desired product (eluting at i 29 minutes) were combined and concentrated to yield o about 400 mg. of the desired product in crystalline 000 form.

13C NMR Data (CD 2 C1 2 6 c= 5 3 8 ppm) 0 ppm ppm ppm t010 9.4 36.5 67.0 10.6 36.8 76.0 24.1 37.7 123.1 25 24.3 39.0 124.5 i ,i 25 24.4 39.6 144.3 24.9 42.7 154.9 32.9 43.3 170.2 33.4 63.1 177.6 203.4 MS analysis showed a weak M+ ion at mlz 432 and fragment ions at m/z 316 and 173 (base). UV spectrum exhibited a %max =290 nm, with c=21,900.

In a similar fashion Nocardia autotrophica subsp. canberrica ATCG 35203 (MA618l) was utilized in the bioconversion reaction with the sodium salt of 7-El ,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)- (2,2-dimethylbutyryloxy)-l(S)-naphthyl]-3(R),5(R)-di-hydroxyheptanoic acid to afford the desired products.

Additionally, the sodium salt of 7-El ,2,6,7,8,8a(R)-hexahydro-2(S), 6()dmty-()(-ehluyyoy-()nptyl3R,() dihydroxyheptanoic acid, the sodium salt of ring opened lovastatin, was subjefcted to analogous bioconversion reactions utilizing both 0 N.autotrophic subsp. amethystina ATOG 35204 (MA6180) and N. autotropi subsp. canberrica ATCC 35203 (MA6181) to afford 6(R)-[2-E8(S)-(2-mlethylo butyryloxy)-2(S),6-dimethyl-3-oxo-i ,2,3,7,8,8a(R)-hexahydronaphthylo a 0EXAMPLE 2 Preparation of 6()[-8S-22dmthluyyoy-()6 o dimethyl-3-oxo-l ,2,3,5,6,7,8,8a(R) Octahydronaphthyl-l(S)]-ethyl]-4(R)- 0 0 hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one Thirty milligrams of the dieneone product of example 1 (R 1 2-mothyl-2-butyl, a double bond), dissolved in 3 ml of ethyl acetate, was 00hydrogenated (1 atm H 2 room temperature) over 6 mg of 10% palladium on carbon for 30 hours. Rmvlo h 0 a 0 N 7' 0 MRC/l 147F r 0019/MW14 36 1770-0IA catalyst by filtration and evaporation of the solvent afforded the title compound. IR(film): 1718 cm -1 1665 cm 1 MS(EI): m/z 434 EXAMPLE 3 Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)- 2(S),6-dimethyl-3-oxo-l,2,3,7,8,8a(R)-hexahydronaphthyl-l(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one 6(R)-[2-[8(S)-(2,2-Dimethylbutyryloxy)-2(S),6(R)dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]-4(R)-(t-butyldimethylsilyloxy)-3,4,5,6tetrahvdro-2H-nvran-2-one a a o o o 9 9 o o 09 9 eo 69 09 a o 0 9 a a 99a O 9 9'; t a '9 a o .9,4 irrl 15 Tert-Butyldimethylsilyl chloride (8 g, 52 mmol) was added to a stirred solution of [8(S)-(2,2-Dimethylbutyryloxy)-2(S),6(R)-dimethyl- 1,2,6,7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]-4(R)hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (20 g, 48 20 mmol) and imidazole (6.8 g, 0.1 mol) in DMF (150 mL) at 0°C. The resulting mixture was stirred at 0 0 C for 5 minutes, then warmed to room temperature and stirred for 5 hours. TLC analysis of an aliquot indicated that the reaction was complete. The 25 reaction mixture was poured into cold water and extracted with ether. The ethereal extract was washed with dilute hydrochloric acid, water and sodium bicarbonate solution. After drying over MgS04, the organic extract was filtered and the filtrate was concentrated in vacuo to afford the desired product as a colorless, viscous oil: NMR (CDC1 3 5 0.84 (3H, t, J 7Hz), 0.89 (3H, d, J

B

11 r

I

i i F9 0019/MW14 37 17700IA 7Hz), 0.90 1.09 (3H, d, J 7Hz), 1.11 (3H, 1.12 (3H, 4.30 4.60 5.33 (H, 5.51 5.77 d of d, J 10, 6Hz), 5.98 d, 7J 6(R)-[2-[5(S)-Chloro-4a(S)-hydroxy-8(S)-(2,2dimethylbutyryloxy)-2(S),6(R)-dimethyl-l,2,4a,5, 6,7,8,8a(S)-octahydronaphthyl-l(S)]ethyl]-4(R)- (t-butyldimethylsilyloxy)-3,4,5,6-tetrahydro-2Hpyran-2-one A solution of phenylselenyl chloride (10 g, 52 mmol) in methylene chloride (50 mL) was added dropwise to a stirred solution of compound 2' (25.2 S° 15 g, 48 mmol) in methylene chloride (350 mL) cooled in Sa dry ice/i-propanol bath (-780C). The resulting mixture was stirred at -78°C for 20 minutes, poured into cold water (300 mL) and extracted with ether o 0 0 twice (400 mL, then 150 mL). The combined extracts were dried (MgS0 4 filtered and concentrated to afford an oily residue which was dissolved in tetrahydrofuran (300 mL). This solution was chilled 0. in an ice-bat \COC), and 30% hydrogen peroxide o mL) was added. The resulting mixture was stirred at .o 25 0°C for 5 minutes, then warmed to room temperature Sand stirring continued for 1 hour. The reaction Smixture was poured into cold water and extracted with chloroform three times (400 mL, then 2 x 100 mL).

The combined extracts were dried (MgSO 4 filtered and concentrated to yield a residue which was purified by flash chromatography on a silica gel column. Elution with hexane:ethyl acetate (5:1/v:v) removed the impurities. Further elution with

I

*"*at 0019/MW14 38 17700IA Bj! 1 I o *0 90 o 00 O O 6 O 000 *t 09 00 0 o 0 00 0 t' t il (s t t t hexane:ethyl acetate provided the title compound as a pa)! yellow gum which later solidified on standing: mp 117-8°C, NMR (CDC13) 5 0.075 (3H, s), 0.08 (3H, 0.85 (3H, t, J 7Hz), 0.88 (9H, s), 0.89 (3H, d, J 7Hz), 1.15 (3H, 1.16 (3H, s), 1.32 (3H, d, J 7Hz), 1.58 (2H, q, J 7Hz), 3.39 4.05 bs), 4.30 4.60 5.32 5.59 d, J 11Hz), 5.79 d of d, J 11, 6Hz).

Anal. Calcd. for C 3 1

H

53 C10 6 Si: C, 63.61; H, 9.13.

Found: C, 63.80; H, 9.04.

6(R)-[2-[4a(S)-hydroxy-8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-l,2,4a,5,6,7,8,8a(S)octahydronaphthyl-l(S)]ethyl]-4(R)-(t-butyldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (41) Tributyltin hydride (7.06 ml, 26.25 mmol) and azobisisobutyronitrile (AIBN) (0.82 g, 5.0 mmol) were added to a magnetically stirred solution of chlorohydrin 3' (8.78 g, 15 mmol) in benzene (100 ml). The resulting solution was refluxed for 2 hours, cooled and concentrated in vacuo to a viscous yellow oil which was stirred with pet ether (200 ml) at -15 0 C (ice/acetone bath) to provide 4' as a fluffy, colorless solid (6.9 g, mp 97-9 0 The filtrate was extracted with CH 3 CN (4 x 50 ml) to remove all of the product contained in the pet ether. The CH 3 CN extracts were combined and concentrated to a colorless oil which was purified by flash chromatography on a silica gel column. Elution with ethyl acetone/hexane gave a colorless 7- 11 F9 0019/MW14 39 17700IA solid (1.0 g) which was stirred in pet ether (25 ml) at'0°C to remove some tin residues. The mixture was filtered to provide the product 4' as a colorless solid. M.P. 103-4 0 C, nmr (CDC13) 6 0.07 (3H, s), 0.08 (3H, 0.88 (9H, 1.15 (3H, 1.16 (3H, 1.20 (3H, d, J 7Hz), 2.78 4.28 m), 4.58 5.30 5.58 d, J 10Hz), 5.67 dd, J 10, Anal. Calcd. for C 31

H

5 4 0 6 Si: C, 67.59; H, 9.88.

Found: C, 67.20; H, 9.99.

6R-[2-[3-oxo-8(S)-(2,2-dimethylbutyryloxy)-2(S)6- (R)-dimethyl-1,2,3,5,6,7,8,8a-octahydronaphthyl S 15 l(S)]-ethyl]-4(R)-(t-butyldimethylsilyloxy)-3,4,5, 6-tetrahydro-2H-pyran-2-one. 7.2 g (12 mmol) of compound was combined with 60 ml of toluene and 42 g of pyridinum o chlorochromate/aluminum oxide. The mixture was stirred and heated on a steam bath for 20 minutes after which time tlc showed the reaction to be complete. The mixture was cooled, filtered and the solids washed with warm toluene (4 X 50 ml). The solvent was evaporated to yield an amber gum. Nmr a 25 (CDC13) 5 0.073 (3H, 0.079 (3H, 0.804 (3H, t, J 7 Hz), 0.881 (9H, 1.026 (2H, d, J 6 Hz), 1.036 (3H, d, J 6 Hz), 1.10 (6H, br 2.55 2.66 (3H, 4.276 4.588 m) 5.42 m), 5.910 d, J 1.5 Hz) r 0019/MW14 40 17700IA i

-A

o 4o 0 o o eQ 00 e o 0 00 00 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)dimethyl-3-(trimethylsilyloxy)-l,2,6,7,8,8a(R)hexahydro-l(S)]ethyl]-4(R)-(t-butyldimethylsilyloxy).3,4,5,6-tetrahydro-2H-pyran-2-one. The amber gum product of Step 3d was dissolved in methylene chloride and cooled to 0 C under argon. The solution was treated with triethylamine (7.2 ml, 50 .mmol) followed by slow addition of trimethylsilyl trifluoromethanesulfonate (5.4 ml, 28 mmol) while maintaining the temperature below 3 0 C. After stirring at 0°C for 15 minutes (tlc showed the reaction to be complete by 5 minutes) the dark solution was diluted with methylene chloride 15 (100 ml), washed with sat. NaHC03 (100 ml), dried and the solvent evaporated.

6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6dimethyl-3-oxo-l,2,3,7,8,8a(R)-hexahydronaphthyl- 20 l(S)]ethyl]-4(R)-(t-butyldimethylsilyloxy)- 3,4,5,6-tetrahydro-2H-pyran-2-one. The dark-amber residue of Step (3e) was dissolved in acetonitrile/tetrahydrofuran. Palladium (II) acetate (3.0g, 13.0 mmol) was added to the mixture and the mixture stirred at room temperature for 22 hours, at which time tic showed the reaction to be complete. The mixture was filtered through a 3 cm pad, of silica gel and then washed with ethyl acetate (150 ml), and the solvent evaporated. Nmr (CDC1 3 8 0.076 (3H, s) 0.082 (3H, s) 0.752 (3H, t, J 7 Hz) 0.883 (9H, s) 1.033 (3H, d, J 7 Hz) 1.059 (3H, s) 1.065 (3H, s) 1.804 (3H, s) 4.295 m) 4.606 m) 5.408 m) 5.781 br 6.136 br s).

4 44 *0 444 I,1 I, (0 0019/MW14 41 17700IA 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6dimethyl-3-oxo-l,2,3,7,8,8a(R)-hexahydronaphthyl- 1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- L The dark brown gum of Step (3f) was dissolved in tetrahydrofuran, and to this was added a mixture of tetra-n-butyl ammonium fluoride (30 ml) and acetic acid (5.6 ml). The combined mixture was stirred at 50 0 C for 4 hours, cooled, diluted with ethyl ether (400 ml) washed with water (5x100 ml), dried and the solvent evaporated. The residue 040 solidified to a brown mass. The brown mass was chromatographed on a 50 mm LP column using 15 hexane-ethylacetate, 1:1 for the first 10 fractions S.o (25 ml fractions) then 1:2 for 11, then 1:4. The 4 titled product was found in fractions 25-53, m.p.

160-174oC. This chromatographed product was then rccrystallized from ethyl acetate (30 ml)-hexane ml). After drying at 60 0 C for 2 hours under a vacuum the titled product was obtained with M.P. 179-180 0

C.

Nmr (CDC1 3 6 0.758 (3H, t, J 7.4 Hz) 1.035 (3H, d, J 7.4 Hz) 1.063 (3H, 1.069 (3H, 1.867 (3H, 2.63 ddd, J 1.47, 3.64, 12.6 Hz), 2.749 (H, dd, 4.94, 12,6 Hz) 4.398 4.645 5.424 i4 5.781 brs), 6.138 brs) Mj Anal. Calcd. for C 2 5

H

36 0 6 C, 69.42; H, 8.39 -Found: C, 69.73; H, 8.54 EXAMPLE 4 Preparation of 6(R)-[2-[3-oxo-8(S)-(2,2-dimethylbutyryloxy)-2(S), 6(R)-dimethyl-1,2,3,5,6,7,8,8aoctahydronaphthyl-l(S)]ethyl]-4(R)-hydroxy-2,4,5,6tetrahydro-2H-pyran-2-one.

e 2 1. j F9 0019/MW14 42 17700IA A solution of compound (500 mg, 0.9 mmol) of example 3 in acetic acid (42 ml) and water ml) was heated at 70 0 C for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with ether. The ethanol extract was washed with water five times, then washed with aqueous sodium bicarbonate and brine. After drying and filtration, the filtrate was evaporated to afford a residue which was purified by flash chromatography on silica gel column. Elution of the column with of acetone in methylene chloride gave the title o compound as a solid: mp 117-8 0 C; nmr (CDC1 3 5 0.80 (3H, t, J 7 Hz), 1.02 (3H, d, J 7 Hz), 1.04 (3H, S0 15 d, J 7 Hz), 1.10 (6H, 2.64 m of d, J 18 2.72 d of d, J 18, 4 Hz), 4.3H m), 4.65 5.44 5.92 bs).

4 Anal. Calcd. for C 2 5

H

3 8 0 6 C, 69.09; H, 8.81 Found: C, 68.85; H, 8.65 EXAMPLE 5-9 Following the procedure of Example 3 and o substituting an equivalent amount of reactant for simvastatin in step the product is formed.

I. iA F9 0019 /MW14 43 1770OIA

HOO,

0

/C

HO

0

/C

kC

H

3 4 ~0 4 4 *4 o 44 4 4 4 44 4 4 4 44 4 4 4 4, 4 4.

4 4 a a4 4.

4 44 15 Examp 1e 2-butyl,

R

2

CH

3 2-butyl, R 2

H;

2-methyl--2-butyl, R 2

=H;

2-methyl-2-butyl, R 2

-CH

2

OH;

2-butyl, R 2

CH

2 0H.

iij EXAM4PLE Preparation of Ammnonium Salts of Compounds II 25 The lactone (1.0 mmol) from Example 1 is dissolved with stirring in O.1N NaOH (1.1 rnmol) at ambient temperature. The resulting solution is cooled and acidified by the dropwise addition of 1N HCl. The resulting mixture is extracted with diethyl ether and the extract washed with brine and dried (MgSO 4 The MgSO 4 is removed by filtration and the F9 0019/MW14 44 17700IA filtrate saturated with ammonia (gas) to give a gum which solidified to provide the ammonium salt.

EXAMPLE 11 Preparation of Alkali and Alkaline Earth Salts of Compounds II To a solution of 42 mg of lactone from Example 1 in 2 ml of ethanol is added 1 ml of aqueous NaOH (1 equivalent). After one hour at room temperature, the mixture is taken to dryness in vacuo to yield the desired sodium salt.

o In like manner, the potassium salt is prepared using one equivalent of potassium hydroxide, 15 and the calcium salt, using one equivalent of CaO.

o EXAMPLE 12 a Preparation of Ethylenediamine Salts of Compounds II a 0 To a solution of 0.50 g of the ammonium salt from Example 10 in 10 ml of methanol is added 0.75 ml of ethylenediamine. The methanol is stripped off BO°° under vacuum to obtain the desired ethylenediamine 0 salt.

EXAMPLE 13 Preparation of Tris(hydroxymethyl)aminomethane Salts I of Compounds II To a solution of 202 mg of the ammonium salt from Example 10 in 5 ml of methanol is added a solution of 60.5 mg of tris(hydroxymethyl) aminomethane in 5 ml of methanol. The solvent is removed in vacuo to afford the desired tris(hydroxymethyl)aminomethane salt.

0019/MW14 45 17700IA a .o o o 0 o0 0 0 0 0 EXAMPLE 14 Preparation of L-Lysine Salts of Compounds II A solution of 0.001 mole of L-lysine and 0.0011 mole of the ammonium salt from Example 10 in ml of 85% ethanol is concentrated to dryness in vacuo to give the desired L-lysine salt.

Similarly prepared are the L-arginine, L-ornithine, and N-methylglucamine salts.

EXAMPLE Preparation of Tetramethvlammonium Salts of Compounds II 15 A mixture of 68 mg of ammonium salt from Example 10 in 2 ml of methylene chloride and 0.08 ml of 24% tetramethylammonium hydroxide in methanol is diluted with ether to yield the desired tetramethylammonium salt.

EXAMPLE 16 Preparation of Methyl Esters of Compounds II To a solution of 400 mg of lactone from Example 1 in 100 ml of absolute methanol is added 25 ml 0.1 M sodium methoxide in absolute methanol. This solution is allowed to stand at room temperature for one hour, then is diluted with water and extracted twice with ethyl acetate. The organic phase is separated, dried (Na 2

SO

4 filtered and evaporated in vacuo to yield the desired methyl ester.

-i 0000 0-00 01 $000 I F9 0019/MW14 46 17700IA In like manner, by the use of equivalent amounts of propanol, butanol, isobutanol, t-butanol, amylalcohol, isoamylalcohol, 2-dimethylaminoethanol, benzylalcohol, 2-acetamidoethanol and the like, the corresponding esters are obtained.

EXAMPLE 17 Preparation of Free Dihydroxy Acids The sodium salt of the compound II from Example 11 is dissolved in 2 ml of ethanol-water v:v) and added tQ 10 ml of 1N hydrochloric acid from which the dihydrc-y acid is extracted with ethyl °o o acetate. The organic extract is washed once with 15 water, dried (Na 2 S04), and evaporated in vacuo with a bath temperature not exceeding 30 0 C. The dihydroxy o 00 acid derivative slowly reverts to the corresponding, o0 parent lactone on standing, but is stable at a pH 0 above 7.

0 0 EXAMPLE 18 As a specific embodiment of a composition of this invention, 20 mg of lactone from Example 1, is Sformulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

m i

Claims (6)

1. A compound represented by the following structural formulae or (II): Ho**..0 2 z 0 0 H P 1 0 R, 0 CH 3 CH 3 a a R 2 0 wherein: 0 Rl is selected from: G 1 10 alkyl; substituted Cl 1 0 alkyl in which one or more substituent(s) is selected from 04(a) halogen, 4:0:0(b) hydroxy, 25 C1_10 alkoxy, Cl 1 5 alkoxycarbonyl, Cl 1 5 acyloxy, C3- 8 cycloalkyl, phenyl, substituted phenyl in which the substituents are X and Y, I 35/MW20 48 1770OIA-B (3) (4) (6) o 00 o *0 00 to 00 0 o a 0 nO o a ~'O 00 o 004 O 0 C 1 10 alkylS(O)n in which n is 0 to 2, C 3 8 cycloalkylS(0)n, phenylS(0)n, substituted phenylS(O)n in which the substituents are X and Y, and (in) oxo; C1_10 alkoxy; C 2 10 alkenyl; C 3 8 cycloalkyl; substituted C 3 8 cycloalkyl in which one substituent is selected from Cl- 10 alkyl substituted C 1 10 alkyl in which the substituent is selected from halogen, (ii) hydroxy, (iii) C 1 10 alkoxy, (iv) C 1 5 alkoxycarbonyl, C 1 5 acyloxy, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y (ix) C 3 8 cycloalkylS(O)n, (x phenylS(0)n, 0 00 00 0 0 0* 0 0 0 O 00 00 00 0 000 0000 *0 0 0 1 /MW20 49 35NW2O1770OIA-B (xi) substituted phenylS(O)n in which the substituents are X and Y, and (xii) oxo, C1_ 10 alkylS(0), C3- 8 cycloalkylS(O)n, phenylS(0)n, substituted phenylS(O)n in which the substituents are X and Y, halogen, hydroxy, Cl- 10 alkoxy, Cl 1 5 alkoxycarbonyl, Cl 1 5 acyloxy, phenyl, and substituted phenyl in which the substituents are X and Y; 0 80 0 0 0 0 00 00 0 o 0 0 00 08 8 o oo 00 O 0~'.0 Q (h) (I) (j) WI. 0008 0 0 8 00 0 0 00 8 8 0 80 8 088 phenyl; substituted phenyl in which the substituents are X and Y; amino; (10) Cl 1 5 alkylamino; (11) di(Cl 1 5 alkyl)amino; (12) phenylamino; (13) substituted phenylamino in which the substituents are X and Y; (14) phenyl Cl- 10 alkylamino; substituted phenyl Cl- 10 alkylamino in which the substituents are X and Y; I #000 35/MW20 50 1770OITA-B (16) a member selected from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; and (17) R 3 S in which R 3 is selected from C1_1 0 alkyl, phenyl, and substituted phenyl in which the substituents are X and Y; R 2 is H, CH 3 or CH 2 OH; Ia *9 EQ a a P II a a 4 9 4* 49 a a 440 00 a a 0 a 0 *446 I I II C a II I I I II .9 I I 15 X and Y are independently selected from: a) OH, b) halogen, c) trifluoromethyl, d) C 1 3 alkox-y, e) Cl.. 3 alkylcarbonyloxy, f) phenylcarbonyloxy, g) Cl 1 3 alkoxycarbonyl, h) phenyloxycarbonyl, i) hydrogen; 25 j) Cl 1 5 alkyl; Z is selected from hydrogen; C 1 5 alkyl; substituted Cl 1 5 alkyl in which the substituent is selected from phenyl, 35/MW20 51 17700IA-B dimethylamino, and acetylamino, and 2,3 hydroxypropyl; halogen is C1 or F; a is a single bond or a double bond; and pharmaceutically acceptable salts of the compound (II) in which Z is hydrogen.

2. A compound of Claim 1 wherein: R 1 is selected from: C1- 1 0 alkyl; substituted C1- 1 0 alkyl in which one or more substituent(s) is selected from S* 15 halogen, hydroxy, C 1 10 alkoxy, C1- 5 alkoxycarbonyl, C1- 5 acyloxy, C 3 -8 cycloalkyl, phenyl, substituted phenyl in which the substituents are X and Y, and 1 oxo; C3-8 cycloalkyl; substituted C3- 8 cycloalkyl in which one substituent is selected from C1- 1 0 alkyl, substituted C 1 10 alkyl in which the substituent is selected from halogen, 35/14W20 52 1770OIA-B (iv) (V) (vi) (vii) hydroxy, Cl- 10 alkoxy Cl 1 5 acyloxy, Cl 1 5 alkoxycdrbonyl, phenyl, substituted phenyl in which the substituents are X and Y, o 0* 9 0 0 to 0~0 00 0 0 0 0 00 0 0 0 0 00 00 0 and (viii) oxo, halogen, hydroxy, C 1 10 alkoxy, Cl 1 5 alkoxycarbonyl, Cl 1 5 acyloxy, phenyl, substituted phenyl in which the substitu'ents are X and Y; phenylamino; substituted phenylamino in which the substituents are X and Y; phenylCl-l 0 alkylamino; and substituted phenyl Cl 1 0 alkylamino in which the substituents are X and Y; 1; 0 00 0 0 0 00 4 4 0 04 00 0 000 ~0 0 I 0000 25 X and Y are independently selected from: OH, F, trifluoromethyl, C 1 3 alkoxy, hydrogen, Cl- 5 alkyl. /1W20 53 177001IA-B

3. A compound of Claim 2 RI is Cl- 10 alkyl.

4. A compound of Claim 3 Rl is 2-butyl or 2-methyl-2-butyl; R 2 is H or Gil 3 A compound of Claim 4 group consisting of: wherein: where in: selected from the o 00 0 0 0 00 00 0 0 0 00 00 0 00 0 000 00 0 0 0 0000 0 8 0 80 0 0 0 0 88 0:0 0 0 0 00 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6- dimethyl-3-oxo-l 3 ,7 8a(R)-hexahydronaphthyl- l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one; 15 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6- dimethyl-3-oxo- 2 ,3 ,7 8a(R)-hexahydronaphthyl- l(S)]ethyll-4(R)-hydroxy-3 6-tetrahydro-2H- pyran-2-one; 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S )-methyl-3- oxo-l,2,3,7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]- 4(R)-hydroxy-3 6-tetrahydro-2H-pyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-3-oxo- 2, 3 ,7 ,8,8a(R)-hexahydronaphthyl- l(S)]ethyl]-4(R)-hydroxy-3,4,5,6--tetrahydro-2H- 25 pyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)- dimethyl-3-oxo-l 8a(R)-octahydro- naphthyl-l(S)]ethyl]-4(R)-hydroxy-3 6-tetra- hydro-2H-pyran-2-one; -4 /MW2O 54 1770OIA-B 9 99 6 4 9 24 94 99 o 9 0 o 99 9 9 9 a 99 o 9 999 9 9 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-3-oxo-1l 2,3,5,6,7,8, 8a(R)-octahydronaphthyl- l(S)lethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one; 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6(R)- dimethyl-3-oxo-1,2,3,5,6,7,8,8a(R)-octahydro-, naphthyl-l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetra- hydro.-2H-pyran-2-one; 6(R)-[2--[8(S)-(2-methylbutyryloxy)-2(S methyl-3-oxo-l 8a(R)-octahydronaphthyl- l(S)]ethyll-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one and the corresponding dihydroxy acid and Iesters thereof. 15 6. A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

7. A composition of Claim 6 wherein the therapeutically effective compound is selected from the group consisting of: 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6- 25 dimethyl-3-oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl- l(S)]ethylJ-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylbutyry1oxy)-2(S) dimethyl-3-oxo- 2 ,3 ,7 8a(R)-hexahydronaphthyl- l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one; 4$ £914 1 9 24 94 £999 35/MW2O 55 -17700IA-B )-(2-methylbutyryloxy)-2(S)-methyl-3- oxo-l,2,3,7,8, 8a(R)-hexahydronaphthyl-l(S)]Iethyl]- 4(R)-hydroxy-3 ,4,5 ,6-tetrahydro-2H-pyran-2-one; ,2-dimethylbutyryloxy)-2(S)- methyl-3-oxo-l,2,3,7,8,8a(R)-hexahydronaphthyl- l(S)lethylil-4(R)-hydroxy-3,4,5,6-tetrahydro-2IH- pyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S) dimethyl-3-oxo-l,2,3,5,6,7,8, 8a(R)-octahydro- naphthyl-l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetra- hydro-2H-pyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-3-oxo-l,2,3,5,6,7,8, 8a(R)-octahydronaphthyl- l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one; 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6(R)- dimethyl-3-oxo-l 8a(R)-octahydro- naphthyl-l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetra- hydro-2H-pyran-2-one; 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-3- oxo-l,2,3,r 5,7,8,8a(R)-octahydronaphthyl-l(S)]- etsat]-4(R)-hydroxy-3 6-tetrahydro-2H-pyran- 2-one and the corresponding dihydroxy acid and Q~ esters thereof.

258. A hypocholesterolimic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable nontoxic cationic polymer capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract and a pharmaceutically acceptable carrier. /MW20 56 1770OIA-B 40 04 4 0 0 0 00 0 0 0 00 04 I 4 2 4 00 00 4 0 4 0 9. A method of treating hypercholest- erolemia comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of Claim 1. A method of Claim 9 wherein the therapeutically effective compound is selected from the group of consisting of: 1) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6- dimethyl-3-oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl- l(S)]ethyl]-4(R)-hydroxy--3,4,5,6-tetrahydro-2H- pyran-2-one; 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S) ,6- dimethyl-3-oxo-1, 2 ,3 ,7 ,8 ,8a(R)-hexahydronaphthyl- 15 l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one; )-(2-methylbutyryloxy)-2(S )-methyl-3- oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]- 4(R)-hydroxy-3 ,4,5 ,6-tetrahydro-2H-pyran-2-one; ,2-dimethylbutyryloxy)-2(S)- methyl-3-oxo-l ,2,3 ,7 8a(R)-hexahydronaphthyl- l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one; 6(R)-[2-1-8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)- dimethyl-3-oxo-1,2,3,5,6,7,8,8a(R)-octahydro- naphthyl--l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetra- hydro-2H--pyran-2-one; 0000 0 04 V V V0 35/MW2O 57 -1770OIA-B 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-3-oxo-1,2,3,5, 6,7,8, 8a (R)-octahydronaphthyl- l(S)]ethyl]-4(R)-hydroxy-3 6-tetrahydro-2H- pyran-2-one; 6(R)-[2-r8(S)-(2-methylbutyryloxy)-2(S),6(R)- dimethyl-3-oxo-1 8a(R)--octahydro-' naphthyl-l(S)]ethyl]-4(R)-hydroxy-3 6-tetra- hydro-211-pyran-2-one; 6(R)-[2-[8(S)-(2--methylbutyryloxy)-2(S methyl-3-oxo-1,2,3,5,6,7,8,8a(R)-octahydronaphthyl- 1(S)]ethyl]-4(R)-hydroxy-3 6-tetrahydro-2H- 00 pyran-2-one and the corresponding dihydroxy acid 0004 and alkyl esters thereof. 58 11. 3-keto HMG-CoA reductase inhibitors substantially as hereinbefore described with reference to any one of the Examples. 12. A process for preparing 3-keto HMG-CoA reductase inhibitors, which process is substantially as hereinbefore described with reference to any one of the Examples. 13. The 3-keto HMG-CoA reductase inhibitor product when produced by the process according to claim 12. 14. A pharmaceutical composition for treating hypercholesterolemia in a subject, which composition comprises an amount effective as an antihypercholesterolemic agent in said subject of a 3-keto HMG-CoA reductase inhibitor as defined in claim 11 together with a pharmaceutically acceptable carrier, diluent, adjuvant and/or excipient. A pharmaceutical composition for treating hypercholesterolemia in a subject, which composition comprises an amount effective as an O o antihypercholesterolemic agent in said subject of a 3-keto HMG-CoA reductase inhibitor as defined in claim 11 in combination with a Spharmaceutically acceptable nontoxic cationic polymer capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract, Stogether with a pharmaceutically acceptable carrier, diluent, adjuvant o 20 and/or excipient. 16. A method of treating hypercholesterolemia in a subject, which method comprises administering to a subject in need of such treatment, an amount effective as an antihypercholesterolemic agent in said subject of a 3-keto HMG-CoA reductase inhibitor as defined in claim 11, or a 25 composition as defined in claim 14 or 17. The method of claim 16 wherein said hypercholesterolemia is associated with a disorder selected from arteriosclerosis, hyperlipidemia or familial hypercholesterolemia. DATED this TWENTY-FIFTH day of SEPTEMBER 1991 Merck Co., Inc. Patent Attorneys for the Applicant SPRUSON FERGUSON LMM/632Z i-