Heterocyclic steroid compounds

Description

FIELD OF THE INVENTION
The present invention relates to novel substituted 15-oxa-, 15-thia-, and 15-aza- dihydrolanosterols, to pharmaceutical compositions containing such compounds, and to methods of using these compounds to suppress the activity of 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMGR), an enzyme which is important in sterol biosynthesis. The overall effect of these heterocyclic lanosterol analogs is to decrease sterol formation, thereby resulting in lower serum cholesterol levels 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 contributing 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 levels in the blood, arterial plaque formation and CHD can potentially be avoided. See, e.g., Brensike et al., Circulation, 69: 313-324 (1984) and Levy et 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 which to date are only partially understood. As Rodwell et al., Adv. Lipid Res., 14: 1074 (1976) indicate, HMGR is generally accepted as the rate-limiting enzyme which controls cholesterol biosynthesis from acetyl-CoA in all organisms.
Brown et al., J. Lipid Res., 21: 505-517 (1980) have shown that regulation of HMGR is a complex process which is under a feedback control mechanism involving both steroidal as well as nonsteroidal isoprenoid metabolites. These authors point out that under normal conditions, the ability of cholesterol to regulate its own biosynthesis when associated with lipoprotein particles is one aspect of this feedback control mechanism.
Moreover, it has been demonstrated that various oxygenated sterols, when used in a highly purified state, are even more effective than cholesterol in attenuating the amount of HMGR activity, see Breslow et al., Biochem. Biophys. Acta, 398: 10-17 (1975), Kandutsch et al., J. Biol. Chem., 252: 409-415 (1977), and Chen et 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 in situ. See, Kandutsch et al., Science, 201: 498-501 (1978).
This proposition stimulated considerable research activity. See, e.g., Chen et al., J. Biol. Chem., 254: 715-720 (1979); Havel et al., J. Biol. Chem., 254: 9573-9582 (1979); Chang et al., J. Biol. Chem., 255: 7787-7795 (1980); Chorvat, U.S. Pat. No. 4,230,626 (1980); Gibbons et al., J. Biol. Chem., 255: 395:400, (1980); Kandutsch et al., J. Biol. Chem., 255: 10814-10821 (1980); Cavenee et al., J. Biol. Chem., 256: 2675-2681 (1981); Tanaka et al., J. Biol. Chem., 258: 13331-13339 (1983) and Trzaskos et al., Fed. Proc., 44: 656, (1985). As a result, a number of inhibitors of HMGR activity have been found.
Gibbons et al., J. Biol. Chem., 255: 395-400 (1980), for example, have shown that certain synthetic oxygenated lanosterol derivatives are active inhibitors of HMGR activity. Trzaskos et al., Fed. Proc., 44: 656 (1985) have established that in situ generation of the Gibbons compounds leads to attenuated HMGR activity and decreased cholesterol biosynthesis.
In addition, Schroepfer et al., U. S. Patent No. 4,202,891 and Schroepfer et al., Proc. Natl. Acad. Sci. USA. 81: 6861-6865 (1984) have revealed that other oxygenated lanosterol derivatives may be successfully employed to lower serum cholesterol levels in animals.
INFORMATION DISCLOSURE
Heterocyclic steroid compounds have been prepared in the past. For example, U.S. Pat. Nos. 3,845,203 (Williams et al.); 3,887,433 (Williams et al.); 3,887,564 (Williams et al.); 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 (Chamberlin) are directed to various aza steroid compounds. Oxa steroid derivatives are disclosed in U.S. Pat. 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 et al., Zhurnal Organicheskoi Khimi, 22: 121-132 (1986).
None of the aforementioned heterocyclic steroid compounds are described as having utility against cholesterol biosynthesis. Thus, additional compounds which affect HMGR and/or other enzymes critical to serum cholesterol biosynthesis are needed. The present invention is directed to this end.
SUMMARY OF THE INVENTION
The present invention provides novel substituted 15-oxa-, 15-thia-, and 15-aza-dihydrolanosterol compounds of the formula: ##STR1## wherein 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 with one site of unsaturation;
R.sub.1 is .dbd.O, OR.sub.7 or OCOR.sub.7 ;
R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, arylalkyl;
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, arylalkyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4)4COR.sub.5, C(R.sub.4).sub.2 CSR.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 N.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6 CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6 CHR.sub.4 CHR.sub. 4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, aryl, arylalkyl;
R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, NR.sub.4 R.sub.6 ;
R.sub.6 is COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4 ;
R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, aryl, arylalkyl;
X is O, S, SO, SO.sub.2, N, NR.sub.4, NR.sub.6, N(O)R.sub.4 ;
Z 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, which is essential in the cholesterol biosynthetic pathway, cholesterol formation is decreased and serum cholesterol levels lowered. Thus, the present invention also includes therapeutic pharmaceutical compositions for suppressing HMGR activity, decreasing cholesterol formation and lowering serum cholesterol levels.
The pharmaceutical compositions comprises (i) an effective amount of a compound of the formula: ##STR2## wherein 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 with one site of unsaturation;
R.sub.1 is .dbd.O, OR.sub.7 or OCOR.sub.7 ;
R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, arylalkyl;
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, arylalkyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.4 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 N.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6 CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6 CHR.sub.4 CHR.sub. 4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, aryl, arylalkyl;
R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, NR.sub.4 R.sub.6 ;
R.sub.6 is COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4 ;
R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, aryl, arylalkyl;
X is O, S, SO, SO.sub.2, N, NR.sub.4, NR.sub.6 N(O)R.sub.4 ;
Z is halogen; and
n is 1 or 2;
and
(ii) a pharmaceutically acceptable carrier or diluent.
In addition, the present invention encompasses methods for suppressing HMGR activity, decreasing cholesterol formation and lowering serum cholesterol levels comprising administering to a host an effective amount of a compound of the formula: ##STR3## wherein 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 with one site of unsaturation;
R.sub.1 is .dbd.O, OR.sub.7 or OCOR.sub.7 ;
R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl;
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.4 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 N.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6 CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6 CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, aryl, benzyl;
R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, NR.sub.4 R.sub.6 ;
R.sub.6 is COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4 ;
R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, aryl, benzyl;
X is O, S, SO, SO.sub.2, N, NR.sub.4, NR.sub.6, N(O)R.sub.4 ;
Z is halogen; and
n is 1 or 2.
In the above formulae, the R side chain is preferably selected from the cholesterol side chain (C.sub.8 H.sub.17) and the ergosterol side chain (C.sub.9 H.sub.17). These are generically represented by the formula: ##STR4## where the dashed line represents an optional double bond and the circled alpha-methyl group is likewise optional. However, when the D ring is piperidine or the N-oxide thereof, the R side chain is not an ergosterol side chain.
Likewise, in the above formulae, the ring structure may be unsaturated between carbons 7 and 8 or 8 and 9. When X is N the structure has an additional double bond between C-14 and N and C-14 does not have R.sub.3 substitution.
As used herein, the substituent designated as "poly-(OR.sub.4, OR.sub.5, epoxy) C.sub.1 -C.sub.6 alkyl" shall be taken to mean a C.sub.1 to C.sub.6 alkyl chain substituted with one or more of any combination of OR.sub.4, OR.sub.5 and epoxy.
As used herein, the term "alkyl" employed either alone or in combination with other terms such as "poly-(OR.sub.4, OR.sub.5, epoxy) C.sub.1 -C.sub.6 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 with 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 with 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.
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 levels in mammals. These compounds can be administered alone, or in combination 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 well-known 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, weight and species of mammal treated.
While not wishing to be bound to theory or conjecture, a brief description of the mechanism by which the active 15-oxa-, 15-thia-, and 15-aza-dihydro-lanosterol compounds of the present invention are believed to function is as follows.
The observed decrease in HMGR activity is thought to occur as a result of a decreased synthesis of HMGR protein and/or an enhanced rate of HMGR degradation (collectively termed herein as "suppression").
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, which involves an opening and a reclosing of the D ring of the steroidal structure, was developed. In the schemes and tables which follow, for simplicity, only the cholesterol side chain (C.sub.8 H.sub.17) is shown. It is to be understood that the ergosterol side chain (C.sub.9 H.sub.17) or modifications of either side chain may be present instead of the illustrated cholesterol side chain.
15-Oxa-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) followed by an oxidative cleavage of the resulting diol, Compound 3 (See, Scheme I). ##STR5##
The starting species, Compound 2a, 4-dimethyl-5a-cholesta-8,14-dien-3b-ol, was prepared from 7-dehydrocholesterol (Sigma Chemical Co., P.O. Box 14508, St. Louis, Mo. 63178) by the method described by Bloch and Gautschi in J. Chem. Soc., 223 (6), 1343 (1958). Treatment of the 8,14-dien-3b-ol (2a) with sodium hydride (Alfa Products, P.O. Box 299, Danvers, Mass. 01923) and 4-methoxybenzyl chloride [prepared by the method described by R. L. Schriner and C. J. Hull in J. Org. Chem., 10, 228 (1945)] in 4 parts of tetrahydrofuran and 1 part of N,N-dimethylformamide at 70.degree. C. afforded the corresponding p-methoxybenzyl ether 2b in near quantitative yield. Hydroxylation of the diene 2b with stoichiometric amount of osmium tetroxide (Alfa) in the presence of 10 equivalents of anhydrous pyridine (Aldrich Chemical Co., Inc., 940 West St., Paul Ave., Milwaukee, Wis. 53233) in benzene provided 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 trimethyl orthoformate (Aldrich) and camphorsulfonic acid (Aldrich) in methanol (>95% yield) ensured the functionalization at C-14 without complication at C-15. The necessary functional groups at 14-position were introduced at this stage by adding various nucleophiles to the carbonyl. Diisobutyl aluminum hydride (Aldrich, 1 molar solution in hexane) reduction of the enone 5b in methyl chloride afforded the alcohol 12b in 85% yield.
A methyl group was introduced by a Grignard reaction with methyl magnesium bromide (Aldrich, 3 molar solution in diethyl ether) in diethyl ether to give the tertiary alcohol 6b in above 90% yield.
Similarly a vinyl group was introduced by treating 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 with introduction of an oxygen at 14 -position by treating the tertiary alcohol 6b in 80% aqueous acetic acid to provide a 3.3:1 mixture of cyclic hemiacetal 7b and cyclic acetal 7c. The acetal 7c was easily separated form the hemiacetal 7b by column chromatography on silica gel (Kieselgel 60), EM Science, 111 Woodcrest Road, Cherry Hill, N.J. 08034-0395) with elution by 15:85 ethyl acetate-hexane followed by 3:7 ethyl acetate - hexane. The acetal 7c was 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 was converted to the corresponding glycal 8b by reacting with methanesulfonyl chloride (Aldrich, filtered freshly through basic alumina) in the presence of excess triethylamine (Aldrich, distilled from calcium hydride) in methylene chloride (See, Scheme II).
The intermediate methanesulfonyl ester was eliminated to form the glycal 8b under conventional 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 with sodium periodate (Aldrich) in 4 parts of diethyl ether, 4 parts of methanol and 1 part of water in the presence of camphorsulfonic acid to give a mixture of p-methoxybenzyl ether of 16-methoxy-15-oxa-dihydrolanosterol 10b and p-methoxybenzyl ether of 16-hydroxy-15-oxa-dihydrolanosterol 10c in about 7:1 ratio. The mixture was then treated with excess triethylsilane (Aldrich) and then redistilled boron trifluoride etherate (Aldrich) in methylene 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 was conveniently cleaved during this process to afford the free hydroxy compound.
In the same manner the C-14 hydride compound 12b and the C-14 vinyl compound 18b have also been transformed successfully into the corresponding 4,4-dimethyl-15-oxa-5a-cholest-8-en-3b-ol (17a) and 4,4-dimethyl-15-oxa-14a-vinyl-5a-cholest-8-en-3b-ol (23a) in 36% and 50% overall yields respectively. The compounds 17a, 11a, and 23a constitute three examples of 15-oxa-lanosterols within the scope of the present invention.
Exposing the 14a-vinyl-oxa-sterol (23a) to acetic anhydride (Fischer Scientific, Fair Lawn, N.J. 07440) in anhydrous pyridine gave 3b-acetoxy-4,4-dimethyl-15-oxavinyl-lanost-8-ene (23c), a compound within the scope of the present invention, in 81% yield. Esters of other lanosterol derivatives within the scope of the invention may be prepared in this or a similar manner. ##STR6##
Further elaboration at the 14-position was achieved by treating the vinyl compound 23c with osmium tetroxide in pyridine to afford a diastereomeric mixture of diols 24c and 25c (2.84:1) in 45% yield (Scheme III).
The mixture of diols 24c and 25c was reacted with sodium metaperiodate in 4 parts of ethanol and 1 part of water to give 3b-acetoxy-15-oxa-lanost-8-en-32-al (26c) in near quantitative yield. Hydrolysis of the acetate-aldehyde 26c by 3 molar potassium hydroxide afforded the corresponding free hydroxy-aldehyde 26a in near quantitative yield. Reduction of the aldehyde 26a with sodium borohydride (Fischer Scientific) in ethanol afforded 15-oxa-lanost-8-ene-3b, 32-diol (27) in near quantitative 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-oxa-lanosterols within the scope of the present invention. ##STR7##
The aldehyde functional group of the Compound 26 allows further functionalization at the 32-position of lanosterol. A Grignard addition to the aldehyde 26c with vinyl magnesium bromide (Alfa, 1.6 molar solution in tetrahydrofuran) in refluxing tetrahydrofuran provided a diasteromeric mixture of allylic alcohols 28 and 29 (1.4:1) in >95% combined yield. Upon exposing the aldehyde 26a to hydroxylamine hydrochloride (Aldrich) in pyridine at 80.degree., the corresponding oxime 30 was obtained in quantitative yield. Compounds 28, 29, and 30 constitute three additional examples of 15-oxa- lanosterols within the scope of the present invention. Table 1 sets forth various oxasterols of the present invention.
TABLE 1__________________________________________________________________________ ##STR8##Ex. No. R.sub.1 R.sub.2 R.sub.3 D No. M.P.__________________________________________________________________________ 1 OH CH.sub.3 CH.sub.3 8 11 amorphous* 2 OH CH.sub.3 H 8 17 amorphous* 3 OH CH.sub.3 CHCH.sub.2 8 23a amorphous* 3a CH.sub.3 CH.sub.3 CHCH.sub.2 8 23c 4 OH CH.sub.3 CHOHCH.sub.2 OH(R) 8 24c 5 OH CH.sub.3 CHOHCH.sub.3 OH(S) 8 25c 6 CH.sub.3 CO CH.sub.3 CHO 8 26c amorphous* 7 OH CH.sub.3 CHO 8 2a amorphous* 8 OH CH.sub.3 CH.sub.2 OH 8 27 9 OH CH.sub.3 CO.sub.2 CH.sub.3 8 10 OH CH.sub. 3 CHNOH 8 30 amorphous* 11 OH CH.sub.3 CHOHCHCH.sub.2 (R) 8 28 amorphous* 12 OH CH.sub.3 CHOHCHCH.sub.2 (S) 8 29 amorphous* 13 OH H CH.sub.3 8 47 14 OH H H 8 15 OH H CHCH.sub.2 8 16 OH H CHOHCH.sub.2 OH(R) 8 17 OH H CHOHCH.sub.2 OH(S) 8 18 OH H CHO 8 19 OH H CH.sub.2 OH 8 20 OH H CO.sub.2 H 8 21 OH H CO.sub.2 CH.sub.3 8 22 OH H CHNOH 8 23 OH H CHOHCHCH.sub.2 (R) 8 24 OH H CHOHCHCH.sub.2 (S) 8 25 OH CH.sub.3 C.sub.3 H.sub.5 8 26 OH CH.sub.3 C.sub.3 H.sub.7 8 27 OH CH.sub.3 i-C.sub.3 H.sub.9 8 28 OH CH.sub.3 C.sub.6 H.sub.13 8 29 OH CH.sub.3 C.sub.6 H.sub.13 8 30 OH CH.sub.3 C.sub.6 H.sub.13 8 31 OH CH.sub.3 CH.sub.2 CHCH.sub.2 8 32 OH CH.sub.3 CCH 8 33 OH CH.sub.3 CH.sub.2 CCH 8 34 OH CH.sub.3 CH.sub.2 Ph 8 35 OH CH.sub.3 CHOHCH.sub.3 8 36 OH CH.sub.3 CHOHCCH 8 37 OH CH.sub.3 CH.sub.2 OCH.sub.3 8 38 OH CH.sub.3 CH.sub.2 OC.sub.2 H.sub.5 8 39 OH CH.sub.3 CH.sub.2 OC.sub.3 H.sub.7 8 40 OH CH.sub.3 CH.sub.2 OCH.sub.2 CHCH.sub.2 8 41 OH CH.sub.3 CH.sub.2 OPh 8 42 OH CH.sub.3 CH.sub.2 OCOCH.sub.3 8 43 OH CH.sub.3 CH.sub.2 SH 8 44 OH CH.sub.3 CH.sub.2 SCH.sub.3 8 45 OH CH.sub.3 CH.sub.2 SC.sub.2 H.sub.5 8 46 OH CH.sub.3 CH.sub.2 SPr 8 47 OH CH.sub.3 CH.sub.2 SCH.sub.2 CHCH.sub.2 8 48 OH CH.sub.3 CH.sub.2 SPh 8 49 OH CH.sub.3 CH.sub.2 SCOH.sub.3 8 50 OH CH.sub.3 CH.sub.2 NH.sub.2 8 51 OH CH.sub.3 CH.sub.2 NHCH.sub.3 8 52 OH CH.sub.3 CH.sub.2 NHC.sub.2 H.sub.5 8 53 OH CH.sub.3 CH.sub.2 NHC.sub.3 H.sub.7 8 54 OH CH.sub.3 CH.sub.2 NHi-Pr 8 55 OH CH.sub.3 CH.sub.2 NHC.sub.6 H.sub.13 8 56 OH CH.sub.3 CH.sub.2 NHPh 8 57 OH CH.sub.3 CH.sub.2 NMe.sub.2 8 58 OH CH.sub.3 CH.sub.2 NEt.sub.2 8 59 OH CH.sub.3 CH.sub.2 NHCHO 8 60 OH CH.sub.3 CH.sub.2 NHCOCH.sub.3 8 61 OH CH.sub.3 CH.sub.2 NHCSCH.sub.3 8 62 OH CH.sub.3 CH.sub.2 NH(CNH)CH.sub.3 8 63 OH CH.sub.3 COCH.sub.3 8 64 OH CH.sub.3 COC.sub.2 H.sub.5 8 65 OH CH.sub.3 COC.sub.3 H.sub.7 8 66 OH CH.sub.3 COi-C.sub.3 H.sub.7 8 67 OH CH.sub.3 COC.sub.6 H.sub.13 8 68 OH CH.sub.3 COCHCH.sub.2 8 69 OH CH.sub.3 COCH.sub.2 CHCH.sub.2 8 70 OH CH.sub.3 COCHCHCH.sub.3 8 71 OH CH.sub.3 COCCH 8 72 OH CH.sub.3 COCH.sub.2 CCH 8 73 OH CH.sub.3 COCCCH.sub.3 8 74 OH CH.sub.3 COPh 8 75 OH CH.sub.3 CSCH.sub.3 8 76 OH CH.sub.3 CSC.sub.2 H.sub.5 8 77 OH CH.sub.3 CSC.sub.3 H.sub.7 8 78 OH CH.sub.3 CSC.sub.3 H.sub.7 (i) 8 79 OH CH.sub.3 CSC.sub.6 H.sub.13 8 80 OH CH.sub.3 CSCHCH.sub.2 8 81 OH CH.sub.3 CSCH.sub.2 CHCH.sub.2 8 82 OH CH.sub.3 CSCHCHCH.sub.3 8 83 OH CH.sub.3 CSCCH 8 84 OH CH.sub.3 CSCH.sub.2 CH 8 85 OH CH.sub.3 CSCCCH.sub.3 8 86 OH CH.sub.3 CSPh 8 87 OH CH.sub.3 C(NH)CH.sub.3 8 88 OH CH.sub.3 C(NH)C.sub.3 H.sub.7 8 89 OH CH.sub.3 C(NH)C.sub.3 H.sub.7 8 90 OH CH.sub.3 C(NH)Ph 8 91 OH CH.sub.3 C(NH)CH.sub.3 8 92 OH CH.sub.3 C(NCH.sub.3)C.sub.2 H.sub.5 8 93 OH CH.sub.3 C(NCH.sub.3)C.sub.3 H.sub.7 8 94 OH CH.sub.3 CO.sub.2 C.sub.2 H.sub.5 8 95 OH CH.sub.3 CO.sub.2 C.sub.3 H.sub.7 8 96 OH CH.sub.3 CO.sub.2 i-C.sub.3 H.sub.7 8 97 OH CH.sub.3 CO.sub.2 C.sub.4 H.sub.9 8 98 OH CH.sub.3 CO.sub.2 C.sub.6 H.sub.13 8 99 OH CH.sub.3 CO.sub.2 CH.sub.2 CHCH.sub.2 8100 OH CH.sub.3 CO.sub.2 Ph 8101 OH CH.sub.3 COSCH.sub.3 8102 OH CH.sub.3 COSC.sub.2 H.sub.5 8103 OH CH.sub.3 COSC.sub.3 H.sub.7 8104 OH CH.sub.3 COSPh 8105 OH CH.sub.3 CONH.sub.2 8106 OH CH.sub.3 CONHCH.sub.3 8107 OH CH.sub.3 CONHC.sub.2 H.sub.5 8108 OH CH.sub.3 CONHC.sub.3 H.sub.7 8109 OH CH.sub.3 CONHi-C.sub.3 H.sub.7 8110 OH CH.sub.3 CONHC.sub.6 H.sub.13 8111 OH CH.sub.3 CONHPh 8112 OH CH.sub.3 CONMe.sub.2 8113 OH CH.sub.3 CONEt2 8114 OH CH.sub.3 CONPr2 8115 OH CH.sub.3 CONHCOCH.sub.3 8116 OH CH.sub.3 CONHCOC.sub.2 H.sub.5 8117 OH CH.sub.3 CSNH.sub.2 8118 OH CH.sub.3 CSNHCH.sub.3 8119 OH CH.sub.3 CSNHC.sub.2 H.sub.5 8120 OH CH.sub.3 CSNHC.sub.3 H.sub.7 8121 OH CH.sub.3 CSNHi-C.sub.3 H.sub.7 8122 OH CH.sub.3 CSNHC.sub.6 H.sub.13 8123 OH CH.sub.3 CSNHPh 8124 OH CH.sub.3 CSNMe.sub.2 8125 OH CH.sub.3 CSNEt.sub.2 8126 OH CH.sub.3 CSNPr2 8127 OH CH.sub.3 SCNHCOCH.sub.3 8128 OH CH.sub.3 CSNHCOC.sub.2 H.sub.5 8129 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 8130 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)OH 8131 OH CH.sub.3 CH.sub.2 CH.sub.2 OCH.sub.3 8132 OH CH.sub.3 CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5 8133 OH CH.sub.3 CH.sub. 2 CH.sub.2 OPh 8134 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)OCH.sub.3 8135 OH CH.sub.3 CH.sub.2 CH.sub.2 OCOCH.sub.3 8136 OH CH.sub.3 CH.sub.2 CH.sub.2 SH 8137 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)SH 8138 OH CH.sub.3 CH.sub.2 CH.sub.2 SCH.sub.3 8139 OH CH.sub.3 CH.sub.2 CH.sub.2 SC.sub.2 H.sub.5 8140 OH CH.sub.3 CH.sub.2 CH.sub.2 SPh 8141 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)SCH.sub.3 8142 OH CH.sub.3 CH.sub.2 CH.sub.2 SCOCH.sub.3 8143 OH CH.sub.3 CH.sub.2 CH.sub.2 NH.sub.2 8144 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)NH.sub.2 8145 OH CH.sub.3 CH.sub.2 CH.sub.2 NHCH.sub.3 8146 OH CH.sub.3 CH.sub.2 CH.sub.2 NHC.sub.2 H.sub.5 8147 OH CH.sub.3 CH.sub.2 CH.sub.2 NHPh 8148 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)NHCH.sub.3 8149 OH CH.sub.3 CH.sub.2 CH.sub.2 NMe.sub.2 8150 OH CH.sub.3 CH.sub.2 CH.sub.2 NHCOCH.sub.3 8151 OH CH.sub.3 CH.sub.2 CH(CH.sub.3 )NHCOCH.sub.3 8152 OH CH.sub.3 CH.sub.2 CH.sub.2 NHCSCH.sub.3 8153 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)NHCSCH.sub.3 8154 OH CH.sub.3 CH.sub.2 CH.sub.2 NHC(NH)CH.sub.3 8155 OH CH.sub.3 CH.sub.2 CH(CH.sub.3)NHC(NH)CH.sub.3 8156 OH CH.sub.3 CH.sub.2 CHO 8157 OH CH.sub.3 CH.sub.2 COCH.sub.3 8158 OH CH.sub.3 CH.sub.2 COC.sub.2 H.sub.5 8159 OH CH.sub.3 CH.sub.2 COCHCH.sub.2 8160 OH CH.sub.3 CH.sub.2 COCH.sub.2 CHCH.sub.2 8161 OH CH.sub.3 CH.sub.2 COCHCHCH.sub.3 8162 OH CH.sub.3 CH.sub.2 COCCH 8163 OH CH.sub.3 CH.sub.2 COPh 8164 OH CH.sub.3 CH.sub.2 CSCH.sub.3 8165 OH CH.sub.3 CH.sub.2 CSC.sub.2 H.sub.5 8166 OH CH.sub.3 CH.sub.2 CSCHCH.sub.2 8167 OH CH.sub.3 CH.sub.2 CSCH.sub.2 CHCH.sub.2 8168 OH CH.sub.3 CH.sub.2 CSCHCHCH.sub.3 8169 OH CH.sub.3 CH.sub.2 CSC CH 8170 OH CH.sub.3 CH.sub.2 CSPh 8171 OH CH.sub.3 CH.sub.2 C(NH)CH.sub.3 8172 OH CH.sub.3 CH.sub.2 C(NH)C.sub.2 H.sub.5 8173 OH CH.sub.3 CH.sub.2 C(NCH.sub.3)CH.sub.3 8174 OH CH.sub.3 CH.sub.2 C(NCH.sub.3)C.sub.2 H.sub.5 8175 OH CH.sub.3 CH.sub.2 C(NH)Ph 8176 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 8177 OH CH.sub.3 CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 8178 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.2 CHCH.sub.2 8179 OH CH.sub.3 CH.sub.2 CO.sub.2 Ph 8180 OH CH.sub.3 CH.sub.2 COSCH.sub.3 8181 OH CH.sub.3 CH.sub.2 COSCH.sub.3 8181 OH CH.sub.3 CH.sub.2 COSC.sub.2 H5 8182 OH CH.sub.3 CH.sub.2 COSPh 8183 OH CH.sub.3 CH.sub.2 CONH.sub.2 8184 OH CH.sub.3 CH.sub.2 CONHCH.sub.3 8185 OH CH.sub.3 CH.sub.2 CONHC.sub.2 H.sub.5 8186 OH CH.sub.3 CH.sub.2 CONHPh 8187 OH CH.sub.3 CH.sub.2 CONMe.sub.2 8188 OH CH.sub. 3 CH.sub.2 CONHCOCH.sub.3 8189 OH CH.sub.3 CH.sub.2 CSNH.sub.2 8190 OH CH.sub.3 CH.sub.2 C(NH)NH.sub.2 8191 OH CH.sub.3 CH.sub.2 Cl 8192 OH CH.sub.3 CH.sub.2 Br 8193 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 8194 OH CH.sub.3 CH.sub.2 CH.sub.2 Br 8195 OH CH.sub.3 CN 8196 OH CH.sub.3 C(CH.sub.3)NOH 8197 OH CH.sub.3 CHNOCH.sub.3 8198 OH CH.sub.3 CHNOC.sub.2 H.sub.5 8199 OH CH.sub.3 CHNOCOCH.sub.3 8200 OH CH.sub.3 CHNNH.sub.2 8201 OH CH.sub.3 CNNNHCH.sub.3 8202 OH CH.sub.3 CHNNHCOCH.sub.3 8203 OH CH.sub.3 CHNNHCSCH.sub.3 8204 OH CH.sub.3 CH.sub.2 NHOH 8205 OH CH.sub.3 CH.sub.2 NHOCH.sub.3 8206 OH CH.sub.3 CH.sub.2 NHOCOCH.sub.3 8207 OH CH.sub.3 CH.sub.2 NHNH.sub.2 8208 OH CH.sub.3 CH.sub.2 NHNHCH.sub.3 8209 OH CH.sub.3 CH.sub.2 NHNHCOCH.sub.3 8210 OH CH.sub.3 CH.sub.2 NHNHCSCH.sub.3 8211 OH CH.sub.3 CH.sub.2 CN 8212 OH CH.sub.3 CH.sub.2 CHNOH 8213 OH CH.sub.3 CH.sub.2 C(CH.sub.3)NOH 8214 OH CH.sub.3 CH.sub.2 CHNOCH.sub.3 8215 OH CH.sub.3 CH.sub.2 CHNOC.sub.2 H.sub.5 8216 OH CH.sub.3 CH.sub.2 CHNOCOCH.sub.3 8217 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 8218 OH CH.sub.3 CH.sub.2 CHNNHCH.sub.3 8219 OH CH.sub.3 CH.sub.2 CHNNHCOCH.sub.3 8220 OH CH.sub.3 CH.sub.2 CHNNHCSCH.sub.3 8221 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 8222 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOCH.sub.3 8223 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOCOCH.sub.3 8224 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 8225 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCH.sub.3 8226 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCOCH.sub.3 8227 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCSCH.sub.3 8228 OH CH.sub.3 CONHOH 8229 OH CH.sub.3 CONHOCH.sub.3 8230 OH CH.sub.3 CONHOC.sub.2 H.sub.5 8231 OH CH.sub.3 CONHOPh 8232 OH CH.sub.3 CONHOCOCH.sub.3 8233 OH CH.sub.3 CSNHOH 8234 OH CH.sub.3 CSNHOCH.sub.3 8235 OH CH.sub.3 CSNHOCOCH.sub.3 8236 OH CH.sub.3 CHCHCHO 8237 OH CH.sub.3 CHCHCOCH.sub.3 8238 OH CH.sub.3 CHCHCOC.sub.2 H.sub.5 8239 OH CH.sub.3 CHCHCSCH.sub.3 8240 OH CH.sub.3 CHCHCSC.sub.2 H.sub.5 8241 OH CH.sub.3 CHCHCHNH 8242 OH CH.sub.3 CHCHC(NH)CH.sub.3 8243 OH CH.sub.3 CCCHO 8244 OH CH.sub.3 CCCOCH.sub.3 8245 OH CH.sub.3 CCCOC.sub.2 H.sub.5 8246 OH CH.sub.3 CCCSCH.sub.3 8247 OH CH.sub.3 CCCSC.sub.2 H.sub.5 8248 OH CH.sub.3 CCCHNH 8249 OH CH.sub.3 C CC(NH)CH.sub.3 8250 OH CH.sub.3 CHCHCH.sub.2 Cl 8251 OH CH.sub.3 CHCHCH.sub.2 Br 8252 OH CH.sub.3 CCCH.sub.2 Cl 8253 OH CH.sub.3 CCCH.sub.2 Br 8254 OH CH.sub.3 CHCHCH.sub.2 OCOCH.sub.3 8255 OH CH.sub.3 CHCHCH.sub.2 OCOC.sub.2 H.sub.5 8256 OH CH.sub.3 CCCH.sub.2 OCOCH.sub.3 8257 OH CH.sub.3 CCCH.sub.2 OCOC.sub.2 H.sub.5 8258 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 8259 OH CH.sub.3 CHOHCHOHCH.sub.2 OH 8260 OH CH.sub.3 ##STR9## 8261 OH CH.sub.3 ##STR10## 8262 OH CH.sub.3 ##STR11## 8263 OH H C.sub.2 H.sub.5 8264 OH H CH.sub.2 CH CH.sub.2 8265 OH H CCH 8266 OH H CH.sub.2 Ph 8267 OH H CH.sub.2 OCH.sub.3 8268 OH H CH.sub.2 OCOCH.sub.3 8269 OH H CH.sub.2 SH 8270 OH H CH.sub.2 SCH.sub.3 8271 OH H CH.sub.2 SCOCH.sub.3 8272 OH H CH.sub.2 NH.sub.2 8273 OH H CH.sub.2 NHCH.sub.3 8274 OH H CH.sub.2 N2(CH.sub.3).sub.2 8275 OH H CH.sub.2 NHCOCH.sub.3 8276 OH H CH.sub.2 NHCSCH.sub.3 8277 OH H CH.sub.2 NHC(NH)CH.sub.3 8278 OH H COCH.sub.3 8279 OH H COCHCH.sub.2 8280 OH H CSCH.sub.3 8281 OH H CSCHCH.sub.2 8282 OH H C(NH)CH.sub.3 8283 OH H C(NCH.sub.3)CH.sub.3 8284 OH H CO.sub.2 C.sub.2 H.sub.5 8285 OH H COSCH.sub.3 8286 OH H CONH.sub.2 8287 OH H CONHCH.sub.3 8288 OH H CON2(CH.sub.3).sub.2 8289 OH H CONHCOCH.sub.3 8290 OH H CSNH.sub.2 8291 OH H CSNHCH.sub.3 8292 OH H CSNMe.sub.2 8293 OH H CSNHCOCH.sub.3 8294 OH H CH.sub.2 CH.sub.2 OH 8295 OH H CH.sub.2 CH.sub.2 OCH.sub.3 8296 OH H CH.sub.2 CH.sub.2 OCOCH.sub.3 8297 OH H CH.sub.2 CH.sub.2 SH 8298 OH H CH.sub.2 CH.sub.2 SCH.sub.3 8299 OH H CH.sub.2 CH.sub.2 SCOCH.sub.3 8300 OH H CH.sub.2 CH.sub.2 NH.sub.2 8301 OH H CH.sub.2 CH.sub.2 NHCH.sub.3 8302 OH H CH.sub.3 CH.sub.2 NMe.sub.2 8303 OH H CH.sub.2 CH.sub.2 NHCOCH.sub.3 8304 OH H CH.sub.2 CH.sub.2 NHCSCH.sub.3 8305 OH H CH.sub.2 CH.sub.2 NHC(NH)CH.sub.3 8306 OH H CH.sub.2 CHO 8307 OH H CH.sub.2 COCH.sub.3 8308 OH H CH.sub.2 COCHCH.sub.2 8309 OH H CH.sub.2 CSCH.sub.3 8310 OH H CH.sub.2 CSCHCH.sub.2 8311 OH H CH.sub.2 C(NH)CH.sub.3 8312 OH H CH.sub.2 C(NCH.sub.3)CH.sub.3 8313 OH H CH.sub.2 CO.sub.2 CH.sub.3 8314 OH H CH.sub.2 COSCH.sub.3 8315 OH H CH.sub.2 CONH.sub.2 8316 OH H CH.sub.2 CONHCH.sub.3 8317 OH H CH.sub.2 CONMe2 8318 OH H CH.sub.2 CONHCOCH.sub.3 8319 OH H CH.sub.2 CSNH.sub.2 8320 OH H CH.sub.2 C(NH)CH.sub.3 8321 OH H CH.sub.2 Cl 8322 OH H CH.sub.2 Br 8323 OH H CH.sub.2 CH.sub.2 Cl 8324 OH H CH.sub.2 CH.sub.2 Br 8325 OH H CN 8326 OH H CHNOCH.sub.3 8327 OH H CHNOCOCH.sub.3 8328 OH H CHNNH.sub.2 8329 OH H CHNNHCH.sub.3 8330 OH H CHNNHCOCH.sub.3 8331 OH H CHNNHCSCH.sub.3 8332 OH H CH.sub.2 NHOH 8333 OH H CH.sub.2 NHOCH.sub.3 8334 OH H CH.sub.2 NHOCOCH.sub.3 8335 OH H CH.sub.2 NHNH.sub.2 8336 OH H CH.sub.2 NHNHCH.sub.3 8337 OH H CH.sub.2 NHNHCOCH.sub.3 8338 OH H CH.sub.2 NHNHCSCH.sub.3 8339 OH H CH.sub.2 CN 8340 OH H CH.sub.2 CHNOH 8341 OH H CH.sub.2 CHNOCH.sub.3 8342 OH H CH.sub.2 CHNOCOCH.sub.3 8343 OH H CH.sub.2 CHNNH.sub.2 8344 OH H CH.sub.2 CHNNHCH.sub.3 8345 OH H CH.sub.2 CHNNHCOCH.sub.3 8346 OH H CH.sub.2 CHNNHCSCH.sub.3 8347 OH H CH.sub.2 CH.sub.2 NHOH 8348 OH H CH.sub.2 CH.sub.2 NHOCH.sub.3 8349 OH H CH.sub.2 CH.sub.2 NHOCOCH.sub.3 8350 OH H CH.sub.2 CH.sub.2 NHNH.sub.2 8351 OH H CH.sub.2 CH.sub.2 NHNHCH.sub.3 8352 OH H CH.sub.2 CH.sub.2 NHNHCOCH.sub.3 8353 OH H CH.sub.2 CH.sub.2 NHNHCSCH.sub.3 8354 OH H CONHOH 8355 OH H CONHOCH.sub.3 8356 OH H CONHOCOCH.sub.3 8357 OH H CSNHOH 8358 OH H CSNHOCH.sub.3 8359 OH H CSNHOCOCH.sub.3 8360 OH H CHCHCHO 8361 OH H CHCHCOCH.sub.3 8362 OH H CHCHCSCH.sub.3 8363 OH H CHCHCHNH 8364 OH H CH CHC(NH)CH.sub.3 8365 OH H CHCCHO 8366 OH H CCCOCH.sub.3 8367 OH H CCCSCH.sub.3 8368 OH H CCCHNH369 OH H CCC(NH)CH.sub.3 8370 OH H CHCHCH.sub.2 Cl 8371 OH H CHCHCH.sub.2 Br 8372 OH H CCCH.sub.2 Cl 8373 OH H CCCH.sub.2 Br 8374 OH H CHCHCH.sub.2 OCOCH.sub.3 8375 OH H CCCH.sub.2 OCOCH.sub.3 8376 OH H CH.sub.2 CHOHCH.sub.2 OH 8377 OH H CHOHCHOHCH.sub.2 OH 8378 OH H ##STR12## 8379 OH H ##STR13## 8380 OH H ##STR14## 8381 O CH.sub.3 CH.sub.3 8382 O CH.sub.3 H 8383 O CH.sub.3 CHCH.sub.2 8384 O CH.sub.3 CHOHCH.sub.2 OH(R) 8385 O CH.sub.3 CHOHCH.sub.2 OHO(S) 8386 O CH.sub.3 CHO 8387 O CH.sub.3 CH.sub.2 OH 8388 O CH.sub.3 CO.sub.2 H 8389 O CH.sub.3 CO.sub.2 CH.sub.3 8390 O CH.sub.3 CHNOH 8391 O CH.sub.3 CHOHCHCH.sub.2 (R) 8392 O CH.sub.3 CHOHCHCH.sub.2 (S) 8393 O CH.sub.3 CH.sub.2 SH 8394 O CH.sub.3 CH.sub.2 NH.sub.2 8395 O CH.sub.3 COCH.sub.3 8396 O CH.sub.3 CONH.sub.2 8397 O CH.sub.3 CSNH.sub.2 8398 O CH.sub.3 CH.sub.2 CH.sub.2 OH 8399 O CH.sub.3 CH.sub.2 CHO 8400 O CH.sub.3 CH.sub.2 COCH.sub.3 8401 O CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 8402 O CH.sub.3 CH.sub.2 CONH.sub.2 8403 O CH.sub.3 CH.sub.2 Cl 8404 O CH.sub.3 CH.sub.2 CH.sub.2 Cl 8405 O CH.sub.3 CN 8406 O CH.sub.3 CHNNH.sub.2 8407 O CH.sub.3 CH.sub.2 NHOH 8408 O CH.sub.3 CH.sub.2 NHNH.sub.2 8409 O CH.sub.3 CH.sub.2 CN 8410 O CH.sub.3 CH.sub.2 CHNOH 8411 O CH.sub.3 CH.sub.2 CHNNH.sub.2 8412 O CH.sub.3 CH.sub.2 CH.sub.2 NHOH 8413 O CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 8414 O CH.sub.3 CONHOH 8415 O CH.sub.3 CHCHCHO 8416 O CH.sub.3 CHCHCOCH.sub.3 8417 O CH.sub.3 CHCHCH.sub.2 Cl 8418 O CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 8419 O CH.sub.3 ##STR15## 8420 O H CH.sub. 3 8421 O H H 8422 O H CHCH.sub.2 8423 O H CHOHCH.sub.2 OH(R) 8424 O H CHOHCH.sub.2 OH(S) 8425 O H CHO 8426 O H CH.sub.2 OH 8427 O H CO.sub.2 H 8428 O H CO.sub.2 CH.sub.3 8429 O H CHNOH 8430 O H CHOHCHCH.sub.2 (R) 8431 O H CHOHCHCH.sub.2 (S) 8432 OCH.sub.3 CH.sub.3 CH.sub.3 8433 OCH.sub.3 CH.sub.3 H 8434 OCH.sub.3 CH.sub.3 CHCH.sub.2 8435 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 8436 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 8437 OCH.sub.3 CH.sub.3 CHO 8438 OCH.sub.3 CH.sub.3 CH.sub.2 OH 8439 OCH.sub.3 CH.sub.3 CO.sub.3 H 8440 OCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 8441 OCH.sub.3 CH.sub.3 CHNOH 8442 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 8443 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 8444 OCH.sub.3 CH.sub.3 CH.sub.2 SH 8445 OCH.sub.3 CH.sub.3 CH.sub.2 NH.sub.2 8446 OCH.sub.3 CH.sub.3 COCH.sub.3 8447 OCH.sub.3 CH.sub.3 CONH.sub.2 8448 OCH.sub.3 CH.sub.3 CSNH.sub.2 8449 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 OH 8450 OCH.sub.3 CH.sub.3 CH.sub.2 CHO 8451 OCH.sub.3 CH.sub.3 CH.sub.2 COCH.sub.3 8452 OCH.sub.3 CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 8453 OCH.sub.3 CH.sub.3 CH.sub.2 CONH.sub.2 8454 OCH.sub.3 CH.sub.3 CH.sub.2 Cl 8455 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 Cl 8456 OCH.sub.2 CH.sub.3 CN 8457 OCH.sub.3 CH.sub.3 CHNNH.sub.2 8458 OCH.sub.3 CH.sub.3 CH.sub.2 NHOH 8459 OCH.sub.3 CH.sub.3 CH.sub.2 NHNH.sub.2 8460 OCH.sub.3 CH.sub.3 CH.sub.2 CN 8461 OCH.sub.3 CH.sub.3 CH.sub.2 CHNOH 8462 OCH.sub.3 CH.sub.3 CH.sub.2 CHNNH.sub.2 8463 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHOH 8464 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub. 2 NHNH.sub.2 8465 OCH.sub.3 CH.sub.3 CONHOH 8466 OCH.sub.3 CH.sub.3 CHCHCHO 8467 OCH.sub.2 CH.sub.3 CHCOCH.sub.3 8468 OCH.sub.3 CH.sub.3 CHCHCH.sub.2 Cl 8469 OCH.sub.3 CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 8470 OCH.sub.3 CH.sub.3 ##STR16## 8471 OCH.sub.3 H CH.sub.3 8472 OCH.sub.3 H H 8473 OCH.sub.3 H CHCH.sub.2 8474 OCH.sub.3 H CHOHCH.sub.2 OH(R) 8475 OCH.sub.3 H CHOHCH.sub.2 OH(S) 8476 OCH.sub.3 H CHO 8477 OCH.sub.3 H CH.sub.2 OH 8478 OCH.sub.3 H CO.sub.2 H 8479 OCH.sub.3 H CO.sub.2 CH.sub.3 8480 OCH.sub.3 H CHNOH 8481 OCH.sub.3 H CHOHCHCH.sub.2 (R) 8482 OCH.sub.3 H CHOHCHCH.sub.2 (S) 8483 OC.sub.2 H.sub.5 CH.sub.3 CH.sub.3 8484 OC.sub.2 H.sub.5 CH.sub.3 CHO 8485 OC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH 8486 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 8487 OC.sub.3 H.sub.7 CH.sub.3 CHO 8488 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH 8489 Oi-C.sub.3 H.sub.7 CH.sub.3 CH.sub.3 8490 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.3 8491 OC.sub.4 H.sub.9 CH.sub.3 CHO 8492 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH 8493 Oi-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 8494 Ot-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 8495 OPh CH.sub.3 CH.sub.3 8496 OPh CH.sub.3 CHO 8497 OPh CH.sub.3 CH.sub.2 OH 8498 OCH.sub.2 Ph CH.sub.3 CH.sub.3 8499 OCH.sub.2 Ph CH.sub.3 CHO 8500 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 8501 OCOCH.sub.3 CH.sub.3 CH.sub.3 8502 OCOCH.sub.3 CH.sub.3 H 8503 OCOCH.sub.3 CH.sub.3 CHCH.sub.2 8 23c amorphous*504 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 8 24c amorphous*505 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 8 25c amorphous*506 OCOCH.sub.3 CH.sub.3 CHO 8 26c amorphous*507 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 8508 OCOCH.sub.3 CH.sub.3 CO.sub.2 H 8509 OCOCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 8510 OCOCH.sub.3 CH.sub.3 CHNOH 8511 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 8512 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 8513 OCOCH.sub.3 CH.sub.3 CH.sub.2 SH 8514 OCOCH.sub.3 CH.sub.3 CH.sub.2 NH.sub.2 8515 OCOCH.sub.3 CH.sub.3 COCH.sub.3 8516 OCOCH.sub.3 CH.sub.3 CONH.sub.2 8517 OCOCH.sub.3 CH.sub.3 CSNH.sub.2 8518 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 OH 8519 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHO 8520 OCOCH.sub.3 CH.sub.3 CH.sub.2 COCH.sub.3 8521 OCOCH.sub.3 CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 8522 OCOCH.sub.3 CH.sub.3 CH.sub.2 CONH.sub.2 8523 OCOCH.sub.3 CH.sub.3 CH.sub.2 Cl 8524 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 Cl 8525 OCOCH.sub.3 CH.sub.3 CN 8526 OCOCH.sub.3 CH.sub.3 CHNNH.sub.2 8527 OCOCH.sub.3 CH.sub.3 CH.sub.2 NHOH 8528 OCOCH.sub.3 CH.sub.3 CH.sub.2 NHNH.sub.2 8529 OCOCH.sub. 3 CH.sub.3 CH.sub.2 CN 8530 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHNOH 8531 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHNNH.sub.2 8532 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHOH 8533 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 8534 OCOCH.sub.3 CH.sub.3 CONHOH 8535 OCOCH.sub.3 CH.sub.3 CHCHCHO 8536 OCOCH.sub.3 CH.sub.3 CHCHCOCH.sub.3 8537 OCOCH.sub.3 CH.sub.3 CHCHCH.sub.2 Cl 8538 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 8539 OCOCH.sub.3 CH.sub.3 ##STR17## 8540 OCOCH.sub.3 H CH.sub.3 8541 OCOCH.sub.3 H H 8542 OCOCH.sub.3 H CHCH.sub.2 8543 OCOCH.sub.3 H CHOHCH.sub.2 OH(R) 8544 OCOCH.sub.3 H CHOHCH.sub.2 OH(S) 8545 OCOCH.sub.3 H CHO 8546 OCOCH.sub.3 H CH.sub.2 OH 8547 OCOCH.sub.3 H CO.sub.2 H 8548 OCOCH.sub.3 H CO.sub.2 CH.sub.3 8549 OCOCH.sub.3 H CHNOH 8550 OCOCH.sub.3 H CHOHCHCH.sub.2 (R) 8551 OCOCH.sub.3 H CHOHCHCH.sub.2 (S) 8552 OCOCH.sub.2 H.sub.5 CH.sub.3 CH.sub.3 8553 OCOC.sub.2 H.sub.5 CH.sub.3 CHO 8554 OCOC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH 8555 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 8556 OCOC.sub.3 H.sub.7 CH.sub.3 CHO 8557 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH 8558 OCOi-C.sub.3 H.sub.7 CH.sub.3 CH.sub.3 8559 OCOC.sub.4 H.sub.9 CH.sub.3 CH.sub.3 8560 OCOC.sub.4 H.sub.9 CH.sub.3 CHO 8561 OCOC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH 8562 OCOi-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 8563 OCOt-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 8564 OCOC15H.sub.31 CH.sub.3 CH.sub.3 8565 OCOC15H.sub.31 CH.sub.3 CHO 8566 OCOC15H.sub.31 CH.sub.3 CH.sub.2 OH 8567 OCOC15H.sub.29 CH.sub.3 CH.sub.3 8568 OCOC17H.sub.35 CH.sub.3 CH.sub.3 8569 OCOC17H.sub.33 CH.sub.3 CH.sub.3 8570 OCOC17H.sub.31 CH.sub.3 CH.sub.3 8571 OCOC17H.sub.29 CH.sub.3 CH.sub.3 8572 OCOC19H.sub.31 CH.sub.3 CH.sub. 3 8573 OCOPh CH.sub.3 CH.sub.3 8574 OCOPh CH.sub.3 CHO 8575 OCOPh CH.sub.3 CH.sub.2 OH 8576 OH CH.sub.3 CH.sub.3 7577 OH CH.sub.3 H 7578 OH CH.sub.3 CHCH.sub.2 7579 OH CH.sub.3 CHOHCH.sub.2 OH(R) 7580 OH CH.sub.3 CHOHCH.sub.2 OH(S) 7581 OH CH.sub.3 CHO 7582 OH CH.sub.3 CH.sub.2 OH 7583 OH CH.sub.3 CO.sub.2 H 7584 OH CH.sub.3 CO.sub.2 CH.sub.3 7585 OH CH.sub.3 CHNOH 7586 OH CH.sub.3 CHOHCHCH.sub.2 (R) 7587 OH CH.sub.3 CHOHCHCH.sub.2 (S) 7588 OH H CH.sub.3 7589 OH H H 7590 OH H CHCH.sub.2 7591 OH H CHOHCH.sub.2 OH(R) 7592 OH H CHOHCH.sub.2 OH(S) 7593 OH H CHO 7594 OH H CH.sub.2 OH 7595 OH H CO.sub.2 H 7596 OH H CO.sub.2 CH.sub.3 7597 OH H CHNOH 7598 OH H CHOHCHCH.sub.2 (R) 7599 OH H CHOHCH CH.sub.2 (S) 7600 O CH.sub.3 CH.sub.3 7601 O CH.sub.3 H 7602 O CH.sub.3 CHCH.sub.2 7603 O CH.sub.3 CHOHCH.sub.2 OH(R) 7604 O CH.sub.3 CHOHCH.sub.2 OH(S) 7605 O CH.sub.3 CHO 7606 O CH.sub.3 CH.sub.2 OH 7607 O CH.sub.3 CO.sub.2 H 7608 O CH.sub.3 CO.sub.2 CH.sub.3 7609 O CH.sub.3 CHNOH 7610 O CH.sub.3 CHOHCHCH.sub.2 (R) 7611 O CH.sub.3 CHOHCHCH.sub.2 (S) 7612 O H CH.sub.3 7613 O H H 7614 O H CHCH.sub.2 7615 O H CHOHCH.sub.2 OH(R) 7616 O H CHOHCH.sub.2 OH(S) 7617 O H CHO 7618 O H CH.sub.2 OH 7619 O H CO.sub.2 H 7620 O H CO.sub.2 CH.sub.3 7621 O H CHNOH 7622 O H CHOHCHCH.sub.2 (R) 7623 O H CHOHCHCH.sub.2 (S) 7624 OCH.sub.3 CH.sub.3 CH.sub.3 7625 OCH.sub.3 CH.sub.3 H 7626 OCH.sub.3 CH.sub.3 CHCH.sub.2 7627 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 7628 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 7629 OCH.sub.3 CH.sub.3 CHO 7630 OCH.sub.3 CH.sub.3 CH.sub.2 OH 7631 OCH.sub.3 CH.sub.3 CO.sub.2 H 7632 OCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 7633 OCH.sub.3 CH.sub.3 CHNOH 7634 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 7635 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 7636 OCH.sub.3 H CH.sub.3 7637 OCH.sub.3 H H 7638 OCH.sub.3 H CHCH.sub.2 7639 OCH.sub.3 H CHOHCH.sub.2 OH(R) 7640 OCH.sub.3 H CHOHCH.sub.2 OH(S) 7641 OCH.sub.3 H CHO 7642 OCH.sub.3 H CH.sub.2 OH 7643 OCH.sub.3 H CO.sub.2 H 7644 OCH.sub.3 H CO.sub.2 CH.sub.3 7645 OCH.sub.3 H CHNOH 7646 OCH.sub.3 H CHOHCHCH.sub.2 (R) 7647 OCH.sub.3 H CHOHCHCH.sub.2 (S) 7648 OCOCH.sub.3 CH.sub.3 CH.sub.3 7649 OCOCH.sub.3 CH.sub.3 H 7650 OCOCH.sub.3 CH.sub.3 CHCH.sub.2 7651 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 7652 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 7653 OCOCH.sub.3 CH.sub.3 CHO 7654 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 7655 OCOCH.sub.3 CH.sub.3 CO.sub.2 H 7656 OCOCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 7657 OCOCH.sub.3 CH.sub.3 CHNOH 7658 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 7659 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 7660 OCOCH.sub.3 H CH.sub.3 7661 OCOCH.sub.3 H H 7662 OCOCH.sub.3 H CHCH.sub.2 7663 OCOCH.sub.3 H CHOHCH.sub.2 OH(R) 7664 OCOCH.sub.3 H CHOHCH.sub.2 OH(S) 7665 OCOCH.sub.3 H CHO 7666 OCOCH.sub.3 H CH.sub.2 OH 7667 OCOCH.sub.3 H CO.sub.2 H 7668 OCOCH.sub.3 H CO.sub.2 CH.sub.3 7669 OCOCH.sub.3 H CHNOH 7670 OCOCH.sub.3 H CHOHCHCH.sub.2 (R) 7671 OCOCH.sub.3 H CHOHCHCH.sub.2 (S) 7__________________________________________________________________________ *Further analytical data are available in the examples section
The six-membered 15-oxa-D-homo-lanosterol derivatives are synthesized by reducing the six-membered cyclic acetals and hemiacetals under conditions similar as those used for the five-membered 15-oxa-lanosterols. However, the entire sequence was carried out more conveniently in higher overall yield without 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-methoxybenzyl protected intermediates (Scheme I). The cyclic hemiacetal 7a was treated with triethylsilane and redistilled boron trifluoride etherate in methylene chloride to afford 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 lower 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-8-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 comparable yields. Compounds 31, 32, and 33 are all within the scope of the present invention. ##STR18##
For further functionalization at the 14-position, 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 sodium metaperiodate in 4 parts of ethanol and 1 part of water to give 15-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. Compounds 34, 35, 36 and 37 also constitute four additional examples of 15-oxa-lanosterols within 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.
Table 2 sets forth additional oxasterols of the present invention.
TABLE 2__________________________________________________________________________ ##STR19##Ex. No. R.sub.1 R.sub.2 R.sub.3 D No. M.P.__________________________________________________________________________672 OH CH.sub.3 CH.sub.3 8 31 amorphous*673 OH CH.sub.3 H 8 32 amorphous*674 OH CH.sub.3 CHCH.sub.2 8 32 amorphous*675 OH CH.sub.3 CHOHCH.sub.2 OH(R) 8 34 amorphous*676 OH CH.sub.3 CHOHCH.sub.2 OH(S) 8 35 amorphous*677 OH CH.sub.3 CHO 8 36 amorphous*678 OH CH.sub.3 CH.sub.2 OH 8 37 amorphous*679 OH CH.sub.3 CO.sub.2 H 8680 OH CH.sub.3 CO.sub.2 CH.sub.3 8681 OH CH.sub.3 CHNOH 8682 OH CH.sub.3 CHOHCHCH.sub.2(R) 8683 OH CH.sub.3 CHOHCHCH.sub.2(S) 8684 OH H CH.sub.3 8685 OH H H 8686 OH H CHCH.sub.2 8687 OH H CHOHCH.sub.2 OH(R) 8689 OH H CHOHCH.sub.2 OH(S) 8690 OH H CHO 8691 OH H CH.sub.2 OH 8692 OH H CO.sub.2 H 8693 OH H CO.sub.2 CH.sub.3 8694 OH H CHNOH 8695 OH H CHOHCHCH.sub.2(R) 8696 OH H CHOHCHCH.sub.2(S) 8697 OH CH.sub.3 CH.sub.2 SH 8698 OH CH.sub.3 CH.sub.2 NH.sub.2 8699 OH CH.sub.3 COCH.sub.3 8700 OH CH.sub.3 CONH.sub.2 8701 OH CH.sub.3 CSNH.sub.2 8702 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 8703 OH CH.sub.3 CH.sub.2 CHO 8704 OH CH.sub.3 CH.sub.2 COCH.sub.3 8705 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 8706 OH CH.sub.3 CH.sub.2 CONH.sub.2 8707 OH CH.sub.3 CH.sub.2 Cl 8708 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 8709 OH CH.sub.3 CN 8710 OH CH.sub.3 CHNNH.sub.2 8711 OH CH.sub.3 CH.sub.2 NHOH 8712 OH CH.sub.3 CH.sub.2 NHNH.sub.2 8713 OH CH.sub.3 CH.sub.2 CN 8714 OH CH.sub.3 CH.sub.2 CHNOH 8715 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 8716 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 8717 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 8718 OH CH.sub.3 CONHOH 8719 OH CH.sub.3 CHCHCHO 8720 OH CH.sub.3 CHCHCOCH.sub.3 8721 OH CH.sub.3 CHCHCH.sub.2 Cl 8722 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 8723 OH CH.sub.3 ##STR20## 8724 O CH.sub.3 CH.sub.3 8725 O CH.sub.3 H 8726 O CH.sub.3 CHCH.sub.2 8727 O CH.sub.3 CHOHCH.sub.2 OH(R) 8728 O CH.sub.3 CHOHCH.sub.2 OH(S) 8729 O CH.sub.3 CHO 8730 O CH.sub.3 CH.sub.2 OH 8731 O CH.sub.3 CO.sub.2 H 8732 O CH.sub.3 CO.sub.2 CH.sub.3 8733 O CH.sub.3 CHNOH 8734 O CH.sub.3 CHOHCHCH.sub.2 O(R) 8735 O CH.sub.3 CHOHCHCH.sub.2(S) 8736 O H CH.sub.3 8737 O H H 8738 O H CHCH.sub.2 8739 O H CHOHCH.sub.2 OH(R) 8740 O H CHOHCH.sub.2 OH(S) 8741 O H CHO 8742 O H CH.sub.2 OH 8743 O H CO.sub.2 H 8744 O H CO.sub.2 CH.sub.3 8745 O H CHNOH 8746 O H CHOHCHCH.sub.2(R) 8747 O H CHOHCHCH.sub.2(S) 8748 OCH.sub.3 CH.sub.3 CH.sub.3 8749 OCH.sub.3 CH.sub.3 H 8750 OCH.sub.3 CH.sub.3 CHCH.sub.2 8751 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 8752 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 8753 OCH.sub.3 CH.sub.3 CHO 8754 OCH.sub.3 CH.sub.3 CH.sub.2 OH 8755 OCH.sub.3 CH.sub.3 CO.sub.2 H 8756 OCH.sub.3 CH.sub.3 CO.sub.2 CH.sub. 3 8757 OCH.sub.3 CH.sub.3 CHNOH 8758 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(R) 8759 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(S) 8760 OCH.sub.3 H CH.sub.3 8761 OCH.sub.3 H H 8762 OCH.sub.3 H CHCH.sub.2 8763 OCH.sub.3 H CHOHCH.sub.2 OH(R) 8764 OCH.sub.3 H CHOHCH.sub.2 OH(S) 8765 OCH.sub.3 H CHO 8766 OCH.sub.3 H CH.sub.2 OH 8767 OCH.sub.3 H CO.sub.2 H 8768 OCH.sub.3 H CO.sub.2 CH.sub.3 8769 OCH.sub.3 H CHNOH 8770 OCH.sub.3 H CHOHCHCH.sub.2(R) 8771 OCH.sub.3 H CHOHCHCH.sub.2(S) 8772 OC.sub.2 H.sub.5 CH.sub.3 CH.sub.3 8773 OC.sub.2 H.sub.5 CH.sub.3 CHO 8774 OC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH 8775 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 8776 OC.sub.3 H.sub.7 CH.sub.3 CHO 8777 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH 8778 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.3 8779 OC.sub.4 H.sub.9 CH.sub.3 CHO 8780 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH 8781 OPh CH.sub.3 CH.sub.3 8782 OPh CH.sub.3 CHO 8783 OPh CH.sub.3 CH.sub.3 OH 8784 OCH.sub.2 Ph CH.sub.3 CH.sub.3 8785 OCH.sub.2 Ph CH.sub.3 CHO 8786 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 8787 OCOCH.sub.3 CH.sub.3 CH.sub.3 8788 OCOCH.sub.3 CH.sub.3 H 8789 OCOCH.sub.3 CH.sub.3 CHCH.sub.2 8790 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 8791 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 8792 OCOCH.sub.3 CH.sub.3 CHO 8793 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 8794 OCOCH.sub.3 CH.sub.3 CO.sub.2 H 8795 OCOCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 8796 OCOCH.sub.3 CH.sub.3 CHNOH 8797 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(R) 8798 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(S) 8799 OCOCH.sub.3 H CH.sub.3 8800 OCOCH.sub.3 H H 8801 OCOCH.sub.3 H CHCH.sub.2 8802 OCOCH.sub.3 H CHOHCH.sub.2 OH(R) 8803 OCOCH.sub. 3 H CHOHCH.sub.2 OH(S) 8804 OCOCH.sub.3 H CHO 8805 OCOCH.sub.3 H CH.sub.2 OH 8806 OCOCH.sub.3 H CO.sub.2 H 8807 OCOCH.sub.3 H CO.sub.2 CH.sub.3 8808 OCOCH.sub.3 H CHNOH 8809 OCOCH.sub.3 H CHOHCHCH.sub.2(R) 8810 OCOCH.sub.3 H CHOHCHCH.sub.2(S) 8811 OCOCO.sub.2 H.sub.5 CH.sub.3 CH.sub.3 8812 OCOC.sub.2 H.sub.5 CH.sub.3 CHO 8813 OCOC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH 8814 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 8815 OCOC.sub.3 H.sub.7 CH.sub.3 CHO 8816 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH 8817 OCOC.sub.4 H.sub.7 CH.sub.3 CH.sub.3 8818 OCOC.sub.4 H.sub.9 CH.sub.3 CHO 8819 OCOC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH 8820 OCOC.sub.15 H.sub.31 CH.sub.3 CH.sub.3 8821 OCOC.sub.15 H.sub.31 CH.sub.3 CHO 8822 OCOC.sub.15 H.sub.31 CH.sub.3 CH.sub.2 OH 8823 OCOC.sub.15 H.sub.29 CH.sub.3 CH.sub.3 8824 OCOC.sub.17 H.sub.35 CH.sub.3 CH.sub.3 8825 OCOC.sub.17 H.sub.33 CH.sub.3 CH.sub.3 8826 OCOC.sub.17 H.sub.31 CH.sub.3 CH.sub.3 8827 OCOC.sub.17 H.sub.29 CH.sub.3 CH.sub.3 8828 OCOC.sub.19 H.sub.31 CH.sub.3 CH.sub.3 8829 OCOPh CH.sub.3 CH.sub.3 8830 OCOCPh CH.sub.3 CH.sub.3 8831 OCOCPh CH.sub.3 CH.sub.3 8832 OH CH.sub.3 CH.sub.3 7833 OH CH.sub.3 CHO 7834 OH CH.sub.3 CH.sub.2 OH 7835 OH CH.sub.3 CO.sub.2 H 7836 OH H CH.sub.3 7837 OH H CHO 7838 OH H CH.sub.2 OH 7839 O CH.sub.3 CH.sub.3 7840 O CH.sub.3 CHO 7841 O CH.sub.3 CH.sub.2 OH 7842 O H CH.sub.3 7843 O H CHO 7844 O H CH.sub.2 OH 7845 OCH.sub.3 CH.sub.3 CH.sub.3 7846 OCH.sub.3 CH.sub.3 CHO 7847 OCH.sub.3 CH.sub.3 CH.sub.2 OH 7848 OCH.sub.3 H CH.sub.3 7849 OCH.sub.3 H CHO 7850 OCH.sub.3 H CH.sub.2 OH 7851 OCOCH.sub.3 CH.sub.3 CH.sub.3 7852 OCOCH.sub.3 CH.sub.3 CHO 7853 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 7854 OCOCH.sub.3 H CH.sub.3 7855 OCOCH.sub.3 H CHO 7856 OCOCH.sub.3 H CH.sub.2 OH 7__________________________________________________________________________ *Further analytical data are available in the examples section.
A 4,4-bis-normethyl 15-oxasterol (R.sub.2 of the general structure 1 is H), 14.alpha.-methyl-15-oxa-5.alpha.-cholest-8-en- 3b-ol (47), has also been synthesized from 5 -cholesta- 8,14-diene-3b-ol by following the sequence 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 followed 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 transformed into the desired 14.alpha.-methyl-15-oxa-5.alpha.-cholest-8-en-3b-ol (47) by glycal formation, osmium tetroxide hydroxylation, oxidative cleavage by sodium metaperiodate, and reduction with triethylsilane and boron trifluoride etherate in 34.5% overall yield from the cyclic hemiacetal 43a. Compound 47 is another example within the scope of the present invention and its synthesis is an example, which demonstrates that preparative methods for compounds with dimethyl at C-4 in the scope (Formula I, with R.sub.2 .dbd.CH.sub.3) are applicable to di-bis-normethyl compounds in the scope (Formula I, with R.sub.2 .dbd.H). ##STR21##
15-Thia-lanosterols
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 internal 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, Conn. 06817) and boron trifluoride etherate in methylene chloride followed by triethylsilane to obtain the desired 15-thia-dihydrolanosterol (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 was 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 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 examples of 15-thia-lanosterols within the scope of the present invention. ##STR22##
Sulfides are easily converted to sulfoxides with various oxidizing agents including sodium metaperiodate. Exposing the cyclic sulfide 50 to sodium metaperiodate in 5 parts of ethanol and 1 part of water 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 within the scope of the present invention.
Using more powerful oxidizing agents such as hydrogen peroxide or potassium permanganate (see S. R. Sandler, and W. Karo, Organic Functional Group Preparations, Vol. I pp. 610-618, Academic Press, 1983) sulfides or sulfoxides may be converted to the corresponding sulfones represented by the general structure 55, which are within the scope of the present invention.
For syntheses of other examples of compounds within 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 supra.
Tables 3, 4, and 5 set forth various thiasterols of the present invention.
TABLE 3__________________________________________________________________________ ##STR23##Ex. No. R.sub.1 R.sub.2 R.sub.3 D No. M.P.__________________________________________________________________________ 857 OH CH.sub.3 CH.sub.3 8 49 amorphous* 858 OH CH.sub.3 H 8 50 amorphous* 859 OH CH.sub.3 CHCH.sub.2 8 51 amorphous* 860 OH CH.sub.3 CHOHCH.sub.2 OH(R) 8 861 OH CH.sub.3 CHOHCH.sub.2 OH(S) 8 862 OH CH.sub.3 CHO 8 863 OH CH.sub.3 CH.sub.2 OH 8 864 OH CH.sub.3 CO.sub.2 H 8 865 OH CH.sub.3 CO.sub.2 CH.sub.3 8 866 OH CH.sub.3 CHNOH 8 867 OH CH.sub.3 CHOHCHCH.sub.2 (R) 8 868 OH CH.sub.3 CHOHCH CH.sub.2 (S) 8 869 OH H CH.sub.3 8 870 OH H H 8 871 OH H CHCH.sub.2 8 872 OH H CHOHCH.sub.2 OH(R) 8 873 OH H CHOHCH.sub.2 OH(S) 8 874 OH H CHO 8 875 OH H CH.sub.2 OH 8 876 OH H CO.sub.2 H 8 877 OH H CO.sub.2 CH.sub.3 8 878 OH H CHNOH 8 879 OH H CHOHCHCH.sub.2 (R) 8 880 OH H CHOHCHCH.sub.2 (S) 8 881 OH CH.sub.3 C.sub.2 H.sub.5 8 882 OH CH.sub.3 CH.sub.2 CHCH.sub.2 8 883 OH CH.sub.3 CCH 8 884 OH CH.sub.3 CH.sub.2 Ph 8 885 OH CH.sub.3 CH.sub.2 OCH.sub.3 8 886 OH CH.sub.3 CH.sub.2 OCOCH.sub.3 8 887 OH CH.sub.3 CH.sub.2 SH 8 888 OH CH.sub.3 CH.sub.2 SCH.sub.3 8 889 OH CH.sub.3 CH.sub.2 SCOCH.sub.3 8 890 OH CH.sub.3 CH.sub.2 NH.sub.2 8 891 OH CH.sub.3 CH.sub.2 NHCH.sub.3 8 892 OH CH.sub.3 CH.sub.2 NHCOCH.sub.3 8 893 OH CH.sub.3 CH.sub.2 NHCSCH.sub.3 8 894 OH CH.sub.3 CH.sub.2 NHC(NH)CH.sub.3 8 895 OH CH.sub.3 COCH.sub.3 8 896 OH CH.sub.3 COCHCH.sub.2 8 897 OH CH.sub.3 CSCH.sub.3 8 898 OH CH.sub.3 CSCHCH.sub.2 8 899 OH CH.sub.3 C(NH)CH.sub.3 8 900 OH CH.sub.3 CO.sub.2 C.sub.2 H.sub.5 8 901 OH CH.sub.3 COSCH.sub.3 8 902 OH CH.sub.3 CONH.sub.2 8 903 OH CH.sub.3 CONHCH.sub.3 8 904 OH CH.sub.3 CONHCOCH.sub.3 8 905 OH CH.sub.3 CSNH.sub.2 8 906 OH CH.sub.3 CSNHCH.sub.3 8 907 OH CH.sub.3 CSNHCOCH.sub.3 8 908 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 8 909 OH CH.sub.3 CH.sub.2 CH.sub.2 OCH.sub.3 8 910 OH CH.sub.3 CH.sub.2 CH.sub.2 OCOCH.sub.3 8 911 OH CH.sub.3 CH.sub.2 CH.sub.2 SH 8 912 OH CH.sub. 3 CH.sub.2 CH.sub.2 SCH.sub.3 8 913 OH CH.sub.3 CH.sub.2 CH.sub.2 SCOCH.sub.3 8 914 OH CH.sub.3 CH.sub.2 CH.sub.2 NH.sub.2 8 915 OH CH.sub.3 CH.sub.2 CH.sub.2 NHCH.sub.3 8 916 OH CH.sub.3 CH.sub.2 CH.sub.2 NHCOCH.sub.3 8 917 OH CH.sub.3 CH.sub.2 CHO 8 918 OH CH.sub.3 CH.sub.2 COCH.sub.3 8 919 OH CH.sub.3 CH.sub.2 COCHCH.sub.2 8 920 OH CH.sub.3 CH.sub.2 CSCH.sub.3 8 921 OH CH.sub.3 CH.sub.2 CSCHCH.sub.2 8 922 OH CH.sub.3 CH.sub.2 (NH)CH.sub.3 8 923 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 8 924 OH CH.sub.3 CH.sub.2 COSCH.sub.3 8 925 OH CH.sub.3 CH.sub.2 CONH.sub.2 8 926 OH CH.sub.3 CH.sub.2 CONHCH.sub.3 8 927 OH CH.sub.3 CH.sub.2 CONHCOCH.sub.3 8 928 OH CH.sub.3 CH.sub.2 CSNH.sub.2 8 929 OH CH.sub.3 CH.sub.2 C(NH)CH.sub.3 8 930 OH CH.sub.3 CH.sub.2 Cl 8 931 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 8 932 OH CH.sub.3 CN 8 933 OH CH.sub.3 CHNOCH.sub.3 8 934 OH CH.sub.3 CHNOCOCH.sub.3 8 935 OH CH.sub.3 CHNNH.sub.2 8 936 OH CH.sub.3 CHNNHCH.sub.3 8 937 OH CH.sub.3 CHNNHCOCH.sub.3 8 938 OH CH.sub.3 CHNNHCSCH.sub.3 8 939 OH CH.sub.3 CH.sub.2 NHOH 8 940 OH CH.sub.3 CH.sub.2 NHOCH.sub.3 8 941 OH CH.sub.3 CH.sub.2 NHOCOCH.sub.3 8 942 OH CH.sub.3 CH.sub.2 NHNH.sub.2 8 943 OH CH.sub.3 CH.sub.2 NHNHCH.sub.3 8 944 OH CH.sub.3 CH.sub.2 NHNHCOCH.sub.3 8 945 OH CH.sub.3 CH.sub.2 NHNHCSCH.sub.3 8 946 OH CH.sub.3 CH.sub.2 CN 8 947 OH CH.sub.3 CH.sub.2 CHNOH 8 948 OH CH.sub.3 CH.sub.2 CHNOCH.sub.3 8 949 OH CH.sub.3 CH.sub.2 CHNOCOCH.sub.3 8 950 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 8 951 OH CH.sub.3 CH.sub.2 CH NNHCH.sub.3 8 952 OH CH.sub.3 CH.sub.2 CHNNHCOCH.sub.3 8 953 OH CH.sub.3 CH.sub.2 CHNNHCSCH.sub.3 8 954 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 8 955 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOCH.sub.3 8 956 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOCOCH.sub.3 8 957 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 8 958 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCH.sub.3 8 959 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCOCH.sub.3 8 960 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCSCH.sub.3 8 961 OH CH.sub.3 CONHOH 8 962 OH CH.sub.3 CONHOCH.sub.3 8 963 OH CH.sub.3 CONHOCOCH.sub.3 8 964 OH CH.sub.3 CSNHOH 8 965 OH CH.sub.3 CSNHOCH.sub.3 8 966 OH CH.sub.3 CSNHOCOCH.sub.3 8 967 OH CH.sub.3 CHCHCHO 8 968 OH CH.sub.3 CHCHCOCH.sub.3 8 969 OH CH.sub.3 CHCHCSCH.sub.3 8 970 OH CH.sub.3 CHCHCHNH 8 971 OH CH.sub.3 CHCHC(NH)CH.sub.3 8 972 OH CH.sub.3 CCCHO 8 973 OH CH.sub.3 CCCOCH.sub.3 8 974 OH CH.sub.3 CCCSCH.sub.3 8 975 OH CH.sub.3 CCCHNH 8 976 OH CH.sub.3 CCC(NH)CH.sub.3 8 977 OH CH.sub.3 CHCHCH.sub.2 Cl 8 978 OH CH.sub.3 CCCH.sub.2 Cl 8 979 OH CH.sub.3 CHCHCH.sub.2 OCOCH.sub.3 8 980 OH CH.sub.3 CCCH.sub.2 OCOCH.sub.3 8 981 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 8 982 OH CH.sub.3 CHOHCHOHCH.sub.2 OH 8 983 OH CH.sub.3 ##STR24## 8 984 OH CH.sub.3 ##STR25## 8 985 OH CH.sub.3 ##STR26## 8 986 OH H CH.sub.2 SH 8 987 OH H CH.sub.2 NH.sub.2 8 988 OH H COCH.sub.3 8 989 OH H CONH.sub.2 8 990 OH H CSNH.sub.2 8 991 OH H CH.sub. 2 CH.sub.2 OH 8 992 OH H CH.sub.2 CHO 8 993 OH H CH.sub.2 COCH.sub.3 8 994 OH H CH.sub.2 CO.sub.2 CH.sub.3 8 995 OH H CH.sub.2 CONH.sub.2 8 996 OH H CH.sub.2 Cl 8 997 OH H CH.sub.2 CH.sub.2 Cl 8 998 OH H CN 8 999 OH H CHNNH.sub.2 81000 OH H CH.sub.2 NHOH 81001 OH H CH.sub.2 NHNH.sub.2 81002 OH H CH.sub.2 CN 81003 OH H CH.sub.2 CHNOH 81004 OH H CH.sub.2 CHNNH.sub.2 81005 OH H CH.sub.2 CH.sub.2 NHOH 81006 OH H CH.sub.2 CH.sub.2 NHNH.sub.2 81007 OH H CONHOH 81008 OH H CHCHCHO 81009 OH H CHCHCOCH.sub.3 81010 OH H CHCHCH.sub.2 Cl 81011 OH H CH.sub.2 CHOHCH.sub.2 OH 81012 OH H ##STR27## 81013 O CH.sub.3 CH.sub.3 81014 O CH.sub.3 H 81015 O CH.sub.3 CHCH.sub.2 81016 O CH.sub.3 CHOHCH.sub.2 OH(R) 81017 O CH.sub.3 CHOHCH.sub.2 OH(S) 81018 O CH.sub.3 CHO 81019 O CH.sub.3 CH.sub.2 OH 81020 O CH.sub.3 CO.sub.2 H 81021 O CH.sub.3 CO.sub.2 CH.sub.3 81022 O CH.sub.3 CHNOH 81023 O CH.sub.3 CHOHCHCH.sub.2 (R) 81024 O CH.sub.3 CHOHCHCH.sub.2 (S) 81025 O CH.sub.3 CH.sub.2 SH 81026 O CH.sub.3 CH.sub.2 NH.sub.2 81027 O CH.sub.3 COCH.sub.3 81028 O CH.sub.3 CONH.sub.2 81029 O CH.sub.3 CSNH.sub.2 81030 O CH.sub.3 CH.sub.2 CH.sub.2 OH 81031 O CH.sub.3 CH.sub.2 CHO 81032 O CH.sub.3 CH.sub.2 COCH.sub.3 81033 O CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81034 O CH.sub.3 CH.sub.2 CONH.sub.2 81035 O CH.sub.3 CH.sub.2 Cl 81036 O CH.sub.3 CH.sub.2 CH.sub.2 Cl 81037 O CH.sub.3 CN 81038 O CH.sub.3 CHNNCH.sub.2 81039 O CH.sub.3 CH.sub.2 NHOH 81040 O CH.sub.3 CH.sub.2 NHNH.sub.2 81041 O CH.sub.3 CH.sub.2 CN 81042 O CH.sub.3 CH.sub.2 CHNOH 81043 O CH.sub.3 CH.sub.2 CHNNH.sub.2 81044 O CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81045 O CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81046 O CH.sub.3 CONHOH 81047 O CH.sub.3 CHCHCHO 81048 O CH.sub.3 CHCHCOCH.sub.3 81049 O CH.sub.3 CHCHCH.sub.2 Cl 81050 O CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81051 O CH.sub.3 ##STR28## 81052 O H CH.sub.3 81053 O H H 81054 O H CHCH.sub.2 81055 O H CHOHCH.sub.2 OH(R) 81056 O H CHOHCH.sub.2 OH(S) 81057 O H CHO 81058 O H CH.sub.2 OH 81059 O H CO.sub.2 H 81060 O H CO.sub.2 CH.sub.3 81061 O H CHNOH 81062 O H CHOHCHCH.sub.2 (R) 81063 O H CHOHCHCH.sub.2 (S) 81064 OCH.sub.3 CH.sub.3 CH.sub.3 81065 OCH.sub.3 CH.sub.3 H 81066 OCH.sub.3 CH.sub.3 CHCH.sub.2 81067 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 81068 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 81069 OCH.sub.3 CH.sub.3 CHO 81070 OCH.sub.3 CH.sub.3 CH.sub.2 OH 81071 OCH.sub.3 CH.sub.3 CO.sub.2 H 81072 OCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 81073 OCH.sub.3 CH.sub.3 CHNOH 81074 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 81075 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 81076 OCH.sub.3 CH.sub.3 CH.sub.2 SH 81077 OCH.sub.3 CH.sub.3 CH.sub.2 NH.sub.2 81078 OCH.sub.3 CH.sub.3 COCH.sub.3 81079 OCH.sub.3 CH.sub.3 CONH.sub.2 81080 OCH.sub.3 CH.sub.3 CSNH.sub.2 81081 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 OH 81082 OCH.sub.3 CH.sub.3 CH.sub.2 CHO 81083 OCH.sub.3 CH.sub.3 CH.sub.2 COCH.sub.3 81084 OCH.sub.3 CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81085 OCH.sub.3 CH.sub.3 CH.sub.2 CONH.sub.2 81086 OCH.sub.3 CH.sub.3 CH.sub.2 Cl 81087 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 Cl 81088 OCH.sub.3 CH.sub.3 CN 81089 OCH.sub.3 CH.sub.3 CHNNH.sub.2 81090 OCH.sub.3 CH.sub.3 CH.sub.2 NHOH 81091 OCH.sub.3 CH.sub.3 CH.sub.2 NHNH.sub.2 81092 OCH.sub.3 CH.sub.3 CH.sub.2 CN 81093 OCH.sub.3 CH.sub.3 CH.sub.2 CHNOH 81094 OCH.sub.3 CH.sub.3 CH.sub.2 CHNNH.sub.2 81095 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81096 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81097 OCH.sub.3 CH.sub.3 CONHOH 81098 OCH.sub.3 CH.sub.3 CHCHCHO 81099 OCH.sub.3 CH.sub.3 CHCHCOCH.sub.3 81100 OCH.sub.3 CH.sub.3 CHCHCH.sub.2 Cl 81101 OCH.sub. 3 CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81102 OCH.sub.2 CH.sub.3 ##STR29## 81103 OCH.sub.3 H CH.sub.3 81104 OCH.sub.3 H H 81105 OCH.sub.3 H CHCH.sub.2 81106 OCH.sub.3 H CHOHCH.sub.2 OH(R) 81107 OCH.sub.3 H CHOHCH.sub.2 OH(S) 81108 OCH.sub.3 H CHO 81109 OCH.sub.3 H CH.sub.2 OH 81110 OCH.sub.3 H CO.sub.2 H 81111 OCH.sub.3 H CO.sub.2 CH.sub.3 81112 OCH.sub.3 H CHOHCHCH.sub.2 (R) 81114 OCH.sub.3 H CHOHCHCH.sub.2 (S) 81115 OC.sub.2 H.sub.5 CH.sub.3 CH.sub.3 81116 OC.sub.2 H.sub.5 CH.sub.3 CHO 81117 OC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH 81118 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 81119 OC.sub.3 H.sub.7 CH.sub.3 CHO 81120 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH 81121 Oi-C.sub.3 H.sub.7 CH.sub.3 CH.sub.3 81122 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.3 81123 OC.sub.4 H.sub. 9 OC.sub.3 CHO 81124 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH 81125 Oi-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 81126 Ot-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 81127 OPh CH.sub.3 CH.sub.3 81128 OPh CH.sub.3 CHO 81129 OPh CH.sub.3 CH.sub.2 OH 81130 OCH.sub.2 Ph CH.sub.3 CH.sub.3 81131 OCH.sub.2 Ph CH.sub.3 CHO 81132 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 81133 OCOCH.sub.3 CH.sub.3 CH.sub.3 81134 OCOCH.sub.3 CH.sub.3 H 81135 OCOCH.sub.3 CH.sub.3 CHCH.sub.2 81136 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 81137 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 81138 OCOCH.sub.3 CH.sub.3 CHO 81139 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 81140 OCOCH.sub.3 CH.sub.3 CO.sub.2 H 81141 OCOCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 81142 OCOCH.sub.3 CH.sub.3 CHNOH 81143 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 81144 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 81145 OCOCH.sub.3 CH.sub.3 CH.sub.2 SH 81146 OCOCH.sub.3 CH.sub.3 CH.sub.2 NH.sub.2 81147 OCOCH.sub.3 CH.sub.3 COCH.sub.3 81148 OCOCH.sub.3 CH.sub.3 CONH.sub.2 81149 OCOCH.sub.3 CH.sub.3 CSNH.sub.2 81150 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 OH 81151 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHO 81152 OCOCH.sub.3 CH.sub.3 CH.sub.2 COCH.sub.3 81153 OCOCH.sub.3 CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81154 OCOCH.sub.3 CH.sub.3 CH.sub.2 CONH.sub.2 81155 OCOCH.sub.3 CH.sub.3 CH.sub.2 Cl 81156 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 Cl 81157 OCOCH.sub.3 CH.sub.3 CN 81158 OCOCH.sub.3 CH.sub.3 CHNNH.sub.2 81159 OCOCH.sub.3 CH.sub.3 CH.sub.2 NHOH 81160 OCOCH.sub.3 CH.sub.3 CH.sub.2 NHNH.sub.2 81161 OCOCH.sub.3 CH.sub.3 CH.sub.2 CN 81162 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHNOH 81163 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHNNH.sub.2 81164 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81165 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81166 OCOCH.sub.3 CH.sub. 3 CONHOH 81167 OCOCH.sub.3 CH.sub.3 CHCHCHO 81168 OCOCH.sub.3 CH.sub.3 CHCHCOCH.sub.3 81169 OCOCH.sub.3 CH.sub.3 CHCHCH.sub.2 Cl 81170 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81171 OCOCH.sub.3 CH.sub.3 ##STR30## 81172 OCOCH.sub.3 H CH.sub.3 81173 OCOCH.sub.3 H H 81174 OCOCH.sub.3 H CHCH.sub.2 81175 OCOCH.sub.3 H CHOHCH.sub.2 OH(R) 81176 OCOCH.sub.3 H CHOHCH.sub.2 OH(S) 81177 OCOCH.sub.3 H CHO 81178 OCOCH.sub.3 H CH.sub.2 OH 81179 OCOCH.sub.3 H CO.sub.2 H 81180 OCOCH.sub.3 H CO.sub.2 CH.sub.3 81181 OCOCH.sub.3 H CHNOH 81182 OCOCH.sub.3 H CHOHCHCH.sub.2 (R) 81183 OCOCH.sub.3 H CHOHCHCH.sub.2 (S) 81184 OCOC.sub.2 H.sub.5 CH.sub.3 CH.sub.3 81185 OCOC.sub.2 H.sub.5 CH.sub.3 CHO 81186 OCOC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH 81187 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 81188 OCOC.sub.3 H.sub.7 CH.sub.3 CHO 81189 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH 81190 OCOi-C.sub.4 H.sub.7 CH.sub.3 CH.sub.3 81191 OCOC.sub.4 H.sub.9 CH.sub.3 CH.sub.3 81192 OCOC.sub.4 H.sub.9 CH.sub.3 CHO 81193 OCOC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH 81194 OCOi-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 81195 OCOt-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 81195 OCOC.sub.15 H.sub.31 CH.sub.3 CH.sub.3 81197 OCOC.sub.15 H.sub.31 CH.sub.3 CHO 81198 OCOC.sub.15 H.sub.31 CH.sub.3 CH.sub.2 OH 81199 OCOC.sub.15 H.sub.29 CH.sub.3 CH.sub.3 81200 OCOC.sub.17 H.sub.35 CH.sub.3 CH.sub.3 81201 OCOC.sub.17 H.sub.33 CH.sub.3 CH.sub.3 81202 OCOC.sub.17 H.sub.31 CH.sub.3 CH.sub.3 81203 OCOC.sub.17 H.sub.29 CH.sub.3 CH.sub.3 81204 OCOC.sub.19 H.sub.31 CH.sub.3 CH.sub.3 81205 OCOPh CH.sub.3 CH.sub.3 81206 OCOPh CH.sub.3 CHO 81207 OCOPh CH.sub.3 CH.sub.2 OH 81208 OH CH.sub.3 CH.sub.3 71209 OH CH.sub.3 H 71210 OH CH.sub.3 CHCH.sub.2 71211 OH CH.sub.3 CHOHCH.sub.2 OH(R) 71212 OH CH.sub.3 CHOHCH.sub.2 OH(S) 71213 OH CH.sub.3 CHO 71214 OH CH.sub.3 CH.sub.2 OH 71215 OH CH.sub.3 CO.sub.2 H 71216 OH CH.sub.3 CO.sub.2 CH.sub.3 71217 OH CH.sub.3 CHNOH 71218 OH CH.sub.3 CHOHCHCH.sub.2 (R) 71219 OH H CH.sub.3 71220 OH H H 71221 OH H CHCH.sub.2 71222 OH H CHOHCH.sub.2 OH(R) 71223 OH H CHOHCH.sub.2 OH(S) 71224 OH H CHO 71225 OH H CH.sub.2 OH 71226 OH H CO.sub.2 H 71227 OH H CO.sub.2 CH.sub.3 71228 OH H CHNOH 71229 OH H CHOHCHCH.sub.2 (R) 71230 OH H CHOHCHCH.sub.2 (S) 71231 O CH.sub.3 CH.sub.3 71232 O CH.sub.3 H 71233 O CH.sub.3 CHCH.sub.2 71234 O CH.sub.3 CHOHCH.sub.2 OH(R) 71235 O CH.sub.3 CHOHCH.sub.2 OH (S) 71236 O CH.sub.3 CHO 71237 O CH.sub.3 CH.sub.2 OH 71238 O CH.sub.3 CO.sub.2 H 71239 O CH.sub.3 CO.sub.2 CH.sub.3 71240 O CH.sub.3 CHNOH 71241 O CH.sub.3 CHOHCHCH.sub.2 (R) 71242 O CH.sub.3 CHOHCHCH.sub.2 (S) 71243 O H CH.sub.3 71244 O H H 71245 O H CHCH.sub.2 71246 O H CHOHCH.sub.2 OH(R) 71247 O H CHOHCH.sub.2 OH(S) 71248 O H CHO 71249 O H CH.sub.2 OH 71250 O H CO.sub.2 H 71251 O H CO.sub.2 CH.sub.3 71252 O H CHNOH 71253 O H CHOHCHCH.sub.2 (R) 71254 O H CHOHCHCH.sub.2 (S) 71255 OCH.sub.3 CH.sub.3 CH.sub.3 71256 OCH.sub.3 CH.sub.3 H 71257 OCH.sub.3 CH.sub.3 CHCH.sub.2 71258 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) 71259 OCH.sub. 3 CH.sub.3 CHOHCH.sub.2 OH(S) 71260 OCH.sub.3 CH.sub.3 CHO 71261 OCH.sub.3 CH.sub.3 CH.sub.2 OH 71262 OCH.sub.3 CH.sub.3 CO.sub.2 H 71263 OCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 71264 OCH.sub.3 CH.sub.3 CHNOH 71265 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 71266 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 71267 OCH.sub.3 H CH.sub.3 71268 OCH.sub.3 H H 71269 OCH.sub.3 H CHCH.sub.2 71270 OCH.sub.3 H CHOHCH.sub.2 OH(R) 71271 OCH.sub.3 H CHOHCH.sub.2 OH(S) 71272 OCH.sub.3 H CHO 71273 OCH.sub.3 H CH.sub.2 OH 71274 OCH.sub.3 H CO.sub.2 H 71275 OCH.sub.3 H CO.sub.2 CH.sub.3 71276 OCH.sub.3 H CHNOH 71277 OCH.sub.3 H CHOHCHCH.sub.2 (R) 71278 OCH.sub.3 H CHOHCHCH.sub.2 (S) 71279 OCOCH.sub.3 CH.sub.3 CH.sub.3 71280 OCOCH.sub.3 CH.sub.3 H 71281 OCOCH.sub.3 CH.sub.3 CHCH.sub.2 71282 OCOCH.sub.3 CH.sub.3 CHOHCH.sub. 2 OH(R) 71283 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) 71284 OCOCH.sub.3 CH.sub.3 CHO 71285 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 71286 OCOCH.sub.3 CH.sub.3 CO.sub.2 H 71287 OCOCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 71288 OCOCH.sub.3 CH.sub.3 CHNOH 71289 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (R) 71290 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2 (S) 71291 OCOCH.sub.3 H CH.sub.3 71292 OCOCH.sub.3 H H 71293 OCOCH.sub.3 H CHCH.sub.2 71294 OCOCH.sub.3 H CHOHCH.sub.2 OH(R) 71295 OCOCH.sub.3 H CHOHCH.sub.2 OH(S) 71296 OCOCH.sub.3 H CHO 71297 OCOCH.sub.3 H CH.sub.2 OH 71298 OCOCH.sub.3 H CO.sub.2 H 71299 OCOCH.sub.3 H CO.sub.2 CH.sub.3 71300 OCOCH.sub.3 H CHNOH 71301 OCOCH.sub.3 H CHOHCHCH.sub.2 (R) 71302 OCOCH.sub.3 H CHOHCHCH.sub.2 (S) 7__________________________________________________________________________ *Further analytical data are available in the examples section.
TABLE 4__________________________________________________________________________ ##STR31##Ex. No. R.sub.1 R.sub.2 R.sub.3 D No. M.P.__________________________________________________________________________1303 OH CH.sub.3 CH.sub.3 8 52 amorphous*1304 OH CH.sub.3 H 8 53 amorphous*1305 OH CH.sub.3 CHCH.sub.2 8 54 amorphous*1306 OH CH.sub.3 CHOHCH.sub.2 OH(R) 81307 OH CH.sub.3 CHOHCH.sub.2 OH(S) 81308 OH CH.sub.3 CHO 81309 OH CH.sub.3 CH.sub.2 OH 81310 OH CH.sub.3 CO.sub.2 H 81311 OH CH.sub.3 CO.sub.2 CH.sub.3 81312 OH CH.sub.3 CHNOH 81313 OH CH.sub.3 CHOHCHCH.sub.2(R) 81314 OH CH.sub.3 CHOHCHCH.sub.2(S) 81315 OH H CH.sub.3 81316 OH H H 81317 OH H CHCH.sub.2 81318 OH H CHOHCH.sub.2 OH(R) 81319 OH H CHOHCH.sub.2 OH(S) 81320 OH H CHO 81321 OH H CH.sub.2 OH 81322 OH H CO.sub.2 CH.sub.3 81323 OH H CHNOH 81324 OH H CHOHCHCH.sub.2(R) 81325 OH H CHOHCHCH.sub.2(S) 81326 OH CH.sub.3 CH.sub.2 SH 81327 OH CH.sub.3 CH.sub.2 NH.sub.2 81328 OH CH.sub.3 COCH.sub.3 81329 OH CH.sub.3 CONH.sub.2 81330 OH CH.sub.3 CSNH.sub.2 81331 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 81332 OH CH.sub.3 CH.sub.2 CHO 81333 OH CH.sub.3 CH.sub.2 COCH.sub.3 81334 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81335 OH CH.sub.3 CH.sub.2 CONH.sub.2 81336 OH CH.sub.3 CH.sub.2 Cl 81337 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 81338 OH CH.sub.3 CN 81339 OH CH.sub.3 CHNNH.sub.2 81340 OH CH.sub.3 CH.sub.2 NHOH 81341 OH CH.sub.3 CH.sub.2 NHNH.sub.2 81342 OH CH.sub.3 CH.sub.2 CN 81343 OH CH.sub.3 CH.sub.2 CHNOH 81344 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 81345 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81346 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81347 OH CH.sub.3 CONHOH 81348 OH CH.sub.3 CHCHCHO 81349 OH CH.sub.3 CHCHCOCH.sub.3 81350 OH CH.sub.3 CHCHCH.sub.2 Cl 81351 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81352 OH CH.sub.3 ##STR32## 81353 O CH.sub.3 CH.sub.3 81354 O CH.sub.3 CHO 81355 O CH.sub.3 CH.sub.2 OH 81356 O H CH.sub.3 81357 O H CHO 81358 O H CH.sub.2 OH 81359 OCH.sub.3 CH.sub.3 CH.sub.3 81360 OCH.sub.3 CH.sub.3 CHO 81361 OCH.sub.3 CH.sub.3 CH.sub.2 OH 81362 OCH.sub.3 H CH.sub.3 81363 OCH.sub.3 H CHO 81364 OCH.sub.3 H CH.sub.2 OH 81365 OPh CH.sub. 3 CH.sub.3 81366 OPh CH.sub.3 CHO 81367 OPh CH.sub.3 CH.sub.2 OH 81368 OCH.sub.2 Ph CH.sub.3 CH.sub.3 81369 OCH.sub.2 Ph CH.sub.3 CHO 81370 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 81371 OCOCH.sub.3 CH.sub.3 CH.sub.3 81372 OCOCH.sub.3 CH.sub.3 CHO 81373 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 81374 OCOCH.sub.3 H CH.sub.3 81375 OCOCH.sub.3 H CHO 81376 OCOCH.sub.3 H CH.sub.2 OH 81377 OCOPh CH.sub.3 CH.sub.3 81378 OCOPh CH.sub.3 CHO 81379 OCOPh CH.sub.3 CH.sub.2 OH 81380 OH CH.sub.3 CH.sub.3 71381 OH CH.sub.3 CHO 71382 OH CH.sub.3 CH.sub.2 OH 71383 OH CH.sub.3 CO.sub.2 H 71384 OH H CH.sub.3 71385 OH H CHO 71386 OH H CH.sub.2 OH 71387 O CH.sub.3 CH.sub.3 71388 O CH.sub.3 CHO 71389 O CH.sub.3 CH.sub.2 OH 71390 O H CH.sub.3 71391 O H CHO 71392 O H CH.sub.2 OH 71393 OCH.sub.3 CH.sub.3 CH.sub.3 71394 OCH.sub.3 CH.sub.3 CHO 71395 OCH.sub.3 CH.sub.3 CH.sub.2 OH 71396 OCH.sub.3 H CH.sub.3 71397 OCH.sub.2 H CHO 71398 OCH.sub.3 H CH.sub.2 OH 71399 OCOCH.sub.3 CH.sub.3 CH.sub.3 71400 OCOCH.sub.3 CH.sub.3 CHO 71401 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 71402 OCOCH.sub.3 H CH.sub.3 71403 OCOCH.sub.3 H CHO 71404 OCOCH.sub.3 H CH.sub.2 OH 7__________________________________________________________________________ *Further analytical data are availble in the examples section.
TABLE 5______________________________________ ##STR33##Ex.No. R.sub.1 R.sub.2 R.sub.3 D No. M.P.______________________________________1405 OH CH.sub.3 CH.sub.3 81406 OH CH.sub.3 H 81407 OH CH.sub.3 CHCH.sub.2 81408 OH CH.sub.3 CHOHCH.sub.2 OH(R) 81409 OH CH.sub.3 CHOHCH.sub.2 OH(S) 81410 OH CH.sub.3 CHO 81411 OH CH.sub.3 CH.sub.2 OH 81412 OH CH.sub.3 CO.sub.2 H 81413 OH CH.sub.3 CO.sub.2 CH.sub.3 81414 OH CH.sub.3 CHNOH 81415 OH CH.sub.3 CHOHCHCH.sub.2(R) 81416 OH CH.sub.3 CHOHCHCH.sub.2(S) 81417 OH H CH.sub. 3 81418 OH H H 81419 OH H CHCH.sub.2 81420 OH H CHOHCH.sub.2 OH(R) 81421 OH H CHOHCH.sub.2 OH(S) 81422 OH H CHO 81423 OH H CH.sub.2 OH 81424 OH H CO.sub.2 H 81425 OH H CO.sub.2 CH.sub.3 81426 OH H CHNOH 81327 OH H CHOHCHCH.sub.2(R) 81428 OH H CHOHCHCH.sub.2(S) 81429 OH CH.sub.3 CH.sub.2 SH 81430 OH CH.sub.3 CH.sub.2 NH.sub.2 81431 OH CH.sub.3 COCH.sub.3 81432 OH CH.sub.3 CONH.sub.2 81433 OH CH.sub.3 CSNH.sub.2 81434 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 81435 OH CH.sub.3 CH.sub.3 CHO 81436 OH CH.sub.3 CH.sub.2 COCH.sub.3 81437 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81438 OH CH.sub.3 CH.sub.2 CONH.sub.2 81439 OH CH.sub.3 CH.sub.2 Cl 81440 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 81441 OH CH.sub.3 CN 81442 OH CH.sub.3 CHNNH.sub.2 81443 OH CH.sub.3 CH.sub.2 NHOH 81444 OH CH.sub.3 CH.sub.2 NHNH.sub.2 81445 OH CH.sub.3 CH.sub.2 CN 81446 OH CH.sub.3 CH.sub.2 CHNOH 81447 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 81448 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81449 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81450 OH CH.sub.3 CONHOH 81451 OH CH.sub.3 CHCHCHO 81452 OH CH.sub.3 CHCHCOCH.sub.3 81453 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81455 OH CH.sub.3 ##STR34## 81456 O CH.sub.3 CH.sub.3 81457 O CH.sub.3 CHO 81458 O CH.sub.3 CH.sub.2 OH 81459 O H CH.sub.3 81460 O H CHO 81461 O H CH.sub.2 OH 81462 OCH.sub.3 CH.sub.3 CH.sub.3 81463 OCH.sub.3 CH.sub.3 CHO 81464 OCH.sub.3 CH.sub.3 CH.sub.2 OH 81465 OCH.sub.3 H CH.sub.3 81466 OCH.sub.3 H CHO 81467 OCH.sub.3 H CH.sub.2 OH 81468 OPh CH.sub.3 CH.sub.3 81469 OPh CH.sub.3 CHO 81470 OPh CH.sub.3 CH.sub.2 OH 81471 OCH.sub.2 Ph CH.sub.3 CH.sub.3 81472 OCH.sub.2 Ph CH.sub.3 CHO 81473 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 81474 OCOCH.sub.3 CH.sub.3 CH.sub.3 81475 OCOCH.sub.3 CH.sub.3 CHO 81476 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 81477 OCOCH.sub.3 H CH.sub.3 81478 OCOCH.sub.3 H CHO 81479 OCOCH.sub.3 H CH.sub.2 OH 81480 OCOPh CH.sub.3 CH.sub.3 81481 OCOPh CH.sub.3 CHO 81482 OCOPh CH.sub.3 CH.sub.2 OH 81483 OH CH.sub.3 CH.sub.3 71484 OH CH.sub.3 CHO 71485 OH CH.sub.3 CH.sub.2 OH 71486 OH CH.sub.3 CH.sub.2 H 71487 OH H CH.sub.3 71488 OH H CHO 71489 OH H CH.sub.2 OH 71490 O CH.sub.3 CH.sub.3 71491 O CH.sub.3 CHO 71492 O CH.sub.3 CH.sub.2 OH 71493 O H CH.sub.3 71494 O H CHO 71495 O H CH.sub.2 OH 71496 OCH.sub.3 CH.sub.3 CH.sub.3 71497 OCH.sub.3 CH.sub.3 CHO 71498 OCH.sub.3 CH.sub.3 CH.sub.2 OH 71499 OCH.sub.3 H CH.sub.3 71500 OCH.sub.3 H CHO 71501 OCH.sub.3 H CH.sub.2 OH 71502 OCOCH.sub.3 CH.sub.3 CH.sub.3 71503 OCOCH.sub.3 CH.sub.3 CHO 71504 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 71505 OCOCH.sub.3 H CH.sub.3 71506 OCOCH.sub.3 H CHO 71507 OCOCH.sub.3 H CH.sub.2 OH 7______________________________________
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 cyclic acetal 7d with hydrogen sulfide and boron trifluoride etherate in methylene chloride followed by triethylsilane afforded the desired 15-thia-D-homo-dihydrolanosterl (57) in 44% yield (See, Scheme VII).
4,4-Dimethyl-15-thia-D-homo-5a-cholest-8-en-3b-ol (56) has also been prepared in the same manner from the compound 13d in 59.2% yield.
4,4-dimethyl-15-thia-14a-vinyl-D-homo-5a-cholest-8-en-3b-ol (58) 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 within the scope of the present invention.
The 15-thia-D-homo-lanosterol 56 was reacted with sodium metaperiodate in 5 parts of ethanol and 1 part of water to provide the corresponding sulfoxide 59, also within the scope of the present invention. The 14-methyl and 14-vinyl derivatives 60 and 61, which are likewise within the scope of the present invention, may also be synthesized in the same manner.
As mentioned earlier in the 5-membered case, sulfones with the general structure 62, which are within the scope of the present invention may be synthesized from the corresponding sulfides or sulfoxides. Further functionalization at C-14 to prepare the compounds within 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. ##STR35##
Tables 6, 7, and 8 set forth various thiasterols of the present invention.
TABLE 6__________________________________________________________________________ ##STR36##Ex. No. R.sub.1 R.sub.2 R.sub.3 D No. M.P.__________________________________________________________________________1508 OH CH.sub.3 CH.sub.3 8 56 amorphous*1509 OH CH.sub.3 H 8 57 amorphous*1510 OH CH.sub.3 CHCH.sub.2 8 58 amorphous*1511 OH CH.sub.3 CHOHCH.sub.2 OH(R) 81512 OH CH.sub.3 CHOHCH.sub.2 OH(S) 81513 OH CH.sub.3 CHO 81514 OH CH.sub.3 CH.sub.2 OH 81515 OH CH.sub.3 CO.sub.2 H 81516 OH CH.sub.3 CH.sub.2 CH.sub.3 81517 OH CH.sub.3 CHNOH 81518 OH CH.sub.3 CHOHCHCH.sub.2(R) 81519 OH CH.sub.3 CHOHCHCH.sub.2(S) 81520 OH H CH.sub.3 81521 OH H H 81522 OH H CHCH.sub.2 81523 OH H CHOHCH.sub.2 OH(R) 81524 OH H CHOHCH.sub.2 OH(S) 81525 OH H CHO 81526 OH H CH.sub.2 OH 81527 OH H CO.sub.2 H 81528 OH H CO.sub.2 CH.sub.3 81529 OH H CHNOH 81530 OH H CHOHCHCH.sub.2(R) 81531 OH H CHOHCHCH.sub.2(S) 81532 OH CH.sub.3 CH.sub.2 SH 81533 OH CH.sub.3 CH.sub.2 NH.sub.2 81534 OH CH.sub.3 COCH.sub.3 81535 OH CH.sub.3 CONH.sub.2 81536 OH CH.sub.3 CSNH.sub.2 81537 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 81538 OH CH.sub.3 CH.sub.2 CHO 81539 OH CH.sub.3 CH.sub.2 COCH.sub.3 81540 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81541 OH CH.sub.3 CH.sub.2 CONH.sub.2 81542 OH CH.sub.3 CH.sub.2 Cl 81543 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 81544 OH CH.sub.3 CN 81545 OH CH.sub.3 CHNNH.sub.2 81546 OH CH.sub.3 CH.sub.2 NHOH 81547 OH CH.sub.3 CH.sub.2 NHNH.sub.2 81548 OH CH.sub.3 CH.sub.2 CN 81549 OH CH.sub.3 CH.sub.2 CHNOH 81550 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 81551 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81552 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81553 OH CH.sub.3 CONHOH 81554 OH CH.sub.3 CHCHCHO 81555 OH CH.sub.3 CHCHOCH.sub.3 81556 OH CH.sub.3 CHCHCH.sub.2 Cl 81557 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81558 OH CH.sub.3 ##STR37## 81560 O CH.sub.3 CHO 81561 O CH.sub.3 CH.sub.2 OH 81562 O H CH.sub.3 81563 O H CHO 81564 O H CH.sub.2 OH 81565 OCH.sub.3 CH.sub.3 CH.sub.3 81566 OCH.sub.3 CH.sub.3 CHO 81567 OCH.sub.3 CH.sub.3 CH.sub.2 OH 81568 OCH.sub.3 H CH.sub.3 81569 OCH.sub.3 H CHO 81570 OCH.sub.3 H CH.sub.2 OH 81571 OPh CH.sub.3 CH.sub. 3 81572 OPh CH.sub.3 CHO 81573 OPh CH.sub.3 CH.sub.2 OH 81574 OCH.sub.2 Ph CH.sub.3 CH.sub.3 81575 OCH.sub.2 Ph CH.sub.3 CHO 81576 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 81577 OCOCH.sub.3 CH.sub.3 CH.sub.3 81578 OCOCH.sub.3 CH.sub.3 CHO 81579 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 81580 OCOCH.sub.3 H CH.sub.3 81581 OCOCH.sub.3 H CHO 81582 OCOCH.sub.3 H CH.sub.2 OH 81583 OCOPh CH.sub.3 CH.sub.3 81584 OCOPh CH.sub.3 CHO 81585 OCOPh CH.sub.3 CH.sub.2 OH 81586 OH CH.sub.3 CH.sub.3 71587 OH CH.sub.3 CHO 71588 OH CH.sub.3 CH.sub.2 OH 71589 OH CH.sub.3 CO.sub.2 H 71590 OH H CH.sub.3 71591 OH H CHO 71592 OH H CH.sub.2 OH 71593 O CH.sub.3 CH.sub.3 7 -1594 O CH.sub.3 CHO 71595 O CH.sub.3 CH.sub.2 OH 71596 O H CH.sub.3 71597 O H CHO 71598 O H CH.sub.2 OH 71599 OCH.sub.3 CH.sub.3 CH.sub.3 71600 OCH.sub.3 CH.sub.3 CHO 71601 OCH.sub.3 CH.sub.3 CH.sub.2 OH 71602 OCH.sub.3 H CH.sub.3 71603 OCH.sub.3 H CHO 71604 OCH.sub.3 H CH.sub.2 OH 71605 OCOCH.sub.3 CH.sub.3 CH.sub.3 71606 OCOCH.sub.3 CH.sub.3 CHO 71607 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 71608 OCOCH.sub.3 H CH.sub.3 71609 OCOCH.sub.3 H CHO 71610 OCOCH.sub.3 H CH.sub.2 OH 7__________________________________________________________________________ *Further analytical data are available in the examples section.
TABLE 7__________________________________________________________________________ ##STR38##No. R.sub.1 R.sub.2 R.sub.3 D No. M. P.__________________________________________________________________________1611 OH CH.sub.3 CH.sub.3 8 59 amorphous*1612 OH CH.sub.3 H 8 60 amorphous*1613 OH CH.sub.3 CHCH.sub.2 8 61 amorphous*1614 OH CH.sub.3 CHOHCH.sub.2 OH(R) 81615 OH CH.sub.3 CHOHCH.sub.2 OH(S) 81616 OH CH.sub.3 CHO 81617 OH CH.sub.3 CH.sub.2 OH 81618 OH CH.sub.3 CO.sub.2 H 81619 OH CH.sub.3 CO.sub.2 CH.sub.3 81620 OH CH.sub.3 CHNOH 81621 OH CH.sub.3 CHOHCHCH.sub.2 (R) 81622 OH CH.sub.3 CHOHCHCH.sub.2 (S) 81623 OH H CH.sub.3 81624 OH H H 81625 OH H CHCH.sub.2 81626 OH H CHOHCH.sub.2 OH(R) 81627 OH H CHOHCH.sub.2 OH(S) 81628 OH H CHO 81629 OH H CH.sub.2 OH 81630 OH H CO.sub.2 H 81631 OH H CO.sub.2 CH.sub.3 81632 OH H CHNOH 81633 OH H CHOHCHCH.sub.2 (R) 81634 OH H CHOHCH CH.sub.2 (S) 81635 OH CH.sub.3 CH.sub.2 SH 81636 OH CH.sub.3 CH.sub.2 NH.sub.2 81637 OH CH.sub.3 COCH.sub.3 81638 OH CH.sub.3 CONH.sub.2 81639 OH CH.sub.3 CSNH.sub.2 81640 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 81641 OH CH.sub.3 CH.sub.2 CHO 81642 OH CH.sub.3 CH.sub.2 COCH.sub.3 81643 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81644 OH CH.sub.3 CH.sub.2 CONH.sub.2 81645 OH CH.sub.3 CH.sub.2 Cl 81646 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 81647 OH CH.sub.3 CN 81648 OH CH.sub.3 CHNNH.sub.2 81649 OH CH.sub.3 CH.sub.2 NHOH 81650 OH CH.sub.3 CH.sub.2 NHNH.sub.2 81651 OH CH.sub.3 CH.sub.2 CN 81652 OH CH.sub.3 CH.sub.2 CHNOH 81653 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 81654 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81655 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81656 OH CH.sub.3 CONHOH 81657 OH CH.sub.3 CHCHCHO 81658 OH CH.sub.3 CHCHCOCH.sub.3 81659 OH CH.sub.3 CHCHCH.sub.2 Cl 81660 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81661 OH CH.sub.3 ##STR39## 81662 O CH.sub.3 CH.sub.3 81663 O CH.sub.3 CHO 81664 O CH.sub.3 CH.sub.2 OH 81665 O H CH.sub.3 81666 O H CHO 81667 O H CH.sub.2 OH 81668 OCH.sub.3 CH.sub.3 CH.sup.3 81669 OCH.sub.3 CH.sub.3 CHO 81670 OCH.sub.3 CH.sub.3 CH.sub.2 OH 81671 OCH.sub.3 H CH.sub.3 81672 OCH.sub.3 H CHO 81673 OCH.sub.3 H CH.sub.2 OH 81674 OPh CH.sub.3 CH.sub.3 81675 OPh CH.sub.3 CHO 81676 OPh CH.sub.3 CH.sub.2 OH 81677 OCH.sub.2 Ph CH.sub.3 CH.sub.3 81678 OCH.sub.2 Ph CH.sub.3 CHO 81679 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 81680 OCOCH.sub.3 CH.sub.3 CH.sub.3 81681 OCOCH.sub.3 CH.sub.3 CHO 81682 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 81683 OCOCH.sub.3 H CH.sub.3 81684 OCOCH.sub.3 H CHO 81685 OCOCH.sub.3 H CH.sub.2 OH 81686 OCOPh CH.sub.3 CH.sub.3 81687 OCOPh CH.sub.3 CHO 81688 OCOPh CH.sub.3 CH.sub.2 OH 81689 OH CH.sub.3 CH.sub.3 71690 OH CH.sub.3 CHO 71691 OH CH.sub.3 CH.sub.2 OH 71692 OH CH.sub.3 CO.sub.2 H 71693 OH H CH.sub.3 71694 OH H CHO 71695 OH H CH.sub.2 OH 71696 O CH.sub.3 CH.sub.3 71697 O CH.sub.3 CHO 71698 O CH.sub.3 CH.sub.2 OH 71699 O H CH.sub.3 71700 O H CHO 71701 O H CH.sub.2 OH 71702 OCH.sub.3 CH.sub.3 CH.sub.3 71703 OCH.sub.3 CH.sub.3 CHO 71704 OCH.sub.3 CH.sub.3 CH.sub.2 OH 71705 OCH.sub.3 H CH.sub.3 71706 OCH.sub.3 H CHO 71707 OCH.sub.3 H CH.sub.2 OH 71708 OCOCH.sub.3 CH.sub.3 CH.sub.3 71709 OCOCH.sub.3 CH.sub.3 CHO 71710 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 71711 OCOCH.sub.3 H CH.sub.3 71712 OCOCH.sub.3 H CHO 71713 OCOCH.sub.3 H CH.sub.2 OH 7__________________________________________________________________________ *Further analytical data are available in the examples section.
TABLE 8______________________________________ ##STR40##No. R.sub.1 R.sub.2 R.sub.3 D No. M.P.______________________________________1714 OH CH.sub.3 CH.sub.3 81715 OH CH.sub.3 H 81716 OH CH.sub.3 CHCH.sub.2 81717 OH CH.sub.3 CHOHCH.sub.2 OH(R) 81718 OH CH.sub.3 CHOHCH.sub.2 OH(S) 81719 OH CH.sub.3 CHO 81720 OH CH.sub.3 CH.sub.2 OH 81721 OH CH.sub.3 CO.sub.2 H 81722 OH CH.sub.3 CO.sub.2 CH.sub.3 81723 OH CH.sub.3 CHNOH 81724 OH CH.sub.3 CHOHCHCH.sub.2 (R) 81725 OH CH.sub.3 CHOHCHCH.sub.2 (S) 81726 OH H CH.sub.3 81727 OH H H 81728 OH H CHCH.sub.2 81729 OH H CHOHCH.sub.2 OH(R) 81730 OH H CHOHCH.sub.2 OH(S) 81731 OH H CHO 81732 OH H CH.sub.2 OH 81733 OH H CO.sub.2 H 81734 OH H CO.sub.2 CH.sub.3 81735 OH H CHNOH 81736 OH H CHOHCHCH.sub.2 (R) 81737 OH H CHOHCHCH.sub.2 (S) 81738 OH CH.sub.3 CH.sub.2 SH 81739 OH CH.sub.3 CH.sub.2 NH.sub.2 81740 OH CH.sub.3 COCH.sub.3 81741 OH CH.sub.3 CONH.sub.2 81742 OH CH.sub.3 CSNH.sub.2 81743 OH CH.sub.3 CH.sub.2 CH.sub.2 OH 81744 OH CH.sub.3 CH.sub.2 CHO 81745 OH CH.sub.3 CH.sub.2 COCH.sub.3 81746 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 81747 OH CH.sub.3 CH.sub.2 CONH.sub.2 81748 OH CH.sub.3 CH.sub.2 Cl 81749 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl 81750 OH CH.sub.3 CN 81751 OH CH.sub.3 CHNNH.sub.2 81752 OH CH.sub.3 CH.sub.2 NHOH 81753 OH CH.sub.3 CH.sub.2 NHNH.sub.2 81754 OH CH.sub.3 CH.sub.2 CN 81755 OH CH.sub.3 CH.sub.2 CHNOH 81756 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 81757 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH 81758 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 81759 OH CH.sub.3 CONHOH 81760 OH CH.sub.3 CHCHCHO 81761 OH CH.sub.3 CHCHCOCH.sub.3 81762 OH CH.sub.3 CHCHCH.sub.2 Cl 81763 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH 81764 OH CH.sub.3 ##STR41## 81765 O CH.sub.3 CH.sub.3 81766 O CH.sub.3 CHO 81767 O CH.sub.3 CH.sub.2 OH 81768 O H CH.sub.3 81769 O H CHO 81770 O H CH.sub.2 OH 81771 OCH.sub.3 CH.sub.3 CH.sub.3 81772 OCH.sub.3 CH.sub.3 CHO 81773 OCH.sub.3 CH.sub.3 CH.sub.2 OH 81774 OCH.sub.3 H CH.sub.3 81775 OCH.sub.3 H CHO 81776 OCH.sub.3 H CH.sub.2 OH 81777 OPh CH.sub.3 CH.sub.3 81778 OPh CH.sub.3 CHO 81779 OPh CH.sub.3 CH.sub.2 OH 81780 OCH.sub.2 Ph CH.sub.3 CH.sub.3 81781 OCH.sub.2 Ph CH.sub.3 CHO 81782 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH 81783 OCOCH.sub.3 CH.sub.3 CH.sub.3 81784 OCOCH.sub.3 CH.sub.3 CHO 81785 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 81786 OCOCH.sub.3 H CH.sub.3 81787 OCOCH.sub.3 H CHO 81788 OCOCH.sub.3 H CH.sub.2 OH 81789 OCOPh CH.sub.3 CH.sub.3 81790 OCOPh CH.sub.3 CHO 81791 OCOPh CH.sub.3 CH.sub.2 OH 81792 OH CH.sub.3 CH.sub.3 71793 OH CH.sub.3 CHO 71794 OH CH.sub.3 CH.sub.2 OH 71795 OH CH.sub.3 CO.sub.2 H 71796 OH H CH.sub.3 61797 OH H CHO 71798 OH H CH.sub.2 OH 71799 O CH.sub.3 CH.sub.3 71800 O CH.sub.3 CHO 71801 O CH.sub.3 CH.sub.2 OH 71802 O H CH.sub.3 71803 O H CHO 71804 O H CH.sub.2 OH 71805 OCH.sub.3 CH.sub.3 CH.sub.3 71806 OCH.sub.3 CH.sub.3 CHO 71807 OCH.sub.3 CH.sub.3 CH.sub.2 OH 71808 OCH.sub.3 H CH.sub.3 71809 OCH.sub.3 H CHO 71810 OCH.sub.3 H CH.sub.2 OH 71811 OCOCH.sub.3 CH.sub.3 CH.sub.3 71812 OCOCH.sub.3 CH.sub.3 CHO 71813 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH 71814 OCOCH.sub.3 H CH.sub.3 71815 OCOCH.sub.3 H CHO 71816 OCOCH.sub.3 H CH.sub.2 OH 7______________________________________
15-Azasterols
Because the same chemistry could not be utilized for 15-azasterols as was used for 15-oxasterols and 15-thiasterols, a new synthetic route, which involves a Curtis rearrangement as the key step, has been developed for 15-aza-lanosterols.
Thus the enone-aldehyde 4b was oxidized with sodium chlorite (Aldrich) in the presence of sulfamic acid (Fisher) in 4 parts of tertiary butanol and 1 part of water to afford the corresponding carboxylic acid 63 in near quantitative yield (See, Scheme VIII).
The acid 63 was converted to an acyl azide under phase transfer catalysis conditions. It was first treated with isobutyl chloroformate (Aldrich) and N-methyl-morpholine (Aldrich) in dry methylene chloride and then the intermediate mixed anhydride was reacted with sodium azide (Fisher) and tetrabutylammonium bromide (Aldrich) in methylene chloride and water 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 which was pure enough to be carried onto the next reaction. The carbamate 65 was hydrolyzed with potassium silanoate (Petrach Systems, Bristol, Pa. 19007) in refluxing tetrahydrofuran to give a five-membered cyclic imine 66b in 73% overall yield for six steps starting from the 8,14-diene 2b.
Finally the p-methoxybenzyl protecting group at C-3 was cleaved by treating with allyltrimethylsilane and boron trifluoride etherate in methylene chloride to afford the unprotected 15-azasterol 66a, a compound within the scope of this invention, in 93% yield. ##STR42##
A bis-4,4-normethyl 15-azasterol (R.sub.2 of the general structure 1 is H) has also been synthesized from the enone-aldehyde 40 by following the sequence of the reaction steps described in the synthesis of 15-azasterol 66a. Oxidation of the aldehyde 40 followed 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 38b. Deprotection of 70b at C-3 gave compound 70a in 96% yield based on the recovered starting material 70b. Compound 70a is another example of a 15-aza-lanosterol within the scope of the present invention.
Further functionalizations at the 14 and 15 positions of 15-azasterol may be achieved by a reduction or an addition to the imine followed by appropriate transformations to synthesize additional compounds within the scope, which have general structure 71 in the scheme.
Tables 9-13 set forth various azasterols of the present invention.
TABLE 9______________________________________ ##STR43##No. R.sub.1 R.sub.2 D n* No. M.P.______________________________________1817 OH CH.sub.3 8 1 66a1818 OH H 8 1 70a1819 OH C.sub.2 H.sub.5 8 11820 O CH.sub.3 8 11821 O H 8 11822 O C.sub.2 H.sub.5 8 11823 OCH.sub.3 CH.sub.3 8 11824 OCH.sub.3 H 8 11825 OCH.sub.3 C.sub.2 H.sub.5 8 11826 OC.sub.2 H.sub.5 CH.sub.3 8 11827 OC.sub.2 H.sub.5 H 8 11828 OC.sub.2 H.sub.5 C.sub.2 H.sub.5 8 11829 OC.sub.3 H.sub.7 CH.sub.3 8 11830 OC.sub.3 H.sub.7 H 8 11831 OC.sub.3 H.sub.7 C.sub.2 H.sub.5 8 11832 Oi-C.sub.3 H.sub.7 CH.sub.3 8 11833 Oi-C.sub.3 H.sub.7 H 8 11834 Oi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 8 11835 OC.sub.4 H.sub.9 CH.sub.3 8 11836 OC.sub.4 H.sub.9 H 8 11837 OC.sub.4 H.sub.9 C.sub.2 H.sub.5 8 11838 Oi-C.sub.4 H.sub.9 CH.sub.3 8 11939 Oi-C.sub.4 H.sub.9 H 8 11840 Oi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 11841 Ot-C.sub.4 H.sub.9 CH.sub.3 8 11842 Ot-C.sub.4 H.sub.9 H 8 11843 Ot-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 11844 OPh CH.sub.3 8 11845 OPh H 8 11846 OPh C.sub.2 H.sub.5 8 11847 OCH.sub.2 Ph CH.sub.3 8 11848 OCH.sub.2 Ph H 8 11849 OCH.sub.2 Ph C.sub.2 H.sub.5 8 11850 OCOH CH.sub.3 8 11851 OCOH H 8 11852 OCOH C.sub.2 H.sub.5 8 11853 OCOCH.sub.3 CH.sub.3 8 11854 OCOCH.sub.3 H 8 11855 OCOCH.sub.3 C.sub.2 H.sub.5 8 11856 OCOC.sub.2 H.sub.5 CH.sub.3 8 11857 OCOC.sub.2 H.sub.5 H 8 11858 OCOC.sub.2 H.sub.5 C.sub.2 H.sub.5 8 11859 OCOC.sub.3 H.sub.7 CH.sub.3 8 11860 OCOC.sub.3 H.sub.7 H 8 11861 OCOC.sub.3 H.sub.7 C.sub.2 H.sub.5 8 11862 OCOi-C.sub.3 H.sub.7 CH.sub.3 8 11863 OCOi-C.sub.3 H.sub.7 H 8 11864 OCOi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 8 11865 OCOC.sub.4 H.sub.9 CH.sub.3 8 11866 OCOC.sub.4 H.sub.9 H 8 11867 OCOC.sub.4 H.sub.9 C.sub.2 H.sub.5 8 11868 OCOi-C.sub.4 H.sub.9 CH.sub.3 8 11869 OCOi-C.sub.4 H.sub.9 H 8 11870 OCOi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 11871 OCOt-C.sub.4 H.sub.9 CH.sub.3 8 11872 OCOt-C.sub.4 H.sub.9 H 8 11873 OCOt-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 11874 OCOC.sub.15 H.sub.31 CH.sub.3 8 11875 OCOC.sub.15 H.sub.31 H 8 11876 OCOC.sub.15 H.sub.31 C.sub. 2 H.sub.5 8 11877 OCOC.sub.15 H.sub.29 CH.sub.3 8 11878 OCOC.sub.15 H.sub.29 H 8 11879 OCOC.sub.15 H.sub.29 C.sub.2 H.sub.5 8 11880 OCOC.sub.17 H.sub.35 CH.sub.3 8 11881 OCOC.sub.17 H.sub.35 H 8 11882 OCOC.sub.17 H.sub.35 C.sub.2 H.sub.5 8 11883 OCOC.sub.17 H.sub.33 CH.sub.3 8 11884 OCOC.sub.17 H.sub.33 H 8 11885 OCOC.sub.17 H.sub.33 C.sub.2 H.sub.5 8 11886 OCOC.sub.17 H.sub.31 CH.sub.3 8 11887 OCOC.sub.17 H.sub.31 H 8 11888 OCOC.sub.17 H.sub.31 C.sub.2 H.sub.5 8 11889 OCOC.sub.17 H.sub.29 CH.sub.3 8 11890 OCOC.sub.17 H.sub.29 H 8 11891 OCOC.sub.17 H.sub.29 C.sub.2 H.sub.5 8 11892 OCOC.sub.19 4.sub.31 CH.sub.3 8 11893 OCOC.sub.19 H.sub.31 H 8 11894 OCOC.sub.19 H.sub.31 C.sub.2 H.sub.5 8 11895 OCOPh CH.sub.3 8 11896 OCOPh H 8 11897 OCOPh C.sub.2 H.sub.5 8 11898 OH CH.sub.3 8 11899 OH H 7 11900 OH C.sub.2 H.sub.5 7 11901 O CH.sub.3 7 11902 O H 7 11903 O C.sub.2 H.sub.5 7 11904 OCH.sub.3 CH.sub.3 7 11905 OCH.sub.3 H 7 11906 OCH.sub.3 C.sub.2 H.sub.5 7 11907 OC.sub.2 H.sub.5 CH.sub.3 7 11908 OC.sub.2 H.sub.5 H 7 11909 OC.sub.2 H.sub.5 C.sub.2 H.sub.5 7 11910 OC.sub.3 H.sub.7 CH.sub.3 7 11911 OC.sub.3 H.sub.7 H 7 11912 OC.sub.3 H.sub.7 C.sub.2 H.sub.5 7 11913 Oi-C.sub.3 H.sub.7 CH.sub.3 7 11914 Oi-C.sub.3 H.sub.7 H 7 11915 Oi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 7 11916 OC.sub.4 H.sub.9 CH.sub.3 7 11917 OC.sub.4 H.sub.9 H 7 11918 OC.sub.4 H.sub.9 C.sub.2 H.sub.5 7 11919 Oi-C.sub.4 H.sub.9 CH.sub.3 7 11920 Oi-C.sub.4 H.sub.9 H 7 11921 Oi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 11922 Ot-C.sub.4 H.sub.9 CH.sub.3 7 11923 Ot-C.sub.4 H.sub.9 H 7 11924 Ot-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 11925 OPh CH.sub.3 7 11926 OPh H 7 11927 OPh C.sub.2 H.sub.5 7 11928 OCH.sub.2 Ph CH.sub.3 7 11929 OCH.sub.2 Ph H 7 11930 OCH.sub.2 Ph C.sub.2 H.sub.5 7 11931 OCOH CH.sub.3 7 11932 OCOH H 7 11933 OCOH C.sub.2 H.sub.5 7 11934 OCOCH.sub.3 CH.sub.3 7 11935 OCOCH.sub.3 H 7 11936 OCOCH.sub.3 C.sub.2 H.sub.5 7 11937 OCOC.sub.2 H.sub.5 CH.sub.3 7 11938 OCOC.sub.2 H.sub.5 H 7 11939 OCOC.sub.2 H.sub.5 C.sub.2 H.sub.5 7 11940 OCOC.sub.3 H.sub.7 CH.sub.3 7 11941 OCOC.sub.3 H.sub.7 H 7 11942 OCOC.sub.3 H.sub.7 C.sub.2 H.sub.5 7 11943 OCOi-C.sub.3 H.sub.7 CH.sub.3 7 11944 OCOi-C.sub.3 H.sub.7 H 7 11945 OCOi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 7 11946 OCOC.sub.4 H.sub.9 CH.sub.3 7 11947 OCOC.sub.4 H.sub.9 H 7 11948 OCOC.sub.4 H.sub.9 C.sub.2 H.sub.5 7 11949 OCOi-C.sub.4 H.sub.9 CH.sub.3 7 11950 OCOi-C.sub.4 H.sub.9 H 7 11951 OCOi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 11952 OCOt-C.sub.4 H.sub.9 CH.sub.3 7 11953 OCOt-C.sub.4 H.sub.9 H 7 11954 OCOt-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 11955 OCOC.sub.15 H.sub.31 CH.sub.3 7 11956 OCOC.sub.15 H.sub.31 H 7 11957 OCOC.sub.15 H.sub.31 C.sub.2 H.sub.5 7 11958 OCOC.sub.15 H.sub.29 CH.sub.3 7 11959 OCOC.sub.15 H.sub.29 H 7 11960 OCOC.sub.15 H.sub.29 C.sub.2 H.sub.5 7 11961 OCOC.sub.17 H.sub.35 CH.sub.3 7 11962 OCOC.sub.17 H.sub.35 H 7 11963 OCOC.sub.17 H.sub.35 C.sub.2 H.sub.5 7 11964 OCOC.sub.17 H.sub.33 CH.sub.3 7 11965 OCOC.sub.17 H.sub.33 H 7 11966 OCOC.sub.17 H.sub.33 C.sub.2 H.sub.5 7 11967 OCOC.sub.17 H.sub.31 CH.sub.3 7 11968 OCOC.sub.17 H.sub.31 H 7 11969 OCOC.sub.17 H.sub.31 C.sub.2 H.sub.5 7 11970 OCOC.sub.17 H.sub.29 CH.sub.3 7 11971 OCOC.sub.17 H.sub.29 H 7 11972 OCOC.sub.17 H.sub.29 C.sub.2 H.sub.5 7 11973 OCOC.sub.19 H.sub.31 CH.sub.3 7 11974 OCOC.sub.19 H.sub.31 H 7 11975 OCOC.sub.19 H.sub.31 C.sub.2 H.sub.5 7 11976 OCOPh CH.sub.3 7 11977 OCOPh H 7 11978 OCOPh C.sub.2 H.sub.5 7 11979 OH CH.sub.3 8 21980 OH H 8 21981 OH C.sub.2 H.sub.5 8 21982 O CH.sub.3 8 21983 O H 8 21984 O C.sub.2 H.sub.5 8 21985 OCH.sub.3 CH.sub.3 8 21986 OCH.sub.3 H 8 21987 OCH.sub.3 C.sub.2 H.sub.5 8 21988 OC.sub.2 H.sub.5 CH.sub.3 8 21989 OC.sub.2 H.sub.5 H 8 21990 OC.sub.2 H.sub.5 C.sub.2 H.sub.5 8 21991 OC.sub.3 H.sub.7 CH.sub.3 8 21992 OC.sub.3 H.sub.7 H 8 21993 OC.sub.3 H.sub.7 C.sub.2 H.sub.5 8 21994 Oi-C.sub.3 H.sub.7 CH.sub.3 8 21995 Oi-C.sub.3 H.sub.7 H 8 21996 Oi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 8 21997 OC.sub.4 H.sub.9 CH.sub.3 8 21998 OC.sub.4 H.sub.9 H 8 21999 OC.sub.4 H.sub.9 C.sub.2 H.sub.5 8 22000 Oi-C.sub.4 H.sub.9 CH.sub.3 8 22001 Oi-C.sub.4 H.sub.9 H 8 22002 Oi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 22003 Ot-C.sub.4 H.sub.9 CH.sub.3 8 22004 Ot-C.sub.4 H.sub.9 H 8 22005 Ot-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 22006 OPh CH.sub.3 8 22007 OPh H 8 22008 OPh C.sub.2 H.sub.5 8 22009 OCH.sub.2 Ph CH.sub.3 8 22010 OCH.sub.2 Ph H 8 22011 OCH.sub.2 Ph C.sub.2 H.sub.5 8 22012 OCOH CH.sub.3 8 22013 OCOH H 8 22014 OCOH C.sub.2 H.sub.5 8 22015 OCOCH.sub.3 CH.sub.3 8 22016 OCOCH.sub.3 H 8 22017 OCOCH.sub.3 C.sub.2 H.sub. 5 8 22018 OCOC.sub.2 H.sub.5 CH.sub.3 8 22019 OCOC.sub.2 H.sub.5 H 8 22020 OCOC.sub.2 H.sub.5 C.sub.2 H.sub.5 8 22021 OCOC.sub.3 H.sub.7 CH.sub.3 8 22022 OCCO.sub.3 H.sub.7 H 8 22023 OCOC.sub.3 H.sub.7 C.sub.2 H.sub.5 8 22024 OCOi-C.sub.3 H.sub.7 CH.sub.3 8 22025 OCOi-C.sub.3 H.sub.7 H 8 22026 OCOi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 8 22027 OCOC.sub.4 H.sub.9 CH.sub.3 8 22028 OCOC.sub.4 H.sub.9 H 8 22029 OCOC.sub.4 H.sub.9 C.sub.2 H.sub.5 8 22030 OCOi-C.sub.4 H.sub.9 CH.sub.3 8 22031 OCOi-C.sub.4 H.sub.9 H 8 22032 OCOi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 22033 OCOt-C.sub.4 H.sub.9 CH.sub.3 8 22034 OCOt-C.sub.4 H.sub.9 H 8 22035 OCOt-C.sub.4 H.sub.9 C.sub.2 H.sub.5 8 22036 OCOC.sub.15 H.sub.31 CH.sub.3 8 22037 OCOC.sub.15 H.sub.31 H 8 22038 OCOC.sub.15 H.sub.31 C.sub.2 H.sub.5 8 22039 OCOC.sub.15 H.sub.29 CH.sub.3 8 22040 OCOC.sub.15 H.sub.29 H 8 22041 OCOC.sub.15 H.sub.29 C.sub.2 H.sub.5 8 22042 OCOC.sub.17 H.sub.35 CH.sub.3 8 22043 OCOC.sub.17 H.sub.35 H 8 22044 OCOC.sub.17 H.sub.35 C.sub.2 H.sub.5 8 22045 OCOC.sub.17 H.sub.33 CH.sub.3 8 22046 OCOC.sub.17 H.sub.33 H 8 22047 OCOC.sub.17 H.sub.33 C.sub.2 H.sub.5 8 22048 OCOC.sub.17 H.sub.31 CH.sub.3 8 22049 OCOC.sub.17 H.sub.31 H 8 22050 OCOC.sub.17 H.sub.31 C.sub.2 H.sub.5 8 22051 OCOC.sub.17 H.sub.29 CH.sub.3 8 22052 OCOC.sub.17 H.sub.29 H 8 22053 OCOC.sub.17 H.sub.29 C.sub.2 H.sub.5 8 22054 OCOC.sub.19 H.sub.31 CH.sub.3 8 22055 OCOC.sub.19 H.sub.31 H 8 22056 OCOC.sub.19 H.sub.31 C.sub.2 H.sub.5 8 22057 OCOPh CH.sub.3 8 22058 OCOPh H 8 22059 OCOPh C.sub.2 H.sub.5 8 22060 OH CH.sub.3 7 22061 OH H 72062 OH C.sub.2 H.sub.5 7 22063 O CH.sub.3 7 22064 O H 7 22065 O C.sub.2 H.sub.5 7 22066 OCH.sub.3 CH.sub.2 7 22067 OCH.sub.3 H 7 22068 OCH.sub.3 C.sub.2 H.sub.5 7 22069 OC.sub.2 H.sub.5 CH.sub.3 7 22070 OC.sub.2 H.sub.5 H 7 22071 OC.sub.2 H.sub.5 C.sub.2 H.sub.5 7 22072 OC.sub.3 H.sub.7 CH.sub.3 7 22073 OC.sub.3 H.sub.7 H 7 22074 OC.sub.3 H.sub.7 C.sub.2 H.sub.5 7 22075 Oi-C.sub.3 H.sub.7 CH.sub.3 7 22076 Oi-C.sub.3 H.sub.7 H 7 22077 Oi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 7 22078 OC.sub.4 H.sub.9 CH.sub.3 7 22079 OC.sub.4 H.sub.9 H 7 22080 OC.sub.4 H.sub.9 C.sub.2 H.sub.5 7 22081 Oi-C.sub.4 H.sub.9 CH.sub.3 7 22082 Oi-C.sub.4 H.sub.9 H 7 22083 Oi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 22084 Ot-C.sub.4 H.sub.9 CH.sub.3 7 22085 Ot-C.sub.4 H.sub.9 H 7 22086 Ot-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 22087 OPh CH.sub.3 7 22088 OPh H 7 22089 OPh C.sub.2 H.sub.5 7 22090 OCH.sub.2 Ph CH.sub.3 7 22091 OCH.sub.2 Ph H 7 22092 OCH.sub.2 Ph C.sub.2 H.sub.5 7 22093 OCOH CH.sub.3 7 22094 OCOH H 7 22095 OCOH C.sub.2 H.sub.5 7 22096 OCOCH.sub.3 CH.sub.3 7 22097 OCOCH.sub.3 H 7 22098 OCOCH.sub.3 C.sub.2 H.sub.5 7 22099 OCOC.sub.2 H.sub.5 CH.sub.3 7 22100 OCOC.sub.2 H.sub.5 H 7 22101 OCOC.sub.2 H.sub.5 C.sub.2 H.sub.5 7 22101 OCOC.sub.3 H.sub.7 CH.sub.3 7 22103 OCOC.sub.3 H.sub.7 H 7 22104 OCOC.sub.3 H.sub.7 C.sub.2 H.sub.5 7 22105 OCOi-C.sub.3 H.sub.7 CH.sub.3 7 22106 OCOi-C.sub.3 H.sub.7 H 7 22107 OCOi-C.sub.3 H.sub.7 C.sub.2 H.sub.5 7 22108 OCOC.sub.4 H.sub.9 CH.sub.3 7 22109 OCOC.sub.4 H.sub.9 H 7 22110 OCOC.sub.4 H.sub.9 C.sub.2 H.sub.5 7 22111 OCOi-C.sub.4 H.sub.9 CH.sub.3 7 22112 OCOi-C.sub.4 H.sub.9 H 7 22113 OCOi-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 22114 OCOt-C.sub.4 H.sub.9 CH.sub.3 7 22115 OCOt-C.sub.4 H.sub.9 H 7 22116 OCOt-C.sub.4 H.sub.9 C.sub.2 H.sub.5 7 22117 OCOC.sub.15 H.sub.31 CH.sub.3 7 22118 OCOC.sub.15 H.sub.31 H 7 22119 OCOC.sub.15 H.sub.31 C.sub.2 H.sub.5 7 22120 OCOC.sub.15 H.sub.29 CH.sub.3 7 22121 OCOC.sub.15 H.sub.29 H 7 22122 OCOC.sub.15 H.sub.29 C.sub.2 H.sub.5 7 22123 OCOC.sub.17 H.sub.35 CH.sub.3 7 22124 OCOC.sub.17 H.sub.35 H 7 22125 OCOC.sub.17 H.sub.35 C.sub.2 H.sub.5 7 22126 OCOC.sub.17 H.sub.33 CH.sub.3 7 22127 OCOC.sub.17 H.sub.33 H 7 22128 OCOC.sub.17 H.sub.33 C.sub.2 H.sub.5 7 22129 OCOC.sub.17 H.sub.31 CH.sub.3 7 22130 OCOC.sub.17 H.sub.31 H 7 22131 OCOC.sub. 17 H.sub.31 C.sub.2 H.sub.5 7 22132 OCOC.sub.17 H.sub.29 CH.sub.3 7 22133 OCOC.sub.17 H.sub.29 H 7 22134 OCOC.sub.17 H.sub.29 C.sub.2 H.sub.5 7 22135 OCOC.sub.19 H.sub.31 CH.sub.3 7 22136 OCOC.sub.19 H.sub.31 H 7 22137 OCOC.sub.19 H.sub.31 C.sub.2 H.sub.5 7 22138 OCOPh CH.sub.3 7 22139 OCOPh H 7 22140 OCOPh C.sub.2 H.sub.5 7 2______________________________________ *provided that when n = 2, the upper side chain (R) is not ergosterol.
TABLE 10__________________________________________________________________________ ##STR44##No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 D No. M.P.__________________________________________________________________________2141 OH CH.sub.3 CH.sub.3 H 8 66a2142 OH CH.sub.3 H H 82143 OH CH.sub.3 CHCH.sub.2 H 82144 OH CH.sub.3 CHOHCH.sub.2 OH(R) H 82145 OH CH.sub.3 CHOHCH.sub.2 OH(S) H 82146 OH CH.sub.3 CHO H 82147 OH CH.sub.3 CH.sub.2 OH H 82148 OH CH.sub.3 CO.sub.2 H H 82149 OH CH.sub.3 CO.sub.2 CH.sub.3 H 82150 OH CH.sub.3 CHNOH H 82151 OH CH.sub.3 CHOHCHCH.sub.2(R) H 82152 OH CH.sub.3 CHOHCHCH.sub. 2(S) H 82153 OH H CH.sub.3 H 82154 OH H H H 8 70a2155 OH H CHCH.sub.2 H 82156 OH H CHOHCH.sub.2 OH(R) H 82157 OH H CHOHCH.sub.2 OH(S) H 82158 OH H CHO H 82159 OH H CH.sub.2 OH H 82160 OH H CO.sub.2 H H 82161 OH H CO.sub.2 CH.sub.3 H 82162 OH H CHNOH H 82163 OH H CHOHCHCH.sub.2(R) H 82164 OH H CHOHCHCH.sub.2(S) H 82165 OH CH.sub.3 C.sub.2 H.sub.5 H 82166 OH CH.sub.3 CH.sub.2 CHCH.sub.2 H 82167 OH CH.sub.3 CCH H 82168 OH CH.sub.3 CH.sub.2 Ph H 82169 OH CH.sub.3 CH.sub.2 OCH.sub.3 H 82170 OH CH.sub.3 CH.sub.2 OCOCH.sub.3 H 82171 OH CH.sub.3 CH.sub.2 SH H 82172 OH CH.sub.3 CH.sub.2 SCH.sub.3 H 82173 OH CH.sub.3 CH.sub.2 SCOCH.sub.3 H 82174 OH CH.sub.3 CH.sub.2 NH.sub.2 H 82175 OH CH.sub. 3 CH.sub.2 NHCH.sub.3 H 82176 OH CH.sub.3 CH.sub.2 NHCOCH.sub.3 H 82177 OH CH.sub.3 CH.sub.2 NHCSCH.sub.3 H 82178 OH CH.sub.3 CH.sub.2 NHC(NH)CH.sub.3 H 82179 OH CH.sub.3 COCH.sub.3 H 82180 OH CH.sub.3 COCHCH.sub.2 H 82181 OH CH.sub.3 CSCH.sub.3 H 82182 OH CH.sub.3 CSCHCH.sub.2 H 82183 OH CH.sub.3 C(NH)CH.sub.3 H 82184 OH CH.sub.3 CO.sub.2 C.sub.2 H.sub.5 H 82185 OH CH.sub.3 COSCH.sub.3 H 82186 OH CH.sub.3 CONH.sub.2 H 82187 OH CH.sub.3 CONHCH.sub.3 H 82188 OH CH.sub.3 CONHCOCH.sub.3 H 82189 OH CH.sub.3 CSNH.sub.2 H 82190 OH CH.sub.3 CSNHCH.sub.3 H 82191 OH CH.sub.3 CSNHCOCH.sub.3 H 82192 OH CH.sub.3 CH.sub.2 CH.sub.2 OH H 82193 OH CH.sub.3 CH.sub.2 CH.sub.2 OCH.sub.3 H 82194 OH CH.sub.3 CH.sub.2 CH.sub.2 OCOCH.sub.3 H 82195 OH CH.sub.3 CH.sub.2 CH.sub.2 SH H 82196 OH CH.sub.3 CH.sub. 2 CH.sub.2 SCH.sub.3 H 82197 OH CH.sub.3 CH.sub.2 CH.sub.2 SCOCH.sub.3 H 82198 OH CH.sub.3 CH.sub.2 CH.sub.2 NH.sub.2 H 82199 OH CH.sub.3 CH.sub.2 CH.sub.2 NHCH.sub.3 H 82200 OH CH.sub.3 CH.sub.2 CH.sub.2 NHCOCH.sub.3 H 82201 OH CH.sub.3 CH.sub.2 CHO H 82202 OH CH.sub.3 CH.sub.2 COCH.sub.3 H 82203 OH CH.sub.3 CH.sub.2 COCHCH.sub.2 H 82204 OH CH.sub.3 CH.sub.2 CSCH.sub.3 H 82205 OH CH.sub.3 CH.sub.2 CSCHCH.sub.2 H 82206 OH CH.sub.3 CH.sub.2 C(NH)CH.sub.3 H 82207 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 H 82208 OH CH.sub.3 CH.sub.2 COSCH.sub.3 H 82209 OH CH.sub.3 CH.sub.2 CONH.sub.2 H 82210 OH CH.sub.3 CH.sub.2 CONHCH.sub.3 H 82211 OH CH.sub.3 CH.sub.2 CONHCOCH.sub.3 H 82212 OH CH.sub.3 CH.sub.2 CSNH.sub.2 H 82213 OH CH.sub.3 CH.sub.2 C(NH)CH.sub.3 H 82214 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl H 82215 OH CH.sub.3 CN H 82216 OH CH.sub.3 CHNOCH.sub.3 H 82217 OH CH.sub.3 CHNOCOCH.sub.3 H 82218 OH CH.sub.3 CHNNH.sub.2 H 82219 OH CH.sub.3 CHNNHCH.sub.3 H 82220 OH CH.sub.3 CHNHCOCH.sub.3 H 82221 OH CH.sub.3 CHNNHCSCH.sub.3 H 82222 OH CH.sub.3 CH.sub.2 NHOH H 82223 OH CH.sub.3 CH.sub.2 NHOCH.sub.3 H 82224 OH CH.sub.3 CH.sub.2 NHOCOCH.sub.3 H 82225 OH CH.sub.3 CH.sub.2 NHNH.sub.2 H 82226 OH CH.sub.3 CH.sub.2 NHNHCH.sub.3 H 82227 OH CH.sub.3 CH.sub.2 NHNHCOCH.sub.3 H 82228 OH CH.sub.3 CH.sub.2 NHNHCSCH.sub.3 H 82229 OH CH.sub.3 CH.sub.2 CN H 82230 OH CH.sub.3 CH.sub.2 CHNOH H 82231 OH CH.sub.3 CH.sub.2 CHNOCH.sub.3 H 82232 OH CH.sub.3 CH.sub.2 CHNOCOCH.sub.3 H 82233 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 H 82234 OH CH.sub.3 CH.sub.2 CHNNHCH.sub.3 H 82235 OH CH.sub.3 CH.sub.2 CHNNHCOCH.sub.3 H 82236 OH CH.sub.3 CH.sub.2 CHNNHCSCH.sub.3 H 82237 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH H 82238 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOCH.sub.3 H 82239 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOCOCH.sub.3 H 82240 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 H 82241 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCH.sub.3 H 82242 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCOCH.sub.3 H 82243 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNHCSCH.sub.3 H 82244 OH CH.sub.3 CONHOH H 82245 OH CH.sub.3 CONHOCH.sub.3 H 82246 OH CH.sub.3 CONHOCOCH.sub.3 H 82247 OH CH.sub.3 CSNHOH H 82248 OH CH.sub.3 CSNHCOCH.sub.3 H 82249 OH CH.sub.3 CSNHOCOCH.sub.3 H 82250 OH CH.sub.3 CHCHCHO H 82251 OH CH.sub.3 CHCHCOCH.sub.3 H 82252 OH CH.sub.3 CHCHCSCH.sub.3 H 82253 OH CH.sub.3 CHCHCHNH H 82254 OH CH.sub.3 CHCHC(NH)CH.sub.3 H 82255 OH CH.sub.3 CCCHO H 82256 OH CH.sub.3 CCCOCH.sub.3 H 82257 OH CH.sub.3 CCCSCH.sub.3 H 82258 OH CH.sub.3 CCCHNH H 82259 OH CH.sub.3 CCC(NH)CH.sub.3 H 82260 OH CH.sub.3 CHCHCH.sub.2 Cl H 82261 OH CH.sub.3 CCCH.sub.2 Cl H 82262 OH CH.sub.3 CHCHCH.sub.2 OCOCH.sub.3 H 82263 OH CH.sub.3 CCCH.sub.2 OCOCH.sub.3 H 82264 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH H 82265 OH CH.sub.3 CHOHCHOHCH.sub.2 OH H 82266 OH CH.sub.3 ##STR45## H 82267 OH CH.sub.3 ##STR46## H 82268 OH CH.sub.3 ##STR47## H 82269 OH H CH.sub.2 SH H 82270 OH H CH.sub.2 NH.sub.2 H 82271 OH H COCH.sub.3 H 82272 OH H CONH.sub.2 H 82273 OH H CSNH.sub.2 H 82274 OH H CH.sub.2 CH.sub.2 OH H 82275 OH H CH.sub. 2 CHO H 82276 OH H CH.sub.2 COCH.sub.3 H 82277 OH H CH.sub.2 CO.sub.2 CH.sub.3 H 82278 OH H CH.sub.2 CONH.sub.2 H 82279 OH H CH.sub.2 CH.sub.2 Cl H 82280 OH H CN H 82281 OH H CHNNH.sub.2 H 82282 OH H CH.sub.2 NHOH H 82283 OH H CH.sub.2 NHNH.sub.2 H 82284 OH H H.sub.2 CN H 82285 OH H CH.sub.2 CHNOH H 82286 OH H CH.sub.2 CHNNH.sub.2 H 82287 OH H CH.sub.2 CH.sub.2 NHOH H 82288 OH H CH.sub.2 CH.sub.2 NHNH.sub.2 H 82289 OH H CONHOH H 82290 OH H CHCHCHO H 82291 OH H CHCHCOCH.sub.3 H 82292 OH H CHCHCH.sub.2 Cl H 82293 OH H CH.sub.2 CHOHCH.sub.2 OH H 82294 OH H ##STR48## H 82295 O CH.sub.3 CH.sub.3 H 82296 O CH.sub.3 H H 82297 O CH.sub.3 CHCH.sub.2 H 82298 O CH.sub.3 CHOHCH.sub.2 OH(R) H 82299 O CH.sub.3 CHOHCH.sub.2 OH(S) H 82300 O CH.sub.3 CHO H 82301 O CH.sub.3 CH.sub.2 OH H 82302 O CH.sub.3 CO.sub.2 H H 82303 O CH.sub.3 CO.sub.2 CH.sub.3 H 82304 O CH.sub.3 CHNOH H 82305 O CH.sub.3 CHOHCHCH.sub.2(R) H 82306 O CH.sub.3 CHOHCHCH.sub.2(S) H 82307 O CH.sub.3 CH.sub.2 SH H 82308 O CH.sub.3 CH.sub.2 NHCH.sub.3 H 82309 O CH.sub.3 COCH.sub.3 H 82310 O CH.sub.3 CONH.sub.2 H 82311 O CH.sub.3 CSNH.sub.2 H 82312 O CH.sub.3 CH.sub.2 CH.sub.2 OH H 82313 O CH.sub.3 CH.sub.2 CHO H 82314 O CH.sub.3 CH.sub.2 COCH.sub.3 H 82315 O CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 H 82316 O CH.sub.3 CH.sub.2 CONH.sub.2 H 82317 O CH.sub.3 CH.sub.2 CH.sub.2 Cl H 82318 O CH.sub.3 CN H 82319 O CH.sub.3 CHNNHCH.sub.3 H 82320 O CH.sub.3 CH.sub.2 NHOH H 82321 O CH.sub.3 CH.sub.2 NHNHCH.sub.3 H 82322 O CH.sub.3 CH.sub.2 CN H 82323 O CH.sub.3 CH.sub.2 CHNOH H 82324 O CH.sub.3 CH.sub.2 CHNNHCH.sub.3 H 82325 O CH.sub.3 CH.sub.2 CH.sub.2 NHOH H 82326 O CH.sub.3 CH.sub.2 CH.sub.2 NHNHCH.sub.3 H 82327 O CH.sub.3 CONHOH H 82328 O CH.sub.3 CHCHCHO H 82329 O CH.sub.3 CHCHCOCH.sub.3 H 82330 O CH.sub.3 CHCHCH.sub.2 Cl H 82331 O CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH H 82332 O CH.sub.3 ##STR49## H 82333 O H CH.sub.3 H 82334 O H H H 82335 O H CHCH.sub. 2 H 82336 O H CHOHCH.sub.2 OH(R) H 82337 O H CHOHCH.sub.2 OH(S) H 82338 O H CHO H 82339 O H CH.sub.2 OH H 82340 O H CO.sub.2 H H 82341 O H CO.sub.2 CH.sub.3 H 82342 O H CHNOH H 82343 O H CHOHCHCH.sub.2(R) H 82344 O H CHOHCHCH.sub.2(S) H 82345 OCH.sub.3 CH.sub.3 CH.sub.3 H 82346 OCH.sub.3 CH.sub.3 H H 82347 OCH.sub.3 CH.sub.3 CHCH.sub.2 H 82348 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) H 82349 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) H 82350 OCH.sub.3 CH.sub.3 CHO H 82351 OCH.sub.3 CH.sub.3 CH.sub.2 OH H 82352 OCH.sub.3 CH.sub.3 CO.sub.2 H H 82353 OCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 H 82354 OCH.sub.3 CH.sub.3 CHNOH H 82355 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(R) H 82356 OCH.sub.3 CH.sub.3 CHOHCH CH.sub.2(S) H 82357 OCH.sub.3 CH.sub.3 CH.sub.2 SH H 82358 OCH.sub.3 CH.sub.3 CH.sub.2 NH.sub.2 H 82359 OCH.sub.3 CH.sub.3 COCH.sub.3 H 82360 OCH.sub.3 CH.sub.3 CONH.sub.2 H 82361 OCH.sub.3 CH.sub.3 CSNH.sub.2 H 82362 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 OH H 82363 OCH.sub.3 CH.sub.3 CH.sub.2 CHO H 82364 OCH.sub.3 CH.sub.3 CH.sub.2 COCH.sub.3 H 82365 OCH.sub.3 CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 H 82366 OCH.sub.3 CH.sub.3 CH.sub.2 CONH.sub.2 H 82367 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 Cl H 82368 OCH.sub.3 CH.sub.3 CN H 82369 OCH.sub.3 CH.sub.3 CHNNH.sub.2 H 82370 OCH.sub.3 CH.sub.3 CH.sub.2 NHOH H 82371 OCH.sub.3 CH.sub.3 CH.sub.2 NHNH.sub.2 H 82372 OCH.sub.3 CH.sub.3 CH.sub.2 CN H 82373 OCH.sub.3 CH.sub.3 CH.sub.2 CHNOH H 82374 OCH.sub.3 CH.sub.3 CH.sub.2 CHNNH.sub.2 H 82375 OCH.sub.3 CH.sub.3 CH.sub. 2 CH.sub.2 NHOH H 82376 OCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 H 82377 OCH.sub.3 CH.sub.3 CONHOH H 82378 OCH.sub.3 CH.sub.3 CHCHCHO H 82379 OCH.sub.3 CH.sub.3 CHCHCOCH.sub.3 H 82380 OCH.sub.3 CH.sub.3 CHCHCH.sub.2 Cl H 82381 OCH.sub.3 CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH H 82382 OCH.sub.3 CH.sub.3 ##STR50## H 82383 OCH.sub.3 H CH.sub.3 H 82384 OCH.sub.3 H H H 82385 OCH.sub.3 H CHCH.sub.2 H 82386 OCH.sub.3 H CHOHCH.sub.2 OH(R) H 82387 OCH.sub.3 H CHOHCH.sub.2 OH(S) H 82388 OCH.sub.3 H CHO H 82389 OCH.sub.3 H CH.sub.2 OH H 82390 OCH.sub.3 H CO.sub.2 H H 82391 OCH.sub.3 H CO.sub.2 CH.sub.3 H 82392 OCH.sub.3 H CHNOH H 82393 OCH.sub.3 H CHOHCHCH.sub.2(R) H 82394 OCH.sub.3 H CHOHCHCH.sub.2(S) H 82395 OC.sub.2 H.sub.5 CH.sub. 3 CH.sub.3 H 82396 OC.sub.2 H.sub.5 CH.sub.3 CHO H 82397 OC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH H 82398 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 H 82399 OC.sub.3 H.sub.7 CH.sub.3 CHO H 82400 OC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH H 82401 Oi-C.sub.3 H.sub.7 CH.sub.3 CH.sub.3 H 82402 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.3 H 82403 OC.sub.4 H.sub.9 CH.sub.3 CHO H 82404 OC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH H 82405 Oi-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 H 82406 Ot-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 H 82407 OPh CH.sub.3 CH.sub.3 H 82408 OPh CH.sub.3 CHO H 82409 OPh CH.sub.3 CH.sub.2 OH H 82410 OCH.sub.2 Ph CH.sub.3 CH.sub.3 H 82411 OCH.sub.2 Ph CH.sub.3 CHO H 82412 OCH.sub.2 Ph CH.sub.3 CH.sub.2 OH H 82413 OCOCH.sub.3 CH.sub.3 CH.sub.3 H 82414 OCOCH.sub.3 CH.sub.3 H H 82415 OCOCH.sub.3 CH.sub.3 CHCH.sub.2 H 82416 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) H 82417 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) H 82418 OCOCH.sub.3 CH.sub.3 CHO H 82419 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH H 82420 OCOCH.sub.3 CH.sub.3 CO.sub.2 H H 82421 OCOCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 H 82422 OCOCH.sub.3 CH.sub.3 CHNOH H 82423 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(R) H 82424 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(S) H 82425 OCOCH.sub.3 CH.sub.3 CH.sub.2 SH H 82426 OCOCH.sub.3 CH.sub.3 CH.sub.2 NH.sub.2 H 82427 OCOCH.sub.3 CH.sub.3 COCH.sub.3 H 82428 OCOCH.sub.3 CH.sub.3 CONH.sub.2 H 82429 OCOCH.sub.3 CH.sub.3 CSNH.sub.2 H 82430 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 OH H 82431 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHO H 82432 OCOCH.sub.3 CH.sub.3 CH.sub.2 COCH.sub.3 H 82433 OCOCH.sub.3 CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 H 82434 OCOCH.sub.3 CH.sub.3 CH.sub.2 CONH.sub.2 H 82435 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 Cl H 82436 OCOCH.sub.3 CH.sub.3 CN H 82437 OCOCH.sub.3 CH.sub.3 CHNNH.sub.2 H 82438 OCOCH.sub.3 CH.sub.3 CH.sub.2 NHOH H 82439 OCOCH.sub.3 CH.sub.3 CH.sub.2 NHNH.sub.2 H 82440 OCOCH.sub.3 CH.sub.3 CH.sub.2 CN H 82441 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHNOH H 82442 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHNNH.sub.2 H 82443 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHOH H 82444 OCOCH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 H 82445 OCOCH.sub.3 CH.sub.3 CONHOH H 82446 OCOCH.sub.3 CH.sub.3 CHCHCHO H 82447 OCOCH.sub.3 CH.sub.3 CHCHCOCH.sub.3 H 82448 OCOCH.sub.3 CH.sub.3 CHCHCH.sub.2 Cl H 82449 OCOCH.sub.3 CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH H 82450 OCOCH.sub.3 CH.sub.3 ##STR51## H 82451 OCOCH.sub.3 H CH.sub.3 H 82452 OCOCH.sub.3 H H H 82453 OCOCH.sub.3 H CHCH.sub.2 H 82454 OCOCH.sub.3 H CHOHCH.sub.2 OH(R) H 82455 OCOCH.sub.3 H CHOHCH.sub.2 OH(S) H 82456 OCOCH.sub.3 H CHO H 82457 OCOCH.sub.3 H CH.sub.2 OH H 82458 OCOCH.sub.3 H CO.sub.2 H H 82459 OCOCH.sub.3 H CO.sub.2 CH.sub.3 H 82460 OCOCH.sub.3 H CHNOH H 82461 OCOCH.sub.3 H CHOHCHCH.sub.2(R) H 82462 OCOCH.sub.3 H CHOHCHCH.sub.2(S) H 82463 OCOC.sub.2 H.sub.5 CH.sub.3 CH.sub.3 H 82464 OCOC.sub.2 H.sub.5 CH.sub.3 CHO H 82465 OCOC.sub.2 H.sub.5 CH.sub.3 CH.sub.2 OH H 82466 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.3 H 82467 OCOC.sub.3 H.sub.7 CH.sub.3 CHO H 82468 OCOC.sub.3 H.sub.7 CH.sub.3 CH.sub.2 OH H 82469 OCOi-C.sub.3 H.sub.7 CH.sub.3 CH.sub.3 H 82470 OCOC.sub.4 H.sub.9 CH.sub.3 CH.sub.3 H 82471 OCOC.sub.4 H.sub.9 CH.sub.3 CHO H 82472 OCOC.sub.4 H.sub.9 CH.sub.3 CH.sub.2 OH H 82473 OCOi-C.sub. 4 H.sub.9 CH.sub.3 CH.sub.3 H 82474 OCOt-C.sub.4 H.sub.9 CH.sub.3 CH.sub.3 H 82475 OCOC.sub.15 H.sub.31 CH.sub.3 CH.sub.3 H 82476 OCOC.sub.15 H.sub.31 CH.sub.3 CHO H 82477 OCOC.sub.15 H.sub.31 CH.sub.3 CH.sub.2 OH H 82478 OCOC.sub.15 H.sub.29 CH.sub.3 CH.sub.3 H 82479 OCOC.sub.17 H.sub.35 CH.sub.3 CH.sub.3 H 82480 OCOC.sub.17 H.sub.33 CH.sub.3 CH.sub.3 H 82481 OCOC.sub.17 H.sub.31 CH.sub.3 CH.sub.3 H 82482 OCOC.sub.17 H.sub.29 CH.sub.3 CH.sub.3 H 82483 OCOC.sub.19 H.sub.31 CH.sub.3 CH.sub.3 H 82484 OCOPh CH.sub.3 CH.sub.3 H 82485 OCOPh CH.sub.3 CHO H 82486 OCOPh CH.sub.3 CH.sub.2 OH H 82487 OH CH.sub.3 CH.sub.3 H 72488 OH CH.sub.3 H H 72489 OH CH.sub.3 CHCH.sub.2 H 72490 OH CH.sub.3 CHOHCH.sub.2 OH(R) H 72491 OH CH.sub.3 CHOHCH.sub.2 OH(S) H 72492 OH CH.sub.3 CHO H 72493 OH CH.sub.3 CH.sub.2 OH H 72494 OH CH.sub.3 CO.sub.2 H H 72495 OH CH.sub.3 CO.sub.2 CH.sub.3 H 72496 OH CH.sub.3 CHNOH H 72497 OH CH.sub.3 CHOHCHCH.sub.2(R) H 72498 OH CH.sub.3 CHOHCHCH.sub.2(S) H 72499 OH H CH.sub.3 H 72500 OH H H H 72501 OH H CHCH.sub.2 H 72502 OH H CHOHCH.sub.2 OH(R) H 72503 OH H CHOHCH.sub.2 OH(S) H 72504 OH H CHO H 72505 OH H CH.sub.2 OH H 72506 OH H CO.sub.2 H H 72507 OH H CO.sub.2 CH.sub.3 H 72508 OH H CHNOH H 72509 OH H CHOHCHCH.sub.2(R) H 72510 OH H CHOHCHCH.sub.2(S) H 72511 O CH.sub.3 CH.sub.3 H 72512 O CH.sub.3 H H 72513 O CH.sub.3 CHCH.sub.2 H 72514 O CH.sub.3 CHOHCH.sub.2 OH(R) H 72515 O CH.sub.3 CHOHCH.sub.2 OH(S) H 72516 O CH.sub.3 CHO H 72517 O CH.sub.3 CH.sub.2 OH H 72518 O CH.sub.3 CO.sub.2 H H 72519 O CH.sub.3 CO.sub.2 CH.sub.3 H 72520 O CH.sub.3 CHNOH H 72521 O CH.sub.3 CHOHCHCH.sub.2(R) H 72522 O CH.sub.3 CHOHCHCH.sub.2(R) H 72523 O H CH.sub.3 H 72524 O H H H 72525 O H CHCH.sub.2 H 72526 O H CHOHCH.sub.2 OH(R) H 72527 O H CHOHCH.sub.2 OH(S) H 72528 O H CHO H 72529 O H CH.sub.2 OH H 72530 O H CO.sub.2 H H 72531 O H CO.sub.2 CH.sub.3 H 72532 O H CHNOH H 72533 O H CHOHCHCH.sub.2(R) H 72534 O H CHOHCHCH.sub.2(S) H 72535 OCH.sub.3 CH.sub.3 CH.sub.3 H 72536 OCH.sub.3 CH.sub.3 H H 72537 OCH.sub.3 CH.sub.3 CHCH.sub.2 H 72538 OCH.sub. 3 CH.sub.3 CHOHCH.sub.2 OH(R) H 72539 OCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) H 72540 OCH.sub.3 CH.sub.3 CHO H 72541 OCH.sub.3 CH.sub.3 CH.sub.2 OH H 72542 OCH.sub.3 CH.sub.3 CO.sub.2 H H 72543 OCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 H 72544 OCH.sub.3 CH.sub.3 CHNOH H 72545 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(R) H 72546 OCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(S) H 72547 OCH.sub.3 H CH.sub.3 H 72548 OCH.sub.3 H H H 72549 OCH.sub.3 H CHCH.sub.2 H 72550 OCH.sub.3 H CHOHCH.sub.2 OH(R) H 72551 OCH.sub.3 H CHOHCH.sub.2 OH(S) H 72552 OCH.sub.3 H CHO H 72553 OCH.sub.3 H CH.sub.2 OH H 72554 OCH.sub.3 H CO.sub.2 H H 72555 OCH.sub.3 H CO.sub.2 CH.sub.3 H 72556 OCH.sub.3 H CHNOH H 72557 OCH.sub.3 H CHOHCHCH.sub.2(R) H 72558 OCH.sub.3 H CHOHCHCH.sub.2(S) H 72559 OCOCH.sub.3 CH.sub.3 CH.sub.3 H 72560 OCOCH.sub.3 CH.sub.3 H H 72561 OCOCH.sub.3 CH.sub.3 CHCH.sub.2 H 72562 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(R) H 72563 OCOCH.sub.3 CH.sub.3 CHOHCH.sub.2 OH(S) H 72564 OCOCH.sub.3 CH.sub.3 CHO H 72565 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH H 72566 OCOCH.sub.3 CH.sub.3 CO.sub.2 H H 72567 OCOCH.sub.3 CH.sub.3 CO.sub.2 CH.sub.3 H 72568 OCOCH.sub.3 CH.sub.3 CHNOH H 72569 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(R) H 72570 OCOCH.sub.3 CH.sub.3 CHOHCHCH.sub.2(S) H 72571 OCOCH.sub.3 H CH.sub.3 H 72572 OCOCH.sub.3 H H H 72573 OCOCH.sub.3 H CHCH.sub.2 H 72574 OCOCH.sub.3 H CHOHCH.sub.2 OH(R) H 72575 OCOCH.sub.3 H CHOHCH.sub.2 OH(S) H 72576 OCOCH.sub.3 H CHO H 72577 OCOCH.sub.3 H CH.sub.2 OH H 72578 OCOCH.sub.3 H CO.sub.2 H H 72579 OCOCH.sub.3 H CO.sub.2 CH.sub.3 H 72580 OCOCH.sub.3 H CH NOH H 72581 OCOCH.sub.3 H CHOHCHCH.sub.2(R) H 72582 OCOCH.sub.3 H CHOHCHCH.sub.2(S) H 72583 OH CH.sub.3 CH.sub.3 CH.sub.3 82584 OH CH.sub.3 H CH.sub.3 82585 OH CH.sub.3 CHO CH.sub.3 82586 OH CH.sub.3 CH.sub.2 OH CH.sub.3 82587 OH CH.sub.3 CO.sub.2 H CH.sub.3 82588 OH H CH.sub.3 CH.sub.3 82589 OH H H CH.sub.3 82590 OH H CHO CH.sub.3 82591 OH H CH.sub.2 OH CH.sub.3 82592 OH H CO.sub.2 H CH.sub.3 82593 O CH.sub.3 CH.sub.3 CH.sub.3 82594 O CH.sub.3 H CH.sub.3 82595 O CH.sub.3 CHO CH.sub.3 82596 O CH.sub.3 CH.sub.2 OH CH.sub.3 82597 O CH.sub.3 CO.sub.2 H CH.sub.3 82598 O H CH.sub.3 CH.sub.3 82599 O H H CH.sub.3 82600 O H CHO CH.sub.3 82601 O H CH.sub.2 OH CH.sub.3 82602 O H CO.sub.2 H CH.sub.3 82603 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 82604 OCH.sub.3 CH.sub.3 H CH.sub.3 82605 OCH.sub.3 CH.sub.3 CHO CH.sub.3 82606 OCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 82607 OCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 82608 OCH.sub.3 H CH.sub.3 CH.sub.3 82609 OCH.sub.3 H H CH.sub.3 82610 OCH.sub.3 H CHO CH.sub.3 82611 OCH.sub.3 H CH.sub.2 OH CH.sub.3 82612 OCH.sub.3 H CH.sub.2 H CH.sub.3 82613 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 82614 OCOCH.sub.3 CH.sub.3 H CH.sub.3 82615 OCOCH.sub.3 CH.sub.3 CHO CH.sub.3 82616 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 82617 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 82618 OCOCH.sub.3 H CH.sub.3 CH.sub.3 82619 OCOCH.sub.3 H H CH.sub.3 82620 OCOCH.sub.3 H CHO CH.sub.3 82621 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 82622 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 82623 OH CH.sub.3 CH.sub.3 CH.sub. 3 72624 OH CH.sub.3 H CH.sub.3 72625 OH CH.sub.3 CHO CH.sub.3 72626 OH CH.sub.3 CH.sub.2 OH CH.sub.3 72627 OH CH.sub.3 CO.sub.2 H CH.sub.3 72628 OH H CH.sub.3 CH.sub.3 72629 OH H H CH.sub.3 72630 OH H CHO CH.sub.3 72631 OH H CH.sub.2 OH CH.sub.3 72632 OH H CO.sub.2 H CH.sub.3 72633 O CH.sub.3 CH.sub.3 CH.sub.3 72634 O CH.sub.3 H CH.sub.3 72635 O CH.sub.3 CHO CH.sub.3 72636 O CH.sub.3 CH.sub.2 OH CH.sub.3 72637 O CH.sub.3 CO.sub.2 H CH.sub.3 72638 O H CH.sub.3 CH.sub.3 72639 O H H CH.sub.3 72640 O H CHO CH.sub.3 72641 O H CH.sub.2 OH CH.sub.3 72642 O H CO.sub.2 H CH.sub.3 72643 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 72644 OCH.sub.3 CH.sub.3 H CH.sub.3 72645 OCH.sub.3 CH.sub.3 CHO CH.sub.3 72646 OCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 72647 OCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 72648 OCH.sub.3 H CH.sub.3 CH.sub.3 72649 OCH.sub.3 H H CH.sub.3 72650 OCH.sub.3 H CHO CH.sub.3 72651 OCH.sub.3 H CH.sub.2 OH CH.sub.3 72652 OCH.sub.3 H CO.sub.2 H CH.sub.3 72653 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 72654 OCOCH.sub.3 CH.sub.3 H CH.sub.3 72655 OCOCH.sub.3 CH.sub.3 CHO CH.sub.3 72656 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 72657 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 72658 OCOCH.sub.3 H CH.sub.3 CH.sub.3 72659 OCOCH.sub.3 H H CH.sub.3 72660 OCOCH.sub.3 H CHO CH.sub.3 72661 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 72662 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 72663 OH CH.sub.3 CH.sub.3 CHO 82664 OH CH.sub.3 H CHO 82665 OH CH.sub.3 CHO CHO 82666 OH CH.sub.3 CH.sub.2 OH CHO 82667 OH CH.sub.3 CO.sub.2 H CHO 82668 OH H CH.sub.3 CHO 82669 OH H H CHO 82670 OH H CHO CHO 82671 OH H CH.sub.2 OH CHO 82672 OH H CO.sub.2 OH CHO 82673 O CH.sub.3 CH.sub.3 CHO 82674 O CH.sub.3 H CHO 82675 O CH.sub.3 CHO CHO 82676 O CH.sub.3 CH.sub.2 OH CHO 82677 O CH.sub.3 CH.sub.2 H CHO 82678 O H CH.sub.3 CHO 82679 O H H CHO 82680 O H CHO CHO 82681 O H CH.sub.2 OH CHO 82682 O H CO.sub.2 H CHO 82683 OCH.sub.3 CH.sub.3 CH.sub.3 CHO 82684 OCH.sub.3 CH.sub.3 H CHO 82685 OCH.sub.3 CH.sub.3 CHO CHO 82686 OCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 82687 OCH.sub.3 CH.sub.3 CO.sub.2 H CHO 82688 OCH.sub.3 H CH.sub.3 CHO 82689 OCH.sub.3 H H CHO 82690 OCH.sub.3 H CHO CHO 82691 OCH.sub.3 H CH.sub.2 OH CHO 82692 OCH.sub. 3 H CO.sub.2 H CHO 82693 OCOCH.sub.3 CH.sub.3 CH.sub.3 CHO 82694 OCOCH.sub.3 CH.sub.3 H CHO 82695 OCOCH.sub.3 CH.sub.3 CHO CHO 82696 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 82697 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CHO 82698 OCOCH.sub.3 H CH.sub.3 CHO 82699 OCOCH.sub.3 H H CHO 82700 OCOCH.sub.3 H CHO CHO 82701 OCOCH.sub.3 H CH.sub.2 OH CHO 82702 OCOCH.sub.3 H CO.sub.2 H CHO 82703 OH CH.sub.3 CH.sub.3 CHO 72704 OH CH.sub.3 H CHO 72705 OH CH.sub.3 CHO CHO 72706 OH CH.sub.3 CH.sub.2 OH CHO 72707 OH CH.sub.3 CO.sub.2 H CHO 72708 OH H CH.sub.3 CHO 72709 OH H H CHO 72710 OH H CHO CHO 72711 OH H CH.sub.2 OH CHO 72712 OH H CO.sub.2 H CHO 72713 O CH.sub.3 CH.sub.3 CHO 72714 O CH.sub.3 H CHO 72715 O CH.sub.3 CHO CHO 72716 O CH.sub.3 CH.sub.2 OH CHO 72717 O CH.sub.3 CO.sub.2 H CHO 72718 O H CH.sub.3 CHO 72719 O H H CHO 72720 O H CHO CHO 72721 O H CH.sub.2 OH CHO 72722 O H CO.sub.2 H CHO 72723 OCH.sub.3 CH.sub.3 CH.sub.3 CHO 72724 OCH.sub.3 CH.sub.3 H CHO 72725 OCH.sub.3 CH.sub.3 CHO CHO 72726 OCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 72727 OCH.sub.3 CH.sub.3 CO.sub.2 H CHO 72728 OCH.sub.3 H CH.sub.3 CHO 72729 OCH.sub.3 H H CHO 72730 OCH.sub.3 H CHO CHO 72731 OCH.sub.3 H CH.sub.2 OH CHO 72732 OCH.sub.3 H CO.sub.2 H CHO 72733 OCOCH.sub.3 CH.sub.3 CH.sub.3 CHO 72734 OCOCH.sub.3 CH.sub.3 H CHO 72735 OCOCH.sub.3 CH.sub.3 CHO CHO 72736 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 72737 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CHO 72738 OCOCH.sub.3 H CH.sub.3 CHO 72739 OCOCH.sub.3 H H CHO 72740 OCOCH.sub.3 H CHO CHO 72741 OCOCH.sub.3 H CH.sub.2 OH CHO 72742 OCOCH.sub.3 H CO.sub.2 H CHO 72743 OH CH.sub.3 CH.sub.3 COCH.sub.3 82744 OH CH.sub.3 H COCH.sub.3 82745 OH CH.sub.3 CHO COCH.sub.3 82746 OH CH.sub.3 CH.sub.2 OH COCH.sub.3 82747 OH CH.sub.3 CO.sub.2 H COCH.sub.3 82748 OH H CH.sub.3 COCH.sub.3 82749 OH H H COCH.sub.3 82750 OH H CHO COCH.sub.3 82751 OH H CH.sub.2 OH COCH.sub.3 82752 OH H CO.sub.2 H COCH.sub.3 82753 O CH.sub.3 CH.sub.3 COCH.sub.3 82754 O CH.sub.3 H COCH.sub.3 82755 O CH.sub.3 CHO COCH.sub.3 82756 O CH.sub.3 CH.sub.2 OH COCH.sub.3 82757 O CH.sub.3 CO.sub.2 H COCH.sub.3 82758 O H CH.sub.3 COCH.sub.3 82759 O H H COCH.sub.3 82760 O H CHO COCH.sub.3 82761 O H CH.sub.2 OH COCH.sub.3 82762 O H CO.sub.2 H COCH.sub.3 82763 OCH.sub.3 CH.sub.3 CH.sub.3 COCH.sub.3 82764 OCH.sub.3 CH.sub.3 H COCH.sub.3 82765 OCH.sub.3 CH.sub.3 CHO COCH.sub.3 82766 OCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 82767 OCH.sub.3 CH.sub.3 CO.sub.2 H COCH.sub.3 82768 OCH.sub.3 H CH.sub.3 COCH.sub.3 82769 OCH.sub.3 H H COCH.sub.3 82770 OCH.sub.3 H CHO COCH.sub.3 82771 OCH.sub.3 H CH.sub.2 OH COCH.sub.3 82772 OCH.sub.3 H CO.sub.2 H COCH.sub.3 82773 OCOCH.sub.3 CH.sub.3 CH.sub.3 COCH.sub.3 82774 OCOCH.sub.3 CH.sub.3 H COCH.sub.3 82775 OCOCH.sub.3 CH.sub.3 CHO COCH.sub.3 82776 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 82777 OCOCH.sub.3 CH.sub.3 CO.sub.2 H COCH.sub.3 82778 OCOCH.sub.3 H CH.sub.3 COCH.sub.3 82779 OCOCH.sub.3 H H COCH.sub.3 82780 OCOCH.sub.3 H CHO COCH.sub.3 82781 OCOCH.sub.3 H CH.sub.2 OH COCH.sub.3 82782 OCOCH.sub.3 H CO.sub.2 H COCH.sub.3 82783 OH CH.sub.3 CH.sub.3 COCH.sub.3 72784 OH CH.sub.3 H COCH.sub.3 72785 OH CH.sub.3 CHO COCH.sub.3 72786 OH CH.sub.3 CH.sub.2 OH COCH.sub.3 72787 OH CH.sub.3 CO.sub.2 H COCH.sub.3 72788 OH H CH.sub.3 COCH.sub.3 72789 OH H H COCH.sub.3 72790 OH H CHO COCH.sub.3 72791 OH H CH.sub.2 OH COCH.sub.3 72792 OH H CO.sub.2 H COCH.sub.3 72793 O CH.sub.3 CH.sub.3 COCH.sub.3 72794 O CH.sub.3 H COCH.sub.3 72795 O CH.sub.3 CHO COCH.sub.3 72796 O CH.sub.3 CH.sub.2 OH COCH.sub.3 72797 O CH.sub.3 CO.sub.2 H COCH.sub.3 72798 O H CH.sub.3 COCH.sub.3 72799 O H H COCH.sub.3 72800 O H CHO COCH.sub.3 72801 O H CH.sub.2 OH COCH.sub.3 72802 O H CO.sub.2 H COCH.sub.3 72803 OCH.sub.3 CH.sub.3 CH.sub.3 COCH.sub.3 72804 OCH.sub.3 CH.sub.3 H COCH.sub.3 72805 OCH.sub.3 CH.sub.3 CHO COCH.sub.3 72806 OCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 72807 OCH.sub.3 CH.sub.3 CO.sub.3 H COCH.sub.3 72808 OCH.sub.3 H CH.sub.3 COCH.sub.3 72809 OCH.sub.3 H H COCH.sub.3 72810 OCH.sub.3 H CHO COCH.sub.3 72811 OCH.sub.3 H CH.sub.3 OH COCH.sub.3 72812 OCH.sub.3 H CO.sub.2 OH COCH.sub.3 72813 OCOCH.sub.3 CH.sub.3 CH.sub.3 COCH.sub.3 72814 OCOCH.sub.3 CH.sub.3 H COCH.sub.3 72815 OCOCH.sub.3 CH.sub.3 CHO COCH.sub.3 72816 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 72817 OCOCH.sub.3 CH.sub.3 CO.sub.2 H COCH.sub.3 72818 OCOCH.sub.3 H CH.sub.3 COCH.sub.3 72819 OCOCH.sub.3 H CHO COCH.sub.3 72821 OCOCH.sub.3 H CH.sub.2 OH COCH.sub.3 72822 OCOCH.sub.3 H CO.sub.2 H COCH.sub.3 7__________________________________________________________________________
TABLE 11__________________________________________________________________________ ##STR52##No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 D No. M.P.__________________________________________________________________________2823 OH CH.sub.3 CH.sub.3 CH.sub.3 82824 OH CH.sub.3 H CH.sub.3 82825 OH CH.sub.3 CHCH.sub.2 CH.sub.3 82826 OH CH.sub.3 CHOHCH.sub.2 OH(R) CH.sub.3 82827 OH CH.sub.3 CHOHCH.sub.2 OH(S) CH.sub.3 82828 OH CH.sub.3 CHO CH.sub.3 82829 OH CH.sub.3 CH.sub.2 OH CH.sub.3 82830 OH CH.sub.3 CO.sub.2 H CH.sub.3 82831 OH CH.sub.3 CO.sub.2 CH.sub.3 CH.sub.3 82832 OH CH.sub.3 CHNOH CH.sub.3 82833 OH CH.sub.3 CHOHCH CH.sub.2(R) CH.sub.3 82834 OH CH.sub.3 CHOHCHCH.sub.2(S) CH.sub.3 82835 OH H CH.sub.3 CH.sub.3 82836 OH H H CH.sub.3 82837 OH H CHCH.sub.2 CH.sub.3 82838 OH H CHOHCH.sub.2 OH(R) CH.sub.3 82839 OH H CHOHCH.sub.2 OH(S) CH.sub.3 82840 OH H CHO CH.sub.3 82841 OH H CH.sub.2 OH CH.sub.3 82842 OH H CO.sub.2 H CH.sub.3 82843 OH H CO.sub.2 CH.sub.3 CH.sub.3 82844 OH H CHNOH CH.sub.3 82845 OH H CHOHCHCH.sub.2(R) CH.sub.32846 OH H CHOHCHCH.sub.2(S) CH.sub.32847 O CH.sub.3 CH.sub.3 CH.sub.32848 O CH.sub.3 H CH.sub.3 82849 O CH.sub.3 CHO CH.sub.3 82850 O CH.sub.3 CH.sub.2 OH CH.sub.3 82851 O CH.sub.3 CO.sub.2 H CH.sub.3 82852 O H CH.sub.3 CH.sub.3 82853 O H H CH.sub.3 82854 O H CHO CH.sub.3 82855 O H CH.sub.2 OH CH.sub.3 82856 O H CO.sub.2 H CH.sub.3 82857 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 82858 OCH.sub.3 CH.sub.3 H CH.sub.3 82859 OCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 82860 OCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 82861 OCH.sub.3 H CH.sub.3 CH.sub.3 82862 OCH.sub.3 H H CH.sub.3 82863 OCH.sub.3 H CHO CH.sub.3 82864 OCH.sub.3 H CH.sub.2 OH CH.sub.3 82865 OCH.sub.3 H CO.sub.2 H CH.sub.3 82866 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 82867 OCOCH.sub.3 CH.sub.3 H CH.sub.3 82868 OCOCH.sub.3 CH.sub.3 CHO CH.sub.3 82869 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 82870 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 82871 OCOCH.sub.3 H CH.sub.3 CH.sub.3 82872 OCOCH.sub.3 H H CH.sub.3 82873 OCOCH.sub.3 H CHO CH.sub.3 82874 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 82875 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 82876 OH CH.sub. 3 CH.sub.3 CH.sub.3 72877 OH CH.sub.3 H CH.sub.3 72878 OH CH.sub.3 CHO CH.sub.3 72879 OH CH.sub.3 CH.sub.2 OH CH.sub.3 72880 OH CH.sub.3 CO.sub.2 H CH.sub.3 72881 OH H CH.sub.32 CH.sub.3 72882 OH H H CH.sub.3 72883 OH H CHO CH.sub.3 72884 OH H CH.sub.2 OH CH.sub.3 72885 OH H CO.sub.2 H CH.sub.3 72886 O CH.sub.3 CH.sub.3 CH.sub.3 72887 O CH.sub.3 H CH.sub.3 72888 O CH.sub.3 CHO CH.sub.3 72889 O CH.sub.3 CH.sub.2 OH CH.sub.3 72890 O CH.sub.3 CO.sub.2 H CH.sub.3 72891 O H CH.sub.3 CH.sub.3 72892 O H H CH.sub.3 72893 O H CHO CH.sub.3 72894 O H CH.sub.2 OH CH.sub.3 72895 O H CO.sub.2 H CH.sub.3 72896 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 72897 OCH.sub.3 CH.sub.3 H CH.sub.3 72898 OCH.sub.3 CH.sub. 3 CHO CH.sub.3 72899 OCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 72900 OCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 72901 OCH.sub.3 H CH.sub.3 CH.sub.3 72902 OCH.sub.3 H H CH.sub.3 72903 OCH.sub.3 H CHO CH.sub.3 72904 OCH.sub.3 H CH.sub.2 OH CH.sub.3 72905 OCH.sub.3 H CO.sub.2 H CH.sub.3 72906 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 72907 OCOCH.sub.3 CH.sub.3 H CH.sub.3 72908 OCOCH.sub.3 CH.sub.3 CHO CH.sub.3 72909 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 72910 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 72911 OCOCH.sub.3 H CH.sub.3 CH.sub.3 72912 OCOCH.sub.3 H H CH.sub.3 72913 OCOCH.sub.3 H CHO CH.sub.3 72914 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 72915 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 7__________________________________________________________________________
TABLE 12__________________________________________________________________________ ##STR53##No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 D No. M.P.__________________________________________________________________________2916 OH CH.sub.3 CH.sub.3 H 82917 OH CH.sub.3 H H 82918 OH CH.sub.3 CHCH.sub.2 H 82919 OH CH.sub.3 CHOHCH.sub.2 OH(R) H 82920 OH CH.sub.3 CHOHCH.sub.2 OH(S) H 82921 OH CH.sub.3 CHO H 82922 OH CH.sub.3 CH.sub.2 OH H 82923 OH CH.sub.3 CO.sub.2 H H 82924 OH CH.sub.3 CO.sub.2 CH.sub.3 H 82925 OH CH.sub.3 CHNOH H 82926 OH CH.sub.3 CHOHCHCH.sub.2(R) H 82927 OH CH.sub.3 CHOHCHCH.sub.2(S) H 82928 OH H CH.sub.3 H 82929 OH H H H 82930 OH H CHCH.sub.2 H 82931 OH H CHOHCH.sub.2 OH(R) H 82932 OH H CHOHCH.sub.2 OH(S) H 82933 OH H CHO H 82934 OH H CH.sub.2 OH H 82935 OH H CO.sub.2 H H 82936 OH H CO.sub.2 CH.sub.3 H 82937 OH H CHNOH H 82938 OH H CHOHCHCH.sub.2(R) H 82939 OH H CHOHCHCH.sub.2(S) H 82940 OH CH.sub.3 CH.sub.2 SH H 82941 OH CH.sub.3 CH.sub.2 NH.sub.2 H 82942 OH CH.sub.3 COCH.sub.3 H 82943 OH CH.sub.3 CONH.sub.2 H 82944 OH CH.sub.3 CSNH.sub.2 H 82945 OH CH.sub.3 CH.sub.2 CH.sub.2 OH H 82946 OH CH.sub.3 CH.sub.2 CHO H 82947 OH CH.sub.3 CH.sub.2 COCH.sub.3 H 82948 OH CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.3 H 82949 OH CH.sub.3 CH.sub.2 CONH.sub.2 H 82950 OH CH.sub.3 CH.sub.2 CH.sub.2 Cl H 82951 OH CH.sub.3 CN H 82952 OH CH.sub.3 CHNNH.sub.2 H 82953 OH CH.sub.3 CH.sub.2 NHOH H 82954 OH CH.sub.3 CH.sub.2 NHNH.sub.2 H 82955 OH CH.sub.3 CH.sub.2 CN H 82956 OH CH.sub.3 CH.sub.2 CHNOH H 82957 OH CH.sub.3 CH.sub.2 CHNNH.sub.2 H 82958 OH CH.sub.3 CH.sub.2 CH.sub.2 NHOH H 82959 OH CH.sub.3 CH.sub.2 CH.sub.2 NHNH.sub.2 H 82960 OH CH.sub.3 CONHOH H 82961 OH CH.sub.3 CHCHCHO H 82962 OH CH.sub.3 CHCHCOCH.sub.3 H 82963 OH CH.sub.3 CHCHCH.sub.2 Cl H 82964 OH CH.sub.3 CH.sub.2 CHOHCH.sub.2 OH H 82965 OH CH.sub.3 ##STR54## H 82966 O CH.sub.3 CH.sub.3 H 82967 O CH.sub.3 H H 82968 O CH.sub.3 CHO H 82969 O CH.sub.3 CH.sub.2 OH H 82970 O CH.sub.3 CO.sub.2 H H 82971 O H CH.sub.3 H 82972 O H H H 82973 O H CHO H 82974 O H CH.sub.2 OH H 82975 O H CO.sub.2 H H 82976 OCH.sub.3 CH.sub.3 CH.sub.3 H 82977 OCH.sub.3 CH.sub.3 H H 82978 OCH.sub.3 CH.sub.3 CH.sub.2 OH H 82979 OCH.sub.3 CH.sub.3 CO.sub.2 H H 82980 OCH.sub.3 H CH.sub.3 H 82981 OCH.sub.3 H H H 82982 OCH.sub.3 H CHO H 82983 OCH.sub.3 H CH.sub.2 OH H 82984 OCH.sub.3 H CO.sub.2 H H 82985 OCOCH.sub.3 CH.sub.3 CH.sub.3 H 82986 OCOCH.sub.3 CH.sub.3 H H 82987 OCOCH.sub.3 CH.sub.3 CHO H 82988 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH H 82989 OCOCH.sub.3 CH.sub.3 CO.sub.2 H H 82990 OCOCH.sub.3 H CH.sub.3 H 82991 OCOCH.sub.3 H H H 82992 OCOCH.sub.3 H CHO H 82993 OCOCH.sub.3 H CH.sub.2 OH H 82994 OCOCH.sub.3 H CO.sub.2 H H 82995 OH CH.sub.3 CH.sub.3 H 72996 OH CH.sub.3 H H 72997 OH CH.sub.3 CHO H 72998 OH CH.sub.3 CH.sub.2 OH H 72999 OH CH.sub.3 CO.sub.2 H H 73000 OH H CH.sub.3 H 73001 OH H H H 73002 OH H CHO H 73003 OH H CH.sub.2 OH H 73004 OH H CO.sub.2 H H 73005 O CH.sub.3 CH.sub.3 H 73006 O CH.sub.3 H H 73007 O CH.sub.3 CHO H 73008 O CH.sub.3 CH.sub.2 OH H 73009 O CH.sub.3 CO.sub.2 H H 73010 O H CH.sub.3 H 73011 O H H H 73012 O H CHO H 73013 O H CH.sub.2 OH H 73014 O H CO.sub.2 H H 73015 OCH.sub.3 CH.sub.3 CH.sub.3 H 73016 OCH.sub.3 CH.sub.3 H H 73017 OCH.sub.3 CH.sub.3 CHO H 73018 OCH.sub.3 CH.sub.3 CH.sub.2 OH H 73019 OCH.sub.3 CH.sub. 3 CO.sub.2 H 73020 OCH.sub.3 H CH.sub.3 H 73021 OCH.sub.3 H H H 73022 OCH.sub.3 H CHO H 73023 OCH.sub.3 H CH.sub.2 OH H 73024 OCH.sub.3 H CO.sub.2 H H 73025 OCOCH.sub.3 CH.sub.3 CH.sub.3 H 73026 OCOCH.sub.3 CH.sub.3 H H 73027 OCOCH.sub.3 CH.sub.3 CHO H 73028 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH H 73029 OCOCH.sub.3 CH.sub.3 CO.sub.2 H H 73030 OCOCH.sub.3 H CH.sub.3 H 73031 OCOCH.sub.3 H H H 73032 OCOCH.sub.3 H CHO H 73033 OCOCH.sub.3 H CH.sub.2 OH H 73034 OCOCH.sub.3 H CO.sub.2 H H 73035 OH CH.sub.3 CH.sub.3 CH.sub.3 83036 OH CH.sub.3 H CH.sub.3 83037 OH CH.sub.3 CHO CH.sub.3 83038 OH CH.sub.3 CH.sub.2 OH CH.sub.3 83039 OH CH.sub.3 CO.sub.2 H CH.sub.3 83040 OH H CH.sub.3 CH.sub.3 83041 OH H H CH.sub.3 83042 OH H CHO CH.sub.3 83043 OH H CH.sub.2 OH CH.sub.3 83044 OH H CO.sub.2 H CH.sub.3 83045 O CH.sub.3 CH.sub.3 CH.sub.3 83046 O CH.sub.3 H CH.sub.3 83047 O CH.sub.3 CHO CH.sub.3 83048 O CH.sub.3 CH.sub.2 OH CH.sub.3 83049 O CH.sub.3 CO.sub.2 H CH.sub.3 83050 O H CH.sub.3 CH.sub.3 83051 O H H CH.sub.3 83052 O H CHO CH.sub.3 83053 O H CH.sub.2 OH CH.sub.3 83054 O H CO.sub.2 H CH.sub.3 83055 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 83056 OCH.sub.3 CH.sub.3 H CH.sub.3 83057 OCH.sub.3 CH.sub.3 CHO CH.sub.3 83058 OCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 83059 OCH.sub.3 CO.sub.3 H CH.sub.3 83060 OCH.sub.3 H CH.sub.3 CH.sub.3 83061 OCH.sub.3 H H CH.sub.3 83062 OCH.sub.3 H CHO CH.sub.3 83063 OCH.sub.3 H CH.sub.2 OH CH.sub.3 83064 OCH.sub.3 H CO.sub.2 H CH.sub.3 83065 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 83066 OCOCH.sub.3 CH.sub.3 H CH.sub.3 83067 OCOCH.sub.3 CH.sub.3 CHO CH.sub.3 83068 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 83069 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 83070 OCOCH.sub.3 H CH.sub.3 CH.sub.3 83071 OCOCH.sub.3 H H CH.sub.3 83072 OCOCH.sub.3 H CHO CH.sub.3 83073 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 83074 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 83075 OH CH.sub.3 CH.sub.3 CH.sub.3 73076 OH CH.sub.3 H CH.sub.3 73077 OH CH.sub.3 CHO CH.sub.3 73078 OH CH.sub.3 CH.sub.2 OH CH.sub.3 73079 OH CH.sub.3 CO.sub.2 H CH.sub.3 73080 OH H CH.sub.3 CH.sub.3 73081 OH H H CH.sub.3 73082 OH H CHO CH.sub.3 73083 OH H CH.sub.2 OH CH.sub.3 73084 OH H CO.sub.2 H CH.sub.3 73085 O CH.sub.3 CH.sub.3 CH.sub.3 73086 O CH.sub.3 H CH.sub.3 73087 O CH.sub.3 CHO CH.sub.3 73088 O CH.sub.3 CH.sub.2 OH CH.sub.3 73089 O CH.sub.3 CO.sub.2 H CH.sub.3 73090 O H CH.sub.3 CH.sub.3 73091 O H H CH.sub.3 73092 O H CHO CH.sub.3 73093 O H CH.sub.2 OH CH.sub.3 73094 O H CO.sub.2 H CH.sub.3 73095 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 73096 OCH.sub.3 CH.sub.3 H CH.sub.3 73097 OCH.sub.3 CH.sub.3 CHO CH.sub.3 73098 OCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 73099 OCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 73100 OCH.sub.3 H CH.sub.3 CH.sub.3 73101 OCH.sub.3 H H CH.sub.3 73102 OCH.sub.3 H CHO CH.sub.3 73103 OCH.sub.3 H CH.sub.2 OH CH.sub.3 73104 OCH.sub.3 H CO.sub.2 H CH.sub.3 73105 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 73106 OCOCH.sub.3 CH.sub.3 H CH.sub.3 73107 OCOCH.sub.3 CH.sub.3 CHO CH.sub. 3 73108 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 73109 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 73110 OCOCH.sub.3 H CH.sub.3 CH.sub.3 73111 OCOCH.sub.3 H H CH.sub.3 73112 OCOCH.sub.3 H CHO CH.sub.3 73113 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 73114 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 73115 OH CH.sub.3 CH.sub.3 CHO 83116 OH CH.sub.3 H CHO 83117 OH CH.sub.3 CH.sub.3 CHO 83118 OH CH.sub.3 CH.sub.2 OH CHO 83119 OH CH.sub.3 CO.sub.2 H CHO 83120 OH H CH.sub.3 CHO 83121 OH H H CHO 83122 OH H CHO CHO 83123 OH H CH.sub.2 OH CHO 83124 OH H CO.sub.2 H CHO 83125 O CH.sub.3 CH.sub.3 CHO 83126 O CH.sub.3 H CHO 83127 O CH.sub.3 CHO CHO 83128 O CH.sub.3 CH.sub.2 OH CHO 83129 O CH.sub.3 CO.sub.2 H CHO 83130 O H CH.sub.3 CHO 83131 O H H CHO 83132 O H CHO CHO 83133 O H CH.sub.2 OH CHO 83134 O H CO.sub.2 H CHO 83135 OCH.sub.3 CH.sub.3 CH.sub.3 CHO 83136 OCH.sub.3 CH.sub.3 H CHO 83137 OCH.sub.3 CH.sub.3 CHO CHO 83138 OCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 83139 OCH.sub.3 CH.sub.3 CO.sub.2 H CHO 83140 OCH.sub.3 H CH.sub.3 CHO 83141 OCH.sub.3 H H CHO 83142 OCH.sub.3 H CHO CHO 83143 OCH.sub.3 H CH.sub.2 OH CHO 83144 OCH.sub.3 H CO.sub.2 H CHO 83145 OCOCH.sub.3 CH.sub.3 CH.sub.3 CHO 83146 OCOCH.sub.3 CH.sub.3 H CHO 83147 OCOCH.sub.3 CH.sub.3 CHO CHO 83148 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 83149 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CHO 83150 OCOCH.sub.3 H CH.sub.3 CHO 83151 OCOCH.sub.3 H H CHO 83152 OCOCH.sub.3 H CHO CHO 83153 OCOCH.sub.3 H CH.sub.2 OH CHO 83154 OCOCH.sub.3 H CO.sub.2 H CHO 83155 OH CH.sub.3 CH.sub.3 CHO 73156 OH CH.sub.3 H CHO 73157 OH CH.sub.3 CHO CHO 73158 OH CH.sub.3 CH.sub.2 OH CHO 73159 OH CH.sub.3 CO.sub.2 H CHO 73160 OH H CH.sub.3 CHO 73161 OH H H CHO 73162 OH H CHO CHO 73163 OH H CH.sub.2 OH CHO 73164 OH H CO.sub.2 H CHO 73165 O CH.sub.3 CH.sub.3 CHO 73166 O CH.sub.3 H CHO 73167 O CH.sub.3 CHO CHO 73168 O CH.sub.3 CH.sub.2 OH CHO 73169 O CH.sub.3 CO.sub.2 H CHO 73170 O H CH.sub.3 CHO 73171 O H H CHO 73172 O H CHO CHO 73173 O H CH.sub.2 OH CHO 73174 O H CO.sub.2 H CHO 73175 OCH.sub.3 CH.sub.3 CH.sub.3 CHO 73176 OCH.sub.3 CH.sub.3 H CHO 73177 OCH.sub.3 CH.sub.3 CHO CHO 73178 OCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 73179 OCH.sub.3 CH.sub.3 CO.sub.2 H CHO 73180 OCH.sub.3 H CH.sub.3 CHO 73181 OCH.sub.3 H H CHO 73182 OCH.sub.3 H CHO CHO 73183 OCH.sub.3 H CH.sub.2 OH CHO 73184 OCH.sub.3 H CO.sub.2 H CHO 73185 OCOCH.sub.3 CH.sub.3 CH.sub.3 CHO 73186 OCOCH.sub.3 CH.sub.3 H CHO 73187 OCOCH.sub.3 CH.sub.3 CHO CHO 73188 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CHO 73189 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CHO 73190 OCOCH.sub.3 H CH.sub.3 CHO 73191 OCOCH.sub.3 H H CHO 73192 OCOCH.sub.3 H CHO CHO 73193 OCOCH.sub.3 H CH.sub.2 OH CHO 73194 OCOCH.sub.3 H CO.sub.2 H CHO 73195 OH CH.sub.3 CH.sub.3 COCH.sub.3 83196 OH C.sub.3 H COCH.sub.3 83197 OH CH.sub.3 CHO COCH.sub.3 83198 OH CH.sub.3 CH.sub.2 OH COCH.sub.3 83199 OH CH.sub.3 CO.sub.2 H COCH.sub.3 83200 OH H CH.sub.3 COCH.sub.3 83201 OH H H COCH.sub.3 83202 OH H CHO COCH.sub.3 83203 OH H CH.sub.2 OH COCH.sub.3 83204 OH H CO.sub.2 H COCH.sub.3 83205 O CH.sub.3 CH.sub.3 COCH.sub.3 83206 O CH.sub.3 H COCH.sub.3 83207 O CH.sub.3 CHO COCH.sub.3 83208 O CH.sub.3 CH.sub.2 OH COCH.sub.3 83209 O CH.sub.3 CO.sub.2 OH COCH.sub.3 83210 O H CH.sub.3 COCH.sub.3 83211 O H H COCH.sub.3 83212 O H CHO COCH.sub.3 83213 O H CH.sub.2 OH COCH.sub.3 83214 O H CO.sub.2 H COCH.sub.3 83215 OCH.sub.3 CH.sub.3 CH.sub.3 COCH.sub.3 83216 OCH.sub.3 CH.sub.3 H COCH.sub.3 83217 OCH.sub.3 CH.sub.3 CHO COCH.sub.3 83218 OCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 83219 OCH.sub.3 CH.sub.3 CO.sub.2 H COCH.sub.3 83220 OCH.sub.3 H CH.sub.3 COCH.sub.3 83221 OCH.sub.3 H H COCH.sub.3 83222 OCH.sub.3 H CHO COCH.sub.3 83223 OCH.sub.3 H CHO COCH.sub.3 83224 OCH.sub.3 H CO.sub.2 H COCH.sub.3 83225 OCOCH.sub.3 CH.sub.3 COCH.sub.3 COCH.sub.3 83226 OCOCH.sub.3 CH.sub.3 H COCH.sub.3 83227 OCOCH.sub.3 CH.sub.3 CHO COCH.sub.3 83228 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 83229 OCOCH.sub.3 CH.sub.3 CO.sub.2 H COCH.sub.3 83230 OCOCH.sub.3 H H COCH.sub.3 83231 OCOCH.sub.3 H CHO COCH.sub.3 83232 OCOCH.sub.3 H CH.sub.2 OH COCH.sub.3 83233 OCOCH.sub.3 H CH.sub.2 OH COCH.sub.3 83234 OCOCH.sub.3 H CO.sub.2 H COCH.sub.3 83235 OH CH.sub.3 CH.sub.3 COCH.sub.3 73236 OH CH.sub.3 H COCH.sub.3 73237 OH CH.sub.3 CHO COCH.sub.3 73228 OH CH.sub.3 CH.sub.2 OH COCH.sub.3 73239 OH CH.sub.3 CO.sub.2 H COCH.sub.3 73240 OH H CH.sub.3 COCH.sub.3 73241 OH H H COCH.sub.3 73242 OH H CHO COCH.sub.3 73243 OH H CH.sub.2 OH COCH.sub.3 73244 OH H CO.sub.2 H COCH.sub.3 73245 O CH.sub.3 CH.sub.3 COCH.sub.3 73246 O CH.sub.3 H COCH.sub.3 73247 O CH.sub.3 CHO COCH.sub.3 73248 O CH.sub.3 CH.sub.2 OH COCH.sub.3 73249 O CH.sub.3 CO.sub.2 H COCH.sub.3 73250 O H CH.sub.3 COCH.sub.3 73251 O H H COCH.sub.3 73252 O H CHO COCH.sub.3 73253 O H CH.sub.2 OH COCH.sub.3 73254 O H CO.sub.2 H COCH.sub.3 73255 OCH.sub.3 CH.sub.3 CH.sub.3 COCH.sub.3 73256 OCH.sub.3 CH.sub.3 H COCH.sub.3 73257 OCH.sub.3 CH.sub.3 CHO COCH.sub.3 73258 OCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 73259 OCH.sub.3 CH.sub.3 CO.sub.2 H COCH.sub.3 73260 OCH.sub.3 H CH.sub.3 COCH.sub.3 73261 OCH.sub.3 H H COCH.sub.3 73262 OCH.sub.3 H CHO COCH.sub.3 73263 OCH.sub.3 H CH.sub.2 OH COCH.sub.3 73264 OCH.sub.3 H CO.sub.2 H COCH.sub.3 73265 OCOCH.sub.3 CH.sub.3 CH.sub.3 COCH.sub.3 73266 OCOCH.sub.3 CH.sub.3 H COCH.sub.3 73267 OCOCH.sub.3 CH.sub.3 CHO COCH.sub. 3 73268 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH COCH.sub.3 73269 OCOCH.sub.3 H CH.sub.3 COCH.sub.3 73270 OCOCH.sub.3 H CH.sub.3 COCH.sub.3 73271 OCOCH.sub.3 H H COCH.sub.3 73272 OCOCH.sub.3 H CHO COCH.sub.3 73273 OCOCH.sub.3 H CH.sub.2 OH COCH.sub.3 73274 OCOCH.sub.3 H CO.sub.2 H COCH.sub.3 7__________________________________________________________________________
TABLE 13__________________________________________________________________________ ##STR55##No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 D No. M.P.__________________________________________________________________________3275 OH CH.sub.3 CH.sub.3 CH.sub.3 83276 OH CH.sub.3 H CH.sub.3 83277 OH CH.sub.3 CHCH.sub.2 CH.sub.3 83278 OH CH.sub.3 CHOHCH.sub.2 OH(R) CH.sub.3 83279 OH CH.sub.3 CHOHCH.sub.2 OH(S) CH.sub.3 83280 OH CH.sub.3 CHO CH.sub.3 83281 OH CH.sub.3 CH.sub.2 OH CH.sub.3 83282 OH CH.sub.3 CH.sub.2 H CH.sub.3 83283 OH CH.sub.3 CO.sub.2 H.sub.3 CH.sub.3 83284 OH CH.sub.3 CHNOH CH.sub.3 83285 OH CH.sub.3 CHOHCH CH.sub.2(R) CH.sub.3 83286 OH CH.sub.3 CHOHCHCH.sub.2(S) CH.sub.3 83287 OH H CH.sub.3 CH.sub.3 83288 OH H H CH.sub.3 83289 OH H CHCH.sub.2 CH.sub.3 83290 OH H CHOHCH.sub.2 OH(R) CH.sub.3 83291 OH H CHOHCH.sub.2 OH(S) CH.sub.3 83292 OH H CHO CH.sub.3 83293 OH H CH.sub.2 OH CH.sub.3 83294 OH H CO.sub.2 H CH.sub.3 83295 OH H CO.sub.2 CH.sub.3 CH.sub.3 83296 OH H CHNOH CH.sub.3 83297 OH H CHOHCHCH.sub.2(R) CH.sub.3 83298 OH H CHOHCHCH.sub.2(S) CH.sub.3 83299 O CH.sub.3 CH.sub.3 CH.sub.3 83300 O CH.sub.3 H CH.sub.3 83301 O CH.sub.3 CHO CH.sub.3 83302 O CH.sub.3 CH.sub.2 OH CH.sub.3 83303 O CH.sub.3 CO.sub.2 H CH.sub.3 83304 O H CH.sub.3 CH.sub.3 83305 O H H CH.sub.3 83306 O H CHO CH.sub.3 83307 O H CH.sub.2 OH CH.sub.3 83308 O H CO.sub.2 H CH.sub.3 83309 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 83310 OCH.sub.3 CH.sub.3 H CH.sub.3 83311 OCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 83312 OCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 83313 OCH.sub.3 H CH.sub.3 CH.sub.3 83314 OCH.sub.3 H H CH.sub.3 83315 OCH.sub.3 H CH.sub.2 OH CH.sub.3 83317 OCH.sub.3 H CO.sub.2 H CH.sub.3 83318 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 83319 OCOCH.sub.3 CH.sub.3 H CH.sub.3 83320 OCOCH.sub.3 CH.sub.3 CHO CH.sub.3 83321 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 83322 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 83323 OCOCH.sub.3 H CH.sub.3 CH.sub.3 83324 OCOCH.sub.3 H H CH.sub.3 83325 OCOCH.sub.3 H CHO CH.sub.3 83326 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 83327 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 83328 OH CH.sub.3 CH.sub.3 CH.sub.3 73329 OH CH.sub.3 H CH.sub.3 73330 OH CH.sub.3 CHO CH.sub.3 73331 OH CH.sub.3 CH.sub.2 OH CH.sub.3 73332 OH CH.sub.3 CO.sub.2 H CH.sub.3 73333 OH H CH.sub.3 CH.sub.3 73334 OH H H CH.sub.3 73335 OH H CHO CH.sub.3 73336 OH H CH.sub.2 OH CH.sub.3 73337 OH H CO.sub.2 H CH.sub.3 73338 O CH.sub.3 CH.sub.3 CH.sub.3 73339 O CH.sub.3 H CH.sub.3 73340 O CH.sub.3 CHO CH.sub.3 73341 O CH.sub.3 CH.sub.2 OH CH.sub.3 73342 O CH.sub.3 CO.sub.2 H CH.sub.3 73343 O H CH.sub.3 CH.sub.3 73344 O H H CH.sub.3 73345 O H CHO CH.sub.3 73346 O H CH.sub.2 OH CH.sub.3 73347 O H CO.sub.2 H CH.sub.3 73348 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 73349 OCH.sub.3 CH.sub.3 H CH.sub.3 73350 OCH.sub.3 CH.sub.3 CHO CH.sub.3 73351 OCH.sub. 3 CH.sub.3 CH.sub.2 OH CH.sub.3 73352 OCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 73353 OCH.sub.3 H CH.sub.3 CH.sub.3 73354 OCH.sub.3 H H CH.sub.3 73355 OCH.sub.3 H CHO CH.sub.3 73356 OCH.sub.3 H CH.sub.2 OH CH.sub.3 73357 OCH.sub.3 H CO.sub.2 H CH.sub.3 73358 OCOCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 73359 OCOCH.sub.3 CH.sub.3 H CH.sub.3 73360 OCOCH.sub.3 CH.sub.3 CHO CH.sub.3 73361 OCOCH.sub.3 CH.sub.3 CH.sub.2 OH CH.sub.3 73362 OCOCH.sub.3 CH.sub.3 CO.sub.2 H CH.sub.3 73363 OCOCH.sub.3 H CH.sub.3 CH.sub.3 73364 OCOCH.sub.3 H H CH.sub.3 73365 OCOCH.sub.3 H CHO CH.sub.3 73366 OCOCH.sub.3 H CH.sub.2 OH CH.sub.3 73367 OCOCH.sub.3 H CO.sub.2 H CH.sub.3 7__________________________________________________________________________ NOTE: When the Dring is piperidine or the Noxide thereof, the upper side chain (R) is not the ergosterol side chain.
SYNTHETIC EXAMPLES
The following examples describe synthetic procedures employed in production of specific compounds within the scope of the present invention. Unless otherwise indicated, all percentages in the following Examples and in the General Procedures set forth above are by weight and all temperatures are reported in degrees Celsius (.degree.C.). All parts for reaction and chromatography solvents were determined by volume. All proton NMR spectra are referenced to tetramethylsilane (TMS) at 0.00 ppm.
The following abbreviations are employed in the examples:
NMR: nuclear magnetic resonance spectroscopy
IR: infrared spectroscopy
MS: mass spectroscopy
HRMS: high resolution mass spectroscopy
EI: electron impact
CI: chemical ionization
EA: elemental analysis
m.p.: melting point
MPLC: medium pressure liquid chromatography
Rf: retention factor on silica gel thin layer chromatography
Particular intermediates or products are identified by reference to the numbered compounds in the general synthetic procedures summarized above. Physical data for various compounds produced by procedures substantially corresponding to the description contained in each example are provided following the individual examples.
EXAMPLE 1
Preparation of 15-Oxadihydrolanosterol (Compound 11a)
A. Preparation of 4,4-dimethyl-3b-[(4-methoxybenzyl)oxyl-5a-cholesta-8,14-diene (Compound 2b)
To a stirred solution of sodium hydride (50% in oil, 23.2 g, washed with 3 portions of 50 ml of dry tetrahydrofuran) in dry tetrahydrofuran (800 ml) and anhydrous N,N-dimethylformamide (200 ml) at 0.degree. was added 4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol (Compound 2a) (40 g, 96.8 mmole) and the mixture was 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)] was added and the mixture was stirred for 24 hr. at 70.degree. under nitrogen atmosphere. After cooling to 5.degree. water (80 ml) was added dropwise to the mixture and it was stirred for 5 min. It was poured into ether (1L) and the layers were separated and the organic phase was washed with water (3.times.300 ml).
The combined aqueous layers were extracted with additional diethyl ether (300 ml). The combined organic solutions were washed with brine, and dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford a crystalline solid residue.
Recrystallization from diethyl ether and methanol provided 42.5 g of purified Compound 2b. The mother liquor residue was column chromatographed on silica gel 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):
NMR (300 MHz, CDCl.sub.3); 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=11.4 Hz, 1H), 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, 24H), 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.sup.-1.
B. Preparation of 4,4-dimethyl-3b-[(4-methoxybenzyl)oxy]-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.degree. was added a solution of osmium tetroxide (8 g, 31.4 mmole) in methylene chloride (160 ml) dropwise over a period of 1 hr.
The dark brown mixture was stirred for 2 hr. at room temperature.
At the end of this period hydrogen sulfide (Union Carbide Corp., Linde Division, Danbury, Conn. 06817) was bubbled through the solution for about 20 min. and the black precipitates that formed were filtered off through Celite (Manville Products Corp. Denver, Colo.).
The filtrate was evaporated under reduced pressure to afford a brown solid residue (17.5 g) of the diol (Compound 3b). This material was routinely used for further transformations without purification.
An analytical sample of Compound 3b was obtained in the following manner:
A solution of the compound in benzene was filtered through a plug of silica gel (Kieselgel 60, EM Science, 111 Woodcrest Rd., Cherry Hill, NJ 08034-0395) with elution by 2:8 ethyl acetate - hexane and the solvents were evaporated under reduced pressure to give a white crystalline solid. This was recrystallized from ethyl acetate and hexane to give a chromatographically homogeneous sample of Compound 3b.
Physical Data (Compound 3b):
m.p.=124.degree.-126.5.degree. (decomposed); NMR (300 MHz, CDCl.sub.3): delta 7.28 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 1H), 4.66 (d, J=11.4 Hz, 1H), 4.37 (d, J=11.4 Hz, 1H), 2.45 (d, J=9.9 Hz, 1H), 2.35-0.80 (m, 26H), 1.02 (s, 3H), 0.97 (s, 3H), 0.86 (d, J=6.3 Hz, 6H), 0.86 (d, J=6.6 Hz, 3H), 0.85 (s, 3H), 0.69 (s, 3H); IR (KBr): 3406, 2949, 2869, 2841, 1615, 1514, 1465, 1376, 1360, 1346, 1245, 1117, 1031 cm-1; HRMS for C.sub.37 H.sub.56 O.sub.3 (M-H.sub.2 O): Calcd. 548.4229; found 548.4252.
C. Preparation of 4,4-Dimethyl-3b-[(4-methoxybenzyl)ozy]-15-oxo-5a-14,15-secocholest-8-en-14-one (Compound 4b)
To a stirred solution of the diol (Compound 3b) (30 mmole in dry benzene (880 ml, distilled from calcium hydride) in the dark was added lead tetraacetate (14 g, 31.5 mmole Aldrich, recrystallized 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 was filtered through Celite and the filter cake rinsed with benzene several times. Evaporation of the solvent under reduced pressure provided an oily residue (17.1 g) of crude keto-aldehyde (Compound 4b). The crude product was routinely used for further transformations without purification.
An analytical sample of Compound 4b was obtained by column chromatography on silica gel with elution by 1:9 ethyl acetate - hexane then 2:8 ethyl acetate - hexane.
Physical Data (Compound 4b):
NMR (300 MHz, CDCl.sub.3): 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=11.4 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, 24H), 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 (film): 2951, 2868, 2719, 1725, 1654, 1623, 1617, 1514, 1465, 1458, 1247, 1098, 1037, cm.sup.-1 ; HRMS for C.sub.36 H.sub.56 O.sub.4 (M+): Calcd. 564.4179; found 564.4209.
D. Preparation of 15,15-Dimethoxy-4,4-dimethyl-3b-[(4-methoxybenzyl)oxy]5a-14,15-secocoholest-8-en-14-one (Compound 5b)
To a solution of the keto-aldehyde (Compound 4b) (30 mmole) in methanol (600 ml) were added trimethyl orthoformate (Aldrich) (48 ml, 439 mmole) and camphorsulfonic acid (Aldrich) 3.2 g, 13.8 mmole) and the mixture was stirred at room temperature for 2 hr. under nitrogen atmosphere. At the end of the stirring saturated sodium bicarbonate solution (120 ml) was added and most of the methanol was evaporated under reduced pressure. The residue was extracted with diethyl ether (3.times.500 ml) and the combined extracts were washed with 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 was normally used for the next reaction. For analytical purposes, Compound 5b was column chromatographed on silica gel with elution by 2:8 ethyl acetate - hexane affording a purified sample of the Compound 5b.
Physical Data (Compound 5b):
NMR (300 MHz, CDCl.sub.3) delta 7.27 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.60 (d, J=11.4 Hz, 1H), 4.37 (d, J=11.4 Hz, 1H), 4.05 (t, J=6 Hz, 1H), 3.26 (s, 3H), 3.21 (s, 3H), 2.90 (dd, J=4 Hz, 12 Hz, 1H), 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, 2869, 1661, 1615, 1514, 1464, 1458, 1248, 1123, 1099, 1077 cm.sup.-1 ; HRMS for C.sub.37 H.sub.54 O.sub.3 : Calcd. 546.4073; found 546.4126.
E. Preparation of 15,15-Dimethoxy-3b-[(4-methoxybenzyl)oxy]-14,15-secolanost-8-en-14-ol (Compound 6b)
To a solution of the keto-acetal (Compound 5b) (30 mmole) in dry diethyl ether (600 ml) was added a solution of methyl magnesium bromide in diethyl ether (3 ml, Aldrich) 50 ml, 150 mmole) dropwise at 0.degree. and the mixture was stirred at 30.degree.-40.degree. for 2 hr. After cooling it to 0.degree., hydrochloric acid (0.5 ml, 400 mmole) was added slowly and it was stirred for about 1 min. The product was extracted with diethyl ether (3.times.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 without purification.
An analytical sample of the Compound 6b was obtained by column chromatography on silica gel with elution by 2:8 ethyl acetate - hexane.
Physical Data (Compound 6b):
NMR (300 MHz, CDCl.sub.3): delta 7.29 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 4.61 (d, J=11.4 Hz, 1H), 4.38 (d, J=11.4 Hz, 1H), 4.21 (dd, J=2.7 Hz, 9 Hz, 1H), 3.81 (s, 3H), 3.49 (s, 3H), 3.48 (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 Hz, 6H), 0.86 (s, 3H); HRMS for C.sub.38 H.sub.56 O.sub.2 (M-2CH.sub.3 OH-H.sub.2 O): Calcd. 544.4280; found 544.4258.
F. Preparation of 3b-[(4-Methoxybenzyl)oxy]-14a-oxa-D-homo-lanost-8-en-15-ol (Compound 7b)
A solution of the tricyclic alcohol (Compound 6b) (30 mmole) in methylene chloride (160 ml) and 80% aqueous acetic acid (600 ml) was stirred at room temperature for 2 days and the solvents were evaporated under reduced pressure to give an oily residue of the cyclic 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 followed by 3:7 ethyl 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, 2:8 ethyl acetate - hexane) as oils.
The compound 7c was dissolved in methylene chloride (55 ml) 80% aqueous acetic acid (160 ml) and 1M hydrochloric acid (1 ml) and the solution was stirred at room temperature for 1 day. It was worked 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% overall yield from Compound 3b).
Physical Data (Compound 7b):
NMR (300 MHz, CDCl.sub.3) delta 7.28 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 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), 3.80 (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); HRMS for C.sub.38 H.sub.56 O.sub.2 : Calcd. 544.4280; found 544.4197.
G. Preparation of 3b-[4-Methoxybenzyl)oxy]-14a-oxa-D-homo-lanosta-8,15-diene (Compound 8b)
To a stirred solution of the cyclic hemiacetal (Compound 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 from phosphorous pentoxide) at 0.degree. was added methanesulfonyl chloride (Aldrich) (5.43 ml, 69.6 mmole, filtered freshly through basic alumina) dropwise over a period of 5 min. and the mixture was stirred at 0.degree. to 20.degree. for 1 hr. under nitrogen atmosphere. The reaction mixture was poured into diethyl ether (1L) and the solution was washed with water, saturated sodium bicarbonate solution, water and brine. After drying over anhydrous magnesium sulfate the solvents were evaporated under the reduced pressure to give an oily residue of the glycal (Compound 8b). This crude material was normally used for next reaction without purification.
The analytical sample was prepared by column chromatography on silica gel with elution by 1:9 ethyl acetate - hexane to afford a purified sample of Compound 8b.
Physical Data (Compound 8b):
NMR (300 MHz, CDCl.sub.3): delta 7.28 (d, J=8 Hz, 2H), 6.88 (d, J=8 Hz, 2H), 6.21 (dd, J=2.5 Hz, 6 Hz, 1H), 4.61 (d, J=11.5 Hz, 1H), 4.52 (dd, J=1.2 Hz, 6.3 Hz, 1H), 4.38 (d, J=11.5 Hz, 1H), 3.81 (s, 3H), 2.94 (dd, J=4 Hz, 11 Hz, 1H), 2.30-0.90 (m, 22H), 1.23 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.87 (d, J=7 Hz, 6H), 0.87 (s, 3H), 0.85 (s, 3H); HRMS for C.sub.38 H.sub.56 O.sub.2 (M-H.sub.2 O): Calcd. 544.4280; found 544.4281.
H. Preparation of 3b-[4-Methoxybenzyl)oxy]-14a-oxa-D-homo-lanost-8-ene-15,16-diol (Compound 9b)
To a stirred solution of the glycal (Compound 8b) (23.2 mmole) and pyridine (18.8 ml, 232 mmole) in benzene (600 ml) at 0.degree. 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 was bubbled through the solution for about 15 min. and the resulting black precipitates were removed by filtration through Celite. The filter cake was rinsed with ethyl acetate several times and the filtrate was evaporated under reduced pressure to give a dark brown oily residue of the diol (Compound 9b) as a mixture of diastereomers.
Due to the complexity and instability of the product, analysis was carried out after the next transformation.
Physical Data (Compound 9b):
NMR (300 MHz, CDCl.sub.3): delta 7.29 (d, J=8 Hz, 2H), 6.88 (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), 3.56 (dd, J=8.5 Hz, 11.5 Hz, 1H), 3.45 (brs, 1H), 2.95 (dd, J=4 Hz, 11 Hz, 1H), 2.35-0.90 (m, 23H), 1.18 (s, 3H), 1.12 (d, J=6 Hz, 3H), 0.97 (s, 3H), 0.89 (s, 3H), 0.88 (d, J=6 Hz, 6H), 0.83 (s, 3H).
I. Preparation of 16-Methoxy-3b-[(4-methoxybenzyl)oxyl-15-oxa-lanost-8-ene (Compound 10b)
To a solution of the diol (Compound 9b) (23.2 mmole) in diethyl ether (550 ml), methanol (550 ml) and water (140 ml) were added sodium metaperiodate (Aldrich) (33 g, 154 mmole) and camphorsulfonic acid (7 g, 30 mmole) and the mixture was stirred at room temperature for 20 hrs. After addition of saturated sodium bicarbonate (350 ml) the mixture was extracted with diethyl ether (3.times.500 ml) and the combined organic layers were washed with brine. The aqueous layers were re-extracted with diethyl ether (300 ml) and the extract was washed with brine.
The combined extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a dark brown oily residue (13 g) of crude five-membered cyclic acetal (Compound 10b). Product of this purity was routinely used for next transformation without further purification.
The analytical sample of purified Compound 10b was obtained by a preparative thin layer chromatography on silica gel with elution by 1:9 ethyl acetate - hexane. Physical Data (Compound 10b):
NMR (300 MHz, CDCl.sub.3): delta 7.29 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 4.59 (d, J=11.6 Hz, 1H), 4.53 (d, J=5.7 Hz, 1H), 4.38 (d, J=11.6 Hz, 1H), 3.81 (s, 3H), 3.36 (s, 3H), 2.98 (dd, J=4.2 Hz, 11.5 Hz, 1H), 2.20-0.80 (m, 22H), 1.13 (s, 3H), 0.98(s, 3H), 0.95 (d, J=5.4 Hz, 3H), 0.95 (s, 3H), 0.88 (s, 3H), 0.87 (d, J=6.3 Hz, 6H), 0.83 (s, 3H); IR (film): 2945, 2869, 1514, 1459, 1375, 1347, 1171, 1108, 1094, 1038, 1011 cm.sup.-1 ; HRMS for C.sub.37 H.sub.56 O.sub.3 : Calcd. 548.4230; found 548.4203.
J. Preparation of 15-Oxa-dihydrolanosterol (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 trifluoride etherate (Aldrich) (2.7 ml, 22 mmole) dropwise and the mixture was stirred at room temperature for 3 hr. under nitrogen atmosphere. The reaction was quenched by addition of saturated sodium bicarbonate and the products were extracted with methylene chloride (3.times.400 ml). The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a dark brown oily residue. The oil was purified by column chromatography on silica gel with elution by 1:9 ethyl acetate - hexane followed by 2:8 ethyl acetate - hexane to provide 15-oxa-dihydrolanosterol (Compound 11a) (4.0 g, 40% overall yield from Compound 7b.
Physical Data (Compound 11a):
NMR (300 MHz, CDCl.sub.3): delta 3.76 (t, J=9 Hz, 1H), 3.44 (dd, J=8.4 Hz, 9 Hz, 1H), 3.25 (dd, J=4.8 Hz, 11.4 Hz, 1H), 2.25-0.80 (m, 23H), 1.11 (s, 3H), 1.02 (s, 3H), 0.95 (d J=6.3 Hz, 3H) 0.95 (s, 3H), 0.86 (d, J=6.6 Hz, 6H), 0.86 (s, 3H), 0.81 (s, 3H); IR (film): 3566, 2934, 1466, 1375, 1097, 1079, 1039, 1030 cm.sup.-1 ; HRMS for C.sub.29 H.sub.50 O.sub.2 (M+): Calcd. 430.3811; found 430.3772; for C.sub.28 H.sub.47 O.sub.2 (M-CH.sub.3) Calcd. 415.3576; found 415.3583.
EXAMPLE 2
Preparation of 4,4-Dimethyl-15-oxa-5a-cholest-8-en-3b-ol (Compound 17a)
K. Preparation of 15,15-Dimethoxy-4,4-dimethyl-3b-[4-methoxybenzyl)oxyl-5a-14,15-Secoholest-8-en-14-ol (Compound 12b)
To a stirred solution of the keto-aldehyde (Compound 5b) (2.7 g, 4.42 mmole) in a dry methylene chloride (60 ml) was added a solution of diisobutyl aluminum hydride in hexane (Aldrich) 1 M/L, 8.84 ml, 8.84 mmole) dropwise at 0.degree. and the mixture was stirred at 0.degree. for 1 hr. at room temperature for 1 hr. The excess reagent was destroyed by dropwise addition of methanol (0.64 ml) at 0.degree. and stirring for 10 min. Then water (1.1 ml) was added dropwise to the mixture and it was stirred at room temperature for 1 hr. The resulting precipitates were filtered off over Celite and the filtrate was evaporated under reduced pressure to give a white foamy residue of the secondary allylic alcohol (Compound 12b) as a mixture of diastereomers. The crude material was used in the next reaction without purification.
L. Preparation of 4,4-Dimethyl-3b-[(4-methoxybenzyl)oxy]-14a-oxa-D-homo-5a-cholest-8-en-15-ol (Compound 13b)
Following the method described for Compound 7b (Example 1-F) the secondary allylic alcohol (Compound 12b) (4.42 mmole) was 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 was 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 with elution by 15:85 ethyl acetate - hexane.
Physical Data (Compound 13b):
NMR (300 MHz, CDCl.sub.3) delta 7.28 (d, J=8.5 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), 3.80 (s, 3H), 2.92 (dd, J=4 Hz, 12 Hz, 1H), 2.20-0.90 (m, 26H), 0.99 (s, 6H), 0.97 (s, 3H), 0.93 (d, J=6.5 Hz, 3H), 0.88 (d, J=6.5 Hz, 6H), 0.86 (s, 3H); IR (film): 3413, 2952, 2930, 2870, 1654, 1636, 1465, 1457, 1376, 1365, 1087, 1065, 1036, 1013 cm.sup.-1.
M. Preparation of 4,4-Dimethyl-3b-[(4-methoxylbenzyl)oxy]-14a-oxa-D-homo-5a-cholest-8,15-diene (Compound 14b)
Following 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 without purification.
The analytical sample was 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-Dimethyl-3b-[(4-methoxybenzyl)oxy]-14a-oxa-D-homo-5a-cholest-8-ene-15,16-diol (Compound 15b)
Following the method described for Compound 9b (Example 1-H) the glycal (Compound 14b) (0.126 g, 0.23 mmole) was transformed to the diol (Compound 15b). The crude product was used for next reaction without purification.
O. Preparation of 4,4-Dimethyl-16-methoxy-3b-[(4-methoxybenzyl)oxy]-15-oxa-5a-cholest-8-ene (Compound 16b)
Following the method described for Compound 10b (Example 1-I) 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 without purification.
P. Preparation of 4,4-Dimethyl-15-oxa-5a-cholest-8-en-3b-ol (Compound 17a)
Following 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).
Physical Data (Compound 17a):
NMR (300 MHz, CDCl.sub.3); 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.sup.-1.
EXAMPLE 3
Preparation of 4,4-Dimethyl-15-oxa-14a-vinyl-5a-cholest-8-en-3b-ol (Compound 23a)
Q. Preparation of 15,15-Dimethoxy-4-4-dimethyl-3b-[(4-methoxybenzyl)oxy]-14-vinyl-5a-14,15-secocholest-8-en-14-ol (Compound 18b)
To a stirred solution of the keto-acetal (Compound 5b) (8.2 g, 13.4 mmole) in dry tetrahydrofuran (270 ml) was added dropwise a solution of vinyl magnesium bromide in THF (1.6 M/L, Aldrich) (82 ml, 131.2 mmole) at 0.degree. and the mixture was stirred at 70.degree. for 2 hr. under nitrogen atmosphere. After cooling to 0.degree. about 300 ml of 0.5M - hydrochloric acid was added to the solution and it was stirred for 0.5 min. The product was extracted with diethyl ether (3.times.300 ml) and the combined extracts were washed with water and brine. The ethereal solution was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the tricyclic alcohol (Compound 18b) as an oil. The crude product was routinely used for the next reaction without purification.
Physical Data (Compound 18b):
IR (film): 3450, 2952, 2870, 1514, 1466, 1247, 1121, 1099, 1078, 1053, 1043 cm.sup.-1.
R. Preparation of 4,4-Dimethyl-3b-[(4-methoxybenzyl)oxy]-14a-oxa-14a-vinyl-D-homo-5a-cholest-8-en-15-ol (Compound 19b)
A solution of the tricyclic alcohol (Compound 18b) (13.4 mmole) in methylene chloride (80 ml) and 80% aqueous acetic acid (300 ml) containing 1M hydrochloric acid (0.5 ml) was stirred at room temperature for 20 hrs. The acid and water were evaporated off under reduced pressure to give an oily residue of the cyclic hemiacetal (Compound 19b) and the cyclic acetal (Compound 19c).
The two products were 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 worked up and purified as described above to provide additional 2.31 g of Compound 19b (Total 5.81 g, 73% overall yield from Compound 18b).
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.28 (d, J=8.5 Hz, 2H), 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); HRMS for C.sub.39 H.sub.58 O.sub.3 (M-H.sub.2 O): Calcd. 574.4386; found 574.4316.
S. Preparation of 4,4-Dimethyl-3b-[(4-methoxybenzyl)oxy]-14a-oxa-14a-vinyl-D-homo-5a-cholesta-8,15-diene (Compound 20b)
By the method described for Compound 8b (Example 1-G) the cyclic hemiacetal (Compound 19b) (2.65 g, 4.46 mmole) 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 without purification. Analytical sample was obtained by filtering a concentrated solution of the crude product in diethyl ether through a short Florisil column with elution by diethyl ether.
T. Preparation of 4,4-Dimethyl-3b-[(4-methoxybenzyl)oxy]-14a-oxa-14a-vinyl-D-homo-5a-cholest-8-ene-15,16-diol (Compound 21b)
By the method described for Compound 9b (Example 1-H) the glycal (Compound 20b) (2.412 g, 4.19 mmole) was converted to the diol (Compound 21b) (2.31 g, 90.5% yield) as an oil. The crude product was routinely used for next reaction without purification.
U. Preparation of 4,4-Dimethyl-16-methoxy-3b-[(4-methoxybenzyl)oxy]-15-oxa-14a-vinyl-5a-cholest-8-ene (Compound 22b)
By the method described for Compound 10b (Example 1-I) the diol (Compound 21b) (2.31 g, 3.79 mmole) was transformed to five-membered cyclic acetal (Compound 22b) (2.125 g, 94.6% yield) as a foamy solid. The crude product was used for the next reaction without purification.
V. Preparation of 4,4-Dimethyl-15-oxa-14a-vinyl-5a-cholest-8-en-3b-ol (Compound 23a)
To a stirred solution of the five-membered cyclic acetal (Compound 22b) (1.17 g, 2.64 mmole) and triethylsilane (1.6 ml, 10 mmole) in dry methylene chloride (50 ml) at -30.degree. was added boron trifluoride etherate (0.2 ml, 1.63 mmole) dropwise and the mixture was stirred at -30.degree. to 20.degree. for 2 hr. The reaction was quenched by addition of saturated sodium bicarbonate (20 ml) and the products were extracted with diethyl ether (2.times.100 ml). The ether extracts were washed 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 with elution by 15:85 ethyl acetate-hexane to give the 15-oxa-sterol (Compound 23a) (0.71 g, 81% yield) as a foamy solid.
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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=8.7 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=67 Hz, 3H), 0.86 (d, J=6.3 Hz, 6H), 0.81 (s, 3H), 0.78 (s, 3H); IR (film): 2933, 2868, 1512, 1467, 1375, 1095, 1040, 1029, 1033 cm.sup.-1 ; HRMS for C.sub.30 H.sub.50 O.sub.2 (M+): Calcd. 442.3811; found 442.3806.
EXAMPLE 4
Preparation of 3b-Acetoxy-4,4-dimethyl-15-oxa-14a-vinyl-5a-cholest-8-ene (Compound 23c)
A solution of the 15-oxa-sterol (Compound 23a) (2g, 4.52 mmole) acetic anhydride (Fischer Scientific) (2 ml, 21.2 mmole) and dimethylaminopyridine (Aldrich) (0.1 g, 0.82 mmole) in anhydrous pyridine (Aldrich) (20 ml) was stirred at room temperature for 18 hr. under nitrogen atmosphere. After addition of methanol (5 ml) the mixture was evaporated under reduced pressure, and the residue was partitioned between water and diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give an oily residue. It was column chromatographed on silica gel with elution by 5:95 ethyl acetate - hexane followed by 1:9 ethyl acetate - hexane to afford the 14-vinyl-15-oxa-sterol acetate (Compound 23c) (1.78 g, 81% yield).
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 5.72 (dd, J=10.8 Hz, 15.9 Hz, 1H), 5.12 (dd, J=1.8 Hz, 1H), 5.00 (dd, J=1.8 Hz, 15.9 Hz, 1H) 4.52 (dd, J=4.8 Hz, 1H), 3.87 (t, J=8.7 Hz, 1H), 3.55 (t, J=8.7 Hz, 1H), 2.06 (s, 3H), 2.06-0.80 (m, 22H), 1.03 (s, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.89 (s, 3H), 0.88 (s, 3H), 0.87 (d, J=6 Hz, 6H), 0.78 (s, 3H).
EXAMPLE 5
Preparation of both Diasteroemers of 3b-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol (Compounds 24c and 25c)
To a solution of the 14-vinyl-15-oxa-sterol acetate (Compound 23c) (1.78 g, 3.67 mmole) was added osmium tetroxide (1 g, 3.94 mmole) and the resulting dark brown solution was stirred at room temperature for 2 days. At the end of the stirring hydrogen sulfide gas was bubbled through the solution and the black precipitates were removed by filtration over Celite. After washing the filter cake with ethyl acetate several times the filtrate and the washings were evaporated to give a black oily residue. It was purified by column chromatography on silica gel with 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.sup.-1 ; HRMS for C.sub.30 H.sub.49 O.sub.3 (M-CHOHCH.sub.2 OH): Calcd. 457.3681;; found 457.3640.
Physical Data (Compound 25c):
HRMS for C.sub.30 H.sub.49 O.sub.3 (M-CHOHCH.sub.2 OH): Calcd. 457.3681; found 457.3659.
EXAMPLE 6
Preparation of 3b-Acetoxy-15-oxa-32-oxolanost-8-ene (Compound 26c)
To a solution of the diol (Compound 24c) (492 mg, 0.95 mmole) in ethanol (34 ml) at 0.degree. was added a solution of sodium periodate (664 mg, 2.85 mmole) in 8.5 ml of water dropwise and the mixture was stirred at 0.degree. for 30 min. It was extracted with diethyl ether (150 ml) and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate the solvents were evaporated under reduced pressure to give an oily residue of the aldehyde (Compound 26c) (460 mg, ca. 100% yield).
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 9.56 (s, 1H), 4.47 (dd, J=4.5 Hz, 11.4 Hz, 1H), 3.98 (t, J=8.4 Hz, 1H), 3.66 (t, J=8.7 Hz, 1H), 2.15-0.90 (m, 22H), 2.02 (s, 3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.91 (d, J=6.3 Hz, 3H), 0.88 (s, 3H), 0.84 (brs, 9H), 0.82 (s, 3H); IR (film): 2949, 2871, 2798, 2689, 1733, 1471, 1466, 1457, 1374, 1366, 1246, 1027 cm.sup.-1.
EXAMPLE 7
Preparation of 15-Oxa 32-oxodihydrolanosterol (Compound 26a)
To a solution of the aldehyde-acetate (Compound 26c) (30 mg, 0.062 mmole) ethanol (0.7 ml) was added 3M potassium hydroxide (41 1, 0.124 mmole) and the mixture was stirred at room temperature for 20 hr. After addition of diethyl ether (15 ml) the organic solution was washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure afforded a foamy solid residue of chromatographically purified free hydroxy compound (Compound 26a) (27.5 mg, 100% yield).
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 9.59 (s, 1H), 4.03 (t, J=8.4 Hz, 1H), 3.70 (dd, J=8.1 Hz, 9.6 Hz, 1H), 3.26 (dd, J=4.5 Hz, 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), 0.86 (d, J=6.3 Hz, 6H), 0.81 (s, 3H); IR (film): 3446, 2946, 2933, 2870, 2691, 1731, 1468, 1383, 1378, 1365, 1064, 1042, 1027 cm.sup.-1 ; HRMS for C.sub.28 H.sub.47 O.sub.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.degree. was added sodium borohydride (Fischer Scientific) (10 mg, 0.26 mmole) and the mixture was stirred at the same temperature for 1 hr. The excess sodium borohydride was destroyed by adding several drops of saturated ammonium chloride solution and the product was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give the diol (Compound 27) (ca. 100% yield) as a white crystalline solid.
Physical Data:
HRMS for C.sub.28 H.sub.47 O.sub.2 (M-CH.sub.2 OH): Calcd. 415.3576; found 415.3562.
EXAMPLE 9
Preparation of both Diastereomers of 15-Oxa-32-vinyl-lanost-8-ene-3b,32-diol (Compounds 28 and 29)
To a stirred solution of the aldehyde (Compound 26c) (23 mg, 0.052 mmole) in dry tetrahydrofuran (1 ml) was added 1M vinyl magnesium bromide in tetrahydrofuran (0.52 ml, 0.52 mmole) dropwise and the mixture was stirred at 70.degree. for 0.5 hr. under nitrogen atmosphere. After cooling to 0.degree. about 2 ml of 0.5M hydrochloric acid was added slowly and the mixture was extracted with diethyl ether. The ether layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give an oily residue of Compounds 28 and 29 (1.4:1 ratio, determined by GC, ca. 100% yield).
EXAMPLE 10
Preparation of 3b-Hydroxy-15-oxa-lanost-8-en-32-aldoxime (Compound 30)
A solution of the aldehyde (Compound 26a) (17 mg, 0.038 mmole) and hydroxylamine hydrochloride (Aldrich) (20 mg, 0.29 mmole) in pyridine (0.5 ml) was stirred at 80.degree. for 7 hr. After addition of diethyl ether the solution was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to give an oily residue. The crude product was purified by preparative thin layer chromatography to obtain purified oxime (Compound 30) as a foamy solid (ca. 100% yield).
Physical Data:
NMR (300 MHz CDCl.sub.3): delta 3.93 (t J=8.1 Hz 1H) 3 62 (t J=8.1 Hz 1H) 3.26 (dd J=4.8 Hz, 11.4 Hz 1H) 2.10-0.70 (m 25H) 1.01 (s 22/33H), 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.sup.-1.
EXAMPLE 11
Preparation of 14a-Oxa-D-homodihydrolanosterol (Compound 31)
W. Preparation of 4-Dimethyl-5a-cholest-8-ene-3b-,14a,15a-triol (Compound 3a)
By the method described for Compound 3b (Example 1-B) the 8,14-diene (Compound 2a) (4.64 g, 11.24 mmole) was transformed to triol (Compound 3a). The crude product was filtered through a plug of silica gel with elution by 4:6 ethyl acetate-hexane followed by 7:3 ethyl 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.degree.-134.degree. (dec.)
Physical Data:
NMR NMR (300 MHz, CDCl.sub.3 -D.sub.20 (5%)): delta 4.11 (dd, J=5 Hz, 9 Hz, 1 Hz), 3.22 (dd, J=5 Hz, 11 Hz, 1H), 2.33 (m, 1H), 2.26 (brm, 1H), 2.09 (brm, 2H), 2.00-1.05 (m, 20H), 1.01 (d, J=3 Hz, 6H), 0.87 (s, 3H), 0.86 (d, J=8 Hz, 3H), 0.85 (s, 3H), 0.82 (s, 3H), 0.69 (s, 3H); IR (film): 3422 (bs, OH), 2950 (s), 1652 (s), 1465 (m), 1036 (m) cm.sup.-1 ; EA for C.sub.29 H.sub.50 O.sub.3 : Calcd. C 77.97%, H 11.28%; found C 78.05%, H 11.19%.
X. Preparation of 4,4-Dimethyl-3b-hydroxy-15-oxo-5a-14,15-Secocholest-8 -en-14-on (Compound 4a)
By the method 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 without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 3.93 (t, J=8.1 Hz, 1H), 3.63 (t, J=8.1 Hz, 1H), 3.26 (dd, J=4.8 Hz, 11.4 Hz, 1H), 2.10-0.70 (m, 25H), 1.01 (s, 3H), 0.98 (s, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.89 (s, 3H), 0.88 (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.sup.-1.
Y. Preparation of 15,15-Dimethoxy-4,4-dimethyl-3b-hydroxy-15-oxo-5a-14,15-secocholest-8-en-14-one (Compound 5a)
By the method described for Compound 5b (Example 1d) the keto-aldehyde (Compound 4a) (0.97 g, 2.18 mmole) was transformed to keto-acetal (Compound 5a) (1.09 g, ca. 100% yield) as a foamy solid. The crude product was normally used for the next reaction without purification. An analytical sample of Compound 5a was obtained by column chromatography on silica gel by elution with 3:7 ethyl acetate - hexane.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 4.06 (t, J=5.8 Hz, 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 (film): 3490, 2952, 2870, 1659, 1622, 1642, 1434, 1373, 1123, 1076, 1061 cm.sup.-1 ; HRMS for C.sub.29 H.sub.46 O.sub.2 (M-2CH.sub.3 OH): Calcd. 426.2498; found 426.3415.
Z. Preparation of 15,15-Dimethoxy-14,15-Secolanost-8-ene-3b,14-diol (Compound 6a)
By the method described for Compound 6b (Example 1-E) the keto-acetal (Compound 5a) (200 mg, 0.41 mmole) was transformed to tricyclic alcohol (Compound 6a) (210 mg, ca. 100% yield) as an oil. The crude material was routinely used for next reaction without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3) delta 4.05 (t, J=6 Hz, 1H), 3.27-3.20 (m, 1H), 3.26 (s, 3H), 3.22 (s, 3H), 2.61 (dd, J=5.1 Hz, 17.7 Hz, 1H), 2.50-0.80 (m, 25H), 1.07 (s, 3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.95 (s, 3H), 0.86 (d, J=6.6 Hz, 6H), 0.85 (s, 3H), 0.84 (s, 3H).
AA. Preparation of 14a-Oxa-D-homo-lanost-8-ene-3b,15-diol (Compound 7a)
A solution of the tricyclic alcohol (Compound 6a) (0.41 mmole) in methylene chloride (2 ml) and 80% aqueous acetic acid (10 ml) was stirred at room temperature for 1.5 hr. and the solvents were evaporated off under reduced pressure to give an oily residue. The residue was dissolved in diethyl ether (20 ml) and washed with saturated sodium bicarbonate and brine.
After drying over anhydrous sodium sulfate the ether solution was evaporated under reduced pressure to give an oily residue that was column chromatographed on silica gel. Elution with 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-Oxa-D-homo dihydrolanosterol (Compound 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.degree. were added triethylsilane (35L, 0.22 mmole) and 2 drops of boron trifluoride etherate and the mixture was stirred at -30.degree. to 8.degree. for 45 min. under nitrogen atmosphere. After addition of saturated sodium bicarbonate (3 ml) the reaction mixture was extracted with diethyl ether (2.times.15 ml). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give an oily residue of Compound 312 (30 mg, 92.4%) yield). It was purified by MPLC on silica gel with elution by 1L (ethyl acetate - hexane to give a purified sample as a white foamy solid.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 3.67 (dd, J=2.7 Hz, 1H), 3.31-3.25 (m, 2H), 2.37 (dd, J=5.5 Hz, 18 Hz, 1H), 2.20-0.909 (m, 24H), 1.12 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.94 (d, J=7.2 Hz, 3H), 0.92 (s, 3H), 0.88 (d, J=6.6 Hz, 6H), 0.83 (s, 3H); HRMS for C.sub.3 OH.sub.52 O.sub.2 (M+), Calcd. 444.3967, found 444.3942; for C.sub.29 H.sub.49 O.sub.2 (M-CH.sub.3), Calcd. 429.3733, found 429.3717.
EXAMPLE 12
Preparation of 4,4-dimethyl-14a-Oxa-D-homo-5a-cholest-8-en-3b-ol (Compound 32)
AC Preparation of 15,15-Dimethyl-4,4-dimethyl-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 without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 5.30 (s, 1H), 4.41 (dd, J=3 Hz, 9 Hz, 1H), 3.91 (d, J=4.2 Hz, 1H), 3.45 (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, 3H), 0.87 (d, J=6.6 Hz, 6H), 0.81 (s, 3H), 0.61 (s, 3H); HRMS for C.sub.30 H.sub.52 O.sub.3 (M-CH.sub.3 OH): Calcd. 460.3916; found 460.3891.
AD. Preparation of 4,4-Dimethyl-14a-oxa-D-homo-5a-cholest-8-ene-3b,15-diol (Compound 13a)
By the method described for Compound 7a (Example 11-AA) with exception of reaction time (4 hr.) the secondary alcohol (Compound 12a) (0.25 mmole) was transformed to the six-membered cyclic hemiacetal (Compound 13a) (70 mg, 62.7% overall yield from Compound 5a) as an oil.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 5.30 (s, 1H), 4.72 (dd, J=3.3 Hz, 8.7 Hz, 1H), 3.79 (brs, 1H), 3.25 (dd, J=4.5 Hz, 11.1 Hz, 1H), 2.20-0.080 (m, 25H), 1.01 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.93 (d, J-6.9 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H), 0.81 (s, 3H);
AE. Preparation of 4,4-Dimethyl-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.degree. was added a drop of boron trifluoride etherate and the mixture was stirred at -15.degree. to -10.degree. for 15 min. After addition of saturated sodium bicarbonate it was extracted with diethyl ether. The ether extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to give an oily residue of Compound 32. It was purified by preparative thin layer chromatography on silica gel plate with elution by 3:7 ethyl acetate - hexane to afford 12 mg of purified sample (39.2% yield) as a white foamy solid.
EXAMPLE 13
Preparation of 4,4-Dimethyl-14a-oxa-14-a oxa-14a-vinyl-D-homo-5a-cholest-8-en-3b-ol (Compound 33)
AF. Preparation of 15,15-Dimethoxy-4,4-dimethyl-14-vinyl-5a-14,15-secocholest-8-ene-3b,14-diol (Compound 18a)
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 without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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.sup.-1.
AG. Preparation of 4,4-Dimethyl-14a-oxa-14a-vinyl-d-homo-5a-cholest-8-ene-3b,15-diol (Compound 19a)
By the method described for Compound 7a (Example 11-AA) the allylic alcohol (Compound 18a) (0.47 mmole) was transformed to six-membered cyclic hemiacetal (Compound 19a) (140 mg, 63% overall yield from Compound 5a).
AH. Preparation of 4,4-Dimethyl-14a-oxa-14a-vinyl-D-homo-5a-cholest-8-en-3b-ol (Compound 33)
By the method described for Compound 31 (Example 11-AB) the cyclic hemiacetal (Compound 19a) (73.8 mg. 0.16 mmole) was transformed to compound 33 (70 mg, 95.8% yield). Purified sample of Compound 33 as a white foamy solid was obtained by column chromatography on silica gel with elution by 1:9 ethyl acetate - hexane.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 5.71 (dd, J=10.8 Hz, 17.4 Hz, 1H), 5.07 (dd, J=1.5 Hz, 10.8 Hz, 1H), 4.96 (dd, J=1.5 Hz, 17.4 Hz, 1H), 3.74 (dd, J=3.3 Hz, 10.5 Hz, 1H), 3.34 (t, J=11.1 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, 1096, 1040, 1027, 1003, 922, 736 cm.sup.-1 ; HRMS for C.sub.31 H.sub.52 O.sub.2 (M+): Calcd. 456.3968; found 456.3955.
EXAMPLE 14
Preparation of both Diastereomers of 32-hydroxy-14a-oxa-lanost-8-ene-3b,32-diol (Compounds 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 osmium tetroxide in methylene chloride (3.4 ml, 0.66 mmole) and the mixture was stirred at room temperature for 7 days. At the end of that period, hydrogen sulfide gas was bubbled through the solution for about 5 min. and the resulting black precipitates were removed by filtration over Celite.
The filter cake was rinsed with ethyl acetate several times and the filtrate and washings were evaporated to give a black oily residue. It was column chromatographed on silica gel with 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-dihydrolanosterol (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) was added a solution of sodium periodate (118 mg, 0.55 mmole) in water (1 ml) dropwise over a 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 was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to give an oily residue. It was 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, CDCl.sub.3) delta 9.51 (s, 1H), 3.91 (dd, J=4.5H, 11.1 Hz, 1H), 3.35 (t, J-11.4 Hz, 1H), 3.27 (dd, J=4.5 Hz, 11.4 Hz, 1H), 2.04-0.80 (m, 25H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (d, J=6.9 Hz, 3H), 0.92 (s, 3H), 0.86 (d, J=6.6 Hz, 6H), 0.81 (s, 3H); IR (film): 3481, 2951, 2868, 2725, 1734, 1466, 1459, 1378, 1365, 1098, 1043, 1027, 1004, 733 cm.sup.-1.
EXAMPLE 16
Preparation of 14a-Methyl-15-oxa-5a-cholest-8-en-3b-ol (Compound 47)
AI. Preparation of 3b-[(4-Methoxybenzyl)oxy]5a-cholesta-8,14-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) was transformed to p-methoxybenzyl ether (Compound 38b) as white crystals (17.4 g, 71.2% yield), m.p.=109.degree.-110.degree. C.
Physical Data:
NMR (300 MHz, CDCl.sub.3) delta 7.28 (d, 8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.36 (m, 1H), 4.52 (d, J=11 Hz, 1H), 4.47 (d, J=11 Hz, 1H), 3.80 (s, 3H), 3.35 (m, 1H), 2.40-0.80 (m, 26H), 0.99 (s, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.5 Hz, 6H), 0.81 (s, 3H); IR (KBr): 3932, 2868, 2835, 1613, 1513, 1465, 1457, 1243, 1086, 1071, 1041 cm.sup.-1.
AJ. Preparation of 3b-[(4-Methoxybenzyl)oxyl]-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 mmole) was transformed to the corresponding diol (Compound 39). The crude white solid product was normally used for next reaction without purification.
Physical Data:
NMR (300 MHz, C.sub.6 D.sub.6); 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, 1587, 1514, 1457, 1374, 1302, 1247, 1171, 1109, 1083, 1035 cm.sup.-1 ; HRMS (EI) for C.sub.35 H.sub.52 O.sub.3 (M-H.sub.2 O), Calcd. 520.3917; found 520.3895.
AK. Preparation of 3b-[(4-Methoxybenzyl)oxy]-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) was transformed to the corresponding keto-aldehyde (Compound 40).
The crude oily product was used for next reaction without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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=11.7 Hz, 1H), 4.47 (d, J=11.7 Hz, 1H), 3.80 (s, 3H), 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 cm.sup.-1 ; HRMS for C.sub.34 H.sub.50 O.sub.3 (M-CH.sub.2 O): Calcd. 506.3760; found 506.3763.
AL. Preparation of 15,15-Dimethoxy-3b-[(4-methoxybenzyl)oxy]5a-14,15-secocholest-8-en-14-one (Compound 41)
By 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 without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.26 (d, J-8.4 Hz, 2H), 6.87 (d, J=-8.4 Hz, 2H), 4.51 (d, J=11.4 Hz, 1H), 4.47 (d, J=11.4 Hz, 1H), 4.07 (t, J=6 Hz, 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 (film): 2934, 2867, 1661, 1654, 1617, 1513, 1465, 1438, 1248, 1078, 1058, 1039 cm.sup.-1 ; HRMS (EI) for C.sub.36 H.sub.54 O.sub.4 (M+--CH.sub.3 OH), Calcd. 550.4022, found 550.4021.
AM. Preparation of 15,15-Dimethoxy-3b-[(4-methoxybenzyl)oxy]-14-methyl-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 41) (7.5 mmole) was transformed to the corresponding tricyclic alcohol (Compound 42). The crude oily product was used for next reaction without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.27 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 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, 1H), 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.sup.-1 ; HRMS (EI) for C.sub.36 H.sub.54 O.sub.3 (M+2CH3OH), Calcd. 534.4073, found 534.4071.
AN. Preparation of 3b-[(4-Methoxybenzyl)oxy]-14a-methyl-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 cyclic acetal (Compound 43b). The oily residue of the mixture was column chromatographed on silica gel with elution by 15:85 ethyl acetate - hexane followed by 3:7 ethyl 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 was subjected to the reaction condition and stirred at room temperature for 4 days. It was worked up and purified as described above to provide additional 0.47 g of the compound 43a (Total 2.07 g, 50% overall yield from Compound 38b) and 0.6 g of the Compound 43b (14.1% overall yield from Compound 38b).
Physical Data:
NMR (300 MHz, CDCl.sub.3) delta 7.27 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H), 4.53 (brs, 1H), 4.49 (brs, 1H), 3.80 (s, 3H), 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 C.sub.36 H.sub.54 O.sub.3 (M-H.sub.2 O): Calcd. 534.4073; found 534.4114.
AO. Preparation of 3b-[(4-Methoxybenzyl)oxy]-14a-methyl-14a-oxa-D-homo-5a-cholesta-8,15-diene (Compound 44)
By the method described for the glycal (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 without purification.
Physical Data:
IR (film): 2950, 2931, 2866, 1660, 1514, 1467, 1248, 1171, 1093, 1072, 1039 cm.sup.-1.
AP. Preparation of 3b-[(4-Methoxybenzyl)oxy]-14a-methyl-14a-oxa-D-homo-5a-cholest-8-ene-15,16-diol (Compound 45)
By the method described for the diol (Compound 9b) (Example 1-H) the glycal (Compound 44) (3.74 mmole) was transformed to the corresponding diol (Compound 45). The crude black oily product was used for next reaction without purification.
AQ. Preparation of 16-Methoxy-3b-[(4-methoxybenzyl)oxy]-14a-methyl-15-oxa-5a-cholest-8-ene (Compound 46)
By the method described for the 5-membered cyclic acetal (Compound 10b) the diol (Compound 45) (3.784 mmole) was transformed to the corresponding 5-membered cyclic acetal (Compound 46). The crude oily product was used for next reaction without purification. Analytical sample of purified Compound 46 was obtained by a preparative thin layer chromatography on silica gel with elution by 1:9 ethyl acetate - hexane.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.27 (d, J=8.5 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), 0.88 (s, 3H), 0.86 (d, J=6.6 Hz, 6H); IR (film): 3923, 3865, 1613, 1514, 1466, 1374, 1248, 1171, 1093, 1071, 1038, 1011 cm.sup.-1 ; HRMS (EI) for C.sub.35 H.sub.52 O.sub.3 (M-CH.sub.3 OH): Calcd. 520.3916; found 520.3880.
AR. Preparation of 14a-Methyl-15-oxa-5a-cholest-8-en-3b-ol (Compound 47)
By the method described for 15-oxa-dihydrolanosterol (Compound 11a) (Example 1-J) the cyclic acetal (Compound 46) (3.74 mmole) was transformed to 15-oxasterol (Compound 47). The crude product was 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).
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 3.75 (t, J=8.4 Hz, 1H), 3.62 (m, 1H), 3.44 (t, J=8.7 Hz, 1H), 2.30 (s, 1H), 2.10-1.00 (m, 24H), 1.12 (s, 3H), 0.95 (d, J=6.3 Hz, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.86 (d, J=6 Hz, 6H); IR (KBr): 3389, 2929, 2861, 1467, 1457, 1375, 1037 cm.sup.-1 ; HRMS (EI) for C.sub.26 H.sub.46 O.sub.2 (M+), Calcd. 402.3498, found 4092.3524.
EXAMPLE 18
Preparation of 4,4-Dimethyl-15-thia-5a-cholest-8-en-3b-ol (Compound 49)
Hydrogen sulfide gas was bubbled through a solution of 4,4-dimethyl-16-methoxy-3b-[(4-methoxybenzyl)oxy]-15-oxa-5a-cholest-8-ene (Compound 16b) (1.426 mmole, crude material, prepared by procedures M, N, and O from Compound 13b (0.81 g, 1.426 mmole) in 40 ml of dry methylene chloride at 0.degree. for 120 min. Boron trifluoride etherate (2.5 ml) was added to the mixture and it was stirred at 0.degree. for 0.5 hr. and at room temperature for 1.5 hr. under nitrogen atmosphere. At the end of the stirring it was cooled to -30.degree. and triethylsilane (2.2 ml, 13.8 mmole) was added dropwise to the solution. The mixture was stirred at room temperature for 1.5 hr. under nitrogen atmosphere and saturated aqueous sodium bicarbonate solution (50 ml) was added to quench the reaction. It was extracted with diethyl ether twice and the combined extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a dark brown oily residue. It was purified by column chromatography on silica gel with elution by 15:85 ethyl acetate-hexane to afford purified Compound 49 (158 mg, 26% overall yield from Compound 13b).
Rf: 0.24, 2:8 ethyl acetate - hexane.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 3.24 (dd, J=4.5 Hz, 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, 1H), 2.11-2.03 (m, 2H), 1.90-0.80 (m, 20H), 1.30 (s, 3H), 1.01 (s, 3H), 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 cm.sup.-1.
EXAMPLE 19
Preparation of 15-thia-dihydrolanosterol (Compound 50)
By the method described for 15-thiasterol (Compound 49) (Example 18) five-membered cyclic acetal (Compound 10b) (198 mg, 0.34 mmole) was transformed to 15-thia-dihydrolanosterol (Compound 50) (65.4 mg, 43% overall yield from Compound 7b).
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 3.24 (dd, J=4.8 Hz, 11 Hz, 3H), 3.23 (s, 1H), 2.85 (t, J=10.2 Hz, 1H), 2.77 (dd, J=7.2 Hz, 10.2 Hz, 1H), 2.20-0.80 (m, 23H), 0.99 (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.sup.-1.
EXAMPLE 20
Preparation of 4,4-Dimethyl-15-thia-14a-vinyl-5a-cholest-8-en-3b-ol (Compound 51)
By the method described 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, CDCl.sub.3): 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, 3H), 0.87 (d, J=6.6 Hz, 6H), 0.81 (s, 3H), 0.80 (s, 3H); IR (film): 3394, 2949, 2867, 1473, 1465, 1457, 1376, 1365, 1093, 1030, 1004, 918 cm.sup.-1.
EXAMPLE 21
Preparation of sulfoxide (Compound 53)
To a stirred solution of 15-thia-dihydrolanosterol (Compound 50) (20 mg, 0.045 mmole) in ethanol (3 ml) was added a solution of sodium periodate (38 mg, 0.18 mmole) in water (1 ml) and the mixture was 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 was evaporated under reduced pressure to give an oily residue. It was purified by preparative thin layer chromatography on silica gel with elution by 5:95 methanol - methylene chloride to give 14 mg of purified sulfoxide (Compound 53) (67% yield).
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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, 3H), 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.sup.-1.
EXAMPLE 22
Preparation of 4,4-Dimethyl-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.degree. was bubbled hydrogen sulfide to saturate the solution and boron trifluoride etherate (0.9 ml, 7.3 mmole) was added dropwise.
After stirring at room temperature for 1.5 hr. it was cooled to 0.degree. and triethylsilane (1.4 ml, 8.76 mmole) was added. It was stirred at the same temperature for 2.5 hr. and saturated sodium carbonate (ca. 20 ml) was added to quench the reaction. The mixture was extracted with diethyl ether (2.times.30 ml) and the combined extracts were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a foamy solid residue. It was purified by column chromatography on silica gel with elution by 15:85 ethyl acetate-hexane to afford purified Compound 56 (172 mg, 59.2% yield) as a white foamy solid.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 3.27 (dd, J=4.8 Hz, 11.4 Hz, 1H), 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, 3H), 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.sup.-1.
EXAMPLE 23
Preparation of 14a-thia-D-homo-dihydrolanosterol (Compound 57)
By the method described for Compound 56 (Example 22) the cyclic acetal (Compound 7d) (300 mg, 0.63 mmole) was transformed to six-membered cyclic sulfide (Compound 57) (129 mg, 44.3% yield) as a white foamy solid.
Physical Data:
NMR (300 MHz, CDCl.sub.3) delta 3.26 (dd, J=4.8 Hz, 11.1 Hz, 1H), 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), 0.81 (s, 3H).
EXAMPLE 24
Preparation of 14-Aza-4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol (Compound 66a)
AS. Preparation of 4,4-dimethyl-3b-[(4-methoxybenzyl)oxy]-14-oxo-5a-14,15-secocholest-8-ene-15-carboxylic acid (Compound 63)
To a stirred solution of the enone aldehyde (Compound 4b) [15 mmole, crude material, prepared from Compound 2b (8 g, 15 mmole)] in tert-butanol (340 ml) and water (85 ml) were added sodium chlorite (Aldrich) (2.91 g, 30 mmole) and the mixture was stirred at room temperature for 1 hr. At the end of the stirring was added methylene chloride (500 ml) to the mixture and it was washed with water (2.times.150 ml). The combined aqueous layers were re-extracted with methylene chloride (200 ml) and washed with water once.
The methylene chloride extracts were 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 was routinely used for next transformation without purification. The analytical sample was obtained by recrystallization from ethyl acetate and hexane, m.p.=126.degree.-126.5.degree. C.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.29 (d, J=8.4 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, 1H), 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), 0.87 (s, 3H), 0.86 (d, J=6.9 Hz, 6H); IR (film): 3435, 2951, 2937, 2869, 1707, 1654, 1624, 1616, 1513, 1465, 1301, 1247, 1098 cm.sup.-1 ; HRMS for C .sub.37 H.sub.54 O.sub.4 (M-H.sub.2 O); Calcd. 562.4022, found 562.4054.
AT. Preparation of 4,4-dimethyl-3b-[(4-methoxybenzyl)oxy]-14-oxo-5a-14.15-secocholest-8-ene-15carboxylic 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.degree. was added isobutyl chloroformate (2.92 ml, 22.5 mmole) dropwise over a period of 5 min. and the mixture was stirred at 0.degree. 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 two phase mixture was stirred at 0.degree. for 1.5 hrs. The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride (2.times.50 ml). The combined extracts were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give an oily residue of the crude acyl azide (Compound 64) (9.1 g, quantitative mass recovery). The crude product was normally used for next reaction without purification.
Physical Data:
IR (film): 3522, 2952, 2938, 2869, 2315, 1720, 1657, 1623, 1615, 1514, 1464, 1248, 1172, 1096 cm.sup.-1.
AU. Preparation of 15-Aza-4.4-dimethyl-3b-[(4-methoxybenzyl)oxy]-15-methoxycarbonyl-5a-14,15-secocholest-8-en-14-one (Compound 65)
A solution of the acyl azide (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 were evaporated off.
The oily residue of the crude carbamate (Compound 65) was normally used for next reaction without purification. Analytical sample of purified Compound 65 was obtained by crystallization from diethyl ether and hexane, m p.=144.degree.-144.5.degree..
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.27 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 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, 3H), 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, 3H), 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.sup.-1 ; HRMS for C.sub.38 H.sub.59 NO.sub.5 (M+): Calcd. 609.4393; found 609.4404.
AV. Preparation of 15-Aza-4,4-dimethyl-3b-[(4-methoxybenzyl)oxy]-5a-cholest-8-,14-diene (Compound 66b)
To a solution of the carbamate (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) was added and the organic layer was washed with water and brine. The combined aqueous layers were re-extracted with diethyl ether and the extracts were washed with brine. The ether extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a solid residue. It was purified by column chromatography on silica gel with elution by 2:8 ethyl acetate - hexane to give 4.5 g of purified cyclic imine (Compound 66b) as white solid (72.7% overall yield from Compound 2b). It was crystallized from methylene chloride and hexane to afford 3.6 g of crystalline product, m.p.=159.degree.-160.degree..
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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), 2.40-0.78 (m, 22H), 1.09 (s, 3H), 1.01 (s, 3H), 0.91 (d, J=5.1 Hz, 3H), 0.88 (s, 3H), 0.87 (d, J=5.7 Hz, 6H), 0.86 (s, 3H); IR (KBr): 2942, 2871, 2848, 1625, 1614, 1600, 1513, 1470, 1456, 1249, 1114, 1100, m 1037, 819 cm.sup.-1 ; HRMS for C.sub.36 H.sub.55 NO.sub.2 (M+): Calcd. 533.4232; found 533.4218.
AW. Preparation of 14-Aza-4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol (Compound 66a)
To a stirred solution of Compound 66b (300 mg, 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) portionwise and the mixture was stirred at room temperature for 16 hr. under nitrogen atmosphere. Saturated sodium bicarbonate solution was added slowly to make the solution basic and the product was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give a solid residue. It was purified by column chromatography on silica gel with elution by 3:7 ethyl acetate-hexane followed by 7:3 ethyl acetate - hexane, to afford 217 mg of purified Compound 66a (93.3% yield).
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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, 1H), 2.30 (dm J=7.5 Hz, 1H), 2.10-0.90 (m, 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.sup.-1 ; HRMS for C.sub.28 H.sub.47 NO (M+): Calcd. 413.3658; found 413.3646.
EXAMPLE 25
Preparation of 14-Aza-5a-cholesta-8,14-dien-3b-ol (Compound 70a)
AX. Preparation of 3b-[(4-Methoxybenzyl)oxy]-14-oxo-5a-14,15-secocholest-8-ene-15-carboxylic acid (Compound 67)
By the method described for carboxylic acid (Compound 63) (Example 24-AS) 3b-[(4-Methoxyl-benzyl) oxy]-15-oxo-5a-14, 15-secocholest-8-ene-14-one (Compound 40) (7.5 mmole, crude material, prepared from Compound 38b) (3.8 g, 7.5 mmole)) was transformed to carboxylic acid (Compound 67) (4.08 g, foamy solid residue) The crude material was used for next transformation without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.27 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H), 4.53 (d, J=11 Hz, 1H), 4.47 (d, J=11 Hz, 1H), 3.80 (s, 3H), 3.39 (m, 1H), 2.43-0.90 (m, 27H), 1.01 (s, 3H), 0.98 (s, 3H), 0.95 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H)); IR (film): 3150, 2935, 2867, 1706, 1657, 1614, 1514, 1466, 1459, 1377, 1302, 1249, 1172, 1036 cm.sup.-1 ; HRMS for C.sub.27 H.sub.43 O.sub.4 (M-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2): Calcd. 431.3161; found 431.3224.
AY. Preparation of 3b-[(4-Methoxybenzyl)oxy]-14-oxo-5a-14,15-secocholest-8-ene-15-carboxylic acid azide (Compound 68)
By the method described for acyl azide (Compound 64) (Example 24-AT) carboxylic acid (Compound 67) (7.5 mmole) was transformed to acyl azide (Compound 68) as an oil. The crude material was used for next transformation without purification.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.27 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.52 (d, J=11.7 Hz, 1H), 4.47 (d, J=11.7 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 (film): 2953, 2935, 2868, 2135, 1720, 1658, 1620, 1614, 1513, 1467, 1377, 1248, 1180, 1172, 1087 cm.sup.-1.
AZ. Preparation of 15-Aza-3b-[(4-methoxybenzyl)oxy]-15-methoxycarbonyl-5a-14,15-secocholest-8-en-14-one (Compound 69)
By the method described for carbamate (Compound 65) (Example 24-AU) acyl azide (Compound 68) (7.5 mmole) was transformed to carbamate (Compound 69) as an oil. The crude product was used for next reaction without purification. The analytical sample of purified Compound 69 was obtained by crystallization from diethyl ether and hexane.
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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 (m, 1H), 2.50-0.90 (m, 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.sup.-1 ; HRMS for C.sub.34 H.sub.50 O.sub.3 (M-NH.sub.2 CO.sub.2 CH.sub.3): Calcd. 506.3760; found 506.3769.
BA. Preparation of 14-Aza-3b-[(4-Methoxybenzyl)oxy]-5a-cholest-8,14-diene (Compound 50b)
By the method described for cyclic imine (Compound 66b) (Example 24-AV) carbamate (Compound 69) (7.5 mmole) was transformed to cyclic imine (Compound 70b). The solid residue was purified by column chromatography on silica gel with elution by 3:7 ethyl acetate-hexane to afford 2.33 g of purified Compound 70b as solid (61.4% overall yield from Compound 38b). It was crystallized from methylene chloride and hexane to give analytically purified sample.
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 7.27 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.52 (d, J=11.4 Hz, 1H), 4.47 (d, J=11.4 Hz, 1H), 3.94 (dd, J=6.9 Hz, 15.3 Hz, 1H), 3.80 (s, 3H), 3.35 (s, 3H), 3.35 (m, 2H), 2.40-0.80 (m, 24H), 1.04 (s, 3H), 1.04 (s, 3H), 0.91 (d, J=6 Hz, 3H), 0.87 (s, 3H), 0.87 (d, J=6.3 Hz, 6H); IR (film): 3921, 2869, 2852, 1620, 1614, 1598, 1515, 1466, 1454, 1369, 1301, 1249, 1104, 1092, 1078, 1032, 820 cm.sup.-1 ; HRMS for C.sub.34 H.sub.51 NOI.sub.2 (M+): Calcd. 505.3920; found 505.3961.
BB. Preparation of 14-Aza-5a-cholesta- 8,14-dien-3b-ol (Compound 70a)
By the method described for azasterol (Compound 66a) (Example 24-AW) cyclic imine (Compound 70b) (1 g, 1.98 mmole) was transformed to azasterol (Compound 70a) as a solid. It was purified by column chromatography on silica gel with elution by 3:& ethyl acetate - hexane followed by 8:2 ethyl acetate - hexane to obtain 207 mg of unreacted starting material (Compound 70b) 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, m.p.=178.degree.-179.degree..
Physical Data:
NMR (300 MHz, CDCl.sub.3): 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), 2.45-0.80 (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, 2858, 1620, 1597, 1467, 1453, 1371, 1056, 1025 cm.sup.-1 ; HRMS for C.sub.26 H.sub.43 BI (M+): Calcd. 385.3344; found 385.3344.
Bioactivity
EXAMPLE 26
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase (HMGR) Suppression Assay
The ability of the compounds of Formula I to suppress the activity of HMGR, the rate limiting enzyme of cholesterol biosynthesis, was tested as follows.
Chinese Hamster Ovary (CHO) cells were divided twice weekly and were maintained in McCoy's 5A medium supplemented with 1% carbosil delipidated Fetal Bovine System (FBS) (obtained from Gibco Laboratories, Chagrin Falls, Ohio). Cells were harvested during the logarithmic phase of growth and cell cultures were prepared by adding 0.5.times.10 cells to each well in a 24 well cluster dish (obtained from Costar, Data Packaging Corp., Cambridge, Mass.) employing 1 ml of the above medium per each well. The cell cultures were incubated for 48 hr. at 37.degree. in a 5% CO.sub.2, 95% air environment. The test compounds in a 2.5% suspension of bovine serum albumin (BSA) (Fatty acid free) in ethanol were then added to the cultures such that the final ethanol and BSA concentrations in the incubation medium were 0.5% and 0.25% respectively. Treated cells were incubated with the indicated compounds for 6 hr. at 37.degree. in a 5% CO.sub.2, 95% air environment. Control cells were treated in an identical fashion to those which received test compound, except they were incubated with the BSA and ethanol suspension only.
HMGR activity was then measured in digitonin-permeabilized cells by the method developed by Leonard et al., J. Biol. Chem., 262: 7914-1719 (1987).
Specifically, the medium in each well was aspirated and the cells rinsed with a 50 mM solution of phosphate buffered saline (PBS). One ml of 30 mg/ml of digitonin in CSK buffer (prepared using 10 mM Pipes [piperazine-N,N'-bis (2-ethansulfonic) acid], 100 mM KCl, 2.5 mM MgCl.sub.2, 300 mM sucrose, 1 mM EGTA, pH 6.8) was added to each well and incubated for 10 min. at 22.degree. to permeabilize the cells. The buffer was carefully aspirated and the wells were rinsed twice each time with 1 ml of PBS. HMGR activity was measured directly by adding 75 ml of PIB buffer (50 mM potassium phosphate, 1 mM Na.sub.2 EDTA, 10 mM dithiothreitol, pH 7.4) to each well and incubating the cells for 30 minutes at 37.degree. as described above. The enzyme assay was initiated by the addition of 83 .mu.l of substrate/cofactor mixture such that the final assay contained the following: 0.1M potassium phosphate, 5 mM dithiothreitol, 20 mM glucose-6-phosphate, 2.5 mM NADP, 0.175 units of glucose-6-phosphate dehydrogenase, 150 mM [.sup.14 C] HMG-Coenzyme A (15 DPM/pmol), pH 7.4. The assay mixture was incubated for 30 min. at 37.degree. and terminated by the addition of 70 ml of [.sup.3 H]-mevalonic acid (35,000 DPM/assay), 0.15 mg/ml in 3N HCl.
The reaction was left to lactonize for an additional 30 min. at 37.degree. or overnight at room temperature.
Reaction products were separated by thin layer chromatography on silica gel G (obtained from Analtech, Newark, Del.) developed in an unsaturated environment with acetone:benzene (3:2, v:v). The band corresponding to mevalonolactone was identified by exposure to iodine vapor and was scraped into counting vials. The extent of conversion of starting substrate, HMG-CoA, to mevalonic acid was determined by liquid scintillation counting in Biofluor (obtained from New England Nuclear, Boston, Mass.). Corrections for recovery and blank values were made for each sample. Protein determinations were made by Bio-Rad (Bio-Rad, Richmond, Calif.) dye binding assay according to the manufacturer's instruction using bovine serum albumin as standard. Cellular protein was solubilized from culture dishes by the addition of 20 .mu.l of 16N KOH and assayed directly for protein amount. Suppression values are expressed as the amount of compound required to suppress HMGR activity by 50% relative to that of the controls. The results of HMGR suppression assays are reported in Table 1.
TABLE I______________________________________3-Hydroxy-3-Methylglutaryl Coenzyme AReductase (HMGR) Suppression Assay Ex. No. IC.sub.50 (.mu.M)______________________________________ 1 0.18 2 0.3 3 0.17 6 0.075 7 0.04 8 2.5 10 0.2 13 2.5 16 2.5 17 1.95 18 0.3 19 2.08 386 0.08 672 -- 673 1.46 677 2.5 678 -- 857 0.06 858 0.55 859 0.06 1303 0.3 1508 1.25 1509 5. 1817 0.5 1818 0.16______________________________________
The ability of compounds of this invention to effectively suppress HMGR activity is demonstrated by the data in Table I. As a comparison, it should be noted that cholesterol, lanosta-8,24-diene-3b-ol and lanost-8-en-3b-ol, when tested under these same conditions, were without effect on measured HMGR activity. Thus, the potent HMGR suppression activities of these compounds make them very attractive as hypocholesterolemic agents.
EXAMPLE 27
Lowering Blood Cholesterol Levels in Hamsters
The ability of the compounds of Formula I to lower blood cholesterol levels has been demonstrated in hamsters utilizing the following protocol.
Male Golden Syrian hamsters (50-60 grams) were obtained from Charles River, Inc. (Wilmington, Mass.).
Animals were housed in individual suspension cages and were maintained on a light cycle consisting of 12 hours of light followed by 12 hours of dark. Animals were allowed free access to water and feed (Agway ground chow, RMH 3200, Agway, Syracuse, N.Y.) containing 1% (w/w) corn oil) for a minimum of 4 weeks.
Following this stabilization period a sample of blood was collected by orbital sinus bleeding under light ether anesthesia into heparinized capillary tubes. Plasma was separated by centrifugation (600.times.g for 10 minutes) and plasma cholesterols were determined by an autoanalyzer (Centrifichem 600, Baker Instruments, Allentown, Pa.). Based upon measured plasma cholesterol values, the animals were randomized into two groups such that the mean plasma cholesterol values were identical for both groups.
Animals in the two groups were then placed on one of two diets: (1) Diet A, consisting of ground chow plus 1% (w/w) corn oil, as described above; or (2) Diet B, consisting of Diet A plus 0.2% (w/w) of a test compound. Animals on Diet B, the treated animals, were allowed free access to feed and water, while animals on Diet A were pair-matched with Diet B animals and served as pair-fed controls. The animals were kept on their respective diets for 7-days at which time they were bled by cardiac puncture under CO.sub.2 anesthesia. Total plasma cholesterol levels were 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 number of animals in each group.
TABLE II______________________________________Effect of Various Test CompoundsUpon Plasma Cholesterol Levels in Hamsters Plasma Cholesterol Control TreatedExample No. (mg/dl).sup.1______________________________________1.sup.2 133.0 .+-. 4.0 120. .+-. 2.0 (N = 20) (N = 10)______________________________________ .sup.1 Values represent means .+-.SEM for the number of animals given in parenthesis .sup.2 Dosed at 0.2% (w/w) in feed
As the data in Table II indicate, blood cholesterol levels can be significantly lowered by administration of compounds of Formula 1.
EXAMPLES 28-31
Scheme IX generally depicts the synthetic sequence 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 conversions are provided in the examples which follow this scheme. ##STR56##
EXAMPLE 28
Preparation of (22E)-4,4-Dimethyl-15-oxa-14.alpha.-vinylergosta-8,22-dien-3.beta.-ol (Compound 78)
BC. Preparation of (22E)-4,4-Dimethyl-ergosta-8,22-diene-3.beta.,14.alpha.,15.alpha.-triol (Compound 73)
To a stirred solution of (22E)-4,4-dimethylergosta-8,14,22-trien-3.beta.-ol (Compound 72, 10 g, 23.5 mmole) prepared by the method described by Dolle, et al. J. Org. Chem., 51: 4027 (1986), in 1,4-dioxane (400 ml) were added pyridine (10 ml), 1,8-diazabicyclo[4.4.0]undec-7-ene (DBU, Aldrich Chemical Co.) (4 ml), an aqueous solution of trimethylamine N-oxide dihydrate (Aldrich Chemical Co.) (5.4 g, 47 mmole in 50 ml of water) and a 20% solution of osmium tetraoxide in methylene chloride (1.5 ml, 1.18 mmole) and the mixture was heated under reflux for 24 hr. After cooling to room temperature was added 20% solution of sodium bisulfite (50 ml) and the mixture was stirred for 0.5 hr. It was extracted with ethyl acetate (3.times.200 ml) and the combined extracts were washed with water and brine. The organic extract was dried over magnesium sulfate and evaporated to give a solid residue. The crude product was dissolved in a minimum amount of ether and passed through a short silica gel column with elution by ether to remove the colored impurities. The solvent was evaporated off to afford a white crystalline solid (7.47 g) of the triol (Compound 73).
Physical data:
NMR (300 MHz, CDCl.sub.3): delta 5.23 (dd, J=7.3 Hz, 15.4 Hz, 1H), 5.13 (dd, J=7.3 Hz, 15.4 Hz, 1H), 4.10 (m, 1H), 3.24 (m, 1H), 2.41 (d, J=9.5 Hz, 1H), 2.38-0.80 (m, 21H), 1.02(s,3H), 1.00(s,3H), 0.97 (d, J=5.8 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H), 0.84-0.81 (m, 9H), 0.71 (s, 3H).
BD. Preparation of (22E)-4,4-Dimethyl-3.beta.-hydroxy-15-oxo-14,15-secoergosta-8,22-dien-14-one (Compound 74)
To a stirred solution of the triol (Compound 73, 13.2 g, 28.9 mmole) in dry benzene (360 ml) in the dark was added lead tetracetate (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 nitrogen atmosphere and in the dark. The mixture was filtered through Celite and the filtercake was rinsed several times. Evaporation of the solvent provide a foamy solid of the enone aldehyde (Compound 74) in near quantitative yield.
Physical data:
NMR (300 MHz, CDCl.sub.3): delta 9.55 (brs, 1H), 5.24-5.22 (m, 2H), 3.30 (dd, J=4.7 Hz, 11.3 Hz, 1H), 2.56-0.80 (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-3.beta.-hydroxy-15-(1'-piperidino)-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 (c.a. 1 hr.). The excess piperidine and the solvent were evaporated off under reduced pressure after cooling to give a foamy solid residue of the enamine (Compound 75) in quantitative yield.
Physical data:
NMR (300 MHz, CDCl.sub.3) delta 5.56 (d, J=13.5 Hz, 1H), 5.28 (dd, J=8.4 Hz, 15.4 Hz, 1H), 5.14 (dd, J=7.7 Hz, 15.4 Hz, 1H), 4.20 (br, 1H), 4.17 (dd, J=10.6 Hz, 13.5 Hz, 1H), 3.28 (dd, J=4.7 Hz, 11.3 Hz, 1H), 2.88 (m, 4H), 2.80-0.80 (m, 19H), 1.60 (m, 4H), 1.04 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H), 0.84-0.79 (m, 9H).
BG. Preparation of (22E)-4,4-Dimethyl-3.beta.-hydroxy-16-oxo-14,16-seco-D-nor-ergosta-8,22-dien-14-one (Compound 76)
A solution of the enamine (Compound 75, 26 mmole) in dry methylene chloride (200 ml), containing c.a. 10 mg of Sudan Red 7B as an indicator, was bubbled with ozone at -78.degree. 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.degree.. The residue after evaporation of the solvent was dissolved in a small amount of ether and passed through a plug of silica gel to remove polar impurities. Evaporation of the solvent afforded a foamy solid of the enone aldehyde (Compound 76).
Physical data:
NMR (300 MHz, CDCl.sub.3): delta 9.73 (d, J=4.7 Hz, 1H), 5.33 (m, 2H), 3.28 (dd, J=4.6 Hz, 11.5 Hz, 1H), 2.32 (br, 2H), 2.18 (dd, J=6.2 Hz, 13.5 Hz, 1H), 2.60-0.8 (m, 15H), 1.21 (s, 3H), 1.07 (s, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.04 (s, 3H), 0.91 (d, J=6.9 Hz, 3H), 0.84-0.81 (m, 9H).
BH. Preparation of (22E)-3.beta.16-Dihydroxy-4,4-dimethyl-14,16-seco-D-nor-ergosta-8,22-dien-14-one (Compound 77)
To a solution of the enone-aldehyde (Compound 76, 26 mmole) in methanol (115 ml) at -40.degree. was added sodium borohydride (0.59 g, 15.6 mmole) and the mixture was stirred for 1 hr. at from about -40.degree., with warming to about 10.degree.. The excess sodium borohydride was destroyed by stirring for 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.times.100 ml) and the combined extracts were washed with water and brine, dried over magnesium sulfate, and evaporated to give an oily residue. The crude product was column chromatographed on silica gel with elution by ethyl acetate - hexane (2:8) to give 6 g of pure enone-alcohol (Compound 77).
Physical data:
NMR (300 MHz, CDCl.sub.3): 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), 2.64-0.8 (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).
BI. Preparation of (22E)-4,4-Dimethyl-15-oxa-14.alpha.-vinyl-ergosta-8,22-dien-3.beta.-ol (Compound 78)
To a solution of the enone-alcohol (Compound 77, 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.degree. was added chlorotrimethysilane (1.7 ml, 13.4 mmole) dropwise and the mixture was stirred for 40 min. at 0.degree. and for 10 min. at 25.degree.. The reaction was quenched by methanol (1 ml) and the mixture was poured into ether. The ether solution was washed with water and brine, dried over magnesium sulfate and evaporated to give a foamy solid residue.
The residue was then dissolved in dry tetrahydrofuran (25 ml) and 1 M-vinyl magnesium bromide in dry tetrahydrofuran (8.9 ml, 8.9 mmole) was added. The mixture was heat under reflux for 1 hr. and cooled to 0.degree.. It was treated with 1N HCl (18 ml) and extracted with ethyl acetate (3.times.30 ml). The combined extracts were washed with water and brine, dried over magnesium sulfate, and evaporated to give an oily residue.
It was dissolved in methanol (25 ml) containing p-toluenesulfonic acid (0.5 g) and the mixture was stirred for 16 hr. at room temperature. Then the reaction mixture was made basic with saturated solution of sodium bicarbonate and extracted with ethyl acetate (3.times.30 ml). The combined organic solutions were washed with brine, dried over magnesium sulfate and evaporated to afford to foamy solid residue. The crude product was purified by column chromatographed on silica gel with elution by ethyl acetate - hexane (1:9) to provide 1.12 g of pure vinyl-oxasterol (Compound 78).
Physical data:
NMR (300 MHz, CDCl.sub.3) 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, 1H), 3.67 (t, J=8.4 Hz, 1H), 3.49 (t, J=8.6 Hz, 1H), 3.29 (brt, J=5.3 Hz, 1H), 2.12-0.8 (m, 18H), 1.02 (s, 3H), 1.01 (s, 3H), 0.90 (d, 6.5 Hz, 3H), 0.84-0.8 (m, 15H).
EXAMPLE 29
BJ. Preparation of (22E)-15-Oxa-14.alpha.-vinyl-ergosta-8,22-dien-3.beta.-ol (Compound 80)
By the method described for 4,4-dimethyl-vinyloxasterol (Compound 79) (Example 28-BC through BI) (22E)-ergosta-8,14,22-trien-3.beta.-ol [prepared by the method described by Dolle, et al. J. Org. Chem., 51: 4027 (1986)] was transformed to the corresponding normethyl-vinyl-oxasterol (Compound 80).
Physical Data:
NMR (300 MHz, CDCl.sub.3): delta 5.71 (dd, J=10.8 Hz, 7.2 Hz, 1H), 5.27 (dd, J=7.7 Hz, 15.1 Hz, 1H), 5.11 (dd, J=2.2 Hz, 10.8 Hz, 1H), 5.10 (m, 1H), 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 Hz, 3H), 0.97 (s, 3H), 0.90 (d, J=7.0 Hz, 3H), 0.84-0.80 (m, 9H).
EXAMPLE 30
BK. Preparation of 14.alpha.-Ethyl-15-oxa-ergost-8-en-3.beta.-ol (Compound 81)
A solution of the vinyl-oxasterol (Compound 80, 50 mg, 0.12 mmole) and 10% palladium on carbon (10 mg) in 3 ml of ethyl acetate - acetic acid (95:5) was stirred under hydrogen atmosphere (1 atm.) for 30 min. After removal of the catalyst by filtration through Celite the solvents were evaporated to give a foamy solid of the ethyl-oxasterol (Compound 81) in quantitative yield.
Physical data:
NMR (300 MHz, CDCl.sub.3): 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, 26H), 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 .sup.14 C-Acetate Incorporation into the Biosynthesis of Cholesterol
The HepG2 cells (a human hepatoma cell line) used in this example were obtained from the American Type Culture Collection (ATCC, Rockville, Md.). They were maintained in Dulbecco's Modified Eagles Medium and Ham's F12 Medium (1:1) supplemented with 10% heat inactivated Fetal Bovine serum, 10 .mu.M Herpes, 1 mM sodium pyruvate, 1.times.Non-essential Amino Acids (Gibco) and 2 mM L-glutamine.
The cells were harvested by washing cultures with 10 ml Hank's Balanced Salt Solution (2.times.) and incubating with 0.125% Trypsin in Versene (0.02% EDTA) for approximately one minute. After the cells are visibly rounded and loosened from the flask, 9 ml of the above medium is added. The cells are transferred to a 100 mM culture dish and syringed up and down through a 20 gauge needle to break up aggregated clumps of cells. Cell cultures are plated at 0.1.times.10.sup.6 /ml and 0.075.times.10.sup.6 /ml in two 24 well plates, respectively, aliquoting 1 ml cells/well. The cells are allowed to attach for 24 hours (48 hours for the lower density plate) before washing 2.times. with HBSS and refed with 1 ml of the above medium with 1% Cabosil delipidated serum instead of Fetal Bovine Serum. The cells are treated with the test 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). All test compounds are added at 50 .mu.M, 25 .mu.M, 10 .mu.M, 1 .mu.M at a final concentration of 0.45% solvent, 0.25% Bovine Serum Albumin (BSA) suspension per well. The solvent BSA is sonicated for 10 seconds to ensure maximum solubilization before addition to the cells. Control wells receive solvent/BSA at the same concentrations as the drug treated cultures. After incubation for one hour at 37.degree. C., 5% CO.sup.2, 20 .mu.Ci/ml .sup.3 H-MVAL is added per well in ethanol/medium so the final concentration of solvent is 1.2%. After 22 hours of incubation with the test compounds 2.5 .mu.Ci of .sup.14 C-acetate is added per well for an additional 2 hours so that the final concentration of ethanol is 1.6%.
Two known cholesterol biosynthesis inhibitors are included with 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 washing twice with ice cold 0.5M Tris, 0.15M NaCl, pH 7.4 to remove excess radiolabel not incorporated into the cells. Stop Reagent (1 ml of 15% potassium hydroxide, 85% methanol, 100 .mu.g/ml butylated hydroxytoluene (BHT) is added to each well and the plate is sonicated in a mild water sonicating bath to release the cells from the bottom of the well. The digested cell extracts are transferred to 15 ml extraction tubes. Each well is rinsed with an additional 1 ml of the Tris/NaCl buffer which is added to the appropriate extraction tube. An aliquot (100 .mu.l) is removed for protein determination at this point if desired.
The cell extracts are saponified at 80.degree. C. for 30 minutes. After cooling 8 ml petroleum ether is added and the tubes are twirled on a rotary extractor for 5-10 minutes to extract the sterols into the organic solvent phase. The top organic phase is removed and passed through a Silica Seppak (Waters) which binds all 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) to ensure reproducibility and accuracy from sample to sample.
The eluted sterols are dried under nitrogen gas and resuspended in 150 .mu.L ethanol. A 15 .mu.L aliquot is removed from each sample and added to a scintillation vial filled with Formula 989 (NEN). The samples are counted on the dual label .sup.3 H:.sup.14 C program on the Beckman scintillation counter Model LS 7800.
The incorporation of both radiolabeled precursors into sterols is compared between the treated and non-treated (control) cultures and expressed as "% control" for each precursor. Test compounds are classified as being "active" or "inactive" from these results and IC.sub.50 values were determined for the active compounds.
Analysis of sterol profiles is performed on the remainder of the sample by reversed phase HPLC. Analyses are done using an Ultrasphere octyl column (Altex) (0.46.times.25 cm), with a mobile phase consisting of acetonitrile:methanol:H.sub.2 O (44.5:44.5:10). Chromatography is performed at a flow rate of 1.5 ml per minute at 45.degree. C.
RESULTS
The following IC.sub.50 values represent the level of inhibition of the incorporation of .sup.14 C-acetate into the cholesterol biosynthesis pathway, as determined above:
______________________________________Compound IC.sub.50 (.mu.M)______________________________________Example 28 (Compound 78) 0.05Example 29 (Compound 80) >50.0Example 30 (Compound 81) 0.60______________________________________
AGRICULTURAL UTILITY
Some compounds of this invention have also shown utility as plant disease control agents. They are effective in controlling a wide range of plant diseases, including economically important diseases caused by fungi of the Ascomycetes, Basidiomycetes, and Oomycetes classes.
Plant disease control is ordinarily accomplished by applying 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 which the plants to be protected are growing. The compound may also be applied to the seed from which the plants to be protected are to be grown.
Rates 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 when treated at a rate of from less than 1 g/ha to 5000 g/ha of active ingredient. Plants growing in soil treated at a rate of from less than 1 g/ha to 5000 g/ha of active ingredient. Plants growing 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 when seed is treated at a rate of from 0.06 to about 3 grams per kilogram of seed.
EXAMPLE A
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on apple seedlings. The following day plants were inoculated with a spore suspension of Venturia inaequalis, the casual agent of apple scab, and incubated in a saturated humidity chamber at 20.degree. C. for 24 hours and then in a growth chamber at 22.degree. C. for 11 days, when disease ratings were made.
EXAMPLE B
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 0124 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on peanut seedlings. The following day plants were incubated in a saturated humidity chamber at 22.degree. C. for 24 hours, then in a high humidity chamber at 27.degree. C. for 7 days, and then in a growth chamber at 29.degree. C. for 7 days, when disease ratings were made.
EXAMPLE C
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 0914 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on broad bean seedlings. The following day plants were inoculated with a spore suspension of Botyrtis cinerea, the causal agent of bean grey mold, and incubated in a saturated humidity chamber at 20.degree. C. for 24 hours when disease ratings were made.
EXAMPLE D
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on wheat seedlings. The following day plants were inoculated with a spore dust of Ersiphe graminis f. sp. tritici, the causal agent of wheat powdery mildew, and incubated in a growth chamber at 20.degree. C. for 6 days, when disease ratings were made.
EXAMPLE E
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on rice seedlings. The following day plants were inoculated with a spore suspension of Pyricularia oryzae, the causal agent of rice blast, and incubated in a saturated humidity chamber at 27.degree. C. for 24 hours and then in a growth chamber at 29.degree. C. for 4 days, when disease ratings were made.
EXAMPLE F
The test 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 was sprayed to the point of run-off on rice seedlings. The following day plants were inoculated with a mycelial suspension of Rhizoctonia solani, the causal agent of rice sheath blight, and incubated in a saturated humidity chamber at 27.degree. C. for 48 hours and then in a growth chamber at 29.degree. C. for 4 days, when disease ratings were made.
EXAMPLE G
The test 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 was sprayed to the point of run-off on wheat seedlings. The following day plants were inoculated with a spore suspension of Puccinia recondita, the causal agent of wheat leaf rust, and incubated in a saturated humidity chamber at 20.degree. C. for 48 hours and then in a growth chamber at 20.degree. C. for 8 days, when disease ratings were made.
EXAMPLE H
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on tomato seedlings. The following day plants were inoculated with a spore suspension of Phytophthora infestans, the causal agent of tomato late blight, and incubated in a saturated humidity chamber at 20.degree. C. for 48 hours and then in a growth chamber at 20.degree. C. for 5 days, when disease ratings were made.
EXAMPLE I
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on grape seedlings. The following day plants were inoculated with a spore suspension of Plasmopara victicola, the causal agent of grape downy mildew, and incubated in a saturated humidity chamber at 20.degree. C. for 24 hours and then in a growth chamber at 20.degree. C. for 7 days, and then held in a saturated humidity chamber at 20.degree. C. for 24 hours, when disease ratings were made.
EXAMPLE J
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on grape seedlings. The following day plants were inoculated with a spore suspension of Botrytis cinerea, the causal agent of grape grey mold, and incubated in a saturated humidity chamber at 20.degree. C. for 96 hours when disease ratings were made.
EXAMPLE K
The test compounds were dissolved in acetone in an amount equal to 6% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant TREM 014 (polyhydric alcohol esters). This suspension was sprayed to the point of run-off on cucumber seedlings. The following day plants were inoculated with a spore suspension of Botrytis cinerea, the causal agent of cucumber grey mold, and incubated in a saturated humidity chamber at 20.degree. C. for 4 days when disease ratings were made.
Results of Examples A-K for two 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 were inoculated and incubated as described in each Example. A dashed entry indicates the specified test was not performed.
TABLE III______________________________________Example A B C D E F G H I J K______________________________________1817 90 25 97 92 1 0 62 -- -- 97 991818 99 95 95 98 6 0 100 94 100 78 100______________________________________
The present invention has been described in detail, including the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of the present disclosure, may make modifications and/or improvements on this invention and still be within the scope and spirit of this invention as set forth in the following claims.

Claims

1. Compounds having the formula: ##STR57## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation; and
the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
R.sub.1 is .dbd.O, OR.sub.7, or OCOR.sub.7 ;
R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 R.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 CHR.sub. 4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NH.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
X is O or s;
Z is halogen; and
n is 1;
and their physiologically acceptable salts.
2. The compounds of claim 1 wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl.
3. The compounds of claim 1, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl.
4. The compounds of claim 1, wherein X is O or S.
5. The compounds of claim 1, wherein n is 1.
6. The compounds of claim 1, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.2).sub.4 COR.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
X is O or S; and
n is 1.
7. The compounds of claim 1, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C(R.sub.4).sub.2 R.sub.4, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.5, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
X is O or S; and
n is 1.
8. The compounds of claim 1, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl; and
R.sub.6 is COR.sub.4.
9. The compounds of claim 1, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
10. The compounds of claim 1, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, or C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
11. The compounds of claim 1, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, CH.sub.2 R.sub.5, CHOHCH.dbd.CH.sub.2, COR.sub.4, COR.sub.5, CH.sub.2 CH.sub.2 R.sub.5, CH.sub.2 COR.sub.4, CN, CH.dbd.NOR.sub.4, CH.dbd.NOR.sub.6, CONHOR.sub.4, CONHOR.sub.6, CH.dbd.CHR.sub.6, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR58## R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ; and
X is O or S.
12. The compounds of claim 1, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, CH.sub.2 R.sub.5, CHOHCH.dbd.CH.sub.2, COR.sub.4, COR.sub.5, CH.sub.2 CH.sub.2 R.sub.5, CH.sub.2 COR.sub.4, CN, CH.dbd.NOR.sub.4, CH.dbd.NOR.sub.6, CONHOR.sub.4, CONHOR.sub.6, CH.dbd.CHR.sub.6, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH ##STR59## R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.4 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
13. The compounds of claim 1, wherein:
R.sub.2 is H or CH.sub.3,
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CH.sub.2 OCOCH.sub.3, CHO, COCH.sub.3, CO.sub.2 H, CONH.sub.2, CO.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 OH, CH.sub.2 CHO, CH.sub.2 CO.sub.2 H, CH.sub.2 CO.sub.2 CH.sub.3, CN, CH.dbd.NOH,CH.dbd.NOCOCH.sub.3, CONHOH, CONHOCOCH.sub.3, CH.dbd.CHCO.sub.2 CH.sub.3, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR60## and X is O or S.
14. The compounds of claim 1, wherein:
R.sub.2 is H or CH.sub.3,
R.sub.3 IS H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CH.sub.2 OCOCH.sub.3, CHO, COCH.sub.3, CO.sub.2 H, CONH.sub.2, CO.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 OH, CH.sub.2 CHO, CH.sub.2 CO.sub.2 H, CH.sub.2 CO.sub.2 CH.sub.3, CN, CH.dbd.NOH, CH.dbd.NOCOCH.sub.3, CONHOH, CONHOCOCH.sub.3, CH.dbd.CHCO.sub.2 CH.sub.3, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR61## X is O or S; and n is 1.
15. The compounds of claim 1, wherein:
R.sub.2 is H, CH.sub.3 ;
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CHO, CO.sub.2 H, CONH.sub.2, COCH.sub.3, CH.dbd.NOH, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH; and
X is O or S.
16. The compounds of claim 1, wherein:
R.sub.2 is H, CH.sub.3 ;
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CHO, CO.sub.2 H, CONH.sub.2, COCH.sub.3, CH.dbd.NOH, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH;
X is O or S; and
n=1.
17. A compound of claim 1 which is selected from the group consisting of:
15-Oxa-dihydrolanosterol,
4,4-Dimethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.-cholest8-en-3.beta.-ol,
3.beta.-Acetoxy-4,4-dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.-cholest-8-ene,
3.beta.-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol,
3.beta.-Acetoxy-15-oxa-32-oxo-lanost-8-ene,
15-Oxa-32-oxo-dihydrolanosterol,
15-Oxa-lanost-8-ene-3.beta.,32-diol,
15-Oxa-32-vinyl-lanost-8-ene-3.beta.,32-diol,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-aldoxime,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid,
14.alpha.-Methyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
15-Oxa-14.alpha.-vinyl-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-(1',2'-Dihydroxy-ethyl)-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-Formyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-Hydroxymethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-thia-5.beta.-cholest-8-en-3.beta.-ol,
15-Thia-dihydrolanosterol,
4,4-Dimethyl-15-thia-14a-vinyl-5.beta.-cholest-8-en 3.beta.-ol,
3.beta.-Hydroxy-15-thia-lanost-8-en-15-oxide.
18. A compound of claim 1 which is selected from the group consisting of:
15-Oxa-dihydrolanosterol,
4,4-Dimethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.-cholest8-en-3.beta.-ol,
3.beta.-Acetoxy-4,4-dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.cholest-8-ene,
3.beta.-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol,
3.beta.-Acetoxy-15-oxa-32-oxo-lanost-8-ene,
15-Oxa-32-oxo-dihydrolanosterol,
15-Oxa-lanost-8-ene-3.beta.,32-diol,
15-Oxa-32-vinyl-lanost-8-ene-3.beta.,32-diol,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-aldoxime,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid,
14.alpha.-Methyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
15-Oxa-14.alpha.-vinyl-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-(1',2'-Dihydroxy-ethyl)-15-oxa-5.alpha.cholest-8-en-3.beta.-ol,
14.alpha.-Formyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-Hydroxymethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-thia-5.alpha.-cholest-8-en-3.beta.-ol,
15-Thia-dihydrolanosterol,
4. 4-Dimethyl-15-thia-14.alpha.-vinyl-5.alpha.cholest-8-en-3.beta.-ol,
3.beta.-Hydroxy-15-thia-lanost-8-en-15-oxide.
19. A composition suitable for decreasing cholesterol formation in mammals, said composition comprising (i) an effective amount of an active compound of the formula: ##STR62## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation; and
wherein the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
R.sub.1 is .dbd.O, OR.sub.7, or OCOR.sub.7 ;
R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 R.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 CHR.sub. 4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
X is O or S;
Z is halogen; and
n is 1;
and their physiologically acceptable salts; and (ii) an acceptable pharmaceutical or veterinary carrier or diluent.
20. The composition of claim 19, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl.
21. The composition of claim 19, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6,CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4,OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl.
22. The composition of claim 19, wherein X is O or S.
23. The composition of claim 19, wherein n is 1.
24. The composition of claim 19, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
X is O or S; and
n is 1.
25. The composition of claim 19, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
X is O or S; and
n is 1.
26. The composition of claim 19, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl; and
R.sub.6 is COR.sub.4.
27. The composition of claim 19, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.5 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
28. The composition of claim 19, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, or C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(R.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, or phenyl or phenyl substituted by C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
29. The composition of claim 19, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, CH.sub.2 R.sub.5, CHOHCH.dbd.CH.sub.2, COR.sub.4, COR.sub.5, CH.sub.2 CH.sub.2 R.sub.5, CH.sub.2 COR.sub.4, CN, CH.dbd.NOR.sub.4, CH.dbd.NOR.sub.6, CONHOR.sub.4, CONHOR.sub.6, CH.dbd.CHR.sub.6, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR63## R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted by C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3, or benzyl;
R.sub.6 is COR.sub.4 ; and
X is O or S.
30. The composition of claim 19, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, CH.sub.2 R.sub.5, CHOHCH.dbd.CH.sub.2, COR.sub.4, COR.sub.5, CH.sub.2 CH.sub.2 R.sub.5, CH.sub.2 COR.sub.4, CN, CH.dbd.NOR.sub.4, CH.dbd.NOR.sub.6, CONHOR.sub.4, CONHOR.sub.6, CH.dbd.CHR.sub.6, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR64## is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkenyl, phenyl or phenyl substituted by C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
31. The composition of claim 19, wherein:
R.sub.2 is H or CH.sub.3,
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CH.sub.2 OCOCH.sub.3, CHO, COCH.sub.3, CO.sub.2 H, CONH.sub.2, CO.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 OH, CH.sub.2 CHO, CH.sub.2 CO.sub.2 H, CH.sub.2 CO.sub.2 CH.sub.3, CN, CH.dbd.NOH, CH.dbd.NOCOCH.sub.3, CONHOH, CONHOCOCH.sub.3, CH.dbd.CHCO.sub.2 CH.sub.3, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR65## and X is O or S.
32. The composition of claim 19, wherein:
R.sub.2 is H or CH.sub.3,
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CH.sub.2 OCOCH.sub.3, CHO, COCH.sub.3, CO.sub.2 H, CONH.sub.2, CO.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 OH, CH.sub.2 CHO, CH.sub.2 CO.sub.2 H, CH.sub.2 CO.sub.2 CH.sub.3, CN, CH.dbd.NOH, CH.dbd.NOCOCH.sub.3, CONHOH, CONHOCOCH.sub.3, CH.dbd.CHCO.sub.2 CH.sub.3, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR66## and X is O or S; and
n is 1.
33. The composition of claim 19, wherein:
R.sub.2 is H, CH.sub.3 ;
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CHO, CO.sub.2 H, CONH.sub.2, COCH.sub.3, CH.dbd.NOH, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH; and
X is O or S.
34. The composition of claim 19, wherein:
R.sub.2 is H, CH.sub.3 ;
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CHO, CO.sub.2 H, CONH.sub.2, COCH.sub.3, CH.dbd.NOH, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH;
X is O or S; and
n is 1.
35. A composition of claim 19, wherein the preferred compound is selected from the group consisting of:
15-Oxa-dihydrolanosterol,
4,4-Dimethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.-cholest8-en-3.beta.-ol,
3.beta.-Acetoxy-4,4-dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.cholest-8-ene,
3.beta.-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol,
3.beta.-Acetoxy-15-oxa-32-oxo-lanost-8-ene,
15-Oxa-32-oxo-dihydrolanosterol,
15-Oxa-lanost-8-ene-3.beta.,32-diol,
15-Oxa-32-vinyl-lanost-8-ene-3.beta.,32-diol,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-aldoxime,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid,
14.alpha.-Methyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
15-Oxa-14.alpha.-vinyl-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-(1',2'-Dihydroxy-ethyl)-15-oxa-5.alpha.cholest-8-en-3.beta.-ol,
14.alpha.-Formyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
14.beta.-Hydroxymethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-thia-5.alpha.-cholest-8-en-3.beta.-ol,
15-Thia-dihydrolanosterol,
4. 4-Dimethyl-15-thia-14.alpha.-vinyl-5.alpha.cholest-8-en-3.beta.-ol,
3.beta.-Hydroxy-15-thia-lanost-8-en-15-oxide.
36. The composition of claim 19, wherein the preferred compound is selected from the group consisting of:
15-Oxa-dihydrolanosterol,
4,4-Dimethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-oxa-14.beta.-vinyl-5.beta.-cholest8-en-3.beta.-ol,
3.beta.-Acetoxy-4,4-dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.cholest-8-ene,
3.beta.-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol,
3.beta.-Acetoxy-15-oxa-32-oxo-lanost-8-ene,
15-Oxa-32-oxo-dihydrolanosterol,
15-Oxa-lanost-8-ene-3.beta.,32-diol,
15-Oxa-32-vinyl-lanost-8-ene-3.beta.,32-diol,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-aldoxime,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid,
14.alpha.-Oxa-D-homo-dihydrolanosterol,
4,4-Dimethyl-14.alpha.-oxa-D-homo-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-14.alpha.-oxa-14.alpha.-vinyl-D-homo-5.alpha.-cholest-8en-3.beta.-ol,
32-Hydroxymethyl-14.alpha.-oxa-D-homo-lanost-8-ene-3.beta.,32-diol,
14.alpha.-Oxa-32-oxo-D-homo-dinhydrolanosterol,
14.alpha.-Methyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
15-Oxa-14.alpha.-vinyl-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-(1',2'-Dihydroxy-ethyl)-15-oxa-5-cholest-8-,en-3.beta.-ol,
14.alpha.-Formyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-Hydroxymethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-thia-5.alpha.-cholest-8-en-3.beta.-ol,
15-Thia-dihydrolanosterol,
4,4-Dimethyl-15-thia-14.alpha.-vinyl-5.alpha.-cholest-8-en-,3.beta.-ol,
3.beta.-Hydroxy-15-thia-lanost-8-en-15-oxide,
4,4-Dimethyl-14.alpha.-thia-D-homo-5.alpha.-cholest-8-en-,3.beta.-ol,
14.alpha.-Thia-D-homo-dihydrolanosterol.
37. A method of decreasing cholesterol formation in mammals in need of such therapy, said method comprising administering an effective amount of an active compound of the formula: ##STR67## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation; and
wherein the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
R.sub.1 is .dbd.O, OR.sub.7, or OCOR.sub.7 ;
R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 R.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
X is O or S;
Z is halogen; and
n is 1;
and their physiologically acceptable salts in an acceptable pharmaceutical or veterinary carrier or diluent to said mammal.
38. The method of claim 37, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6,C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(R.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl.
39. The method of claim 37, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl.
40. The method of claim 37, wherein x is O or S.
41. The method of claim 37, wherein n is 1.
42. The method of claim 37, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
X is O or S; and
n is 1.
43. The method of claim 37, wherein:
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
X is O or S; and
n is 1.
44. The method of claim 37, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl; and
R.sub.6 is COR.sub.4.
45. The method of claim 37, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
46. The method of claim 37, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, or C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, COR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 COR.sub.5, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.4 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted by C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3, or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
47. The method of claim 37, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, CH.sub.2 R.sub.5, CHOHCH.dbd.CH.sub.2, COR.sub.4, COR.sub.5, CH.sub.2 CH.sub.2 R.sub.5, CH.sub.2 COR.sub.4, CN, CH.dbd.NOR.sub.6, CH.dbd.NOR.sub.5, CONHOR.sub.4, CONHOR.sub.6, CH.dbd.CHR.sub.6, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR68## R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, phenyl or phenyl substituted by C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3, or benzyl;
R.sub.6 is COR.sub.4 ; and
X is O or S.
48. The method of claim 37, wherein:
R.sub.2 is H, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl;
R.sub.3 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, CH.sub.2 R.sub.5, CHOHCH.dbd.CH.sub.2, COR.sub.4, COR.sub.6, CH.sub.2 COR.sub.4, CN, CH.dbd.NOR.sub.4, CH.dbd.NOR.sub.6, CONHOR.sub.4, CONHOR.sub.6, CH.dbd.CHR.sub.6, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR69## R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, phenyl or phenyl substituted by C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3, or benzyl;
R.sub.6 is COR.sub.4 ;
X is O or S; and
n is 1.
49. The method of claim 37, wherein:
R.sub.2 is H or CH.sub.3,
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CH.sub.2 OCOCH.sub.3, CHO, COCH.sub.3, CO.sub.2 H, CONH.sub.2, CO.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 OH, CH.sub.2 CHO, CH.sub.2 CO.sub.2 H, CH.sub.2 CO.sub.2 CH.sub.3, CN, CH.dbd.NOH, CH.dbd.NOCOCH.sub.3, CONHOH, CONHOCOCH.sub.3, CH.dbd.CHCO.sub.2 CH.sub.3, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR70## and X is O or S.
50. The method of claim 37, wherein:
R.sub.2 is H or CH.sub.3,
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.ident.CH.sub.2, CH.sub.2 OCOCH.sub.3, CHO, COCH.sub.3, CO.sub.2 H, CONH.sub.2, CO.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 OH, CH.sub.2 CHO, CH.sub.2 CO.sub.2 H, CH.sub.2 CO.sub.2 CH.sub.3, CN, CH.dbd.NOH, CH.dbd.NOCOCH.sub.3, CONHOH, CONHOCOCH.sub.3, CH.dbd.CHCO.sub.2 CH.sub.3, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH, ##STR71## and X is O or S; and
n is 1.
51. The method of claim 37, wherein:
R.sub.2 is H, CH.sub.3 ;
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CHO, CO.sub.2 H, CONH.sub.2, COCH.sub.3, CH.dbd.NOH, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH; and
X is O or S.
52. The method of claim 37, wherein:
R.sub.2 is H, CH.sub.3 ;
R.sub.3 is H, CH.sub.3, CH.dbd.CH.sub.2, CH.sub.2 OH, CHOHCH.dbd.CH.sub.2, CHO, CO.sub.2 H, CONH.sub.2, COCH.sub.3, CH.dbd.NOH, CHOHCH.sub.2 OH, CHOHCHOHCH.sub.2 OH;
X is O or S; and
n is 1.
53. The method of claim 37, wherein the preferred compound is selected from the group consisting of:
15-Oxa-dihydrolanosterol,
4. 4-Dimethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.-cholest8-en-3.beta.-ol,
3.beta.-Acetoxy-4,4-dimethyl-15-oxa-14.alpha.-vinyl-5-cholest-8-ene,
3.beta.-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol,
3.beta.-Acetoxy-15-oxa-32-oxo-lanost-8-ene,
15-Oxa-32-oxo-dihydrolanosterol,
15-Oxa-lanost-8-ene-3.beta.,32-diol,
15-Oxa-32-vinyl-lanost-8-ene-3.beta.,32-diol,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-aldoxime,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid,
14.alpha.-Oxa-32-oxo-D-homo-dihydrolanosterol,
14.alpha.-Methyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
15-Oxa-14.alpha.-vinyl-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-(1',2'-Dihydroxy-ethyl)-15-oxa-5.alpha.-cholest-8en-.beta.-ol,
14.alpha.-Formyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-Hydroxymethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-thia-5.alpha.-cholest-8-en-3.beta.-ol,
15-Thia-dihydrolanosterol,
4,4-Dimethyl-15-thia-14-vinyl-5.alpha.-cholest-8-en-,3.beta.-ol,
3.beta.-Hydroxy-15-thia-lanost-8-en-15-oxide,
4,4-Dimethyl-14.alpha.-thia-D-homo-5.alpha.-cholest-8-en3.beta.-ol.
54. The method of claim 37, wherein the preferred compound is selected from the group consisting of:
15-Oxa-dihydrolanosterol,
4,4-Dimethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.-cholest8-en-3.beta.-ol,
3.beta.-Acetoxy-4,4-dimethyl-15-oxa-14.alpha.-vinyl-5.alpha.cholest-8-ene,
3.beta.-Acetoxy-32-hydroxymethyl-15-oxa-lanost-8-en-32-ol,
3.beta.-Acetoxy-15-oxa-32-oxo-lanost-8-ene,
15-Oxa-32-oxo-dihydrolanosterol,
15-Oxa-lanost-8-ene-3.beta.,32-diol,
15-Oxa-32-vinyl-lanost-8-ene-3.beta.,32-diol,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-aldoxime,
3.beta.-Hydroxy-15-oxa-lanost-8-en-32-carboxylic acid,
1.alpha. -Oxa-32-D-homo-dihydrolanosterol,
14.alpha.-Methyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
15-Oxa-14.alpha.-vinyl-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-(1',2'-Dihydroxy-ethyl)-15-oxa-5.alpha.-cholest-8-, en-3.beta.-ol,
14.alpha.-Formyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
14.alpha.-Hydroxymethyl-15-oxa-5.alpha.-cholest-8-en-3.beta.-ol,
4,4-Dimethyl-15-thia-5.alpha.-cholest-8-en-3.beta.-ol,
15-Thia-dihydrolanosterol,
4,4-Dimethyl-15-thia-14.alpha.-vinyl-5.alpha.-cholest-8-en-, 3.beta.-ol,
3.beta.-Hydroxy-15-thia-lanost-8-en-15-oxide.
55. A process for the formation of 15-thia-lanosterols having the formula: ##STR72## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation; and
wherein the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
R.sub.1 is OR.sub.7 or OCOR.sub.7 ;
R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6 ;
R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ; or benzyl;
X is S;
Z is halogen; and
n is 1;
which process comprises treating a cyclic hemiacetal of the corresponding 15-oxa-dihydrolanosterol (X.dbd.O) with hydrogen sulfide and boron trifluoride etherate in a suitable reaction medium, under suitable reaction conditions, followed by reaction of the unisolated cyclic thioacetal intermediate with a trialkylsilane to yield the desired 15-thiadihydrolanosterol.
56. The process of claim 55, wherein 15-thiadihydrolanesterol (R.sub.3 .dbd.CH.sub.3) is formed.
57. The process of claim 55, wherein 4,4-Dimethyl-15-thia-5.alpha.-cholest-8-en-3.beta.-ol (R.sub.3 .dbd.H) is formed.
58. The process of claim 55, wherein 4,4-dimethyl-15-thia-14.alpha.-vinyl-5.alpha.-cholest-8-en-3.beta.-ol (R.sub.3 .dbd.CH.dbd.CH.sub.2) is formed.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of our copending application U.S. Ser. No. 07/489,093, filed 5 March 1990 now abandoned, the disclosure of which is hereby incorporated herein by reference.

US Referenced Citations (10)

Number	Name	Date
3872076	Rosen	Mar 1975
3947453	Jones	Mar 1976
3972884	Jones	Aug 1976
4001246	Jones	Jan 1977
4008238	Jones	Feb 1977
4039547	Chamberlin	Aug 1977
4053487	Rosen	Oct 1977
4202891	Schroepfer, Jr. et al.	May 1980
4230626	Chorvat	Oct 1980
5034548	Gaylor et al.	Jul 1991

Non-Patent Literature Citations (22)

Entry
Grynkiewicz, Carbohydrate Res. 128 (1984) C9-C10.
Chang, et al., Journal of Biological Chemistry, vol. 255, pp. 7787-7794, (1980).
Gibbons, et al., Journal of Biological Chemistry, vol. 255, pp. 395-400, (1980).
Kandutsch, et al., Journal of Biological Chemistry, vol. 252, pp. 409-415, (1977).
Journal of Chronic Disease, vol. 31, pp. 201-306 (1978).
Cavenee, et al., Journal of Biological Chemistry, vol. 256, pp. 2675-2681 (1981).
Breslow, et al., Biochem. Biophysica Acta, vol. 398, 10-17, (1975).
Rodwell, et al., "Advances in Lipid Research" vol. 14, pp. 2-74, (1976).
Bresike, et al., Circulation, vol. 69, pp. 313-324, (1984).
Kannel, et al., Annals of Internal Medicine, vol. 90, pp. 85-91, (1979).
Kandutsch, et al., Science, vol. 21, pp. 498-501 (1978).
Schroepfer, et al., Proc. Natl. Acad. Sci. USA, vol. 81, pp. 6861-6865, (1984).
Schriner, et al, J. Org. Chem., vol. 10, pp. 228, (1945).
Dolle, et al., J. Org. Chem., vol. 51, pp. 4047, (1986).
Brown, et al., J. Lipid Res., vol. 21, pp. 505-517, (1980).
Leonard, et al., J. Biol. Chem., vol. 262, pp. 7914-1719, (1987).
Tanaka, et al., J. Biol. Chem., vol. 258, pp. 13331-13339, (1983).
Havel, et al., J. Biol. Chem., vol. 254, pp. 9573-9582, (1979).
Chen, et al., J. Biol. Chem., vol. 254, pp. 714-720, (1979).
Kandutsch, et al., J. Biol. Chem., vol. 255, pp. 10813-10821, (1980).
Levy, Circulation, vol. 69, pp. 325-336, (1984).
Trzaskos, et al., Fed. Proc., vol. 44, p. 656, Abstract No. 1437 (1985).

Continuation in Parts (1)

	Number	Date	Country
Parent	489093	Mar 1990

Heterocyclic steroid compounds

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