5-OXA, 5-THIA, 5-AZA HMG-CoA REDUCTASE INHIBITORS

Abstract: Novel HMG-CoA reductase inhibitors are useful as antihypercholesterolemic agents and are represented by structural formulae (I) and (II), wherein A is O, S(O)n or N-R13.

Description: TITLE OF INVENTION 5-OXA, 5-THIA, 5-AZA HMG-CoA REDUCTASE INHIBITORS BACKGROUND OF THE INVENTION Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid εeguestrants 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 antihyper¬ cholesterolemic agents that functions 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 semi-synthetic and totally synthetic analogs thereof. - 2 - The naturally occurring compounds .and their semi-synthetic analogs have the following general structural formulae: wherein: R 3 is hydrogen, Cχ-5 alkyl or C j _5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and R* is wherein N is R5-C- or R 5 -CH; R 5 is H or OH; M is -CHR 6 , R 6 is hydrogen or hydroxy; R 2 is hydrogen or methyl; and a, b, c, .and d represent single bonds, one of a, b, 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, N is -C= or CH 3 I C- and when d is a double bond, M is = H U.S. Patent application S.N. 048,136 filed May 15, 1987 discloses 6-substituted compounds of the above general formula wherein R* is O 0 wherein R is CH 2 0H, CH 2 θ!R 4 , CO 2 R 7 or CN 8 9; and R 1 , R 4 , R 7 , R 8 and R 9 are broadly defined organic moieties. _" ."^** U.S. Patent application S.N. 142,361 filed January 7, 1988 discloses lovastatin analogs wherein the 6-position is gem-disubstituted: R 2 and R 3 are alkyl or substituted alkyl moieties DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel compounds which are useful as HMG-CoA reductase inhibitors. The specific HMG CoA reductase inhibitors of this invention are the compounds represented by structural formulae (I) and (II): wherein: A is 0 or S or N (0)n R 13 n is 0 to 2; Rl is selected from: (1) Cι_ιo alkyl; (2) substituted Cι_ιo alkyl in which one or more εubstituent(s) is selected from (a) halogen, (b) hydroxy, (c) Cι_ιo alkoxy, (d) Cι_5 alkoxycarbonyl, (e) Cχ_5 acyloxy, (f) C3-.8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, (i) C1--10 alkylS(0) n in which n is 0 to 2, (j) C3_B cycloalkylS(0) n , (k) phenylS(0) n , (1) substituted phenylS(0) n in which the substituents are X and Y, and ( ) oxo; (3) Cι_ιo alkoxy; (4) C2-10 alkenyl; (5) C3_8 cycloalkyl; (6) substituted 03-8 cycloalkyl in which one εubstituent is selected from (a) Cχ-10 alkyl (b) substituted Cι_ιo alkyl in which the εubstituent is selected from & ' ■■ 7- ' (i) halogen, (ii) hydroxy, (iii) Cι_ιo alkoxy, (iv) Cι_5 alkoxycarbonyl, (v) Cι_5 acyloxy, (vi) phenyl, (vii) substituted phenyl in 10 which the substituents are X and Y (viii) Cι_ιo alkylS(0) n , (ix) C 3 _8 cycloalkylS(0) n , 15 (x) phenylS(0) n , (xi) substituted phenylS(0) n in which the substituents are X and Y, and 20 (xii) oxo, (c) Cχ-10 alkylS(0) n , (d) C3_8 cycloalkylS(0) n , (e) phenylS(0) n , (f) substituted phenylS(0) n in 25 which the substituents are X and Y, (g) halogen, (h) hydroxy, (i) Cι_ιo alkoxy, 30 (j) Cι-5 alkoxycarbonyl, (k) Cι_5 acyloxy, (1) phenyl , and (m) substituted phenyl in which the substituents are X and Y; (7) phenyl; (8) substituted phenyl in which the substituents are X and Y; (9) amino; 10 (10) Cι_5 alkylamino; (11) di(Cι_5 alkyl)amino; (12) phenylamino; (13) substituted phenylamino in which the substituents are X and Y; 15 (14) phenyl Cι_ιo alkylamino; (15) substituted phenyl Cι_ιo alkylamino in which the substituents are X and Y; (16) a member selected from (a) piperidinyl, (b) pyrrolidinyl, 20 (c) piperazinyl, (d) morpholinyl, and (e) thio orpholinyl; and (17) R5S in which R5 is selected from 25 (a) Cι_ιo alkyl, (b) phenyl, and (c) substituted phenyl in which the substituents are X and Y; R 2 and R3 are independently selected from: 30 (1) hydrogen; (2) Cι-10 alkyl; and (3) substituted Cι-10 alkyl in which one or more substituents is selected from (a) halogen, (b) hydroacy, ( c ) Cι_ιo alkoxy, , t -^ -__.. -.,,_ _. fmm Λ . f mm (d) C1..5 alkoxycarbonyl, (e) Cχ_5 alkylacyloxy, (f) phenylacy1oxy, (g) phenoxycarbony1, (h) phenyl Cι_5 alkylacyloxy, (i) phenyl Cχ_5 alkoxy, 10 (j) amino, (k) Cι_5 alkylamino, (1) di(Cι_5 alkyl)amino, ( ) phenylamino, (n) substituted phenylamino in which 15 the substituents are X and Y; (o phenyl Ci-s alkylamino, ( P substituted phenyl Cχ_5 alkylamino in which the substituents are X and Y, 20 (g C3_8 cycloalkyl, (r phenyl, (ε substituted phenyl in which the substituents are X and Y, (t phenylS(0) n , 25 (u substituted phenyl S(0) n in which the substituents are X and Y, (v phenyl C1-5 alkyl S(0) n , (v Cι_5 alkylS(0) n , (x phenylaminoacyloxy, 30 Cy Cχ__5alkylaminoacyloxy, (z Cι_5alkylacylamino, (aa) di(phenylCχ_5alkyl)phosphonyl, (bb) di(Cχ_5alkyl)phosphinyl, (cc) phenylCι_5alkylacylamino; (4) R 2 and R3 together with the carbon atom to which they are attached form a C3_8 carbocyclic ring; - 9 - R is selected from: (1) hydrogen; (2) CT.-5 alkyl; (3) substituted Cι_ 5 alkyl in which the εubstituent is εelected from (a) phenyl , (b) dimethylamino, and (c) acetylamino, and (4) 2,3-dihydroxypropyl; 1 3 is selected from: (1) hydrogen; (2) C ! _ 5 alkyl; (3) substituted Cι_5 alkyl in which the subεtituent is selected from: ( ) phenyl, (b) dimethylamino, and (c) acetylamino, and (d) hydroxy, provided that hydroxy is substituted only at C-2, C-3, C-4 or C-5; and (e) Cι_ 5 alkoxy; (4) C 1 .-.5 alkylcarbonyl; (5) Cι_5 alkyloxycarbonyl; (6) Cχ_5 alkylaminocarbonyl; X and Y independently are hydrogen, halogen, trifluoromethyl, Cχ-3 alkyl, nitro, cyano or a group selected from: (1) 6 θ(CH ) m in which m is 0 to 3 and R 6 is hydrogen, Ci^alkyl or hydroxy~C 2 _3alkyl; O 0 (2) R 7 cO(CH 2 ) ro or R 7 θdθ(CH 2 ) m in which R 7 is hydrogen, C 1 -.3alkyl, hydroxy-C 2 -3alkyl, phenyl, naphthyl, amino-Cι_-3alkyl, Cι_3alkylamino- Cι_3alkyl, di(Cι_3alkyl)amino-Cι_3alkyl, hydroxy-C 2 -.-3alkylamino-Cι-_3alkyl, or di(hydroxy-C -3alkyl)amino-Cι_3alkyl; provided that in 7OCO(CH 2 ) m R7 iε not H; O O (3) R8θC(CH2)m n which e is hydrogen, 10 Cι_3alkyl, hydroxy-C 2 -3- alkyl, Cι_3 lkoxy-Ci-_-3al yl, phenyl or naphthyl; O 15 (4) R 9 R 10 N(CH 2 ) m , R 9 R 10 NC(CH 2 ) m O li or RgRιoNCO(CH 2 ) m in which R9 and Rχo independently are hydrogen, Cχ_3 alkyl, hydroxy-C 2 _3alkyl or R9 and Rχo ,,. together with the nitrogen atom to which they are attached form a heterocyclic group selected from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl or thiomorpholinyl; 25 (5) RnS(0) n (CH ) m in which Rn is hydrogen, Cχ_3alkyl, .amino, Cι_3alkylamino or di(Cχ_3alkyl)amino; a is a single bond or a double bond; halogen iε F or Cl; 30 or a pharmaceutically acceptable salt thereof. Except where specifically defined to the contrary, the terms "alkyl", "alkoxy" and "acyl" include both the straight-chain and branched-chain species of the term. One embodiment of this invention is the class of compounds of the formulae (I) and (II) wherein: A is 0 or S(0) n ; Rl is selected from: (1) Cx-xo alkyl; (2) εubεtituted Cι_ιo alkyl in which one or more substituent(s) is selected from (a) halogen, (b) hydroxy, (c) Cι_ιo alkoxy, (d) Cι_5 alkoxycarbonyl, (e) Cχ_5 acyloxy, (f) C3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, and (i) oxo; (3) C3_8 cycloalkyl; (4) substituted C3_s cycloalkyl in which one substituent is selected from (a) Cι_ιo alkyl, (b) substituted Ci-io alkyl in which the substituent is selected from (i) halogen, (ii) hydroxy, (iii) Cx-io alkoxy, (iv) Cι_5 acyloxy, (v) Cχ-5 alkoxycarbonyl, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y, and (viii) oxo, . ;:_.-TE r= O 'T: - 12 - (c) halogen, (d) hydroxy, (e) Cι_ιo alkoxy, (f) Cχ_5 alkoxycarbonyl, (9) Cχ_5 acyloxy, (h) phenyl, (i) εubεtituted phenyl in which the εubstituents are X and Y; (5) phenyl mino; (6) substituted phenylamino in which the substituents are X and Y; (7) phenylCi-ioalkylamino; and (8) substituted phenyl Cχ_χo alkylamino in which the substituents are X and Y; R 2 and R3 are independently selected from • - (1) hydrogen; (2) Cτ-τ .0 alkyl; (3) substituted Cχ_χo alkyl in which one or more substituents is selected from: (a) halogen, (b) hydroxy, or (c) amino; (4) CH 2 Rχ2 iu which Rχ 2 is selected from: (a) Cχ_ 5 alkoxy, (b) Cχ_5 alkoxycarbonyl, (c) Cχ_5 alkylacyloxy, (d) phenylacy1oxy, (e) phenoxycarbony1, (f) phenylCχ_5alkylacyloxy, (g) phenylCχ_5alkoxy (h) Cχ_5alkylamino, (i) di(Cχ_5alkyl)amino, (j) phenylamino. - 13 - (k) substituted phenylamino in which the substituents are X and Y, (1) phenyl Cχ_5alkylamino, ( ) substituted phenyl Cχ-5 alkyl amino in which the substituents are X and Y, (n) C3_8 cycloalkyl, (o) phenyl, (p) substituted phenyl in which the substituents are X and Y, (g) ρhenylS(0) n , (r) substituted phenylS(0) n in which the substituents are X and Y, (ε) phenyl C1-.5 alkylS(0) n , (t) Cχ_5 alkylS(0) n , (u) phenylaminoacyloxy, (v) Cχ_5 alkylaminoacyloxy, (w) C _5 alkylacylamino, (x) di(phenylCι_5alkyl)phosphonyl, (y) di(Cχ-_5alkyl)phosphinyl, (z) phenylCχ_5alkylacylamino; (5) R2 and R3 together with the carbon atom to which they are attached form a C3-8 carbocyclic ring. One subclass of this embodiment is the compounds of the formulae (I) and (II) wherein: x is selected from: (1) Cx-xo alkyl; (2) C3.-8 cycloalkyl; (3) phenylamino; and (4) substituted phenylamino in which the substituents are X and Y. - 14 - Illustrative of this subclass are those compounds of the formulae (I) and (II) wherein 2 and R3 are independently selected from: (1) hydrogen; (2) Cχ_ 5 alkyl; (3) Cχ_5alkyl substituted with hydroxy; (4) CH2RX2 in which R 2 is selected from: (a) Cχ_5alkoxy, (b) Cχ_5alkoxycarbonyl, (c) Cχ_5alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbony1, (f) phenylCχ_5alkylacyloxy, (g) phenylCχ__5alkoxy, (h) phenyl S(0) n , (i) substituted phenyl S(0) n in which the substituents are X and Y, (j) phenylC _5alkyl S(0) n , (k) Cχ- 5 alkyl S(0) n , (1) phenylamino cyloxy, (m) Cχ-5alkylaminoacyloxy, (n) phenyl, (o) substituted phenyl in which the substituents are X and Y; (p) Cχ-5alkylacylamino; (g) phenylCχ_5alkylacylamino; (r) di(phenylCχ__5alkyl)phosphonyl; (ε) di(Cχ-5alkyl)ρhosρhinyl. Further illustrating this subclass are those compounds of formulae (I) and (II) wherein: A is O; a is a single bond; and is 2-methyl-2-butyl or 2-butyl; and R2 and R3 are independently selected from: H, CH3, phenylthiomethyl and. hydroxymethyl. Exemplifying this illuεtration are the following compoundε of the formulae (I) and (II): (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6,6-dimethyl-l,2,3,4, a(R),7,8,- 8a(R)-octahydronaphthyl-l(S)]ethyl]-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one. (hereafter referred to as compound 9) (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)- l,2,3,4,4a(R) ,7,8,8a(R)-octahydronaphthyl-l(S)3- ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one. (hereafter referred to as compound 10) (3) 6(R)-[-2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)- l,2,3,4,4a ( R ) ,7,8,8a ( R ) -octahydronaphthyl-l(S)3- ethyl 3- (R)-hydroxy-3 ,4,5, 6-tetrahydro-2H-pyran- 2-one. (hereafter referred to as compound 11) (4) 6(R)-[2-[8(S)-( 2-methy Ibutyry 1 oxy ) -2 ( S ) -methy 1-5- oxa-6 , 6-dimethyl-l ,2,3,4,4a(R),7,8, 8a(R)-octa- hydronaphthyl-KS) lethyl 3- (R)-hydroxy-3 ,4,5,6- tetrahydro-2H-pyran-2-one . (5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(hydroxymethyl, methyl)-l,2,3, ,4a(R) ,7,8,8a(R)-octahydronaphthyl-l(S)lethyl3 4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. (6) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(hydroxymethyl, methyl)-1,2,3, 4,4a(R),7,8,8a(R)-octahydronaphthyl-l(S)3ethyl] 4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. , » \ » j • * * *-; **.—~t~*ι !™?"*™* Λ« •*•""""•»*• "" (7) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(phenylthiomethyl, hydroxy¬ methyl)-l,2,3, ,4a(R),7,8,8a(R)-octahydro- naphthyl-l(S)3ethyl]-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one. (8) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(phenylthiomethyl, hydroxy¬ methyl)-l,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl- 1(S)3ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H- pyran-2-one. A second illustration of this subclass are those compounds of formulae (I) and (II) wherein: 5 A is S(0) n ; a is a single bond; R l iε 2-methyl-2-butyl or 2-butyl; and R 2 and R3 are independently selected from: H, CH3 and hydroxymethyl. Exemplifying this second illustration are the following compounds of formulae (I) and (II): (1) 6(R)-r2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-thia-6,6-dimethyl-l,2,3,4,4a(R),7,8,8a(R) -cctahydronaphthyl-KS)lethyl3-4(R)-hydroxy- 3,4,5.6-tetrahydro-2H-pyran-2-one. (2) 6(R)-[2-C8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-thia-6(S)-(hydroxymethyl, methyl)- 1,2,3,4,4a,7,8,8a(R)-octahydronaphthyl- l(S)3ethyll-4(R)-hydroxy-3,4,5.6-tetrahydro- 2H-pyran-2-one. (3) 6(R)-[2-[8(S ) -(2,2-dimethylbutyryloxy)-2(S)-met*yl- 5-thia-6(R)-(hydroxymethyl, methyl)-l,2,3, ,4a,- 7,8,8a(R)-octahydronaphthyl-l(S)]ethyl]-4(R)- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. (4) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl- 5-thia-6(S)-(hydroxymethyl)-l,2,3,4,4a,6,7,8,8a(R)- nonahydronaphthyl-KS)lethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one. (5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl- 5-thia-6(R)-(hydroxymethyl)-l,2,3,4,4a,6,7,8,8a(R)- nonahydronaphthyl-1(S)3ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one. (6) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl- 5-thia-5,5-dioxide-6,6-dimethyl-l,2,3,4,4a(R),7,8,- 8a(R)-octahydronaphthyl-l(S)3ethyl3-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one. In a second embodiment is the compounds of formula (I) and (II) wherein A is -Rχ3; Rx is selected from: (1) Cx-xo alkyl; (2) substituted Cχ_χo alkyl in which one or more substituent(ε) iε selected from (a) halogen, (b) hydroxy, (c) Cχ_χo alkoxy, (d) C _5 alkoxycarbonyl, (e) Cχ~5 acyloxy, (f) C 3 __8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, and (i) oxo; (3) C3_8 cycloalkyl; (4) substituted C3_β cycloalkyl in which 10 one substituent is selected from (a) Cχ.χo alkyl, (b) substituted Cχ_χo alkyl in which the subεtituent is selected from (i) halogen, 15 (ii) hydroxy, (iii) Cχ__χo alkoxy (iv) C _5 acyloxy, (v) C _5 alkoxycarbonyl, (vi) phenyl, 20 (vii) substituted phenyl in which the substituents are X and Y, and (viii) oxo, (c) halogen, 25 (d) hydroxy, (e) Cχ_χo alkoxy, (f) Cχ_5 alkoxycarbonyl, (g) Cχ-5 acyloxy, (h) phenyl, 30 (i) substituted phenyl in which the substituents are X and Y; (5) phenylamino; (6) εubεtituted phenylamino in which the substituents are X and Y; (7) phenylCχ_χoalkylamino; and (8) εubεtituted phenyl Cχ_χo alkylamino in which the εubεtituentε are X and Y; R 2 and R3 are independently εelected from (1) hydrogen; (2) Cχ_χo alkyl; (3) εubstituted Cχ_χo alkyl in which one or more substituents is selected from: (a) halogen, (b) hydroxy, (c) amino; (4) CH 2 i2 n which Rχ is εelected from: (a) Cι_5 alkoxy, (b) Cι_5 alkoxycarbonyl, (c) Cχ_5 alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbonyl, (f) phenylCχ_5alkoxy, (h) Cι-5alkylamino, (i) di(Cχ_5alkyl)amino, (j) phenylamino, (k) εubstituted phenylamino in which . the subεtituentε are X and Y, (1) phenyl Cχ_5alkylamino, (m) εubεtituted phenyl Cχ_5 alkyl amino in which the substituents are X and Y, (n) C3_8 cycloalkyl, (o) phenyl, (p) substituted phenyl in which the substituents are X and Y, (g) phenylS(0) n , ( r ) substituted phenyis(0) n in which the substituents are X and Y, "= Q ". (ε) phenyl Cχ_ 5 alkylS(0) n , (t) Cχ_5 alkylS(0) n , (u) phenylaminoacyloxy, (v) Cχ_5 alkylaminoacyloxy, (w) Cχ_5 alkylacylamino, (x) di(phenylCχ__5alkyl)ρhoεphonyl, (y) di(Cχ-5alkyl)phoεpinyl; (5) R and R3 together with the carbon atom to which they are attached form a C3_8 carbocyclic ring. One subclasε of this embodiment is the compounds of the formulae (I) and (II) wherein: R is selected from: (1) Cχ_χ 0 alkyl; (2) C3.-8 cycloalkyl; (3) phenylamino; and (4) * substituted phenyl-amino in which the substituents are X and Y. Rχ3 is selected from: (1) hydrogen; (2) Cχ-5 alkyl; (3) phenylCχ-5 alkyl; (4) Cχ_5 alkylcarbony1. Illustrative of this subclass are those compounds of the formulae (I) and (II) wherein R 2 and R3 are independently selected from: (1) hydrogen; (2) Cχ- 5 alkyl; (3) Cχ_5alkyl εubεtituted with hydroxy; (4) CH Rχ 2 in which Rχ 2 is selected from; (a) Cχ_5alkoxy, (b) Cχ_5alkoxycarbonyl, (c Cχ_5alkylacyloxy, (d phenylacyloxy, (e phenoxycarbonyl, (f phenylCχ_5alkylacyloxy, (g phenylCχ_5alkoxy, (h phenyl S(0) n , (i εubstituted phenyl S(O) n in which the substituents are X and Y, (j phenylalkyl S(0) n , (k Cχ- 5 alkyl S(0) n , (1 phenylaminoacyloxy, (m Ci-salkylaminoacyloxy, (n phenyl, (o εubstituted phenyl in which the substituentε are X and Y. The compounds of formula (I) wherein A iε O and a iε a εingle bond are prepared following Scheme 1: SiS∑ΞSTΠ"T~ _ ~"^ -JLJ- (1-2) (1-3) n-BUgSnH. AIBN C1-9) Compound (1-1) may be prepared from lovastatin or mevaεtatin by replacement, if neceεsary, of the 2-methylbutyryloxy moiety by RχCO 2 . The hydrolysis of the 8-acyloxy moiety and reesterifica- tion may be accomplished following the procedure in U.S. patent 4,444,784. The conversion to compounds (1-1) wherein Q is CH 2 OH and its εilyl protected form can be carried out following the procedures in U.S. patent applications S.N. 161530, S.N. 161579, S.N. 161529 all filed on February 29, 1988. Compound (1-1) iε converted to compound (1-2) by the reduction of the 3,4-double bond following the detailed procedure in U.S. patent application S.N. 092,804 filed September 3, 1987. The monoene (1-2) iε treated with ozone in methanol at about -78°C followed by reduction of the ozonide with Zn/acetic acid and reduction of the intermediate ketoaldehyde with NaBH4 to yield compound (1-3) which after contact with toεyl chloride giveε the toεylate (1-4). Treatment of the toεylate (1-4) with sodium iodide in acetone gives an iodide (1-5). Compound (1-7) iε obtained from the iodide (1-5) by selenation with o-0 2 NPhSeCN followed by oxidative elimination with THF/H O 2 . Treatment of compound (1-7) with iodine/CH 2 Cl in the preεence of NaHCO3 yieldε compound (1-8) as a mixture of epimerε. The epimeric iodides (1-8) can be reduced with a trialkyl tin hydride to afford compounds (1-9). Alternatively (Scheme 2), the epimeric iodides (1-8) can be converted to compounds of formula (2-10) by reaction with an alkyl or heteroatom moiety either by a substitution or radical coupling reaction. One example of such methodology iε the cross-coupling reaction between an alkyl halide and an organo- metallic reagent (e.g. alkyl iodides with lithium dialkylcopper-Posner, Org. React. 22, 253-400 (1975)) SCHEME 2 In the preparation of compounds (I), where R 2 and R3 are both alkyl other than methyl or both substituted alkyl, compounds of formula (1-1) are utilized wherein Q is t-Bu(Me) 2 SiOCH 2 -. The silyloxy protecting group of compound (2-10) is removed employing εtandard techniques and the resulting - hydroxymethyl moiety is halogenated, e.g. triphenyl- phosphine, iodine, imidazole, followed by substitution or radical coupling with an alkyl or heteroatom moiety which reεults in the elaboration of CH 2 I to R3 (Scheme 2a) . SCHEME 2a * Compounds of formulae (I) and (II) wherein a is a double bond may be prepared following the method¬ ology of Scheme 3. This scheme employs εimiliar sequences to that of Scheme 1 but useε one equivalent of NaBH4 to reduce the ketoaldehyde, formed from the Zn/HOAc treatment of the ozonide, to the ketone (3-3) which iε followed by a Pd catalyzed dehydrogenation to insert the 3,4-double bond. The ketone (3-4) is then reduced with a second equivalent of aBH . The primary alcohol (3-5) is iodinated (3-6), converted to the εeleniu derivative (3-7) and oxidized to the olefin (3-8). Treatment of compound (3-8) with iodine/CH 2 Cl 2 in the presence of NaHCθ3 yie ds compounds (3-9) as a mixture of epimers. The epimeric iodides (3-9) can be reduced to compounds of formula (3-10) by reaction with a trialkyl tin hydride. SCHEME 3 Alternatively one can start with a hexahydronaphthyl moiety as in Scheme 2 and protect the 3,4 double bond, using the method described by Kuo in U.S. patent 4,490,546, while the chemical transformations of Scheme 1 are conducted at the 4a, 5 and 6 εites. The protecting group is ultimately removed following the procedure of Kuo. The compounds of formulae (I) and (II) wherein A iε S(0) n are prepared following Schemes 4 and 4a. The lactone is reduced with diisobutyl aluminum hydride (DIBAL) followed by reaction with methanol and para-toluene sulfonic acid (PTSA) to form the acetal (4-4). Acetal (4-4) is then carried through a series of reactions, analogous to those discusε.ed in Scheme 1, to form the olefin (4-8). The 4a alcohol group of Compound (4-8) iε converted to the ketone (4-9) via a Swern oxidation. If desired a double bond can be inserted into the 3,4-poεition of Compound (4-9) by a Pd catalyzed dehydrogenation to form Compound (4-10). The 4a-keto moiety of Compound (4-10) iε converted to a thioketone (4-11) by employing 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadi- phosphetane-2,4-disulfide and following the procedure of Pederson et al... Bull. Soc. Chem. Belg., 8_7 223, (1978). The thioketone (4-11) is reduced to the mercaptan (4-12) followed by cyclization to the sulfide (4-13) employing the method described by Stacey et al.. Organic Reactions, Vol. 13, p. 150, John Wiley & Sons (1963). The acetal moiety iε converted back to the lactone, the hydroxyl protecting group removed, and if deεired the sulfide group oxidized with m-chloroperbenzoic acid ( -CPBA) to form Compound (4-14). The hydroxymethyl moiety of Compound (4-14) can be elaborated to R 2 (Compound - 28 - (4-15)) by conversion to the halomethyl group followed by substitution or coupling with an alkyl or heteroatom moiety as discuεεed above in Scheme 2. The identity and employment of Q iε analogous to that previously discuεsed in Schemes 2 .and 3. In Scheme 4a, azaisobutyronitrile (AIBN) iε employed in the cyclization step to form Compound (4-16) which is then transformed as described above to ultimately form Compound (4-19). SCHCfiE A «-»> -«-10) 1 .S . hy β r..,.. pr β l,« tl», ,1-eup ,u.h .. *iph.« y | r ,. buty l , yl SCHEME4 a The compounds of formula (I) and (II) wherein A is N-R13 are prepared following Scheme 5. The conversions in Scheme 5 proceeding to ketone (5-7) are analogous to those described earlier in Schemes 1 and 4. The insertion of nitrogen iε accomplished through a reductive amination utilizing benzylamine (BnNH 2 ) and reεulting in Compound (5-8). The amine (5-8) is converted to a carbamate (5-9) and then cyclized to the 5-aza analog (5-10) following the procedure of Newcomb et al., Tetrahedron Letters, 26, 5651, (1985) and J. Am. Chem. Soc. , 109, 3163 (1987). The hydroxyl protecting is removed employing tetra-butylammonium fluoride and the N-benzyl group S U BSTI TUTESHEET - 31 - replaced by N-H by reaction with H /Pd/C. The identity and employment of Q in Scheme 5 iε analogous to that as previouεly discuεsed in Schemes 2 and 3. If desired the 3,4-double bond can be inserted in the aza compounds by reaction of Compound (5-7) with PdCl 2 /Pd(OAc) 2 following an analogous methodology to that expresεed in Scheme 4. The enone product iε then tranεformed further to Compound (5-8) etc. following the reactions of Scheme 5. SCHEttE 5 βn*benzy_ Where the reaction conditions of the above described chemical transformations would be deleterious to the substituents contained in R j _, the acetoxy group can be employed as protecting group which after the insertion of the 5-heteroatom moiety and the elaboration of the 6,6-poεitionε can be removed by hydrolysis to give the 8-hydroxy derivative which can then be acylated according to the general procedures described in U.S. Patent 4,661,483 and co-pending U.S. applications S.N. 859,513, 859,524, 859,525, 859,520, 859,534 and 859,535 all filed on May 5, 1986. The alkanoyl chloride for preparing the 8-acyloxy moiety can be formed by standard chemical transformationε such aε substitution with an aϊkyl moiety or other appropriate electrophile at an acidic C-H site on an available starting material; more specifically the 8-a . cyloxy moiety can be prepared following the descriptions in the aforementioned copending patent applications filed on May 5, 1986. It may be necessary to protect substituentε on the R 2 , 3 moieties during such chemical tranεfor ationε aε compoundε (1-8) ► compounds (2-10). Suitable protective groups can be found in Protective Groups in Organic Synthesis, Greene, John Wiley & Sons (1981). Where the product formed by the above described synthetic pathwayε iε not the deεired form of that compound, then that product may be εubjected to one or more further reactions such aε hydrolysis, salification, esterification, acylation, ammonolysiε, deεilylation or lactonization by conventional methods, as described in more detail hereafter. Preferred metal salts are saltε with alkali metals, εuch as sodium or potassium, salts with alkaline earth etalε, such aε calcium, or εaltε with other metalε εuch aε magnesium, aluminum, iron, zinc copper, nickel or cobalt, of which the alkali metal, alkaline earth metal, magnesium and aluminum saltε are preferred, the sodium, calcium and aluminum εaltε being most preferred. Preferred amino acids to form amino acid salts are basic amino acids, εuch aε arginine, lysine, α,β-diaminobutyric acid or ornithine. Preferred amines to form amine salts include t-octylamine, dibenzylamine, ethylenediamine, morpholine, and triε(hydroxymethyl)aminomethane. Alεo preferred is ammonia to form the ammonium εalt. Eεters are preferably the alkyl esters, such as the methyl, ethyl, propyl, isopropyl, butyl, iεobutyl or pentyl esters, of which the methyl ester is preferred. However, other eεterε such aε phenyl- Cι_._5 l yl, dimethylamino-Ci-salkyl, or acetyl- amino-Ci-salkyl may be employed if deεired. Metal εaltε of the carboxylic acidε of formula (II) may be obtained by contacting a hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous εolvent with the carboxylic acid of formula (II). The aqueous solvent employed is preferably water, or it may be a mixture of water with an organic solvent, preferably an alcohol (εuch aε methanol or ethanol), a ketone (εuch as acetone), an aliphatic hydrocarbon (εuch aε hexane) or an ester (εuch aε ethyl acetate). It iε preferred to use a 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 saltε of the carboxylic acidε of formula (II) may be obtained by contacting an amine in an aqueouε solvent with the carboxylic acid of formula (II). Suitable aqueous solvents include water and mixtures of water with alcohols (εuch aε methanol or ethanol), ethers (such aε diethyl ether and tetrahydrofuran) , nitrileε (such as acetonitrile) or ketones (such as acetone); it iε preferred to uεe aqueouε acetone as the solvent for thiε reaction. The reaction iε preferably carried out at a temperature of ambient or below, more preferably a temperature of from 5° to 10°C. The reaction immediately goeε to completion. Alternatively, a metal salt of the carboxylic acid of formula (II) (which may have been obtained aε deεcribed above) can 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 iε then obtained by metatheεiε. Amino acid εaltε of the carboxylic acidε of formula (II) may be obtained by contacting an amino acid in aqueouε εolution with the carboxylic acid of formula (II). Suitable aqueouε solventε include water and mixtureε of water with alcoholε (εuch aε methanol or ethanol) or ethers (εuch as tetrahydrofuran). Esters, preferably alkyl esterε, of the carboxylic acidε of formula (II) may be obtained by contacting the carboxylic acid of formula (II) with an appropriate alcohol, preferably in the preεence of _, .____._—.,-—. •«—— fir ' an acid catalyst, for example a mineral acid (such as hydrochloric acid or sulphuric acid), a Lewis acid (for example boron trifluoride) o * r an acidic ion exchange resin. The solvent employed for this reaction iε not critical, provided that it doeε not adverεely affect the reaction; suitable εolventε include the alcohol itεelf, 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 subεtituted or unsubstituted. Thiε 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 εalt of the carboxylic acid of formula (II) with a halide, preferably an alkyl halide, in a εuitable εolvent; preferred εolvents include dimethylformamide, tetrahydrofuran, dimethylsulfoxide and acetone. Finally, esters may also be obtained from the lactone of formula (I) 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 εyεtem, the reactionε may be conducted with heating or cooling. Lactoneε of the carboxylic acidε of formula (I) may be obtained by lactonizing the carboxylic acidε 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. 347-358 (1985). For estimation of relative inhibitory potencies, compactin (i.e., mevastatin) waε assigned a value of 100 and the IC50 value of the test compound was compared with that of compactin determined εimultaneouεly in the published in vitro protocol. Representative of the intrinsic HMG-CoA reductase inhibitory activities of the claimed compoundε are the following potencieε. Relative Compound No. Rj R 2 R3 Potency 9 2-methyl-2-butyl CH3 CH3 96 10 (α-epimer) 2-methyl-2-butyl CH3 PhSCH 2 258 11 (β-epimer) 2-methyl-2-butyl PhSCH 2 CH 3 280 The compoundε of thiε invention are uεeful as antihypercholeεterolemic agentε for the treatment of " arterioεcleroεiε, hyperlipidemia, familial hyperchόl- esterolemia and 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 end other conditions of human patientε but daily dosage for adults is within a range of from about 10 mg to 2000 mg (preferably 10 to 100 mg) which may be given in two to four divided doses. Higher doses may be favorably employed as required. The compoundε of thiε invention may also be coad inistered with pharmaceutically acceptable - sos(HU £?___"-•—- nontoxic cationic polymers capable of binding bile acidε in a non-reabεorbable form in the gastro¬ intestinal tract. Examples of εuch polymers include choleεtyramine, coleεtipol and poly[methyl-(3-tri- methyla inopropyDimino-trimethylene dihalide] . The relative amountε of the compoundε of thiε invention and theεe polymerε iε between 1:100 and 1:15,000. Included within the εcope of thiε invention is the method of treating arteriosclerosis, familial hypercholesterolemia or hyperlipidemia which compriεes administering to a subject in need of such treatment a nontoxic, therapeutically-effeetive amount of the compounds of formulae (I) or (II) or pharmaceutical compositionε thereof. The following exa pleε illuεtrate the preparation of the compoundε of the formulae (I) and (II) and their incorporation into pharmaceutical compoεitionε and aε such are not to be considered aε limiting the invention set forth in the claims appended hereto. EXAMPLE 1 Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)- 2(S)-methyl-5-oxa-6,6-dimethyl-l,2 ,3, , a(R) ,7,8, βa(R)-octahydronaphthyl-KS)3ethyl]-4(R)-hydroxy- 3,4,5,6-tetrahvdro-2H-pyr n-2-one. Step 1: Preparation of 6(R)-[2-(8(S)-(2,2-dimethyl- butyryloxy)-2(S)-methyl-6(R)-methyl-l,2,3,4, 6,7 ,8,8a(S)-octahydronaphthyl-l(s)]ethyl]- 4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2- one (2) . Nitrogen was bubbled through a εolution of 50% toluene in abεolute ethanol (300 mL) for 5 minuteε. Wilkinεon'ε catalyst (5.0 g, 33%/wt.) was added to the solvent and the mixture reduced at room temperature under 50 psi H 2 for 1 hour. Simvastatin (15 g, 36 mmol) waε added and the resulting pale yellow εolution reduced at room temperature under H 2 (60 psi) for 40 hours. The mixture was concentrated and the residue heated in toluene (700 mL) at 60°C in the presence of thiourea (5.0 g, 64 mmol) for 1.5 hours. The mixture was cooled to 0°C (ice bath), filtered, and concentrated. The residue was diluted with 50% EtOAc/hexane and passed through a pad of • silica (-250 cc) to give 2 as a beige solid; mp * • 128-129 β C (ethyl/hexane); TLC Rf = 0.65 (EtOAc); *H NMR (CDC1 3 ) δ 5.36 (bε, 1H), 5.30 (m,lH), 4.58 (m,lH)., 4-33 (m,lH), 2.68 (dd,J = 17 and 5Hz,lH), 2.68 (m,lH), 2.59 (dd, J ■ 17 and 4Hz,lH), 2.30-1.20 (m), 1.13 (ε,3H), 1.12 (ε,3H), 1.05 (d, J - 7Hz,3H), 0.87 (d, J = 7Hz,3H), 0.82 (t, J - 7Hz,3H). Step 2: Preparation of 6(R)-[2-[6(R)-(l(S)-2,2- dimethylbutyryloxy-3(R)-methyl-butan-4-ol)- 2(S)-methyl-5(R)-hydroxy-cyclohexyl-l(S) 3- ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one (3) . Ozone was passed through a red solution of monoene 2 (420 mg, 1.0 mmol) .and l-(p-phenylazo- phenylazo)-2-naphthol (εudan III) (5 mg) in CH3OH (10 mL) at -78 β C until the red color diεsipated (10 minutes). Argon was then bubbled through the εolution to remove excess ozone. Addition of zinc (200 mg, 3.0 mmol) and acetic acid (1.0 mL) was followed by removal of the cooling bath and vigorous stirring for 15 minutes. The reaction mixture was diluted with :t f T" -"*."?"- 1 **"* " m ethyl acetate and filtered through celite. The filtrate was waεhed with H 0 and brine, dried (MgSO.4), and concentrated. The crude keto-aldehyde was immediately dissolved in THF/H 2 O (10:1, 8.0 mL), cooled to 0°C, and treated with NaBH (100 mg, 3.0 mmol) in 2 portionε. After 20 minutes the reaction mixture was diluted with ethyl acetate, washed with H 2 0, and brine, dried (MgSO-4), and concentrated. Flash chromatography (silica, EtOAc) gave the desired product as an oil. λ H NMR (CDCI3): δ 5.55 ( , IH), 4.72 (m, IH), 4.38 (m, IH), 3.61 (dd, IH, J=10 and 3Hz), 3.44 (dd, IH, J=10 and 3Hz), 3.39 (m, IH) , 2.73 (dd, IH, J=15 and 3Hz), 2.63 ( , IH), 2.01-1.20 (m) , 1.15 (s, 6H) , 0.96 (d, 3H, J=4Hz), 0.85 (t, 3H, J=6Hz) 0.83 (d, 3H, J=7Hz). Elemental Anal. C 2 5H44θ7»l.OH 2 0 Calc'd: C, 63.26; H, 9.77 Found: C, 63.13; H, 9.51 Step 3: Preparation of 6(R)-[2-[6(R)-(l(S)-2,2- dimethylbutyryloxy-3(R)-methyl-4-p-toluene- εulfonyl-butane)-2(S)-methyl-5(R)-hydroxy- cyclohexyl-1(S)3ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one■ ( ) To a εtirred εolution of the triol 3 (100 mg, 0.22 mmol), pyridine (71 ml, 1.0.mmol), and dry CH 2 C1 2 (l.l mL) at 0°C, waε added p-toluenesulfonyl chloride (50 mg, 0.26 mmol). After 5 minutes the cooling bath was removed and the reaction εtirred overnight. The reaction mixture waε diluted with ethyl acetate, waεhed with H 0 and brine, dried (MgSC*4), .and concentrated. Flaεh chromatography (εilica, 8% acetone/CH 2 Cl ) furniεhed the desired product as a colorless foam. λ H NMR (CDCI3): δ 7.75 (d, 2H, J«8Hz), 7.31 (d. 2H, J«8Hz), 5.45 (m, IH) , 4.66 (m, IH), 4.33 (m, IH) , 4.02 (dd, IH, J=10 and 5Hz), 3.79 (dd, IH, J-10 and 4Hz), 3.32 ( , IH) , 2.63 (m, 2H) , 2.40 (S, 3H), 2.00-1.20 (m), 1.10 (S, 6H) , 0.90 (d, 3H, J=7Hz), 0.80 (d, 3H, J=7Hz), 0.78 (t, 3H, J=7Hz) Step 4: Preparation of 6(R)-[2-[6(R)-(l(S)-2,2- dimethylbutyryloxy-3(R)-methyl-4-iodo- butane)-2(S)-methyl-5(R)-hydroxy-cyclohexyl- l(S)3ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one. (5) A εtirred mixture of the toεylate 4_ (0.80g, 1.3 mmol), Nal (1.2g, 7.8 mmol), and acetone (8.0 L) waε heated to reflux for 2.Oh. The cooled reaction mixture waε diluted with ether, waεhed εeguentially with H 2 0, 10% a Sθ3, and brine, dried (MgSC.4), and concentrated. Flaεh chromatography (εilica, ether) gave the desired product 5 aε a colorleεε oil. --•H NMR (CDCI3): 6 5.44 (m, IH), 4.68 (m, IH) , 4.37 (m, IH), 3.40 (m, IH), 3.32 (dd, IH, J-15 and 5 Hz), 3.25 (dd, IH, J-15 and 3 Hz), 2.70 (dd, IH, J-15 and 4 Hz), 2.61 (m, IH) , 2.00-1.28 (m), 1.13 (S, 6H) , 0.98 (d, 3H, J-7HZ), 0.83 (t, 3H, J«=7Hz), 0.82 (d, 3H, J=7Hz) " Step 5: Preparation of 6(R)-[2-[6(R)-(l(S)-2,2- dimethylbutyryloxy-3(R)-methyl-4-o-nitro- phenylεeleno-butane)-2(S)-methyl-5(R)- hydroxy-cyclohexyl-l(S)3'ethyl3-e(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one■ (6) A εtirred εolution of the iodide 5. (208 mg, 0.37 mmol), 2-nitrophenyl εelenocyanate (167 g, 0.75 mmol), and dry DMF (2.0 ml) waε degaεεed, cooled to 0°C and then treated with NaBH (14 mg, 0.37 mmol). After 10 minuteε the cooling bath waε removed and the mixture εtirred for 2.0 hours. The reaction mixture was diluted with ethyl acetate, washed with H 2 0 and brine, dried (MgSC-4), and concentrated. Flash chromatography (εilica, 70% EtOAc/hexane) afforded the desired product 6 as a yellow oil. iH NMR (CDCI3): δ 8.23 (m, IH), 7.54 (m, 2H) , 7.28 ( , IH), 5.60 (m, IH) , 4.67 (m, IH) , 4.38 (m, IH) , 3.35 (m. IH), 3.05 (dd, IH, J=ll and 4Hz), 2.80 (dd, IH, J-ll and 4 Hz), 2.68 (m, 2H), 2.00-1.30 (m) , 1.55 (S, 3H), 1.54 (d, 3H), 1.16 (d, 3H), 1.14 (S, 3H), 0.81 (t, J=6Hz) step 6 : Preparation of 6 (R)-[2-[ 6(R)-( l (S)-2 ,2- dimethylbutyry loxy-3-methy 1-3-butene ) -2 ( S ) - methyl-5 ( R)-hydroxy-cyclohexyl-l (S ) 3ethyl 3- 4 (R)-hydroacy-3 , 4 , 5 , 6-tetr ahydro-2H-pyran-2- one . ( 7 ) To a stirred εolution of the εelenide 6. (250 g, 0.33 mmol) in THF (3 ml) at 0 β C was added 30% H 0 2 (75 μl, 0.66 mmol) dropwise. After 5 minutes the cooling bath was removed and the reaction mixture εtirred overnight. The orange εolution was diluted with ethyl acetate, washed with εat. NaHCC*3 and brine, dried (MgSC-4), and concentrated. Flash chromatography (εilica, ether) furniεhed the desired product 2 aε an oil. ■ -•H NMR (CDCI3): δ 5.48 (m, IH), 4.78 (d, 2H, J«5Hz), 4.70 ( , IH), 4.40 (m, IH) , 3.43 (m, IH), 2.74 (dd, IH, J=16 and 3Hz), 2.64 (m, IH) , 2.55-2.27 (m, 2H), 2.05-1.24 (m), 1.15 (ε, 6H), 0.85 (d, 3H, J=7Hz), 0.84 (t, 3H, J=7Hz). Elemental Anal. C 2 5H4 2 C*6 β 0.5 H 2 0: Calc'd: C, 67.08; H, 9.68 Found: C, 66.91; H, 9.61 Step 7: a) Preparatio of 6(R)-[2-[8(S)-(2,2- dimethyIbutyry1oxy)-2(S)-methyl-5-oxa-6(S)- (iodomethyl, methyl)-l,2,3,4,4a(R) , 7,8,8a- ' (R)-octahydronaphthyl-l(S)]ethyl3-4(R)- - hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(8a) b) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)- 2(S)-methyl-5-oxa-6(R)-(iodomethyl, methyl)- 1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl- 1(s)ethyl3- (R)-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one. (8b) A εtirred mixture of the olefin 2 (1*9 m 9' 0.34 mmol), HCO3 (115 g, 1.3 mmol), and CH 2 C1 2 (3.4 mL) at 0°C was treated with iodine (173 mg, 0.68 mmol) in one portion. After 15 minutes the dark red mixture was diluted with ethyl acetate, waεhed sequentially with H 2 0, 10% Na 2 SC*3, and brine, dried (MgSC*4), and concentrated. Flash chromatography " (silica, ether) afforded the crude product & (1:1 mixture of epimerε) aε a red oil. iH NMR of mixture (CDCI3): δ 5.20 (m, IH) , 4.58 (m, IH), 4.35 (m, IH) , 3.79 (d, 0.5H, J-8Hz), 3.61 (m, 0.5H), 3.48 (m, 0.5H), 3.34 (d, 0.5H, J-8Hz), 3.17 (m, IH), 2.71 (dd, IH, J-15 and 5Hz), 2.30-1.10 (m) , 0.84 (m, 6H). Step 8: 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6,6-dimethyl-l,2,3,4,4a(R),7,8,- 8a(R)-octahydronaphthyl-l(S)3ethyl3-4(R)- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. 12 ) A stirred mixture of iodides 13 (153 mg, 0.27 mmol), tributyltin hydride (237 μl, 0.81 mmol), and azaisobutyronitrile (AIBN) (2mg) in degasεed toluene (1.4 ml) waε heated at 80°C for 4.0 hours. The • cooled reaction mixture waε concentrated to dryneεs. The residue was disεolved in CH3CN (10 ml) and waεhed with hexanes (10X). The hexane waεhes, containing tin byproducts, were decanted away from the acetonitrile. The acetonitrile was evaporated and the residue subjected to flaεh chromatography (εilica, 20% EtOAc/CH Cl 2 ) to furniεh the crude product. The crude material waε purified by preparative plate (0.5 mm, εilica, 20% EtOAc/CH 2 Cl 2 ) chromatography to yield the deεired product 9 as a colorlesε oil. f * *. _» iH NMR (CDC1 3 ): δ 5.20 (m, IH), 4.59 (m, IH), 4.37 (m, IH), 3.63 (m, IH), 2.73 (dd, IH, J-16 .and 4Hz), 2.61 (m, IH), 2.00-1.15 (m) , 1.32 (S, 3H) , 1.27 (S, 3H), 1.25 (S, 3H), 1.24 (S, 3H) , ' 0.87 (d, 3H, J-6Hz), 0.84 (t, 3H, J-7HZ) Elemental Anal. C 2 5H4 2 Og*»1.0H 2 O Calc'd: C, 67.23; H, 9.93 Found: C, 66.87; H, 9.61 EXAMPLE 2 Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)- 2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)-l,- 2,3,4,4a(R) ,7,8,8a(R)-ρctahydronaphthyl-l(S) 3ethyl3- 4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. (10) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5- oxa-6(R)-(phenylthiomethyl, methyl)-l,2,3,4,4a(R) ,7,- 8,8a(R)-octahydronaphthyl-l(S)]ethyl3-4(R)-hydroxy- 3-,4,5,6-tetrahydro-2H-pyran-2-one. (11) Stepε 1-7 were repeated following the procedure of Example 1 . Step 8 ; Preparation of 6(R)-[2-[ 8(S)-(2 ,2-dimethyl- butyryloxy)-2(S)-methyl-5-oxa-6(S)-(p enyl- thiomethyl , methyl )-l , 2,3 , 4 , 4a(R) , 7 , 8 ,8a(R)- octahydronaphthyl-1 (S) 3ethyl 3-4 (R)-hydroxy- 3 , 4 , 5 , 6-tetrahydro-2H-pyran-2-one . ( 10 ) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)- l,2,3,4,4a(R),7,-8,8a(R)-octahydronaphthyl- 1(S)3ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one. (11) A degassed εolution of iodideε 8 (120 mg, 0.21 mmol), thiophenol (110 μl, 1.0 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (150 μl, 1.0 mmol), and dry DMF was heated at 80°C for 4.0 hours. The cooled reaction mixture was diluted with ether, washed with H 2 0 (2X) and brine, dried (MgS04), and concentrated. Flash chromatography (silica, 80% EtOAc/hexane) gave a 1:1 mixture of epimerε as a colorleεε oil. Separation of the epimerε was accomplished by preparative plate chromatography (0.5 mir. silica, 65% EtOAc/benzene) to furnish the faster moving α-epimer _ip_ and the slower moving β-epimer 1JL aε colorless oils. α-epimer: ^ NMR (CDCI3): δ 7.40-7.10 (m, 5H), 5.23 (bε, IH), 4.56 (m, IH), 4.34 (m, IH), 3.62 (m, IH), 3.06 (d, IH, J-13HZ), 2.95 (d, IH, J-13Hz), 2.70 (dd, IH, J-15 and 5Hz), 2.58 (dd, IH, J-15 and 2Hz), 2.14 (m, IH), 2.00-1.14 (m), 1.40 (S, 3H), 1.17 (S, 3H), 1.16 (S, 3H), 0.84 (d, 3H, J«7Hz), 0.83 (t, 3H, J-7Hz) β-epimer: λ H NMR (CDCI3): δ 7.40-7.10 (m, 5H>, 5.20 (m, IH), 4.56 (m, IH), 4.33 (m, IH), 3.64 (d, IH, J-12HZ), 3.48 (m, IH) , 3.04 (d, IH, J«12Hz), 2.70 (dd, IH, J-15 and 5Hz), 2.58 (m, IH), 2.22-1.10 (m), 1.29 (S, 3H), 1.13 (S, 3H), 1.12 (S, 3H) , 0.83 (d, 3H, J-7Hz), 0.82 (t, 3H, J-7Hz). EXAMPLE 3 Preparation of 6(R)-[8(S)-(2-methylbutyryloxy)- 2(S)-methyl-5-oxa-6,6-dimethyl-l,2,3,4,4a(R),7,8, 8a(R)-octahydronaphthyl-l(S)ethyl3-4(R)-hydroxy-3,4,5 6-tetrahydro-2H-pyran-2-one. (12) Utilizing the general procedure of Example 1 but substituting 6(R)-[2-8(S)-(2-methylbutyryloxy)- 2(S)-methyl-6(R)-methyl-l,2,6,7,8,8a(R)-hexahydro- naphthyl-l(S)3ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one, for the starting polyhydronaphthyl moiety, the titled compound iε prepared. EXAMPLES 4-33 Utilizing the general procedureε in Exampleε 1-2 and, where a iε a double bond, the modificationε of Scheme 3, the following compoundε of formula I wherein Ri - 2-methyl-2-butyl and A - O are prepared from the appropriately substituted starting materials sb = single bond db - double bond ■EXAMPLE 34 Preparation of Ammonium Salts of Compounds II The lactone (1.0 mmol) from Example 1, Step 8, is dissolved with stirring in 0.1N NaOH (l.l mmol) at ambient temperature. The resulting εolution iε cooled and acidified by the dropwiεe addition of IN HCl. The reεulting mix.ture is extracted with diethyl ether and the extract waεhed with brine and dried ' (MgS04 . The gS04 iε removed by filtration and the filtrate εaturated with ammonia (gas) to give a gum which solidified to provide the ammonium salt. EXAMPLE 35 Preparation of Alkali and Alkaline Earth Saltε of Compounds II To a solution of 44 mg o'f lactone from Example 1, Step 8, in 2 ml of ethanol iε added 1 ml of aqueouε NaOH (1 equivalent). After one hour at room temperature, the mixture iε taken to dryneεs in vacuo to yield the deεired sodium salt. In like manner, the potassium salt is 0 prepared using one equivalent of potassium hydroxide, and the calcium salt, using one equivalent of CaO. EXAMPLE 36 Preparation of Ethylenediamine Salts of Compounds II 5 To a solution of 0.50 g of the ammonium salt from Example 34 in 10 ml of methanol is added 0.04 ml of ethylenedi mine. The methanol is stripped off under vacuum to obtain the desired ethylenediamine ■ . salt. 0 EXAMPLE 37 Preparation of Triε(hydroxymethyl)aminomethane Saltε of Compoundε II To a εolution of 202 mg of the ammonium εalt 5 from Example 34 in 5 ml of methanol iε added a εolution of 50 mg of triε(hydroxymethyl) aminomethane in 5 ml of methanol. The εolvent iε removed in vacuo to afford the desired tris(hydroxymethyl)aminomethane salt. 0 " EXAMPLE 38 Preparation of L-Lysine Saltε of Compoundε II A εolution of 0.001 mole of L-lyεine and 0.0011 mole of the ammonium εalt-from Example 34 in 15 ml of 85% ethanol iε concentrated to drynesε in vacuo to give the desired L-lysine εalt. Similarly prepared are the L-arginine, L-ornithine, and N-methylglucamine salts. EXAMPLE 39 Preparation of Tetramethylammonium Saltε of Compoundε II A mixture of 68 mg of ammonium εalt from Example 34 in 2 ml of methylene chloride and 0.08 ml of 24% tetramethylammonium hydroxide in methanol is diluted with ether to yield the desired tetramethyl¬ ammonium salt». EXAMPLE 40 Preparation of Methyl Eεters of Compoundε II To a solution of 400 mg of lactone from Example 1, Step 8, in 100 ml of absolute methanol is added 10 ml 0.1 M sodium ethoxide in absolute methanol. Thiε solution iε allowed to εtand at room temperature for one hour, then iε diluted with water and extracted twice with ethyl acetate. The organic phaεe iε separated, dried (Na 2 S04), filtered and evaporated in vacuo to yield the deεired methyl ester, In like manner, by the uεe of equivalent amountε of propanol, butanol, iεobutanol, t-butanol, a ylalcohol, iεoamylalcohol, 2,2-dimethylamino- ethanol, benzylalcohol, phenethanol, 2-acetamido- ethanol and the like, the correεponding esters are obtained. EXAMPLE 41 Preparation of Free Dihydroxy Acidε The sodium salt of the compound II from Example 35 iε dissolved in 2 ml'of ethanol-water (1:1; v:v) and added to 10 ml of IN hydrochloric acid from which the dihydroxy acid is extracted with ethyl acetate. The organic extract iε waεhed once with water,' dried (Na 2 S04), and evaporated in vacuo with a bath temperature not exceeding 30°C. The dihydroxy acid derivative derived εlowly reverts to the corresponding, parent lactone on standing. The compound can be maintained in the dihydroxy acid form by increasing the pH above 7.0. , . EXAMPLE 42 As a specific embodiment of a composition of this invention, 20 mg of lactone from Example 1, Step 8, iε formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

Claims: WHAT IS CLAIMED IS: 1. A compound represented by the following εtructural formulae (I) and (II): Ci) Cti) wherein: A is O or S(0) n or N-R 3; n is 0 to 2; is selected from: (1) Cι_ιo alkyl; (2) εubεtituted Cι_ιo alkyl in which one or more substituent(s) is selected from (a) halogen, (b) hydroxy, (c) Cι_ιo alkoxy, (d) Cι_5 alkoxycarbonyl, (e) Cι_5 acyloxy, (f) C3-8 cycloalkyl, (g) phenyl. (h) εubstituted phenyl in which the subεtituentε are X and Y, (i) Cι_ιo alkylS(0) n in which n is 0 to 2, 5 (j) C3_8 cycloalkylS(0) n , (k) phenylS(0) n , (1) substituted phenylS(0) n in which the substituents are X and Y, and 10 (m) oxo; (3) Cι_ιo alkoxy; (4) C 2 _ιo alkenyl; (5) C3-8 cycloalkyl; (6) substituted C3_g cycloalkyl in which 15 one εubstituent is εelected from (a) Ci-io alkyl, (b) εubstituted Cι_ιo alkyl in which the substituent is εelected from 20 (i) halogen, (ii) hydroxy, (iii) CI-K) alkoxy, (iv) Cχ_5 alkoxycarbonyl, (v) Cι_5 acyloxy, 25 (vi) phenyl, (vii) εubstituted phenyl in which the substituents are X and Y (viii) Cι- 10 alkylS(O) n , 30 (ix) C3_ 8 cycloalkylS(0) n , (x) phenylS(0) n , (xi) εubεtituted phenylS(0) n in which the substituents are X and Ϋ, and 5 (xii) oxo, (c) Ci-io alkyis(0) n , (d) C3-8 cycloalkylS(0) n , (e) phenylS(0) n , (f) substituted phenylS(0) n in 10 which the substituents are X and Y, (g) halogen, (h) hydroxy, (i) Cι_ιo alkoxy, 15 (j) Cι_5 alkoxycarbonyl, (k) Cι_5 acyloxy, (1) phenyl, and (m) --substituted phenyl in which the " substituents are X and Y; 20 (7) phenyl; (8) subεtituted phenyl in which the εubstituen ε are X and Y; (9) amino; (10) Cι_5 alkylamino; 25 (11) di(Cχ_5 alkyDamino; (12) phenylamino; (13) εubstituted phenylamino in which the εubεtituentε are X and Y; (14) phenyl Cχ_ιo alkylamino; 30 (15) εubstituted phenyl Cι_ιo alkylamino in which the εubεtituentε are X and Y; (16) a member εelected from (a) piperidinyl, (b) pyrrolidinyl, (c) piperazinyl, (d) morpholinyl, and (e) thiomorpholinyl; and (17) R5S in which R5 iε εelected from (a) Cι_ιo alkyl, (b) phenyl, and (c) εubstituted phenyl in which the εubstituentε are X and Y; 10 R and R3 are independently selected from: (1) hydrogen; (2) Cι_ιo alkyl; and (3) substituted CI_IQ alkyl in which one or more subεtituentε iε selected from - 15 (a halogen, (b hydroxy, (c c l-10 alkoxy (d Cι_5 alkoxycarbonyl, (e Cι_5 alkylacyloxy, 20 (f phenylacy1oxy, ( g phenoxycarbonyl, (h phenyl Cι_5 alkylacyloxy, (i phenyl C1-5 alkyloxy, (j amino, 25 (k C1-5 alkylamino, (1 di(Cι_5 alkyl)amino, (m phenylamino, (n εubεtituted phenylamino in which the substituents are X and Y; 30 (o phenyl Cχ-5 alkylamino, (P εubstituted phenyl Cι_5 alkylamino in which the substituentε are X and Y, ( g ) C3--8 cycloalkyl, «_ Λ. »••». (r) phenyl, (ε) εubεtituted phenyl in which the substituents are X and Y, (t) phenylS(0) n , (u) εubstituted phenyl S(0) n in which the substituents are X and Y, (v) phenyl Cι_s alkyl S(0) n , (w) Cι-5 alkylS(0) n ; (x) phenylaminoacyloxy, (y) Cι_5alkylaminoacyloxy, (z) Cι_5alkylacylamino, (aa) di(phenylCι_5alkyl)phosphonyl, (bb) di(Cι_-5alkyl)phosphinyl, (cc) phenylC1_-.5alkylacylan.ino; (4) R and R3 together with the carbon atom to which they are attached form a C3_g carbocyclic ring; R4 is εelected from: (1) hydrogen; (2) Cι_5 alkyl; (3) εubstituted Cι_5 alkyl in which the εubstituent is selected from (a) phenyl, (b) dimethylamino, and (c) acetylamino, and (4) 2,3-dihydroxypropyl; l3 iε εelected from: (1) hydrogen; (2) Ci-s alkyl; (3) εubstituted Cι_5 alkyl in which the substituent is εelected from: (a) phenyl, (b) dimethylamino, and (c) acety1amino, and (d) hydroxy, provided that hydroxy iε εubstituted only at C-2, C-3, C-4 or C-5; and ' (e) Cι_5 alkoxy; (4) Cι-5 alkylcarbonyl; (5) Cι_5 alkyloxycarbonyl; (6) C _5 alkylaminocarbonyl; X and Y independently are hydrogen, halogen, trifluoromethyl, C _3 alkyl, nitro, cyano or group εelected from: (1) 6θ(CH 2 ) m in which m is 0 to 3 and g iε hydrogen, Cι_3alkyl or hydroxy-C 2 _3alkyl; - (2) R 7 ?CιO(C ■' H 2 ) m or R 7 OCI?O(CH 2 ) m in which R7 is hydrogen, Cι_3alkyl, hydroxy-C 2 _3alkyl, phenyl, naphthyl, amino-Cι__3alkyl, Cι_3alkylamino- Cι_-3alkyl, di(Cι_3alkyl)amino- Cι_3alkyl, hydroxy-C 2 _3 alkylamino- Cι_3 lkyl or di(hydroxy-C 2 _3alkyl) amino-Cι_3alkyl; provided that in R 7 CO(CH 2 ) m R 7 is not H; 0 O (3) R8θC(CH 2 ) m in which Re is hydrogen, Cι_3alkyl, hydroxy-C 2 _3 alkyl, Cι_3alkoxy-Cι__-3alkyl, phenyl or naphthyl; (4) R 9 Rι 0 N(CH 2 ) m , R 9 RιoNC l (CH 2 ) m O l i or R9 ιoNCO( CH 2 ) m in which Rg and R Q - 58 - independently are hydrogen, Cι_3 alkyl, hydroxy-C -3alkyl or R 9 an ^ R l θ together with the nitrogen atom to which they are attached form a heterocyclic group εelected from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl or thiomorpholinyl; (5) RnS(0) n (CH 2 ) m in which Rn is hydrogen, C 1 -.3alkyl, amino, Cι_3alkylamino or di(Cι_3alkyl)amino; a is a single bond or a double bond; halogen is F or Cl; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 wherein: A is O or S(0 ' ) n ; R 2 and R3 are independently selected from: (1) hydrogen; (2) Cι_ιo alkyl; (3) substituted Cι_ιo alkyl in which one or more substituents is εelected from: (a) halogen, (b) hydroxy, (c) amino; (4) CH 2 Rι in which R i2 iε εelected from: (a) Cι_5 alkoxy, (b) Cι_5 alkoxycarbonyl, (c) Cι_-5 alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbonyl, (f) phenylC _5alkylacyloxy, (g) phenylCι_5alkoxy, - 59 - (h) C1__.5alkylan.ino, (i) di(Cι-5alkyl)amino, (j) phenylamino, (k) εubεtituted phenylamino in which the εubεtituentε are X and Y, (1 phenyl Ci-salkylamino, (m εubεtituted phenyl C1-5 alkyl amino in which the εubstituents are X and Y, (n C3_8 cycloalkyl, (o phenyl, (P substituted phenyl in which the substituents are X and Y, (q phenylS(0) n (r substituted phenylS(0) n in which the substituentε are X and Y, (s phenyl Cι_5 alkylS(0) n , (t Cι_5 alkylS(0) n , (u phenylaminoacyloxy, (v Cι_5 alkylaminoacyloxy, (w Cι_5 alkylacylamino, (x di(phenylCi-salkyl)phoεphonyl, (y di(Cι_5alkyl)phosphinyl, (z phenylCι__5alkylacylamino; (5) R 2 and R3 together with the carbon atom to which they are attached from a C3-8 carbocyclic ring. 3. A compound of Claim 2 wherein: iε selected from: (1) Ci-no alkyl; (2) substituted Cι_ιo alkyl in which one or more εubstituent(s) is selected from (a) halogen, (b) hydroxy, (c) Cι_ιo alkoxy, (d) Cι_5 alkoxycarbonyl, (e) Cι_5 acyloxy, (f) C3-8 cycloalkyl, (g) phenyl, (h) εubstituted phenyl in which the εubstituentε are X and Y, and (i) oxo; (3) C3-8 cycloalkyl; (4) substituted ^-B cycloalkyl in which one subεtituent iε εelected from (a) Cι__ιo alkyl, (b) substituted Cι_ιo alkyl in which the εubstituent is selected from (i) halogen, (ii) hydroxy, (iii) Cι_ιo alkoxy, (iv) C1-.5 acyloxy, (v) C _5 alkoxycarbonyl, (vi) phenyl, (vii) εubεtituted phenyl in which the εubεtituentε are X and Y, and (viii) oxo, (c) halogen, (d) hydroxy, (e) Cι-10 alkoxy, (f) Cι_5 alkoxycarbonyl, (g) C1-.5 acyloxy, (h) phenyl, (i) εubstituted phenyl in which the εubstituentε are X and Y; (5) phenylamino; (6) εubstituted phenyl-amino in which the substituents are X and Y; (7) phenyl Cι_ιo alkylaminb; and (8) εubstituted phenyl Cι_ιo alkylamino in which the εubstituentε are X and Y. 4. A compound of Claim 3 wherein: Rl is selected from: (1) Cι_ιo alkyl; (2) C3_8 cycloalkyl; (3) phenylamino; and (4) substituted phenylamino in which the substituents are X and Y. 5. A compound, of Claim 4 wherein: R 2 and R3 are independently selected from: (1) hydrogen; (m) Cι_5alkylaminoacyloxy, (n) phenyl, (o) εubεtituted phenyl in which the εubstituentε -are X and Y; (p) C1-_.5alkylacylan.ino; (q) phenylCι_5alkylacylamino; (r) di(ρhenylCι_5alkyl)phoεphonyl; (ε) di(Cι_5alkyl)phosphinyl. 6. A compound of Claim 5 wherein: R 2 and R3 are independently selected from: (1) hydrogen; (2) Cι- 5 alkyl; (3) Cι_salkyl substituted with hydroxy; (4) CH 2 Rι 2 in which Rι 2 is εelected from: (a) Cι_5alkoxy, (bf phenyl S(0)n, (c) phenylCι_>5 alkyl S(0)n, (d) phenylaminoacyloxy, (e) Cι_5 alkylacylamino, ( f ) phenylC 1 __.5alkylacylan.ino , (g) di(phenylCι_5alkyl)phoεphonyl, (h) di(Cι__.5alkyl)phoεphinyl. 7. A compound of Claim 6 wherein: R 2 and R3 are independently εelected from: (l) hydrogen; (2) Cι_ 5 alkyl; (3) Cι_5alkyl εubεtituted with hydroxy; (4) phenyl S(0)nCH 2 . 8. A compound of Claim 7 wherein: A iε O; a is a single bond; and Rl is 2-methyl-2-butyl or 2-butyl; and R 2 and R3 are independently εelected from CH3, H, phenylthiomethyl and hydroxymethyl. 9. A compound of Claim 8 εelected from: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6,6-dimethyl-l,2,3,4,4a(R),7,8, 8a(R)-octahydronaphthyl-l(S)lethyl]-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)- l,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-l(S)3- ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one ; (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)- - l , 2 , 3 , 4 , 4a(R) , 7 , 8 , 8a(R)-octahydronaphthyl-l (S ) 3- ethyl 3-4(R)-hydroxy-3 , 4 , 5 , 6-tetrahydro-2H-pyran- 2-one • (4) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5- oxa-6,6-dimethyl-l,2,3,4 ,4a(R),7,8,8a(R)-octa- hydronaphthyl-1(S)]ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one ; (5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(hydroxymethyl, methyl)-l,2, 3,4,4a(R) ,7,8,8a(R)-octahydronaphthyl-l(S)3- ethyl3-4(R)-hydroxy-3,4,5,6-tetr hydro-2H-pyran- 2-one• ■ - ? (6) 6 ( R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2 ( S)- methyl-5-oxa-6(R ) -(hydroxymethyl, methyl ) -l,2, 3,4, a(R ) ,7,8,8a(R)-octahydronaphthyl-l(S) - ethyl3- (R ) -hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one ; ( 7 ) 6(R)-[2-[8 ( S ) -(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6 ( S ) - ( phenylthiomethyl, hydroxy- methyl ) -l,2,-3,4,4a(R),7,8,8a(R)-octahydro- naphthyl-l ( S ) 3ethyl]-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one; ( 8 ) 6 ( R ) -r2-[8 ( S ) - ( 2,2-dimethylbutyryloxy)-2 ( S ) - methyl-5-oxa-6 ( R ) - ( phenylthiomethyl, hydroxy- methyl ) -l,2,-3,4,4a(R),7,8,8a(R)-octahydro- naphthyl-1 ( S ) 3ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one; and the corresponding ring opened dihydroxy acids and esters thereof. 10. A compound of Claim 9 which is: (1) 6 ( R)-[2-[8(S)- ( 2,2-dimethylbutyryloxy)-2 ( S)- methyl-5-oxa-6,6-dimethyl-l,2,3,4,4a(R) ,7,8, 8a ( R ) -octahydronaphthyl-l(S) ethyl3-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one ; and the corresponding ring opened dihydroxy acids and esters thereof. - 65 - 11. A compound of Claim 7 wherein: A iε S(0) n ; a is a single bond; and Rl iε 2-methy1-2-butyl or 2-butyl; .and R 2 and 3 are independently εel'ected from CH3, H and hydroxymethyl. (vii) εubεtituted phenyl in which the substituents are X and Y, and (viii) oxo, (c) halogen, (d) hydroxy, (e) Cι_ιo alkoxy, (f ) Cι___5 alkoxycarbonyl , (g) Cι_5 acyloxy, (h) phenyl, (i) εubstituted phenyl in which the substituents are X and Y; (5) phenyl mino; (6) εubstituted phenylamino in which the substituents are X and Y; (7) phenylCι_ιoalkylamino; and (8) substituted phenyl Cι_ιo alkylamino in which the substituents are X and Y; nd R3 are independently εelected from (1) hydrogen; (2) Cι_ιo alkyl; (3) εubstituted Ci-io alkyl in which one or more substituents is εelected from: (a) halogen, (b) hydroxy, (c) .amino; (4) CH Rι in which Rι 2 iε εelected from: (a) Cι_5 alkoxy, (b) C1-5 alkoxycarbonyl, (c) Cι__5 alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbonyl, (f) phenylCι_5alkylacyloxy, (g) phenylCι_5alkoxy, Ci-salkylamino, di(Cι_5alkylamino), phenylamino, εubεtituted phenylamino in which the substituents are X and Y, phenyl Ci-salkylamino, substituted phenyl Cι_5 alkyl amino in which the subεtituents are X and Y, C3_8 cycloalkyl, phenyl, substituted phenyl in which the substituents are X and Y, phenylS(0) n εubstituted phenylS(0) n in which the substituents are X and Y, phenyl Cι_5 alkylS(0) n , ' Cι_5 alkylS(0) n , phenylaminoacyloxy, Cι_5 alkylaminoacyloxy, Cι_5 alkylacylamino, di(phenylCi-salkyl)phoεphonyl, di(Cι_-5alkyl)phosphinyl; (5) R 2 and 3 together with the carbon atom to which they are attached form a C3- carbocyclic ring. 13. A compound of Claim 12 wherein: R iε εelected from: (1) Cι_ι 0 alkyl; (2) C3_8 cylcoalkyl; (3) phenylamino; and (4) εubstituted phenylamino in which the εubεtituentε are X and Y; - 68 - Rl3 is εelected from: (1) hydrogen; (2) C!«5 alkyl; (3) phenylCι_5 alkyl; ' (4) C -5 alkylcarbonyl. 14. A compound of Claim 13 wherein R 2 and R3 are independently εelected from: (1) hydrogen; 15. A hypocholesterolemic hypolipidemic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as , defined in Claim 1. 16. A composition of Claim 15 in which the compound is selected from: 0 (l) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6,6-dimethyl-l,2,3,4,4a(R),7,8, 8a(R)-octahydronaphthyl-l(S)lethyl3-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one ; 5 (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)- l,2,3,4,4a(R ) ,7,8,8a(R)-octahydronaphthyl-l(S)3- ethyl3- (R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one• 0 (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)- l,2,3,4,4a(R) ,7,8,8a(R)-octahydronaphthyl-l(S) 3- ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 5 2-one. (4) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5- oxa- ,6-dimethyl-l,2,3, , a(R),7,8,8a(R)-octa- hydronaphthyl-1(S)lethyl3-4(R)-hydroxy-3,4,5,6- 0 tetrahydro-2H-pyran-2-one ; (5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(hydroxymethyl, methyl)-1,2, 3,4,4a(R),7,8,8a(R)-octahydronaphthyl-l(S)3- ethyl3-4(R)-hydrox.y-3,4,5,6-tetrahydro-2H-pyran- 2-one; - 70 - (6) 6(R)-[2-[8(S)-(2 ,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6 (R)-( hydroxymethyl , methyl )-l , 2 , 3 , 4 ,4a(R) , 7 , 8 , βa(R)-octahydronaphthyl-KS) 3- ethyl 3-4(R)-hydroxy-3 ,4 ,5 , 6-tetr ahydr o-2H-pyran- 2-one; (7) 6(R)-[2-t8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(phenylthiomethyl, hydroxy¬ methyl)-l,2,-3,4,4a(R),7,8,8a(R)-octahydro- naphthyl-1(S)3ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one; (8) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(phenylthiomethyl, hydroxy- methyl)-l,2,-3,4,4a(R) ,7,8,8a(R)-octahydro- naphthyl-1(S)3ethyl3-4(R)-hydroxy-3,4,5,6- tetr hydro-2H-pyran-2-one; and the corresponding ring opened dihydroxy acids and esterε thereof. 17. A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable nontoxic cationic polymer capable of binding bile acidε in a non-reabsorbable form in the gaεtrointeεtinal tract and a pharmaceutically acceptable carrier. 18. A method of inhibiting choleεterol biosynthesiε compriεing the administration to a subject in need of εuch treatment a nontoxic therapeutically effective amount of a compound of Claim 1. 19. A method of Claim 18 in which the compound iε εelected from: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6,6-dimethyl-l,2,3,4,4a(R),7,8, 8a(R)-octahydronaphthyl-1(S)lethyl1-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one ; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)- l,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-l(S)3- ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one• (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)- 1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthy1-1(S) 3- ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one• (4) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5- oxa-6,6-dimethyl-l,2,3,4, a(R) ,7,8,8a(R)-octa- hydronaphthyl-l(S)3ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one ; (5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(S)-(hydroxymethyl, methyl)-l,2, 3,4,4a(R) ,7,8,8a(R)-octahydronaphthyl-l(S)3- ethyl3-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one ; (6) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-5-oxa-6(R)-(hydroxymethyl, methyl)-1,2, 3,4,4a ( R ) ,7,8,8a ( R ) -octahydronaphthyl-l(S)3- ethyl3-4 ( R ) -hydroxy-3,4,5,6-tetrahydro-2H-pyran- 2-one. ( 7 ) 6(R)-[2-[8(S ) -(2,2-dimethylbύtyryloxy)-2(S ) - methyl-5-oxa-6(S)-(phenylthiomethyl, hydroxy ¬ methyl ) -1,2,-3,4,4a(R),7,8,8a(R)-octahydro- naphthyl-l ( S)3ethyl3-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one ; ( 8) 6 ( R ) -[2-[8 ( S)-(2,2-dimethylbutyryloxy ) -2 ( S ) - methyl-5-oxa-6 ( R ) -(phenylthiomethyl, hydroxy ¬ methyl ) -l,2,-3, ,4a(R) ,7,8,8a(R)-octahydro- naphthyl-1(S)3ethyl3-4( )-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one; and the correεponding ring opened dihydroxy acidε and esters thereof. - 73 - 20. A compound of structural formula B: B wherein: A iε HO, SH or HN-Rjj; Q is CH 3 , CH 2 OT, or H; T is H, tert-butyldimethylεilyl, tert-butyldiphenylεilyl, trimethylεilyl, triethylsilyl, triiεopropylεilyl or tetrahydropyrany1; 2 is OCH3, or Z together with the carbon to which it is attached represents C«0; Rl is selected from: (1) Ci-10 alkyl; (2) substituted Cι_ιo alkyl in which one or more εubstituent(ε) iε selected from (a) halogen. (b) hydroxy, (c) Cι_ιo alkoxy, (d) Cι_5 alkoxycarbonyl, (e) Cι«5 acyloxy, (f) C3_8 cycloalkyl, (g) phenyl, 5 (h) εubεtituted phenyl in which the εubstituentε are X and Y, (i) Cι_ιo alkylS(O) n in which n iε 0 to 2, (j) C3-8 cycloalkylS(0) n , 10 (k) phenylS(O) n , (1) subεtituted phenylS(O) n in which the εubεtituentε are X • and Y, and (m) oxo; 15 (3) Cι_ιo alko-xy; (4) C 2 _ιo alkenyl; (5) C3_8 cycloalkyl; (6) εubstituted 03-8 cycloalkyl in which one εubstituent iε εelected from 20 * (a) Cι_ιo alkyl, (b) εubεtituted Cι_ιo alkyl in which " the εubεtituent iε εelected from (i) halogen. 25 (ii) hydrox-y, (iii) Cι-10 alkoxy, (iv) C1-5 alkoxycarbonyl, (v) C1-5 acyloxy, (vi) phenyl, 30 (vii) εubstituted phenyl in which the εubεtituents are X and Y (viii) Cι_ιo alkylS(O) n , (ix) C 3 . 8 cycloalkylS(O) n , 5 (x) .phenylS(0) n , (xi) εubεtituted phenylS(0) n in which the εubεtituentε are X and Y, and 10 (xii) oxo, (c) Cι_ιo alkylS(0) n , (d) C3-8 cycloalkylS(0) n , (e) phenylS(0) n , (f) εubstituted phenylS(O) n in 15 which the substituents are X and Y, (q) halogen, (h) hydroxy, (i) Cι_ιo alkoscy, 20 (j) Cι_5 alkoxycarbonyl, (k) Cι_5 acyloxy, (1) phenyl, and (m) εubstituted phenyl in which the substituen ε are X and Y; 25 (7) phenyl; (8) subεtituted phenyl in which the substituents are X and Y; 30 - 76 - ( 9 ) amino ; ( 10 ) Cι_5 alkylamino; ( 11 ) di (Cι_5 alkyDamino ; ( 12) phenylamino; (13) εubεtituted phenylamino in which the εubεtituents are X and Y; (14) phenyl Ci-io alkylamino; (15) εubstituted phenyl Cι-ιo alkylamino in which the substituentε are X and Y; (16) a member selected from (a) piperidinyl, (b) pyrrolidinyl, (c) piper zinyl, (d) orpholinyl, and (e) thiomorpholinyl; and (17) R5S in which R5 is εelected from (a) Cι-10 alkyl, (b) phenyl, and (c) εubstituted phenyl in which the substituents are X and Y; R N is εelected from: (a) Ci-salkyl; (b) phenylCι_5alkyl; X and Y independently are hydrogen, halogen, trifluoromethyl, C1-3 alkyl, nitro, cyano or group εelected from: (1) RgO(CH ) ffi in which m iε 0 to 3 and Rβ iε hydrogen, Cι-3βlkyl or hydroxy-C 2 _3alkyl, 0 O (2 ) R 7 CO(CH 2 ) m or R 7 OCO(CH 2 )ιn in which 7 is hydrogen, Ci^alky , hydroxy-C 2 -3alkyl, phenyl, naphthyl, 5 amino-Cι_3alkyl, Cι_3alkylamino- Cι-3al yl, di(Cι_3alkyl)amino- Cι_3alkyl, hydroxy-C 2 -3 alkylamino- C1-3alkyl or di(hydro^-C 2 -3alkyl) amino-Cι__3alkyl; provided that in 10 R 7 OCO(CH 2 ) m R 7 iε not H; 0 0 (3) R8θC(CH 2 ) m in which e iε hydrogen, Cι_3alkyl, hydro^-C 2 -3 15 alkyl, Cι_3alkoxy-Cι_3alkyl, phenyl or naphthyl; O (4) R 9 Rι 0 N(CH 2 ) m , R 9 RιoNC(CH ) m 0 20 or R9RιoNCO(CH 2 ) m in which R9 and Rio independently are hydrogen, C1-.3 alkyl, hydroxy-C 2 -3alkyl or R9 and Rio together with the nitrogen atom to which they are attached form a 25 heterocyclic group εelected from piperidinyl, pyrrolidinyl, piperazinyl, orpholinyl or thiomorpholinyl; 30 ( 5 > RiiSCWaCCHa ia which Rn is hydrogen, Cι_ 3 alkyl, amino, Ci_3alkylamino or di(c* ι , a ι t „n • halogen iε F or Cl; n iε 0 to 2.

Inventors: DUGGAN MARK E, HARTMAN GEORGE D, DUGGAN, MARK, E., HARTMAN, GEORGE, D.
Applicants: MERCK & CO INC, MERCK & CO., INC.
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P9, C07D215, C07D311, C07D335, C07D405, C07D407, C07D409, C07F9