LV10719B - Heterocyclic steroid compounds - Google Patents

Abstract

The invention relates to novel substitutes of 15-oxa, 15-thio and 15-aza-dihydroanosterine. compounds that contain an effective amount of one of these compounds and are useful in cholesterol for reducing the formation of warm-blooded animals and their application methods for 3-hydroxymethylglutaryl coenzyme A Reductase (HMGR), which is essential for the synthesis of cholesterol. Heterocyclic lanosterin analogues reduces the formation of cholesterol in the serum, lowers the synthesis of ergosterol in fungi.

Description

HETEROCYCLIC STEROID COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to novel substituted 15-oxa-, 15-thia-, and 15-aza- dihydrolanosterols, to phannaceutical compositions containing such compounds, and to methods of using these compounds to suppress the activity of 3-hydrcxy-3- methylglutaryl coenzyme A reductase (HMGR), an enzyme vhich is important in sterol biosynthesis. The overall effect of these heterocvclic lanosterol analogs is to decrease sterol formation, thereby resulting in lover serum cholesterol Ievels in mammals, and impaired ergosterol synthesis in fungi.

STATE OF THE ART

Clinical studies have demonstrated that elevated concentrations of serum cholesterol are a major 2 ccntributing factor in the development and progression of atherosclerosis, a disease characterized by the formation of cholesterol-containing plaques in the aorta and lesser arteries. These plaques tend to clog the arterial passageways, making it difficult, if not impossible, for blood to flow from the heart to various tissues in the body. This pathobiological condition can ultimately lead to Coronary Heart Disease (CHD). See, e.g. , Kannel et al.. Ann. Intern. Med.. 90: 85-91 (1979); Final Report of the Pooling Project, J. Chron. Dis.. 31: 201-306 (1978). By maintaining low cholesterol Ievels in the blood, arterial plaque formation and CHD can potentially be avoided. See, e.g.. Brensike ai al.. Circulation. 69: 313-324 (1984) and Levy ϋ al.. Circulation. 69: 325-336 (1984).

In mammals, serum cholesterol is derived from exogenous dietary sources as well as through endogenous de novo synthesis. Endogenous synthesis of cholesterol involves a complex set of enzyme-catalyzed reactions and regulatory mechanisms vhich to datē are only partially understood. As Rodvell et al.. Adv. Lipid Res.. 14: 1074 (1976) indicate, HMGR is generally accepted as the rate-limiting enzyme vhich Controls cholesterol biosynthesis from acetyl-CoA in ali organisms.

Brovn ai aL·./ J. Lioid Res. . 21: 505-517 (1980) have shovn that regulation of HMGR is a complex process vhich is under a feedback control mechanism involving both steroidal as veli as nonsteroidal isoprenoid metabolites. These authors point out that under normai conditions, the ability of cholesterol to regulate its ovn biosynthesis vhen associated vith lipoprotein pārticies is one aspect of this feedback control mechanism.

Moreover, it has been demonstrated that various - 3 - LV 10719 oxygenated sterols, when used in a highly purified State, are even more effective than cholesterol in attenuating the amount of KMGR activity, see Breslov et al.. Biochem. Bioohvs. Acta. 398: 10-17 (1975), Kandutsch et al., J. Biol. Chem.. 252: 409-415 (1977), and Chen e£ al. J. Biol. Chem.. 254: 714-720 (1979), leading to the hypothesis that oxysterols may also be endogenous mediators which regulate HMGR activity and cholesterol synthesis ļņ situ. See, Kandutsch et al.. Science, 201: 498-501 (1978).

This proposition stimulated considerable research activity. See, e.g.. Chen et al.. J. Biol. Chen.. 254: 715-720 (1979); Havel e£ aj^, J. Biol. Chem.. 254: 9573-9582 (1979); Chang gt J. Biol. Chen.. 255: 7787-7795 (1980); Chorvat, U.S. Patent No. 4,230,626 (1980); Gibbons et al^., J. Biol. Chem.. 255: 395:400, (1980); Kandutsch et &L., J. Biol. Chem.. 255: 10814-10821 (1980) ; Cavenee gj: al.. J. Biol. Chem.. 256: 2675-2681 (1981); Tanaka et J. Biol. Chem.. 258: 13331-13339 (1983) and Trzaskos gt Fed.

Proc.. 44: 656, (1985). As a result, a number of inhibitors of HMGR activity have been found.

Gibbons e£ al.. J. Biol. Chem.. 255: 395-400 (1980), for example, have shown that certain synthetic oxygenated lanosterol deriv-cives ar-: active inhibitors of HMGR activity. Trzaskos al.. Fed. Proc.. 44: 656 (1985) have established that jyņ situ generation of the Gibbons compounds leads to attenuated KMGR activity and decreased cholesterol biosynthesis.

In addition, Schroepfer et a1.. u. S. Patent No. 4,202,891 and Schroepfer et al.. Proc. Nati. Acad. Sci. USA. 81: 6861-6865 (1984) have revealed that other oxygenated lanosterol derivatives may be successfullv employed to lower serum cholesterol Ievels in animals. 4

INFORMATION DISCLOSURE

Heterocyclic steroid compounds have been prepared in the past. For example, U.S. Patent Nos. 3,345,203 (Vīilliams et a 1.) : 3,837,433 (Viilliaras et al.) : 3,887,564 (Vīilliams et al_J ; 3,947,453 (Jones); 3,987,055 (Berlin et aL) ; 3,972,884 (Jones); 4,001,246 (Jones); 4,008,238 (Jones); and 4,039,547 (Chanberlin) are directed to various aza steroid compounds. Oxa steroid derivatives ars disclosed in U.S. Patent Nos. 3,872,076 and 4,053,487 (Rosen), and in Ferland and Lefebfre, Can. J. Chem.. 62; 315-319 (1984). Thia steroids are disclosed in Tolstikov e£ al♦. Zhurnal Oroanicheskoi Khimi. 22: 121-132 (1986).

None of the aforeaentioned heterocyclic steroid compounds are described as having utility against cholesterol biosynthesis. Thus, additional compounds vhich affect HMGR and/or other enzymes critical to serum cholesterol biosynthesis are needed. The present invention is directed to this end.

SUKMARY OF THE INVENTION

The present invention provides novel substituted 15-oxa-, 15-thia-, and l5-aza-dihydrolanosterol compounds of the formula;

R

Formula 1 - 5 - - 5 -LV 10719 vherein the broken lines represent optional double bonds and: R is a side chain having either 8 or 9 carbon atoms and frora 15 to 20 hydrogen atoms, optionally with one site of unsaturation; R1 is *0, 0R7 or 0C0R7; R2 is H, Cļ-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, arylalkyl; R3 is H, Cļ-Cg a1ky1, C2-Cg alkenyl, C2-C6 alkynyl, arylalkyl, C(R4)2R5, cor4, csr4, C(=NR4)R4, cor5, csr5, C(R4)2C(R4)2R5i C(R4)2C0R4, C(R4)2CSR4, C(R4)2C(=NR4)R4, C(R4)4COR5, C(R4)2CSR5, C(R4)2Z, C(R4)2C(R4)2Z, cn, cr4nor4, CR4NOR6, CR4NN(R4)2, cr4nnr4r6, chr4nhor4, chr4nhor6, CHR4NHN(R4)2, chr4nhnr4n6, chr4cr4nor4, chr4cr4nor6 CHR4CR4NN(R4)2, chr4cr4nnr4r6 chr4chr4nhor4, chr4chr4nhor6, CHR4CHR4NHN(R4)2, C(0)NR40R4, C(0)NR40R6, C(S)NR4OR4, C(S)KR4OR6, cr4=cr4r6, c=cr6, CR4=CR4C(R4)2Z, CrCC(R4)2Z, CR4-CR4C(R4)2OR6, C=CC(R4)20R6, poly-(0R4, ORg, epoxy)-C1-Cg alkyl; R4 is H, C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, aryl, arylalkyl;

Rg is OR4, SR4, N(R4)2, NR4Rg;

Rg is C0R4, CSR4, C(=NR4)R4; R? is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, aryl, arylalkyl; 6 X is O, S, SO, S02, N, NR4, NRg, N(0)R4; 2 is halogen; and n is 1 or 2; and their physiologically acceptable salts.

The compounds of Formula I are effective suppressants of 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMGR) activity. By interfering with this enzyme, vhich is essential in the cholesterol biosynthetic pathway, cholesterol formaticn is decreased and serum cholesterol Ievels lovered. Thus, the present invention also includes therapeutic pharmaceutical compositions for suppressing HMGR activity, decreasing cholesterol formation and lovering serum cholesterol Ievels.

The pharmaceutical compositions comprises (i) an effective amount of a compound of the formula:

R

Formula 1 vherein the broken lines represent optional double bonds and: R is a side chain having either 8 or 9 carbon - 7 - - 7 - LV 10719 atoms and frora 15 to 20 hydrogen atoms, optionally with one sita of unsaturation; R^ is =0, ORy OE" OCOR-7 R2 is K, C^-Cg aikvl, C2-Cg alkenyl, C2-Cg alkynyl, arylalkyl; R-j is H, C^-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, arylalkyl, C(R4)2R5, COR4, CSR4, C(=NR4)R4, cor5, csr5, C(R4)2C(R4)2*5' C(R4)2COR4, C(R4)2CSR4, C(R4)2C(=NR4)R4, C(R4)4CORs, C(R4)2CRS5, C(R4)2Z, C(R4)2C(R4)2Z, cn, cr4nor4, cr4nor6, CR4NN(R4)2, cr4nnr4r6, chr4nhor4, chr4khor6, CHR4NHN(R4)2, chr4nhnr4n6, chr4 cr4nor4, chr4 cr4nor6 chr4cr4nn(r4)2, chr4cr4nhr4r6 ckr4chr4nhor4, chr4chr4nhor6, CHR4CHR4NtHN(R4)2, C(0)NR40R4, C(0)NR40Rg, C(S)NR4OR4, C(S)NR40Rg, CR4=CR4Rg, C=CRg, CR4=CR4C(R4)2Z, C^CC(R4)2Z, CR4=CR4C(R4)2ORg, C^CC(R4)2ORg, poly-(OR4, ORg, epoxy)-C1-Cg alkyl; R4 is H, Cļ^-Cg alkyl, C2-Cζ alkenyl, C2-Cg alkynyl, aryl, arylalkyl;

Rg is OR4, SR4, N(R4)2, NR4Rg ?

Rg is COR4, CSR4, C(=NR4)R4; R7 is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, aryl, arylalkyl; X is 0, S, SO, S02, N, NR4, NRg N(0)R4; Z is halogen; and n is 1 or 2; 3 and (ii) a pharmaceutically acceptable carrier or diluent.

In addition, the present invention encompasses methods for suppressing HMGR actj.vi.ty, decreasing cholesterol fonaation and lowering serum cholesterol Ievels comprising administering to a host an effective amount of a compound of the formula:

vherein the broken lines represent optional double bonds and: R is a side Chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally vith one site of unsaturation; R1 is =0, 0R7 or OCOR7; R2 is H, Cļ-Cg alkyl, C2-C6 alkenyl, C2'Cg alkynyl, arylalkyl; R3 is H, C^-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, arylalkyl, C(R4)2R5, cor4, csr4, C(=NR4)R4, cor5, csr5, 9 LV 10719 C (R4 ) 2^· (^4 ) 2^5 ' *-(^4 ) 2^"^^4 ' C(R4)2CSR4, C (R4 ) 2C (=fTR4 ) R4 , C(R4)4CORg( C(R4)2CRSg, C (R4) 2Z, ^ (^4 ) 2^ ^4 ^ 2^f CR4NOR4, CR4NORg, CR4KN(R4)2, cr4nnr4r6, chr4nhor4i chr4nhor6, CHR4NKN(R4)2/ ckr4hhnr4n6, chr4cr4nor4, chr4cr4nor6 CKR4CR4KK(R4)2/ chr4cr4nkr4r6 ckr4chs4nkor4, chr4chr4khor6, CHR4CHR4NHN(R4)2» C(0)NR4OR4, C(0)NR40R6< C(S)NR40R4/ C (S) NR4ORg , CR4=CR4R6, CiCRg, CR4*CR4CCR4)22/ CR4-CR4C(R4)2OR6/ C2CC(R4)2OR6, poly-(OR4, ORg, epojcy)-C^-Cg alkyl; R4 is H, Cļ^-Cg alJcyl, C2-C6 alkenyl, C2-Cg alkynyl, aryl, arylalkyl; R5 is OR4/ SR4, N(R4)2, ^4^s*

Rg is COR4, CSR4, C(=NR4)R4; R7 is K, C1-C20 alkyl, C2-C20 alkenyl, c2“c20 alkynyl, aryl, arylalkyl; X is 0, S, S0, S02, V, K?4, NRf. N(0)R4; Z is halogen; ar.d n is 1 or 2.

In the above foraulae, the R side chain is preferably selected from the cholesterol side chain (c8^17) and the ergosterol side chain (CgH17j ^

These are genericaliv represented by the formula:

'0*31 V ! J

10 where the dashed line represents an optional double bond and the circled alpha-methyl group is likevise optional. Hovever, when the D ring is piperidine or the N-oxide thereof, the R side chain is not an ergosterol side chain.

Likevise, in the above formulae, the ring structure may be unsaturated betveen carbons 7 and 8 or 8 and 9. When X is N the structure has an additional double bond betveen C-14 and N and C-14 does not have R3 substitution.

As used herein, the substituent designated as "poly-(0R4, 0RS, epoxy) Cļ-Cg alkyl” shall be taken to mean a Cļ to Cg alkyl chain substituted vith one or lore of any combination of 0R4, OR5 and epoxy.

As used herein, the term ,,alkyl" employed either alone or in combination vith other terms such as "poly-(OR4, 0RS, epoxy) C^-Cg alkyl" or "arylalkyl'', denotes straight chain or branched alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, and the different butyl, pentyl or hexyl isomers.

As used herein, the term ,,alkynyl", employed either alone or in combination vith other terms, denotes straight chain or branched mono- or poly- unsaturated alkyl, e.g., ethynyl, propynyl (propargyl), 2-butynyl isomers, and the different pentynyl, hexadiynyl and hexynyl isomers.

As used herein, the term "acyl", employed either alone or in combination vith other terms, denotes a carbonyl group attached to an alkyl, alkenyl, alkynyl, arylalkyl or aryl group e.g. acetate, butyrate, benzoate, and different alkyl, alkenyl, alkynyl, or aryl isomers. - 11 - LV 10719

As used herein, the term "halogen" denotes fluorine, chlorine, bromine and iodine.

As used herein the term "physiologically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids and/or bases, including inorganic acids/bases and organic acids/bases.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula I can be employed to suppress HMGR activity, decrease cholesterol formation and lower serum cholesterol Ievels in mammals. These compounds can be administered alone, or in combinaticn with pharmaceutically acceptable carriers or diluents appropriate to the indicated route of administration. Administration can be oral, sublingual, buccal, topical and parenteral such as intravenous, subcutaneous or intramuscular.

Acceptable carriers and diluents are vell-knovn in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Gennaro, A. R., ed., Mack Publishing Co., Easton, PA (1985). The useful dosage to be administered and the mode of administration will vary depending upon the age, veight and species of mammai treatsd.

While not vishing to be bound to theory or conjecture, a brief description of the mechanism by vhich the active 15-oxa-, 15-thia-, and 15-aza-dihydro-lanosterol compounds of the present invention are believed to function is as follovs.

The observed decrease in HMGR activity is thought to occur as a result of a decreased synthesis of HMGR protein and/or an enhanced rāte of HMGR degradation (collectively termed herein as "suppression”). 12

General Procedures for the Preparation of Heterocyclic Lanosterol Derivatives

The compounds of the present invention accommodate the necessary requirements for suppression of HMGR activity. To allow the introduction of various functional groups at 14-position, a strategy; vhich involves an opening and a reclosing of the D ring of the steroidal structure, vas developed. In the schemes and tables vhich follov, for simplicity, only the cholesterol side Chain (C8H17^ is shovn. It is to be understood that the ergosterol side Chain (C9H17) or nodifications of either side chain may be present instead of the illustrated cholesterol side chain. 15-0xa-Lanosterols

The common intermediate for 15-oxa-, thia- and aza-dihydrolanosterols, the enone-aldehyde 4, has been obtained by an osmium tetroxide hydroxylation on the 8,14-diene (Compound 2) folloved by an oxidative cleavage of the resulting diol, Compound 3 (See, Scheme I) · I - 13 - L V 10719

V

SCH

2 a R,-H 3a R, H 2 b R, - p-CH3OCsH4CH2 ( pMBn ) 3 b R, « pWBn

4 b R, · pM8n

5 a R, » h 5 b R, pM8n

6a Ri -H. Rj. -CH, 7 a R, H, Rj R7 CHj 6b Ri pMSn, Rj CHļ 7b Ri - pMBn, Rj-CHj, R7- .Η 1 2a Ri -Rj-H 7e R, pM8n, Rļ · Rj m CH3 12b Ri pMBn, Rj-H 13a Ri Rj - H, F^-CRj 18a Ri -H. Rj: -CH-CH, 13b R, pW8n, Rj a Ry H 13b Ri pW8n, R, . CH-CH2 13c Rt -pMBn, Rj-H, Rj * CHj 19a Ri »H, Rj-CH-CHj. R^. «CHj 19b R, pM8n, Rj-CH-CHj. r7- h 19e «1 - pW8n, Rj-CH-CHj, R7-CHj 14

The starting species, Compcund 2a, 4-diiaethvl-5a-chclesta-3,14-dien-3b-ol, was prepared fron 7-dehvdrccholesterol (Signa Chenical Co., P.O. 3ox 14508, St. Louis, MO 63173) by the method described by Bloch and Gautschi in J. Chem. Soc., 223 (6), 1343 (1953). Treataent of the 8,14-dien-3b-ol (2a) with sodium hydride (Alfa Products, P.O. Box 299, Danvers, MA 01923) and 4-methoxybenzyl chloride (prepared by the method described by R. L. Schriner and C. J. Kuli in J. Ora. Chem.. 10, 223 (1945)] in 4 parts of tetrahvdrofuran and l part of N,N-dimethylforraamide at 70°C afforded the corresponding p-methoxybenzyl ether 2b in near quantltative yield. Hydroxylation of the diene 2b with stoichiometric anount of osmium tetroxide (Alfa) in the presence of 10 ecruivalents of anhydrcus pyridine (Aldrich Chenical Co., Inc., 940 West St.,

Paul Ave., Milvaukee, WI 53233) in benzene prcvided the 14,15-diol in 82% yield. opening of the steroid D-ring was achieved by reacting the diol 3b with lead tetraacetate (Aldrich, recrystallized from acetic acid) in benzene to give the corresponding tricyclic enone-aldehyde 4b in quantitative yield. Selective conversion of the enone-aldehyde 4b to a dimethyl acetal 5b by with triinethyl orthoformate (Aldrich) and canphorsulfonic acid (Aldrich) in methanol (>95% yield) ensured the functionalization at C-14 vithout complication at C-15. The necessary functional groups at 14-position were introduced at this stage by adding various nucleophiles to the carbonyl. Diisobutyl aluninum hydride (Aldrich, 1 molar solution in hexane) reduction of the enone 5b in nethyl chloride affcrded the alcohol 12b in 85% yield. A methyl group was introduced by a Grignard reaction with methyl magnesiun bromide (Aldrich, 3 - 15 - - 15 - LV 10719 molar solution in diethyl ether) in diethyl ether to give the tertiary alcchol 6b in above 90% yield.

Sinilarly a vinyl grcup was introduced by treati.ng the enone acetal 5b with vinyl magnesium bromide (Alfa, 1.6 molar solution in tetrahydrofuran) in refluxing dry tetrahydrofuran to give the doubly allylic alcohol 18b in near 90% yield.

The steroid D-ring was reclosed to form a six-membered ring vith introduction of an oxygen at 14 -position by treating the tertiary alcohol 6b in 80% agueous acetic acid to provide a 3.3:1 mixture of cyclic hemiacetal 7b and cyclic acetal 7c. The acetal 7c vas easily separated form the hemiacetal 7b by column chromatography on silica gel (Kieselgel 60), EM Science, 111 Woodcrest Road, Cherry Hill, NJ 08034-0395) with elution by 15:85 ethyl acetate -hexane folloved by 3:7 ethyl acetate - hexane. The acetal 7c vas further hydrolyzed to the hemiacetal 7b by exposing to 80% aqueous acetic acid containing a catalytic amount of 1M - hydrochloric acid (78% overall yield for the hemiacetal from the diene 2b) .

For the extrusion of the extra carbon atom to form the five-membered heterocyclic D-ring the hemiacetal 7b vas converted to the corresponding glycal 8b by reacting vith methanesulfonyl chloride (Aldrich, filtered freshly through basie alumina) in'the presence of excess triethylamine (Aldrich, distilled from calcium hydride) in methylene chloride (See, Scheme II) ·

The intermediate methanesulfonyl ester vas eliminated to form the glycal 8b under convent'ional reaction conditions. Osmium tetroxide hydroxylation of the glycal 8b in benzene containing 10 equivalents of pyridine afforded a diasteromeric mixture of diols 9b.·

This unstable mixture of diols 9b was reacted vith sodiun periodate (Aidrich) ir. 4 parts of diethvl ether, 4 parts of metharol and 1 part of water in the presence of camphorsulfonic acid to give a mixture of p-methoxy-benzyl ether cf 16-methoxy-15-oxa-dihydrolanosterol 10b and p-methoxybenzyi ether of 16-hydroxy-15-oxa-dihydrolanosterol 10c in about 7:1 ratio. The mixture was then treated vith excess triethylsilane (Aidrich) and then redistilled boron trifluoride etherate (Aidrich) in methyler.e chloride to give the desired 15-oxa-dihydrolanosterol (11a) in 40% overall yield from the compound 7b. The p-methoxy benzyl protecting group at C-3 vas conveniently cleaved during this process to afford the free hydroxy compound.

In the same raanner the C-14 hydride compound 12b and the C-14 vinyl compound 13b have also been transformed successfully into the corresponding 4.4- dimethyl-15-oxa-5a-cholest-3-en-3b-ol (17a) and 4.4- dimethyl-15-oxa-l4a-vinyl-5a-cholest-8-en-2b-oi (23a) in 36% and 50% overall yields respectively. The compounds 17a, 11a, and 23a constitute three examples of 15-oxa-lancsterols vithin'the scope of the present invention.

Exposing the 14a-vinyl-oxa-sterol (23a) to acetic anhydride (Fischer Scientific, Fair Lavn, NJ 07440) in anhydrous pyridine gavē 3b-acetoxy-4,4-dimethyl-15-oxa-vinyl-lanost-8-ene (23c), a compound vithin the sccpe cf the present invention, in 31% yield. Esters of ether lanosterol derivatives vithin the scope cf the invention mav be prepared in this or a similar manner. - 17 - LV 10719

SCKEMZ II

pMBnO

7b R3»CH3 13b Rj.H 19b Rļ CH«CH2 8b Rj * CH3 14b Rj H 20b P^.CH-CHj

16b R^H 22b Rj-CH-CH.

Sb r3-ch3 15b Rj-H 21b R3-CH»CHt

11 R, - H, Rj CHj 17 R, -H, F^.H 23· R1 -H, F^-CH-CKj 23c R, - CH3CO. Rļ-CH-CHj 13

Further elaboration at the 14-pcsition was achieved by treatir.g the vinyi compound 23c with osmium tetroxide in pyridins to afford a diastereomeric mixture of diols 24c and 25c (2.34:1) in 45% yield (Scheme III).

The mixture of diols 24c and 25c was reacted vith sodium metaperiodate in 4 parts of ethanol and 1 part of vater to give 3b-acetoxy-15-oxa-lanost-8-en-32-al (26c) in near quantitative yield. Hydrolysis of the acetate-aldehvde 26c by 3 molar potassium hydroxide afforded the ccrresponding free hydroxy-aldehyde 26a in near guantitative yield. Reduction of the aldehyde 26a vith sodium borohydride (Fischer Scientific) in ethanol afforded 15-oxa-lanost-8-ene-3b, 32-diol (27) in near guantitative yield.

The same chemistry is also applicable to the free hydroxy-vinyl compound 23a to provide 24a, 25a, and 26a directly. Compounds 24a, 24c, 25a, 25c, 26a, 26c and 27 are seven additional examples of 15-cxa-lanosterols vithin the scope of the present invention.

- 19 - SCHEMZ III LV 10719

30 23, 29 20

The aldehvde functicnal group of the Conpound 26 allcvs further functionalization at the 32-positicn cf lancsterol. A Grignard addition to the aldehyde 25c with vinyl magnesium bromide (Alfa, 1.6 molar soluticn in tetrahydrofuran) in refluxing tetrahydrofuran provided a diasteromeric mixture of allylic alcohois 23 and 29 (1.4:1) in >95% combined yield. Upon exposing the aldehyde 26a to hydroxylamine hydrochloride (Aldrich) in pyridine at 80°, the corresponding oxine 30 was obtained in guantitative yield. Corapounds 23, 29, and 30 constitute three additional examples cf 15-oxa- lanosterols within the scope of the present invention. LV 10719 - 21 -

Table 1 sets forth various oxasterols of the preser.t invent ion. 22

Table 1

frx. 1 t~ (K o 2Ί Rn R-> D No. Μ. P. 1 OH 4m ch3 ch3 8 11 amorphous* 2 OH ch3 H 8 17 amorphous* 3 OH ch3 ch=ch2 3 23a amorphous* 3a ch3 ch3 ch=ch2 8 23c 4 OH ch3 CHOHCH2OH-(R) 8 24c 5 OH ch3 CHOHCH3OH-(S) 8 25c 6 CH3CO ch3 CHO 8 26c amorphous* 7 OH ch3 CHO 8 2a amorphous* 8 OH ch3 CH2OH 8 27 9 OH ch3 co2ch3 8 10 OH ch3 CH=NOH 8 30 amorphous* 11 OH ch3 CHOHCH=CH2-(R) 3 28 amorphous* 12 OH ch3 CHOHCH=CH2-(S) 8 29 amorphous* 13 OH H ch3 8 47 14 OH Η H S 15 OH H ch=ch2 8 16 OH H CHOHCH20K-(R) 8 17 OH H CHOHCH,OH-(S) 8 - 23 - - 23 -LV 10719

Table 1 (Continued)

Ex. No. Ri , Rn ..... R3 D 18 - 1 OH H CHO 8 19 OH H ch2oh 8 20 OH H co2h 8 21 OH K co2ch3 8 22 OH H ch=noh 8 23 OH H CHOHCH=CH2-(R) 8 24 OH H CHOHCH=CH2-(S) 8 25 OH ch3 c3h5 8 26 OH ch3 c3h7 8 27 OH ch3 i-C3H9 8 23 OH ch3 C6h'l3 8 29 OH ch3 C6H13 8 30 OH ch3 C6H13 8 31 OH ch3 ch2ch=ch2 8 32 OH ch3 C*CH 8 33 OH ch3 o n: K> n tll o te 8 34 OH ch3 Ch'2Ph 8 35 OH ch3 CHOHCH3 8 36 OH ch3 chohc^ch 8 37 OH ch3 ch2och3 8 38 OH ch3 ck2oc2h5 8 39 OH ch3 ch2oc3h7 8 40 OH ch3 ck2och2ch=ch2 8 41 OH ch3 CH2OPh 8 42 OH ch3 ch2ococh3 8 - 24 - labie 1 (Ccntinued)

Ex. No. Rn __ ... R-> D 43 1 OH ch3 ch2sh 8 A A *t OH ch3 ch2sch3 3 4 5 OH ch3 ch2sc2h5 8 46 OH ch3 CH2S?r 8 47 OH ch3 ch2sch2ch=ch2 8 43 OH ch3 CH2SPh 8 49 OH ch3 ch2scoh3 3 50 OH ch3 ch2nh2 8 51 OH ch3 ch2nhch3 8 52 OH ch3 ch2nhc2h5 8 53 OH ch3 ch2nhc3h7 8 54 OH ch3 CH2NHi-Pr 8 5 5 OH ch3 ch2nhc6h13 3 5 6 OH ch3 CH2NHPh 8 57 OH ch3 CH2NMe2- 8 53 OH ch3 CH2NEt2 8 59 OH ch3 ch2nhcho 8 60 OH ch3 ch2nhcoch3 8 61 OH ch3 ch2nhcsch3 8 62 OH ch3 CH2NH(C=NH)ch3 8 63 OH ch3 coch3 8 64 OH ch3 coc2h5 8 6 5 OH ch3 coc3h7 8 66 OH ch3 COi-C3H7 8 67 OH ch3 coc6h13 8 - 25 - - 25 -LV 10719

Table 1 (Continued)

R-, R-> D 1 £ OH ch3 COCH=CH2 8 OH ch3 coch2ch=ch2 8 OH ch3 coch=chch3 8 OH ch3 COC=CH 8 OH ch3 cock2c=ch 8 OH ch3 COC=CC"3 8 OH ch3 coph 8 OH ch3 csch3 3 OH ch3 csc2h5 8 OH ch3 csc3h7 8 OH ch3 csc3h7 (i) 8 OH ch3 csc6h13 8 OH ch3 csch=ch2 8 OH ch3 csch2ch=ch2 8 OH ch3 csch=ohch3 8 OH ch3 CSC^CH 8 OH ch3 csch2ch 6 OH ch3 csc=cch3 8 OH ch3 CSPh 8 OH ch3 C(=NH)CH3 8 OH Ch'3 C(=NH)C3H7 8 OH ch3 C(=NH)C3H7 8 OH ch3 C(=NH)Ph 8 OH ch3 C(=NH)ch3 8 OH ch3 C(=NCH3)C2H5 S -26-

Table 1 (Continued) Ξ X - No. R, R-v. r3 D 93 OH t» CH-» C(=NCH3)c3h7 8 94 OH ch3 co2c2h5 8 95 OH ck3 c02C3H7 8 96 OH ch3 co2ī-c3h7 8 97 OH ch3 co2c4h9 3 93 OH ch3 c02C6H13 8 99 OH ch3 co2ch2ch=ch2 8 100 OH ch3 co2Ph 8 101 OH ch3 cosch3 8 102 OH ch3 cosc2h5 8 103 OH ch3 cosc3h7 8 104 OH ch3 COSPh 8 105 OH ch3 conh2 8 106 OH ch3 conhch3 8 107 OH ch3 conhc2h5 3 108 OH ch3 conhc3h7 8 109 OH ch3 CONHi-C3H7 8 110 OH ch3 CONHC6H13 8 111 OH ch3 CONHPh 8 112 OH ch3 CONHe2 8 113 OH ch3 CONEt2 8 114 OH ch3 CONPr2 8 115 OH ch3 CONHCOCH-j 8 116 OH ch3 conhcoc2h5 8 117 OH ch3 csnh2 8 -27- -27-LV 10719

Table 1 (Continued) R1 R-> R3 D OH ch3 csnhch3 8 OH ck3 csnhc2h5 8 OH ch3 csnhc3h7 8 OH ch3 CSNHi-C3H7 8 OH ch3 csnhc6h13 8 OH ch3 CSNHPh 8 OH ch3 CSNHe2 8 OH ch3 CSNEt2 8 OH ch3 CSNPr2 8 OH ch3 scnhcoch3 8 OH ch3 csnhcoc2h5 8 OH ch3 ch2ch2oh 8 OH ch3 CH2CH(CH3)OH 8 OH ch3 ch2ch2och3 8 OH ch3 ch2ch2oc2h5 8 OH ch3 CH2CH20Ph 8 OH ch3 CH2CH(CH3)OCH3 8 OH ch3 ch2ch2ococh3 8 OH ch3 ch2ch2sh 8 OH ch3 CH2CH(CH3)SH 8 OH ch3 ch2ch2sch3 8 OH ch3 ch2ch2sc2k5 8 OH ch3 CH2CH2SPh 8 OH ch3 CH2CH(CH3)sch3 8 OH ch3 ch2ch2scoch3 8 -23- Table 1 (Continued) R1 Rn... R3 OH ch3 ch2ch2nh2 OH ch3 CH2CH(CH3)NH2 OH ch3 ch2ch2nhch3 OH ch3 ch2ch2nhc2h5 OH ch3 CH2CH2NHPh OH ch3 CH2CH(CH3)NHCH3 OH ch3 CH2CH2NMe2 OH ch3 CH2CH2NHCOCH3 OH ch3 CH2CH(CH3)NHCOCH3 OH ch3 ch2ch2nhcsch3 OH ch3 CH2CH(CH3)NHCSCH3 OH ch3 CH2CH2NHC(=NH)ch3 OH ch3 CH2CH(CH3)NHC(=NH)ch OH ch3 ch2cho OH ch3 ch2coch3 OH ch3 ch2coc2h5 OH ch3 ch2coch=ch2 OH ch3 ch2coch2ch=ch2 OH ch3 ch2coch=chch3 OH ch3 ch2coc=ch OH ch3 CH2C0Ph OH ch3 ch2csch3 OH ch3 ch2csc2h5 OH ch3 ch2csch=ch2 OH ch3 ch2csch2ch=ch2

D No. MP

3 3 3 S 3 3 S 3 3 3 3 3 5 3 3 3 3 8 3 3 3 3 8 3 -29- -29-LV 10719

Table 1 (Continued)

Ex. No. R1 . R-i. - R3 D 168 1 OH ch3 ch2csch=chch3 8 169 OH ch3 Ch’2CSCrCH 8 170 OH ck3 CH2CSPh 8 171 OH ch3 CH2C(=NH)ch3 8 172 OH ch3 CH2C(=NH)c2k5 8 173 OH ch3 CH2C(=NCH3)CH3 8 174 OH ch3 CH2C(=NCH3)c2h5 8 175 OH ch3 CH2C(=NH)Ph 8 176 OH ch3 ch2co2ch3 8 177 OH ch3 ck2co2c2h5 8 178 OH ch3 ch2co2ch2ch=ch2 8 179 OH ch3 Ολ2 CO2 Ph 8 180 OH ch3 ch2cosch3 8 181 OH ch3 ch2cosch3 8 181 OH ch3 CH2COSC2H5 8 182 OH ck3 cK2cosPh 8 183 OH ch3 ck2conh2 8 184 OH ch3 ch2conhch3 8 185 OH ch3 ch2conhc2h5 8 186 OH ch3 CH2CONHPh 8 187 OH ch3 CH2CONMe2 8 188 OH ch3 CH2CONHCOCH3 8 189 OH ch3 ch2csnh2 6 190 OH ch3 CH2C(=NH)nh2 8 191 OH ch3 ch2ci 8 -30-

Table 1 (Continued)

Ex. No. Ri R3 D 192 OH ch3 CH2Br 8 193 OK ch3 ch2ch2ci 3 194 OH ch3 CH2CH2Br 3 195 OH ch3 CN 8 196 OH ch3 C(CH3)=NOH 8 197 OH ch3 ch=noch3 3 198 OH ch3 ch=noc2h5 3 199 OH ch3 ch=nococh3 8 200 OH ch3 ch=nnh2 3 201 OH ch3 ch=nnhch3 8 202 OH ch3 ch=nnhcoch3 8 203 OH ch3 ch=nnhcsch3 8 204 OH ch3 ch2nhoh 3 205 OH ch3 ch2nhoch3 8 206 OH ch3 ch2nhococh3 8 207 OH ch3 ch2nhnh.2 3 208 OH ch3 ch2nhnhch3 8 209 OH ch3 ch2nhnhcoch3 8 210 OH ch3 ch2nhnhcsch3 3 211 OH ch3 ch2cn 8 212 OH ch3 ch2ch=noh 8 213 OH ch3 CH2C(CH3)=NOH 8 214 OH ch3 ch2ch=noch3 3 215 OH ch3 ch2ch=noc2h5 8 216 OH ch3 ch2ch=nococh3 8 -31- -31-LV 10719

Table 1 (Continued)

Ex. No. R1 . R-i_ -R3 D 217 OH ch3 ch2ch=nnh2 8 218 OH ch3 ch2ch=nnhch3 8 219 OH ch3 ch2ch=nnhcoch3 8 220 OH ch3 ch2ch=nnhcsch3 8 221 OH ch3 ch2ch2nhoh 8 222 OH ch3 ch2ch2nhoch3 8 223 OH ch3 ch2ch2nhococh3 8 224 OH ch3 ch2ch2nhnh2 8 225 OH ch3 ch2ch2nhnhch3 8 226 OH ch3 ch2ch2nhnhcoch3 8 227 OH ch3 ch2ch2nhnhcsch3 8 228 OH ch3 CONHOH 8 229 OH ch3 conhoch3 8 230 OH ch3 conhoc2h5 8 231 OH ch3 CONHOPh 8 232 OH ch3 conhococh3 8 233 OH ch3 csnhoh 8 234 OH ch3 csnhoch3 8 235 OH CH3 csnhococh3 8 236 OH ch3 ch=chcho 8 237 OH ch3 ch=chcoch3 8 238 OH ch3 ch=chcoc2h5 8 239 OH CK3 ch=chcsch3 8 240 OH ch3 ch=chcsc2h5 8 241 OH ch3 ch=chch=nh 8 -32-

Table 1 (Continued) R1 R-> R3 D OH ch3 CH=CHC(=NH)ch3 3 OH ch3 C=CCHO 3 OH ch3 c=ccoch2 8 OH ch3 c=ccoc2h5 8 OH ch3 c=ccsch3 3 OH ch3 c=ccsc2h5 •3 OH ch3 C=CCH=NH 8 OH ch3 C=CC(=NH)ch3 8 OH ch3 ch=chch2ci 8 OH ch3 CH=CHCH2Br 3 OH ch3 c=ccn2ci 8 OH ch3 C^CCH2Br 8 OH ch3 CH=CHCH2OCOCH3 8 OH ch3 ch=chch2ococ2h5 8 OH ch3 c=cch2ococh3 8 OH ch3 c^cch2ococ2h5 8 OH ch3 ch2chohch2oh 8 OH ch3 chohchohch2oh 8 OH ch3 ch-ch, 0 8 OH ch3 CH-)CH-CH, V 8 OH ch3 CHOHCH-CH-, V 8 OH H C2H5 8 -33- -33-LV 10719

Table 1 (Continued) R1 R-i_ R3 D OH H ck2ch=ch2 8 OH H CjfCH 8 OK H CH2Ph 8 OH H ch2och3 8 OH H ch2ococh3 8 OH H ch2sh 8 OH H ch2sch3 8 OH H ch2scoch3 8 OH H ch2nh2 8 OH H ch2nhch3 8 OH H CH2N2(CH3)2 8 OH H CH2NHCOCH3 8 OH H ch2nhcsch3 8 OH H CH2NHC(=NH)ch3 8 OH H coch3 8 OH H coch=ch2 8 OH H csch3 8 OH H csch=ch2 8 OH H C(=NK)CH3 8 OH K C(=NCH3)ch3 8 OH K co2c2h5 8 OH H cosch3 8 OH K conh2 8 OH H cohhch3 8 OH H C0N2(CH3)2 8 -34- Table 1 (Continued)

No ._Rļ__Ķ2_S3 D No. M.P. 0H H CONHCOCH3 OH H csnh2 OH H CSNHCK3 OH H CSNMe2 OH H CSNHCOCH3 OH H CH2CH2OH OH H ch2ch2och3 OH H ch2ch2ococh3 OH H ch2ch2sh OH H ch2ch2sch3 OH H ch2ch2scoch3 OH H ch2ch2nh2 OH H ch2ch2nhch3 OH H CH3CH2NHe2 OH H CH2CH2NHCOCH3 OH H ch2ch2nhcsch3 OH H CH2CH2NHC(=NH)ch OH H ch2cho OH H ch2coch3 OH H ch2coch=ch2 OH H ch2csch3 OH H ch2csch=ch2 OH H CH2C(=NH)ch3 OH H ch2c(=nch3)ch3 OH H ch2co2ch3 3 8 8 8 8 8 8 8 3 8 8 8 8 8 8 8 8 8 8 8 8 3 8 8 8 -35-

Table 1 (Continued) R1 R-i Ri D 1 ----- i. OH K CH2COSCH3 8 OH H ch2conh2 8 OH H ch2conhch3 8 OH H CH2CON>ie2 8 OH K ch2conhcoch3 8 OH H ch2csnh2 8 OH H CH2C(=NH)ch3 8 OH V 44 ch2ci 8 OH K CH2Br 8 OH K CH2CH2C1 8 OH H CH2CH2Br 8 OH H CN 8 OH H CH=N0CH3 8 OH H ch=nococh3 8 OH H CH=NNH2 8 OH H ch=nnhch3 8 OH H ch=nnhcoch3 8 OH K ch=mnhcsch3 8 OH H ch2nhok 8 OH H ch2nhoch3 8 OH H ch2nhococh3 8 OH H ch2nhnh2 8 OH H ch2hhnhch3 8 OH H ch2nhnhcoch3 8 -36- Table 1 (Contir.ued)

Ex. No. R1 R2 R3 D 338 1 OH L· H ch2nhnhcsch3 8 339 OH H ch2cn 8 340 OH H ch2ch=noh 8 341 OH H ch2ch=noch3 8 342 OH H ch2ch=nococh3 8 343 OH H ch2ch=nnh2 3 344 OH H ch2ch=nnhch3 8 345 OH H ch2ch=nnhcoch3 3 346 OH H ch2ch=nnhcsch3 8 347 OH H ch2ch2nhoh 8 348 OH H ch2ch2nhoch3 8 349 OH H ch2ch2nhococh3 3 350 OH H ch2ch2nhnh2 3 351 OH H ch2ch2nhnhch3 8 352 OH H ch2ch2nhnhcoch3 8 353 OH H ch2ch2nhnhcsch3 3 354 OH H conhoh 8 355 OH H conhoch3 8 356 OH H conhococh3 3 357 OH H CSNHOH 8 358 OH H csnhoch3 8 359 OH H csnhococh3 8 360 OH H ch=chcho 8 361 OH H ch=chcoch3 8 Μ. ?. -37- -37-LV 10719

Table 1 (Continued)

Ex. No. R1 Po R-, D 362 OH «L K ch=chcsck3 8 363 OK H ch=chch=nh 8 364 OH H CH=CHC(=NH)CH3 8 365 OH H CiCCHO 8 366 OH H C=CC0CH3 8 367 OH H c=ccsch3 8 368 OH H c=cch*nh 8 365 OH H C^CC(=NH)CH3 8 3 7 C OH H ch=chch2ci 8 371 OH H CH=CHCH2Br 8 372 OH H C^CCH2C1 8 373 OK H C^CCH2Br 8 374 OH H ch=chch2ococh3 8 375 OH H c^cch2ococh3 8 376 OH H ch2chohch2oh 8 377 OH H chohchohch2ok 8 378 OH H ch-ch, 8 379 OH K CH,CH-CH, V 8 380 OH H CHOHCH-CH, \ / 2 0 8 381 =0 ck3 ch3 8 382 =0 ch3 H 8 383 =0 ch3 CH=CH -5 8 384 =0 ch3 CHOHCK2OH-(R) 8 -38-

Table 1 (Continued) Νο . R- R-

No. Μ.P 0 ch3 CHOHCH2OH-0(S) 8 •0 ch3 CHO 3 :0 oh3 CH20H 8 Ό ch3 co2h 8 >0 ch3 co2ch3 8 '0 ch3 CH=N0H 3 :0 ch3 CHOHCH=CH2-(R) 8 o ch3 CHOHCH=CH2-(S) 8 >0 ch3 ch2sh 8 0 ch3 ch2nh2 8 0 ch3 coch3 8 0 ch3 conh2 8 0 ch3 csnh2 8 0 ch3 ch2ch2oh 8 0 ch3 ch2cho 8 0 ch3 ch2coch3 8 0 ch3 ch2co2ch3 8 0 ch3 ch2conh2 8 0 ch3 ch2ci . 8 o ch3 ch2ch2ci 8 0 ch3 CN 8 0 ch3 ch=nnh2 8 0 ch3 ch2nhoh 8 0 ch3 ch2nhnh2 8 8 -35-

Table 1 (Continued)

R 2

R 3 D No. =0 ch3 Ch'2CH=NOH 8 =0 ch3 ch2ch=nnh2 8 =0 ch3 ch2ch2nhoh 8 =0 ck3 ch2ch2nhnh2 8 =0 ch3 COKriOH 8 =0 ch3 CH=CHCHO 8 =0 ch3 ch=ckcoch3 8 =0 ch3 ch=chch2ci 8 =0 ch3 ch2chohch2oh 8 =0 ch3 CHOHCK-CH, \ / 1 8 0

=0 H ch3 =0 K H =0 H ch=ch2 =0 H CHOHCH2OH-(R) =0 H CHOHCH2OH-(S) =0 H CHO =0 H ch2oh =0 H co2k =0 H C02CK3 =0 H CK=NOH =0 H CKOHCH=CH2-(R) =0 H CHOHCH=CH2-(S) och3 ch3 ch3 och3 ch3 H 8 8 8 8 8 8 8 8 8 8 8 8 8 8 -40- Νο .

Table 1 (Continued) R1 R-i R3 D och3 ch3 ch=ch2 3 och3 ch3 chohch2oh-(R) 3 och3 ch3 CHOHCH2OH-(S) 8 och3 ch3 CHO 3 och3 ch3 ch2oh 3 och3 ch3 co3h 3 och3 ch3 co2ch3 3 och3 ch3 CH=NOH 3 och3 ch3 CHOHCH=CH2-(R) 3 ock3 ch3 CHOHCH=CH2-(S) 3 och3 ch3 ch2sh 3 och3 ch3 ch2nh2 3 och3 ch3 coch3 3 och3 ch3 conh2 3 och3 ch3 csnh2 3 och3 ch3 ch2ch2oh 3 och3 ch3 ch2cho 8 och3 ch3 ch2coch3 8 och3 ch3 ch2co2ch3 3 och3 ch3 ch2conh2 8 och3 ch3 ch2ci 8 och3 ch3 ch2ch2ci 3 och2 ch3 CN 3 och3 ch3 ch=nnh2 8 och3 ch3 ch2nhoh 3 -41- -41-LV 10719

Table 1 (Continued) R, R-> R3 D 1 OCK3 ch3 ch2nknh2 8 OCH3 ch3 ch2cn 8 OCH3 ck3 ck2ch=noh 8 0CH3 ch3 ch2ch=nnh2 8 OCK3 ch3 ch2ch2nhoh c OCH3 ck3 ch2ch2nhnh2 8 0CH3 CK3 CONKOH s och3 ch3 CK=CHCHO 3 och2 ch3 ch=coch3 g och3 ch3 ch=chch2ci 3 OCK3 ch3 ch2ckohch2oh 8 OCK3 ch3 CHOHCK-CH, \ / * 0 8 OCH3 H ch3 8 0CH3 H H S OCH3 K ch=ch2 8 OCR 3 H CHOHCH2OH-(R) S 0CH3 K CHOKCK2OH-(S) 8 0CH3 H CHO 8 OCH3 K ch2oh 8 0CH3 K co2h 8 0CK3 H CO 2 Cn ^ s 0CH3 H CH*NOH 8 0CH3 H CHOHCH=CH2-(R) S 0CK3 H CHOHCH=CH2-(S) 8 -42-

Table 1 (Continued)

Ex. No. R1 *1 R3 D No . M. ?. 433 OC2H5 ch3 ch3 3 434 oc2h5 ch3 CHO 8 4 3 5 oc2h5 ch3 ch2oh 8 436 oc3h7 ch3 ch3 3 437 OC3K7 ch3 CHO 8 488 oc3h7 ch3 CH2OH 8 439 0 i-C3^7 ch3 ch3 8 490 oc4h9 ch3 ch3 8 491 oc4h9 ch3 CHO 3 492 oc4h9 ch3 ch2oh 8 493 Oi-C4H9 ch3 ch3 8 494 Ot-C4H9 ch3 ch3 3 495 OPh ch3 ch3 8 496 OPh ch3 CHO 8 497 OPh ch3 ch2oh 8 493 OCH2Ph ch3 ch3 3 499 OCH2Ph ch3 CHO 3 500 OCH2Ph ch3 ch2oh 8 501 ococh3 ck3 ch3 8 502 ococh3 ch3 Η 8 503 ococh3 ch3 ch=ch2 8 23c amcrphcus* 504 ococh3 ch3 CHOHCH2OH-(R) 8 24c amorphcus * 505 ococh3 ch3 CHOHCH2OH-(S) 8 25c amorphcus * 506 OCOCH-J ch3 CHO 8 26c amorphccs x 507 OCOCH-J ch3 ch2oh 8 -43-LV 10719

Table 1 (Continued) NO. M. ?.

No. R ^ R2 R3 D OCOCH3 ch3 co2h 8 OCOCH3 CK3 co2ch3 8 OCOCH3 CH3 CH=NOH 8 OCOCH3 CK3 CHOHCH=CH2- (R) 8 OCOCH3 ch3 CHOHCH*CH2-(S) 8 OCOCH3 ch3 ch2sh 8 OCOCH3 ch3 ch2nh2 8 ococh3 ch3 COCH3 8 OCOCH3 ch3 conk2 8 OCOCH3 ch3 csnh2 8 OCOCH3 ch3 ch2ch2oh 8 OCOCH3 ch3 ch2cho 8 OCOCH3 ch3 ch2coch3 8 OCOCH3 ch3 ch2co2ch3 8 OCOCH3 ch3 ch2conh2 8 OCOCH3 ch3 ch2ci 8 OCOCH3 ch3 ch2ch2ci 8 OCOCH3 ch3 · cn 8 OCOCH3 ch3 ch=nnh2 • 8 OCOCH3 ch3 ch2nhoh 8 OCOCH3 ch3 ch2nhnh2 8 OCOCH3 ck3 ch2cn 8 OCOCH3 CK3 ch2ch=noh 8 OCOCH3 CK3 ch2ch=nnh2 8 OCOCH3 C«3 ch2ch2nhoh 8 -44-

Table 1 (Continued) R1 — 2. OCOCH3 ch3 ococh3 ch3 ococh3 ch3 OCOCH-j ch3 OCOCH3 ch3 ococh3 CH3 ococh3 ch3 ococh3 H ococh3 H ococh3 H OCOCH3 H ococh3 H ococh3 H ococh3 H ococh3 H OCOCH3 H OCOCH3 H OCOCH3 H OCOCH3 H OCOCH2H5 ch3 ococ2h5 ch3 ococ2h5 ch3 ococ3h7 ch3 ococ3h7 ch3 ch2ch2nhnh2

CONHOH

CH=CHCHO ch=chcoch3 ch=chch2ci ch2chohch2oh CHOHCH-CH, \ / ^ 0 ch3

H ch=ch2

CHOHCH2OH-(R) CHOHCH2OH-(S) CHO ch2oh co2h co2ch3

CH=NOH CHOHCH=CH2-(R) CHOHCH=CH2-(S) ch3

CHO ch2oh ch3

CHO -45-

Table 1 (Continued) -Bl- —2. R3 D ococ3h7 ch3 ch2oh 8 ocoi-c3H7 ch3 ch3 8 OCOC4H9 ch3 ch3 8 ococ4h9 ck3 CHO 8 OCOC4K9 ch3 ch2oh 8 OCOi-C4H9 ch3 ch3 8 OCOt-C4H9 ck3 ch3 8 OCOC15H31 ch3 ch3 8 OCOC15H31 ch3 CHO 8 OCOC15H31 ch3 CH2OH 8 OCOC15H29 ch3 ch3 8 OCOC17H35 ch3 ch3 8 0C0C17Hi3 ch3 ch3 8 OCOC17H31 ch3 ch3 8 OCOC17H29 ch3 · ch3 8 OCOC19H31 ch3 ch3 8 OCOPh ch3 ch3 8 OCOPh ch3 CHC 8 OCOPh ch3 ch2oh 8 OH ch3 ch3 7 OH ch3 H 7 OH ch3 CH=Ch’2 7 OH ch3 CHOHCH2OH-(R) 7 OH ch3 CHOHCH2OH-(S) 7 OH ch3 CHO 7 -46-

Table 1 (Continued) Νσ. R1 e2 R3 J2 OH ch3 ch2oh 7 OH CH3 co2h 7 OH ch3 co2ch3 7 OH ch3 ch=noh 7 OH ch3 CHOHCH=CH2-(R) 7 OH ch3 CHOHCH=CH2-(S) 7 OH Η ch3 7 OH H Η 7 OH H ch=ch2 7 OH H CHOHCH2OH-(R) 7 OH H CHOHCH2OH-(S) 7 OH H CHO 7 OH H ch2oh 7 OH H co2h 7 OH H co2ch3 7 OH H CH=HOH 7 OH H CHOHCH=CH2-(R) 7 OH H CHOHCH=CH2-(S) 7 =0 ch3 ch3 7 =0 ch3 H 7 =0 ch3 ch=ch2 7 =0 ch3 CHOHCH2OH-(R) 7 =0 ch3 CHOHCH2OH-(S) 7 =0 ch3 CHO 7 =0 ch3 ch2oh 7 =0 ch3 co2h 7 -47-

Table 1 (Continued) *2 R3 D =0 ch3 co2ch3 7 =0 ch3 CH=NOH 7 =0 ch3 CHOHCH=CH2-(R) 7 =0 ch3 CHOHCH=CH2- (S) 7 =0 H ch3 7 =0 K K 7 =0 H ch=ch2 7 =0 H CHOHCH2OH-(R) 7 =0 H CHOHCH2OH-(S) 7 =0 H CKO 7 =0 H CK2OH 7 =0 H co2h 7 =0 H co2ch3 7 =0 H CH-HOH 7 =0 H CKOKCH=CH2-(R) 7 =0 H CH0HCH=CH2-(S) 7 och3 ch3 ch3 7 och3 ch3 H 7 och3 ch3 ch=ch2 7 och3 ch3 CKOHCH2OH-(R) 7 och3 ch3 CHOKCH2OH-(S) 7 och3 ch3 CHO 7 och3 ch3 ch2oh 7 och3 ch3 co2k 7 och3 ch3 C02CK3 7 -43-

Table 1 (Continued) R1 och3 ch3 och3 ch3 och3 ch3 och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 OCOCH-j ch3 OCOCH-J ch3 OCOCH3 ch3 OCOCH-J ch3

CH=N0H CHOHCH=CH2-(R) CHOHCH=CH2-(S) ch3

H ch=ch2 CHOHCH2OH-(R) CHOHCH2OH-(S)

CHO ch2oh co2h co2ch3

CH“NOH CHOHCH*CH2-(R) CHOHCH=CH2-(S) ch3

H ch=ch2 CHOHCH2OH-(R) CHOHCH2OH-(S)

CHO ch2oh co2h co2ch3

CH=NOH -4 9-

Table 1 (Continued)

Ex. No. R1 R2 R3 D 658 OCOCK3 ch3 chohch=ch2-(R) 7 659 OCOCh’3 ch3 CHOHCH=CH2-(S) 7 660 OCOCH3 H ch3 7 661 OCOCK3 H H 7 662 OCOCH3 H ch=ch2 7 663 OCOCH3 H CHOHCH2OH-(R) 7 664 OCOCH3 H CHOHCH2OH-(S) 7 665 OCOCH3 H CHO 7 666 OCOCH3 H ck2oh 7 667 OCOCK3 H K <M 0 u 7 668 OCOCH3 H co2ch3 7 669 OCOCH3 H CH=NOH 7 670 OCOCH3 H CHOHCH=CH2-(R) 7 671 OCOCH3 H CHOHCH»CH2-(S) 7 LV 10719 M. ?. * Further analytical data are available in the examplrs sec -50-

The six-membered 15-oxa-D-homo-lanosterol derivatives are synthesized by reducing the six-mer.bered cyclic acetals and hemiacetals under conditions sinilar as those used fcr the five-membered 15-oxa-lanosterols. Hovever, the entire sequence was carried out more conveniently in higher overall yield vithout the protecting group at the 3-position. Thus the unprotected 8,14-diene 2a was converted to a mixture of six-membered cyclic acetal 7a in the same manner as described earlier for p-methcxybenzyl protected intermediates (Scheme I). The cyclic hemiacetal 7a was treated with triethylsilane and redistilled boron trifluoride etherate in methylene chloride to affcrd 15-oxa-D-homo-dihydrolanosterol (31) in 92% yield (See, Scheme IV). The corresponding cyclic acetal 7d is also converted to the compound 31 in slightly lover yield than the acetal 7a. 4,4-Dimethyl-15-oxa-D-homo-5a-cholest-8-en-3b-ol (32) and 4,4-dimethyl-15-oxa- 14a-vinyl-5a-cholest-3-en-3b-ol (33) have also been prepared in the same manner through the secondary alcohol 6a and the doubly allylic alcohol 8a respectively in čomparable yields. Compounds 31, 32, and 33 are ali vithin the scope of the present invention.

-51- SCHEME IV LV 10719

13« H 19« Ra-CH-CH,

31 Ra-CH,

32 R^-H 3 3 Rj · CH»CH2

37 -52-

For further functionalization at the 14-positicn, the vinyl compound 33 was converted to a 1:1 mixture of diasteromeric diols 34 and 35 in 84% combined yield by reacting with osmium tetroxide as described earlier for five-membered 15-oxa-lanosterols. The mixture of diols 34 and 35 was treated with sodiua metaperiodate in 4 parts of ethanol and 1 part of vater to give l5-oxa-32-oxo-D-homo-dihydrolanosterol (36) in near quantitative yield. Reduction of the aldehyde 36 with sodium borohydride in ethanol provided 15-oxa-D-homo-lanost-8-ene-3b-32-diol (37) in near quantitative yield. Coinpounds 34, 35, 36 and 37 also constitute four additional examples of 15-oxa-lanosterols vithin the scope of the present invention.

Elaborations of the aldehyde 36 may yield the corresponding oxime, allylic alcohol, etc., which are within the scope of the present invention, as described in the synthesis of five-membered 15-oxa-lanosterols. LV 10719 - 53 -

Table 2 sets forth additional oxasterols of the present inventior.. 54 Table 2

Ex. NO. 672 —— OH R, r3 E No. ch3 ch3 3 31 673 OH ch3 H 3 32 674 OH ch3 ch=ch2 8 32 675 OH ch3 CH0HCH2OH-(R) 8 34 676 OH ch3 CHOHCH2OH-(S) 8 35 677 OH ch3 CHO 8 36 673 OH ch3 CH20H 8 37 679 OH ch3 co2h 3 630 OH ch3 co2ch3 8 631 OH ch3 CH=NOH 3 632 OH ch3 CHOHCH=CH2-(R) 8 683 OH ch3 CHOHCH=CH2-(S) 3 634 OH H ch3 8 635 OH Η H 3 636 OH H ch=ch2 8 687 OH H CHOHCH2OH-(R) 3 M. P. amorphous* amorphous* amorphous* amorphous* amorphous* amorphous* amorphous * 55

Table 2 (Continued) R1 -2 R3 D OH H CHOHCH2OH-(S) 8 OH H CHO 8 OH H CH2OH 8 OH K co2h 8 OH H co2ch3 8 OH H ch=noh 8 OH H CHOHCH=CH2-(R) 8 OH H CHOHCH=CH2-(S) 8 OH ch3 ch2sh 8 OH ch3 ch2nh2 8 OH ch3 coch3 8 OH ch3 conh2 8 OH ch3 csnh2 8 OH ch3 ch2ch2oh 8 OH ch3 ch2cho 8 OH ch3 ch2coch3 8 OH ch3 ch2co2ch3 8 OK ch3 ch2conh2 8 OK ch3 ch2ci 8 OH ch3 ch2ch2ci 8 OH ch3 CN 8 OH ch3 ch=nnh2 8 OH ch3 ch2nhoh 8 OH ch3 ch2nhnh2 8 OH ch3 ch2cn 0 56

Table 2 (Continued) -*1- —2. OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 ch2ch=noh ch2ch-nnh2 ch2ch2nhoh ch2ch2nhnh2

CONHOH

CH=CHCHO ch=chcoch3 ch=chch2ci ch2chohch2oh CHOHCH-CH, \ / 2 0

=0 ch3 »0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 ch3 =0 H

H ch=ch2 CHOHCH2OH“(R) CHOHCH2OH-(S)

CHO ch2oh co2h co2ch3

CH=NOH CHOHCH=CH20(R) CHOHCH=CH2-(S) - 57 - - 57 -LV 10719

Table 2 (Continued)

Ex. No. R1 R2 R3 D 737 =0 H H 8 738 =0 H ch=ch2 8 739 =0 H CHOh'CH2OH- (R) 8 740 =0 H CHOHCH20H-(S) 8 741 =0 H CHO 8 742 =0 H ch2oh 8 743 =0 H co2h 8 744 =0 H co2ch3 8 745 =0 H CH=NOH 8 746 =0 H CHOKCH=CH2-(R) 8 747 =0 H CKOKCH=CH2-(S) 8 748 och3 ck3 ch3 8 749 och3 ch3 H 8 750 och3 ch3 ch=ch2 8 751 och3 ch3 CHOHCH2OH-(R) 8 752 och3 ch3 ČHOKCH2OH-(S) 8 753 och3 ch3 CHO 8 754 och3 ch3 ch2oh 8 755 och3 ch3 co2h 8 756 och3 ch3 co2ch3 8 757 och3 ch3 CH=NOH 8 758 och3 ch3 CHOHCH=CH2=(R) 8 759 och3 ch3 CHOKCH=CH2-(S) 8 760 och3 H ch3 8 761 och3 H H 8 53

Table 2 (Continued)

R1 S2 R-, och3 H ch=ch2 och3 H CHOKCH2OH- och3 H chohch2oh- och3 H CHO och3 H ch2oh och3 H co2h och3 H co2 ch3 och3 H CH»NOH och3 H chohch=ch2 och3 H CHOHCH=CH: oc2h5 ch3 ch3 oc2h5 ch3 CHO oc2h5 ch3 ch2oh oc3h7 ch3 ch3 oc3h7 ch3 CHO OC3H7 ch3 ch2oh oc4h9 ch3 ch3 oc4h9 ch3 CHO oc4h9 ch3 ch2oh oph ch3 ch3 OPh ch3 CHO OPh ch3 ch3oh OCH2Ph ch3 ch3 OCH2Ph ch3 CHO OCH2Ph CH3 CH2OH (R) (S) -(R) -<s) 59

Table 2 (Continued)

No . R1 R2 R3 D OCOCH3 ch3 ch3 8 OCOCH3 ch3 K 8 OCOCH3 ch3 ch=ch2 8 OCOCH3 ch3 CHOHCH2OH-(R) 8 OCOCH3 ch3 CH0HCH20H-(S) 8 OCOCH3 ch3 CHO 8 OCOCH3 ch3 ck2oh 8 OCOCH3 ch3 co2h 8 OCOCH3 ch3 co2ch3 8 OCOCH3 ch3 CH=NOH 8 OCOCH3 ch3 CKOHCH=CH2-(R) 8 OCOCK3 ch3 CHOHCH=CH2-(S) 8 OCOCH3 H ch3 8 OCOCH3 H H 8 OCOCH3 H ch=ch2 8 OCOCH3 H CHOHCH2OH-(R) 8 OCOCH3 H ckohch2oh-(S) 8 OCOCH3 H CHO 8 OCOCH3 H ch2oh 8 OCOCH3 H co2h 8 OCOCH3 H co2ch3 8 OCOCH3 H CH=NOH 8 OCOCH3 H CHOHCH=CH2-(R) 8 OCOCH3 H CHOHCH=CH2-(S) 8 0C0C02K5 ch3 ch3 8 60

Table 2 (Continued) _ £2 _£3 ococ2h5 ch3 CHO ococ2h5 ch3 ch2oh ococ3h7 ch3 ch3 ococ3h7 ch3 CHO ococ3h7 ch3 CH2OH ococ4h7 ch3 ch3 ococ4h9 ch3 CHO ococ4h9 ch3 ch2oh OCOC15H31 ch3 ch3 ococ15h31 ch3 CHO OCOC15K31 ch3 ch2oh ococ15h29 ch3 ch3 OCOCi7H35 ch3 ch3 ococ17h33 ch3 ch3 ococ17h31 ch3 ch3 ococ17h29 ch3 . ch3 ococ19h31 ch3 ch3 OCOPh ch3 CH3 OCOCPh ch3 ch3 OCOCPh ch3 ch3 OH ch3 ch3 OH ch3 CHO OH ch3 ch2oh OH ch3 co2h OH H ch3 - 61 -LV 10719

Table 2 (Ccntinued)

Ex. No. R1 - r2 R-> D c.m 837 OH H CHO 7 838 OH K ch2oh 7 839 =0 ch3 ch3 7 840 =0 ch3 CHO 7 841 =0 ch3 ch2oh 7 842 =0 K ch3 7 843 =0 K CHO 7 844 =0 H ch2oh 7 845 och3 ch3 ch3 7 846 och3 ch3 CHO 7 847 och3 ch3 ch2oh 7 848 och3 H ch3 7 849 och3 H CHO 7 850 och3 H ch2oh 7 851 ococh3 ch3 CH3 7 852 ococh3 ch3 CHO 7 853 ococh3 ch3 ch2oh 7 854 ococh3 H ch3 7 855 ococh3 H CHO 7 856 ococh3 K ch2oh 7 M. ? * Further analytical data are available in the exanples section. 62 Α 4,4-bis-normethyl 15-oxasterol (R2 of the general strucrure 1 is H), 14 -methyl-15-oxa-5 -cholest-3-en- 3b-ol (47), has also been synthesized from 5 -cholesta- 8,14-diene-3b-ol by folloving the sequer.ce of the reaction steps depicted in the synthesis of 15-oxa-dihydrolansterol (11a). Conversion of the normethyl 8,14-diene 38a to the corresponding p-methoxybenzyl ether 38b folloved by an osmium tetroxide hydroxylation, an acetalization, a Grignard reaction with methyl magnesium bromide and hydrolysis in 80% aqueous acetic acid provided the six-membered cyclic hemiacetal 43a in 50% overall yield (See, Scheme V) .

The compound 43a was subsequently transforroed into the desired 14 -methyl-15-oxa-5 -cholest-8-en-3b-ol (47) by glycal fornation, osniun tetroxide hydroxylation, oxidative cleavage by sodium netaperiodate, and reduction vith triethylsilane and boron trifluoride etherate in 34.5% overall yield from the cyclic hemiacetal 43a. Compound 47 is another example vithin the scope of the present invention and its synthesis is an example, vhich demonstrates that preparative methods for compounds vith dimethyl at C-4 in the scope (Formula I, vith R2 = CH3) are applicable to di-bis-normethyl compounds in the scope (Formula I, vith R2 = H). - 63 - LV 10719

SCHZMZ V

pMBflO

42 43 pMBnO

46 47 64 15-Thia-Ianosterois

For the synthesis of 15-thia-lanosterols, a novel class of compounds, a convenient and novel process has been developed.

Traditionally cyclic sulfides are prepared by displacing a halide, a sulfonate or an equivalent leaving group by an internai thiol.

Taking advantage of the ability to form a stable carbonium ion at the 14-position, a mixture of the cyclic hemiacetal 10b, and cyclic hemiacetal 10c, the intermediates for 15-oxa-dihydrolanosterol, was treated with gaseous hydrogen sulfide (Union Carbide Corp., Linde Division, Danbury, CT 06817) and boron trifluoride etherate in methylene chloride folloved by triethylsilane to obtain the desired 15-thia-dihydro-lanosterol (50) in 60% yield (43% overall yield from the six-membered cyclic hemiacetal 7b) (See, Scheme VI) . '

The one pot cyclic sulfide formation reaction presumably occurs via cyclic thioacetal 48 and the intermediate 48 is reduced by triethylsilane in the presence of boron trifluoride etherate. The p-methoxybenzyl protecting group at the 3-position vas conveniently cleaved during the hydrogen sulfide and boron trifluoride treatment to carry out three operations in a single reaction vessel. This novel cyclic sulfide preparation method may also be operable when a stable carbonium ion formation is possible at the latent alcoholic center by other functional groups such as alkynyl, aryl and other alkenyl. 4,4-Dimethyl-15-thia-5a-cholest-8-en-3b-ol (49) and 4,4-dimethyl-15-thia-14a-vinyl-5a-cholest-8-en-3b-ol (51) have also LV 10719 - 65 - been synthesized from the compounds 16b and 22b in 26% and 27% overall yields from the compounds 13b and 19b respectively.

Compounds 49, 50, and 52 constitute three examp3.es of 15-thia-lanosterols vithin the scope of the present invention.

66

SCHZME VI 10b Rj » CHj 165 Rj» H 22b Rj - CH-CHj

ir SH

49 Rj-CHg

30 Rj H 31 R^-CH-CHj - 67 - 67 LV 10719

Sulfides are easily converted to sulfoxides vith various oxidizing aģents including sodium metaperiodate. Exposing the cyclic sulfide 50 to sodium metaperiodate in 5 parts of ethanol and 1 part of vater produced the corresponding sulfoxide 53 in 67% yield. In the same manner C-14 hydride analog 52 and vinyl analog 54 may also be synthesized from the compounds 49 and 51 respectively. Compounds 52, 53, and 54 are three additional examples vithin the scope of the present invention.

Using more poverful oxidizing aģents such as hydrogen peroxide or potassium permanganate (see S. R. Sandler, and W. Karo, Orcanic Functional Group Preparations. Vol. I pp. 610-618, Academic Press, 1983) sulfides or sulfoxides mav be converted to the corresponding sulfones represented by the general structure 55, vhich are vithin the scope of the present invention.

For syntheses of other examples of compounds vithin the scope of this invention, further functionalization at the 14-position may also be achieved by converting the vinyl group of the compound 51 to an aldehyde and carrying out other necessary chemistry as discussed in the 15-oxa-lanosterols section, vide suora. 63

Tables 3, 4, and 5 set forth various thiasterols of the present invention. - 69 - Table 3

LV 10719 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 673 874 875 876 877

No. R, £2 R3 ū No. Μ. P. A Λ. OH ch3 ch3 8 49 aacrphcus* OH ch3 H 8 50 amcrphcus* OH ch3 ch=ch2 8 51 amorpr.cus* OH ch3 CHOHCH2OH-(R) 8 OH ch3 CHOHCH2OH-(S) 8 OH ch3 CHO 8 OH ch3 C'H2OH 8 OH ch3 co2h 8 OH ch3 CO-CH- 8 OH ch3 CH=NOH 8 OH ch3 CHOHCH=CH2-(R) 8 OH ch3 CHOKCH=CH2-(S) 8 OH K ch3 S OH H H 8 OH H ch=ch2 8 OH K CHOHCH2OH-(R) 8 OH H CKOHCH2OH-(S) 8 OH H CHO 8 OH H CH2OH 8 OH K co2h 8 OH K co2ch3 8 70

Table 3 (Continued) -Sl- -2 OH H OH H OH H OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3

CH=NOH chohch-ch2-(R) CHOHCH=CH2-(S) c2h5 ch2ch=ch2

C=CK CH2Ph ch2och3 ch2ococh3 ch2sh ch2sch3 ch2scoch3 ch2nh2 CH2miCH3 ch2nhcoch3 ch2khcsch3 CH2NHC(=NH)ch3 coch3 coch=ch2 csch3 csch=ch2 C(=NH)CH3 co2c2h5 cosch3 conh2 conhch3 CONHCOCH3 csnh2 - 71 - - 71 -LV 10719

Table 3 (Continued) -£i- —2. R3 D OH ch3 csnhch3 8 OH ch3 csnhcoch3 8 OH ch3 ch2ch2oh 8 OH ch3 ch2ch2och3 8 OH ch3 ch2ch2ococh3 8 OH ch3 ch2ch2sh 8 OH ch3 ch2ch2sch3 8 OH ch3 ck2ch2scock3 8 OH ch3 ch2ch2nh2 8 OH ch3 ch2ch2nhch3 8 OH ch3 ch2ch2nhcoch3 8 OH ch3 ch2cho 8 OH ch3 ch2coch3 8 OH ch3 ch2coch=ch2 8 OH ch3 ch2csch3 8 OH ch3 ch2csch=ch2 8 OH ch3 ch2(=NH)CH3 8 OH ch3 ch2co2ch3 8 OH ch3 ch2cosch3 8 OH ch3 ch2conh2 8 OH ch3 ch2conhch3 8 OH ch3 ck2conhcoch3 8 OH ch3 ch2csnh2 8 OH ch3 CH2C(=NH)CH3 8 OH ch3 ch2ci 8 OH ch3 ch2ch2ci 8 OH ch3 CN 8 OH ch3 ch=noch3 8 (Continued)

Ex. No. R1 R3 λ 934 OH ch3 ch=nococh3 935 OH ch3 ch=nnh2 936 OH ch3 ch=nnhch3 937 OH ch3 ch=nnhcoch3 933 OH ch3 ch=nnhcsch3 939 OH ch3 ch2nhoh 940 OH ch3 ch2nhoch3 941 OH ch3 ch2nhococh3 942 OH ch3 ch2nhnh2 943 OH ch3 ch2nhnhch3 944 OH ch3 ch2nhnhcoch3 945 OH ch3 ch2nhnhcsch3 946 OH ch3 ch2cn 947 OH ch3 ch2ch=noh 948 OH ch3 ch2ch=noch3 949 OH ch3 ch2ch=nococh3 950 OH ch3 ch2ch=nnh2 951 OH ch3 ch2ch=nnhch3 952 OH ch3 ch2ch=nnhcoch3 953 OH ch3 CH2CH=N>rHCSCH3 954 OH ch3 ch2ch2nhoh 955 OH ch3 ch2ch2nhoch3 956 OH ch3 ch2ch2nhococh3 957 OH ch3 ch2ch2nhnh2 953 OH ch3 ch2ch2nhnhch3 959 OH ch3 ch2ch2nhnhcoch 960 OH ch3 ch2ch2nhnhcsch 961 OH ch3 conhoh - 73 -LV 10719

Table 3 (Continued)

Ex. No. R1 R3 D 962 OH ch3 conhoch3 8 963 OH ch3 CONHOCOCH-J 8 964 OH ch3 CSNHOH 8 965 OH ch3 CSNHOCH-J 8 966 OH ch3 CSNHOCOCH-J 8 967 OH ch3 CK=CHCHO 8 968 OH ch3 ch=chcoch3 8 969 OH ch3 ch=chcsch3 8 970 OH ch3 CH=CHCH-NH 8 971 OH ch3 CH=CHC(=NH)CH3 8 972 OH ch3 C=CCHO 8 973 OH ch3 c=ccoch3 8 974 OH ch3 c=ccsch3 8 975 OH ch3 C=CCH=NH 8 976 OH ch3 C=CC(=NH)CH3 8 977 OH ck3 . ch=chch2ci 8 978 OH ch3 c=cch2ci 8 979 OH ch3 CH=CHCH2OCOCH3 8 980 OH ch3 c=cch2ocock3 8 981 OH ch3 ck2chohch2oh 8 982 OH ch3 chohchohch2ok 8 983 OH ch3 CH-CH-j \ / 0 8 984 OH ch3 ch,ch-ch, 0 8 985 OH ch3 CHOHCH-CH-, \ / 2 S

986 OH H ch2sh 8 0 - 74 -

Table 3 (Continued)

Rļ % R3 λ OH H ch2nh2 OH H coch3 OH H conk2 OH H csnk2 OH H ch2ch2oh OH H ch2cho OH H ch2coch3 OH H ch2co2ch3 OH H ch2cohh2 OH H ch2ci OH H ch2ch2ci OH H CN OH H ch=nnh2 OH H ch2nhoh OH H ch2nhnh2 OH H ch2cn OH H ch2ch=noh OH H ch2ch=nnh2 OH H ch2ch2nhoh OH H ch2ch2nhnh OH H conhoh OH H ch=chcho OH H ch=chcoch3 OH H ch=chch2ci OH H ch2chohch2 OH H chohch-ch, \ / z 0 =0 ch3 ch3 =0 ch3 H - 75 - - 75 -LV 10719

Table 3 (Continued)

Ex. No. R1 R2 R3 D 1015 =0 ch3 ch=ch2 8 1016 =0 ch3 CHOHCH2OH-(R) 8 1017 =0 ch3 CHOHCH2OH-(S) 8 1018 =0 ch3 CHO 8 1015 =0 ch3 ch2oh 8 1020 =0 ch3 co2h 8 1021 =0 ch3 co2ch3 8 1022 =0 ch3 CH=N0H 8 1023 =0 ch3 CKOHCH=CH2-(R) 8 1024 =0 ch3 CHOHCH=CH2-(S) 8 1025 =0 ch3 ck2sh 8 1026 =0 ch3 ch2nh2 8 1027 =0 ch3 coch3 8 1028 =0 ch3 conh2 8 1025 =0 ch3 csnh2 8 1030 =0 ch3 ch2ch2oh 8 1031 =0 ch3 ch2cho 8 1032 =0 ch3 ch2coch3 8 103 3 =0 ch3 ch2co2ch3 8 1034 =0 ch3 ch2conh2 8 1035 =0 ch3 ch2ci 8 1036 =0 ch3 ck2ch2ci 8 1037 =0 ch3 CN 8 1038 =0 ch3 ck=nnch2 8 1035 =0 ch3 ch2nhoh 8 1040 =0 ch3 ch2nhnh2 8 - 76 -Table 3 (Continusd)

Rl -2 R3 =0 ch3 ch2cn =0 ch3 ch2ch=noh =0 ch3 ch2ch*nnh2 =0 ch3 ch2ch2nhoh =0 ch3 ch2ch2nhnh2 =0 ch3 CONHOH =0 ch3 CH=CHCHO =0 ch3 ch=chcoch3 =0 ch3 ch=chch2ci =0 ch3 ch2chohch2oh =0 ch3 CHOHCH-CH-j =0 H \ / £ 0 ch3 =0 H H =0 H ch=ch2 =0 H CHOHCH2OH-(R) =0 H CH0HCH20H-(S) =0 H CHO =0 H ch2oh =0 H (M o o =0 H co2ch3 =0 H CH=N0H =0 H CH0HCH=CH2-(R) =0 H CH0HCH=CH2-(S) och3 ch3 ch3 och3 ch3 H - 77 - - 77 -LV 10719

Table 3 (Continued) —2. R3 D och3 CK3 ch=ch2 8 och3 ch3 CHOHCH2OH-(R) 8 och3 ch3 CHOHCH2OH-(S) 8 och3 ch3 CHO 8 och3 ch3 ch2oh s och3 ck3 co2h 8 och3 ch3 co2ch3 8 och3 ch3 CH=NOH 8 och3 ch3 CHOHCH=CH2-(R) 8 och3 ch3 CHOHCH=CH2-(S) 8 och3 ch3 ch2sh 8 och3 ch3 ch2kh2 8 och3 ch3 coch3 8 och3 ch3 cokh2 8 och3 ch3 csnh2 8 och3 ck3 ch2ch2oh 8 och3 ch3 ch2cho 8 ock3 ch3 ch2coch3 8 och3 CK3 ch2co2ch3 8 och3 ch3 ch2conh2 s och3 ch3 ch2ci 8 och3 ch3 ck2ch2ci 8 och3 ch3 CN 8 och3 ck3 ch=nnh2 8 och3 ch3 ch2nhoh 8 och3 ch3 ch2nhnh2 o och3 ch3 ch2cn 8 73

Table 3 (Ccntinued) R1 och3 ch3 och3 ch3 och3 ch3 och3 ch3 och2 ch3 och3 ch3 och3 ch3 och3 ch3 och3 ch3 och2 ch3 och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 H och3 Η oc2h5 ch3 oc2h5 ch3 oc2h5 ch3 OC3H7 ch3 oc3h7 ch3 ch2ch=noh ch2ck=knh2 ch2ch2nhoh ch2ch2nhnh2

CONHOH

CH=CHCHO ch=chcoch3 ch=chch2ci ch2chohch2oh CHOHCH-CH, \ / 2 0 ch3

H ch=ch2 CHOKCH2OH-(R) CHOHCH2OH-(S)

CHO ch2oh co2h co2ch3 CHOHCH=CH2“(R) CHOHCH=CH2-(S) ch3

CHO ch2oh ch3

CHO - 79 - Table 3 (Continued)

Ex. No. Ri R2 . .R-J D 1120 CC3H7 ch3 ch2oh 8 1121 Oi-C3H7 ch3 ch3 8 1122 oc4h9 ck3 ch3 b 1123 oc4h9 oc3 CHO 8 1124 oc4h9 CK3 ch2oh 8 1125 0 i**C4 Hg ch3 ch3 8 1126 Ot-C4H9 ck3 ch3 8 1127 OPh ch3 ch3 8 1128 OPh ch3 CHO 8 1129 OPh ch3 ch2oh 8 1130 OCH2Ph ck3 ch3 s 1131 OCH2Ph ch3 CHO 8 1132 OCH2Ph ck3 ch2oh 8 1133 OCOCH3 ch3 ch3 8 1134 OCOCH3 ch3 Η 8 1135 OCOCH3 ch3 ch=ch2 8 1136 OCOCH3 ch3 CHOHCH2OH-(R) 8 1137 OCOCK3 ch3 CHOHCH2OH-(S) 8 1138 OCOCK3 ch3 CHO 8 1139 OCOCH3 ch3 ch2oh 8 1140 OCOCH3 ch3 co2h 8 1141 OCOCH3 ch3 co2ch3 8 1142 OCOCH3 ch3 ch=noh 8 1143 OCOCH3 ch3 CHOHCH=CH2-(R) 8 1144 OCOCH3 ch3 CHOHCH=CH2-(S) 8 1145 OCOCH3 ch3 ch2sh 8 1146 OCOCH3 ch3 ch2nh2 S 1147 ococh3 ch3 COCH3 8 LV 10719 Μ . P. 80

Table 3 (Continued)

L 1»—* 1 OCOCH3 ch3 ococh3 ch3 OCOCH-j ch3 OCOCH3 ch3 ococh3 ch3 OCOCH-j ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 OCOCH-j ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 ococh3 ch3 OCOCH-j ch3 0C0CH3 ch3 ococh3 ch3 OCOCH-j ch3 OCOCH-j H ococh3 Η ococh3 H conh2 csnh2 ch2ch2oh ch2cho ch2coch3 ch2co2ch3 ch2conh2 ch2ci ch2ch2ci

CN ch-nnh2 ch2nhoh ch2nhnh2 ch2cn ch2ch=noh ch2ch=nnh2 ch2ch2nhoh ch2ch2nhnh2

CONHOH

CH=CHCHO ch=chcoch3 ch=chch2ci ch2chohch2oh CHOHCH-CH, \ / 2 0 ch3

K ch=ch2 LV 10719 - 81 - labie 3 (Continued) R1 H R3 D OCOCH3 CHOHCH2OK-(R) 8 OCOCH3 H CHOHCH2OH-(S) 8 OCOCH3 H CHO 8 OCOCK3 H ch2oh 8 OCOCH3 K co2h S OCOCK-J K CO 2Ch ^ 8 OCOCH3 H CH=NOH l“i 0 OCOCH3 H CHOHCH=CH2-(R) 8 OCOCH3 H CHOHCH=CH2-(S) 8 OCOC2K5 ch3 ch3 8 OCOC2K5 ch3 CHO 8 ococ2h5 ch3 ch2oh 8 ococ3h7 ch3 ch3 8 ococ3h7 ch3 CHO 8 ococ3h7 ch3 ch2oh 8 OCOi-C4H7 ck3 ch3 8 ococ4h9 ch3 ch3 8 ococ4h9 ch3 CHO 8 ococ4h9 ch3 ck2oh 8 OCOi-C4H9 ch3 ch3 8 OCOt-C4H9 ck3 ch3 8 ococ15H31 ch3 ch3 S ococ15h31 CK3 cho 8 ococ15h31 ch3 ch2oh 8 OCOCi5H29 ch3 ch3 8 OCOC ^ 7 H3 5 CK3 ch3 8 ococ17h33 ch3 ch3 S ococ17h31 ch3 ck3 8

Table 3 (Continued)

Ex. No. *1 R2 R3 1203 OCOC17H29 ch3 ch3 1204 OCOC2_9^3 l ch3 ch3 1205 OCOPh ch3 ch3 1206 OCOPh ch3 CHO 1207 OCOPh ch3 ch2oh 1208 OH ch3 ch3 1209 OH ch3 H 1210 OH ch3 ch=ch2 1211 OH ch3 chohch2oh- (R) 1212 OH ch3 chohch2oh- (S) 1213 OH ch3 CHO 1214 OH ch3 CH2OH 1215 OH ch3 co2h 1216 OH ch3 C02CH3 1217 OH ch3 CH=N0H 1213 OH ch3 CHOHCH=CH2 -(R) 1219 OH H ch3 1220 OH H Η 1221 OH H ch=ch2 1222 OH H chohch2oh- (R) 1223 OH H chohch2oh- (S) 1224 OH H CHO 1225 OH H CH2OH 1226 OH H co2h 1227 OH H co2ch3 1228 OH H CH=NOH 1229 OH H chohch-ch2 -(R) 1230 OH H chohch-ch2 -(S) LV 10719 - 33 -Table 3 (Continued)

Ex. No. R, r2 R-» D Jl 1231 =0 ch3 ch3 7 1232 =0 ch3 K 7 1233 =0 ch3 ch=ch2 7 1234 =0 ch3 CHOHCH2OH-(R) 7 1235 =0 ch3 CHOHCH2OH-(S) 7 1236 =0 ch3 CHO 7 1237 =0 ch3 ch2oh 7 1238 =0 ch3 co2h 7 1239 =0 ch3 co2ch3 7 1240 =0 ch3 CH=NOH 7 1241 =0 ch3 CHOHCH=CH2-(R) 7 1242 =0 ch3 CHOHCH=CH2-(S) 7 1243 =0 H ch3 7 1244 =0 H H 7 1245 =0 H ch=ch2 7 1246 =0 H CHOHCH2OH-(R) 7 1247 =0 H CHOHCH2OH-(S) 7 1248 =0 H CHO 7 1249 =0 H ch2oh 7 1250 =0 H co2h 7 1251 =0 H co2ch3 7 1252 =0 H CH=NOH 7 1253 =0 H CHOHCH=CH2-(R) 7 1254 =0 H CHOHCH=CH2-(S) 7 1255 och3 ch3 ch3 7 1256 och3 ch3 H 7 1257 och3 ch3 ch=ch2 7 1258 och3 ch3 CHOHCH2OH-(R) 7 34 Table 3 (Ccntinued) -Bl- och3 och3 och3 och3 och3 och3 och3 och3 och3 och3 OCH 3 och3 och3 och3 och3 och3 och3 och3 och3 och3 ococh3 OCOCH-j ococh3 ococh3 ococh3 ococh3 ococh3 ococh3 S1 R3 ch3 CHOHCH2OH-(S) ch3 CHO ch3 CH2OH ch3 co2h ch3 co2ch3 ch3 CH=NOH ch3 CHOHCH=CH2-(R) ch3 CHOHCH=CH2-(S) H ch3 H H H ch*ch2 H CHOHCH2OH-(R) H CHOHCH2OH-(S) H CHO H ch2oh H co2h H co2ch3 H CH=NOH H CHOHCH=CH2-(R) H CHOHCH»CH2-(S) ch3 ch3 ch3 H ch3 ch=ch2 ch3 CHOHCH2OH-(R) ch3 CHOHCH2OH-(S) ch3 CHO ch3 CH2OH ch3 co2h - 85 - Table 3 (Continued)

Ex. No. £2 R3 D 1287 ococh3 ch3 co2ch3 7 1288 ococh3 ch3 CH=NOH 7 1289 OCOCH3 ch3 CHOHCH=CH2-(R) 7 1290 OCOCH3 ch3 chohch=ch2-(S) 7 1291 OCOCH3 H ch3 7 1292 OCOCH3 K K 7 1293 ococh3 K ck=ch2 / 1294 OCOCH3 H CHOHCH2OH-(R) 7 1295 OCOCH3 H CHOHCH2OH-(S) 7 1296 OCOCH3 H CKO 7 1297 OCOCH3 H ch2oh 7 1298 OCOCH3 H co2h 7 1299 OCOCH3 H co2ch3 7 1300 OCOCH3 H CH=NOH 7 1301 OCOCH3 K CHOHCH=CH2-(R) 7 1302 OCOCH3 K CHOHCH=CH2-(S) 7 LV 10719 * Further analytical data are available in the cxa:?.ples secticr.. 17 36 Tabls 4

Ex· No. R·. b2 R-. D 1303 A. OH i. ch3 ch3 8 1304 OH ch3 Η 8 1305 OH ch3 ch*ch2 8 1306 OH ch3 CH0KCH20H-(R) 8 1307 OH ch3 CHOHCH2OH-(S) 8 1308 OH ch3 CHO 8 1309 OH ch3 ch2oh 8 1310 OH ch3 co2h 8 1311 OH ch3 co2ch3 8 1312 OH ch3 CH=NOH 8 1313 OH ch3 CHOHCH=CH2-(R) 8 1314 OH ch3 CHOHCH=«CH2-(S) 3 1315 OH H ch3 8 1316 OH Η H 8 1317 OH H ck=ch2 8 1313 OH Η CH0HCH20H-(R) 8 1319 OH H CHOHCH2OH-(S) 8 1320 OH H CHO 8 1321 OH H ch2oh 8 1322 OH H co2ch3 8 1323 OH H CH=NOK 8 Μ. P. amorphous* amorphous* amorphous* - 87 - - 87 - LV 10719

Table 4 (Continued)

Ex. No. Ri R2 R3 D 1324 OH H CHOHCH=CH2-(R) 8 1325 OH H CHOHCH=CH2-(S) 8 1326 OH ch3 ch2sh 8 1327 OH ch3 ch2nh2 8 1328 OH ch3 coch3 8 1329 OH ch3 conh2 s 1330 OH ch3 csnh2 8 1331 OH ch3 ch2ch2oh 8 1332 OH ch3 ch2cho 8 1333 OH ch3 ch2coch3 8 1334 OH ch3 CH2C02CH3 8 1335 OH ch3 ch2conh2 8 1336 OH ch3 ch2ci 8 1337 OH CH3 ch2ch2ci 8 1338 OH ch3 CN 8 1339 OH CH3 ch=nnh2 8 1340 OH CH3 ch2nhoh 8 1341 OH CH3 ch2nhnh2 8 1342 OH ch3 ch2cn 8 1343 OH ch3 ch2ch=noh 8 1344 OH ch3 ch2ch-nnh2 8 1345 OH ch3 ch2ch2nhoh 8 1346 OH ch3 ch2ch2nhnh2 8 1347 OH ch3 conhoh S 1348 OH ch3 CH=CHCHO 8 33

Table 4 (Continued) EX. No. R1 S1 ch3 _ r3 . D 1349 OH ch=chcoch3 3 1350 OH ch3 CH=CHCH2C1 3 1351 OH ch3 CH2CHOHCH2OH 3 1352 OH ch3 CHOHCH-CH, 0 3 1353 =0 ch3 ch3 3 1354 =0 ch3 CHO 3 1355 =0 ch3 CH2OH 3 1356 =0 H ch3 3 1357 =0 H CHO 3 1353 =0 H CH2OH 3 1359 och3 ch3 ch3 3 1360 och3 ch3 CHO 3 1361 och3 ch3 CH2OH 3 1362 och3 H ch3 3 1363 och3 Η CHO 3 1364 och3 H CH2OH 3 1365 OPh ch3 ch3 8 1366 OPh ch3 CHO 0 1367 OPh ch3 CH2OH 3 1363 OCH2Ph ch3 ch3 3 1369 OCH2Ph ch3 CHO 3 1370 OCH2Ph ch3 CH2OH 8 1371 ococh3 ch3 ch3 8 1372 ococh3 ch3 CHO 8 1373 ococh3 ch3 CH2OH 0 1374 OCOCH-J Η ch3 3 1375 OCOCH-J H CHO s 1376 OCOCH-J H ch2oh 8 - 89 - Table 4 (Continued)

Ex. No. R1 R-) R3 D «J 1377 OCOPh ch3 ch3 8 1378 OCOPh ch3 cko 8 1379 OCOPh ch3 ch2oh 8 1380 OH ch3 ch3 7 1381 OH ch3 CHO 7 1382 OH ck3 ch2oh 7 1383 OH ch3 co2h 7 1384 OH H ch3 7 1385 OH H CHO 7 1386 OH H ch2oh 7 1387 =0 ch3 ch3 7 1388 =0 ch3 CHO 7 1389 =0 ch3 ch2oh 7 1390 -0 H ch3 7 1391 =0 H CHO 7 1392 =0 H ch2oh 7 1393 och3 ch3 ch3 7 1394 och3 ch3 CHO 7 1395 och3 ch3 CH20H 7 1396 och3 H ch3 7 1397 och2 H CHO <* / 1398 och3 H ch2oh 7 1399 ococh3 ch3 ch3 7 1400 ococh3 ch3 CHO 7 1401 ocock3 ch3 ch2oh 7 LV 10719 M. F. 90

Table 4 (Continued)

EX. Ko. -21- 22 1402 OCOCH3 H 14 0 3 OCOCH3 H 1404 OCOCH3 H R1 D ch3 7 CHO 7 ch2oh 7 N c. M p * Furbher analytical data are available in the exai?.ples section. 91 labie 5

*1 *2 R3 D ΟΗ ch3 ck3 8 ΟΗ ch3 H 8 ΟΗ ch3 ck*ch2 8 ΟΗ ch3 CHOHCH2OH-(R) 8 ΟΗ ch3 CHOHCH2OH-(S) 8 ΟΗ ch3 CHO 8 ΟΗ ch3 CH2OH 8 ΟΗ ch3 co2h 8 ΟΗ ch3 co2ch3 8 ΟΗ ch3 CH=NOH 8 ΟΗ ch3 CHOHCH=CH2-(R) 8 ΟΗ ch3 CHOHCH»CH2-(S) 8 ΟΗ Η ch3 8 ΟΗ H K 8 ΟΗ H ch=ch2 8 ΟΗ H CHOHCH2OH-(R) S ΟΗ H CHOHCH2OH-(S) 8 ΟΗ H CHO S ΟΗ H CH2OH 8 ΟΗ H co2h 8 ΟΗ H co2ch3 8 ΟΗ H CH=NOH 8 (Continued)

Ex. No. —2 R, 1327 OH H CHOHCH=CH2- (R) 1428 OH H chohch»ch2- (S) 1429 OH ch3 ch2sh 1430 OH ch3 ch2nh2 1431 OH ch3 coch3 1432 OH ch3 conh2 1433 OH ch3 csnh2 1434 OH ch3 ch2ch2oh 1435 OH ch3 ch3cho 1436 OH ch3 ch2coch3 1437 OH ch3 ch2co2ch3 1433 OH ch3 ch2conh2 1439 OH ch3 ch2ci 1440 OH ch3 ch2ch2ci· 1441 OH ch3 CN 1442 OH ch3 ch=nnh2 1443 OH ch3 ch2nhoh 1444 OH ch3 ch2nhnh2 1445 OH ch3 ch2cn 1446 OH ch3 ch2ch=noh 1447 OH ch3 ch2ch=nhh2 1448 OH ch3 ch2ch2nhoh 1449 OH ch3 ch2ch2nhnh2 1450 OH ch3 conhoh 1451 OH CH-ļ ch=chcho - 93 -LV 10719

Table 5

Continued

Ex. No. _Rļ_ E2

R 3 1452 OH ch3 ch=chcoch3 1453 OH ch3 ch2chohch2 1455 OH ch3 CHOHCH-CH-3 V 1456 =0 ch3 ch3 1457 =0 ch3 CHO 145S =0 ch3 ch2oh 145S =0 H ch3 1460 =0 H CHO 1461 =0 H ch2oh 1462 0CH3 ch3 ch3 1463 0CH3 ch3 CHO 1464 0CH3 ch3 ch2oh 1465 0CH3 H ch3 1466 0CH3 H CHO 1467 0CH3 H CH2OH 1463 OPh ch3 ch3 1469 OPh ck3 CHO 1470 OPh ch3 ch2oh 1471 OCH2Ph ch3 ch3 1472 OCH2Ph ch3 CHO 1473 OCH2Ph ch3 0 ro O 33 1474 OCOCH3 ch3 ch3 1475 OCOCH3 ch3 CHO 1476 OCOCH3 ch3 ch2oh 3 3 3 3 3 3 8 3 3 8

3 8 8 8 S 8 9

Tabie 5 (Continued) R1 R2 ococh3 H ch3 ococh3 H CHO OCOCH3 H ch2oh ocoph CH3 ch3 OCOPh ch3 CHO OCOPh ch3 ch2oh OH ch3 ch3 OH ch3 CHO OH ch3 CH2OH OH ch3 ch2h OH H ch3 OH H CHO OH H ch2oh =0 ch3 ch3 =0 ch3 CHO =0 ch3 ch2oh =0 H ch3 =0 H CHO =0 H CH 2 OH och3 ch3 ch3 0CH3 ch3 CHO 0CH3 ch3 ch2oh 0CH3 H ch3 0CH3 H CHO 0CH3 H ch2oh - 95 -

Table 5 (Continued) LV 10719 D No. Μ. P.

Ex. No. _Εχ_ 1502 OCOCK3 ch3 ch3 7 1503 OCOCH3 ch3 CHO 7 1504 OCOCH3 ch3 ch2oh 7 1505 OCOCH3 H ch3 7 1506 OCOCH3 H CHO 7 1507 OCOCH3 H ch2oh 7 96

The six-membered 15-thia-D-homo-lanosterol derivatives have also been synthesized from the six-membered 15-thia-lanosterols synthesis. Treatment of the mixture of the cvclic acetal 7d with hydrogen sulfide and boron trifluoride etherate in methylene chloride folloved by triethylsilane afforded the desired l5-thia-D-homo-dihydrolanosterl (57) in 44% yield (See, Scheme VII). 4 , 4-Dimethyl-15-thia-D-hoao-5a-cholest-8-en-3b-ol (56) has also been prepared in the same raanner from the compound 13d in 59.2% yield. 4,4-dimethyl-15-thia-14a-vinyl-D-homo-5a-cholest-3-en-3b-ol (53) may also be synthesized in the same manner from the corresponding cyclic acetal 19a or cyclic acetal 19d. Compounds 56, 57 and 58 constitute three additional examples vithin the scope of the present invention.

The 15-thia-D-homo-lanosterol 56 was reacted vith sodium metaperiodate in 5 parts of ethanol and 1 part of vater to provide the corresponding sulfoxide 59, also vithin the scope of the present invention. The 14-methyl and 14-vinyl derivatives 60 and 61, vhich are likevise vithin the scope of the present invention, mav also be synthesized in the same manner.

As mentioned earlier in the 5-membered case, sulfones vith the general structure 62, vhich are vithin the scope of the present invention may be synthesized from the corresponding sulfides or sulfoxides. Further functionalization at c-14 to prepare the compounds vithin the scope may also be achieved by converting the vinyl group of 58 to an aldehyde and carrying out other necessary chemistry as discussed in 15-oxa-lanosterol section, supra.

- 97 - SCHZME VII LV 10719

7· · CHj 13· Rg » H 19« R, * CH«CHj 5 6 Ra-CH, 57 R3-H 53 R3 CHeCHj

19 R^-CJ^ 50 Rj » H 51 R3.CH.CH2 - 93 -

Tables 6, 7, and 8 set forth various thiasterois of the present: invention. - 99 - LV 10719

Table 6

V M7 -*1- *2 *3 D OH ch3 ch3 3 OH ch3 H 3 OH ch3 ch»ch2 8 OH ch3 CHOHCH2OH-(R) 8 OH ch3 CHCHCH2OH-(S) 8 OH ch3 CHO 8 OH ch3 CH2OH 3 OH ch3 co2h 3 OH ch3 ch2ch3 8 OH ch3 CH-NOH 8 OH ch3 CHCHCH-CH2-(R) 3 OH ch3 CHOHCH=CH2-(S) 8 OH H ch3 8 OH H H 8 OH H ch=ch2 8 OH H CHOHCH2OH-(R) 8 OH H CHOHCH2OH-(S) 8 OH H CHO 8 OH H CH2OH 8 OH H co2h 8 OH H co2ch3 8 OH K CH=NOH Λ

No. M. ?. 56 araorphcus* 57 amcrphcus* 58 amcrphcus·* 100

Table 6 (Contir.ued) OH H OH H OH ch3 OH ch3 OH ck3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 CHOHCH=CH2-(R) CHOHCH=CH2-(S) ch2sh ch2nh2 coch3 conh2 csnh2 ch2ch2oh ch2cho ch2coch3 ch2co2ch3 ch2conh2 ch2ci ch2ch2ci

CN ch=nnh2 ch2nhoh ch2nhnh2 ch2cn ch2ch=noh ch2ch=nnh2 ch2ch2nhoh ch2ch2nhnh2

CONKOH

CH=CHCHO LV 10719 - 101 -Table 6 (Continued)

Ex. No. R1 % ch3 R3 D 1555 OH ch=chcoch3 3 1556 OH ch3 ch=chch2ci 8 1557 OH ch3 ch2chohch2oh 8 1553 OH ch3 CH0HCH-CH, 0 8 1560 =0 ch3 CHO 8 1561 =0 ch3 CK2OH 8 1562 =0 H ch3 8 1563 =0 H CHO 3 1564 =0 H ch2oh 8 1565 och3 ch3 ch3 8 1566 och3 ch3 CHO 8 1567 och3 ch3 CH2OH 8 1563 och3 H ch3 8 1569 och3 H CHO 8 1570 och3 H ch2oh a 0 1571 OPh ch3 ch3 8 1572 oPh ch3 CHO 8 1573 OPh ch3 ch2oh 8 1574 OCH2Ph ch3 ch3 8 1575 OCH2Ph Ch’3 CHO 8 1576 OCH2Ph ch3 ch2oh 8 1577 ococh3 ch3 ch3 8 1578 ococh3 ck3 CHO 8 1579 ococh3 ch3 ch2oh S 102

Table 6 (Continued)

—Bl— E1 ococh3 H ch3 ococh3 H CHO OCOCH3 H ch2oh ocoph ch3 ch3 OCCPh oh3 CHO OCOPh ch3 ch2oh OH ch3 ch3 OH ch3 CHO OH ch3 ch2oh OH ch3 co2h OH H ch3 OH H CHO OH H ch2oh =0 CH3 ch3 =0 ch3 CHO =0 ch3 ch2oh =0 H ch3 =0 H CHO =0 H ch2oh OCH3 ch3 ch3 OCH3 ch3 CHO OCH3 ch3 CH2OH OCH3 Η ch3 OCH3 H CHO OCH3 H CH2OH - 103 - Table 6 (Continued)

Ex. No. R1 H R3 D 1605 OCOCH3 ch3 ch3 7 1606 OCOCH3 ch3 CHO 7 1607 OCOCH3 ck3 ch2oh 7 1603 OCOCH3 H ch3 7 1609 OCOCK3 H CHO 7 1610 OCOCH3 H ch2oh < LV 10719 * Further analytical data are available in the exasples secrion. 104 Table 7

R1 *2 ch3 r3...... D OH ch3 8 OH ch3 Η 8 OH ch3 ch=ch2 8 OH ch3 CHOHCH2OH-(R) 8 OH ch3 CHOHCH2OH-(S) 8 OH ch3 CHO 8 OH ch3 ch2oh 8 OH ch3 co2h S OH ch3 co2ch3 S OH ch3 ch=noh 8 OH ch3 CHOHCH=CH2-(R) 8 OH ch3 CHOHCK=CH2-(S) 3 OH H ch3 3 OH Η H 8 OH Η ch=ch2 8 OH Η CHOHCHjOH-(R) 8 OH Η CHOHCH2OH-(S) 8 OH Η CHO 8 OH Η ch2oh 8 OH Η co2h 8 OH Η co2ch3 8 OH Η CH=NOH 8

No. 59 60 61 - 105 -LV 10719

No. 1633 OH H 1634 OH H 1635 OH ch3 1636 OH ch3 1637 OH ch3 1633 OH ch3 1639 OH ch3 1640 OH ch3 1641 OH ch3 1642 OH ch3 1643 OH ch3 1644 OH ch3 1645 OH ch3 1646 OH ch3 1647 OH ch3 1643 OH ch3 1649 OH ck3 1650 OH ch3 1651 OH ch3 1652 OH ch3 1653 OH ch3 1654 OH ch3 1655 OH ch3 1656 OH ch3 1657 OH ch3 1653 OH ch3 1659 OH ch3 1660 OH ch3 1661 OH ch3 1662 =0 ch3

Table 7 (Ccntinued) CHOHCH*CH2-(R) CHOHCH-CH2-(S) ch2sh ck2nh2 coch3 conh2 csnh2 ch2ch2oh ch2cho ch2coch3 ch2co2ch3 ch2conh2 ch2ci ch2ch2ci

CN ch=nnh2

CHjNHOH ch2nhnh2 ch2cn ch2ch=noh ch2ch=nnh2 ch2ch2nhoh ch2ch2nhnh2

CONHOH

CH=CHCHO ch=chcoch3 ch=chch2ci ch2chohch2oh chohch-ch2 0 D No. M. ? 3 3 3 3 8 8 8 8 8 8 8 8 8 8 8 8 3 8 8 3 8 8 8 8 8 8 3 8 8 8 106

Table 7 (Continued)

Rt £2- ch3 D =0 CHO 8 =0 ch3 CH2OH 8 =0 H ch3 8 =0 H CHO 8 =0 H ch2oh 8 och3 ch3 CH3 8 och3 ch3 CHO 8 och3 ch3 ch2oh 8 och3 H ch3 3 och3 H CHO 8 och3 H CH20H 8 OPh ch3 ch3 8 OPh ch3 CHO 8 OPh ch3 ch2oh 8 0CH2Ph ch3 ch3 3 OCH2Ph ch3 CHO 8 0CH2Ph ch3 CH2OH 8 ococh3 ch3 ch3 8 ococh3 ch3 CHO 8 ococh3 ch3 ch2oh 8 ococh3 H ch3 8 ococh3 H CHO 8 ococh3 H CH2OH 8 OCOPh ch3 ch3 8 OCOPh ch3 CHO 8 OCOPh ch3 ch2oh 8 OH ch3 ch3 7 OH ch3 CHO 7 OH ch3 ch2oh 7 OH ch3 co2h 7 OH H ch3 7 - 107 -

Table 7 (Continued)

No. —Bi- *2- R3 D 1694 OH H CHO 7 1695 OK H ch2oh 7 1696 =0 ch3 ch3 7 1657 =0 ch3 CHO 7 1693 =0 ck3 ch2oh 7 1699 =0 H ch3 7 1700 =0 H CHO 7 1701 =0 K ck2oh 7 1702 och3 ch3 ch3 7 1703 och3 ch3 CHO 7 1704 och3 ch3 ch2oh 7 1705 och3 H ch3 7 1706 och3 H CHO 7 1707 och3 H ch2oh 7 1708 ococh3 ch3 ch3 7 1709 ococh3 ch3 CHO 7 1710 ococh3 ck3 ch2oh 7 1711 ococh3 H ch3 7 1712 ococh3 H CHO 7 1713 ococh3 H ch2oh 7 LV 10719 *Further analytical data are available in the examples section.

103 R 1—

Table 3

hr

No

OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH

CH- CH: CH- CH- CH- CH- CH-CH: ch:CH: CH- CH- H H H H H H H H H H

ch3 H ch=ch2 CHOHCH2OH-(R) CHOHCH2OH-(S) CHO CH2OH co2h co2ch3 CH=NOH CHOHCH»CH2-(R) CHOHCH=CH2-(S) ch3 H ch=ch2 CHOHCH2OH-(R) CHOHCH2OH-(S) CHO ch2oh co2h co2ch3 CH=NOH s 8 8 8 8 3 8 8 8 S 8 8 8 8 8 8 8 8 8 3 8 8 - 109 -LV 10719

Table 8 (Continued) -Bl- -2- R3 D OH H chohch=ch2-(R) 8 OH H CHOHCH=CH2-(S) 8 OH ch3 ch2sh 8 OH ch3 ch2nh2 8 OH ck3 cock3 8 OK ch3 conh2 8 OH ch3 csnh2 8 OH ch3 ch2ch2oh 8 OH ch3 ch2cho 8 OH ch3 ch2coch3 8 OH ch3 ch2co2ch3 8 OH ch3 ch2conh2 8 OH ch3 ch2ci 8 OH ch3 ch2ch2ci 8 OH ch3 CN 8 OH ch3 ch=nnh2 8 OH ch3 ch2nhoh 8 OH ch3 ch2nhnh2 8 OH ch3 ch2cn 8 OH ch3 ch2ch=noh 8 OH ch3 ch2ch=nnh2 8 OH ch3 ch2ch2nhoh 8 OH ch3 ch2ch2nhnh2 8 OH ch3 CONHOH 8 OH ch3 CH=CHCHO 8 OH ch3 ch=chcoch3 8 OH ch3 ch=chch2ci 8 OH ch3 ch2chohch2oh 8 OH ch3 chohch-ch2 8 8 M . ?| =o ch3 ch3 0 110

Table 3 (Continued) R1 *3- =0 ch3 CHO =0 ch3 ch2oh =0 H ch3 =0 H CHO =0 H ch2oh och3 ch3 ch3 och3 ch3 CHO och3 ch3 ch2oh och3 H ch3 och3 H CHO och3 H ch2oh OPh ch3 ch3 OPh ch3 CHO OPh ch3 ch2oh OCH2Ph ch3 ch3 OCH2Ph ch3 CHO OCH2Ph ch3 ch2oh ococh3 ch3 ch3 ococh3 ch3 CHO ococh3 ch3 ch2oh OCOCH-J H ch3 ococh3 H CHO ococh3 H ch2oh OCOPh ch3 ch3 OCOPh ch3 CHO OCOPh ch3 CH2OH OH ch3 ch3 OH ch3 CHO OH ch3 CH2OH OH ch3 co2h OH Η ch3 - 111 -LV 10719

Table 8 (Ccntinusd) —Ei— —2,— R3 D OH H CHO 7 OH H ch2oh 7 =0 ch3 ch3 7 =0 ch3 CHO 7 =0 ch3 ch2oh 7 =0 H ch3 7 =0 H CHO 7 =0 H ch2oh 7 och3 ch3 ch3 7 och3 ch3 CHO 7 och3 ch3 ch2oh 7 och3 H ch3 7 och3 H CHO 7 och3 H ch2oh 7 ococh3 ch3 ch3 7 ococh3 ck3 CHO 7 ococh3 ch3 ch2oh 7 ococh3 H ch3 7 ococh3 H CHO 7 OCOCH-j H ch2oh 7 112 15-Azasterols 3ecause the same chemistry cculd not be utilized fcr 15-azasterols as vas used fcr 15-oxasterols and 15-thiasterols, a new synthetic route, vhich involves a Curtis rearrangement as the key step, has been develcped for 15-aza-lanosterols.

Thus the enone-aldehyde 4b vas oxidized vith sodiun chlorite (Aldrich) in the presence of sulfamic acid (Fisher) in 4 parts of tertiary butanol and 1 part of vater to afford the corresponding carboxylic acid 63 in near quantitative yield (See, Scheme VIII).

The acid 63 vas converted to an acyl azide under phase transfer catalysis conditions. It vas first treated vith isobutyl chloroforaate (Aldrich) and N-methyl-morpholine (Aldrich) in dry methylene chloride and then the intermediate mixed anhydride vas reacted vith sodium azide (Fisher) and tetrabutylammonium bromide (Aldrich) in methylene chloride and vater to give acyl azide 64 in quantitative yield. A Curtis rearrangement of the acyl azide 64 in a refluxing mixture of ethyl acetate and methanol (1:5) provided the corresponding carbamate 65 vhich vas pure enough to be carried onto the next reaction. The carbamate 65 vas hydrolyzed vith potassium silanoate (Fetrach Systems, Bristol, PA 19007) in refluxing tetrahydrofuran to give a five-membered cyclic iaine 66b in 73% overall yield for six steps starting from the 8,14-diene 2b.

Finally the p-methoxybenzyl protecting group at C-3 vas cleaved by treating vith allyltrimethylsilane and boron trifluoride etherate in methylene chloride to afford the unprotected 15-azasterol 66a, a compound vithin the scope of this invention, in 93% yield.

- 113 - SCHEME VIII LV 10719

4 b Rj CHj 40 Rj-H

6 3 R^-CH, 6 7 Rj-H

5 5 R^-CHj 69 Rj-H

6 4 Rj-CH, 66 Rj-H

66fl Rj H, R^ · CHj 71 6 6b R, . pMBn, Rj - CM,

70· R., H, Rj H 70b R, -pW8n. Rj-H 114 A bis-4 , 4-nomethy 1 15-azasterol (R2 of the general structure 1 is H) has also been synthesized fron the er.one-aidehyde 4 0 by folloving the sequence cf the reaction steps described in the synthesis of 15-azasterol 66a. Oxidation of the aldehyde 40 follcved by acyl azide formation, Curtis rearrangement and hydrolysis of carbamate provided the protected 15-azasterol 70b in 61% overall yield for six steps starting from the 8,14-diene 33b. Deprotection of 70b at 03 gavē compound 70a in 96% yield based on the reccvered starting material 70b. Compound 70a is another example of a 15-aza-lanosterol vithin the scope of the present invention.

Further functionalizations at the 14 and 15 positions of 15-azasterol raay be achieved by a reduction or an addition to the imine folloved by appropriate transformations to synthesize additional compounds vithin the scope, vhich have general structure 71 in the scheme.

Tables 9-13 set forth various azasterols of the present invention.

- 115 -LV

Table 9

No. i. -¾ D n 1817 OH ch3 8 1 1818 OH H 8 1 1819 OH c2h5 8 1 1820 =0 ch3 8 1 1821 =0 H 8 1 1822 =0 c2h5 8 1 1823 och3 ch3 8 1 1824 och3 H 8 1 1825 och3 c2h5 8 1 1826 oc2h5 ch3 8 1 1827 OC2K5 H 8 1 1828 oc2h5 c2h5 8 1 1829 oc3h7 ch3 8 1 1830 oc3h7 H 8 1 1831 oc3h7 c2h5 8 1 1832 Oi-C3H7 ch3 8 1 1833 Oi-C3H7 H 8 1 1834 Oi-C3H7 C2K5 8 1 1835 OC4K9 ch3 8 1 1836 oc4h9 H 8 1 1837 oc4h9 c2h5 8 1 1838 Oi-C4H9 ch3 8 1

Μ. P 116

Table 9 (Continued) -Sl- —2 D n Oi-C4H9 H 8 1 Oi-C4H9 c2h5 8 1 Ot-C4Hg ch3 8 1 Ot-C4H9 H 8 1 Ot-C4H9 c2h5 8 1 oph ch3 8 1 OPh H 8 1 OPh c2h5 8 1 OCH2Ph ch3 8 1 OCH2Ph H 8 1 OCH2Ph c2h5 8 1 OCOH ch3 8 1 OCOH H 8 1 OCOH c2h5 8 1 OCOCH3 ch3 8 1 OCOCH3 H 8 1 OCOCH3 c2h5 8 1 OCOC2H5 ch3 8 1 ococ2h5 H 8 1 ococ2h5 c2h5 8 1 ococ3h7 ch3 8 1 ococ3h7 H 8 1 ococ3h7 c2h5 8 1 OCOi-C3H7 ch3 8 1 OCOi-C3H7 H 8 1 OCOi-C3H7 c2h5 8 1 OCOC4H9 ch3 8 1 ococ4h9 H 8 1 ococ4h9 c2h5 8 1 0C0i-C4H9 ch3 8 1 OCOi-C4H9 H 8 1 - 117 -LV 10719

Table 9 (Continued) *1 —2. D G ocoi-c4H9 c2h5 8 1 OCOt-C4H9 ch3 8 1 OCOt-C4H9 H 8 1 ocot-c4K9 c2h5 S 1 OCOC15H31 ch3 8 1 ococ15h31 K 8 1 OCOC15H31 c2h5 8 1 0000^^29 ch3 8 1 OCOC15H29 H 8 1 ococ15h29 c2h5 8 1 ococ17h35 ch3 8 1 ococ17h35 H 8 1 OCOCļ^H^2 c2H5 8 1 ococ17h33 ch3 8 1 OCOC^7^33 H 8 1 OCOCļ_7H3 3 C2H5 8 1 ococ17h31 ch3 8 1 OCOC27H2ļ H 8 1 OCOC^-jH^ ^ c2h5 8 1 OCOC 17^29 ch3 8 1 OCOC^^H29 H 8 1 OCOC ļ_ 7^2 9 C2K5 8 1 OCOCig42 ļ ch3 8 1 OCOCļ_gH3 ļ H 8 1 OCOC19Kļ ^ C2H5 8 1 OCOPh ch3 8 1 OCOPh H 8 1 OCOPh C2H5 £ 1 OH ch3 8 1 OH H 7 1 OH c2h5 7 1 118

Tabls 9 (Continued)

No. *1 -¾ fi n 1901 =0 C«3 7 1 1902 =0 H 7 1 1903 =0 c2h5 7 1 1904 och3 ch3 7 1 1905 och3 H 7 1 1906 och3 C2H5 7 1 1907 oc2h5 ch3 7 1 1908 oc2h5 H 7 1 1909 OC2H5 C2H5 7 1 1910 oc3h7 ch3 7 1 1911 oc3h7 H 7 1 1912 oc3h7 C2H5 7 1 1913 Oi-C3H7 ch3 7 1 1914 Oi-C3H7 H 7 1 1913 Oi-C3H7 c2h5 7 1 1916 oc4h9 ch3 7 1 1917 OC4H9 H 7 1 1913 oc4H9 C2n5 7 1 1919 Oi-C4H9 ch3 7 1 1920 0i-c4H9 H 7 1 1921 Oi-C4H9 C2H5 7 1 1922 Ot-C4H9 ch3 7 1 1923 Ot-C4H9 H 7 1 1924 Ot-C4Hg c2h5 7 1 1925 OPh ch3 7 1 1926 OPh H 7 1 1927 OPh c2h5 7 1 1928 0CH2Ph ch3 7 1 1929 0CH2Ph H 7 1 1930 OCH2Ph C2H5 7 1 1931 OCOH ch3 7 1 - 119 - LV 10719

Table 9 (Continued) —-1.— -¾ β ņ OCOH H 7 1 OCOH c2h5 7 1 OCOCH3 ch3 7 1 OCOCH3 H 7 1 OCOCH3 c2h5 7 1 OCOC2K5 ch3 7 1 OCOC2H5 H 7 1 ococ2h5 c2h5 7 1 OCOC3K7 ch3 7 1 OCOC3 h7 H 7 1 OCOC3H7 c2h5 7 1 OCOi-C3H7 ch3 7 1 OCOi-C3H7 K 7 1 OCOi-C3H7 c2h5 7 1 ococ4h9 ch3 7 1 OCOC4K9 H 7 1 ococ4h9 c2h5 7 1 OCOi-C4H9 CH3 7 1 ocoi-c4H9 H 7 1 OCOi-C4H9 c2h5 7 1_ OCOt-C4H9 ch3 7 1. OCOt-C4H9 K 7 1 OCOt-C4H9 c2h5 7 1 ococ15h31 ch3 7 1 ococ15h31 H 7 1 ococ15h31 c2h5 7 1 ococ15h29 CH3 7 1 ococ15h29 K 7 1 ococ15h29 C2H5 7 1 ococ17h35 ch3 7 1 ococ17h35 H 7 1 M. ? , 120

Table 9 (Continued) R1 —2, £ * n ococ17h35 C2H5 7 1 ococ17h33 ch3 7 1 ococ17h33 H 7 1 ococ17h33 c2h5 7 1 ococ17h31 ch3 7 1 ococ17h31 H 7 1 ococ17h31 c2h5 7 1 OCOCļ-yH29 ch3 7 1 0C0CļyH29 H 7 1 OCOC^ ^ H 2 9 c2H5 7 1 ococ19h31 ch3 7 1 ococ19h31 H 7 1 ococ19h31 c2H5 7 1 ocoph ch3 7 1 ocoph H 7 1 ocoph c2h5 7 1 OH ch3 8 2 OH H 3 2 OH c2h5 8 2 -0 ch3 8 2 =0 H 8 2 =0 C2H5 8 2 och3 ch3 3 2 och3 H 8 2 och3 c2h5 3 2 oc2h5 ch3 3 2 oc2h5 H 8 2 OC2H5 c2h5 8 2 oc3h7 ch3 8 2 oc3h7 H 8 2 o o u> c2h5 3 2 - 121 ~LV 10719

Table 9 (Continued) Ri -¾ ΰ ņ Oi-C3H7 ch3 8 2 Oi-C3H7 H 8 2 Oi-C3H7 c2H5 8 2 oc4H9 ch3 8 2 oc4h9 H 8 2 oc4h9 C2K5 8 2 0i-c4Hg ch3 8 2 0 i-C^Kg H 8 2 oi-c4H9 c2h5 8 2 Ot-C4H9 ch3 8 2 0 (1 1 o KO H 8 2 Ot-C4Hg c2h5 8 2 oPh ch3 8 2 OPh H 8 2 OPh c2h5 8 2 0CH2Ph ch3 8 2 OCH2Ph H ' 8 2 0CH2Ph c2h5 8 2 OCOH ’ ch3 8 2 OCOH K 8 2 OCOK C2K5 8 2 ococh3 ch3 8 2 OCOCH3 H 8 2 ococh3 c2h5 8 2 ococ2h5 ch3 8 2 ococ2h5 H 8 2 ococ2h5 c2h5 8 2 ococ3h7 ch3 8 2 ococ3h7 H 8 2 ococ3h7 c2h5 8 2 OCOi-C3H7 ch3 8 2 122

Table 9 (Continued) R1 -¾ 12 * n OCOi-C3H7 H 8 2 0001-03Η7 c2H5 8 2 ococ4h9 ch3 8 2 ococ4h9 H 8 2 ococ4h9 c2h5 8 2 OCOi-C4H9 ch3 3 2 OCOi-C4H9 H 8 2 OCOi-C4H9 c2h5 8 2 OCOt-C4H9 ch3 8 2 0C0t-C4Hg H 8 2 OCOt-C4H9 c2h5 8 2 OCOC15H31 ch3 3 2 ococ15h31 H 8 2 OCOCi5H31 c2h5 8 2 ococ15h29 ch3 8 2 OCOC15H29 H 3 2 ococ15h29 c2h5 8 2 ococ17h35 ch3 8 2 ococ17h35 H 8 2 ococ17h35 c2h5 8 2 ococ17h33 ch3 3 2 ococ17h33 H 3 2 OCOCļ^H^2 c2h5 8 2 ococ17h31 ch3 8 2 ococ17h31 H 3 2 OCOCi7H3i c2h5 8 2 OCOC^^i^g ch3 8 2 OCOC ^7H2 9 H 8 2 ococ17h29 c2h5 8 2 ococ19h31 ch3 8 2 ococ19h31 H 8 2 - 123 -LV 10719

Table 9 (Continued) _Ei_ -¾ Ώ. n ococ15h31 C2h5 8 2 OCOPh ch3 8 2 ocoPh H 8 2 OCOPh c2h5 8 2 OH ck3 7 2 OH OK K c2K5 7 7 2 =0 ch3 7 2 =0 H 7 2 =0 C2K5 7 2 och3 ch2 7 2 och3 H 7 2 och3 c2h5 7 2 OC2H5 ch3 7 2 oc2h5 H 7 2 oc2h5 c2h5 7 2 oc3h7 ch3 7 2 oc3h7 H 7 2 oc3h7 C2H5 7 2 0i“C3K7 ch3 7 2 O i —C3 H7 H 7 2 Oi-C3H7 c2k5 7 2 oc4H9 ch3 7 2 oc4h9 K 7 2 oc4h9 C2H5 7 2 0i-C4H9 ch3 7 2 Oi-C4H9 H 7 2 Oi-C4H9 c2h5 7 2 Ot-C4H9 ch3 7 2 Ot-C4H9 H 7 2 Ot-C4H9 c2h5 7 2 124

Table 9 (Continued) R1 -¾ D π OPh ch3 7 2 OPh H 7 2 OPh c2h5 7 2 OCH2Ph ch3 7 2 OCH2Ph H 7 2 OCH2Ph C2H5 7 2 OCOH ch3 7 2 OCOH H 7 2 OCOH c2h5 7 2 OCOCH3 ch3 7 2 OCOCH3 H 7 2 OCOCH3 c2h5 7 2 ococ2h5 ch3 7 2 ococ2h5 H 7 2 ococ2h5 c2h5 7 2 ococ3h7 ch3 . 7 2 ococ3h7 H 7 2 ococ3h7 c2h5 7 2 OCOi-C3H7 ch3 7 2 OCOi-C3H7 H 7 2 OCOi-C3H7 c2h5 7 2 OCOC4H9 ch3 7 2 ococ4h9 H 7 2 ococ4h9 c2h5 7 2 OCOi-C4H9 ch3 7 2 0C0i-C4H9 H 7 2 ocoi-c4H9 c2h5 7 2 0C0t-C4H9 ch3 7 2 0C0t-C4H9 H 7 2 OCOt-C4Hg c2h5 7 2 ococ15h31 ch3 7 2 - 125 - LV 10719

Table 9 (Continued) '^L -¾ J2 * ņ ococ15h31 H 7 2 ococ15k31 c2h5 7 2 ococ15h29 ch3 7 2 OCOC25H29 H 7 2 c2h5 7 2 ococ17k35 ch3 7 2 OCOC^7K3 g H 7 2 OCOCi7H35 c2h5 7 2 ococ17k33 ch3 7 2 OCOC17H3 3 H 7 2 ococ17h33 C2H5 7 2 ococ17h31 ch3 7 2 OCOC17h3^ H 7 2 ococ17h31 c2h5 7 2 OCOCļ7H29 ch3 7 2 OCOCļ7H29 H 7 2 ococ17h29 c2h5 7 2 ococ39h3^ ch3 7 2 ococ19h31 H 7 2 ococ19h31 c2h5 7 2 ocoph ch3 7 2 OCOPh H 7 2 OCOPh c2k5 7 2 provided that when n=2, the upper side chain (R) is not ergosterol. 126 Table 10

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

Sl R3 B± ch3 ch3 H ch3 H H ch3 ch»ch2 H ch3 CHOHCH2OH-(R) H ch3 CHOHCH2OH-(S) H ch3 CHO H ch3 CH2OH H ch3 co2h H ch3 co2ch3 H ch3 CH=NOH H ch3 CHOHCH=CH2-(R) Η ch3 CHOHCH»CH2-(S) H H ch3 H H H H H ch=ch2 H H CHOHCH2OH-(R) H H CHOHCH2OH-(S) H H CHO H H CH2OH H H co2h H H co2ch3 H H CK=NOK H 127

Table 10 (Continued)

-Bi- R3 Ei D OH H CHOHCH=CH2-(R) H 3 OH H CHOHCH=CH2-(S) H 8 OH ch3 c2h5 H 8 OH ch3 ch2ch=ch2 Η 8 CH ch3 C=CH K <> 0 CH ch3 CH2Ph H 8 OH ch3 ch2och3 H 8 OH ch3 ch2ococh3 Η 8 OH ch3 ch2sh H 8 OH ch3 ch2sch3 u 8 OH ch3 ch2scoch3 H 3 OH ch3 ch2nh2 H 3 OH ch3 ch2nhch3 H 8 OH ch3 ch2nhcoch3 H 8 OH ch3 ch2nkcsch3 H 8 OH ch3 CH2NHC(=NH)ch3 H 8 OH ch3 coch3 H 8 OH ch3 coch=ch2 H 8 OH ch3 csch3 H 8 OH ch3 csch=ch2 H 8 OH ch3 C(=NK)CH3 ' H 8 OH ch3 C02C2H5 H 8 OH ch3 cosch3 H 8 OH ch3 conh2 H 8 OH ch3 conhch3 H 8 OH ch3 conhcoch3 H 8 OH ch3 csnh2 H 8 OH ch3 csnhch3 H 8 OH CH3 CSNKCOCH-j H 8 OH ch3 ck2ch2ok H S 123

Table 10 (Continued)

No. -Bl- — 2. R3 D 2193 OH ch3 ch2ch2och3 H 3 2194 OH ch3 ch2ch2ococh3 H 3 2195 OH ch3 ch2ch2sh H 3 2196 OH ch3 ch2ch2sch3 H 8 2197 OH ch3 ch2ch2scoch3 H 8 2198 OH ch3 ch2ch2nh2 w 8 2199 OH ch3 ch2ch2nhch3 H 8 2200 OH ch3 ch2ch2nhcoch3 H 8 2201 OH ch3 ch2cho H 8 2202 OH ch3 ch2coch3 H 8 2203 OH ch3 ch2coch=ch2 H 8 2204 OH ch3 ch2csch3 H 3 2205 OH ch3 ch2csch=ch2 H 3 2206 OH ch3 CH2C(=NH)ch3 H 8 2207 OH ch3 ch2co2ch3 H 8 2208 OH ch3 ch2cosch3 H 8 2209 OH ch3 ch2conh2 H 8 2210 OH ch3 ch2conhch3 H 8 2211 OH ch3 ch2conhcoch3 H 8 2212 OH ch3 ch2csnh2 H 8 2213 OH ch3 CH2C(=NH)CH3 . H 8 2214 OH ch3 ch2ch2ci H 8 2215 OH ch3 CN H 8 2216 OH ch3 ch=noch3 H 8 2217 OH ch3 ch=nococh3 H 8 2218 OH ch3 ch=nnh2 H 8 2219 OH ch3 ch=nnhch3 H 8 2220 OH ch3 ch=nnhcoch3 H o 2221 OH ch3 ch=nnhcsch3 H 8 2222 OH ch3 ch2nhoh H 8 2223 OH ch3 ch2nhoch3 H 8 129

Table 10 (Continued)

JBi- s2 R3 R. -*T OH ck3 ch2nhococh3 K OH ch3 ch2nhnk2 H OH ch3 ch2nhnhch3 K OH ch3 ch2nhnhcoch3 H OH ch3 ch2nhnkcsch3 H OH ch3 ch2cn H OH ch3 ch2ch=noh H OH ch3 ch2ch=noch3 H OH ch3 ch2ch=nococh3 H OH ch3 ch2ch=nnh2 H OH ch3 ch2ch*nnhch3 OH ch3 ch2ch=nnhcoch3 K OH ch3 ch2ch=nnhcsch3 K OH oh3 ch2ch2nhoh K OH ch3 ch2ch2nhoch3 K OH ch3 ch2ch2khococh3 H OH ch3 ch2ch2nhnh2 H OH ch3 ch2ch2nhnhch3 K OH ch3 ch2ch2nhnhcoch3 H OH ch3 ch2ch2nhnhcsck3 K OH ch3 conhoh K OH ch3 conhoch3 K OH ch3 COiTriOCOCH3 H OH ch3 CSNHOH H OH ch3 CSNHOCH-J K OH ch3 csnhococh3 H OH ch3 CH=CHCHO H OH ch3 ch=chcoch3 H 130 Table 10 (Cont ir.ued) _Ei_ *3 D OH ch3 ch=chcsch3 Η 3 OH ch3 CH=CHCH-NH Η 3 OH ch3 CH=CHC(=NH)ch3 Η 3 OH ch3 C=CCHO Η 8 OH ch3 c=ccoch3 Η 8 OH ch3 c=ccsch3 Η 3 OH ch3 c=cck=nh Η 3 OH ch3 C=CC(=NH)ch3 Η 8 OH ch3 ch=chch2ci Η 8 OH ch3 c=cch2ci Η 3 OH ch3 ch=chch2ococh3 Η 8 OH ch3 c=cch2ococh3 Η 3 OH ch3 ch2chohch2oh κ 8 OH ch3 chohchohch2oh Η 8 OH ch3 ΓΜ a\ 1 o u Η 8 OH ch3 CH,CH-CH, 1 \ / 1 0 Η 3 OH ch3 chohch-ch, \ / 2 0 Η 8 OH H ch2sh Η 3 OH H ch2nh2 Η 8 OH H coch3 Η 8 OH H conh2 Η 3 OH H csnh2 Η 3 OH H ch2ch2oh Η 3 OH H ch2cho Η 8 OH H ch2coch3 Η 3 OH H ch2co2ch3 Η 8 M p - 131 - LV 10719

Table 10 (Continued) J&l- —2. R3 E! D OH H ch2conh2 H 8 OH H ch2ch2ci H 8 OH H CN H 8 OH H ck=nnh2 H 8 OH H ch2nhoh H 8 OK H ch2nhnh2 H 8 Ori H h2cn H 8 OH H ch2ch=noh H 8 OH H ch2ch=nnh2 H 8 OH H ch2ch2nhoh H 8 OH H ch2ch2nhnh2 H 8 OH H conhoh H 8 OH H ch=chcho H 8 OH H ch=chcoch3 H 8 OH H ch=chch2ci H 8 OH H ch2chohch2oh H 8 OH H chohch-ch, \ / 2 0 H 8 =0 ch3 ch3 H 8 =0 ch3 Η H 8 =0 ch3 ch=ch2 H 8 =0 ch3 CHOHCH2OH-(R) H 8 =0 ch3 chohch2oh-(S) H 8 =0 ch3 CHO H 8 =0 ch3 ck2oh H 8 =0 ch3 co2h H 8 =0 ch3 co2ch3 H S =0 ch3 ch=noh H 8 =0 ch3 CH0HCK=CH2-(R) H 8 132

Table 10 (Continued) R3 si D =0 ch3 CH0HCH=CH2-(S) H 8 o o II II ch3 ch3 CK_3H ch2nhch3 K H 8 8 =0 ch3 coch3 H 8 =0 ch3 conh2 H 8 =0 ch3 csnh2 H 3 =0 ch3 ch2ch2oh H 8 =0 ch3 ch2cho H 3 =0 ch3 ch2coch3 H 8 =0 ch3 ch2co2ch3 H 3 =0 ch3 ch2conh2 H 8 =0 ch3 ch2ch2ci H 8 =0 ch3 CN H 8 =0 ch3 ch=nnhch3 H 8 —0 ch3 ch2nhoh H 8 »0 ch3 ch2nhnhch3 H 8 =0 ch3 ch2cn H 8 —0 ch3 ch2ch-noh H 3 =0 ch3 ch2ch=nnhch3 H 3 =0 ch3 ch2ch2nhoh H 8 =0 ch3 ch2ch2nhnhch3 H 3 =0 ch3 CONHOH H 8 =0 ch3 CH=CHCH0 H S =0 ch3 ch=chcoch3 H 8 =0 ch3 ch=chch2ci H 8 =0 ch3 ch2chohch2oh H 8 =0 ch3 CHOHCH-CH, \ / i 0 H = =0 H ch3 H 8 - 133 -LV 10719

Table 10 (Continued) -*i- e2 R3 £4 D =0 K K H r> c =0 K ch=ch2 K 3 =0 H CHOHCHjOH-(R) H 8 =0 V CHOHCH2OH-(S) H 3 =0 u λ 4 CHO H 8 =0 H ch2oh H 8 =0 H C02h* H 8 =0 H C02CK3 H 3 =0 H CH=N0H H 8 »0 « CHOHCH=CH2-(R) H 8 =0 K CKOHCH=CH2-(S) H 8 och3 ch3 ch3 H 8 0CK3 CH3 K H 3 0CH3 ch3 ch=ch2 H 8 0CH3 ch3 CHOHCH2OH-(R) H 8 0CH3 ch3 CHOHCHjOH-(S) H 8 0CH3 ch3 CHO H 8 0CH3 ch3 ch2oh H 8 0CH3 ch3 co2h H 8 OCH3 ch3 co2ch3 H 8 0CH3 ch3 CH=NOH H 8 OCH3 ch3 CHOKCH=CH2-(R) H 8 0CH3 CK3 CHOHCH=CH2-(S) H 8 0CH3 ch3 ch2sh K 8 0CH3 ch3 ch2nh2 H 8 0CH3 ch3 COCK 3 H 2 OCH3 ck3 conh2 H 6 0CH3 ch3 csnh2 H 8 OCH3 ch3 ch2ch2oh H 8 134

Tabie 10 (Continued)

—1- — 2. R3 R, och3 ch3 cr2cho H OCR 3 ch3 ch2coch3 H 0CH3 ch3 ch2co2ch3 H OCH3 ch3 ch2conh2 H 0CK3 ch3 ch2ch2ci H OCH3 ch3 CN H OCR 3 ch3 ch=nnh2 H OCH3 ch3 ch2nhoh H OCH3 cr3 ch2nhnh2 H OCH3 ch3 ch2cn H OCH3 ch3 ch2ch=noh H OCR 3 cr3 ch2ch=nnh2 H OCR 3 ch3 ch2ch2nhoh H OCH3 ch3 ch2ch2nhnh2 H OCR 3 ch3 CONHOH H OCH3 ch3 CH=CHCHO H OCH3 ch3 ch=chcoch3 H OCH3 ch3 oh=chch2ci H OCR 3 ch3 ch2chohch2oh H OCH3 ch3 CHOHCH-CH, \ / ^ 0 H OCR 3 H ch3 U l λ OCR3 H H H OCH3 H ch=ch2 H OCH3 H CHOHCH2OH-(R) . H OCR 3 H CHOHCH2OH-(S) H OCH3 H CRO H OCH3 H ch2oh H OCH3 H co2h H 135

Table 10 (Continued) -Bl- *2 R3 Ei B och3 H co2ch3 H 8 och3 K CH=NOH H 8 och3 H CHOHCH=CH2-(R) H 8 och3 H CHOHCH=CH2-(S) H 8 oc2h5 ch3 ck3 H 8 oc2h5 ch3 CHO H 8 oc2h5 ch3 ch2oh H 8 oc3h7 ck3 ch3 K 8 oc3h7 ch3 CHO H 8 oc3h7 ch3 ch2oh H 8 Oi-C3K7 ch3 ch3 K 8 OC4H9 ch3 ch3 H 8 oc4h9 ch3 CHO H 8 oc4h9 ch3 ch2oh H 8 oi-c4K9 ch3 ch3 H 8 ot-c4K9 ch3 ch3 H 8 OPh ch3 ch3 H 8 OPh ck3 CHO H 8 OPh ch3 CH2OH H 8 OCH2Ph ch3 ch3 H 8 OCH2Ph ch3 CHO H 8 OCH2Ph ch3 ch2oh H 8 ococh3 ch3 ch3 H 8 OCOCH3 ch3 H H 8 OCOCK3 ck3 ch=ch2 K 8 ococh3 ch3 CHOHCH2OH-(R) K 8 OCOCH-j ch3 CHOHCH2OH-(S) H c ococh3 ch3 CHO H 8 ococh3 ch3 ch2oh H 8 136

Table 10 (Conrinued)

-*1- —2. R3 si OCOCH3 ch3 co2h H OCOCH3 ch3 co2ch3 H OCOCH3 ch3 CH-NOH H OCOCH3 ch3 CHOHCH=CH2-(R) H OCOCH3 ch3 CHOHCH=CH2-(S) H OCOCH3 ch3 CH2SH H OCOCH3 ch3 ch2nh2 H OCOCH3 ch3 COCH3 H OCOCH3 ch3 conh2 H ococh3 ch3 csnh2 H OCOCH3 ch3 ch2ch2oh H OCOCH3 ch3 ch2cho H OCOCH3 ch3 ch2coch3 H OCOCH3 ch3 ch2co2ch3 H OCOCH3 ch3 ch2conh2 H OCOCH3 ch3 ck2ch2ci H ococh3 ch3 CN H OCOCH3 ch3 ch=nkh2 H OCOCH3 ch3 ch2nhoh H OCOCH3 ch3 ch2nhnh2 H OCOCH3 ch3 ch2cn H OCOCH3 ch3 ch2ch=noh H OCOCH3 ch3 ch2ch*nnh2 H OCOCH3 ch3 ch2ch2nhoh H OCOCH3 ch3 ch2ch2nhnh2 H OCOCH3 ch3 CONHOH H OCOCH3 ch3 CH=CHCK0 H OCOCH3 ch3 ch=chcoch3 H OCOCH3 ch3 ch=chch2ci H - 137 -LV 10719

Table 10 (Continued) No. r2 R3 R, D 2449 OCOCH3 ch3 ch2chohch2ok fJ 2450 0 C0 Cri 2 ch3 CHOHCH-CH, 0 K 8 2451 0C0CK3 H ch3 H 8 2452 0COCK3 H H H 8 2453 ocockj K ch=ch2 K S 2454 ocockj H CHOHCHjOH-(R) H 8 2455 0C0CK3 H CHOHCH2OH-(S) H 8 2456 0C0CH3 H CHO H 8 2457 0COCK3 H ch2oh H 0 2458 0C0CH3 H co2h K 3 2459 ococh3 H co2ch3 H 8 2460 OCOCK3 H CH=NOH H 8 2461 OCOCH3 H CHOHCH=CK2-(R) K 2462 OCOCH3 H CHOHCH=CH2-(S) H 2463 ococ2h5 CH3 ch3 K 8 2464 ococ2h5 ch3 CHO H 8 2465 ococ2h5 ch3 ch2oh H 8 2466 OCOC3K7 ch3 ch3 H 8 2467 OCOC3K7 ch3 CHO H 8 2468 OCOC3K7 ch3 ch2oh H 8 2469 OCOi-C3H7 ch3 ch3 H 8 2470 ococ4h9 ch3 ch3 H 8 2471 OCOC4K9 ch3 CHO u 8 2472 OCOC4H9 ch3 ch2oh H 8 2473 OCO ch3 ch3 H * 2474 OCOt-C4H9 ch3 ch3 H 2475 ococ15h31 ch3 ch3 H S 2476 ococ15h31 ch3 CHO H 8 138

Table 10 (Continued)

-Bi- -2 *3 % ococ15h31 ch3 ch2oh H OCOCļgi^g ch3 ch3 H ococ17h35 ch3 ch3 H ococ17h33 ch3 ch3 H ococ17h31 ch3 ch3 H OCOCļ^fr^ g ch3 ch3 K OCOC^gH^^ ch3 ch3 H OCOPh ch3 ch3 H OCOPh ch3 CHO H OCOPh ch3 ch2oh H OH ch3 ch3 H OH ch3 H H OH ch3 ch=ch2 H OH ch3 chohch2oh-(R) H OH ch3 CHOHCH2OH-(S) H OH ch3 cho H OH ch3 ch2oh H OH ch3 co2h H OH ch3 co2ch3 H OH ch3 CH=NOH H OH ch3 CHOHCH=CH2-(R) H OH ch3 CHOHCH=CH2-(S) H OH Η ch3 H OH H H H OH H ch=ch2 H OH H CHOHCH2OH-(R) H OH Η CHOHCH2OH-(S) H OH H CHO H OH H CH2OH H - 139 -LV 10719

Table 10 (Continued) -*1- -2. -*3 Ei D OH H co2h H 7 OH H co2ch3 H 7 OH H CH=NOH H 7 OH H CHOHCH=CH2-(R) H 7 OH H CHOHCH=CH2-(S) H 7 =0 ch3 ch3 H / =0 ch3 H H 7 =0 ch3 ch=ch2 H 7 =0 ch3 CHOHCH2OH-(R) H 7 =»0 ch3 CHOHCH2OH-(S) H 7 *0 ch3 CHO H 7 =0 ch3 ch2oh H 7 =0 ch3 co2h H 7 »0 ch3 co2ch3 H n / =*0 ch3 CH*NOH H 7 =0 ch3 CHOHCH=CH2-(R) H 7 =0 ch3 CHOHCH=CH2-(S) H 7 =0 Η ch3 H 7 =0 H H H 7 =0 H ch=ch2 H 7 =0 H CHOHCH2OH-(R) ' H 7 *0 H CHOHCH2OH-(S) H 7 -0 H CHO H ·* =0 H ch2oh H 7 =0 H co2h H 7 =0 H co2ch3 H / =0 H CH=NOH H 7 =0 H CHOHCH=CH2-(R) H 7 =0 H CHOHCH*CH2-(S) H 7 140

-Bi- -2 Table 10 (Continued) Ri . R4 och3 ch3 ch3 H och3 ch3 H H och3 ch3 ch=ch2 H och3 ch3 CHOHCH2OH-(R) H och3 ch3 CHOHCH2OH-(S) H och3 ch3 CHO H och3 ch3 ch2oh H och3 ch3 co2h H och3 ch3 co2ch3 H och3 ch3 CH=NOH H och3 ch3 CHOHCH=CH2-(R) H och3 ch3 CHOHCH=CH2-(S) H och3 H ch3 H och3 H H H och3 H ch=ch2 H och3 H CHOHCH2OH-(R) H och3 H CHOHCH2OH-(S) H och3 H CHO H och3 H ch2oh H och3 H co2h H och3 H co2ch3 H och3 H CH=NOH H och3 H CHOHCH=CH2-(R) H och3 H CHOHCH=CH2-(S) H ococh3 ch3 ch3 H ococh3 ch3 H H ococh3 ch3 ch=ch2 H ococh3 ch3 CHOHCH2OH-(R) H ococh3 ch3 CHOHCH2OH-(S) H - 141 -LV 10719

Table 10 (Continued) No. _Ei_ —2. R3 D 2564 OCOCH3 ch3 CHO K 7 2565 OCOCH3 ch3 ch2oh K 7 2 5 6 6 OCOCH3 ch3 co2h H 7 2567 OCOCH3 ch3 co2ch3 H 7 2568 OCOCH3 ch3 ch*noh H 7 2569 OCOCH3 ch3 CH0HCH=CH2-(R) K 7 2570 OCOCH3 ch3 CH0HCH=CH2-(S) K 7 2571 OCOCH3 H ch3 H 7 2572 OCOCH3 H H H 7 2573 OCOCH3 H ch»ch2 H 7 2574 OCOCK3 H CHOHCH2OH-(R) K 7 2575 OCOCH3 H CHOHCH2OH-(S) K 7 2576 OCOCH3 H CHO K 7 2577 OCOCH3 H CH2OH K 7 2578 OCOCH3 H co2h H 7 2579 OCOCH3 H co2ch3 H 7 2580 OCOCH3 H CH=NOH K 7 2581 OCOCH3 H CHOHCH=CH2-(R) K 7 2582 OCOCH3 H CHOHCH=CH2-(S) H 7 2583 OH ch3 ch3 ch3 8 2584 OH ch3 H ck3 8 2585 OH ch3 CHO ch3 8 2586 OH ch3 CH2OH ch3 8 2587 OH ch3 co2h ch3 8 2588 OH Η ch3 ch3 8 2589 OH Η H ch3 8 2590 OH Η CHO ch3 8 2591 OH Η Ch'2OH ch3 8 2592 OH Η co2h ch3 8 142

Table 10 (Continued)

No . 21 R, -^- R, — H D 2593 =0 ch3 ch3 ch3 8 2594 =0 ch3 H ch3 3 2595 =0 ch3 CHO ch3 3 2596 =0 ch3 ch2ch ch3 8 2597 =0 C«3 co2h ch3 3 2593 =0 H ch3 ch3 8 2599 =0 H H ch3 3 2600 =0 H CHO ch3 3 2601 =0 H ch2oh ch3 3 2602 =0 H co2h ch3 3 2603 och3 ch3 ch3 ch3 3 2604 och3 ch3 H ch3 3 2605 och3 ch3 CHO ch3 3 2606 och3 ch3 ch2oh ch3 3 2607 och3 ch3 co2h ch3 8 2603 och3 H ch3 ch3 3 2609 och3 H Η ch3 8 2610 och3 H CHO ch3 3 2611 och3 H ch2ch ch3 3 2612 och3 H ch2h ch3 8 2613 ococh3 ch3 ch3 ch3 3 2614 ococh3 ch3 Η ch3 8 2615 ococh3 ck3 CHO ch3 3 2616 0C0CH-J ch3 ch2ok ch3 3 2617 ococh3 ch3 co2h ch3 3 2613 ococh3 H ch3 ch3 8 2619 OCOCH-j H H ch3 5 2620 ococh3 H CHO ch3 8 262 1 ococh3 H ch2oh ch3 8 143

Table 10 (Continued) —1- -2 R. R, ococh. K co2h ch3 CH ch3 ch3 ch3 OH ch3 H ch3 — GK ck3 CKO ch3 -* OH CK3 CH -> OH ch3 OH ch3 co2h ch3 OH Η ch3 CH, - OH Η Η ch3 - OH Η CHO ch3 OH Η CH 2 OH ck3 ** OH Η co2h ch3 =0 οκ3 ch3 ch3 =0 ch3 H ch3 =0 ck3 CHO ch3 — =0 ch3 ch2oh ch3 - =0 ch3 co2h ck3 - =0 H ch3 ch3 ** =0 H H ck3 * =0 K CHO ch3 ** =0 H ch2oh ch3 - =0 H co2h ch3 — och3 ch3 ch3 ch3 * och3 ch3 H ch3 — och3 ch3 CHO ch3 och3 ch3 ch2oh ch3 och3 ch3 co2h ck3 och3 H ch3 ch3 och3 Η Η ch3 "* och3 Η CHO ch3 7 144

Table 10 (Continued)

No . -2 Ei 2651 ock3 K ch2oh ch3 2 552 och3 H 00 2 H CH3 2553 ococh3 CH3 ch3 ch3 2654 OCOCH3 ch3 H ch3 2 6 5 5 OCOCH3 ch3 CHO ch3 2656 OCOCH3 ch3 ch2oh CH 3 2657 OCOCH3 ch3 C0 2 Η ch3 2658 OCOCH3 H ch3 ch3 2659 OCOCK3 H Η ch3 2660 OCOCH3 H CHO ch3 2661 OCOCH3 H ch2oh ch3 2662 OCOCH3 H co2h ch3 2663 0H ch3 ch3 CHO 2664 OH ch3 H CHO 2665 OH ch3 CHO CHO 2666 OH ch3 ' ch2oh CHO 2667 OH ch3 co2h CHO 2663 OH H ch-, CHO 2669 OH H H CHO 2670 OH H CHO CHO 2671 OH H ch2ch CHO 2672 OH H co2k CHO 2673 =0 ch3 ch3 CHO 2674 =0 ch3 H CHO 2 67 5 =0 ch3 CHO CHO 2675 =0 ch3 ch2oh CHO 145

No . _Ei_ 2677 =0 CH 2 6 7 S = 0 H 2675 =0 H 2630 =0 K 2 63 1 =0 H 2632 =0 H 2 633 och3 CH 2634 och3 CH 2635 och3 CH 2636 och3 CH 2637 och3 CH 2638 och3 H 2639 och3 H 2650 och3 H 2651 och3 H 2652 och3 H 2693 ococh3 CH 2694 ococh3 CH 2 695 ococh3 CH 2656 0C0CH-J CH 2657 ococh3 CH 2693 OCOCK-J H 2659 ococh3 H 2700 ococh3 H 2701 ococh3 H 2702 ococh3 H 2703 OH CH

Table 10 (Continued) R3 R, ck2h CHO ch3 CHO Η CHO CHO CHO ch2oh CHO co2h CHO ch3 CHO Η CHO CHO CHO ch2oh CHO co2h CHO ch3 CHO H CHO CHO CHO ch2ok CHO co2h CHO ch3 CHO H CHO CHO CHO ch2ok CHO co2h CHO ch3 CHO H CHO CHO CHO ch2ok CHO co2h CHO ch3 CHO 146

Table 10 (Continuad)

-3i- —2 R3 R, — n CH ch3 H CHO OH ch3 CHO CHO CH ch3 ch2oh CHO CH ch3 co2h CHO CH Η ch3 CHO OH Η H CHO OH Η CHO CHO OH Η ch2oh CHO OH Η co2h CHO =0 ch3 ch3 CHO =0 ch3 H CHO =0 ch3 CHO CHO =0 ch3 ch2oh CHO =0 ch3 co2h CHO =0 H ch3 CHO =0 H H CHO =0 H CHO CHO =0 H ch2oh CHO =0 H o o KJ Ή CHO och3 ch3 ch3 CHO och3 ch3 H CHO och3 ch3 CHO CHO och3 ch3 ch2oh CHO och3 ch3 co2h CHO och3 H ch3 CHO och3 H Η CHO 147

Table 10 (Continued) —1- E1 R3 -4 c och3 H CHO CHO /' och3 H ch2oh CHO 7 och3 H co2k CHO / OCOCH-j ch3 ch3 CHO 7 ococh3 ch3 H CHO 7 ococh3 ch3 CHO CHO 7 ocock3 ch3 ch2oh CHO 7 0C0CK3 ch3 co2h CHO i 0C0CH3 H ch3 CHO -ī / ocock3 H H CHO 7 ococh3 H CHO CHO 7 OCOCH3 H ck2oh CHO 7 ococh3 H co2h CHO 7 OK ch3 ch3 coch3 3 OK ch3 Η coch3 8 OH ch3 CHO coch3 3 OH ch3 ch2oh coch3 s OH ch3 co2h coch3 s OH Η ch3 coch3 8 OH Η H coch3 r» O OK Η CHO COCH-j 3 OH Η ch2oh COCH-j 8 OH Η co2h COCH-j S =0 ch3 ch3 COCH-j 8 =0 ch3 H COCH-j c =0 ch3 CHO COCH-j c =0 ch3 ch2oh COCH3 8 =0 ch3 co2h coch3 s =0 Η ch3 coch3 s 143

Table 10 (Continued) _Si_ £2 S3 - ?-4 =0 H H coch3 =0 u CHO coch3 =0 H ch2oh coch3 =0 H co2h coch3 och3 ch3 ch3 COCH-j OCn 2 ch3 H coch3 och3 CK3 CHO coch3 och3 CK3 ch2oh coch3 och3 ch3 co2h coch3 och3 H ch3 coch3 och3 H H coch3 och3 Η CHO coch3 och3 Η ch2oh coch3 och3 Η co2h coch3 ococh3 ch3 ch3 coch3 ococh3 ch3 H coch3 ococh3 ch3 CHO coch3 ococh3 ch3 ch2oh coch3 ococh3 ch3 co2h coch3 ococh3 H ch3 coch3 ococh3 H H coch3 ococh3 H CHO coch3 ococh3 Η ch2oh coch3 OCOCH-j Η co2h coch3 OH ch3 ch3 coch3 0H ch3 H coch3 OH ch3 CHO coch3 OH ch3 ch2oh coch3 OH ch3 cq2h coch3 - 149 -LV 10719

Table 10 (Continued) _Ei_ — 2. R3 F., — OH H ch3 C0CH3 1 OH K Η C0CH3 7 OH H CHO coch3 - OH H ck2oh coch3 / OH H co2h coch3 / =0 ch3 ch3 COCH-j 7 =0 ch3 H coch3 7 =0 ch3 CHO coch3 / =0 ch3 ch2oh coch3 7 =0 ch3 co2h C0CK-J 7 =0 H ch3 coch3 1 =0 H H coch3 7 =0 Η CHO cock3 / =0 H Ch’2OK coch3 7 =0 H co2h coch3 7 och3 ch3 ch3 coch3 7 och3 ch3 .H coch3 7 och3 ch3 CHO cock3 / och3 ch3 ch2oh COCK-J - och3 ch3 co3h coch3 7 och3 H ck3 COCH3 r och3 Η H C0CH3 7 OCH-j H CHO COCH3 7 och3 H ch3oh COCH3 7 och3 H co2oh COCH3 7 OCOCK3 ch3 ch3 COCH3 / OCOCH3 ch3 H COCH3 7 OCOCK3 ch3 CHO COCH3 r OCOCH3 ch3 ck2oh COCH3 1 150

Table 10 (Ccntinued)

No . Ri . _r3 - R4 2317 OCOCH3 ch3 co2h coch3 2318 OCOCH3 H ch3 COCH3 2819 OCOCH3 H CHO coch3 2321 OCOCH3 H ch2oh COCH3 2322 OCOCH3 H co2h COCH3 - 151 - - 151 -LV 10719

Table 11

No. _Rj_ *2 R3 E1 D 2323 OH ch3 οκ3 ch3 3 2824 OK ch3 Η ck3 8 2325 OK ch3 ch=ch2 ch3 3 2326 OH ch3 CHOKCH2OH-(R) ch3 8 2327 OH ch3 CHOKCH2OH-(S) ch3 3 2328 OK ch3 CHO ch3 3 2829 OH ch3 ch2oh ch3 s 2830 OH ch3 co2h ch3 8 233 1 CH ch3 co2ch3 ch3 8 2332 OH ch3 CH=NOH ch3 3 2333 OH ch3 CHOHCH=CH2-(R) ch3 8 2334 OH ch3 CKOHCH=CH2-(S) ch3 S 283 5 OK Η oh3 ch3 8 2 33 6 OH Η K ch3 S 233 7 OH Η ch=ch2 ch3 3 23 33 OH Η CHOHCH2OH-(R) ch3 S 2339 OH Η CHOHCH2OH-(S) ch3 8 2840 OK Η CHO ch3 S 2341 OH Η CH2OK ch3 8 2 S 4 2 OH Η co2h oh3 8 2 S 4 3 OK Η co2ch3 ch3 8 23 4 4 OH Η CH=NOH ch3 8 152

Tabie 11 (Continued) —i- *2 R3 R < ** OH H CH0HCH=CH2-(R) ch3 OH H CH0HCH=CH2-(S) ch3 =0 ch3 ch3 ch3 =0 ch3 H ch3 =0 ch3 CHO ch3 =0 ch3 ch2oh ch3 =0 ch3 co2h ch3 =0 H ch3 ch3 =0 H H ch3 =0 H CHO ch3 =0 H ch2oh ch3 =0 H co2h ch3 och3 ch3 ch3 ch3 och3 ch3 H ch3 och3 ch3 ch2oh ch3 och3 ch3 co2h ch3 och3 H ch3 ch3 och3 H H ch3 och3 H CHO ch3 och3 H ch2oh ch3 och3 H co2h ch3 ococh3 ch3 ch3 ch3 ococh3 ch3 H CH3 OCOCH-J ch3 CHO ch3 ococh3 ch3 ch2oh ch3 ococh3 ch3 co2h ck3 ococh3 H ch3 ch3 OCOCH-J H H ch3 LV 10719 - 153 -labie 11 (Ccr.t inued)

No . -Bl- EI R3 E1 2873 ococh3 H cho ch3 r> c 2874 ococh3 K ch2oh ch3 = 2875 OCOCK3 H co2h ch3 5 2876 OH ch3 ch3 ch3 7 2877 OK ch3 H ck3 - 2878 OH ch3 CHO ch3 - 2879 OH ch3 ch2oh ch3 - 2880 OH ch3 co2h ch3 - 2881 OH H ch32 ch3 “ 2882 OK H H ch3 / 2883 OH H CHO ch3 7 2884 OH H ch2oh ch3 - 2885 OK H co2h ch3 - 2886 =0 ch3 ch3 ch3 - 2887 =0 ch3 H ch3 - 2888 =0 CHt CHO ch3 - 2889 =0 ch3 ch2oh ch3 - 2890 =0 ch3 co2h ch3 7 2891 =0 H ch3 ch3 - 2892 =0 H Η ch3 - 2893 =0 H CHO ck3 i 289 4 =0 K ch2oh ch3 η 2895 =0 H co2h ch3 2896 och3 ch3 ch3 ch3 - 2897 och3 ch3 H ch3 - 2898 0CH3 ch3 CHO ch3 7 2899 0CH3 ch3 ch2oh ch3 - 2900 0CH3 ch3 co2h CK3 -

Table 11 (Continued) ΝτΟ . S2 *3 b4 2901 och3 H CK3 ch3 2902 och3 H H ch3 2903 och3 H CHO ch3 2504 och3 H ch2oh ch3 2905 OCK3 H co2h ch3 2906 ococh3 ch3 ch3 ch3 2907 OCOCH3 ch3 H ch3 2908 OCOCH3 ch3 CHO ch3 2909 ococh3 ch3 ch2oh ch3 2910 OCOCH3 ch3 co2h ch3 2911 OCOCH3 H ch3 ch3 2912 OCOCH3 H H ch3 2913 OCOCH3 H CHO ch3 2914 OCOCH3 H 0 X tv> 0 ch3 2915 OCOCH3 H co2h ch3

155 Table 12 CaH

Ei- E1 R3 Ei U OK CH: ch3 H 3 OH ck3 Η K 8 OH ch3 ch=ch2 H 8 OK ch3 CHOHCH2OH-(R) H S OK ch3 CHOHCH2OH-(S) H S OH ch3 CHO H 8 OH ch3 ch2oh K 8 OH ch3 co2h H 8 OH ck3 co2ch3 H S OH ch3 ch=noh K 8 OH ch3 CHOHCH=CK2-(R) . H 8 OH ch3 CHOHCH=CK2-(S) H S OH Η ch3 H S OH Η K K S OH Η ck=ch2 H o OH Η CHOHCH2OH-(R) H S OH Η CHOHCH2OH-(S) H 8 OK Η CHO H S OH Η CK2OH K s 156

Table 12 (Continued)

Λ Ί *2 R3 e4 OH H co2h H OH H C°2CH3 H OH H CH=NOH H OH H CHCHCH=CH2-(R) H OH H CHOHCH=CH2-(S) H OH ch3 ch2sh H OH ch3 ch2nh2 H OH ch3 coch3 H OH ch3 conh2 H OH ch3 csnh2 H OH ch3 ch2ch2oh H OH ch3 ch2cho H OH ch3 ch2coch3 H OH ch3 ch2co2ch3 H OH ch3 ch2conh2 H OH ch3 ch2ch2ci H OH ch3 CN H OH ch3 ch=nnh2 H OH ch3 ch2nhoh H OH ch3 ch2nhnh2 H OH ch3 ch2cn H OH ch3 ch2ch=noh H OH ch3 ch2ch=nnh2 H OH ch3 ch2ch2nhoh H OH ch3 ch2ch2nhnh2 H OH ch3 conhoh H OH ch3 ch=chcho H OH ch3 ch=chcoch3 H 157

Table 12 (Continued) -Si- β2 R3 *4 D OH ch3 ch=chch2ci Η 8 OH ch3 ch2chohch2oh H 8 CH ch3 CKOHCH-CH, \ / 0 Η r> 0 =0 ck3 CK3 K 0 =0 ch3 H K 8 =0 CH3 CHO Η Λ r =0 ch3 ch2oh H 3 =0 ch3 co2h H 8 =0 H ck3 H 8 =0 H H H 8 =0 K CHO H 8 =0 H ch2oh H 8 =0 H co2h H 3 och3 ch3 ch3 H S och3 ch3 H H S och3 ch3 ch2oh H 8 och3 ch3 co2h H 8 och3 H ck3 K £ ohc3 H H H 8 och3 H CHO H 8 och3 H ch2oh H 8 och3 H co2h H 8 ococh3 ch3 ch3 H 8 ococh3 ch3 H H 8 ococh3 ch3 CHO H 8 ococh3 ch3 ch2oh H S ococh3 ch3 co2h H 8

Table 12 (Continued)

_B_ļ— Ez R3 ococh3 H ch3 occ :h3 H H 0CCCH3 H CHO OCOCH3 H ch2oh OCOCK3 H co2h OH ch3 ch3 OH ch3 H OH ch3 CHO OH ch3 ch2oh OH ch3 co2h OH Η ch3 OH Η H OH Η CHO OH Η CH20H OH Η co2h =0 ch3 ch3 =0 ch3 H =0 ch3 CHO =0 ch3 ch2oh =0 ch3 co2h =0 Η ch3 =0 H H =0 H CHO =0 H ch2oh =0 Η co2h 0CH3 ch3 ch3 0CH3 ch3 H 0CH3 ch3 CHO 159

Table 12 (Cor.tinued) —2. R3 R„ D och3 ch3 ch2oh H 7 OCK3 ch3 C02 H t 0CH3 Η ch3 K 7 0CH3 Η H H 7 OCH3 H CHO H 7 0CH3 K ch2oh H 7 0CH3 H co2h H 7 OCOCH3 ch3 ch3 H 7 OCOCH3 ch3 Η H 7 OCOCK3 ch3 CHO H 7 OCOCH3 ch3 ck2oh H 7 ococh3 ch3 co2h H 7 OCOCH3 H ch3 K 7 OCOCH3 H K H 7 OCOCH3 H CHO K 7 OCOCH3 H ch2oh H 7 OCOCH3 H co2h H 7 OH ch3 ch3 CK3 8 OH ch3 H ch3 8 OH ch3 CHO ch3 8 OK ch3 CH2OH ch3 8 OH ch3 co2h ch3 8 OH H ck3 ch3 8 OH H K ch3 8 OH H CHO ch3 8 OH H CK2OK ch3 8 OH H co2h ch3 8 =0 CH3 CH3 ch3 8 160 labie 12 (Ccncinued) Λ i S1 *3 *4 =0 CK3 Η ch3 3 =0 CK3 CHO ch3 3 =0 ch3 ch2oh ch3 3 =0 ch3 co2h ch3 3 =0 H ch3 ch3 3 =0 H Η ch3 3 =0 H CHO CK3 3 =0 H ch2oh CH-J 3 =0 H co2h ch3 3 och3 ch3 ch3 ch3 3 och3 ch3 Η ch3 3 och3 ch3 CHO ch3 3 och3 ch3 ch2oh ch3 3 och3 cc3h ch3 3 och3 H ch3 ch3 3 och3 H Η ch3 8 och3 H CHO ch3 3 och3 H ch2oh ch3 3 och3 H co2h ch3 8 ococh3 ch3 ch3 ck3 3 ococh3 CH3 H ch3 3 OCOCH-j ch3 CHO ch3 3 ococh3 ch3 ch2oh ch3 3 OCOCH-j CH-j co2h ch3 3 OCOCH3 Η CH-j CH-J 3 OCOCH3 Η H CK3 *·* 0 OCOCH-J Η CHO CH-j 3 OCOCH-J Η ch2oh CH3 S OCOCH-J Η co2h ch3 3 LV 10719 - 161 -Table 12 (Continued) _2]_ R3 n CH ch3 ch3 ch3 7 OH ch3 Η ch3 7 OH ch3 CHO ch3 7 OH ch3 ch2oh ch3 7 OH ch3 co2h ch3 7 OH H ch3 ch3 7 OH H H ch3 η OH H CHO ch3 1 OH H ch2oh ch3 1 OH H co2h ch3 1 =0 ch3 ch3 ch3 7 =0 ch3 Η ch3 7 =0 ch3 CHO ch3 7 =0 ch3 ch2oh ch3 7 =0 ch3 co2h ch3 7 =0 H ch3 ch3 7 =0 Η H ch3 / =0 H CHO ch3 7 =0 H ch2oh ch3 7 =0 H co2h ch3 - och3 ch3 ch3 ch3 - och3 ch3 Η ch3 J och3 ch3 CHO ch3 7 och3 ch3 CH20H ch3 7 och3 ch3 co2h ch3 7 och3 Η ch3 ch3 7 och3 Η Η ch3 7 och3 Η CHO ch3 7 (Continued)

No. _Bi _ £2 R3 E, 3 103 och3 H ch2oh ch3 3104 och3 H co2h ch3 3 105 ococh3 ch3 ch3 CH3 3106 OCOCH3 CH3 H c:-:3 3 107 OCOCH3 CH·, ν’ CHO ch3 3103 OCOCH3 ch3 ch2oh ch3 3109 OCOCK3 ch3 co2h ch3 3110 OCOCH3 H ch3 ch3 3111 OCOCH3 H H ch3 3112 OCOCH3 H CHO ch3 3113 OCOCH3 u ch2oh ch3 3114 OCOCH3 H co2h ch3 3115 OH CH3 ch3 CHO 3116 OH ch3 H CHO 3 117 OH ch3 ch3 CHO 3113 OH ch3 ch2oh CHO 3119 OH CH3 co2h CHO 3120 OH H ch3 CHO 3121 OH H H CHO 3122 OH H CHO CHO 312 3 OH H ch2oh CHO 3124 OH H co2h CHO 3125 =0 CH 3 ch3 CHO 3126 =0 ch3 H CHO 3127 =0 ch3 CHO CHO 3 123 =0 ch3 ch2oh CHO 3 129 =0 ch3 co2h CHO 3130 =0 H ch3 CHO 163 labie 12 (Continued) -*1- e2 R3 £4 0 =0 H Η CHO 0 =0 CHO CHO 0 =0 H ch2oh CHO s =0 H co2h CHO Λ 0 och3 ch3 ch3 CHO 0 cck3 CH, m! H CHO 8 och3 C«3 CHO CHO 8 0CK3 CH3 ch2oh CHO S och3 ch3 co2h CHO 8 och3 H ch3 CHO 3 0CK3 U H CHO r** O 0CH3 H CHO CHO 8 0CK3 H ch2oh CHO 8 0CH3 H co2h CHO S OCOCH3 ch3 ch3 CHO 3 OCOCH3 ch3 H CHO 8 OCOCH3 ch3 CHO CHO 8 OCOCH3 ch3 CH20H CHO 8 OCOCK3 ch3 co2h CHO 8 OCOCK3 Η CH-, . CHO 8 ococh3 Η Η CHO 8 OCOCK3 Η CHO CHO 8 0C0CK3 Η ch2oh CHO 8 ococh3 Η co2h CHO 8 OH ch3 ch3 CHO 7 OH ch3 V CHO - OH οη3 CHO CHO 7 OH ch3 ch2oh CHO r 164

Table 12 (Continued) -Bi- S1 R3 R 4 3. D OH ch3 co2h CHO 7 OH Η ch3 CHO 7 OH H Η CHO 7 OH H CHO CHO 7 OH ch2oh CHO 7 OH H co2h CHO 7 =0 ch3 ch3 CHO 7 =0 ch3 Η CHO 7 =0 ch3 CHO CHO 7 =0 ch3 ch2oh CHO 7 =0 ch3 co2h CHO 7 =0 Η ch3 CHO 7 =0 H H CHO 7 =0 u k k CHO CHO 7 =0 Η ch2oh CHO 7 =0 Η co2h CHO 7 och3 ch3 ch3 CHO 7 och3 ch3 Η CHO 7 och3 ch3 CHO CHO 7 och3 ch3 ch2oh CHO 7 och3 ch3 co2k CHO 7 och3 Η ch3 CHO 7 och3 H H CHO 7 och3 Η CHO CHO 7 och3 H ch2oh CHO 7 och3 Η co2h CHO 7 OCOCH-j ch3 ch3 CHO 7 OCOCH3 ch3 H CHO 7 165 Table 12 (Cont ir.ued) -*1- S1 R3 OCOCH3 CK3 CKO OCOCH3 CK3 CK2OH OCOCK3 CK3 co2h OCOCH3 H ck3 OCOCK3 H Κ OCOCK3 H CKO OCOCK3 H CK2 OH OCOCH3 K co2h OH CK3 ch3 OH C3 V OH ch3 CHO OH ch3 ch2oh OH ch3 co2h OH Η ch3 OH Η Η OH Η CHO OH Η CH2OH OH Η co2h =0 ch3 v_.n3 = 0 ch3 H =0 ch3 CHO =0 ch3 ch2oh = 0 ch3 co2oh = 0 K ch3 = 0 Η H = 0 Η CKO = 0 Η ch2oh = 0 Η CO-,Η R, —h_

CKO

CHO

CKO

CHO

CKO

CKO

CHO

CKO COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCK3 COCH3

Table 12 (Continued)

No . R1— B2 R3 R 4 — «-» 3215 och3 ch3 ch3 coch3 3216 och3 ch3 H coch3 3217 och3 ch3 CHO coch3 3213 och3 ch3 CH.CH coch3 32 19 och3 CH3 co2h coch3 3220 ock3 H ch3 coch3 3221 och3 H H coch3 3222 och3 H CHO coch3 3223 och3 H CHO coch3 3224 o ch3 H co2h coch3 3225 ococh3 ch3 coch3 coch3 3226 ococh3 ch3 H coch3 3227 ococh3 ch3 CHO coch3 3223 ococh3 ch3 ch2oh coch3 3229 ococh3 ch3 co2h coch3 3230 ococh3 H Η coch3 3231 ococh3 K CHO coch3 3232 ococh3 H ch2oh coch3 3233 OCOCH3 H ch2oh coch3 3234 ococh3 H co2h coch3 3235 OH ch3 ch3 coch3 3236 OH ch3 Η coch3 3237 OH ch3 CHO coch3 3233 OH ch3 ch2oh coch3 3239 OH ch3 co2h COCH-j 3240 OH H CH 3 coch3 3241 CH H H coch3 3242 OH H CHO coch3 LV 10719 - 157 -Tafcle 12 (Cor.tinued)

Nc . P'l p2 R3 £4 c 2 24 2 OH H CKjOH COCh'3 7 2 2 4 4 OH K co2k COCH-j 7 2245 = 0 ch3 ch3 COCH3 / 2 2 4 5 = 0 ch3 K COCH3 r 2 24 7 = 0 ch3 CHO COCH3 1 2 245 = 0 CK3 ch2oh COCH-j - 2 245 = 0 Ch’3 co2h coch3 7 2 250 = 0 H ch3 coch3 / 2 25 1 = 0 H H coch3 / 3 252 = 0 H CHO COCK3 — 3 253 = 0 K ch2oh coch3 / 3 254 = 0 K co2h coch3 I 3 2 5 5 och3 ch3 ch3 COCH-j * 3256 och3 ch3 H COCH-J 3 2 57 och3 ch3 CHO COCH3 7 3 2 55 och3 ck3 ch2oh COCH-J T 3255 och3 ch3 co2h COCK3 32 60 och3 H ch3 coch3 t 3 261 och3 H K COCH-j i 3 2 62 och3 H CHO COCH3 *7 3263 och3 H ch2oh coch3 / 3 2 6 4 och3 H co2h COCH-j — 3265 ocock3 ck3 ch3 COCh’3 7 3 266 ococh3 ch3 p coch3 7 3267 ococh3 ch3 CHO COCH-j — 3 263 ococh3 ch3 ck2oh coch3 3255 ococh3 H ch3 COCH-j / 3 270 ococh3 H ch3 COCH-j / 327 1 OCOCH-j H H coch3 7 163

Table 12 (Continued)

No. *2 R-» R, D 3272 OCOCH3 H CHO coch3 7 3273 ococh3 H ch2oh coch3 7 3274 ococh3 H co2h coch3 7 - 169 - :1- B2

LV 10719 D No.

OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH

CH- CH- CH- OH ; CH- CH- CH. CH- CH- CH- CH- CH; H H H H H H H H H H H ch3 H ch=ch2 CHOHCH2OH-(R) CHOHCH2OH-(S) CHO CH2OH ch2h co2h3 CH=NOH CHOHCH=CH2-(R) CHOHCH=CH2-(S) ch3 H CH=CH2 CHOHCH2OH-(R) CHOHCH2OH-(S) CHO CH2OH co2h co2ch3 CH=NOH CHOHCH=CH2-(R) CH- CH; CH- CH- CH. CH- CH. CH; CH. CH; CH- CH- CH; CH; CH- CH- CH- CH- CH- CH- CH- CH; CH- 8 8 8 8 8 8 8 8 8 £ 8 8 8 8 8 8 8 8 8 8 8 8 8 170 Table 13 (Ccntinued) No. -Bi- *2 *3 E- D 3293 OH H CH0HCH=CH2-(S) ch3 3 3299 =0 ch3 ch3 ch3 3 3 300 =0 ch3 K ch3 3 3301 =0 ch3 CHO ch3 3 3302 —0 ch3 ch2oh ch3 3 3303 =0 ch3 co2h ch3 3 3 304 =0 H ch3 ch3 3 3305 =0 H H ch3 3 3306 =0 H CHO ch3 3 3307 =*0 H ch2oh ch3 3 3303 =0 H co2h ch3 3 3309 och3 ch3 ch3 ch3 3 3310 och3 ch3 H ch3 3 3311 och3 ch3 ch2oh ch3 3 3312 och3 ch3 co2h ch3 3 3313 och3 H ch3 ch3 3 3314 och3 H H ch3 3 3315 och3 H ch2oh ch3 3 3317 och3 H co2h ch3 3 3313 ococh3 ch3 ch3 ch3 8 3319 ococh3 ch3 H ch3 3 3 320 OCOCH-j ch3 CHO ch3 3 3321 OCOCH-J ch3 ch2oh ch3 3 3322 ococh3 ch3 co2h ch3 8 3323 ococh3 H ch3 ch3 8 3324 ococh3 H H ch3 3 3325 OCOCH-j H CHO ch3 8 3326 ococh3 H ch2oh ch3 8 Μ. P. LV 10719 - 171 -Table 13 (Continued) _Rl_ H R3 Si D OCOCH3 H co2h ch3 3 OH ch3 ch3 ch3 7 OH ch3 H ch3 7 OH ch3 CHO ch3 7 OH ch3 CH2 OH ch3 7 OH ch3 co2h ch3 7 OH H ch3 ch3 7 OH H H ch3 7 OH H CHO ch3 7 OH H ch2oh ch3 7 OH H co2h ch3 7 =0 ch3 ch3 ch3 7 —0 ch3 H ch3 7 =*0 ch3 CHO ch3 7 =0 ch3 ch2oh ch3 7 =0 ch3 co2h ch3 7 =0 H CH 3 ch3 7 *0 H H ch3 7 =0 H CHO ch3 / =0 H CH2OH ch3 7 =0 H co2h ch3 7 OCH3 ch3 ch3 ch3 7 0CH3 ch3 H ch3 7 0CH3 ch3 CHO ch3 7 0CH3 ch3 ch2oh ch3 7 0CH3 ch3 co2h ch3 7 0CH3 H ch3 ch3 7 0CH3 H H ch3 7 Μ. P. 172

Table 13 (Continued)

No. -&1- B2 *3 *4 2 3355 och3 H CHO ch3 7 3356 och3 H ch2oh ch3 7 3357 och3 H co2h ch3 7 3358 ococh3 ch3 ch3 ch3 7 3359 ococh3 ch3 H ch3 7 3360 ococh3 ch3 CHO ch3 3 3361 ococh3 ch3 ch2oh ch3 7 3362 ococh3 ch3 co2h ch3 7 3363 ococh3 H ch3 ch3 7 3364 ococh3 H H ch3 7 3365 ococh3 H CHO ch3 7 3366 ococh3 H ch2oh ch3 7 3367 ococh3 H co2h ch3 7 ΝΟΤΕ

When the D-ring is piperidine or the N-oxide thereof, the upper side chain (R) is not the ergosterol side Chain. - 173 - - 173 - LV 10719

SYNTHETIC EXAMPLES

The folloving examples aescribe synthetic procedures eraploved in produccion of specific ccmpounds vithin the scope of the preser.t invention. Cnless othervise indicated, ali percencages in the folloving Examples and in the General Frccedures set forth above are by veight and ali temperatures are reported in degrees Celsius (°C) . Ali parts for reactior. and chromatographv sclvents were cetermined by vciume. Ali proton NMR spectra are referenced to tetramethvlsilar.e (TMS) at 0.00 ppn.

The folloving abbreviaticns are employed in the Exanūles: NīīR: nuclear magr.etic resonance spectrosccpv IR: infrared spectroscopv MS: mass spectroscopy HRMS: high resolution mass spectros EI: electron impact CI: Chemical, ionization EA: elemental analysis m.p. : melting pcint MPLC: medium pressure liquid chromatography Rf: retention factor on silica ge laver chromatographv

Particular intermediates or products are identified bv reference to the numbered conpounds in the general svnthetic procedures surnarized above. Physicai data 174 for various ccnpcunds produced by procedures substantially corresponding to the description contained in each Example are provided folloving the individual Examples. EXAMPLZ 1

Preoaration of 15-OxadihvdrolanosteroI (Compound 11a) A. Preoaration of 4,4-dinethvl-3b-r(4- methoxvbenzvl) oxvl-5a-cholesta-3 . 14-diena rcomoound 2 b)

To a stirred solution of sodium hydride (50% in oil, 23.2 g, vashed vith 3 portions of 50 ml of dry tetrahydrofuran) in dry tetrahydrofuran (800 ml) and anhvdrous N, N-dinethylformamide (200 ml) at 0° vas added 4,4-dimethyl-5a-cholesta-3,14-dien-3b-ol (Compound 2a) (40 g, 96.8 mmole) and the mixture vas stirred for 10 min. 4-Methoxybenzyl chloride [16.8 ml 193.6 mmole, prepared by the method described by Schriner, et al. J. Org. Chem.. 10: 228 (1945)] vas added and the mixture vas stirred for 24 hr. at 70° under nitrogen atmosphere.' After cooling to 5° vater (80 ml) vas added dropvise to the mixture and it vas stirred for 5 min. It vas pcured into ether (1 L) and the layers vēra separated and the organic phase vas vashed vith vater (3 X 300 ml) .

The combined agueous layers vere extracted vith additional diethyl ether (300 ml). The combined organic Solutions vere vashed vith brine, and dried over anhydrous roagnesium sulfate and evaporated under reduced pressure to afford a crystalline solid residue LV 10719 - 17 5 -

Recrvstallization from diethyl ether and metha.nol provided 42.5 g of purified Compound 2b. The mot.her licfuor residue was column chromatographed on silica gei with elution by 1:9 ethyl acetate - hexane to give additional 8.2 g of Compound 2b (50,7 g total, 98% yield) .

Physical Data (Compound 2b) : NKR (300 MHz, CDC13); delta 7.28 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 5.35 (br s, 1H), 4.60 (d, J=ll.4 HZ, IK), 4.37 (d, J-11.4 Hz, 1H), 3.80 (S, 3H), 2.92 (dd, J=3.6 Hz, 11.7 Hz, 1H), 2.40-1.00 (m, 24K), 1.04 (S, 3H) , 0.99 (S, 3H) , 0.93 (d, J=6.3 Hz, 3H) , 0.87 (d, J = 6.3 HZ, 6H) , 0.86 (s, 3H) , 0.80 (s, 3H) ; IR (KBr): 2939, 2888, 2870, 1513, 1470, 1249, 1101, 1095 cm'1. B. Precaration of 4.4-dimethvl-3b-r(4- methoxvbenzvl)οχνί-5a-cholest-8-ene-14a. 15a-diol (Compound 3b)

To a solution of the 8,14-diene (Compound 2b) (16 g, 30 mmole) and dry pyridine (24.4 ml, 300 mmole) in benzene (640 ml) at 0° vas added a solution of osmium tetroxide (8 g, 31.4 mmole) in methylene chloride (160 ml) dropvise over a period of 1 hr.

The dark brovn mixture vas stirred for 2 hr. at room temperature.

At the end of this period hydrogen sulfide (Union Carbide Corp., Linde Division, Danbury, CT 06817) vas bubbled through the solution for about 20 min. and the black precipitates that formed vere filtered off through Celite (Manville Products Corp. Denver, CO).

The filtrate vas evaporated under reduced pressure to afford a brcvn solid residue (17.5 g) of the dicl (Compound 3b) . This material vas routinely used fcr further transforsations vithout purification.

An analytical sample of Compound 3b vas obtained i the folloving manner: A solution of the compound in benzene vas filtered through a plug of silica gel (Kieselgel 60, EM Science 111 Woodcrest Rd. , Cherry Hill, NJ 08034-0395) vith elution by 2:8 ethyl acetate - hexane and the solvents vere evaporated under reduced pressure to give a vhite crystalline solid. This vas recrystallized from ethvl acetate and hexane to give a chromatographically homogeneous sample of Compound 3b. ?hysical Data (Compound 3b): m.p. = 124-126.5° (decompcsed); NMR (300 KHz, CDC13): delta 7.23 (d, J=8.7 Hz, 2H) , 6.87 (d, J=3.7 Hz, 1H) , 4.66 (d, J=ll. 4 Hz , 1H) , 4.37 (d, J=11.4 Hz, 1H) , 2.45 (d, J=9.9 HZ, 1H) , 2.35-0.80 (m, 26H), 1.C2 (S, 3H), 0.97 (s, 3H), 0.86 (d, J=6.3 Hz, 6H), 0-36 (d J=6.6 Hz, 3H), 0.35 (s, 3H) , 0.59 (s, 3H); IR (K3r) : 3406, 2949, 2869, 2841, 1615, 1514, 1465, 1376, 1360, 1346, 1245, 1117, 1031 cm"1; HRHS for C37H5603 (M-H20) : Calcd. 548.4229 ; found 548.4252. - 177 - - 177 - LV 10719 C· Preoaration of 4 , 4-Dimethvl-3b-ri4-methoxybenzvl) czv 1 -15-oxo-5a-14 , 15-secochoIest-8-er.-14-one (Compound 4b)

To a stirred solution of the diol (Compound 3b) (30 nraole in dry benzene (830 ml, distilled from calcium hvdride) in the dark was added lead tetraacetare (14 g, 31.5 mmole Aldrich, recrvstallizēd from acetic acid) in small portions over a period of 1 hr. and the mixture was stirred at room temperature for 1 hr. under nitrogen atmosphere and in the dark. The mixture vas filtered through Celite and the filter cake rinsed vith benzene several times. Evaporation of the solvent under reduced pressure provided an oily residue (17. i g) of crude ketc-aldehyde (Compound 4b) . The crude product vas roucinely used for further transformations vithout purification.

An analytical sample of Compound 4b vas cbtained by column chromatography on silica gel vith elution by 1:9 ethyl acetate - hexane then 2:3 ethyl acetate - hexane. Phvsical Data (Compound 4b): NMR (300 MHz, CDC13): delta 9.57 (s, 1H), 7.28 (d, J=8.4 HZ, 2H) , 6.87 (d, J=8.4 Hz, 2H), 4.60 (d, J-l1·4 Hz, 1H), 4.40 (d, J=11.4 Hz, 1H), 3.80 (s, 3H), 3.01 (dd, J=4 Hz, 11.7 Hz, 1H), 2.58-1.00 (m, 24K), 1.07 (s, 3H), 1.02 (S, 3H), 0.97 (S, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.87 (s, 3H) , 0.86 (d, J=6.6 Hz, 6H) ; IR (f ilm) : 2951, 2368, 2719, 1725, 1654, 1623, 1617, 1514, 1465, 1458, 1247, 1093, 1037, cm"1; HRMS for C36H56°4 (m+): Calcd. 564.4179; found 564.4209. 173 D . Preparātiem cf 15 . 15-Dimethoxv-4 , 4-dirretr.vl-3 b - Γ ( 4-methoxvbenzvl1 oxvl 5a-14 . 15-secocoholest-3-en-l4-one iCompound 5b)

To a solution of the keto-aldehyde (Compound 4b) (30 mmole) in methanol (600 ml) vere added trimethyl orthoformate (Aldrich) (43 ml, 439 mmole) and camphorsulfonic acid (Aldrich) 3.2 g, 13.8 mmole) and the mixture was stirred at room teroperature for 2 hr. under nitrogen atncsphere. At the end of the stirring saturated sodium bicarbonate solution (120 ml) vas added and most of the methanol vas evaporated under reduced pressure. The residue vas extracted vith diethyl ether (3 x 500 ml) and the combined extracts vere vashed vith brine, dried over anhydrous magnesium sulfate, and evaporated to give an oil residue (18.12 g) of the crude keto-acetal (Compound 5b).

The crude material vas normally used for the r.ext reaction. For analytical purposes, Compound 5b vas column chromatographed on silica gel vith elution by 2:8 ethyl acetate - hexane affording a purified sample of the Compound 5b.

Physical Data (Compound 5b): NKR (300 MHz, CDC13): delta 7.27 (d, J=8.4 Hz, 2H) , 6.86 (d, J=8.4 Η z, 2H) , 4.60 (d, J*ll.‘4 Hz, 1H) , 4.37 (d, J=ll.4 HZ, 1H), 4.05 (t, J=5 Hz, 1H), 3.26 (S, 3H), 3.21 (S, 3H), 2.90 (dd, J=4 Hz, 12 Hz, IK), 2.60 (dd, J=5 Hz, 17 HZ), 2.40-0.90 (m, 26H), 1.08 (S, 3H), 1.10 (s, 3H), 0.99 (d, J=6.5 Hz, 6H); IR (film): 2952, 2369, 1661, 1615, 1514, 1464, 1453, 1248, 1123, 1099, 1077 cm-1; HRMS for C37H5403: Calcd. 546.4073; found 546.4126. - 179 - - 179 - LV 10719

Preoaration of 15 . 15-Dimethoxv-3b-'( 4-~ethoxvbenzvl ) cxvi -14 . 15-secolanost-3-en-l4-n fCompound 6b)

To a soluticn of the keto-acetal (Compound 5b) (30 mmole) in dry diethyl ether (600 ml) was added a solution of methyl magnesium broraide in diethyl ether (3 ml, Aldrich) 50 ml, 150 mmole) dropvise at 0° and the mixture was stirred at 30-40° for 2 hr. After cooling it to 0°, hvdrochloric acid (0.5 ml, 400 mmole) was added slowly and it was stirred for about l min. The product was extracted with diethyi ether (3 x 500 ml), and the combined extracts washed with water and brine and dried over anhydrous magnesium sulfate) .

Evaporation of the solvent afforded an oily residue of the tricyclic alcohol (Compound 6b). The crude product was routinely used for next reaction vithout purification.

An analytical sample of the Compound 6b was obtained by column chromatography on silica gel with eiution by 2:8 ethyl acetate - hexane.

Physical Data (Compound 6b) : NKR (300 MHz, CDC13): delta 7.29 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.61 (d, J*11.4 HZ, 1H), 4.33 (d, J=ll.4 Hz, 1H), 4.21 (dd, J=2.7 Hz, 9 Hz, 1H), 3.31 (s, 3H), 3.49 (s, 3H), 3.43 (s, 3H), 2.95 (dd, J=3.9 Hz, 11.7 HZ, 1H), 2.35 (dd, J=5.4 Hz, 18 Hz, 1H), 2.20-0.90 (m, 24H), 1.19 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.93 (d, J=6.9 Hz, 3H), 0.90 (s, 3H), 0.86 (d, J=6.3 H2, 6H), 0.86 (s, 3H); HRMS for C38H5602 (M-2CH30H-H20): Calcd. 544.4230; found 544.4253. 130 F. Preparation of 3b-ff4-Methoxvbenzvl)oxyi-14a-oxa-D-homo-lanost-3-en-15-ol (Compound 7b) A solution cf the tricyclic alcohol (Compound 6c) (30 mmole) in methylene chlcride (160 ml) and 80% agueous acetic acid (600 ml) vas stirred at room temperature for 2 days and the solvents vere evaporaced under reduced pressure to give an oily residue of the cvclic hemiacetal (Compound 7b) and the cyclic acetal (Compound 7c) . Compound 7b was separated from Compound 7c by column chromatography on silica gel with elution by 15:85 ethyl acetate - hexane folloved by 3:7 ethvl acetate - hexane to afford 3.5 g of the Compound 7c (Rf = 0.48, 2:8 ethyl acetate - hexane) and 11.6 g of the Compound 7b (Rf *0.23, 2:3 ethyl acetate - hexane) as oils.

The compound 7c was dissolved in methylene chloride (55 ml) 80% agueous acetic acid (160 ml) and 1M hydrochloric acid (1 ml) and the solution was stirred at room temperature for 1 day. It vas vorked up and purified as described above to provide an additional 1.9 g of Compound 7b (total 13.5 g, 77.5% overall yield from Compound 3b) and 1.2 g of Compound 7c (6.7% cverall yield from Compound 3b).

Physical Data (Compound 7b): NHR (300 MHZ, CDC13): delta 7.23 (d, J=3.7 Hz, HRMS for 2H), 6.87 (d, J=3.7 Hz, 2H), 4.60 (d, J=11.5 Hz, 1H), 4.52 (t, J=7.5 HZ, 1H), 4.37 (d, J-11.5 Hz, 1H), 3.30 (s, 3H), 2.93 (dd, J=4.2 Hz, 11.7 Hz, 1H) 2.32 (dd, J=4 Hz, 11 Hz, 1H), 1.95-0.90 (m, 24H), 1.17 (s, 3H), 0.99 (s, 3H), 087 (d, J=6.6 Hz, 6H), 0.85 (s, 3H); C38H56°2: Calcd· 544.4230; found 544.4197. 181 181LV 10719 G . Preoararion of 3b-' 4-Methoxvbenzvl) oxv -14a-cxa-D-horno-lanosta-3.15-diene (Conpound Sb)

To a stirred solution of the cyclic hemiacetal (Conpound 7b) (13.5 g, 23.2 mmole) and anhydrous triethylamine (Aldrich) (33 ml, 232 mmole, distilled from calcium hydride) in dry methylene chloride (310 ml, distilled frcn phosphorous pentoxide) at C° vas added nethanesul:onyl chloride (Aldrich) (5.43 ml, 69.6 mmole, filtered freshly through basie alumina) drepvise over a period cf 5 min. and the mixture vas stirred at 0° to 20° for 1 hr. under nitrogen atmospnere. The reaction mixture vas poured into diethyl ether (1 L) and the solution vas vashed vith vater, saturated sodium bicarbor.ate solution, vater and brine. After drying over anhvdrous magnesium sulfate the solver.ts vere evaporated under the reduced pressure to give an oily residue of the glvcal (Compound 8b). This crude material vas normally used for next reaction vithcut purification.

The analytical sample vas prepared by column chromatography on silica gel vith elution by 1:9 ethyl acetate - hexar.e to afford a purified sample cf Compound 8b. ?hysical Data (Conpound 8b): NKR (300 MKz, CDCl3): delta 7.28 (d, J=8 Hz, 2K) , 6.88 (d, J = 8 HZ, 2H) , 6.21 (dd, J=2.5 Hz, 6 Kz, 1H) , 4.61 (d, J=11.5 HZ, 1H) , 4.52 (dd, J=1.2 Hz, 6.3 Kz, 1H), 4.38 (d, J=ll.5 KZ, 1H), 3.81 (s, 3H), 2.54 (dd, 182 J = 4 Hz, 11 Hz, 1H) , 2.30-0.90 (m, 22H), 1.23 (S, 3H) , 1.01 (3, 3H) , 0.93 (S, 3H) , 0.87 (d, J=7 Hz , 6H) , 0.37

(S, 3 (m-h2 H. Preoaration of 3b-r 4-Methoxvbenzy1) oxv i -14a-oxa-D-horao-lanost-3-ene-15,16-diol (Compound 9b)

To a stirred solution of the glycal (Compound 8b) (23.2 mmole) and pvridine (18.8 ml, 232 mmole) in benze.ne (600 ml) at 0° was added a solution of osmium tetroxide (6 g, 23.6 mmole) in methylene chloride (120 ml) over a period of 10 min. and the dark brown solution was stirred at room temperature for 1 hr. At the end of the stirring hydrogen sulfide gas vas bubbled through the solution for about 15 min. and the resulting black precipitates wera removed by filtration through Celite. The filter cake vas rinsed with ethyl acetate several times and the filtrate vas evaporated under reduced pressure to give a dark brovn oily residue of the diol (Compound 9b) as a mixture of diastereomers.

Due to the complexity and instability of the product, analysis vas carried cut after the next transforaation.

Phvsical Data (Compound 9b): NMR (300 KHz, CDC13): delta 7.29 (d, J=3 Hz, 2H) , 6.38 (d, J=8 Hz, 2H) , 4.60 (d, J=12 Hz, 1H) , 4.39 (d, J=12 Hz, 1H), 4.34 (d, J=7 Hz, 1H), 3.81 (s, 3H), 3.55 (dd, J = S . 5 HZ, 11.5 Hz, 1H) , 3.45 (brs, 1H) , 2.95 - 133 - - 133 - LV 10719 (dd, J=4 Hz, 11 Hz, IK), 2.35-0.90 (a, 23H), 1.13 (s, 3H) , 1.12 (d, J = 5 KZ, 3K) , 0.97 (s, 3H) , 0.39 (s, 3K), 0.33 (d, J=6 Hz, 6H), 0.33 (s, 3H). I. Preoaration of 16-Methoxv-3b-fi4- methoxvbenzvl) oxvl-15-oxa-lanost-3-ene ('Compound 10b)

To a solution of the diol (Compound 9b) (23.2 mmole) in diethyl ether (550 ml), methanoi (550 ml) and vater (140 ml) were added sodium metaperiodate (Aldrich) (33 g, 154 mmole) and camphorsulfonic acid (7 g, 3 0 nunole) and the mixture vas stirred at room temperatūra for 20 hrs. After addition of saturated sodium bicarbonate (350 ml) the mixture vas extracted vith diethyl ether (3 x 500 ml) and the combined organic layers vere vashed vith brine. The aqueous lavers vere re-extracted vith diethyl ether (300 ml) and the extract vas vashed vith brine.

The combined extracts vere dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a dark brovn oily residue (13 g) of crude five-membered cyclic acetal (Compound 10b). Product of this purity vas routinely used for next transformation vithout further purificaticn.

The analytical sample of purified Compound 10b vas cbtained by a preparative thin layer chromatographv cn silica gel vith elution by 1:9 ethvl acetate - hexar.e. Phvsical Data (Compound 10b) : 134 NMR (3 00 ΜΗ Z, CDCI3): delta 7.2 9 (d, J=8.7 Kz, »- *1 / , 6.8 S ( d , u — 3 . 7 HZ, 2H) , 4 . 5 9 (d, J = 1 Ί t 6 Hz , IK) , 4.53 (d, J =5.7 Hz, 1H) , 4 . 33 (d, J = ll . 6 H — t IK) , 3.31 (s, 3H) , 3 .36 (s, 3H) , 2.93 (dd, J=4 . 2 Hz t 11.5 Hz, 1H) , 2.2 0- 0.80 (m, 22H) , 1.1 3 (s , 3H) , o- 93 (s, 3H) , 0 . S 5 (d, J =5.4 Hz, 3H) , 0.95 (s, 3H) , 0.8 o (S, 3H) , 0.37 (d, ’Ύ =6.3 Hz, 6H) , 0.83 (s, 3H) ; IR (f ilm) : 2945 2369 , 15 14 , 1459, 1375, 1347 , 1171, 1108, 1094, 1033 , 1011 cm” 1 . / HRMS fo r C37 H56C3 : Ca Icd. 548 . 42 30; fcund 543.4203. J. Preparation of 15-Oxa-dihvdrolanosterol (Compound 11a)

To a solution of Compound 10b (23.2 mmole) and triethylsilane (Aldrich) (16 ml, 0.1 mmole) in dry methylene chloride (420 ml) was added boron triflucride etherate (Aldrich) (2.7 ml, 22 mmole) dropvise and the mixture was stirred at room temperature for 3 hr. under nitrogen atmosphere. The reaction vas quenched by addition of saturated sodiun bicarbonate and the products vere extracted vith methylene chloride ( 3 x 4c0 ml) . The combined extracts vere vashed vith vater, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a dark brovn oily residue. The oil vas purified by column chromatography on silica gel vith elution by 1:9 ethyl acetate -hexane folloved by 2:3 ethvl acetate - hexane to provide 15-oxa-dihydrolanosterol (Compound 11a) (4.0 g, 40% overall yield from Compound 7b.

Fhvsical Data (Compound 11a): - 185 - - 185 - LV 10719 NMR (300 MHz, CDCI3): delta 3.76 (t, J=9 Hz, IK), 3.44 (dd, J = 3.4 H2, 9 Hz, 1H) , 3.25 (dd, J=4.3 Hz, 11.4 KZ, IK), 2.25-0.80 (m, 23K), 1.11 (S, 3H), 1.C2 (s, 3H) , 0.95 (d, J=6.3 Hz, 3K) , 0.95 (s, 3K) , 0.86 (d, J=6.6 Hz, 6H) , 0.36 (s, 3H) , 0.81 (s, 3H) ; IR (filr.): 3566, 2934, 1466, 1375, 1097, 1079, 1039, 1030 cm"1; HRMS for C29K5Q02 (M+): Calcd. 430.3811; found 430.3772; for C2SH4702 (M-CK3): Calcd. 415.3576; found 415.3533. EXAM?LE 2

Preparation of 4.4-Dimethyl-15-oxa-5a-cholest-8-er.-3b-ol (Compound 17a) K. Preparation of 15.15-Diroethoxv-4.4-dimethvl-3b-r 4-methoxvbenzvl)oxvl-5a-14,15-Secoholest-8-en-14-oI (Compound 12b)

To a-stirred solution of the keto-aldehyde (Compound 5b) (2.7 g, 4.42 mroole) in a dry methylene chloride (60 ml) was added a solution of diisobutyl aluminuro hydride in hexane (Aldrich) 1 K/L, 8.84 ml, 8.84 mmole) dropvise at 0° and the mixture was stirred at 0° for 1 hr. at roora temperature for 1 hr. The excess reaģent vas destroyed by dropvise addition of methanol (0.64 ml) at 0° and stirring for 10 min. Then vater (1.1 ml) vas added dropvise to the mixture and it vas stirred at room temperature for 1 hr. The resulting precipitates vere filtered off 136 over Cslits and the filtrate vas evaporated under reduced pressure to give a vhite foamy residue cf the secondary allylic alcohol (Compound 12b) as a raixture of diastereomers. The crude material vas used in the next reactior. vithout purification. L. Precaration of 4 , 4-Dinethvl-3b-r f 4- methoxybanzvl)οχνί-14a-oxa-D-homo-5a-choiest-3-en-15-ol fConpound 13b^

Follcving the method described for Compound 7b (Example 1-F) the secondary allylic alcohol (Compound 12b) (4.42 mmole) vas transformed to the six-membered cyclic hemiacetal (Compound 13b) (0.81 g) and the corresponding cyclic acetal (Compound 13c) (1.34 g) as oils. The Compound 13c vas resubjected to the reaction to afford an additional 0.69 g of Compound 13b (total 1.5, 60% overall yield from Compound 12b) after purification by column chromatography on silica gel vith elution by 15:35 ethyl acetate - hexane.

Physical Data (Compound 13b): nhr (: 300 MHZ , CDC13 ) delta 7 . 28 ( d, J=3.5 Hz, 2H) , 6.86 (d, J=8 .5 HZ, 2H) , 4 . 69 (t, J« 6 HZ, 1H), 4.59 (d, J=12 Hz, 1H) , 4.37 (d, J = 12 Hz , 1H ) , 3.30 (s, 3H), 2.9: i (dd, J = 4 HZ, 12 HZ , IK) , 2 . 20 -0.9 0 (m, 26H), 0.99 (S, 6H), ( 3.97 (s, 3H) , 0.93 (d, J= 6.5 HZ , 3H) , 0.88 (d, J=6. . 5 HZ, 6H) / o. 86 (s, 3H) ; IR (film) : 3413 , 2952 , 2 9 3 C 5, 2 87( 3, 1 654 , 163 6, 1465 , 1457 , 13 76 , 1365 , 1087, 106; 5, 103 < 5, 1 013 cm”1. - 137 - - 137 -LV 10719 Μ. Preparation of 4,4-DimethvI-3b-rf4- methoxvlbenzvl·)oxvi -14a-oxa-D-homo-5a-cholest-8.15-diene fCompound 14b)

Folloving the method described for Compound 8b (Example 1-G) the cyclic hemiacetal (Compound 13b) (0.15 g, 0.26 mmole) was transformed to the glycal (Compound 14b) in 87% yield. The crude product from the reaction was routinely used for next conversion vithout purificatlon.

The analytical sample vas obtained by filtering a concentrated solution of the crude Compound 14b in diethyl ether through a Florisil (Fischer Scientific) column with elution by diethyl ether. N. Preparation of 4,4-Dimethvl-3b-ff4- methoxvben2vl)οχνl -14a-oxa-D-homo-5a-cholest-8-ene-15,16-diol ^Compound 15b)

Folloving the method described for Compound 9b (Example 1-H) the glycal (Compound 14b) (0.126 g, 0.23 mmole) vas transformed to the diol (Compound 15b). The crude product vas used for next reaction vithout purification. 188 Ο . Freoaration of 4 , 4-Dir?.ethvl-16-methoxv-3b-Γ (4-raethoxvbenzvl) oxvl -15-oxa-5a-cholest:-3-ene (Compound 16b)

Folloving the method described for Compound 10b (Example 1-1) the diol (Compound 15b) (0.23 mmole) was transformed to the five-membered cyclic acetal (Compound 16b). The crude product (0.139 mg) was used for the next reaction vithout purification. P. Preparation of 4.4-Dimethyl-15-oxa-5a-cholest-8-en-3b-ol (Compound 17a)

Folloving the method described for Compound 11a (Example 1-J) the cyclic acetal (Compound 16b) (0.23 mmole) was converted to the 15-oxa steroid (Compound 17a) (0.04 g, 35.7% overall yield from Compound 13b). ?hysical Data (Compound 17a): HMR (300 MHz, CDC13); delta 3.96 (t, J-8.1 Hz, 1H), 3.72 (s, 1H), 3.65 (br s, 1H), 3.51 (dd, J=9.9 Hz), 8.1 Hz, 1H), 3.25 (dd, J=4.5 Hz, 11.1 Hz, 1H), 2.27 (m, 1H), 2.02-0.70 (m, 21H), 1.01 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 HZ, 6H), 0.81 (s, 3H); IR (film): 3448, 2951, 2932, 2869, 1465, 1458, 1376, 1365, 1091, 1032 cm"1. LV 10719 - 189 -EXAMPLE 3

PreDaraticr. of 4 . 4-Dimethvl-15-oxa-14a-vinvl-5a-cholest-3-en-3b-ol (Compound 23a) Q. Preparation of 15.15-Dimethoxy-4-4-dimethyļ-3b-Γ f 4-methoxvbenzyl)oxvi-14-vinvl-5a-14.15-secjchoIest-8-en-14-ol (Compound lSb^

To a stirred solution of the keto-acetal (Compound 5b) (S. 2 g, 13.4 rnole) in dry tetrahydrcfuran (2 70 r.i) was added dropvise a solution of vinyl magnesium bremide in TKF (1.6 M/L, Aldrich) (82 ml, 131.2 rnr.oie) at 0° and the mixture vas stirred at 70° for 2 hr. under nitrogen atmcsphere. After cooling to 0° about 300 ml of 0.5 M - hydrochloric acid vas added to the solution and it vas stirred for 0.5 min. The predvet vas extracted vith diethyl ether (3 x 300 ml) and the combined extracts vere vashed vith vater and brine.

The ethereal solution vas dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the tricyclic alcohol (Compound 18b) as an oil. The crude product vas routinely used fer the next reaction vithout purification.

Physical Data (Compound 18b) : IR (filo): 3450, 2952, 2870, 1514, 1466, 1247, 1121, 1099, 1078, 1053, 1043 cm-1. R. Preparation of 4,4-Dinethyl-3b-r(4-methoxvbenzvl) οχνί -14a-oxa-14a-vinvl-D-r.orne-5a-cholest-8-en-15-ol (Compound 19b^ A solution of the tricyclic alcohol (Compound 18b) (13.4 mmole) in methylene chlcride (80 ml) and 80¾ 190 aquecus acetic acid (300 ml) ccntaining 1 M hydrcchlcric acid (0.5 ml) was stirred at room temperature for 20 hrs. The acid and vater were evaporated off under reduced pressure to give an oily residue of the cyclic hemiacetal (Compound 19b) and the cyclic acetal (Compound 15c).

The tvo products vere separated by column chromatography on silica gel with elution by 1:9 ethyl acetate - hexane followed by 2:8 ethyl acetate - hexane to afford 3.2 g of the compound 19c (Rf = 0.32, 2:8 ethyl acetate-hexane) as oils.

The Compound 19c was dissolved in methylene chloride (40 ml) and 80% aqueous acetic acid (150 ml) and the solution was stirred at room temperature for 7 days. It was wor)ced up and purified as described above to prcvide additional 2.31 g of Compound 19b (Total 5.81 g, 73% overall yield frcm Compound 18b).

Physical Data: NMR (300 MHz, CDCI3): delta 7.28 (d, J=8.5 Hz, 2K), 6.87 (d, J*8.5 HZ, 2H), 5.74 (dd, J-10.8 Hz, 174. Hz, 1H) , 5.05 (dd, J=1.8 Hz., 10.8 Hz, 17.4 Hz, 1H) , 4.65 (d, J=2.1 Hz, 1H), 4.61 (d, J-11.4 HZ, 1H), 4.38 (d, J-11.4 HZ, 1H), 3.80 (s, 3H), 2.95 (dd, J=4.5 Hz,10.5 Hz, 1H), 1.95-1.00 (m, 26H), 1.03 (s, 3H), 0.99 (s, 3H) , 0.94 (d, J=6.9 HZ, 3H) , 0.86 (d, J=6.6 Hz, 6H), 0.84 (s, 3H), 0.82 (s, 3H); HRHS for C39H53°3 (M-H20): Calcd. 574.4386; found 574.4316. - 191 - LV 10719 S . Precaration of 4.4-Dir,ethvl-3b-r(4- methoxyber, zvl) oxv i -l4a-oxa-14a-vir,vl-D-homo-5a-cholesta-3,15-diene (Compound 20b^

By the method described for Compound 8b (Exampie 1-G) the cyclic hemiacetal (Compound 19b) (2.65 g, 4.46 mmoie) was transformed to the glycal (Compound 20b) (2.412 g, 94% yield) as a foamy solid. The crude product was normally used for next reaction vithout purificaticn. Analvtical sample was obtained by filtering a concentrated sclution of the crude product in diethyl ether through a short Florisil column vith elution by diethvl ether. T. Preparation of 4,4-Dimethvl-3b-Γ(4-methoxvber.2vl) oxvi -14a-oxa~14a~vinvl-D-homo-5a-cholest-3-ene-15,16-diol (Compound 21b) 3y the methcd described for Compound 9b (Example 1-H) the glycal (Compound 20b) (2.412 g, 4.19 mmoie)

IO was converted to the diol (Compound 21b) (2.31 g, 90. yield) as an oil. The crude product was routinely used for next reaction vithout purification. U. Preparation of 4.4-Dimethvl-16-methoxv-3b~ f(4-methoxvben2vl)oxvl-15-oxa-14a~vinvl-5a-cholest-8-ene (Compound 22b)

Bv the method described for Compound 10b (Example 1-1) the diol (Compound 21b) (2.31 g, 3.79 mmoie) vas transformed to five-membered cyclic acetal (Compound 22b) (2.125 g, 94.6% yield) as a foamy solid. The crude product vas used for the next reaction vithout 192 purification. V. Preparation of 4.4-Dimethvl-15-oxa-14a-vinvi-5a-cholest-8-en-3b-ol (Compound 23a)

To a stirred solution of the five-metrJbered cyclic acetal (Compound 22b) (1.17 g, 2.64 mmole) and triethvlsilane (1.6 ml, 10 mmole) in dry methylene chloride (50 ml) at -30° was added boron trifluoride etherate (0.2 ml, 1.63 mmole) dropvise and the mixture was stirred at -30° to 20° for 2 hr. The reaction was guenched by addition of saturated sodium bicarbonate (20 ml) and the products were extracted with diethyl ether (2 X 100 ml). The ether extracts were vashed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give an oily residue. It was purified by column chromatography on silica gel vith elution by 15:35 ethyl acetate-hexane to give the 15-cxa-sterol (Compound 23a) (0.71 g, 81% yield) as a foamy solid.

Phvsical Data: NMR (300 MHz, CDC13): delta 5.73 (dd, J=10.8 Hz, 17.4 Hz, 1H) , 5.12 (dd, J=1.8 Hz, 10.8 Hz, 1H) , 5.00 (dd, J=1.8 Hz, 17.4 Hz, 1H), 3.88 (t, J=3.7 Hz, 1H), 3.55 (t, J=9 HZ, 1H), 3.26 (dd, J=4.8 Hz, 11.7 Hz, 1H) , 2.07-0.80 (m, 23H), 1.01 (s, 6H) , 0.95 (d, J=6 Hz, 3H) , 0.S6 (d, J=6.3 Hz, 6H), 0.81 (s, 3H), 0.73 (s, 3H); IR (film): 2933, 2868, 1512, 1467, 1375, 1095, 1040, 1029, 1033 cm-1; HRMS for C30H50O2 (H+): Calcd. 442.3811; found 442.3806. LV 10719 - 193 -EXA*MPLE 4

Preparation of 3b-Acet:oxv-4.4-di^«»thvl-15-oxa-14a-vinvl-5a-cholest-a-pnA iCompound 23c) A solution of the 15-oxa-sterol (Conpound 23a) (2g, 4.52 mmole) acetic anhydride (Fischer Scientific) (2 ml, 21.2 mnole) and dimethylaminopyridine (Aldrich) (0.1 g, 0.82 mmole) in anhydrous pyridine (Aldrich) (20 ml) was stirred at room temperature for 13 hr. under nitrogen atmosphere. After addition of methanol (5 ml) the mixture vas evaporated under reduced pressure, and the residue vas partitioned betveen water and diethvl ether. The organic layer vas vashed vith brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give an oily residue. It vas column chromatographed cn silica gel vith elution bv 5:95 ethyl acetate - hexane folloved bv 1:5 ethyl acetate - hexane to afford the 14-vinyl-15-oxa-sterol acetate (Compound 23c) (1.73 g, 81% yield).

Phvsical Data: NMR (300 MH2, CDCI3): delta 5.72 (dd, J-10.8 Kz, 15.9 Hz, 1H), 5.12 (dd, J=1.S Kz, 1H), 5.00 (dd, J=1.8 Kz, 15.9 Hz, 1H) 4.52 (dd, J«4.8 Hz, IK), 3.87 (t, J=8.7 Kz, IK), 3.55 (t, J=S.7 Hz, 1H), 2.06 (s, 3K), 2.06-0.80 (m, 22H) , 1.03 (s, 3H) , 0.94 (d, J=6.3 Kz, 3K) , 0.89 (s, 3H), 0.83 (s, 3K) , 0.87 (d, J=6 Hz, 6H) , 0.78 (S, 3K). 19 4 EXA.M?L£ 5

Preoaration of both Diasteroemers of 3b-Acetoxv-32-hvdroxvmethvl-15-oxa-lanosr-8-en-32-ol (Cojspounds 24c and 25c)

To a solution of the 14-vinyl-15-oxa-sterol acetate (Compound 23c) (1.78 g, 3.67 mmole) vas added osmium tetroxide (1 g, 3.94 mmole) and the resulting dark brovn solution vas stirred at roora temperature for 2 days. At the end of the stirring hydrogen sulfide gas vas bubbled through the solution and the black precipitates vere removed by filtration over Celite. After vashing the filter cake vith ethyl acetate several times the filtrate and the vashings vere evaporated to give a black oily residue. It vas purified by column chromatography on silica gel vith elution by 3:7 ethyl acetate - hexane to afford 0.25 g of unreacted starting Compound 23c, 0.54 g of Compound 24c (Rf = 0.20, 3:7 ethyl acetate - hexane) and 0.19 g of Compound 25c (Rf =0.16, 3:7 ethyl acetate - hexane) in 44.6% combined corrected yield.

Physical Data (Compound 24c): IR (Film): 3451, 2951, 2870, 1733, 1650, 1642, 1632, 1467, 1366, 1246, 1100, 1028 cm"1; HR.MS for C30H49°3 (M-CK0HCH20H): Calcd. 457.3681 ;; found 457.3640.

Physical Data (Compound 25c): HRMS for C30H49O3 (M-CH0KCH20H): Calcd. 457.3631; found 457.3659. LV 10719 - 195 -EXAM?L£ 6

Pracaration of 3b-Acetoxv-15-oxa-32-oxo-lanost-8-ene (Compound 26c)

To a solution of the diol (Compound 24c) ( 492 mg, 0.95 mmole) in ethanol (34 ml) at 0° vas added a solution of sodium periodate (664 mg, 2.85 mmole) ir. 8.5 ml of vater dropvise and the mixture vas stirred at C° fcr 30 min. It vas extracted with diethyl ether (150 ml) and the organic layer vas vashed vith brir.e. After drying over anhydrous magnesium sulfate the solvents vere evaporated under reduced pressure to cive an oily residue of the aldehyde (Compound 26c) (460 mg, ca. 100% yield). ?hysical Data: NKR (300MHz, C DC13) : delta 9. , 56 (s, 1H) A t -* · 4 7 (dd, J= 4.5 Hz , 11. 4 HZ, 1H), 3.98 (t, J=8.4 Hz , IK) 3.66 (t , J=8 . 7 HZ, 1H) , 2.15-0.90 (m, 2 2H) , 2.02 (s 3H) , 1. 02 (s, 3H) , 1.02 (s, 3H), C 3.91 (d, J= = 6.3 Hz, 3H) , 0. 33 (S, 3H) , 0.84 (brs, 9H), . 0 . 82 (s, 3H) ? IR (f ilm ') : 2949 , 2871 , 279 3, 2689, 1733, 1471, 1466 , i 1374 , 1 366, 1246, 1027 cm"1. EXAMPL£ 7

Preoaration of I5-Oxa 32-oxo-dihvdrolanosterol (Compound 26a)

To a solution of the aldehyde-acetate (Compound 26c) (30 mg, 0.062 mmole) ethanol (0.7 ml) vas added 3>! potassium hydroxide (41 1, 0.124 mmole) and the mixture vas stirred at room temperatūra for 20 hr. After 196 addition of diethyl ether (15 ml) the organic solution vas vashed with vater and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure afforded a foany solid residue of chromatographically purified free hydrcxy compound (Compound 26a) (27.5 mg, 100% yield).

Physical Data: N7ĪR (300 MHz, CDC13): delta 9.59 (s, 1H) , 4.03 (t, J=8.4 HZ, 1H) , 3.70 (dd, J-8.1 Hz, 9.6 Hz , IK), 3.26 (dd, J = 4.5 Kz, 11.4 Hz, 1H) , 2.20-0.90 (m, 24H), 1.04 (s, 3H), 1.01 (s, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.92 (s, 3H), 0.36 (d, J=6.3 Hz, 6H), 0.81 (s, 3H); IR (film): 3446, 2946, 2933, 2870, 2691, 1731, 1463, 1383, 1378, 1365, 1064, 1042, 1027 cm-1; HRMS for C28H47°2 (M-CHO): Calcd. 415.3576; found 415.3600. EXAMPLE 8

Preparation of 15-Oxa-lanost-8-ene-3b,32-diol (Compound 27)

To a stirred solution of the aldehyde (Compound 26a) (15 mg, 0.034 mmole) in ethanol (1 ml) at 0° was added sodium borohydride (Fischer Scientifi-c) (10 mg, 0.26 mmole) and the mixture vas stirred at the same temperature for 1 hr. The excess sodium borohydride vas destroyed by adding several drops of saturated ammonium chloride solution and the product vas extracted vith diethyl ether. The organic layer vas - 197 - - 197 - LV 10719 washed with brine, dried over anhydrous magnesium sulfate and evaporated to give the diol (Compour.d 27) (ca. 100% yield) as a vhite crvstalline solid. Physical Data: HRMS for C23h4702 (M-CK2OH): Calcd. 415.3576; found 415.3562. ΞΧΑΜΡΙ.Ε 9

Preoaration of both Diastereomers of 15-Oxa-32-vinvl-lanost-8-ene-3b.32-diol (Comoounds 23 and 29)

To a stirred solutior. of the aldehyde (Compour.d 25c) (23 mg, 0.052 mmole) in dry tetrahvdrofurar. (1 ml) was added 1 M vinyl magnesium bromide in tetrahydrofuran (0.52 ml, 0.52 mmole) dropvise and the mixture was stirred at 70° for 0.5 hr. under nitrogen atmosphere. After cooling to 0° about 2 ml of 0.5 M hvdrcchloric acid was added slovly and the mixture was extracted with diethyl ether. The ether layer was vashed vith saturated sodium bicarbonate, vater and brine, dried over anhvdrous magnesium sulfate and evaporated under reduced pressure to give an oilv residue of Compcu.nds 26 and 29 (1.4:1 ratio, determined by GC, ca. 100% yield). 193 EXAMPLE 10

Presaration of 3b-Kvdroxv-15-oxa-lancst-3-en-3 2-aldoxime (Compound 30) A solution of the aldehyde (Compound 26a) (17 ag, 0.033 mmole) and hydroxylamine hydrochloride (Aldrich) (20 rr.g, 0.29 mmole) in pyridine (0.5 ml) vas stirred at 30° fcr 7 hr. After addition of diethyl ether the solution vas vashed vith vater and brine, dried over anhydrous magnesium sulfate and evaporated to give an oily residue. The crude product vas purified by preparative thin layer chromatography to obtain purified oxime (Compound 30) as a foamy solid (ca. 100% yield).

Physical Data:

NttR (300 MHz, CDC13): delta 3.93 (t, J=8.1 Hz, 1H), 3.62 (t, J-8.1 HZ, 1H) , 3.26 (dd, J=4.3 Hz, 11.4 HZ, 1H), 2.10-0.70 (m, 25H), 1.01 (s, 2\3H), 0.98 (S, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.89 (s, 3H), 0.86 (d, J=6.6 HZ, 6H), 0.81 (s, 3H); IR (film): 3336, 2932, 2870, 1467, 1458, 1383, 1377, 1266, 1040, 1028, 924, 737 cm"1. EXAMPLE 11

Preoaration of 14a-Oxa-D-homo-dihvdrolanosterol (Compound 31) W. Preparation of 4,4-Dinethvl-5a-cholest-8-e.ne-3b-, 14a ,15a-trio! (Compound 3a)

By the method described for Compound 3b (Example ' 1 — B) the 8,14-diene (Compound 2a) (4.64 g, 11.2' mm.ola) - 199 - - 199 - LV 10719 was transformed to triol (Compound 3a). The crude prcduct was filtered through a plug of silica gel vith elution by 4:6 ethyl acetate-hexane follcved by 7:3 ethvl acetate-hexane and crystallized from diethyl ether and hexane to afford purified Compound 3a as white short needles (4.18 g, 83.3% yield), m.p. = 133-134° (dec.)

Physical Data: NMR NMR (300 MHz, CDCl3-D20 (5%)): delta 4.11 (dd, J=5 Kz, 9 Hz, 1 Hz), 3.22 (dd, J=5 Hz, 11 Hz, 1H), 2.33 (ir, IK), 2.26 (bra, 1H) , 2.09 (brm, 2K) , 2.00-1.05 (m, 20K) , 1.01 (d, J = 3 Kz, 6H) , 0.87 (s, 3K) , 0.86 (d, J=8 HZ, 3K), 0.85 (s, 3H), 0.82 (s, 3H), 0.69 (s, 3H) ; IR (filn): 3422 (bs, OH), 2950 (s), 1652 (s), 1465 (m), 1036 (m) cm"1; EA for C29H5Q03: Calcd. C 77.97%, H 11.28%; found C 78.05%, H 11.19%. X. Preparation of 4.4-Dimethvl-3b-hvdrcxv-15-oxo-5a-14,15-Secocholest-8-en-14-on fCompound 4a)

By the roethod described for Compound 4b (Example 1-C) the triol (Compound 3a) (1 g, 2.24 mmole) was transformed to keto-aldehyde (Compound 4a) (0.97 g, 97.4% yield) the crude material was normally used for next reaction vithout purification.

Physical Data: NMR (3 00 MHz, CDC13 ) : delta 3 . 93 ( t, J =3.1 K ^ / IK), , 3.63 (t, J=8 .1 Hz, IK) , 3 . 26 (dd, J= 4 .8 Hz, 11 HZ, 1H), 2 . 10 -0.7 0 (m, 25H) , 1. 01 (s, 3H) f o vo 00 (S, 3K) , , 0.95 (d, J=6 .3 Hz, 3H) , 0. 89 (s, 3K) t 0.88 (d, II cr> .6 HZ, 6H) , 0. 81 (s, 3H) ; IR (f :ilm) : 3 3 36, 29 32, 2 8 7 ( 3, 1467 , i 45S, 1383 , 1377 , 1266 i, 1040, 1028, 924 7 3 7 cm 200 Υ. Preparation of 15,15-Diraethoxv-4,4-dimethvl-3b-hvdroxv-15-oxo-5a-14 , 15-secocholest-8-en--14-one fComoound 5a) 3y the method described for Compound 5b (Example ld) the keto-aldehyde (Compound 4a) (0.97 g, 2.18 mmole) vas transformed to keto-acetal (Compound 5a) (1.03 g, ca. 100% yield) as a foamy solid. The crude product vas normally used for the next reaction vlthcut purification. An analytical sample of Compound 5a vas obtained by column chromatography on silica gel by elution vith 3:7 ethyl acetate - hexane.

Physical Data: HMR (300 MHz, CDC13): delta 4.06 (t, J=5.8 H z, 1H) , 3.26 (S, 3H) , 3.26-3.27 (m, 1H) , 3.22 (s, 3H) , 2.62 (dd, J=6 Hz, 17 Hz , 1H), 2.35-0.90 (m, 25H), 1.07 (s, 3H) , 1.02 (S, 3H) , 0.98 (d, J=7.2 Hz, 3H) , 0.95 (s, 3H) , 0.86 (d, J=6.6 HZ, 6H), 0.84 (s, 3H) ; IR (fils): 3490, 2952, 2870, 1659, 1622, 1642, 1434, 1373, 1123, 1076, 1061 cm"1; HRMS for C29H4602 (M-2CH3OH): Calcd. 426.2498; found 426.3415. 2. Preparation of 15.15-Dimethoxv-14,15-

Secolanost-3-ene-3b . 14-diol (Corooound 6aλ,

By the method described for Compound 6b (Example 1-E) the keto-acetal (Compound 5a) (200 mg, 0.41 mmole) vas transformed to tricyclic alcohol (Compound 6a) (210 mg, ca. 100% yield) as an oil. The crude material vas routinely used for next reaction vithout purification. Phvsical Data: KHR (300 HHz, CDCl3): delta 4.05 (t, J=6 Hz, 1H), 3.27-3.20 (m, 1H), 3.25 (s, 3H), 3.22 (s, 3K), 2.61 (dd, J=5.1 Hz, 17.7 Hz, 1H), 2.50-0.80 (m, 25H), . - 201 - - 201 - LV 10719 1.07 (s, 3H), 1.02 (s, 3K), 1.02 (s, 3K), 0.98 (d, J = 6.9 Hz, 2H) , 0.95 (s, 3H), 0.86 (d, J=6.6 Hz, 6H) , 0.35 (S, 3K) , 0.34 (s, 3 H}. AA. Preparation of 14a-Oxa-D-homo-lanost-S-ene-3b,15-diol fCor.pound 7a) A solution of the tricyclic alcohol (Compound 6a) (0.41 mmole) in methylene chloride (2 ml) and 80% aqueous acetic acid (10 ml) vas stirred at room tem.perature for 1.5 hr. and the solvents vere evaporated off under reduced pressure to give an oily residue. The residue vas dissolved in diethyl ether (20 ml) and vashed vith saturated sodium bicarbonate and brine.

After drying over anhydrous sodium sulfate the ether solution vas evaporated under reduced pressure to give an oily residue that vas column chromatographed cr. silica gel. Elution vith 25:75 ethyl acetate-hexane afforded 117 mg of cyclic hemiacetal (Compound 7a) (28% overall yield from Compound 6a) as an oil. AB. Preparation of 14a-0xa-D-homo dihvdrolanosterol iCompound 31)

To a stirred solution of the cyclic hemiacetal (Compound 7a) (34 mg. 0.073 mmole) in dry' methylene chloride (1.5 ml) at -30° vere added triethylsilane (35 L, 0.22 mmole) and 2 drops of boron trifluoride etherate and the mixture vas stirred at -30° to 8° for 45 min. under nitrogen atmosphere. After addition of saturated sodium bicarbonate (3 ml) the reaction mixture vas extracted vith diethyl ether (2 x 15 ml). The combined extracts vere vashed vith brine, dried 202 over anhydrous sodium sulfate and evaporated under reauced pressure to give an oily residue of Compound 312 (30 mg, 92.4%) yie!d). It vas purified by MPLC on silica gel vith elution by 1L (ethyl acetate - hexane to give a purified sample as a vhite foamy solid. Physical Data: NKR (300 MHz, CDC13): delta 3.67 (dd, J = 2.7 H2; 1H) , 3.31-3.25 (m, 2H) , 2.37 (dd, J = 5.5 Hz, 13 Hz, 1H) , 2.20-0.909 (m, 24H), 1.12 (s, 3H), 1.04 (s, 3H) , 0.93 (s, 3H), 0.94 (d, J=7.2 Hz, 3H) , 0.92 (s, 3H), 0.33 (d, J=6.6 Hz, 6H), 0.83 (s, 3H); HRMS for C30H52O2 (M+), Calcd. 444.3967, found 444.3942; for C29K49°2 (m_CH3)» Calcd. 429.3733, found 429.3717 . EXAMPLZ 12

Preoaration of 4.4-dimethvI-14a-Oxa-D-homo-5a-cholest-8-en-3b-ol fCompound 32) AC. Preparation of 15.15-Dimethvl-4,4-dimethvl -5a-14.15-Secocholest-8-ene-3b.14-diol (Compound 12)

By the method described for Compound 12b (Example 2-K) the keto-acetal (Compound 5a) (121 mg, 0.25 mmole) was transformed to tricyclic secondary alcohol (Compound 12a) as an oil. The crude product was used for next reaction vithout purification.

Physical Data: NKR (300MHz, CDCl3) : delta 5.30 (s, 1H), 4.41 (dd, J=3 Hz, 9 Hz, 1H) , 3.91 (d, J=4.2 Hz, 1H) , 3.45 - 203 - - 203 - LV 10719 (S, 3H) , 3.36 (s, 3H) , 3.36 (s, 3H) , 3.21 (m, 1H) , 2.15-0.95 (m, 25H), 0.99 (s, 6H) , 0.92 (d, J = 6.6 Hz, 3K) , 0.87 (d, J=6.6 HZ, 6H) , 0.81 (s, 3H) , 0.61 (s, 3H) ; HRMS for C30H52O3 (M-CH3OH) : Calcd. 460.3916; found 460.3891. AD. Preparation of 4,4-Dimethvl-14a-oxa-D-horoo-5a-cholest-8-ene-3b. 15-diol (Comoound 13a)

By the method described for Coinpound 7a (Example 11-AA) vith exception of reaction time (4 hr.) the secondary alcohol (Compound 12a) (0.25 mmole) was transformed to the six-menbered cyclic hemiacetal (Compound 13a) (70 mg, 62.7% overall yield from Compound 5a) as an oil.

Physical Data: m.R (300MHz, CDCl3): delta 5.30 (s, 1H), 4.72 (dd, J*3.3 Hz, 8.7 Hz, IK), 3.79 (brs, 1H), 3.25 (dd, J=4.5 HZ, 11.1 HZ, 1H), 2.20-.080 (m, 25H), 1.01 (s, 3K) , 0.98 (S, 3H), 0.96 (S, 3H) , 0.93 (d, J-6.9 Hz, 3K) , 0.86 (d, J=6.6 HZ, 6H) , 0.81 (s, 3H) ; AE. Preparation of 4.4-Dimethvl-14a-Oxa-D-homo-5a-cholest-8-en-3b-ol (Compound 32)

To a stirred solution of the cyclic hemiacetal (Compound 13a) (31.8 mg, 0.071 mmole) and triethylsilane (34 1, 0.21 mmole) in dry acetonitrile (1.5 ml) and dry methylene chloride (0.5 ml) at -15° vas added a drop of boron trifluoride etherate and the mixture vas stirred at -15° to -10° for 15 min.

After addition of saturated sodium bicarbonate it vas extracted vith diethyl ether. The ether extract vas vashed vith brine, dried over anhydrous sodium sulfate 204 and evaporated to give an oily residue of Compound 32 It was purified by preparative thin layer chromatography cn silica gel plate with eluticn by 3: ethyl acetate - hexane to afford 12 mg of purified sample (39.2% yield) as a vhite foamy solid. EXAMPLE 13

Preoaration of 4.4-Dimethvl-14a-oxa-14-a oxa-14a-vinvl-D-homo-5a-cholest-8-en-3b-ol (Compound 33^ AF. Preparation of 15.15-Dimethoxv-4.4-dimethvl-14-vinvl-5a-l4.15-secocholest-8-ene-3b.14-diol (Comoound 13a)

By the method described for Compound 18b the keto-acetal (Compound 5a) (230 mg, 0.47 mmole) was transformed to a tricyclic allylic alcohol (Compound 18a) as an oil. The crude material was normally used for next reaction vithout purification.

Physical Data: NMP (300 MH2, CDC13): delta 5.80 (dd, J=9.9 Hz, 17.7 HZ, 1H), 5.08 (d, J=9.9 Hz, 1H), 5.05 (d, J-17.1 Hz, 1H), 4.50 (dd, J=2.7 Hz, 9 Hz, 1H), 4.20 (S, 1H) , 3.42 (s, 3H), 3.28 (s, 3H), 3.24 (dd, J=4.8 Hz, 12 Hz 1H), 2.47 (dd, J-10.8 Hz, 14.4 Hz, 1H), 2.15-0.90 (m, 24H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (S, 3H), 0.93 (d, J=4.5 Hz, 3H), 0.87 (d, J=6.3 Hz, 6H), 0.82 (s, 3H); IR (film): 3455, 2954, 2871, 1466, 1375, 1122, 1067, 1045 cm-1. - 205 - - 205 - LV 10719 AG. Preparation of 4.4-Pimethvl-14a-oxa-14a-vinvl-d-honio-5ž-choiest-6-ene-3b . 15-d i ni (Compound 19a)

By the method described for Compound 7a (Exa.T.cie 11-AA) the allylic alcohol (Compound 18a) (0.47 nmole) vas transformed to six-membered cyclic hemiacetal (Compound 19a) (140 mg, 63% overall yield from Compound 5a) . AH. Preparation of 4,4-DimethvL-14a-oxa-14a-vinvl-D-homo-5a-cholest-8-en-3b-ol (Compound 33)

By the method described for Compound 31 (Exaapie 11-AB) the cyclic hemiacetal (Compound 19a) (73.8 mg. 0.16 mmole) vas transformed to compound 33 (70 mg, 95.8% yield). Purified sample of Compound 33 as a vhite foamy solid vas obtained by column chromatographv on silica gel vith elution by 1:9 ethyl acetate -hexane.

Physical Data: NMR (300MHz, CDCI3): delta 5.71 (dd, J*10.8 Kz, 17.4 HZ, 1H) , 5.07 (dd, J-1.5 Hz, 10.8 Hz, 1H) , 4.96 (dd, J=1.5 Hz, 17.4 Kz, 1H) , 3.74 (dd, J=3.3 Hz, 10.5

Hz, 1H) , 3.34 (t, J-ll.l Hz, 1H) , 3.28 (dd, J=3.9 Hz, 11.1 Hz, 1H), 2.10-0.80 (m, 25H), 1.04 (s, 3H), 1.03 (s, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H) , 0.83 (s, 3H), 0.82 (S, 3H) ; IR (film): 3438, 2947, 2933, 2868, 1635, 1466, 1399, 1377, 1265, 1056, 1040, 1027, 1003, 922, 736 cm"1; HRMS for C31K52°2 (M+): Calcd. 456.3968; found 456.3955. 206 EXAMPLE 14

Preparation of both Diastereomers of 32-hvdroxv-14a-oxa-lanost-3-ene-3b,3 2-diol fconpounds 34 and 35)

To a solution of the 14-vinyl-D-homo-oxasterol (Compound 33) (250 mg, 0.55 mmole) in anhydrous pyridine (10 ml) was added a 5% solution of csmium tetroxide in methylene chloride (3.4 ml, 0.66 mmole) and the mixture was stirred at room temperature fcr 7 days. At the end of that period, hydrogen sulfide gas vas bubbled through the solution for about 5 min. and the resulting black precipitates were removed by filtration over Celite.

The filter cake vas rinsed with ethyl acetate several times and the filtrate and vashings were evaporated to give a black oily residue. It vas column chromatographed on silica gel vith elution by 6:4 ethyl acetate - hexane to afford 150 mg of the unreacted starting material (compound 33) and 90 mg (foamy solid) of the triols 34 and 35 as a mixture (83.8% corrected yield). EXAMPLE 15

Preparation of 14a-Oxa-32-oxo-D-homo-dihvdro-lanosterol (Compound 36)

To a stirred solution of the diasteromeric mixture of triols (Compounds 34 and 35) (90 mg, 0.184 mmole) in ethanol (4 ml) vas added a solution of sodiun periodate (118 mg, 0.55 mmole) in vater (1 ml) dropvise over a - 207 - - 207 - LV 10719 period of 3 min. The mixture was stirred at room temperature of 0.5 hr. and diethyl ether (30 ml) was added to the mixture. The ether solution vas vashed with vater and brine, dried over anhydrous magnesium sulfate and evaporated to give an oily residue. It vas purified by MPLC on silica gel with elution by 2:8 ethyl acetate-hexane to provide purified aldehyde (Compound 36) as a white foamy solid (80-90% yield). Physical Data: NMR (300 MHz, C0C13): delta 9.51 (s, 1H), 3.91 (dd, J=4.5K, 11.1 Hz, IK), 3.35 (t, J-11.4 Hz, 1H), 3.27 (dd, J=4.5 Kz, 11.4 Hz, 1H), 2.04-0.80 (m, 25H), 1.05 (S, 3K), 1.02 (S, 3H), 0.94 (d, J=6.9 Hz, 3K), 0.92 (s, 3K), 0.86 (d, J=6.6 Kz, 6H), 0.81 (s, 3H); IR (film): 3431, 2951, 2868, 2725, 1734, 1466, 1459, 1378, 1365, 1098, 1043, 1027, 1004, 733 cm-1. EXAMPLE 16

Preparation of 14a-Methvl-15-oxa-5a-cholest -8-en-3b-ol (Compound 47) AI. Preparation of 3b-f(4-Methoxvbenzvl)oxvl5a-choIesta-3.14-diene (Compound 38b)

By the method described for the diene p-methoxybenzyl ether (Compound 2b) (Example 1-A) 5a-cholesta-8,14-dien-3b-ol (18.6 g, 48.4 mmole) vas transformed to p-methoxybenzyl ether (Compound 38b) as vhite crystals (17.4 g, 71.2% yield), m.p. = 109 -110°C.

Fhvsical Data: NMR (300 MHz, CDCI3): delta 7.28 (d, 8.7 Hz, 208 2Η), 6.82 (d, J=8.7 Hz, 2K), 5.36 (m, 1H), 4.52 (d, J=ll Hz, 1H) , 4.47 (d, J=ll Hz, 1H) , 3.80 (s, 3H), 3.35 (m, IK), 2.40-0.80 (m, 26H), 0.99 (s, 3H), 0.94 (d, J = 6.3 HZ, 3H) , 0.87 (d, J=6.5 Kz, 6H), 0.81 (s, 3H) ; IR (KBr): 3932, 2363, 2835, 1613, 1513, 1465, 1457, 1243, 1036, 1071, 1041 ca'1. AJ . Preparation of 3b-r(4-Methoxvbenzvl)οχνίτ-5a-cholest-8-ene-14a,15a-diol (Compound 39)

By the method described for the diol (Compound 3b) (Example 1-b) the diene (Compound 38b) (3.8 g, 7.5 mmcle) was transformed to the corresponding diol (Compound 39) . The crude vhite solid product vas normally used for next reaction vithout purification. Physical Data: NTCR (300 MHz, CgDg); delta 7.34 (d, J=8.2 Hz, 2H), 6.86 (d, J*8.2 Hz, 2H), 4.51 (d, J=12 Hz, 1H), 4.46 (d, J=12 Hz, 12H), 4.05 (dd, J=7.5 Hz, 17 Hz, 1H), 3.30 (S, 3H), 3.30 (m, 1H), 2.45-0.80 (m, 28H), 0.95 (d, J=6.5 HZ, 3H), 0.90 (d, J=6.6 Hz, 6H), 0.84 (s, 3H), 0.62 (s, 3H); IR (film): 3500, 2933, 2889, 1615, 1537, 1514, 1457, 1374, 1302, 1247, 1171, 1109, 1083, 1035 cm-1; HRMS (EI) for C35H5203 (M-H20),

Calcd. 520.3917; found 520.3895. AK. Preoaration of 3b-f M-Methoxvbenzvl)οχνT-15-oxo-5a-14.15-secocholest-8-en-14-one (Compound 40)

By the method described for the keto-aldehyde (Compound 4b) (Example 1-C) the diol (Compound 39) (7.5 mmole) vas transformed to the corresponding 209 - 209 - LV 10719 keto-aldehyde (Compound 40).

The crude ciiy product was used for next reaction vithout purification.

Physical Data: NMR (300 MHz, CDCl3): delta 9.56 (S, 1H), 7.27 (d, J=8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.52 (d, J=ll.7 Hz, 1H) , 4.47 (d, J=11.7 Hz( 1H) , 3.80 (s, 3K) , 3.41 (m, 1H), 2.57-0.90 (m, 26H), 1.02 (s, 3H), 0.97 (s, 3H) , 0.91 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.6 Hz, 6H); IR (film): 2950, 2934, 2869, 1725, 1655, 1615, 1513, 1442, 1375, 1301, 1248, 1103, 1077, 1037 ca'1; HRMS for C34H5003 (M-CH20): Calcd. 506.3760; found 506.3763. AL. Preoaration of 15.15-Dimethoxv-3b-Γ(4- methoxvbenzvl)οχνί5a-14.15-secocholest-S-en-14-one (Compound 41)

Bv the method described for the keto-acetal (Compound 5b) (Example 1-D) the keto-aldehyde (Compound 40) (7.5 mmole) was transformed to the corresponding keto-acetal (Compound 41). The crude oily product was used for next reaction vithout purification.

Physical Data: NMR (300 KKz, CDCl3): delta 7.26 (d, J-8.4 Hz, 2H), 6.87 (d, J=-8.4 Hz, 2K), 4.51 (d, J=11.4 Hz, 1H), 4.47 (d, J=ll.4 Hz, 1H) , 4.07 (t, J=6 F.Z, 1H) , 3.80 (s, 3H), 3.30 (m, 1H), 3.26 (s, 3H), 3.21 (s, 3H), 2.53 (brd, J=16.5 Hz, 1H), 2.40-1.00 (m, 25H), 1.02 (s, 3H), 0.98 (d, J=7.2 Hz, 3H), 0.96 (S, 3H), 0.86 (d, J=6.6 HZ, 6H); IR (filn): 2934, 2867, 1661, 1654, 1617, 1513, 1465, 1438, 1248, 1078, 1058, 1039 cm-1; HRMS (EI) fcr C36H5,04 (M-i—CH30H) , Calcd. 550.4022, found 550.4021. 210 Α.Μ. Preoaration of 15.15-Dimethoxv-3b-r(4-methoxvbenzy1) oxv1 -14-methvl-14.15-secocholest-8-en-14-ol (Compound 42)

By the method described for the tricyclic alcohol (Compound 6b) (Example 1-E) the keto-acetal (Compound 4 1) (7.5 mmole) was transformed to the corresponding tricyclic alcohol (Compound 42). The crude oily product was used for next reaction vithout purification.

Physical Data: NMR (300 MHZ, CDC13): delta 7.27 (d, J=8.7 Hz, 2H) , 6.87 (d, Js8.7 Hz , 2H) , 4.50 (brs, 1H) , 4.52 (d, J=14.1 Hz, 1H), 4.49 (t, J=3 Hz, 1H), 4.46 (d, J»14.1 Hz, IK), 3.80 (s, 3H), 3.49 (s, 6H), 3.35 (m, 1H), 2.30-0.90 (m, 26H), 1.19 (s, 3H), 0.92 (d, J=5.7 Hz, 3H) , 0.90 (s, 3H) , 0.86 (s, 3H) , 0.86 (d, J=6.6 Hz, 6H); IR (film): 3464, 2933, 2869, 1514, 1465, 1457, 1120, 1063, 1052, 1040 cm"1; KRMS (EI) for C36H54°3 (M+2CH30H), Calcd. 534.4073, found 534.4071. AN. Preparation of 3b-r(4-Methoxvbenzvl^oxvl-14a-methvl-14a-oxa-D-homo-5a-cholest-8-en-15-ol (Compound)

By the method described for the six-membered cyclic hemiacetal (Compound 7b) (Example 1-F) the tricyclic alcohol (Compound 42) (Example 1-F) the tricyclic alcohol (Compound 42) (7.5 mmole) was transformed to the corresponding cyclic hemiacetal (Compound 43a) and cvclic acetal (Compound 43b). The oily residue of the mixture was column chromatographed on silica gel vith elution by 15:85 ethyl acetate - hexane folloved by 3:7 - 211 - - 211 - LV 10719 ethvl acetate - hexane to afford 1.6 g of the cyclic hemiacetal (Compound 43a) and 1.19 g of the cyclic acetal (Compound 43b). The compound 43b vas subjected to the reaction condition and stirred at room tempera tūre for 4 days. It was vorked up and purified as described above to provide additional 0.47 g of the compound 43a (Total 2.07 g, 50% overall yield fron Compound 38b) and 0.6 g of the Compound 43b (14.1% overall yield frcm Compound 38b).

Physical Data: NMR (300 MHZ, CDC13): delta 7.27 (d, J=3.1 Kz, 2H) , 6.87 (d, J=8.1 Hz, 2K) , 4.53 (brs, 1H) , 4.49 (brs, 1H), 3.80 (s, 3K) , 3.34 (m, 1H) , 2.23 (brd, J-17.1 Hz, 1H) , 2.10-1.00 (m, 26H), 1.18 (s, 3H), 0.86 (d, J=6.3 Hz, 6H); HRMS for C36H5403 (M-H20): Calcd. 534.4073; found 534.4114. AO. Preparation of 3b-C(4-Methoxvbenzvl)oxv1- 14a-methvl-14a-oxa-D-homo-5a-cholesta-8.15-diene (Compound 44)

By the method described.for the glvcal (Compound 8b) (Example 1-G) the cyclic hemiacetal (43a) (2.07 g, 3.74 mmole) was transformed to the corresponding glycal (Compound 44). The crude oily product was used for the next reaction vithout purification.

Physical Data: IR (film): 2950, 2931, 2866, 1660, 1514, 1467, 1248, 1171, 1093, 1072, 1039 cm"1. 212 AP. Preoaration of 3b-r(4-Methoxvbenzvl)oxy1-i4a-rr,sthvI-14a-oxa-D-homo-5a-cholest-8-ene-15 ,15-diol fCcnpour.d 45)

By the nethcd described for the diol (Compound 9b) (Exarople 1-H) the glycal (Compound 44) (3.74 nmole) vas transformed to the corresponding diol (Compound 45) .

The crude black oily product vas used for next reaction vithout purification. AQ. Precaration cf 16-Methoxv-3b-Γ(4-methoxv- benzvl) οχνί -14a-methvl-15-oxa-5a-choles'C-3-ene (Comoour.d 4 6) 3y the methcd described for the 5-raembered cvclic acetal (Compound 10b) the diol (Compound 45) (3.734 mmole) vas transformed to the corresponding 5-menbered cyclic acetal (Compound 46). The crude oily product vas used for next reaction vithout purification. Analytical saaple of purified Compound 46 vas obtained by a preparative thin layer chromatography on silica gel vith eluticn by 1:9 ethyl acetate - hexane. Physical Data: NMR (300 KHz, CDC13): delta 7.27 (d, J=S.5 Hz, 2H) , 6.87 (d, J=8.5 Hz, 2H), 4.52 (d, J=5.4 Hz, 1H) , 4.51 (d, J=12 Hz, 1H), 4.51 (d, J=12 Hz, 1H), 4.46 (d, J=12 Hz, 1H) , 3.81 (s, 3H), 3.37 (m, 1H) , 3.35 (s, 3H) , 2.35 (S, 3H), 2.35-1.00 (m, 24H), 1.13 (S, 3H), 0.94 (d, J=6.6 Hz, 3H) , 0.90 (s, 3H) , 0.83 (s, 3H) , 0.86 (d, J=6.6 Hz, 6H); IR (film): 3923, 3365, 1613, 1514, 1466, 1374, 1248, 1171, 1093, 1071, 1038, 1011 cm"1; HRMS (EI) fc: C35H5203 (M-CH3CH): Calcd. 520.3916; found 520.3330. - 213 - - 213 - LV 10719 AP.. Preoaration of 14a-Methvl-15-oxa-5a-cholest-8-en-3b-ol iComcound 47)

By the method described for 15-oxa-dihydro-lanosterol (Compound 11a) (Exanple 1-J) the cyclic acetal (Compound 46) (3.74 mmole) was transformed to 15-oxasterol (Compound 47). The crude product vas purified by MPLC on silica gel with elution by 2:8 ethyl acetate-hexane to provide 0.52 g of the purified compound as foamy solid (34.5% of overall yield from Compound 43a).

Phvsical Data: NHR (300 MHz, CDC13): delta 3.75 (t, J = 8.4 Hz , IK), 3.62 (m, 1H), 3.44 (t, J=8.7 Hz, 1H), 2.30 (s, IK), 2.10-1.00 (m, 24H), 1.12 (s, 3H), 0.95 (d, J=6.3 HZ, 3K), 0.91 (s, 3K), 0.87 (S, 3H), 0.86 (d, J=6 Hz, 6K) ; IR (KBr): 3389, 2929, 2861, 1467, 1457, 1375, 1037 cm"1; HRMS (EI) for C26’H4602 (M+) , Calcd. 402.3498, found 4092.3524. EJCAMPLE 18

Preoaration of 4.4-Dimethvl-15-thia-5a-cholest-8-en-3b-ol (Compound 491 .

Kydrogen sulfide gas vas bubbled through a solution of 4,4-dimethyl-16-methcxy-3b- [ (4-methoxybenzyl) cxy ] -15-oxa-5a-cholest-S-ene (Compound 16b) (1.426 mmole, crude material, prepared by procedures Μ, N, and 0 "rom Compound 13b (0.81 g, 1.426 mmole) in 40 ml of dry methylene chloride at 0° for 120 min. Boron trifluoride etherate (2.5 ml) vas added to the mixture and it vas stirred at 0° for 0.5 hr. and at room 214 temperatūre for 1.5 hr. under nitrogen atmosphere. At the er.d of the stirring it was cooled to -30° and triethyisilane (2.2 ml, 13.8 nmole) was added dropvise to the solution. The mixture vas stirred at room temperature for 1.5 hr. under nitrogen atinosphere and saturated agueous sodium bicarbonate solution (50 ml) vas added to quench the reaction. It vas extracted vith diethyl ether tvice and the combined extracts vere vashed vith brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a dark brovn oily residue. It vas purified by column chrcmatography on silica gel vith elution by 15:85 ethyl acetate-hexane to afford purified Compound 49 (158 mg, 26% overall yield frora Compound 13b).

Rf: 0.24, 2:8 ethyl acetate - hexane.

Physical Data: tfMR (300 MHz, CDC13): delta 3.24 (dd, J=*4.5 Kz, 11.1 Hz, 1H), 2.75 (t, J=8.4 Hz, 1H), 2.66 (dd, J=9.6 HZ, 11.7 Hz, 1H), 2.57 (m, IK), 2.11-2.03 (m, 2H), 1.90-0.80 (m, 20H), 1.30 (s, 3H), 1.01 (s, 3K), 1.01 (d, J=6.6 Hz, 3H), 0.94 (s, 3H), 0.88 (s, 3H), 0.87 (d, J-6.3 Hz, 6H), 0.80 (s, 3H); IR (film): 3415, 2950, 2869, 1465, 1439, 1376, 1367, 1082, 1026, 1001, 736 EXAMPLE 19

Preoaration of 15-thia-dihvdrolanosterol fComoound 50)

By the method described for 15-thiasterol (Compound 49) (Exaraple 18) five-membered cyclic acetal (Compound 10b) (198 mg, 0.34 mmole) vas transformed to - 215 - - 215 -LV 10719 15-thia-dihydrolanostercl (Compound 50) (65.4 mg, 42¾ overall vield frcm Compound 7b) .

Phvsical Data: NKR (300 MHz, CDC13): delta 3.24 (dd, J=4.3 Kz, 11 Hz, 3HJ, 3.23 (s, 1H), 2.85 (t, J=10.2 Hz, 1H), 2.77 (dd, J=7.2 H2, 10.2 Hz, 1H), 2.20-0.80 (m, 23H), O.SS (s, 3H), 0.95 (s, 3H), 0.88 (d, J=8.7 Hz, 3H), 0.87 (d, J=6.6 Hz, 6H), 0.81 (s, 3H); IR (film): 3443, 2953, 2932, 2869, 1465, 1457, 1382, 1375, 1366, 1089, 1034, 1016, 1004, 736 cm-1. EXAM?LE 20

Preparātiem of 4,4-Dimethvl-15-thia-14a-vir.vl -5a-cholest-8-en-3b-ol (Compound 51)

By the method deseribed for 15-thiasteroid (Compound 49) (Example 18) five-membered cyclic acetal (Compound 22b) (274 mg, 0.46 mmole) was transformed to 15-thia-14-vinyl-sterol (Compound 51) (57.3 mg, 27.2% overall yield from Compound 19b).

Physical Data: NMR (300 MHz, CDC13): delta 5.84 (dd, J=109.5 Hz, 1H) , 5.12 (dd, J-1.5 Hz, 10.5 Hz, 1H.) , 4.94 (dd, J=1.5 HZ, 17.1 HZ, 1H), 3.26 (dd, J=4.8 Hz, 1H), 2.85 (dd, J=7.2 Hz, 9.6 Hz, 1H), 2.74 (dd, J=10.8 Hz, 11.7 Hz, 1H), 2.46 (m, 1H), 2.06 (dd, , J=3.9 Hz, 7.2 Hz, 114 Hz, 1H), 1.96-0.75 (m, 21H), 1.02 (s, 3H), 1.01 (s, 3H), 1.01 (d, J=6 Hz, 3K), 0.87 (d, J=6.6 Hz, 6H), C.S1 (S, 3H), 0.80 (s, 3H); IR (film): 3394, 2949, 2867, 1473, 1465, 1457, 1376, 1365, 1093, 1030, 1004, 918 216 EXAMPLE 21

Preparātiem of sulfoxide iCompound 53)

To a stirred solution of 15-thia-dihydrolano-sterol (Compound 50) (20 mg, 0.045 mmole) in ethancl (3 ml) was added a solution of sodium periodate (38 mg, 0.13 mmole) in water (1 ml) and the mixture vas stirred at room temperature for 30 mins.

After addition of diethyl ether (ca. 10 ml) it was filtered to remove the precipitates and the filtrate vas evaporated under reduced pressure to give an oily residue. It vas purified by preparative thin layer chromatography on silica gel vith elution by 5:95 methanol - methylene chloride to give 14 mg of purified sulfoxide (Compound 53) (67% yield) .

Physical Data: NTīR (300 MHz, CDC13): delta 3.74 (dd, J=7.2 Hz, 13.2 Hz, 1H), 3.22 (dd, J=4.8 Hz, 11.4 Hz, 1H), 2.49 (t, J-13.2 HZ, 1H) , 2.36-0.80 (m, 23H) , 1.34 (s, 3K) , 1.01 (d, J=6 Hz, 3H) , 1.01 (s, 3H) , 0.98 (s, 3H), 0.87 (d, J=6.6 Hz, 6H), 0.81 (s, 3H); IR (film): 3394, 2950, 2932, 2868, 1457, 1437, 1384, 1376, 1364, 1015, 731 cm"1. EXAMPLE 22

Preoaration of 4,4-Dimethvl-14a-thia-D-homo 5a-cholest-8-en-eb-ol (Compound 56)

To a stirred solution of the cyclic acetal (Compound 13d) (300 mg, 0.65 mmole) in dry methylene chloride (10 ml) at 0° was bubbled hydrogen sulfide - 217 - - 217 - LV 10719 to saturate the sclution and boron trifluoride etherate (0.9 ml, 7.3 mmole) was added dropvise.

After stirring at room temperature for 1.5 hr. it vas cooled to 0° and triethylsilane (1.4 ml, 8.76 mmole) vas added. It was stirred at the same temperature for 2.5 hr. and saturated sodium carbcr.ate (ca. 20 ml) vas added to quench the reaction. The mixture vas extracted vith diethyl ether (2 x 30 ml) and the ccmbined extracts vere vashed vith vater and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a foarnv solid residue. It vas purified by column chromatographv on silica gel vith elution by 15:85 ethyl acetate-hexane to afford purified Compound 56 (172 mg, 59.2% yie!d) as a vhite foamy solid.

Physical Data: NMR (300 MHz, CDC13): delta 3.27 (dd, J=*4.8 Hz, 11.4 Hz, IK), 2.33-2.23 (m, 4H), 1.90-0.80 (m, 21H) , 1.12 (s, 3H) , 1.09 (s, 3H), 1.03 (s, 3H), 0.99 (s, 3K) , 0.90 (d, J»6.9 Hz, 3H), 0.87 (d, J=6.6 Hz, 6H), 0.82 (s, 3H); IR (film): 3427, 2951, 2869, 2853, 1467, 1457, 1376, 1025, 1002, 734 cm'1. EXAMPLE 23

Preparation of 14a-thia-D-homo-dihvdro-lanosterol (Compound 57)

By the method described for Compound 56 (Exanple 22) the cyclic acetal (Compound 7d) (300 mg, 0.63 mmole) vas transformed to six-membered cyclic sulfide (Compound 57) (129 mg, 44.3% yield) as a vhite foamy solid. 213

Phvsical Data: NMR (300 KHz, CDC13): delta 3.26 (dd, J = 4.S Hz, 11.1 Hz, IK), 2.75 (s, 1H) , 2.50-2.25 (m, 3H) , 2.05-0.90 (m, 24H) , 1.13 (s, 3H) , 1.01 (s, 3H) , 0.99 (s, 3H), 0.89 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H) , 0.61 (s, 3H) . EXAMPL£ 24

Preparation of 14-Aza-4 . 4-dimethvl-5a-cholesta-8.14-dien-3b-ol fCompound 6 6a) AS. Preparation of 4.4-dimethvl-3b-r(4-methoxvber.2vl) oxvT-14-oxo-5a-14.15-secocholest-8-ene-15-carboxvlic acid (Compound 63)

To a stirred solution of the enone aldehyde (Compound 4b) (15 nurole, crude material, prepared from

Corapound 2b (8 g, 15 nunole) ] in tert-butanol (340 ml) and vater (85 ml) vere added sodium chlorite (Aldrich) (2.91 g, 30 mmole) and the m'ixture vas stirred at room temperature for 1 hr. At the end of the stirring vas added methylene chloride (500 ml) to the mixture and i vas vashed vith vater (2 x 150 ml). The combined aqueous layers vere re-extracted vith methylene chloride (200 ml) and vashed vith vater once.

The methylene chloride extracts vere dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a solid residue of crude acid (Compound 63) in near quantitative yield. The crude material vas routinely used for next transformation vithout purification. The analytical sample vas - 219 - - 219 - LV 10719 * obtained by recrystallization from ethyl acetate and hexane, n.p. = 126-126.5°C.

Physical Data: NTCR (300 MHz, CDCI3): delta 7.29 (d, J=3.4 Hz , 2H), 6.87 (d, J=8.4 Hz, 2H), 4.60 (d, J-11.4 Hz, 1H), 4.40 (d, J=11.4 Hz, 1H), 3.80 (s, 3H), 3.00 (dd, J=3.6 Hz, 11.4 HZ, 1H) , 2.47 (dd, J=7 Hz, 17.5 Hz, IK), 2.38-0.80 (m, 22H), 1.06 (S, 3H), 1.05 (S, 3H), 0.97 (s, 3H) , 0.96 (d, J = 6.6 Hz, 3H) , 0.37 (s, 3H) , 0.86 (d, J = 5.9 Hz, 6H) ; IR (film): 3435, 2951, 2937, 2369, 1707, 1654, 1624, 1616, 1513, 1465, 1301, 1247, 1093 cr.'1; HRKS for C 37H5404 (M-H20) ; Calcd. 562.4022, found 562.4054. AT. Preparation of 4 . 4-dimethvl-3b-r(4-rethoxvbenzvl) oxvl-14-oxo-5a-i4.15-secocholest-8-ene-15carboxvlic acid azide (Compound 64)

To a solution of the carboxylic acid (Compound 63) (15 mmole) and N-methylmorpholine (4.96 ml, 45 mmole) in dry methylene chloride (270 ml) at 0° vas added isobutyl chloroformate (2.92 ml, 22.5 mmole) dropvise over a period of 5 min. and the mixture was stirred at 0° for 1 hr. Then a solution of sodium azide (9.78 g, 75 mmole) and tetrabutylammonium bromide (1.1 g, 3.4 mmole) in water (90 ml) was added and the tvo phase mixture was stirred at 0° for 1.5 hrs. The methvlene chloride layer vas separated and the agueous layer was extracted with methylene chloride (2 x 50 ml). The ccnbined extracts were vashed with vater and brine, dried over anhvdrous magnesium sulfate and evaporated under reduced pressure to give an oily residue of the crude acvl azide (Compound 64) (9.1 g, guantitative 220 mass recovery) . The crude product was normally used fcr next reaction vithout purification.

Physical Data: IR (film): 3522, 2952, 2938, 2869, 2315, 1720, 1657, 1623, 1615, 1514, 1464, 1248, 1172, 1096 ca”1. AU. Preoaration of 15-Aza-4 . 4-dimethvl-3b-rūme thoxvbenzvl)οχν1-15-methoxvcarbonvl-5a-14 , 15-secocholest-3-en-14-one (Compound 65 i A solution of the acyl a2ide (Compound 64) (7 g, 11.6 mmole, crude material) in ethyl acetate (20 ml) and methanol (100 ml) was refluxed under nitrogen atmosphere for 5 hr. and the solvents vere evaporated cff.

The oily residue of the crude carbamate (Compound 65) was normally used for next reaction vithout purification. Analytical sample of purified Compound 65 vas obtained bv crystallization from diethyl ether and hexane, m.p. = 144-144.5°.

Physical Data: NMR (300 MHZ, CDCI3): delta 7.27 (d, J=8.4 Hz, 2H) , 6.86 (d, J=8.4 ΗZ, 2K) , 4.60 (dm J*11.4 Hz, 1H) , 4.52 (t, J=6 HZ, 1H), 4.35 (d, J=11.4 HZ, 1H), 3.80 (S, 3K), 3.53 (s, 3H), 3.33 (dd, J=7.5 Hz, 13.5 Hz, 1H), 2.90 (dd, J=3.9 Hz, 11.4 Hz, 1H) , 2.84 (m, 1H), 2.56 (dd, J=6 Hz, 18 Hz, 1H), 2.25-0.80 (m, 21H), 1.13 (d, J = 6.6 HZ, 3H) , 1.06 (s, 3H) , 1.00 (s, 3H), 0.97 (s, 3K) , 0.86 (d, J=6.6 Hz, 6H) , 0.86 (s, 3H) ; IR (film): 3464, 3366, 2952, 2869, 1727, 1654, 1623, 1617, 1514, 14654, 1458, 1380, 1247, 1099, 1037 cm'1? HRMS for C33K59N05 ; Calcd* 609.4393; found 609.4404. - 221 - - 221 - LV 10719 AV. Preparation of l5-Aza-4 , 4-dimethvl-3b-r i-:-methoxybenzvI) oxvi -5a-cholest-3-. 14-di°r,e fComocund 66b)

To a solution of the carbainate (Compound 65) (11.6 mmole) in dry tetrahydrofuran (150 ml) was added potassium trimethylsilanolate (12.8 g, 100 mmole) and the mixture was refluxed under nitrogen atmosphere for 2 hrs. After cooling to room temperature diethyl ether (200 ml) vas added and the organic layer was vashed with vater and brine. The ccmbined aqueous layers were re-extracted vith diethyl ether and the extracts vere vashed vith brine. The ether extracts vere dried over anhydrous sodiun sulfate and evaporated under reduced pressure to give a solid residue. It vas purified bv coluron chromatography on silica gel vith elution by 2:8 ethyl acetate - hexane to give 4.5 g of purified cvciic inine (Compound 66b) as vhite solid (72.7% overall yield from Compound 2b). It vas crystallized frcm methylene chloride and hexane to afford 3.6 g of crystalline product, m.p. » 159-160°.

Physical Data: NMR (300 MHZ, CDCl3): delta 7.28 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.61 (d, J-11.7 Hz, 1H), 4.39 (d, J*11.7 Hz, 1H), 3.93 (dd, J=6 Hz, 14.5 Hz, 1H), 3.81 (s, 3H), 3.34 (dd, J=9.3 Hz, 14,5 Hz, 1H), 2.93 (dd, J=3.9 Hz, 11.7 Hz, 1H), 2.40-0.73 (m, 22H), 1.09 (S, 3H), 1.01 (s, 3K), 0.91 (d, J=5.1 Hz, 3H), 0.83 (s, 3H), 0.87 (d, J=5.7 Hz, 6H), 0.86 (S, 3H); IR (KBr): 2942, 2371, 2348, 1625, 1614, 1600, 1513, 1470, 1456, 1249, 1114, 1100, m 1037, 819 cm'1; HR.MS for C36H55N02 : Calcd. 533.4232; found 533.4213. 222 AV. Preoaration of 14-Aza-4.4-dimethvl-5a-cholesta-S.14-dien-3b-ol (Compound 66a)

To a stirred solution of Compound 66b (300 ng, 0.56 mmole) and allyltrimethylsilane (0.18 ml, 1.12 mmole) in dry methylene chloride (6 ml) was added boron trifluoride etherate (0.39 ml, 2.53 mmole) portionvise and the mixture was stirred at room temperature for 15 hr. under nitrogen atmosphere. Saturated sodium bicarbonate solution was added slowly to make the solution basie and the product vas extracted vith ethyl acetate. The extract vas vashed vith vater and brine, dried over anhydrous sodium sulfate and evaporated to give a solid residue. It vas purified by column chromatography on silica gel vith elution by 3:7 ethvl acetate-hexane folloved by 7:3 ethyl acetate - hexane, to afford 217 mg of purified Compound 66a (93.3% yield).

Phvsical Data: NMR (300 MHz, CDCI3): delta 3.94 (dd, J»6.6 Hz, 15.6 Hz, 1H), 3.35 (dd, J=9.6 Hz, 15.3 Hz, 1H), 3.25 (dd, J=4.5 Hz, 11.4 Hz, 1H) , 2.42 (d, J=6 Hz, IK), 2.30 (dm J=7.5 Hz, 1H), 2.10-0.90 (η, 21H), 1.08 (s, 3H), 1.03 (s, 3H), 0.91 (d, J=5.7 Hz, 3H), 0.87 (d, J=6.6 Hz, 6H) , 0.87 (s, 3H) , 0.85 (s, 3H) ; IR (KBr) : 3442, 3432, 2945, 2932, 2870, 1618, 1465, 1457, 1388, 1092, 1043, 1026, 1009 cm"1; HRMS for C2gH47NO (M+):

Calcd. 413.3658; found 413.3646. LV 10719 - 223 -ΕΧΑΜΡ1Ξ 25

Preparātiem of 14-Aza-5a-cholesta-3,14-dien-3b-ol iCompound 7 0a) AX. Precaration of 3b-i(4-Methoxvbenzvl)oxv1-14-oxo-5a-14,15-secocholest-8-ene-15-carboxyIic acid (Compound 67)

By the method deseribed for carboxylic acid (Compound 63) (Example 24-AS) 3b-[ (4-Methoxyl-benzyi) oxy]-15-oxc-5a-14, 15-secocholest-3-ene-14-one (Ccmpound 40) (7.5 mmole, crude material, prepared frem Compound 38b) (3.8 g, 7.5 mmole)) was transformed to carboxylic acid (Compound 67) (4.03 g, foamy solid residue) The crude material vas used for next transformation vithout purification.

Physical Data: NKR (300 MHZ, CDC13): delta 7.27 (d, J=8.1 Kz, 2H), 6.37 (d, J»8.1 Hz, 2H), 4.53 (d, J=ll Hz, 1H), 4.47 (d, J=ll HZ, 1H), 3.80 (S, 3H), 3.39 (m, 1H), 2.43-0.90 (m, 27H), 1.01 (S, 3K), 0.98 (S, 3H), 0.95 (d, J=6.9 Hz, 3H) , 0.86 (d, J=5.6 Hz, 6H) ) ; IR (fiirn): 3150, 2935, 2867, 1706, 1657, 1614, 1514, 1466, 1459, 1377, 1302, 1249, 1172, 1036 cm”1; HRMS for C27H43°4 (M-CH3OC6H4CH2): Calcd. 431.3161; found 431.3224. AY. Preparation of 3b-rf4-Methoxvbenzvl)oxvi-14-oxo-5a-14.15-secocholest-3-ene-15-carboxvlic acid azide (Compound 63) 3y the method deseribed fc-r acvl azide (Compound 64) (Example 24-AT) carboxylic acid (Compound 67) (7.5· 224 mmole) was transformed to acyl azide (Compound 63) as an oil. The crude material was used for next transformaticn vithout purification.

Fhysical Data: NMR ( 300 MHz, CDC13): delta 7.27 (d, J=8.4 Hz, 2H) , 6.87 (d, J=8.4 Hz , 2H) , 4.52 (d, J=11.7 ΗZ, 1H) , 4.47 (d, J=ll.7 HZ, 1H) , 3.80 (s, 3H) , 3.39 (m, 1H), 2.42-0.90 (m, 26H) , 1.02 (s, 3H) , 0.96 (s, 3H) , 0.93 (d, J=6.3 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H); IR (filn): 2953, 2935, 2863, 2135, 1720, 1658, 1620, 1614, 1513, 1467, 1377, 1243, 1180, 1172, 1087 cm-1. A2. Preoaration of 15-Aza-3b-f(4-methoxvbenzvl)-oxv) -15-methoxvcarbonvl-5a-14.15-secocholest-8-en-14-one (Compound 69)

By the method described for carbamate (Coinpound 65) (Example 24-AU) acyl azide (Compound 68) (7.5 nunole) was transformed to carbamate (Compound 69) as an oil. The crude product was used for next reaction vithout purification. The analytical sample of purified Compound 69 vas obtained by crystallization from diethyl ether and hexane.

Fhysical Data: NHR (300 MHz, CDCI3): delta 7.25 (d, J=8.2 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.48 (s, 2H), 3.79 (s, 3H) , 3.51 (s, 3H) , 3.30 (m, 1H) , 2.85 (τη, 1H) , 2.50-0.90 (τη, 26H) , 1.11 (d, J=6.6 Hz, 3H) , 1.01 (s, 6H) , 0.86 (dm J=6.6 Hz, 6H) ; IR (KBr) : 3463 , 3363 , 2952, 2934, 2867, 1726, 1654, 1617, 1513, 1466, 1457, 1376, 1247, 1109, 1104, 1075, 1034 cm"1; HRMS for C34H50°3 (M-NH2C02CH3): Calcd. 506.3760; found 506.3769. LV 10719 - 22 5 - BA. Preparation of 14-Aza-3b-i f 4-MethoxybenzvI l-oxv--5a-cholest-8,14-diene iCompound 50b^

By the method described for cyclic imine (Compound 66b) (Example 24-AV) carbamate (Compound 65) (7.5 mmole) vas transformed to cyclic imine (Compound 70b). The solid residue vas purified by column chromatography on silica gel vith elution by 3:7 ethyl acetate-hexane to afford 2.33 g cf purified Compound 70b as sclid (61.4% overall yield from Compound 38b). It vas crystallized from methylene chloride and hexane to give analytically purified sample.

Physical Data: NMR (300 MHz, CDCI3): delta 7.27 (d, J=8.7 Kz, 2H), 6.87 (d, J-8.7 Hz, 2H), 4.52 (d, J=11.4 Hz , IK), 4.47 (d, J-11.4 Hz, 1H), 3.94 (dd, J=6.9 H2, 15.3 Hz, 1H) , 3.80 (s, 3K) , 3.35 (s, 3H) , 3.35 (m, 2H), 2.40-0.80 (m, 2 4 H) , 1.04 (s, 3H) , 1.04 (S, 3H) , 0.91 (d, J=6 HZ, 3H), 0.87 (s, 3K), 0.87 (d, J=6.3 Hz, €K) ; IR (film): 3921, 2869, 2852, 1620, 1614, 1598, 1515, 1466, 1454, 1369, 1301, 1249, 1104, 1092, 1078, 1032, 820 cm-1; HRMS for C34H51NOI2 (M+): Calcd. 505.3920; found 505.3961. ' BB. Preparation of 14-Aza-5a-cholesta-8.14-dier.-3b-ol (Compound 70a)

Bv the method described for azasterol (Compound 66a) (Example 24-AW) cyc!ic imine (Compound 70b) (1 g, 1.93 mmole) vas transformed to azasterol (Compound 70a) as a solid. It vas purified by column chromatcgraphv on silica gel vith elution by 3:& ethvl acetate -hexane folloved by 6:2 ethyl acetate - hexane to cbtain 207 mg of unreacted starting material (Compound 70b) 226 and 673 mg of azasterol (Compound 70a) (96.3% yield based on the recovered starting material). The product was crystallized from diethyl ether and hexane, n.p. = 178-179°.

Physical Data: NKR (300 MHz, CDCl3): delta 3.94 (dd, J=6.9 Hz, 15.3 Hz, 1H), 3.60 (m, 1H, 3.34 (dd, J=9.6 Hz, 15 Hz, 1H) , 2.45-0.30 (m, 25H), 1.04 (s, 3H) , 0.92 (d, J=6 Hz, 3H), 0.87 (s, 3H), 0.87 (d, J=6.6 Hz, 6H) ? IR (film): 3304, 2931, 2867, 2853, 1620, 1597, 1467, 1453, 1371, 1056, 1025 ca'1; HRMS for C26H43BI (M+): Calcd. 385.3344; found 385.3344. - 227 - - 227 - LV 10719 BIGACTIVITĪ EXAM?LE 26 3-Hvdroxv-3-Methvlqlutarvl Coenzvne A Reductase fHMGR) Suppression Assav

The ability of the compounds of Formula I to suppress the activity of KMGR, the rāte limiting er.zyme of cholesterol biosynthesis, was tested as follovs.

Chinese Hamster Ovary (CHO) celis vere divided twice veekly and vere maintained in McCoy's 5A medium supplemented with 1% carbosil delipidated Fetal Bovine System (FBS) (obtained from Gibco Laboratories, Chagrin Fails, OH) . Celis vere harvested during the logarithmic phase of grovth and celi cultures vere prepared by adding 0.5 x 10 celis to each veli in a 24 veli cluster dish (obtained from Costar, Data Packaging Corp., Cambridge, MA) employing l ml of the above medium per each veli. The celi cultures vere incubated for 48 hr. at 37° in a 5% C02, 95% air environment. The tēst compounds in a 2.5% suspension of bovine serum albumin (BSA) (Fatty acid free) in ethanol vere then added to the cultures such that the final ethanol and BSA concentrations in the incubation medium vere 0.5% and 0.25% respectively. Treated celis vere incubated vith the indicated compounds for 6 hr. at 37° in a 5% 002, 951 air environment. Control celis vere treated in an identical fashion to those vhich received tēst compound, except they vere incubated vith the BSA and ethanol suspension only. KMGR activity vas then measured in digitonin-permeabilized celis by the method developed by Leonard et al.. J. Biol. Chem.. 262: 7914-1719 223 (1937) .

Specifically, the medium in each well was aspiraced and the celis rinsed with a 50 mM solution of phcsphate buffered saline (P3S) . One ml of 30 mg/ml of digitcr.in in CSK buffer (prepared using 10 mM Pīpes (piperazine-N,N'-bis (2-ethansulfonic) acid], 100 mM KC1, 2.5 mM Mgci2, 300 mM sucrose, 1 mM EGTA, pH 6.3) vas added to each well and incubated for 10 min. at 22° to permeabilize the celis. The buffer vas carefully aspirated and the velis vere rinsed tvice each time vith 1 ml of P3S. KMGR activity vas measured directly by adding 75 ml of PI3 buffer (50 mM potassium phosphate, 1 mM Na2EDTA, 10 mM dithiothreitol, pH 7.4) to each veli and incubating the celis for 30 minūtes at 37° as described above. The enzyme assav vas initiated by the addition of 83 μΐ of substrate/cofactor mixture such that the final assay contained the folloving: 0.1 M potassium phosphate, 5 mM dithiothreitol, 20 mM glucose-6-phosphate, 2.5 mM NADP, 0.175 units of glucose-6-phosphate dehydrogenase, 150 mM [14C] HMG-Coenzyme A (15 DPM/pmol), pH 7.4.

The assay mixture vas incubated for 30 min. at 37° and terminated by the addition of 70 ml of [3H]-mevalonic acid (35,000 DPM/assay), 0.15 mg/ml in 3 N HCl.

The reaction vas left to lactonize for. an additional 30 min. at 37° or overnight at room temperature.

Reaction products vere separated by thin layer chromatography on silica gel G (obtained from Analtech, Nevark, DE) daveloped in an unsaturated environment vith acetone:benzene (3:2, v:v). The band corresponding to mevalonolactcne vas identified by exposure to iodine vapor and vas scraped into counting vials. The extent of conversion of starting substrate, - 229 - - 229 - LV 10719 KMG-CoA, to mevalonic acid was deterroined by liguid scintillation counting in Biofluor (obtained fron Nev 'England Nuclear, Boston, MA) . Corrections for reccvery and blank values were made for each sample. Protein determinations were made by Bio-Rad (Bio-Rad, Richmond, CA) dye binding assay according to the manufacturer's instruction using bovine serum albumin as Standard. Cellular protein was solubili2ed from culture dishes by the addition of 20 μΐ of 16 N KOH and assayed directly for protein amount. Suppression values are expressed as the amcunt of compound reguired to suppress H.MGR activity by 50% relative to that of the Controls. The results of HMGR suppression assays are reported in Table 1. 230 TABLE I 3-Hvdroxv-3-Methvlqlutarvl Coenzvme A Reductase !HMGR) Suppression Assav

Ex. No. 1 2 3 6 7 3 10 13 16 17 13 19 386 672 673 677 673 857 858 859 1303 1503 1509 1817 1318 IC50IcM1 0.13 0.3 0.17 0.075 0.04 2.5 0.2 2.5 2.5 1.95 0.3 2.08 0.08 1.46 2.5 0.06 0.55 0.06 0.3 1.25 5. 0.5 0.16 231 231 LV 10719

The ability of compounds of this invention tc effectively suppress HMGR activity is demonstrated fcy the data in Table I. As a conparison, it should be noted that cholesterol, lanosta-8,24-diene-3b-ol and lanost-8-en-3b-ol, vhen tested under these same conditions, vere vithout effect on measured HMGR activity. Thus, the potent HMGR suppression activities cf these compounds make them very attractive as hypccholesteroleraic aģents. EXAMPLE 27

Loverinc Blood Cholesterol Levels in Hamsters

The abilitv of the compounds of Formula I to Iever blood cholesterol Ievels has been demonstrated in hamsters utilizing the folloving protocol.

Male Golden Syrian hamsters (50-60 grams) vere obtained from Charles River, Inc. (Wilmington, MA).

Animals vere housed in individual suspension cages and vere maintained on a light cycle consisting of 12 hours of light folloved by 12 hours of dark. Animals vere alloved free access to vater and feed (Agvav grcund ehov, RMH 3200, Agvay; Svracuse, Ν.Υ.) ccntaining 1% (v/w) corn oil) for a minimum of 4 veeVs.

Folloving this stabilization period a sample cf blood vas collected by orbital sinus bleeding under light ether anesthesia into heparinized capillarv tubes. Plasma vas separated by centrifugation (600 x g for 10 minūtes) and plasma cholesterols vere detemined bv an autoanalyzer (Centrifichem 600, Baker 232

Instruments, Allentovn, PA). Based upon measured pLasma cholesterol values, the animals vere randomized into tvo groups such that the Dean plasma cholesterol values vere identical for both groups.

Animals in the tvo groups vere then placed on one of tvo diets: (1) Diet A, consisting of ground chcv plus 1% (v/v) corn oil, as described above; or (2) Diet B, consisting of Diet A plus 0.2% (v/v) of a tēst compound. Animals on Diet B, the treated animals, vere alloved free access to feed and vater, vhile animals cn Diet A vere pair-matched vith Diet B animals and served as pair-fed Controls. The animals vere ķept on their respective diets for 7-days at vhich time they vere bled by cardiac puncture under C02 anesthesia. Total plasma cholesterol Ievels vere determined as described above.

The results are presented in Table II. The data is reported as means + SEM (Standard error of the mean), in units of mg/dl. The value "N" represents the r.umber of animals in each group. LV 10719 - 2 3 3 -

TABLE II

Effect of Various Tēst Comoounds Uoon Plasrna Cholesterol Levels in Hansters

Plasma Cholesterol

Exanūle Ko. Control Treated (mg/dl) 1 l1 13 3.0 + 4.0 120. ± 2.0 (N=2 0) (N=10) 1 Values represent means +SEM for the number of animals given in parenthesis 1

Dosed at 0.2% (v/w) in feed 234

As the data in Table II indicate, blood cholesterol Ievels can be significantly lovered by administration of compounds of Formula 1. - 235 - LV 10719 EXAMPLES 28-31

Scheme IX generally depicts the synthetic seguence for the preparation of the compounds of Examples 28-30. In the initial reaction, Compound 72 is preferably converted to Compound 73 using catalytic osmium tetroxide. Preferred methods for the other synthetic conversior.s are provided in the exasples vhich follov this scheme.

236 SCHSME IX

72 R2aCH3 79 R2 = H

73 R2 = CH3 30 R2 = H - 237 -LV 10719 EXAM?LE 23 r.ethv I -15 - cxa -14a-vir.vl -1 (Compour.d 7S) '-sparaticr. o erccsta- '2 2Ξ}-4,4-> 22-dier.-33

Preparation 0f (22E)-4, dier.e-3fi,14a, 15a-t 4-Dimethyl-ergosta ;riol (Compound 73) ,22-

To a stirred sclutior. of (22E)-4,4-dimethyl-ergosta-8, 14,22-crier.-33-ol (Compound 72, 1C g, 23.5 m-τ.ο 1 e) prepared by the emthod described bv Dclle, et al. _Chg.T..^, 51: 4027 (153 6), in l,4-dicxane (4C0 ml) were added pyridine (10 ml), 1,8-diazabicvcio-[4.4.0.]undec-7-ene (DBU, Aldrich Chemical Co.) (4 ml),

lO ar. aaueous solution of trimethylamine N-oxide dihvdrate (Aldrich Chemcial Co.) (5.4 g, 47 mmoie ir. 50 ml of water) ar.d a 20% solution of osmium tetracxide ir methvler.e chloride (1.5 ml, 1.18 mmoie) ar.d the mixture was heated urder reflux fcr 24 hr. After coolir.g to room temperature was added 20% solution of sodiem bisulfite (50 ml) ard the mixture was stirred for 0. hr. It vas extracted vith ethyl acetate (3 x 200 ml) ard the combined extracts were washed vith water ard brine. The organic extracxt vas dried over magr.esium sulfate and evaporated to give a solid residue. The crude product vas dissolved in a minimum amour.t of ether and passed through a short silica gei coiumn vith elution bv ether to remove the colored impurities. The solvent vas evaporated off to afford a vhite crvstallir.e solid (7.47 g) of the trio! (Compcur.d 73) .

Fhysical data: NMK (300 MKZ, CDCL3) : delta 5.23 (dd, J=7.3 Hz, 15.4 Hz, IK), 5.13 (dd, J=7.3 Hz, 15.4 Hz, IK), 4.10 (m, 238 IK), 3.24 (m, IK), 2.4 1 (d, J = 9.5 Kz, 1H) , 2.3S-0.C3 21H) , 1.02(s,3 K) , 1.00(s,3K), 0.97 (d, J=5.8 Kz, 3K) , 0.91 (d, J=6.6Hz, 3H), 0.84-0.81 (m, 9K), 0.71 (s, 3H) . 30. Preparation of (22Ξ)-4,4-Dimet'nyl-3a-hydroxy-15-oxo-14,15-secoergosta-8,22-dien-l4-one (Compound 74)

To a stirred solucion of the triol (Compounc 73, 13.2 g, 28.9 mmole) in dry benzene (360 ml) in the cark was added lead tetraacetate (12.8 g, 28,9 mmole) in small portions over a period of 1 hr. and the mixture was stirred at room temperature for 1 hr. under r.itroget atomosphere and in the dark. The mixture was filtered through Celite and the filtercake was rinsed several times. Evaporation of the solvent provide a foamv solid of the enone aldehyde (Compound 74) in near guantitative yield.

Physical datē: NMR (300 MHz, CDC13): delta 9.55 (brs, 1H), 5.24-5.22 (m, 2H), 3.30 (dd, J=4.7 Hz, 11.3 Hz, 1H), 2.56-0.08 (m, 20H), 1.03 (s, 3H), 1.01 (s, 3H), 0.93 (d, J-6.9 Hz, 3H), 0.93 (s, 3H), 0.89 (d, J=6.9 Hz, 3H), 0.82-0.77 (m, 9H). BE. Preparation of (22E)-4,4-Dimethyl-3U-hydroxy-15-(1'-piperdino)-14,15-secoergosta-8,15,22-trien-14-one (Compound 75)

To a solution of the enone-aldehyde (Compound 74, 11.9 g, 26 mmole) in benzene (240 ml) was added piperidine (12 ml) and the mixture was refluxed under a Dean-Stark trap until the removal of water is completed LV 10719 - 23 9 - (c.a. 1 hr.) . The excess piperidine and the solvent were evaporated off under reduced pressure after cociirg to cive a foamy solid residue of the enamine (Ccrr.pour.d 75) in ouantitative yield.

Physical data: NMR (300 MHz, CDC13): delta 5.56 (d, j-13.5 Kz, 1H), 5.28 (dd, J=8.4 Hz, 15.4 Kz, 1H), 5.14 (dd, J-7.7 Hz, 15.4 Hz, IK), 4.20 (br, 1H), 4.17 (dd, J=10.6 Hz, 13.5 Hz, IK), 3.28 (dd, J=4.7 Kz, 11.3 Kz, IK), 2.8S ir., 4K) , 2.8C-0.8C (m, 19H), 1.60 (m, 4H) , 1.04 (s, 3.K) , 1.03 (s, 3.H) , 0.95 (s, 3H) , 0.93 (d, J-6.6 Kz, 3H) , 0.91 (d, J=6.6 Kz, 3H) , 0.84-0.75 (m, 9H) . BG. Preparation of (22E)-4,4-Dimethyl-33-hydroxy-l6- ΟΧΟ-14,16-seco-D-nor-ergosta-8,22-dien-14-or.e (Compound 76) A solution of the enamine (Compound 75, 26 mmole) in dry methyiene chloride (200 ml), containing c.a. 10 mg of Sudan Red 7b as an indicator, was bubbled vith ozone at -78° until the color become light pink. After stirring for 5 min. dimethyl sulfide (5 ml) was added and the mixture was stirred for 30 min. at -78°. The residue after evaporation of the solvent was dissolved in a small amount of ether ari passed through a plug cf silica gel to remove polar impurities. Evaporation cf the solvent afforded a foamy solid of the enone aldehvde (Compound 76).

Physical data: NMR (300 MHz, CDC13): delta 9.73 (d, J=4.7 Kz, IK), 5.33 (m, 2K), 3.28 (dd, J=4.6 Kz, 11.5 Hz, 1H) , 2.32 (br, 2H), 2.18 (dd, J=6.2 Hz, 13.5 Hz, 1H), 2.60-0.8 240 240 (m, 15H) , 1.21 (3, 3H) , 1.07 (s, 3H) , 1.04 3H), 1.C4 (s, 3K), 0.91 (d, J-6.9 Hz, 3H) , 9 H) . (d , J ~ o . z r.z, 0.84-0.31 (n, BH. Preparation of (22E)3Q16-Dihydroxy-4,4-dimethyl-14,16-seco-D-nor-ergosta-8, 22-dien-14-or.e (Compound 77)

To a solution of the enone-aldehyde (Compour.d 75, 26 mmole) in methanol (115 ml) at -40° was added sodium borohydride (0.59 g, 15.6 mmole) and the mixture was stirred for 1 hr. at from about -40°, with warming to about 10°. The excess sodium borohydride was destroved by stirring fcr 5 min. with acetic acid (1 ml). It was then neutralized with saturated solution of sodium bicarbonate and concentrated under reduced pressure.

The residue was extracted with ethyl acetate (3 x 100 ml) and the combined extracts were washed with water and brine, dried ove: magnesium sulfate, and evaporated to give an oily residue. The crude product was column chromatographed on silica gel with elution by ethvl acetate - hexane (2 : 8) to give 6 g of pure enone-alcohol (Compound 77).

Physicai data: NMR (300 MHz, CDCI3): delta 5.32-5.28 (m, 2H), 3.69 (dd, J=5.3 Hz, 6.8 Hz, 1H) , 3.61 (dd, J«4.4 Hz, 6.8 Hz, 1H), 2.64-.8 (m, 19H), 1.14 (d, J*7.0 Hz, 3H), 1.07 (S, 6H), 1.03 (s, 3H), 0.92 (d, J=7.0 Hz, 3H), 0.85-0.80 (m, 9H) . 31. Preparation of (22Ξ)-4, 4-Dimethyl-15-oxa-14(X-vinyi-ergosta-8,22-dien-3B-ol (Compound 78)

To a solution of the enone-alcohol (Compound - 241 - LV 10719 1.98 g, 4.45 mmole), 2,6-lutidine (1.71 ml, 14.7 mmole) and 4-dimethylamino-pyridine (0.1 g) in dry methylene chloride (22 ml) at 0° was added chlorotrimethysilane (1.7 ml, 13.4 mmole) dropvise and the mixture was stirred for 40 min. at 0° and for 10 min. at 25°.

The reaction was guenched by methanol (1 ml) and the mixture vas poured into ether. The ether solution was vashed with vater and brine, dried over magnesium sulfate and evaporated to give a foamy solid residue.

The residue vas then dissolved in dry tetrahydrofuran (25 ml) and vas added lM-vinyl magnesium bromide in dry tetrahydrofuran (8.9 ml, 8.5 mmole). The mixture vas heat under reflux for 1 hr. and cooled to 0°. It vas treated vith IN HC1 (18 ml) and extracted vith ethyl acetate (3 x 30 ml). The combined extracts vere vashed vith vater and brine, dried over magnesium sulfate, and evaporated to give an oily residue.

It vas dissolved in methanol (25 ml) containing p-toluenesulfonic acid (0.5 g) and the mixture vas stirred for 16 hr. at room temperatūre. Then the reaction mixture vas made basie vith saturated solution of sodium bicarbonate and extracted vith ethyl acetate (3 x 30 ml). The combined organic Solutions vere vashed vith brine, dried over magnesium sulfate and evaporated to afford to foamy solid residue. The crade product vas purified by column chromatographed on silica gel vith elution by ethyl acetate - hexane (1 : 9) to provide 1.12 g of pure vinyl-oxasterol (Compound 78) .

Physical data: NKR (300 MHz, CDC13): delta 5.71 (dd, J=11.0 Hz, 17.6 Hz, 1H), 5.26 (dd, J=7.9 Hz, 15.2 Hz, 1H), 5.11 (d, J=11.0 Hz, 1H), 5.10 (m, 1H), 5.00 (d, J=17.4 Hz, 242 IK), 3.67 (t, J=8.4 Hz, 1H) , 3.49 (t, J=3.6 Kz, IK), 3.29 (brt, J=5.3 Kz, IK), 2.12-0.8 (m, 18K), 1.02 (s, 3K), 1.C1 (s, 3K), 0.90 (d, 6.5 Kz, 3H), 0.84-0.8 (m, 15 K) . EXAM?LE 29 BJ. Preparation of (22E)-15-0xa-140t-vinyl-ergosta-c, dien-3B-ol (Compound 80)

By the method described for 4,4-dimethyi-vinyl-oxasterol (Compound 79) (Example 28-BC through BI) (22Ξ)-ergosta-8,14,22-trien-3i3-ol [prepared by the method described bv Dolle, et al. J. Org. Cheir... 51: 4027 (1986)3 was transformed to the corresponding normethyl-vinyl-oxasterol (Compound 80).

Fhysical Data: NMR (300 MHz, CDCI3) : delta 5.71 (dd, J-10.8 Kz, 17.2 Hz, 1H), 5.27 (dd, J=7.7 Hz, 15.1 Hz, IK), 5.11 (dd, J-2.2 Hz, 10.8 Hz, 1H), 5.10 (m, IK), 5.01 (dd, J-2.2 Hz, 17.2 Hz, 1H), 3.67 (t, J-8.10 Hz, 1H) , 3.49 (t, J-8.8 Hz, 1H), 2.08-0.89 <m,21H), 1.04 (d, J-5.9 Kz, 3K), 0.97 (s, 3K>, 0.90 (d, J*7.0 Hz, 3H) , 0.84-0.80 (m, 9K) . EXAMPLE 30 BK. Preparation of 14a-Ethyl-15-oxa-ergost-8-en-3£-ol (Compound 81) A solution of the vinyl-oxasterol (Compound 80, 51 mg, 0.12 mmole) and 10% palladium on carbon (10 mg) ir. 3 ml of ethyl acetate - acetic acid (95 : 5) was - 243 - LV 10719 stirred under hydrogen atmosphere (1 atm.) for 30 min. After removal of the catalyst by filtration through Celite the solvents vere evaporated to give a foamy solid of the ethyl-oxasterol (Compound 81) in guantitative yield.

Physical data: NMR (300 MHz, CDCI3): delta 3.76 (t, J=8.5 Hz, 1H), 3.66 (m, 1H) , 3.43 (t, J=8.6 Hz, 1H), 2.17-0.75 (m, 2 6H) , 0.97 (s, 3H), 0.94 (s, 3H) , 0.84 (d, J=6.9 Hz, 3H), 0.81-0.73 (m, 12H). EXAMPLE 31

Assay of 14C-Acetate Incorporation into the Biosynthesis of Cholesterol

The HepG2 celis (a human hepatoma celi line) used in this example vere obtained from the American Type Culture Collection (ATCC, Rockville, MD). They vere maintained in Dulbecco's Modified Eagles Medium and Ham's F12 Medium (1:1) isuppleinented vith 10% heat inactivated Fetal Bovine serum, 10 μΜ Herpes, l mM sodium pyruvate, 1 x Non-essential Amino Acids (Gibco) and 2 mM L-glutamine.

The celis vere harvested by vashing cultures vith 10 ml Hank's Balanced Salt Solution (2X) and incubating vith 0.125% Trypsin in Versene (0.02% EDTA) for approximately one minūte. After the celis are visibly rounded and loosened from the flask, 9 ml of the above medium is added. The celis are transferred to a 100 mM culture dish and syringed up and dovn through a 20 gauge needle to break up aggregated clumps of celis. 244

Celi cultures are plated at 0.1 x l06/ml and 0.075 x 106/ml in two 24 veli plates, respectively, aliquoting 1 ml cells/vell. The celis are alloved to attach for 24 hours (48 hours for the lover density plate) before vashing 2X vith HBSS and refed vith 1 ml of the above medium vith 1% Cabosil delipidated serum instead of Fetal Bovine Serum. The celis are treated vith the tēst compounds after 24 hours of exposure to the delipidated serum media.

Chemicals are routinely prepared as a 10 mM solution in 100% ethanol or dimethyl sulfoxide (DMSO). Ali tēst compounds are added at 50 μΜ, 25 μΜ, 10 μΜ, 1 μΜ at a final concentration of 0.45% solvent, 0.25% Bovine Serum Albumin (BSA) suspension per veli. The solvent BSA is sonicated for 10 seconds to ensure maximum solubilization before addition to the celis. Control velis receive solvent/BSA at the same concentrations as the drug treated cultures. After incubation for one hour at 37°C, 5% CO2, 20 μΟί/πιΙ 3H-MVAL is added per veli in ethanol/medium so the final concentration of solvent is 1.2%. After 22 hours of incubation vith the tēst compounds 2.5 μΟί of 14C-acetate is added per veli for an additional 2 hours so that the final concentration of ethanol is 1.6%.

Tvo knovn cholesterol biosynthesis inhibitors are included vith each assay, namely 25-hydroxycholesterol and Lovastatin, to determine the reliability and validity of each assay.

The cultures are harvested by aspirating the media and vashing tvice vith ice cold 0.5 M Tris, 0.15 M LV 10719 245

NaCl/ pH 7.4 to reraove excess radiolabel not incorporated ir.co the celis. Stop Reaģent (1 ni cf 1 pctassium hydroxide, 85% raethanol, 100 μς/ml butvlated hydroxytoluene (BHT) is added to each well and the tlate is sonicated in a mild water sonicating bath tc release the celis from the bottom of the well. The digested celi extracts are transferred to 15 ml extracti.cn tubes. Each well is rinsed with an additional 1 ml cf the Tris/NaCl buffer which is added to the appropriate extraction tube. An aliguot (100 μΐ) is removed fcr protein determination at this point if desired.

The celi extracts are saponified at 80°C fcr 30 minūtes. After cooling 8 ml petroleum ether is added and the tubes are tvirled on a rotary extractor fcr 5-10 minūtes to extract the sterols into the organic sclver.t phase. The top organic phase is removed and passed through a Silica Seppak (Waters) which binds ali sterols and free fatty acids. Sterols are eluted with a 5 ml diethyl ether:hexane (1:1) rinse. This sterols extraction is automated using the Millilab (Waters) tc ensure reproducibility and accuracy from sample to sample.

The eluted sterols are dried under .nitroger. gas and resuspended in 150 μΰ ethanol. A 15 μμ aliguot is removed from each sample and added to a scintiHatior. vial filled with Formula 98 9 (NEN) . The samples are counted on the dual label ^κ:14ς program on the Beckman scintillation counter Modei LS 7800. 246 246 U»

The incorporation of both radiolabeled precursors into sterols is compared betveen the treated and nor.-treated (control) cultures and expressed as "% contrcl" for each precursor. Tēst compounds are classified as being "active" or "inactive" from these results and IC values were determined for active compounds.

Analysis of sterol profilēs is performed on the remainder of the sample by reversed phase KPLC. Analyses are done using an Ultrasphere octyl column (Altex) (0.46 x 25 cm), with a mobile phase consistir.c cf acetonitrilermethanol:H2O (44.5:44.5:10).

Chromatography is performed at a flow rāte of 1.5 ml ce minūte at 45°C.

RESULTS

The folloving IC50 values represent the Ievel c: inhibition of the incorporation of ^^C-acetate into the cholesterol biosynthesis pathway, as determined above:

Compaund Ι£^_ΐμΜΐ

Example 28 (Compound 78) 0.05

Example 29 (Compound 80) >50.0

Example 30 (Compound 81) 0.60 - 247 - LV 10719 ACRICULTURAL UTILITī

Some compounds of this invention have also shovn utility as plant disease control aģents. They are effective in controlling a vide range of plant diseases, including economically important diseases caused by fungi of the Ascomvcetes. Basidiomvcetes. and Oomvcetes classes.

Plant disease control is ordinarily accomplished by appiying an effective amount of the compound either pre- or post-infection to the portion of the plant to be protected, such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in vhich the plants to be protected are groving. The compound may also be applied to the seed froo vhich the plants to be protected are to be grovn. Rātes of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions. Foliage can normally be protected vhen treated at a rāte of from less than 1 g/ha to 5000 g/ha of active ingredient. Plants groving in soil treated at a rāte of from less than 1 g/ha to 5000 g/ha of active ingredient. Plants groving in soil treated at a concentration from 0.1 to about 20 kg/ha can be protected from disease. Seed and seedlings can normally be protected vhen seed is treated at a rāte 0* from 0.06 to about 3 grams per kilogram of seed.

EXAMPLE A

The tēst compounds vere dissolved in acetone ir. amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified 248 vater containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on apple seedlings.

The folloving day plants vere inoculated with a spore suspension of Venturia inaecualis, the casual aģent of apple scab, and incubated in a saturated humidity chamber at 20°C for 2 4 hours and then in a grovth chamber at 22°C for 11 days, vhen disease ratings vere made.

EXAMPLE B

The tēst compounds vere dissolved in acetone in an amount egual to 6% of the final volume and then suspended at a concentration of 200 ppm in purified vater containing 250 ppm of the surfactant TREM 0124 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on peanut seedlings. The folloving day plants vere incubated in a saturated humidity chamber at 22°C for 24 hours, then in a high humidity chamber at 27°C for 7 days, and then in a grovth chamber at 29°C for 7 days, vhen disease ratings vere made.

EXAMPL£ C

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified vater containing 250 ppm of the surfactant TREM 0914 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on broad bean - 249 - - 249 -LV 10719 seedlings. The folloving day plants vere inoculated vith a spore suspension of Botvrtis cinerea. the causal aģent of bean grey mold, and incubated in a saturated humidity chamber at 20°C for 24 hours when disease ratings vere made.

EXAMPLE D

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified vater containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on vheat seedlings.

The folloving day plants vere inoculated vith a spore dust of Ersiphe araminis f. sp. tritici. the causal aģent of vheat povdery mildev, and incubated in a grovth chamber at 20°C for 6 days, vhen disease ratings vere aade.

EXAMPLE E

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified vater containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on rice seedlings. The folloving day plants vere inoculated vith a spore suspension of Pvricularia orvzae. the causal aģent of rice blast, and incubated in a saturated humiditv chamber at 27°C for 24 hours and then in a grovth 250 chamber at 29°C for 4 days, when disease ratings vere made.

EXAMPLE F

The tēst compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 220 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on rice seedlings.

The folloving day plants vere inoculated with a mycelial suspension of Rhizoctonia solani. the causal aģent of rice sheath blight, and incubated in a saturated humidity chamber at 27°C for 48 hours and then in a grovth chamber at 29°C for 4 days, when disease ratings vere made.

ΕΧΑΜΡΙΕ G

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 220 ppm in purified vater containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on vheat seedlings.

The folloving day plants vere inoculated vith a spore suspension of Puccinia recondita. the causal aģent of vheat leaf rust, and incubated in a saturated humiditv chamber at 20°C for 4 8 hours and then in a grovth chamber at 20°C for 8 days, vhen disease ratings vere made. LV 10719 - 251 -EXA-MPL£ Η

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified vater containing 250 ppm of the surfactant TR£M 014 (polyhydric alcohol esters). This suspension vas sprayed to the point cf run-off on tomato seedlings. The folloving day plants vere inoculated vith a spore suspension of Phvtoohthora infestans. the causal aģent of tomato late blight, and incubated in a saturated humidity chamber at 20°C for 48 hours and then in a grovth chamber at 20°C for 5 days, when disease ratings vere made.

EXAMPLE I

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified vater containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on grape seedlings. M»

The folloving day plants vere inoculated vith a spore suspension of Plasmooara victicola, the causal aģent o grape dovny mildev, and incubated in a saturated humidity chamber at 20°C for 24 hours and then in a grovth chamber at 20°C for 7 days, and then held in a saturated humidity chamber at 20°C for 24 hours, vhen disease ratings vere made. 252

EXAMPLE J

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purif^·1 water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on grape seedlings.

The folloving day plants vere inoculated vith a spore suspension of Botrvtis cinerea. the causal aģent of grape grey mold, and incubated in a saturated humidity chamber at 20°C for 96 hours vhen disease ratings vere made.

EXAMPL£ K

The tēst compounds vere dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified vater containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension vas sprayed to the point of run-off on cucum.ber seedlings. The folloving day plants vere inoculated vith a spore suspension of Botrvtis cinerea. the causal aģent of cucumber grey mold, and incubated in a saturated humidity chamber at 20°C for 4 days vhen disease ratings vere made.

Results of Examples A-K for tvo compounds of the invention are presented in Table III. In this table, a rating of 100 indicated 100% disease control, and a rating of 0 indicates no disease control relative to untreated plants that vere inoculated and incubated as described in each Example. A dashed entry indicates the specified tēst vas not performed. LV 10719

- 253 -TABLE III

Examole A B C D £ F Ģ £ T J ;< 1817 90 25 97 92 1 0 62 - - 97 99 1818 99 95 95 98 6 0 100 94 100 78 100 254

The present invention has been described in detail, including the preferred embodiments thereof. Hovever, it vill be appreciated that those skilled in the art, upon consideration of the present disclosure, may make modifications and/or improvements on this invention and stili be vithin the scope and spirit of this invention as set forth in the folloving claims. -255- LV 10719 WHAT IS CLAIMīD IS: 1. Compounds having the formula:

R

vherein R is a side Chain having either 8 or S carbcr. atoms and from 15 to 20 hydrogen atoms, optionally vith one site of unsaturation; and the substituents R^, independently each of R2, and R3, are selected from the groups defined as follovs: R1 o II V) •H ORy , or OCOR^! R2 is K, Cj^-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or benzyl; R3 is K, Cļ-Cg alkyl, C2-Cg alkenyl, C2"C6 alkynyl, benzyl, C(R4)2R5, cor4, csr4, c(=nr4)R4, cor5, csr5 -256- C(R^) 2^(^-4) 2^5' ^ (^4) ' C(K4)2CSR4, C(R4)2C(=NR4)R4, C(R4)2COR5/ C(R4)2 CRS 5, C(R4)2Z, C(R4)2C(R4)2Z, cn, cr4ncr4, cr4nor6/ CR4KN(R4)2, cr4nnr4r6, chr4nhor4, chr4nhor6, CHR4NHN(R4)2, chr4nknr4r6, chr4cr4nor4/ chr4cr4nor6, chr4cr4n-n(R4)2, chr4cr4nnr4r6, chr4chr4nhor4, chr4chr4nhor6, CHR4CHR4NHN(R4)2> C(0)NR40R4, C(0)KR4OR6, C(S)NR4OR4, C(S)NR4OR6/ CR4=CR4R6, C^CRg, CR4=CR4C(R4)2Z, C2CC(R4)2Z, CR4=CR4C(R4)2OR6, C=CC(R4)2OR6, or poly-(OR4, ORg, epoxy)-Cļ-Cg alkyl; R4 is H, Cļ-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, phenyl or phenyl substituted with alkyl, 0R2, Z, N(R2)2, or CFj; or benzyl;

Rg is 0R4, SR4, N(R4)2, or NR4Rg;

Rg is COR4, CSR4, or C(=NR4)R4; R7 is H, C^-C^ alkyl, C2-C20 alkenyl, C2-C2o alkynyl, phenyl or phenyl substituted vith Cļ-C3 alkyl/ 0R2, Z, N (R2) 21 or ci<3' or benzyl; X is 0, S, SO, S02> N, NR4> NRg, or N(0)R4; Z is halogen; and n is 1 or 2; and their physiologically acceptable salts. -257- -257- LV 10719 2. The compounds of Claim 1, vherein: R3 is H, C^-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, benzyl, C(R4)2R5, COR^, CORg/ C(R4)2C(R4)2R5/ C(R4)2COR4, C(R4)2COR5, C(R4)2Z, C(R4)2C(R4)2Z, cn, cr4nor4, cr4nor6, chr4nhor4, chr4nhor6, chr4cr4nor4, CHR4CR4NORg, CHR4Ch'R4KHOR4 , CKR4CHR4NHOR6, C(0)NR40R4, C(0)NR40R6, CR4=CR4Rg, C^CRg, CR4=CR4C(R4)2ORg t C^CC(R4)2ORg, or poly-(OR4, ORg; epoxy)-C^-Cg alkvl. 3. The compounds of Claim 1, vherein: R3 is H, C^-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C(R4)2R5, C0R4, CORg, C(R4)2C(R4)2R5, c(r4)2cor4, ccr4)2cor5, cn, CR4NOR4, CR4NORg, C(0)NR40R4, C(0)NR40Rg, CR4=CR4Rg, CR4*CR4C(R4)20Rg, or poly-(0R4 , OR6, epoxy)-C1-C6 alkyl. 4. The compounds of Claim 1, vherein X is 0, S, so, N, NR4, or NRg. 5. The compounds of Claim 1, vherein n is 1. 6. The compounds of Claim 1, vherein: R3 is H, C1-C6 alkvl, C2-Cg alkenyl, -258- C2-C6 alkynyl, benzyl, C(R4)2R5, COR4, CORg, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2COR5, C(R4)2Z, C(R4)2C(R4)2Z, cn, CR4NOR4, CR4HOR6, CHR4raOR4, chr4nhor6, chr4cr4nor4, chr4cr4nor6> chr4chr4nhor4, CHR4CHR4NHOR6, C(0)KR40R4, C(0)NR40R6, cr4=cr4r6, c=cr6, CR4=CR4C(R4)2OR6/

CrCC(R4)2OR6, or poly-(OR4, ORg, epoxy)-C1-C6 alkyl? X is 0, S, SO, N, KR4, or NR6; and n is 1 7. The compounds of Claim 1, vherein R3 is H, Cļ^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C(R4)2R5, C0R4, cor5, C(R4)2C(R4)2R5, c(r4)2cor4, c(r4)2cor5, CN, CR4NOR4, CR4N0Rg, C(0)NR40R4, C(0)NR40Rg, CR4=CR4Rg, CR4=CR4C(R4)2OR6, or poly-(0R4, ORg, epoxy)-C2_-C4 alkyl; X is 0, S, SO, N, NR4, or NRg; and n is 1. 8. The compounds of Claim 1, vherein R2 is H, C1-C3 alkyl, C2-C3 alkenyl; C2-C3 alkynyl, or benzyl; R3 is H, C2_-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(R4)2R5, C0R4, cor5, C(R4)2C(R4)2R5, -259- -259- LV 10719 C(R4)2COR4, C(R4)2COR5, cn, cr4nor4, cr4nor6, C(0)NR40R4, C(0)NR40R6, cr4=cr4r6, CR4=CR4C(R4)2OR6, or poly-(OR4, 0R6, epoxy)-C3_-C4 alkyl; R4 is H, alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted vith alkyl, OR2, Z, N(R2)2> or CF3; or benzyl; and R6 is C0R4. 9. The compounds of Claim 1, vherein: R2 is H, C3^-03 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or benzyl; R3 is H, alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(R4)2R5, COR4, cor5/ C(R4)2C(R4)2R5/ C(R4)2COR4> C(R4)2CORs, cn, cr4nor4, cr4nor6, C(0)NR40R4, C(0)NR40Rg, cr4«cr4r6, CR4=CR4C(R4)2ORg, or poly-(0R4, ORg, epoxy)-C1-C4 alkyl; R4 is H, Cļ-04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted vith C3_-C3 alkyl, OR2, Z, N(R2)2· or CF3' or benzyl;

Rg is COR4; X is 0, S, SO, N, NR4, or NRg; and n is 1. 10. The compounds of Claim 1, vherein: R2 is H, C2-C3 alkyl, or C2-C3 alkenyl; R3 is H, C1-C4 alkyl, C2-C4 alkenyl, -260- C (R4 )^5, COR4 / CORg , C(R4)2C(R4)2R5< C(r4)2cor4, c(r4)2cor5, cn, cr4nor4, cr4nor6, C(0)NR4OR4, C(0)NR40R6, CR4=CR4Rg, CR4=CR4C(R4)2OR6, or poly-(OR4, ORg, epoxy)-0^-04 alkyl; R4 is H, alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted with Cļ-Cj alkyl, OR2, Z, N(R2)2/ or CF3; or benzyl; R6 is COR4; X is 0, S, SO, N, NR4, or NRg; and n is 1. 11. The compounds of Claim 1, vherein R2 is Η, Cļ -C3 alkyl, C2-C3 alkenyl; R3 is H, -C4 alkyl, C2-C4 alkenyl, ch2r5, chohch=ch2, cor4, cor5, ch2ch2r5, ch2cor4, cn, ch»nor6, CH*N0R5, CONHOR4/ CONHORg, CH=CHRg, chohch2oh, chohchohch2oh, ch-ch2, chohch-^h2 ; o R4 is H, Cļ-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl/ phenyl or phenyl substituted with C1-C3 alkyl, OR2, Z, N(R2)2, or CF3; or benzyl; R6 is C0R4; and X is 0, S, S0, N, NR4, or NRg. 12 . The compounds of Claim 1, vherein R2 is H, Cļ -C3 alkyl, C2-C3 alkenyl; R3 is H, Cļ -C4 alkyl, C2-C4 alkenyl, -261-LV 10719 ch2r5 CHOHCH=CH- COR, CORc ch2ch2r5, ch2cor4, cn, ch=nor4, CH=NORg, COKHOR4, CONHORg, CH=CHRg, chohch2oh, chohchohch2oh, ch-ch2, CHOHCH-CH-,; ^0

V R4 is H, Cx-C4 alkyl, C2-C4 alkenyl, -C2-C4 alkynyl, phenyl or phenyl substituted with C]_-C3 alkyl, OR2, Z, N(R2)2r or CF2; or benzyl;

Rg is C0R4; X is 0, S, SO, N, NR4, or NRg; and n is 1. 13. The compounds of Claim 1, vherein: is H or CH3, is h, ch3, ch=ch2, ch2oh, chohch=ch2, ch2ococh3, cho, coch3, co2k, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3/ cn, ch=noh, ch=nococh3, conhoh, conhococh3, ch-chco2ch3, chohch2oh, chohchohch2ck, CH-CH,, CH0HCH-CH-); and \/ 2 \/2 0 0

X is 0, S, SO, N, NH, NCH3, NCHO, or NC0CH3. 14. The compounds of Claim 1, vherein: R2 is H or CH3, r3 is h, ch3, ch=ch2, ch2oh, chohch=ch2, ch2ococh3, cho, coch3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch=noh, CH=NOCOCH3, CONHOH, CONHOCOCH3, -262- ch=chco2ch3, ckohch2oh, chohchohch2oh, CH-CH,, CHOHCH-CH,; \ / 2 S/ 2 X is 0, S, SO, N, NH, NCH3, or NCOCH3; and NCHO; n is 1. 15. The compounds of Claim 1, vherein: R2 is H, CH3; R3 is h, ch3, ck=ch2> ch2oh, chohch=ch2, cko, co2h, conh2, coch3, CH=NOH, chohch2oh, CHOHCHOHCH2OH; and X is 0, S, SO, N, NH, or NCHO. 16. The compounds of Claim 1, vherein: R2 is H, CH3; R3 is h, ch3, ch-ch2, ch2oh, chohch=ch2, cho, co2h, conh2, coch3, chohch2oh, CHOHCHOHCH2OH; CH=NOH, X is O, S, SO, Ņ, NH, or HCHO; and η * 1. 17. A compound of Claim 1 vhich is selected frora the group consisting of: 15-Oxa-dihydrolanosterol, 4.4- Dimethyl-15-oxa-5a-cholest-8-en-3B-ol, 4.4- Dimethyl-15-oxa-14c -vinyl-5a-cholest- 8-en-35-ol, 3fi-Acetoxy-4,4-dimethyl-15-oxa-14a”Vinyl-5 -cholest-8-ene, 36-Acetoxy-32-hydroxymethyl-15-oxa-lanost-S-en- 32-ol, 3B-Acetoxy-15-oxa-3 2-oxo-lanost-8-ene, -263- LV 10719 15-Oxa-3 2-oxo-dihydrolanosterol, 15-Oxa-lanost-3-ene-3S,32-diol, 15-Oxa-32-vinyl-lanost-8-ene-38,32-diol, 3S-Hydroxy-15-oxa-lanost-8-en-32-aldoxime, 3B-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid, 14a-Oxa-D-homo-dihydrolanosterol, 4.4- Dimethyl-14a-oxa-D-homo-5a“Cholest-8-en-3fl-cl, 4.4- Dimethyl-14a-oxa-14 a-vinyl-D-homo-5«-chclest-8- en-3B-ol, 32-Hydroxymethyl-14a-oxa-D-homo-lanost-3-ene-38 32-diol, 14a-Oxa-3 2-oxo-D-homo-dihydrolanosterol, 14a-Methyl-15-oxa-5a-cholest-8-en-3S-ol, 15-Oxa-14a-vinyl-5a-cholest-8-en-36-ol, 14α -(1',2'-Dihydroxy-ethyl)-15-oxa-5a-cholest-8-en-3S-ol, 14a-Fonnyl-15-oxa-5a-cholest-8-en-3S-ol, 14a-Hydroxymethyl-15-oxa-5a-cholest-8-en-38-ol, 4, 4-Dioethyl-15-thia-5a-cholest-8-en-38-ol, 15-Thia-dihydrolanosterol, 4, 4-Dimethyl-15-thia-14a-vinyl-5a-cholest-8-en- 38-ol, 3B-Hydroxy-15-thia-lanost-8-en-15-oxide, 4.4- Dimethyl-14a-thia-D-homo-5a-cholest-8-en- 3S-ol, 14a-Thia-D-homo-dihydrolanosterol, 15-Aza-4,4-dimethyl-5a-cholesta-8,14-dien-35-ol, and 15-Aza-5a-cholesta-8,14-dien-3S-ol. 18. A compound of claim 1, vhich is selected fror. the group consisting of: 15-0xa-dihydrolanosterol, 4.4- Dimethyl-15-oxa-5a-cholest-8-en-36-ol, -264- 4.4- Dimethyl-15-oxa-14a-vinyl-5a-cholest- 8-en-3S-ol, 38-Acetoxy-4,4-dimethyl-15-oxa-14£i -vinyl-5a - j cholest-8-ene, 3S-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en- 32-01, 3B-Acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-Oxa-32-oxo-dihydrolanosterol, 15-Oxa-lanost-8-ene-3B,32-diol, 15-Oxa-32-vinyl-lanost-8-ene-3B,32-diol, •3B-Hydroxy-15-oxa-lanost-8-en-32-aldoxime, 3S-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid, 14a -Methyl-15-oxa-5a-cholest-8-en-3fl-ol, 15-Oxa-14a-vinyl-5a-cholest-8-en-3B-ol, 14a -(1 ',2' -Dihydroxy-ethyl)-15-oxa-5a-cholest-8-en-3B-ol, 14a -Formyl-15-oxa-5a -choelst-8-en-3B-ol, 14 a-Hydroxymethyl-15-oxa-5a-cholest-8-en-3B-ol-, 4.4- Dimethyl-15-thia-5a-cholest-8-en-3B-ol, 15-Thia-dihydrolanosterol, 4.4- Dimethyl-15-thia-14a-vinyl-5a- cholest-8-en-3S-ol, 3B-Hydroxy-15-thia-lanost-8-en-15-oxide, 15-Aza-4,4-dimethyl-5a-cholesta-8,14-dien-3B-ol, and 15-Aza-5a-cholesta-8,14-dien-3B-ol. 19. A composition suitable for decreasing cholesterol formation in mammals, said composition comprising (i) an effective amount of an active compound of the formula: -265- LV 10719

R

vherein R is a side Chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally vith one site of unsaturation; and wherein the substituents R^, independently each of R2, and R3, are selected from the groups defined as follovs: Rļ is *0, 0R7, or 0C0R7; R2 is H, Cļ-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, or benzyl; R3 is H, C1-C6 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, benzyl, C(R4)2R5, cor4, csr4, C(=NR4)R4, cor5, csr5, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2CSR4, C(R4)2C(=NR4)R4, •C(R4)2COR5, C(R4)2CRS5, C(R4)2Z, C(R4)2C(R4)2Z, cn, CR4NOR4, CR4NOR6, CR4KN(R4)2, cr4nnr4r6, chr4nhor4, chr4nhor6, CKR4NHN(R4)2, chr4nhnr4r6, -266- chr4cr4nor4, chr4cr4nor6, CHR4CR4NN(R4)2, ckr4cr4nnr4r6, ckr4chr4nhor4, chr4chr4nhor6, CHR4CHR4NHK(R4)2, C(0)NR40R4, C(0)NR40R6) C(S)NR4OR4, C(S)NR4OR6, CR4=CR4R6, C=CRg, CR4=CR4C(R4)2Z/ C5CC(R4)2Z, CR4—CR4 C(R4)2 ORg, C=CC(R4)20Rg, or poly-(0R4, ORg, epoxy)-C1-Cg alkyl; R4 is H, C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, phenyl or phenyl substituted with alkyl, OR2, Z, N(R2)2' or CF3 » benzyl;

Rg is OR4, SR4, N(R4)2i NR4Rg!

Rg is COR4, CSR4, or C(=NR4)R4; R7 is H, Cļ_-C2Q alkyl, C2-C20 alkenyl, C2-C20 alkynyl, phenyl or phenyl substituted with C1-C3 alkyl, OR2, Z, N(R2)2/ or CF3; or benzyl; X is 0, S, SO, S02, N, KR4> KRg, or N(0)R4; Z is halogen; and n is 1 or 2; and their physiologically acceptable salts; and (ii) an acceptable pharmaceutical or veterinary carrier or diluent. 20. The composition of claim 19, vherein: R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, benzyl, C(R4)2R5, cor4, cor5, C(R4)2C(R4)2R5, -267- -267-LV 10719 c(r4)2cor4, c(r4)2cor5, C(R4)2Z, C(R4)2C(R4)22, CN, cr4nor4, cr4nor6, chr4nhor4, chr4nhor6, ckr4cr4nor4, chr4cr4nor6, chr4chr4nhor4, CHR4CHR4NHOR6, C(0)NR4OR4, C(0)NR40R6, cr4=cr4r6, C^CRg, cr4=cr4c(R4)20R6,c=cc(R4)2or6, or poly-{OR4, ORg, epoxy)-C1“Cg alkyl. 21. The composition cf claim 19, vherein: R3 is H, C^-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C(R4)2R5, COR4, CORg, C(R4)2C(R4)2R5/ C(R4)2COR4, C(R4)2COR5, cn, CR4NOR4, CR4NOR6, C(0)NR40R4, C(0)NR4OR6, cr4=cr4r6, CR4=CR4C(R4)20Rg, or poly-(OR4, ORg, epoxy)-C1-C6 alkyl. 22. The composition of claim 19, vherein X is 0, S, SO, N, NR4, or NRg. 23. The composition cf claim 19, vherein n is 1. 24. The composition of claim 19, vherein: R3 is H, Cļ-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, benzyl, C(R4)2R5, cor4, cor5, C(R4)2C(R4)2Rs, C(R4)2COR4, C(R4)2COR5, C(R4)2Z, C(R4)2C(R4)2Z, cn, cr4nor4, cr4nor6, chr4nhor4, chr4nhor6, chr4cr4nor4, -268- chr4cr4nor6, chr4chr4nhor4, CHR4CHR4NHOR6> C(0)KR40R4> C(0)NR40R6> cr4=cr4r6, C=CRg/ CR4=CR4C(R4)2OR6/ C^CC(R4)2OR6, or poly-(OR4, 0Rg, epoxy)-C1-Cg alkyl; X is 0, S, SO, N, NR4, or NRg; and n is 1 25. The composition of claim 19, vherein R3 is H, C1-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C(R4)2R5, C0R4, CORj, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2C0Rs, cn, CR4NOR4, CR4NOR6, C(0)NR40R4, C(0)NR40R6, cr4=cr4r6, CR4«CR4C(R4)2OR6, or poly-(0R4, 0Rg, epoxy)-C1-C4 alkyl; X is 0, S, SO, N, NR4, or NRg,· and n is 1. 26. The composition of claim 19, vherein R2 is H, 0χ-03 alkyl, C2-C3 alkenyl, c2“c3 alkynyl, or benzyl; R3 is H, 03-04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(R4)2R5, C0R4, cor5, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2C0R5, cn, CR4NOR4, CR4N0Rg, C(0)KR40R4, C(0)NR40R6, cr4=cr4r6, CR4=CR4C(R4)20Rg, or poly-(0R4, ORg, epoxy)-C1-C4 alkyl; R4 is H, 03-04 alkyl, C2-C4 alkenyl, -269- -269- LV 10719 C2-C4 alkynyl, phenyl or phenyl substituted vith C1-C3 alkyl, OR2, Z, N(R2)2, or CF3; or benzyl; and

Rg is COR^· 27. The composition of claim 19, vherein: R2 is H, Cļ-Cļ alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or benzyl; R3 is H, Cļ-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(R4)2R5, COR4, CORj, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2COR5, cn, cr4nor4, cr4nor6, C(0)NR40R4, C(0)NR40R6, cr4*cr4r6, CR4*CR4C(R4)2OR6, or poly-(OR4, ORg, epoxy) alkyl; R4 is H, alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted vith alkyl, OR2, Z, N (R2) 2 i or CJ>3? or benzyl? R6 is COR4; X is 0, S, SO, N, NR4, or NRg; and n is 1. 28. The composition of claim 19, vherein: R2 is H, Cļ^-C^ alkyl, or C2-C3 alkenyl; R3 is H, Cj_-C4 alkyl, C2-C4 alkenyl, C(R4)2R5, cor4, cor5, C(R4)2C(R4)2R5/ C(R4)2COR4, C(R4)2C0R5, cn, cr4nor4, CR4NOR6, C(0)NR40R4, C(0)NR40R6, cr4=cr4r6, CR4=CR4C(R4)2OR6, or poly-(OR4, ORg, epoxy)-Cļ-C4 alkyl; -270- R4 is H, Cļ_-C4 alkyl, C2-C4 alkenyl, or phenyl or phenyl substituted by Cļ-C alkyl, OR2, Z, N(R2)2, or CF^; or R6 benzyl; is C0R4; X is 0, S, SO, N, NR 4, or KRg; and n is l. 29 . The composition of claim 19, vherein CM is H, Cļ-Cļ alkyl, C2-C3 alkenyl; R3 is H, C1-C4 alkyl, C2-C4 alkenyl, ch2r5, chohch=ch2, C0R4, COR^, ch2ch2r5, ch2cor4, CN, CH=N0R4, ch*nor6, conhor4, COKHORg, CH=CHR6, CH0HCH,0H, CHOHCHOHCH^OH, CH-CH,, CHOHCH-CH,; Y R4 V 2 is H, Cļ-04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted by 0^-03 alkylf OR2, Z, N(R2)2, or cf3' or benzyl? R6 is COR4; and X is 0, S, SO, N, NR4, or NRg. 30. The composition of claim 19, vherein R2 is H, Cļ-03 alkyl, C2’C3 alkenyl; R3 is H, Cļ-C^ alkyl, C2-C4 alkenyl, ch2r5, chohch=ch2, cor4, cor5, ch2ch2r5, ch2cor4, CN, CH :=nor4 , ch=nor6, conhor4, CONHORg , ch=chr6, CHOHCH^OH, CHOHCHOHCHoOH, CH-CH-, , i z \ / *

CHOHCH-CH-, ; O

V -271- -271-LV 10719 R4 is H, C1-C4 alky1, C2-C4 alkenyl, C2-C4 alkenyl, phenyl or phenyl substituted by C^-C^ alkyl, OR2 , z, N(R2)2, or CF3; or benzyl;

Rg is COR4r X is 0, S, S0, N, NR4, or NRg; and n is 1. 31. The composition of claim 19, vherein: R2 is H or CH3> r3 is h, ch3, ch=ch2, ch2oh, chohch=ch2, ch2ococh3, cho, coch3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch=noh, ch=nococh3, conhoh, conhococh3, ch=chco2ch3, chohch2oh, chohchohch2oh, CH-CH,, CHOHCH-CH,; and

V V X is 0, S, SO, N, NH, NCH3, NCHO, OR NCOCH3. 32. The composition of claim 19, vherein: R2 is H or CH3, r3 is h, ch3, ch=ch2, ch2oh, chohch-ch2, ch2ococh3, cho, coch3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch=noh, ch=nococh3, conhoh, conhococh3, ch=chco2ch3, chohch2oh, chohchohch2oh, CH-CH,, \/ 2 CHOHCH-CH->; v 0 0 X is 0, S, SO, N, NH, NCH3, NCHO, or NCOCH 3; and n is 1. -272- 33. The composition of claim 19, vherein: r2 is H, CH3; r3 is h, ch3, ch*ch2, ch2oh, chohch=ch2, cho, co2h, conh2, coch3, ch=noh, CHOHCH2OH, CHOHCHOHCH2OH; and X is 0, S, SO, N, NH, or HCHO. 34. The composition of claim 19, vherein: R2 is H, CH3; r3 is h, ch3, ch=ch2, ch2oh, chohch=ch2, cho, co2h, conh2, coch3, ch=noh, chohch2oh, CHOHCHOHCH2OH; X is 0, S, SO, Η, NH, or NCHO; and n is 1. 35. The composition of claim 19, vherein the preferred compound is selected from the group consisting of: 15-Oxa-dihydrolanosterol, 4.4- Dimethyl-15-oxa-5a-cholest-8-en-35-ol, 4.4- Dimethyl-15-oxa-14c -vinyl-5a-cholest- 8-en-36-ol, 3B-Acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5c:-cholest-8-ene, 35- Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en- 32-ol, 3B-Acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-Oxa-32-oxo-dihydrolanosterol, 15-Oxa-lanost-8-ene-3B,32-diol, 15-Oxa-32-vinyl-lanost-8-ene-3B,32-diol, 3B-Hydroxy-15-oxa-lanost-8-en-3 2-aldoxime, 36- Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid, -273- LV 10719 14α-Oxa-D-homo-dihydrolanosterol, 4, 4-Dimethyl-14a-oxa-D-homo-52-cholest-8-en-36-ol, 4.4- Dimethyl-14a-oxa-14a-vinyl-D-homo-5a-cholest-3- en-36-ol, 3 2-Hydroxymethyl-14 a-oxa-D-homo-lanost-8-ene-3 β 32-diol, 14a-Oxa-32-oxo-D-homo-dihydrolanosterol, 14a-Methyl-15-oxa-5a-cholest-8-en-3fi-ol, 15-Oxa-14a-vinyl-5a-cholest-8-en-3e-ol, 14α-(1',2'-Dihydroxy-ethyl)-15-oxa-5e-cholest-8-en-3B-ol, 14a-Fonnyl-15-oxa-5a-cholest-8-en-3B-ol, 140“HydroxyTnethyl-15-oxa-5 a-cholest-8-en-3e-ol, 4.4- Dimethyl-15-thia-5a-cholest-8-en-3fi-ol, 15-Thia-dihydrolanosterol, 4.4- Dimethyl-15-thia-14a-vinyl-5a-cholest-8-en- 3B-ol, 3fi-Hydroxy-15-thia-lanost-8-en-15-oxide, 4.4- Dimethyl-14a-thia-D-homo-5a-cholest-8-en- 3fi-ol, 14a-Thia-D-homo-dihydrolanosterol, 15-Aza-4,4-dimethyl-5a-cholesta-8,14-dien-3fi-ol, and 15-Aza-5a-cholesta-8,14-dien-3fi-ol. 36. The composition of claim 19, vherein the preferred compound is selected from the grcup consisting of: 15-Oxa-dihydrolanosterol, 4.4- Dimethyl-15-oxa-5a-cholest-8-en-3B-ol, 4.4- Dimethyl-15-oxa-14a -vinyl-5a-cholest- 8-en-3B-ol, 3fi-Acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5a-cholest-8-ene, -274- 35- Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en- 32-ol, 36- Acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-Oxa-32-oxo-dihydrolanosterol, 15-Oxa-lanost-8-ene-3B,32-diol, 15-Oxa-32-vinyl-lanost-8-ene-3B,32-diol, 3B-Hydroxy-15-oxa-lanost-8-en-32-aldoxime, 3S-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid, 14a-Oxa-D-homo-dihydrolanosterol, 4.4- Dimethyl-14a-oxa-D-homo-53-cholest-8-en-36-ol 4.4- Dimethyl-14a-oxa-14a-vinyl-D-homo-5a-cholest- en-36-ol, 32-Hydroxymethyl-14a-oxa-D-homo-lanost-8-ene-3B, 32-diol, 140-Oxa-32-oxo-D-homo-dihydrolanosterol, 143-Hethyl-15-oxa-5a -cholest-8-en-3B-ol, 15-Oxa-14a-vinyl-5a-cholest-8-en-3B-ol, 14a - (l',2'-Dihydroxy-ethyl)-15-oxa-5a-cholest-8-, en-3B-ol, 14a-Forayl-15-oxa-5a-cholest-8-en-3S-ol, 14 a-Hydroxymethyl-15-oxa-5a-cholest-8-en-3B-ol, 4.4- Dimethyl-15-thia-5 a-cholest-8-en-3B-ol, 15-Thia-dihydrolanosterol, 4.4- Dimethyl-15-thia-14o-vinyl-5a-cholest-8-en-, 3B-ol, 3B-Hydroxy-15-thia-lanost-8-en-15-oxide, 4.4- Dimethyl-14a -thia-D-homo-5a-cholest-8-εη-, 3B-ol, 14a -Thia-D-homo-dihydrolanosterol, 15-Aza-4,4-dimethyl-5a-cholesta-8,14-dien-3B-ol, and 15-Aza-5a-cholesta-8,14-dien-3B-ol. 37. A method of decreasing cholesterol forraation in mammals in need of such therapy, said method -275- LV 10719 coraprising administering an effective amcunt of an active compound of the formula:

vherein R is a side Chain having either 8 or 9 carbon atoms and frcm 15 to 20 hydrogen atoms, optionally vith one site of unsaturation; and vherein the substituents R^, independentlv each of R2, and R3, are selected from the groups defined as follovs: Rļ is =0, OR7, or OCOR7 $ R2 is H, Cļ-Cg alkyL, C2-Cg alkenyl, C2-Cg alkynyl, or benzyl; R3 is H, Cļ-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, benzyl, C(R4)2R5, cor4, csr4, C(=NR4)R4, cor5, csr5, C (^4 ) 2^ (^4) 2^5 ' ^ (^4 ) ' C(R4)2CSR4, C(R4)2C(=NR4)R4, C(R4)2COR5, C(R4)2CRS5, C(R4)22, C(R4)2C(R4)2Z, CN, cr4nor4, cr4nor6, CR4NN(R4)2, cr4knr4r6> chr4nhor4, chr4nhor6, chr4nhn(r4)2, chr4nhnr4r6, -276- chr4cr4nor4, chr4cr4nor6, chr4cr4kn(r4)2, chr4cr4nnr4r6, chr4chr4nhor4, chr4chr4khor6, CHR4CHR4NHN(R4)2, C(0)KR40R4, C(0)NR4OR6, C(S)NR4OR4, C(S)NR40R6/ cr4=cr4r6, c=cr6, CR4=CR4C(R4)2Z, C^CC(R4)2Z, CR4=CR4C(R4)2OR6, C5CC(R4)2OR6, or poly-(OR4, 0Rg, epoi^-C^-Cg alkyl; R4 is H, Cļ-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, phenyl or phenyl substituted with Cļ-C3 alkyl, 0R2, Z, N(R2)2, or CF3; or benzyl; R5 is OR4, SR4, N(R4)2, or HR4R6; R6 is COR4, CSR4, or C(=NR4)R4; R7 is H, C1-C20 alkyl, C2-C20 alkenyl, c2“c20 phenyl or phenyl substituted vith C^-C3 alkyl, OR2, Z, N(R2)2» or CF3; or benzyl; X is 0, S, SO, S02, N, KR4, NRg, or N(0)R4; Z is halogen; and n is 1 or 2; and their physiologically acceptable salts in an acceptable pharmaceutical or veterinary carrier or diluent to said mammai. 38. The method of claim 37, vherein: R3 is H, Cļ-Cg alkyl, C2-Cg alkenyl, c2"Cg alkynyl, benzyl, C(R4)2R5, cor4, cor5, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2CORs, -277- LV 10719 C(R4)2Z, c(r4)2c(r4)2z, CN, cr4nor4, cr4nor6, chr4khor4, chr4nhor6, chr4cr4nor4, chr4cr4nor6, chr4chr4nhor4, chr4chr4nhor6, C(0)NR4OR4, C(0)NR40R6, cr4=cr4r6, C=CRg, cr4=cr4c(R4)2or6,c=cc(r4)2or6, or poly-(OR4, ORg, epoxy)-C1-Cg alkyl. 39. The method of claim 37, vherein: R3 is H, Cj_-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C(R4)2R5, COR4, cor5, c(R4)2c(r4)2r5, C(R4)2COR4, C(R4)2CORs, CN, CR4NOR4, CR4NOR6, C(0)NR40R4, C(0)NR40R6, cr4*cr4r6, CR4=CR4C(R4)2OR6, or poly-(OR4, ORg, epoxy)-C1-Cg alkyl. 40. The method of claim 37, vherein X is 0, S, SO, N, NR4, or NRg. 41. The method of claim 37, vherein n is 1. 42. The method of claim 37, vherein: R3 is H, Cļ-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, benzyl, C(R4)2R5, cor4, cor5, c(r4)2c(r4)2r5, C(R4)2COR4, C(R4)2COR5, C(R4)2Z, C(R4)2C(R4)2Z, CN, cr4nor4, cr4nor6, chr4nhor4, chr4nhor6, chr4cr4nor4, CHR4CR4NORg, CHR4CHR4NHOR4, -278- chr4chr4nhor6, C(0)NR40R4, C(0)KR40R6, CR4=CR4R6/ C=CRg, CR4=CR4C(R4)2OR6, C5CC(R4)20R6, or poly-(OR4, 0Rg, alJcyl; X is 0, S, SO, N, NR4, or NRg; and n is 1 43. The method of claim 37, vherein: R3 is H, Cļ-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C(R4)2R5, C0R4, CORg, C(R4)2C(R4)2Rg, C(R4)2COR4, C(R4)2COR5, cn, CR4NOR4, CR4N0Rg, C(0)KR40R4, C(0)NR40Rg, CR4=CR4Rg, CR4=CR4C(R4)20Rg, or poly-(0R4, ORg, epoxy)alkyl; X is 0, S, SO, N, NR4, or NRg; and is 1. 44. The method of· claim 37, vherein: R2 is H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or benzyl; R3 is H, Cļ-04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(R4)2R5, C0R4, COR5, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2COR5, cn, CR4NOR4, CR4N0Rg, C(0)NR40R4, C(0)NR40Rg, CR4=CR4R6, CR4=CR4C(R4)2OR6, or poly-(0R4, ORg, epoxy)-C1-C4 alkyl; R4 is H, Cļ-C^ alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl -279- -279-LV 10719 substituted with Cļ-c3 alkyl, OR2, Z, N(R2)2, or cf3; or benzyl; and Rg is COR4. 45. The method of claim 37, vherein: R2 is H, 03^-03 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or benzyl; R3 is H, 0^04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(R4)2R5, COR4, cor5, C(R4)2C(R4)2r5, C(R4)2COR4, C(R4)2COR5, cn, CR4NOR4, CR4NOR6, C(0)NR40R4, C(0)NR40R6, cr4=cr4r6, CR4=CR4C(R4)20R6, or poly-(OR4, ORg, βροχγ)^^ alkyl; R4 is H, 0^-04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted vith Cļ-Cj alkyl, OR2, Z, N(R2)2i or CF3; or benzyl;

Rg is C0R4; X is 0, S, S0, N, NR4, or NRg; and n is 1. 46. The method of claim 37, vherein: R2 is H, ¢3^-03 alkyl, or C2-C3 alkenyl; R3 is H, C3_-C4 alkyl, C2-C4 alkenyl, C(R4)2r5' cor4' cor5/ C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2COR5, cn, cr4nor4, CR4NOR6, C(0)NR40R4, C(0)NR40Rg, cr4=cr4r6, CR4=CR4C(R4)2OR6, or poly-(0R4, ORg, epoxy )-0^04 alkyl; R4 is H, C^-C4 alkyl, C2-C4 alkenyl, -280- C2-C4 alkynyl, phenyl or phenyl substituted by Cļ - C3 alkyl, 0R2 N(R2)2, or CF3, or benzyl; R6 is C0R4; X is 0, s, so, k, nr4 , or NR6; and n is 1. 47. The method of claim 37, vherein: R2 is H, C1-C3 alkyl, C2~C3 alkenyl; R3 is H, C1-C4 alkyl, C2-C4 alkenyl, ch2r5, chohch=ch2, C0R4, CORg, ch2ch2r5, ch2cor4, CN, CH=N0Rg, CH*K0Rs# C0NH0R4> CONHORg, CH=CHR CHOHCH2OH, CHOHCHOHCH2OH, CH-CH2, CHOHCH-CH,; V M R4 is H, alkyl, C2-C4 alkenyl, phenyl or phenyl substituted by C alkyl, 0R2, Z, N(R2 benzyl; )2, or CF3, or R6 is C0R4; and X is 0, S, SO, N, NR4 , or NRg. 48. The method of claim 37, vherein: R2 is H, C1-C3 alkyl, C2-C3 alkenyl; R3 is H, C1-C4 alkyl, C2-C4 alkenyl, z, ch2r5, chohch=ch2, cor4, cor6, ch2cor4, cn, ch=nor4, ch=nor6, CONHOR4, CONHORg, CH=CHRg, CHOHCH2OH, CHOHCHOHCH5OH, CH-CH,, CH0HCH-CH2

V V is H, Cx-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl -281-LV 10719 substituted by C·^ - c3 alkyl, OR2, 2, N(R2)2I or CF3 / benzyl; R6 1. s COR^ * X is 0, S, SO, N, NR4 , or NRg; and n is 1. 49. The method of claim 37, vherein: R2 is K or CH3, R3 is H, CK3, CH=CH2, ch2oh, chohck=ch2, ck2ococh3, cho, coch3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, CN, CH=N0H, ch=nococh3< conhoh, conhococh3, ch=chco2ch3, chohch 2oh, chohchohch2oh, ch-ch5, CHOHCH-CH,; V V and X is 0, S, SO, N, NH, nch3, NCHO, or ncoch 50. The method of claim 37, vherein: R2 is H or CH3, R3 is H, CH3, CH=CH2, ch2oh, chohch=ch2, ch2ococh3, cho, coch3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, CN, CH=NOH, ch=nococh3, conhoh, conhococh3, ch=chco2ch3, chohch 2oh, chohchohch2oh, CH-CH-,, CHOHCH-CH-j ; V X is 0, S, SO, N, NH, or NCOCH3; and nch3, NCHO; n is 1. -282- 51. The method of claim 37, vherein: R2 is H, CH3; r3 is H, ch3, ch=ch2, ch2oh, chohch=ch2, cho, co2h, conh2, coch3, ch=noh, CHOHCH2OH, CHOHCHOHCH2OH; and X is 0, S, SO, N, NH, or NCHO, 52. The method of claim 37, vherein: R2 is H, CH3; R3 is H, CH3, CH=CH2, CHjOH, chohch=ch2, cho, co2h, conh2, coch3, ch=noh, chohch2oh, CH0HCH0HCH20H; X is 0, S, SO, N, NH, or NCHO; and n is 1. 53. The method of claim 37, vherein the preferred compound is selected from the group consisting of: 15-0xa-dihydrolanosterol, 4.4- Dimethyl-15-oxa-5a-cholest-3-en-3S-ol, 4.4- Dimethyl-15-oxa-14a-vinyl-5a-cholest- 8-en-3B-ol, 3B-Acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5s-cholest-8-ene, 3S-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol, 3B-Acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-Oxa-32-oxo-dihydrolanosterol, 15-Oxa-lanost-8-ene-3B,32-diol, 15-Oxa-32-vinyl-lanost-8-ene-35,32-diol, 3B-Hydroxy-15-oxa-lanost-8-en-32-aldoxime, 3B-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid, 14a-Oxa-D-homo-dihydrolanosterol, -283- LV 10719 4.4- Dimethyl-14 a-oxa-D-homo-5a-cholest-8-en-3B-oi, 4.4- Dimethyl-14a-oxa-14a-vinyl-D-homo-5a-cholest-3- en-3B-ol, 32-Hydroxymethyl-14a-oxa-D-homo-lanost-8-ene-3B 32-diol, 14 a-oxa-32-oxo-D-homo-dihydrolanosterol, 14 a-Methyl-15-oxa-5a -cholest-8-en-3B-ol, 15-Oxa-14a-vinyl-5a-cholest-8-en-3B-ol, 14 a-(l',2 '-Dihydroxy-ethyl)-15-oxa-5a-cholast-8-en-36-ol, 14a-Fonnyl-15-oxa-5a-cholest-8-en-3B-ol, 14a-HydroxyTnethyl-15-oxa-5a-cholest-8-en-3B-cl, 4.4- Dimethyl-15-thia-5a-cholest-8-en-3B-ol, 15-Thia-dihydrolanosterol, 4.4- Dimethyl-15-thia-14a-vinyl-5o-cholest-8-en- 3B-ol, 3S-Hydroxy-15-thia-lanost-8-en-15-oxide, 4.4- Dimethyl-14«-thia-D-homo-5a-cholest-8-en- 3B-ol, 14 a-Thia-D-homo-dihydrolanosterol, 15-Aza-4,4-dimethyl-5o-cholesta-8,14-dien-3B-ol, and 15-Aza-5a-cholesta-8,14-dien-3B-ol. 54. The method of claim 37, vherein the preferrec compound is selected from the group consisting of: 15-Oxa-dihydrolanosterol, 4.4- Dimethyl-15-oxa-5a-cholest-8-en-3B-ol, 4.4- Dimethyl-15-oxa-14e-vinyl-5a-cholest- 8-en-3B-ol, 3B-Acetoxy-4,4-dimethyl-15-oxa-14a -vinyl-5a-cholest-8-ene, 3B-Acetoxy-32-hydroxynethyl-15-oxa-lanost-8-en-32-ol, -284- 3e-Acetoxy-15-oxa-3 2-oxo-lanost-8-ene, 15-Oxa-32-oxo-dihydrolanosterol, 15-Oxa-lanost-8-ene-3S,32-diol, 15-Oxa-32-vinyl-lanost-8-ene-35,3 2-diol, 3S-Hydroxy-15-oxa-lanost-8-en-3 2-aldoxime, 3fi-Hydroxy-15-oxa-lanost-8-en-3 2-carboxylic acid, 14a-Oxa-D-homo-dihydrolancsterol, 4.4- Dimethyl-14a-oxa-D-homo-5 a-cholest-8-en-3S-ol, 4.4- Dimethyl-14a-oxa-14a -vinyl-D-homo-5a-cholest-3- en-35-ol, 3 2-Hydroxymethyl-14a-oxa-D-homo-lanost-8-ene-3 5, 32-diol, 14a-Oxa-3 2-oxo-D-homo-dihydrolanosterol, 14a-Methyl-15-oxa-5a-cholest-8-en-3B-ol, 15-Oxa-14a-vinyl-5a-cholest-8-en-3S-ol, 14a- (i', 2'-Dihydroxy-ethyl) -15-oxa-5a-cholest-8-, en-3B-ol, 14 o-Formy 1-15-oxa-5a-cholest-8-en-3fl-ol, 14o -Hydroxymethyl-15-oxa-5a”Cholest-8-en-3S-ol, 4.4- Dimethyl-15-thia-5a-cholest-8-en-3B-ol, 15-Thia-dihydrolanosterol, 4.4- Dimethyl-15-thia-14a-vinyl-5 a-cholest-8-en-, 3S-ol, 3fl-Hydroxy-15-thia-lanost-8-en-15-oxide, 4.4- Dimethyl-14a-thia-D-homo-5a-cholest-8-en-, 3B-ol, 14a-Thia-D-homo-dihydrolanosterol, 15-Aza-4,4-dimethyl-5o-cholesta-8,14-dien-36-ol, and 15-Aza-5o-cholesta-8,14-dien-3B-ol. 55· A process for the formation of 15-thia-lanosterols having the formula: LV 10719

R

vherein R is a side Chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally vith one site of unsaturation; and vherein the substituents R^, independently each of R2, and R3, are selected from the groups defined as follovs: Rļ is OR7 or OCOR7; R2 is H, C^-Cg alkyl, C2-Cg alJcenyl, C2-Cg alkynyl, or benzyl; R3 is H, C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, benzyl, C(R4)2R5, C(R4)2C(R4)2R5, cr4=cr4r6, CčCRg; R4 is H, C.ļ-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, phenyl or phenyl substituted vith C2-C3 alkyl, OR2, 2, N(R2)2, or CF3; or benzyl;

Rg is OR4, SR4, Ν’ (R4) 2 r ^^4^6'

Rg is COR4, CSR4, or C(=NR4)R4; R7 is H, C1-C20 alkvl, C2-C20 alkenyl, -236- c2~c20 al*ynyl, phenyl or pher.yl substituted vit h Cl-c3 alkyl, 0R2 N(R2)2· or CF3 ; or benzyl; X is S; z is halogen; and n is 1 or 2. vhich process comprises treating a cyclic hemiacetal of the corresponding 15-oxa-dihydrolanosterol (X=o) vith hydrogen sulfide and boron trifluoride etherate in a suitable reaction medium, under suitable reaction conditions, fclloved by reaction of the unisolated cyclic thioacetal intermediate vith a trialkylsi!ane to yield the desired 15-thia-dihydrolanosterol. 56. The process of claim 55, vherein 15-thia-dihydrolanesterol (R3 * CH3) is formed. 57. The process of claim 55, vherein 4.4- Dimethyl-15-thia-5 -cholest-8-en-3S-ol (R3 = H) is formed. 58. The process of claim 55, vherein 4.4- dimethyl-15-thia-14 -vinvl-5 -cholest-8-en-3fi-ol (R3 = ch=CH2) is formed. 59. A method of controlling plant fungal diseases caused by fungi of the Ascometes. Basidiomvcetes, and Oomvcetes classes, vhich method comprises treating plants in need of such treatment vith an effective antifungal amount of one or more compounds having the formula: LV 10719

R

FcrmuJa 1 vhžrsir. R is a sida cbain having either 8 c: S carbcn at oas and froa 15 to 20 hvdrcgen atcns, cp cicnallv vith cne sita of unsaturatisn; and vherei.n the substituants R-! , * independer.tlv each oi R2, ar.d ?.3, ara seieczed f roa the groups deiir.ed as follovs: R1 is »0 , CR-, or OCOR7; *2 is H, C^-Cg alkvi, c2~c6 a-'*snYl' c.-c- L 0 aikvnvi, or benzyl; R3 is E, Cj^-Cg aikvi, C2-C6 ai:<enyl, C2~C6 alkynyi, tenzyl, C(R4-)2R5, ccr4, csr4, c(=nr4)R4, ccr5, csr5 C(R4)2c(R4) 2r5, c(R4'2ccr4< C(R4)2CSR4/ C(R4)2C(=KR4)R,, C(R4)2COR5, C(R4)2CRS5, C(R4)2Z, C(R4)2C(R4)2z, cm, CR4NOR4i CR,MORg, CR4NN(R4)2, CR„ MMR, Rc , CHR, MHOR, , CH?., N’KOR< , CHR4 MHN (R4 ) 2 , CH?.4 MHMR4 Rg , chr4cr4nor4, chr4cr4ncr6, CKR4CR4MM(R4) 2, chr4cr4nmr4r6, CHR4CHR4NKOR4, CKR4CHR4MHORg, -288- N( •Λ ** x r4)2, C(0)NR40R4, C(CiS-?.4CR6, CCS)kr4cr4, c(s;s~.4cr6/ CR4=CR4R6/ C=CRg, cr4=cr4c(r4) 2 *" ' C=CC (R4 ) 2 Z , CR4=CR4C(R4) 2OR5' C5CC(R4)2OR6, or poly-(OR4> ORg, e?c>cy)-C^-Cg alkvl ; R4 is H, Cj_-Cs alkvl, C2-Cg alkenyl, C2-Cg aikynyl, phenyl or phenyl substituted vith C^-C^ alkyl, CR2, K(?.2;2, or CF3; cr benzyl;

Rg is CR,, S?-4, N (R4) 2 , or NR4Rg,*

Rg is ccr4, CSR4, or C(=NR4)R4; R7 is H, C1-C2Ū alkvl, C2-C20 alkenvl, C2-C2q alkvnvl, phenyl or phenvl suistituted vith C^-C^ alkyl, 0R2, N(R2)2/ or CF3; cr benzyl; X is N, NR4, KRg, or N(0)R4? Z is halccen; and n is 1 cr 2; and salts thereof. 60. The zethod of Clain 59, vherein: R2 is K, C^-Cg alkvl, C2-Cg alkenvl, C2-C6 alkynyl, benzyl, C(R4)2R5, C0^4, CORg, C(R4)2C(R4)2R5, C(R4)2COR4, C(R,)2COR5, C(R4)2Z, C(R4)2C(R4)2Z, cn, cr4nor4, cr4nor6, chr4nhor4, c:-r4kkor6 , chr4 cr4nop.4 , ckr4cr4nor6, ckr4ckr4nhor4, CHR4CKR4NHORg, C(0)KR40R4, c (0) NR_.ORg , CR4=CR4Rg, C=CRg , -289- -289- LV 10719 CR^=CR^ C (R4)2ORg , C^CC(R4)2OR6, or poly-(OR4, ORg, epcxy)-C^-Cg alkyl. 61. The method of Claim 59, vherein: R3 is H, Cļ-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C(R4)2R5, C0R4, cor5, C(R4)2C(R4)2R5, C(R4)2COR4, C(R4)2COR5, cn, cr4nor4, CR4NORg, C(0)NR40R4, C(0)NR40R6, cr4=cr4r6, CR4=CR4C(R4)2OR6, or poly-(0R4, ORg, epoxy)-C1-Cg alkyl. 62. The method of Claim 59 , vherein X is N, NR4, or NRg. 63. The method of Claim 60, vherein n is 1. 64. The method of Claim 1, vherein: R3 is H, Cļ-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, benzyl, C(R4)3^5, COR4, C0Rs, C(R4)2C(R4)2R5, C(R4)2COR4, C(R2)4COR5, C(R4)22, C(R4)2C(R4)2Z, CN, cr4nor4, cr4nor6, chr4nhor4, CHR4NHOR6, CHR4CR4NOR4, ckr4cr4nor6, chr4chr4nhor4, CHR4CHR4NHORg, C(0)NR40R4, C(0)NR4OR6, CR4=CR4Rg, C=CRg, CR4=CR4C(R4)2ORg, C=CC(R4)2ORg, or poly-(OR4, ORg, epoxy)-C1-Cg alkyl; -290- X is N, NR4 , or NRg ; and n is 1. 65. The nethod of Claia 59, vherein: r2 is H, Cļ-C2 alkyl, or C2-C3 alkenyl; R3 is H, alkyl, C2-C4 alkenyl, C(R4) 2^5' C0R4, *-0Rg, C(R4)2c(R4)2Rj , C(R4)2COR4, C(R4)2COR5, cn, cr4nor4, CR4N0R6, C(0)NR4OR4, C(0)NR40R6> CR4=CR4Rg, CR4=CR4C(R4)2OR6, or poly-(0R4, 0Rg, epoxy)-C1-C4 alkyl; R4 is H, alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted vith alkyl, 0R2, Z, N(R2)2, - or CF3; or benzyl? R6 is C0R4 ? X is 0, S, SO, N, NR4, or NRg; and n is 1. 66. The method of Claim 59, vherein: R2 is H, Cj^ -C3 alkyl, C2-C3 alkenyl; R3 is H, Cļ -C4 alkyl, C2-C4 alkenyl, ch2r5, chohch=ch2, cor4, cor5, ch2ch2r5, ck2cor4, cn, ch=nor4, CH=N0Rg, C0NH0R4, CONHORg , CH=CKRg,

chohch2oh, chohchohch2oh, ch-ch2, CHOHCH-CH,; V

V R4 is H, Cļ-04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted vith Cļ-C3 alkyl, OR2, Z, N(R2)2, or CF3< or benzyl;

The method of Claim 59, vherein: is H, Cļ_-C3 alkyl, C2-C3 alkenyl; is H, Cļ_-C4 alkyl, C2~C4 alkenyl, ch2r5, chohch=ch2, cor4, cor5, ch2cor5, cn, ch*nor4, ch=nor6, conhor4, CONHORg, CH=CHRg, CHOHCH chohchohch2oh, ςΗ- CH,, CHOHCH-CH·, r v is H, C-L -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted with alkyl, 0R2, Z, N(R2)2, or CF3; or benzyl; is COR4; is N, NR4, or NRg; and is l.

The method of Claim 59, vherein: is H or CH3, is h, ch3, ch=ch2, ch2oh, chohch*ch2, CH2OCOCH3, CKO, COCK3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ck=noh, CH=NOCOCH3, CONHOH, CONHOCOCH3, ch=chco2ch3, chohck2oh, chohchohch2oh, CH-CH-j , CHOHCH-CH, ; and

V V is N, NH, NCH3, NCHO, or NCOCH3. -292- 69. The method of Claim 59, vherein: is K or CH3, is h, ch3, ch=ch2, ch2oh, chqhch=ch2, ch2ococh3, cho, coch3, co2h, conh2, co2ch3, ch2ch2ok, ch2cho, ch2co2h, ch2co2ch3, cn, ch=kok, ch=nococh3, conhoh, conhococh3, ch=chco2ch3, chohch2oh, chohchohch2oh, CH-CK-

CHOHCH-CH 2 '

V *' V is N, NH, NCH3, NCHO, or KCOCH3; and n is 1. 70. The method of claim 59, vherein: R2 is K, CH3; R3 is K, CH3, ch=ch2, ch2oh, chohch=ch2, cko, co2h, conh2, coch3, ch=noh, cho- KCH20H, CHOHCHOHCH2OH; and X is K, NH, or NCHO. 71. The method of claim 59, vherein: R2 is K, CH3; R3 is H, CH3, ch=ch2, ch2oh, chohch=ch2, CHO, C02H, conh2, coch3, ch=noh, chohch2oh, chohchohch2oh; X is N, NH, or NCHO; and n is 1. 72. The method of claim 59, vherein the preferred compound is selected from the group consisting of: -293- LV 10719 15-Aza-4,4-dimethyl-5--cholesta-8,14-dien-38-ol, 15-Aza-5a-cholesta-8,14-dien-3B-ol, 15-Aza-4,4-dimethyl-5a-cholest-8-en-3S-ol, 15-Aza-5a-cholest-8-en-3B-ol, 15-Aza-4,4-dimethyl-15-fonnyl-5 -cholest-8-en-38-ol, 15-Aza-15-fonnyl-5a-cholest-8-en-3fl-ol, 15-Aza-4,4-dimethyl-15-acetyl-5 -cholest-8-en-38-ol, l5-Aza-15-acetyl-5d-cholest-8-en-3S-ol, 15-Aza-14a-cyano-4,4-dimethyl-5 -cholest-8-en-3S-ol, and 15-Aza-14 s-cyano-5a-cholest-8-en-3S-ol. 73. The method of claim 59, vherein the preferred compound is selected from the group consisting of: 15-Aza-4,4-diaethyl-5c-cholesta-8,14-dien-38-ol and 15-Aza-5a-cholesta-8,14-dien-3fl-ol.

Claims (61)

LV 10719 “HETEROCYCLIC STEROID COMPOUNDS1 * PATENT FORMULA POINTS wherein R is a side chain with 8 or 9 carbon atoms and 15-20 hydrogen atoms, not necessarily with one unsaturated reaction center; and the substituents R2 and R3 are independently selected from the group consisting of: Rt is = O, OR; or OCOR ?; R 2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or benzyl; R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; benzyl group CCR1) ^ COR4. CSR4. C (= NR 4) R 4. cor5. csr5. C (R4) 2C (R4) 2R <. C (R4) 2 COR4. C (R 4) 2 cs 4, C (R 4) 2 C (= NR 4) R 4. C (R 4) 2 COR 5, C (R 4) 2 CSR 5, C (R 4) 2 z. 1 C (R 4) 2 C (R 4) 2 Z, CN, CR 4 NOR 4, CR 4 NOR 4, CR 4 NN (R 4) 2 CR 4 NHR 4 R 6, CHR 4 NHOR 4, CHR 4 NHOR 6 > CHR4NHN (R4) 2, cr4 nhnr4r6, chr4cr4nor4, chr4cr4nor6, CHR4CR4NN (R4; 2, chr4cr4nr4r4, chr4 chr4 nhor4, CHR4 CHR4 NHOR *. CHR4 CHR4 NHN (R4) 2, C (O) NR40R4, C (O) NR40R6) , C (S) NR4OR4, C (S) NR4OR6i cr4 = CR4R6, OCR6, CR4 = CR4C (R4) 2Z, C = CC (R4) 2z, CR4 = CR4C (R4; 2 OR6, C = CC (R4) ) 2 OR 4, or poly-OR 4, OR 6, epoxy) -C 1 -C 6 alkyl, R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; R5 is OR4, SR4 > N (R4) 2 or NR4R6; R6 is COR4, CSR4, or C (= NR4) R4; R7 is H, Cp10alkyl, C2-C20 alkenyl, C2-C20 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3: or benzyl, X is O, S, So, SO: N, NR 4 > NR 4, or N (O) R 4; Z is halogen: and n is I or 2, and their physiological combinations of salt. Compounds according to claim 1, wherein R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or benzyl C (R 4) 2 R 5, C (R 4) 2 COR 4. COR4, C (R4) 2Z, CfR4) 2C (R4) 2Z, cn, cr4 nor4. cr4 nor6, chr4nhor4) chr4nhor6, chr4cr4nor4. chr4cr4nor6, cfir4chr4nhor4, CHR4CHR4NOROR0, C (O) NR40R4, CfO) NR4OR6, CR4 = CR4R6, C = CR0. CR 4 = CR 4 Q R 4) 2 OR 6, C = CCf R 4) OR 4, or pol- (OR 4 OR 0, epoxy) -C 1 -C 6 alkyl. Compounds after I: wherein: H, Ct-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C (R4) 2R5, COR4, COR5i C (R4) 2C (R4) 2R5, C (R4) ) 2COR4, C (R4) 2COR5, CN, CR4 NOR4, CR4 NOR6, C (O) NR40R4, C (O) NR40R0, CR4 = CR4R6, CR4 = CR4C (R4) 2OR6, or poly (OR4, OR6, Compounds after I, wherein X is O, S, SO, N, NR 4, or NR 4 Compounds of formula I wherein n is I, Compounds after I, wherein: is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or benzyl C (R 4) 2 R 5, COR 4) COR 5, C (R 4) 2 R 5, C (R 4) 2 OR 4, C (R 4) 2 COR 5, C (R 4) 2 Z, C (R 4) 2 C (R 4) 2 Z, c n, cr 4 nor 4, cr 4 nor n, chr 4 nhor 4, chr 4 nhor 6, chr 4 chr 4 nhor 4, chr 4 chr 4 nhor «, C (O) NR 40 R 4, C (O) NR 40 R 6, CR 4 = CR 4 R 6, C = CR 6, CR 4 = CR 4 C (R 4) 2 OR 6, or poly (OR 4, OR 6, epoxy-C 1-4 alkylalkyl is O, S, SO, N, NR 4, or NR 4, and iri. wherein: H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C (R 4) 2 R 5, COR 4, COR 5, C (R 4) 2 C (R 4) 2 R 5, C (R 4) 2 CO 4, C (R 4) 2 OR 5, CN , CR4 NOR4, CR4 NOR ^ C (O) NR 40 R 4, C (O) NR 40 R 6, CR 4 = CR 4 R 6, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl; and O.S, So, N, NR4. or NR6; and is I. Compounds of formula I wherein: H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or benzyl: is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C (R 4) 2R5, COR4, COR5, C (R4) 2C (R4): R3. C (R4): C0R4. C (R4) 2COR5, CN, CR4 NOR4, CR4 NOR6 > C (O) NR 40 R 4j C (O) NR 40 R 6, CR 4 = CR 4 R 6, CR 4 = CR 4 C (R 4) 2 OR 6, or poly (OR 4, R 6, epoxy) -C 1 -C 4 alkyl; R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; and R 4 is COR 4. Compounds according to claim 1, wherein: R 2 is H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or benzyl; R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl C (R 4) 2 R 5, COR 4, COR 5, C (R 4) 2 C (R 4) 2 R 5, C (R 4) 2 CO 4, C (R 4) 2 OR 5, CN , CR 4 NORs, C (O) NR 40 R 4, C (O) NR 40 R 6, CR 4 = CR 4 R 6, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl; R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R6 and COR4; X is O, S, SO, N, NR 4, or NR 6; and n is I. Compounds according to claim 1, wherein: R 2 is H, C 1 -C 3 alkyl or C 2 -C 3 alkenyl R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C (R 4) 2 R 5, COR 4, COR 5, C (R 4) 2 C (R4) 2R5, C (R4) 2COR4, C (R4) 2COR5, CN. CR 4 NOR 4, CR 4 NOR 0, C (O) NR 40 R 4, C (O) NR 40 R 6, CR 4 = CR 4 R 10, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4, OR 4, epoxy) -C 1 -C 4 alkyl; R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R6 and COR4; X is O, S, SO, N, NR 4, or NR 6; and n is I. is. r2 Compounds of formula I wherein: H, C 1 -C 3 alkyl or C 2 -C 3 alkenyl; and H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, CH 2 R 5, CHOHCH = CH 2, cor 4, COR 5, CH 2 CH 2 R 5, CH 2 CO 4, CN, CH = NOR 6, CH NOR 5, CONHOR 4, CONHOR g, CH = CHR 6, CHOHCH, OH, CHOHCHOHCH.OH, CH -CH, • CHOHCH-CH2; V R4 Rf X is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; and COR4; and is O, S, SO, N, NR 4, or NR 4. 12. R2 R3 Compounds of formula I wherein: H, C1-C3 alkyl or C2-C3 alkenyl; is C 1 -C 4 alkyl, C 2 -C 4 alkenyl; ch2r5, chohch = ch2, cor4, cor5, ch2ch2r5, ch2cor4, CN, CH = NOR4, CH = NOR6, CONHOR4, conhor6, ch = chr6, CHOHCH-iOH. CHOHCHOHCH.OH, CH-CH1 CHOHCH-CH,; ^ R4 R4 R n n is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl. phenyl or phenyl substituted with C1-C3 alkyl, OR2. Z, N (R 2) 2 or CF 3; or benzyl; and COR4; is 0, S, SO, N, NR 4, or NR 6; and iri. Compounds according to claim 1, wherein: R2 is H, CH3, R3 is H, CH3, CH = CH2, CH2OH, CHOHCH = CH2, CH2OCOCH3, CHO, coch3, co2h, conh2. co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch = noh, ch = nococh3, conhoh, conhococh3, ch = chco2ch3, CHOHCH2OH, CHOHCHOHCH, OH, CH-CH2, CHOHCH-CH ,; and V V X is O, S, SO, N, NH, NCH 3, NCHO, or NCOCH 3. Compounds according to claim 1, wherein: R2 is H, CH3) R3 is H, CH3i CH = CH2, CH2OH, CHOHCH = CH2 > CH2OCOCH3, CHO, coch3, co2h, conh2. co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch = noh, ch = nococh3, conhoh, CONHOCOCH1, CH = CHCO2CH3, CHOHCH1OH, CHOHCHOHCH2OH, CH-CH, CHOHCH-CH, V'X and 0, S, SO, N, NH. NCH3, NCHO, or NCOCH3; and n is I. Compounds according to claim 1, wherein: R2 is H, CH3, R3 is H, CH3, CH = CH2, CH2OH, CHOHCH = CH2, CHO, CO2H, CONH2, COCH3, CH = NOH, CHOHCH2OH, CHOHCHOHCH2OH; and X is O.S., SO. N, NH. or NCHO. Compounds according to claim 1, wherein: R2 is H, CH3, R3 is H, CH3, CH = CH:. CH: OH, CHOHCH = CH2, CHO. CO: H. CONH2. COCH3, CH = NOH, CHOHCH2OH. CHOHCHOHCH.OH: X is O. S, SO, N, NH, or NCHO; and 6 LV 10719 n is I. 17. The compound of claim 1, which is taken from the group of compounds: 15-oxa-dihydrolanosterine, 4.4-dimethyl-15-oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15-oxa. -14a-vinyl-5α-holest-8-ene-3β-ol, 3β-acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5α-holest-8-ene, 3β-acetoxy-32-hydroxymethyl -15-oxazanost-8-ene-32-ol, 3β-acetoxy-15-oxa-32-oxa-lanost-8-ene, 15-oxa-32-oxo-dihydrolanosterin, 15-oxa-lanost-8 -ene-3β-, 32-diol, 15-oxa-32-vinyl-lanost-8-ene-3β-, 32-diol, 3β-hydroxy-15-oxa-Ianost-8-ene-32-aldoxime, 3P -hydroxy-15-oxananost-8-ene-32-carboxylic acid, 14a-oxa-D-homo-dihydrolanosterine, 4.4-dimethyl-14a-oxa-D-homo-5α-holest-8-ene-3β-ol , 4.4-Dimethyl-14a-oxa-14a-vinyl-D-homo-5α-holest-8-en-3β-ol, 32-hydroxymethyl-14a-oxa-D-homoanost-8-en-3P-32 diol. 14α-Oxa-32-oxo-D-homo-dihydrolanosterine, 14α-methyl-15-oxa-5α-holest-8-ene-3β-ol, 15-oxa-14a-vinyl-5α-holest-8-ene 3β-ol, 14α- (2'-dihydroxy-ethyl) -15-oxa-5α-holest-8-en-3β-ol. 14a-formyl-15-oxa-5α-holest-8-ene-3β-ol, 14a-hydroxymethyl-15-oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15-thio-14α vinyl 5α-holest-8-ene-3β-ol, 15-thio-dihydrolanosterine, 3β-hydroxy-15-thiolane-8e-15-oxide. 4.4-Dimethyl-14a-thio-D-homo-5α-holest-8-ene-3β-ol, 14a-thio-D-homohydro-dihydrolanosterine, 15-aza-4,4-dimethyl-5α-holest-8. 14-dien-3β-ol, and 15-aza-5α-holesta-8,14-diene-3β-ol. 7 18. The compound of claim 1, which is taken from the group of compounds: 15-oxa-dihydrolanosterine, 4.4-dimethyl-15-oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15-oxa. -14α-vinyl-5α-holest-8-en-3β-ol, 3β-acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5α-holest-8-ene, 3β-acetoxy-32-hydroxymethyl -15-oxa-lanost-8-ene-32-ol, 3β-acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-oxa-32-oxo-dihydrolanosterin, 15-oxa-lanost-8 -ene-3β, 32-diol, 15-oxa-32-vinyl-lanost-8-ene-3β, 32-diol, 3β-hydroxy-15-oxazanost-8-ene-32-aldoxime, 3P-hydroxy -15-oxa-lanost-8-ene-32-carboxylic acid, 14a-methyl-15-oxa-5α-cholest-8-ene-3β-ol, 15-oxa-14a-vinyl-5α-holest-8-ene -3p-ols, 14α- (2'-dihydroxy-ethyl) -15-oxa-5α-cholest-8-ene-3β-ol, 14a-formyl-15-oxa-5α-holest-8-ene 3β-ol, 14α-hydroxymethyl-15-oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15-thio-5α-holest-8-en-3β-ol. 15-Thio-dihydrolanosterine, 4.4-Dimethyl-15-thio-14a-vinyl-5α-holest-8-ene-3β-ol, 3β-hydroxy-15-thiolanostene-8-oxide, 15-aza -4,4-dimethyl-5α-holesta-8,14-diene-3β-ol; and 15-aza-5α-holesta-8,14-diene-3β-ol. 19. A composition useful for reducing cholesterol formation in warm-blooded animals comprising (i) an effective amount of the active compound, formula I: 8 LV 10719 wherein: R is a side chain with 8 or 9 carbon atoms and 15-20 hydrogen atoms, not necessarily one unsaturated reaction center; and substitutes Rj. R2 and R:. independently of one another are taken from the groups designated: R [is = O, OR7 or OCOR7; R 2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or benzyl; R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl C (R 4) 2 R 5, COR 4, CSR 4, C (= NR 4) R 4, cor 5, C 5, C (R 4) 2 C (R 4) 2 R 5, C ( R4) 2 COR4i C (R4) 2 CSR4, C (R4) 2C (= NR4) R4i C (R4) 2 COR5, C (R4) 2 CRS5, C (R4) 2Z. C (R 4) 2 C (R 4) 2 z, cn, CR 4 NOR 4 j CR 4 NOR 6, CR 4 NN (R 4) 2. cr4 nnr4r6, chr4nhor4, CHR4NHOR6, CHR4NHN (R4) 2, c4nrr4, chr4cr4nor4, chr4cr4nor6, chr4cr4nn (R4) 2, chr4cr4nnr4r6, chr4 chr4 nhor4, CHR4 CHR4 NHOR4, CHR4 CHR4 NHN (R4) 2i C (O) NR40R4i C (O) NR 40 R 6, C (S) NR 4 OR 4, C (S) NR 4 OR 6, cr 4 = C 4 R 6, C = CR 6, CR 4 = CR 4 C (R 4) 2 Z, OCC (R 4) 2 z, CR 4 = CR 4 C (R 4) 2 OR 6, C = CC (R4) 2OR6, or poly-OR4, OR6, epoxy) -CrC6alkyl. R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl: R5 is OR4, SR4, N (R4) 2 or NR4R6; R 4 is COR 4, CSR 4, or C (= NR 4) R 4: R 7 is H. C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z. N (R 2) 2 or CF 3; or benzyl; X is O, S, SO, SO 2. N, NR 4, NR 6, or N (O) R 4; Z is halogen; and n is I or 2; and its physiologically acceptable salts; and (ii) a pharmaceutically acceptable or diluent carrier or diluent. 9 A composition according to claim 19, wherein R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl C (R 4) 2 R 5, COR 4, COR 5, C (R 4) 2 C (R 4): R 5. C (R 4) 2 COR 4, Cf R 4) COR 5, C (R 4) 2 Z. C (R 4) 2 C (R 4) 2 Z, CN, CR 4 NOR 4, CR 4 NOR 6, CHR 4 NHOR 4. CHR4NHOR < "chr4cr4nor4, chr4cr4nor6, chr4chr4nhor4. chr4chr4nhor6, C (O) NR40R4, CfO) NR4OR6, CR4 = CR4R6, c = CR6, CR4 = CR4C (R4) 2OR6, C = CC (R4) 2OR0. or poly-OR 4, OR 6, epoxy) -C 1 -C 6 alkyl. Composition according to claim 19, wherein: R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C (R 4) 2 R 5, COR 4, COR 3, C (R 4) 2 C (R 4) 2 R 5, C (R 4) 2 COR4i C (R4) 2 COR3, CN, CR4 NOR4, CR4 NOR0, C (O) NR40R4i C (O) NR40R6, CR4 = CR4R6, CR4 = CR4C (R4) 2OR6, or poly (OR4, OR6, epoxy) -C 1 -C 6 alkyl. The composition of claim 19, wherein X is O, S. SO, N, NR 4, or NR 4 23. Composition according to p. 19 wherein n is I. 24. A composition according to claim 19, wherein: R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, benzyl, C (R4) 2R5, COR4, COR5, C (R4) 2C (R4) 2R5, C (R4) R4) 2COR4, C (R4) 2COR5, C (R4) 2Z, C (R4) 2C (R4) 2Z, CN, CR4NOR4, cr4nor6, chr4nhor4, chr4nhor6, chr4cr4nor4. CHR4CR4NOR0, CHR4CHR4NOROR4, CHR4CHR4NOROR6, C (O) NR40R4, C (O) NR40R6, CR4 = CR4R6, C = CR6, CR4 = CR4C (R4) 2OR6, CsCC1R4 OR6. or poly (OR4.OR6, epoxy) -C1-C6alkyl. X is O, S. SO. N, NR 4, or NR 6, n is I. The composition of claim 19, wherein: R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C (R 4) 2 R 5, COR 4. COR5, C (R4); C (R4) 2R5, C (R4) 2COR4, 10U10719 C (R4) 2COR5, CN, CR4NOR4) CR4NOR6) C (O) NR40R4, C (O) NR40R6, CR4 = CR4R6, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4 OR 0, epoxy) -C 1 -C 6 alkyl. X is O, S, SO, N, NR 4, or NR 0, and n is I. The composition of claim 19, wherein: R 2 is H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or benzyl; R3 is H, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, benzyl, C (R4) 2R5i COR4, COR5, C (R4) 2C (R4) 2R5, C (R4) 2COR4, C (R4) 2COR5 , CN, CR4NOR4, CR1NOR4, C (O) NR40R4, C (O) NR40R11, CR11 CR11, CR4 = CR4C (R4) 2OR6, or pol- (OR4, OR6, epoxy) -C1-C4alkyl. R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; and R < 5 and COR4. The composition of claim 19, wherein: R 2 is H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or benzyl; R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl. C (R4) 2R5, COR4, COR5, C (R4) 2C (R4) 2R5, C (R4) 2COR4, C (R4) 2COR3, CN, CR4NOR4, CR4NOR6, C (O) NR40R4, C (O) NR40R6, CR 4 = CR 4 R 6, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl. R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R;) 2 or CF 3; or benzyl; R6 and CORj. X is O, S. So, N. NR 4, or NR 6, and n is I. 11 Composition after 19, wherein: is H, C 1 -C 3 alkyl, or C 2 -C 3 alkenyl is H, C [- C4 alkyl, C2-C4 alkenyl, C (R4) 2R5, COR4, COR5, C (R4) 2C (R4) 2R5, C (R4) 2COR4, C (R4) 2COR5, CN, CR4NOR4, CR4NOR6, C (O) NR40R4i C (O) NR 40 R 6i CR 1 CR 1 R 4, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl. and COR4; X is O, S, So, N, NR 4, or NR 6; and n is I. Composition according to claim 19, wherein: is H, C 1 -C 3 alkyl, or C 2 -C 3 alkenyl is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, CH 2 R 5, CHOHCH = CH 2, COR 4, COR 5) CH 2 CH 2 R 5, CH 2 CO 4 , CN, CH = NOR4, ch = nor6, conhor4, conhor6, ch = chr6, chohch2oh, chohchohch2oh, CH-CH-, CHOHCH-CH- »; o 'V' is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z. N (R 2) 2 or CF 3; or benzyl; and COR4; and X is O, S, SO, N, NR 4, or NR 6. Composition 19, wherein: is H, C 1 -C 3 alkyl, or C 2 -C 3 alkenyl is H. C 1 -C 4 alkyl, C 2 -C 4 alkenyl, CH 2 R 5, CHOHCH = CH 2, COR 4, cor 5, CH 2 CH 2 R 5, CH 2 CO 4, CN, CH = NOR4, CH = NOR6, conhor4, conhorl, ch = chr6, chohch2oh, chohchohch2oh, CH-CH-), CHOHCH-CH ,; V 'V' is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkenyl, LV 10719 phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R6 and COR4; X is O, S, SO, N, NR 4, or NR 6; and n is I. The composition of claim 19, wherein: R 2 is H, or CH 3. R3 is H, CH3 -CH = CH2, CH2OH, CHOHCH = CH2, CH2OCOCH3, CHO, coch3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch = noh, ch = nococh3, CONHOH, CONHOCOCH3 ) CH = CHCO2 CH3, CHOHCH2OH, CHOHCHOHCH1OH, CH-CH,. CHOHCH-CH; and V " V X is O, S, SO, N, NH, NCH 3, NCHO, or NCOCH 3. The composition of claim 19, wherein: R 2 is H, or CH 3. R3 is H, CH3, CH = CH2, CH2OH, CHOHCH = CH2, CH2OCOCH3, CHO, COCH3, co2h, conh2, co2ch3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch = noh, ch = nococh3, CONHOH, CONHOCOCH3 , CH = CHCO2 CH3, CHOHCH2OH, CHOHCHOHCH.OH, CH-CH,. CHOHCH-CH; Xo '' V 'X is 0, S, SO. N, NH, NCH 3. NCHO, or NCOCH3; and n is I. The composition of claim 19, wherein: R is H, or CH 3. R3 is H. CH3, CH = CH2, CH2OH, CHOHCH = CH2, CHO, CO2H, CONH2, COCH3. CH = NOH, CHOHCH2OH, CHOHCHOHCH2OH. and 1 X is O, S, SO. N, NH, or NCHO. 34. Composition according to claim 19 which: R is H or CH3. R3 is H. CH3 CH = CH; CH2OH, CHOHCH = CH2, CHO, CO2H, CONH; COCH3, CH = NOH, CHOHCH: OH, CHOHCHOHCH.OH; X irO, S, SO. N, NH, or NCHO; and n is I. 35. A composition according to claim 19, wherein the desired compound is taken from the group of compounds: 15-oxa-dihydrolanosterine, 4.4-dimethyl-15-oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15 -oxa-14a-vinyl-5α-holest-8-en-3β-ol, 3-p-acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5α-holest-8-ene. 33-Acetoxy-32-hydroxymethyl-15-oxananost-8-ene-32-ol, 3β-acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-oxa-32-oxo-dihydrolanosterin, -oxane-8-ene-3β, 32-diol. 15-oxa-32-vinyl-lanost-8-ene-3β-, 32-diol, 3β-hydroxy-15-oxazanost-8-ene-32-aldoxime, 3β-hydroxy-15-oxa-lanost-8 -en-32-carboxylic acid, 14a-oxa-D-homo-dihydrolane terine. 4.4-Dimethyl-14a-oxa-D-homo-5α-holest-8-ene-3β-ol, 4.4-Dimethyl-14α-α-α-14α-vinyl-D-homo-5α-holest-8-ene 3P-ols. 32-Hydroxymethyl-14a-oxa-D-homoanost-8-ene-3β-32-diol, 14α-oxa-32-oxo-D-homohydrolanosterine, 14α-methyl-15-oxa-5α-holestol 8-ene-3β-ol, 15-oxa-14a-vinyl-5α-holest-8-ene-3β-ol, 14α (I ', 2'-dihydroxyethyl) -15-oxa-5α-holestol 8-ene-3β-ol, 14a-formyl-15-oxa-5α-cholest-8-ene-3β-ol, 14α-hydroxymethyl-15-thio-5α-holest-8-en-3β-ol, 10719 14α-Dimethyl-15-oxa-5α-holest-8-ene-3β-ol, 15-thio-dihydrolanosterine, 4.4-dimethyl-15-thio-14a-vinyl-5α-holest-8-en-3β-ol , 3β-Hydroxy-15-thiolane-8-ene-15-oxide, 4.4-dimethyl-14a-thio-D-homo-5α-holest-8-ene-3β-ol, 14a-thio-D-homohydro dihydrolanosterine , 15-aza-4,4-dimethyl-5α-holesta-8, 14-diene-3β-ol, and 15-aza-5α-holesta-8,14-diene-3β-ol. 36. A composition according to claim 19, wherein the desired compound is taken from the group of compounds: 15-oxa-dihydrolanosterine, 4.4-dimethyl-15-oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15 -oxa-14a-vinyl-5α-holest-8-en-3β-ol, 3β-acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5α-holest-8-ene, 3β-acetoxy- 32-hydroxymethyl-15-oxananost-8-en-32-ol. 3 β-acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-oxa-32-oxo-dihydrolanosterine, 15-oxazanost-8-ene-3β, 32-diol, 15-oxa-32 -vinylanost-8-ene-3β, 32-diol, 3β-hydroxy-15-oxananost-8-ene-32-aldoxime, 3β-hydroxy-15-oxazanost-8-ene-32-carboxylic acid , 14a-oxa-D-homo-dohydrolanosterine, 4.4-dimethyl-14a-oxa-D-homo-5α-holest-8-ene-3β-ol. 4.4-Dimethyl-14a-oxa-14a-vinyl-D-homo-5α-holest-8-ene-3β-ol, 32-hydroxymethyl-14a-oxa-D-homoanost-8-en-3p. 32-diol, 14a-oxa-32-oxo-D-homo-dihydro-olanterine, 14a-methyl-15-oxa-5α-holest-5-ene-3β-ol, 15-oxa-14a-vinyl-5α-cholesto- 8-ene-3β-ol, 14α- (2'-dihydroxy-ethyl) -15-oxa-5α-holest-8-ene-3β-ol, 14a-formyl-15-oxa-5α-holest-S -en-3β-ol, 14α-hydroxymethyl-15-oxa-5α-holest-8-en-3β-ol, 4.4-dimethyl-15-thio-14α-vinyl-5α-holest-8-en-3β-ol , 15-thio-dihydrolanosterl. 4.4-Dimethyl-15-thio-14a-vinyl-5α-holest-8-ene-3β-ol, 3β-hydroxy-15-thioanost-8-ene-15-oxide, 4.4-dimethyl-14a-thio- D-homo-5α-holest-8-ene-3β-ol, 14α-thio-D-homohydrolanosterin. 15-aza-4,4-dimethyl-5α-holesta-8, 14-diene-3β-ol, and 15-aza-5α-holest-8. 14-diene-3β-ol. 37. A method for reducing cholesterol formation in warm-blooded animals, if they require a therapy consisting of an effective amount of the active compound of formula I: wherein: R is a side chain with 8 or 9 carbon atoms and 15-20 hydrogen atoms, optionally with one unsaturated reaction center; and wherein the substituents R 1 R 2 and R 3 are independently selected from the group consisting of: R 1 is = O, O R 7, or OCOR 7; R 2 is H. C 1 -C 6 alkyl, C 2 -C 6 alkenyl. C2-C6 alkynyl or benzyl; R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl. C2-C6 alkynyl. benzyl group C (R4) 2R5, COR4, CSR4i C (= NR4iR4c5c5cr5, C (R4): C (R4) 2R5, C (R4) 2 COR4C (R4) 2 cs4. C (R4) 2C (= NR 4) R 4 C (R 4) 2 COR 5 C (R 4) 2 CSR 5, C (R 4) 2 z, C (R 4) 2 C (R 4) 2 Z. CN, CR 4 NOR 4 CR 4 N 0 R 6, CR 4 NN (R 4) ) 2 CR4 NNR4R6.CHR4NHOR4, CHR4NHOR6, CHR4NHN (R4) 2, 16EU 10719 CHR4 NHNR4R6, CHR4CR4NOR4, CHR4CR4NOR6i CHR4CR4NN ('R4) 2, chr4cr4nnr4r6, chr4 chr4 nhor4, chr4 chr4 nhor *, CHR4 CHR4 NHN (R4) 2, CHR4 CHR4 NHN (R4) 2, C (O) NR 4 OR 4, C (O) NR 40 R 6, C (S) NR 4 OR 4, Q S) NR 4 OR 6, CR 4 = CR 4 R 6, OCR 0, CR 4 = CR 4 C (R 4) 2 Z, C = CC (R 4) 2 z, CR 4 = CR 4 C ( R4) 2OR6, C5- or *, or poly-OR4, OR6, epoxy) -C [-C6] alkyl. R 4 is H, C 1 -C 6 alkyl. C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R 5 is OR 4, SR 4, N (R 4) 2 or NR 4; R6 is COR4, CSR4, or C (= NR4) R4; R7 is H, CrC20alkyl. C2-C20alkenyl, C2-C20 alkynyl. phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; X is O, S, SO, SO 2. N. NR4, NR6, or N (O) R4; Z is halogen; and n is or 2; and its physiologically acceptable salts; and (ii) carriers or solvents acceptable in pharmacy or veterinary administration to said animal. 38. The method of claim 37 wherein: R3 is H, C1-C6 alkyl. C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl C (R 4) 2 R 5, COR 4. C0R5. C (R 4) 2 C (R 4) 2 R 5, C (R 4) 2 COR 4, C (R 4) 2 COR 5, C (R 4) 2 Z, C (R 4) 2 C (R 4) 2 Z, CN, cr 4 nor 4. cr4 nor6. chr4 nhor4 chr4nhor6, chr4cr4nor4, CHR4CR4NOR0, CHR4CHR4NHOR4. CHR4CHR4NHORb, C (O) NR40R4. C (O) NR 40 R 6, CR 4 = CR 4 R 6, C 5 -C 10 CR 4 = CR 4 C (R 4); C = CC (R 4) 2 OR 6, or poly-OR 4, OR 6, epoxy) C 1 -C 6 alkyl. 17 39. The method of claim 37, wherein: R3 is H.C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C (R4) 2R5. COR4. COR5, C (R4) 2C (R4) 2R5, C (R4) 2 COR4. C (R4) 2 COR5, CN, CR4 NOR4 > CR4 NOR0, C (O) NR40R4, C (O) NR40R0, CR4 = CR4R6, CR4 = CR4C (R4) 2OR6, or pol- (OR4, OR6, epoxy) -C1-C6 alkyl. 40. The method of claim 37, wherein X is O, S, SO, N, NR 4, or NR 4 ,. 41. The method of claim 37, wherein n is I. 42. The method of claim 37, wherein: R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, benzyl, C (R 4) 2 R 5, COR 4, COR 5, C (R 4) 2 C (R 4) 2 R 5, C ( R4) 2COR4, C (R4) 2COR5, C (R4) 2Z, C (R4) 2C (R4) 2Z, CN, cr4nor4, cr4nor6, chr4nhor4, chr4nhor6, chr4cr4nor4, CHR4CR4NOR6, CHR4CHR4NHOR4, CHR4CHR4NHOR6, C (O) NR40R4, C (O) NR40R4, C (O) NR 40 R 6, CR 4 = CR 4 R 6, C = CR 6, CR 4 = CR 4 C (R 4) 2 OR 6, C = CC (R 4) 2 OR 11, or pol- (OR 4, OR 6, epoxy) -C 1 -C 6 alkyl. X is O, S, SO, N, NR 4, or NR 6; and n is I. The method of claim 37, wherein: R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C (R 4) 2 R 5, COR 4, COR 5, C (R 4) 2 C (R 4) 2 R 5, C ( R 4) 2 cor 4, C (R 4) 2 COR 5, CN, CR 4 NOR 4, CR 4 NOR 0, C (O) NR 40 R 4, C (O) NR 40 R 6, CR 4 = CR 4 R 10, CR 4 = CR 4 C (R 4) 2 OR 6, or poly (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl. X is O, S, SO, N, NR 4, or NR 6; and n is I. The method of claim 37, wherein: R 2 is H. C 1 -C 3 alkyl, C 2 -C 3 alkenyl. C2-C3 alkynyl or benzyl; R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl. C2-C4 alkynyl, 18 LV 10719 C (R4) 2R3, COR4, COR5, C (R4) 2C (R4) 2R3, C (R4) 2COR4i C (R4) 2COR3, CN, CR4NOR4, CR4NOR6, C (O) NR40R4, C (O) NR 40 R 6, CR 4 = CR 4 R 6, CR 4 = CR 4 C (R 4) 2 OR 6, or poly (OR 1 OR 4, epoxy) -C 1 -C 4 alkyl. R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1-4 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; and R 6 is COR 4. The method of claim 37, wherein: R 2 is H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or benzyl; R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C (R 4) 2 R 5, COR 4, COR 5, C (R 4) 2 C (R 4) 2 R 5 > C (R4) 2COR4, C (R4) 2COR5, CN. CR 4 NR 4, CR 4 NR 6, C (O) NR 40 R 4, C (O) NR 40 R 6, CR 4 = CR 4 R 6, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl; R4 is H, C1-C4 alkyl, C2-C4 alkenyl. C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R6 and COR4. X is O, S, SO, N, NR 4, or NR 6, and n is I. The method of claim 37, wherein: R 2 is H, C 1 -C 3 alkyl, or C 2 -C 3 alkenyl, R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C (R 4) 2 R 5, COR 4, COR 5, C (R 4) ) 2C (R4) 2R3, C (R4) 2COR4, C (R4) 2COR3. CN, CR4NOR4. CR4NOR6. C (O) NR 40 R 4, C (O) NR 40 R 6, CR 4 = CR 4 R d, CR 4 = CR 4 C (R 4) 2 OR 6, or pol- (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl. R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, 19 N (R 2) 2 or CF 3; or benzyl; R6 and COR4. X is O, S, SO. N, NR4, or NR0: and n are I. The method of claim 37, wherein: R 2 is H, C 1 -C 3 alkyl, or C 2 -C 3 alkenyl, R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, CH 2 R 5, CHOHCH = CH 2, CONHOR4, CONHOR * CH = CHR6, CHOHCH2OH, CHOHCHOHCH2OH, C2, CHOHCH-CH2; R 4 is H, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, No (R 2) 2 or CF 3; or benzyl; R 4 and COR 4; and X is O, S, SO, N, NR 4, or NR 6. 48. The method of claim 37 wherein: R2 is H, C1-C3 alkyl, C2-C3 alkenyl, R3 is H, C1-C4 alkyl, C2-C4 alkenyl, CH2R5, CHOHCH = CH2, COR4, COR6, CH2COR4, CN, CH = NOR4 , CF ^ NOR ^, RONHOR4, conhor6, ch = chr6, chohch2oh, chohchohch2oh, CH-CH ·,. CHOHCH-CH2; R4 is H, C1-C4 alkyl, C2-C4 alkenyl. C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl: R6 is COR4; X is O, S, SO. N, NR4. or NR6: and n are I. 20 EN 10719 49. The method of claim 37, wherein: R2 is H, or CH3. R3 is H. CH3-CH = CH: CH2OH, CHOHCH = CH2, CH2OCOCH3, CHO, coch3, co2h, conh2, co2ch3, ch2ch2, ch2cho, ch2co2h, ch2co2ch3, cn, ch = noh, ch = nococh3, CONHOH CONHOCOCH3, CH = CHCO2CH3, CHOHCH2OH, CHOHCHOHCH-, OH, CH-CH1CHOHCH-CH,; and V V X is O, S, SO, N, NH, NCH 3, NCHO, or NCOCH 3. 50. The method of claim 37 wherein: R2 is H or CH3. R3 is H, CH3, CH = CH2,, CH2OH, CHOHCH = CH2, CH2OCOCH3, CHO, COCH3, CO2H, conh2, co2ch3, ch2 ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch = well. ch = nococh3, CONHOH, CONHOCOCH1, CH = CHCO, CH3, CHOHCH; OH, CHOHCH2OH, CH-CH2, CHOHCH-CH2; X is O, S, SO, N, NH, NCH 3 >NCHO; or NCOCH3; and n is I. 51. The method of claim 37, wherein: R2 is H or CH3; R3 is H. CH3 CH = CH2, CH2OH, CHOHCH = CH2, CHO, CO2H. CONH2. COCH3. CH = NOH, CHOHCH2OH, CHOHCHOHCH2OH; X is O, S. SO, N, NH, or NCHO. n and I. 52. The method of claim 37 wherein: R2 is H. CH3: R3 is H. CH3, CH = CH ;, CH2OH, CHOHCH = CH2. CHO, CO2H. CONH2, COCH3. CH = NOH, CHOHCHOH, CHOHCHOHCH2OH; X X is O, S, SO, N, NH, or NCHO; and iri. n 53. The method of claim 37, wherein the desired compound is taken from the following group of compounds: 15-oxa-dihydrolanosterol. 4.4-Dimethyl-15-oxa-5α-holest-8-en-3β-ol, 4.4-Dimethyl-15-oxa-14a-vinyl-5α-holest-8-ene-3β-ol, 3P-acetoxy-4, 4-Dimethyl-15-oxa-14a-vinyl-5α-holest-8-ene, 3β-acetoxy-32-hydroxymethyl-15-oxananost-8-en-32-ol. 3β-acetoxy-15-oxa-32-oxo-lanost-8-ene, 15-oxa-32-oxo-dihydrolanosterine, 15-oxananost-8-ene-3β-, 32-diol, 15-oxa-32 -vinylanost-8-ene-3β-, 32-diol, 3β-hydroxy-15-oxazanost-8-ene-32-aldoxime, 3β-hydroxy-15-oxazanost-8-en-32- Carboxylic acid, 14α-oxa-D-homo-dihydro-lanolin, 4.4-dimethyl-14a-oxa-D-homo-5α-holest-8-ene-3β-ol, 4.4-dimethyl-14a-oxa-14α vinyl-D-homo-5α-holest-8-en-3β-ol, 32-hydroxymethyl-14a-oxa-D-homoanost-8-ene-3β-32-diol, 14α-oxa-32-oxo D-homo-dihydrolanosterine, 14α-methyl-15-oxa-5α-holest-8-ene-3β-ol, 15-oxa-14α-vinyl-5α-holest-8-en-3β-ol, 14α (I ', 2'-dihydroxyethyl-15-oxa-5α-holest-8-ene-3β-ol, 14a-formyl-15-oxa-5α-holest-8-ene-3β-ol, 14a-hydroxymethyl-15 oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15-thio-5α-holest-8-ene-3β-ol, 15-thio-dihydrolanosterine, 4.4-dimethyl-15-thio-14a -vinyl-5α-cholest-8-ene-3β-ol, 3β-hydroxy-15-thioanost-8-ene-15-oxide, 4.4-dimethyl-14a-thio-D-homo-5α-holest-8-ene -3P-ol, I 4α-Thio-D-homo-dihydrolanosterin, LV 10719 15-aza-4,4-dimethyl-5α-holesta-8,14-diene-3β-ol, and 15-aza-5α-holesta-8, 14-diene -3p-ol. 54. The method of claim 37, wherein the desired compound is taken from the group of compounds: 15-oxa-dihydrolanosterine, 4.4-dimethyl-15-oxa-5α-holest-8-ene-3β-ol, 4.4-dimethyl-15 -oxa-14a-vinyl-5α-holest-8-en-3β-ol, 3β-acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5α-holest-8-ene, 3β-acetoxy-32 -hydroxymethyl-15-oxazanost-8-en-32-ol, 3β-acetoxy-15-oxa-32-oxo-1anost-8-ene, 15-oxa-32-oxo-dihydrolanosterine, 15-oxa-lanostane -8-ene-3β, 32-diol, 15-oxa-32-vinyl-lanost-8-ene-3β, 32-diol, 3β-hydroxy-15-oxazanost-8-ene-32-aldoxime, 3p -hydroxy-15-oxananost-8-ene-32-carboxylic acid. 14a-oxa-D-homo-dihydrolanosterine, 4.4-dimethyl-14a-oxa-D-homo-5α-holest-8-ene-3β-ol, 4.4-dimethyl-14a-oxa-14a-vinyl-D-homo 5α-Cholest-8-ene-3β-ol, 32-hydroxymethyl-14α-oxa-D-homo -lanost-8-ene-3β, 32-diol, 14α-oxa-32-oxo-D-homohydrohydanolanosterin, 14α-Methyl-15-oxa-5α-holest-8-ene-3β-ol, 15-oxa-14α-vinyl-5α-holest-8-ene-3β-ol, 14α (η, 2'-dihydroxy) ethyl) -15-oxa-5α-holest-8-ene-3β-ol, 14a-formyl-15-oxa-5α-holest-8-ene-3β-ol, 14α-hydroxymethyl-15-oxa-5α-holest -8-en-3β-ol, 4.4-dimethyl-15-thio-5α-holest-8-ene-3β-ol, 15-thio-dihydrolanosterine, 4.4-dimethyl-15-thio-14a-vinyl-5α-holest -8-ene-3β-ol, 3β-hydroxy-15-thiolanost-8-ene-15-oxide, 4.4-dimethyl-14a-thio-D-homo-5α-holest-8-ene-3β-ol , 14α-Thio-D-homohydrolanosterine, 23 β-aza-4,4-dimethyl-5α-holesta-8,14-diene-3β-ol, and 15-aza-5α-holesta-8, 14-diene -3P-ol. 55. A method for obtaining 15-thio-lanosterins of the formula: wherein: R is a side chain with 8 or 9 carbon atoms and 15-20 hydrogen atoms, optionally with one unsaturated reaction center; and wherein the substituents R 1, R 1, and R 3 are independently selected from the group consisting of: R! is OR7 or OCOR7; R; is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or benzyl: R 3 is H, C 1 -C 6 alkyl. C 2 -C 6 alkenyl, C 2 -C 6 alkynyl. benzyl. C (R4) 2R5, C (R4) 2C (R4) 2R5, CR4 = CR4R6, C = CR6; R 4 is H, C 1 -C 4 alkyl. C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR: Z, N (R 2) 2 or CF 3; or benzyl:. . R5 is OR4, SR4, N (R4) 2 or NR4R6; R6 and COR4. CSR4. or C (= NR 4) R 4: R 7 is H. C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl. phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzylgmpu: X is S; Z is halogen; and n is I or 2; 10719 which consists of cyclic semi-acetal (from the corresponding 15-oxa-dihydrolanosterine: X = 0) treated with hydrogen sulphide and boron trifluoride etherate in a suitable reaction medium and under the reaction of the following undissolved cyclic thioacetal intermediate with trialkylsilane to give the desired 15-thio -dihydrolanosterol. 56. The method of claim 55, wherein 15-thio-dihydrolanosterol is obtained (R3 = CH3). 57. The method of claim 55, wherein 4,4-dimethyl-15-thio-5-holest-8-en-3β-ol is obtained (R3 = H). 58. The method of claim 55, wherein 4.4-dimethyl-15-thio-14-vinyl-5-holest-8-en-3β-ol (R3 = CH = CH :) is obtained. 59. A method for controlling plant fungi caused by fungi of the following classes: Ascometes, Basidiomycetes and Oomycetes, consisting of an effective amount of the treatment of the plants for which it is needed with one or more compounds of formula: R F% 2 Rz wherein R is a side chain with 8 or 9 carbon atoms and 15 to 20 hydrogen atoms, not necessarily with one unsaturated reaction center; and wherein the substituents R 2 and R 3 are selected from the group consisting of: R 1 is = O, OR 7 or OCOR 7: R 1 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or benzyl; R 3 is H, C 1 -C 6 alkyl. C 2 -C 6 alkenyl, C 2 -C 6 alkynyl benzyl C 1 -C 4 R 1, COR 4. CSR4, C (= NR4) R4, cor5, cs5, C (R4) 2C (R4) 2R5. C (R4) 2 COR4. C (R4) 2 csr4. 25 C (R4) 2C (= NR4) R4, C (R4) 2 COR5, C (R4) 2 CSR5, C (R4) 2Z, C (R4) 2C (R4) 2 Z, CN, CR4 NOR4, CR4 NOR6, CR4 NH (R4) 2 CR4 NNR4R6. CHR4NHOR4, CHRjNHOR *, CHR4NHN (R4) 2l chr4 nhnr4r6, chr4cr4nor4, chr4cr4nor6, CHR4CR4NN (R4) 2, chr4cr4nnr4r6, chr4 chr4 nhor4, CHR4 CHR4 NHOR4, CHR4 CHR4 NHN (R4) 2, C (O) NR40R4, C (O) NR40R4, C (O) NR40R4, C (O) NR40R4, C (0) NR40R4, C 0) NR40R6i C (S) NR4OR4 > C (S) NR4OR6, CR4 = CR4R6, C = CR6, CR4 = CR4C (R4) 2Z, CsCC (R4) 2z, CR4 = CR4C (R4) 2 OR6, C = CC (R4) 2OR6, or (OR 4, OR 6, epoxy) -C 1 -C 6 alkyl. R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R 5 is OR 4, SR 4, N (R 4) 2 or NR 4; R < 5 > COR4, CSR4, or C (= NR4) R4; R7 is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl. phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; X is N, NR 4, NR 6, or N (O) R 4; Z is halogen; and n is I or 2; and their salts. 60. The method of claim 59, wherein: R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or benzyl C (R4) 2R5, COR4, COR5, C (R4) 2C (R4) 2R5C (R4) ) 2COR4, C (R4) 2COR3, C (R4) 2Z, C (R4) 2C (R4) 2Z, cn, cr4 nor4, cr4 nor6, chr4nhor4, chr4nhor6, chr4cr4nor4, chr4cr4nor6, chr4chr4nhor4, CHR4CHR4NHOR6, C (0) NR40R4, C (O) NR40R6 cr4 = CR4R6, ChCR6, CR4 = CR4C (R4) 2 OR6, C = CC (R4) 2 or6, or pol- (OR4, OR6, epoxy) -C [-C6alkyl]. 26 EN 10719 61. The method of claim 59, wherein: R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynylC (R4) 2, COR4, COR5, C (R4) 2C (R4) 2R5, C (R4) 2COR4, C (R2) 4COR5, CN, CR4 NOR4i CR4 NOR6) C (O) NR40R4, C (O) NR4OR6, CR4 = CR11, CR4 = CR4C (R4) 2OR6, or poly (OR4, OR6, epoxy) ) -C 1 -C 6 alkyl. 62. The method of claim 59, wherein: X is N, NR 4 or NR 6. 63. The method of claim 60, wherein: n is I. 64. The method of claim 1, wherein: R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl benzyl, C (R4) 2, COR4) COR5, C (R4) 2C (R4) 2R5 > C (R4) 2COR4, C (R4) 2COR4, C (R2) 4COR5, C (R4) 2Z, C (R4) 2C (R4) 2Z, CN, CR4 nor4, cr4 nor6, chr4nhor4, chr4nhor6, chr4cr4nor4, chr4cr4nor6, chr4chr4nhor4, CHR4CHR4NOROR6, C (O) NR40R4, C (O) NR40R6 cr4 = cr4r6, C = CR6, CR4 = CR4C (R4) 2 OR4C = CC (R4) 2 ORs, or poly (OR4, OR4, R4) Epoxyl-C 1 -C 8 alkylalkyl: X is N, NR 4, NR 6, and n is I. 65. The method of claim 59, wherein: R2 is H, C1-C3 alkyl, or C2-C3 alkenyl, R3 is H, C1-C4 alkyl, C2-C4 alkenyl, C (R4) 2R5, COR4, COR5, C (R4) 2C (R4) ); R5, C (R4) 2COR4, C (R4) 2COR5, CN, CR4 NOR4, CR4 NOR6, C (O) NR40R4j C (O) NR40R6, CR4 = CR4R6, CR4 = CR4C (R4) 2OR6, or poly - (OR 4, OR 6, epoxy) -C 1 -C 4 alkyl; R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R6 and COR4; 27 X is O, S, SO, N, NR 4, or NR g; and n iri. 66. The method of claim 59, wherein: R2 is H, C1-C3 alkyl, C2-C3 alkenyl; R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, CH 2 R 5, CHOHCH = CH 2, COR4, COR5, CH2CH2R5, CH2COR4, CN, CH = NOR4, CH = NOR *, CONHOR4, CONHORe, CH = CHR6, CHOHCH2 = OH, CHOHCHOHCH2OH, C4 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; Re is COR4; and X is N, NR 4, or NR 6. 67. The method of claim 59, wherein: R2 is H, C1-C3 alkyl, C2-C3 alkenyl; N, N 2, R 2, nuncn-c, R 3 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, CH 2 R 5, CHOHCH = CH 2, COR 4, cor 5, CH 2 COR 5, CN, CH = NOR 4, CH = nor 6, CONHOR 4, CONHORe, CH = CHR6, CHOHCH2 = OH, CHOHCHOHCH2OH, CH-CH2, CHOHCH-CH2; R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl or phenyl substituted with C 1 -C 3 alkyl, OR 2, Z, N (R 2) 2 or CF 3; or benzyl; R6 and COR4; X is N, NR 4, or NR 6; and n is I. 28 EN 10719 68. A method according to claim 59, wherein: R 2 is H a CH 3, R 3 is H, CH 3, CH = CH 2, CH 2 OH, CHOHCH = CH 2, CH 2 OCOCH 3, cho, coch 3, co 2h, con 2, co 2 ch 3, ch2ch2oh, ch2cho, ch2co2h, ch2co2ch3, cn, ch = noh, ch = nococh3, conhoh, conhococh3, ch = chco2ch3 > chohch2oh, chohchohch2oh, CH-CH2, CHOHCH-CH2; and 2 0 0 X is N, NH, NH 3, NCHO, or NCOCH 3. 69. The method of claim 59, wherein: R2 is H, or CH3; R3 is H, CH3, CH = CH2, CH2OH, CHOHCH = CH2, CH2OCOCH3, CHO, COCH3, co2h, conh2, co2ch3, CH2CH2OH, ch2cho, ch2co2h, ch2co2ch3, cn, ch = noh, ch = nococh3, conhoh. conhococh3, ch = chco2ch3, chohch2oh, chohchohch2oh, CH-CH-, CHOHCH-CH '.; and V 'V! '0 ° X n is N, NH, NCH 3, NCHO, or NCOCH 3; and is I. 70. The method of claim 59, wherein: R2 is H, or CH3; R3 is H, CH3i CH = CH2, CH2OH, CHOHCH = CH2, CHO, CO2H, CONH: COCH3, CH = NOH, CHOHCH2OH, CHOHCHOHCH2OH: and X is N, NH, or NCHO. 71. The method of claim 59, wherein: R2 is H, or CH3; R3 is H, CH3, CH = CH:. CH2OH, CHOHCH = CH: CHO, CO2H. CONH ,. COCH3, CH = NOH, CHOHCH, OH, CHOHCHOHCH6OH; X is N, NH, or NCHO; and 29 η is I. The method of claim 59, wherein the desired compound is selected from the group consisting of 15-aza-4,4-dimethyl-5α-holesta-8,14-dienol-4-ol. and 15-aza-5α-holesta-8,14-diene-3β-ol. 15-Aza-4,4-dimethyl-5α-cholest-8-ene-3β-ols, 15-aza-5α-holest-8-ene-3β-ol, 15-aza-4,4-dimethyl-15 -formyl-5-holest-8-en-3β-ol, 15-aza-15-formyl-5α-holest-8-en-3β-ol, 15-aza-4,4-dimethyl-15-acetyl-5 -cholest-8-en-3β-ol, 15-aza-15-acetyl-5α-holest-8-ene-3β-ol, 15-aza-14a-cyano-4,4-dimethyl-5-cholesterol 8-ene-3β-ol, and 15-aza-14α-cyano-5-holest-8-en-3β-ol. 73. The method of claim 59, wherein the desired compound is selected from the group consisting of 15-aza-4,4-dimethyl-5cc-cholest-8,14-dienol-4-ol, and 15-aza-5a-holol. -8,14-diene-3β-ol. 30