25-METHYLENE AND 24,25-EPOXY MARCFORTINES AND PARAHERQUAMIDES

Abstract: The present invention are marcfortines and paraherquamides where the 7-member oxygenated ring has been modified to produce 25-methylene compounds (VII) and 24,25-epoxy compounds (VIII) all of which are useful as antiparasitic agents against endo and ecto parasites, particularly helminths and arthropods.

Description: 25-METHYLENE AND 24.25-EP XY MARCFORTINES AND PARAHER Q UAMIDES BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is (substituted) 25-methylene and 24,25-epoxy marcfortines and paraherquamides which are useful as antiparasitic agents. 2. Description of the Related Art The marcfortines are known compounds, see Journal of the Chemical Society Chemical Communications, 601-602 (1980) for Marcfortine A and Tetrahedron Letters, 22, 1977-1980 (1981) for Marcfortines B and C. These compounds are fungal metabolites of Penicillium roqueforti. The marcfortines are structurally related to the paraherquamides which are also known compounds. The paraherquamides are disclosed in Tetrahedron Letters, 22, 135-136 (1981), and Journal of Antibiotics, 44, 492-497 (1991). U.S. Patents 4,866,060 and 4,923,867 disclose the use of the marcfortines A, B, and C, and certain derivatives thereof as useful for the treatment and prevention of parasitic diseases in animals. WO 92/22555 (published 23 December 1992) genetically describes a marcfortine or paraherqua ide derivative (i.e. partial formula (III) substituted at position 14 with methyl or methyl and hydroxy, however no description of how to prepare such 14-methyl-14-hydroxymarcfortine compounds is provided. The Journal of Antibiotics, 43, 1380-1386 (1990) discloses Paraherquamide A which has the following structure: Marcfortine A has the following structure: Marcfortine B has the following structure: Marcfortine C has the following structure: Marcfortine D has the following structure: WO 91/09961 (published 11 July 1991) discloses various derivatives of marcfortine and paraherquamide, and 12a-N-oxides thereof, as well as the production the production of VM 29919 (paraherquamide) and VM 55596 (the 12a-N- oxide of paraherquamide) inter alia from Penicillium Sp. IMI 332995. US Patent 4,873,247 discloses derivatives of paraherquamide and a strain of Penicillium charlessi MF 5123 (ATCC 20841) for the production of paraherquamide. US Patent 4,978,656 (as well as EP 390532-A, EP-301742-A) discloses various synthetic derivatives of paraherquamide as well as the production of paraherquamide from Penicillium charlessi MF 5123 (ATCC 20841). International Publication WO 92/22555 (published 23 December 1992) generically discloses 14α-hydroxymarcfortine compounds and a process which uses the 14-hydroxy-14-methylmarcfortine compounds for the production of antiparasitic drugs. However, no enabling description of any means of preparation of 14α- hydroxymarcfortine or 14α-hydroxy-14β-methylmarcfortine compounds is provided. International Publication WO94/29319 discloses various 14-substituted marcfortines and derivatives thereof. The 15-alkyl-14-hydroxy compounds (III) where n, is 0 are known, see International Publication WO94/29319. SUMMARY OF INVENTION Disclosed are 25-methylene compounds of the formula (VII) where for: (I) Marcfortine A (a) n is 1, (b) R 14 is 1 4 0t : 1 4β where R 14α is -H and R 14 β is -H, (c) R 15 is R 15α :R 15 β where R 15α is -H and R 15β is -H; (II) Paraherquamide A (a) n is 0, (b) R 14 is Rι 4α :Rι 4 β where R 14α is -OH and R 14β is -CH 3 , (c) R 15 is Rι 5α :R 15 β where R 15α is -H and R 15β is -H; (III) 14-hydroxy-14-alkyl Marcfortine A (a) n is 1, (b -R I4 is Ri4 α : i4β where R 14α is -OH and R 14 β is C j -C 4 alkyl, (c) R 15 is R 15α :R 15β where R 15α is -H and R 15β is -H; (IV) 14-hydroxy-15-methyl Marcfortine A (a) n is 1, (b) R 14 is Rι 4α : 14 β where R 14α is -OH and R 14β is -H, (c) R 15 is Ri5 α :Ri5 where i5 α is C j -C^ alkyl and R 15β is -H and pharmaceutically acceptable salts thereof. Also disclosed are 24,25-epoxy compounds of the formula (VIII) where for: (I) Marcfortine A (a) n is 1, (b) R 14 is ι 4α :Rι β where R 14α is -H and R 14β is -H, (c) R 15 is i5 α :Ri5β where R 15α is -H and R 15β is -H; (II) Paraherquamide A (a) n is 0, (b) R 14 is Rι 4α : ι 4 where R 14α is -OH and R 14β is -CHg, (c) R 15 is R 15α :R 15β where R 15α is -H and R 15β is -H; (III) 14-hydroxy-14-alkyl Marcfortine A (a) n is 1, (b) R 14 is ι 4α : i4β where R 14α is -OH and R 14β is C r C 4 alkyl, (c) R 15 is Rι 5α :R 15β where R 15α is -H and R 15β is -H; (TV) 14-hydroxy-15-methyl Marcfortine A (a) n is 1, (b) R 14 is Ri4 α .R 1 where R 14α is -OH and R 14β is -H, (c) R 15 is i5 α : i5 where R 15α is C C alkyl and R 15β is -H and pharmaceutically acceptable salts thereof. Disclosed is N-(18a)-demethyl-2-deoxoparaherquamide A and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention is 25-methylene (VII) and 24,25-epoxy (VIII) marcfortines and paraherquamides. These compounds are made by two different reactions from known compounds. The 25-methylene marcfortines and paraherquamides (VII) are produced from the known corresponding cyclic olefins (I). When (a) n is 1, (b) R 14 is ι 4α - ι 4β where j4a is -H and R 14β is -H and (c) R 15 is Ri5 α - i5 β where i α is -H and R 15 g is -H the starting cyclic olefin (I) is marcfortine A; when (a) n is 0, (b) R 14 is R 14α :R 14β where R 14α is -OH and R 14 is -CH 3 and (c) R 15 is i5 α : χ5 β where R 15α is -H and R 15β is -H the starting cyclic olefin (I) is paraherquamide A; when (a) n is 1, (b) R 14 is i4 α - i4β where R 14α is -OH and R 14 is -CH 3 and (c) R J5 is ^15α : ^15β w ^ ere Ri5α s "** anc * ^158 * s "^ ^e Par ing cyclic olefin (I) is 14- hydroxy-14-methyl marcfortine A and when (a) n is 1, (b) R 14 is ι 4α -Rι 4β where R 14α is -OH and R 14β is -H and (c) R 15 is i5 α - i5β where R 15α is -CH 3 and R 15β is -H the starting cyclic olefin (I) is 14-hydroxy-15-methyl marcfortine A. Marcfortine A and paraherquamide A are well known compounds. The 14-Hydroxy- 14-alkyl marcfortine A and 14-hydroxy-15-alkyl marcfortine A compounds are produced by the processes set forth in CHARTS C-H and PREPARATIONS 1-31. The CHARTS and PREPARATIONS exemplify methyl as the alkyl substituent, however ethyl, propyl and butyl (including isomers thereof where such exist) are prepared in an analogous fashion as is known to those skilled in the art. The 25-methylene compounds (VTI) are produced from the corresponding cyclic olefin (I) first by cleavage of the seven member cyclic ether containing the olefin by use of a reagent such as formic acid to produce the diol (II). The diol (II) is then alkylated with an alkylating reagent to produce the corresponding olefin (III). The olefin (III) must have the double bond at the specified position to produce the desired product that when cyclized and oxidized will have a hydroxyl group at C-25. Such a reagent includes compounds of the formula, X 1 -CH 2 -CH=C(CH 3 ) 2 where X j is a leaving group such as -Br or -Cl; it is preferred that X j is -Br, it is more preferred that the reagent be 4-bromo-2-methyl-2-butene. This reaction is performed in the presence of potassium iodide and a weak base such as bicarbonate or carbonate (preferably potassium carbonate) in an aqueous-organic solvent mixture, preferably acetone water. The olefin (III) is then oxidized to the corresponding epoxy-phenol (TV) by use of a peracid, preferably /π-chloroperbenzoic acid followed by sodium bisulfite workup. The epoxy-phenol (IV) is then cyclized to the corresponding cyclic alcohol (V) by use of tin (IV) chloride. The cyclic alcohol (V) is then oxidized under Swern conditions (oxalyl chloride, DMSO followed by TEA) to give the corresponding ketone (VI). The ketone (VI) is then transformed to the desired 25-methylene compound (VII) by a Wittig reaction using methyltriphenylphosphonium bromide and a strong base such as n-butyl lithium. It is realized that the 25-methylene compound (VII) is a 24,25-dihydro compound. The 24,25-epoxy compounds (VIII) are produced from the corresponding cyclic olefin (I) by oxidation with a peracid under normal conditions for peracid oxidation to epoxides followed by aqueous sodium bisulfite workup. It is preferred that the peracid be -chloroperbenzoic acid. N-(18a)-demethyl-2-deoxoparaherquamide A is also known as (l'α, 5 , aβ,7'β,8'aβ,9'aβ)-(-)-2,2',3,3 , ,8a',9'-hexahydro-l '-hydroxy-1 ',4,4,8',8'-pentamethyl- spiro[4H,8H,-[l ,4]dioxepino[2,3-g]_ndole-8,7'(8Η)-[5H,6H- 5a,9a](iminomethano)[lH]cyclopent[f]indolizine]-9-one]. N-(18a)-demethyl-2- deoxoparaherqua ide A can be prepared by two different methods, see EXAMPLES 14 and 15. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A are amines, and as such form acid addition salts when reacted with acids of sufficient strength. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The pharmaceutically acceptable salts are preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline. The preferred pharmaceutically acceptable salts include salts of the following acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH -(CH 2 ) n -COOH where n is 0 thru 4, HOOC-(CH2)n-COOH where n is as defined above. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A of this invention are unexpectedly potent antiparasitic agents against endo and ecto parasites, particularly helminths and arthropods, which cause numerous parasitic diseases in humans, animals, and plants. Parasitic diseases may be caused by either endoparasites or ectoparasites. Endoparasites are those parasites which live inside the body of the host, either within an organ (such as the stomach, lungs, heart, intestines, etc.) or simply under the skin. Ectoparasites are those parasites which live on the outer surface of the host but still draw nutrients from the host. The endoparasitic diseases generally referred to as helminthiasis are due to infection of the host with parasitic worms known as helminths. Helminthiasis is a prevalent and serious worldwide economic problem due to infection of domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats, and poultry. Many of these infections are caused by the group of worms described as nematodes which cause diseases in various species of animals throughout the world. These diseases are frequently serious and can result in the death of the infected animal. The most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris, and Parascaris. Many parasites are species specific (infect only one host) and most also have a preferred site of infection within the animal. Thus Haemonchus and Ostertagia primarily infect the stomach while Nematodirus and Cooperia mostly attack the intestines. Other parasites prefer to reside in the heart, eyes, lungs, blood vessels, and the like while still others are subcutaneous parasites. Helminthiasis can lead to weakness, weight loss, anemia, intestinal damage, malnutrition, and damage to other organs. If left untreated these diseases can result in the death of the animal. Infections by ectoparasitic arthropods such as ticks, mites, lice, stable flies, hornflies, blowflies, fleas, and the like are also a serious problem. Infection by these parasites results in loss of blood, skin lesions, and can interfere with normal eating habits thus causing weight loss. These infections can also result in transmission of serious diseases such as encephalitis, anaplasmosis, swine pox, and the like which can be fatal. Animals may be infected by several species of parasite at the same time since infection by one parasite may weaken the animal and make it more susceptible to infection by a second species of parasite. Thus a compound with a broad spectrum of activity is particularly advantageous in the treatment of these diseases. The 25- methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2- deoxoparaherquamide A have unexpectedly high activity against these parasites, and in addition, are also active against Dirofilaria in dogs, Nematospiroides and Syphacia in rodents, biting insects and migrating dipterous larvae such as Hypoderma sp. in cattle, and Gastrophilus in horses. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A are also useful against endo and ecto parasites which cause parasitic diseases in humans. Examples of such endoparasites which infect man include gastro intestinal parasites of the genera Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, Enterobius, and the like. Other endoparasites which infect man are found in the blood or in other organs. Examples of such parasites are the filarial worms Wucheria, Brugia, Onchocerca, and the like as well as extra intestinal stages of the intestinal worms Strongylides and Trichinella. Ectoparasites which parasitize man include arthropods such as ticks, fleas, mites, lice, and the like and, as with domestic animals, infections by these parasites can result in transmission of serious and even fatal diseases. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A are active against these endo and ecto parasites and in addition are also active against biting insects and other dipterous pests which annoy humans. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A when administered orally or parenterally are administered at a dosage rate of from 0.05 to 20 mg/kg of animal body weight. The 25 -methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A are also useful against common household pests such as Blatella sp. (cockroach), Tineola sp. (clothes moth), Attagenus sp. (carpet beetle), Musca domestica (housefly) and against Solenopsis Invicta (imported fire ant). The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A are furthermore useful against agricultural pests such as aphids (Acyrthio siphon sp.), locusts, and boll weevils as well as against insect pests which attack stored grains such as Tribolium sp. and against immature stages of insects living on plant tissue. The 25-methylene compounds (VII), 24,25- epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A are also useful as a nematocide for the control of soil nematodes which may be agriculturally important. For use as an antiparasitic agent in animals the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A may be administered internally either orally or by injection, or topically as a liquid drench or as a shampoo. For oral administration, the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A may be administered in capsule, tablet, or drench bolus form or alternatively they can be mixed in the animals feed. The capsules, tablets, and drenches boluses are comprised of the active ingredient in combination with an appropriate carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate. These unit dosage forms are prepared by intimately mixing the active ingredient with suitable finely-powdered inert ingredients including diluents, fillers, disintegrating agents, suspending agents, and/or binders such that a uniform mixture solution or suspension is obtained. An inert ingredient is one that will not react with the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A and which is non toxic to the animal being treated. Suitable inert ingredients include starch, lactose, talc, magnesium stearate, vegetable gums and oils, and the like. These formulations may contain a widely variable amount of the active and inactive ingredients depending on numerous factors such as the size and type of the animal species to be treated and the type and severity of the infection. The active ingredient may also be administered as an additive to the feed by simply mixing the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A with the feedstuff or by applying the compound to the surface of the feed. Alternatively the active ingredient may be mixed with an inert carrier and the resulting composition may then either be mixed with the feed or fed directly to die animal. Suitable inert carriers include corn meal, citrus meal, fermentation residues, soya grits, dried grains and the like. The active ingredients are intimately mixed with these inert carriers by grinding, stirring, milling, or tumbling such that the final composition contains from 0.001 to 5.0% by weight of the active ingredient. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A may alternatively be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. Injection may be either intramuscular, intraruminal, intratracheal, or subcutaneous. The injectable formulation consists of the active ingredient mixed with an appropriate inert liquid carrier. Acceptable liquid carriers include the vegetable oils such as peanut oil, cotton seed oil, sesame oil and the like as well as organic solvents such as solketal, glycerol formal and the like. As an alternative, aqueous parenteral formulations may also be used. The vegetable oils are the preferred liquid carriers. The formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.005 to 20% by weight of the active ingredient. Topical application of the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A is possible through the use of a liquid drench or a shampoo containing the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A as an aqueous solution or suspension. These formulations generally contain a suspending agent such as bentonite and normally will also contain an antifoaming agent. Formulations containing from 0.005 to 20% by weight of the active ingredient are acceptable. Preferred formulations are those containing from 0.5 to 5% by weight of the 25-methylene compounds (VII), 24,25-epoxy compounds (VOI) and N-(18a)- demethyl-2-deoxoparaherquamide A. The 25 -methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A are primarily useful as antiparasitic agents for the treatment and or prevention of helminthiasis in domestic animals such as cattle, sheep, horses, dogs, cats, goats, swine, and poultry. They are also useful in the prevention and treatment of parasitic infections of these animals by ectoparasites such as ticks, mites, lice, fleas and the like. They are also effective in the treatment of parasitic infections of humans. In treating such infections the 25 -methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A may be used individually or in combination with each other or with other unrelated antiparasitic agents. The dosage of the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A required for best results depends on several factors such as the species and size of the animal, the type and severity of the infection, the method of administration and the particular 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A used. Oral administration of the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A at dose level of from 0.005 to 50 mg per kg of animal body weight either in a single dose or in several doses spaced a few days apart, generally gives good results. A single dose of one of the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)- demethyl-2-deoxoparaherquamide A normally gives excellent control however repeat doses may be given to combat re-infection or for parasite species which are unusually persistent. The techniques for administering the 25-methylene compounds (VII), 24,25- epoxy compounds ~ (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A to animals are known to those skilled in the veterinary field. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N- (18a)-demethyl-2-deoxoparaherquamide A may also be used to combat agricultural pests which attack crops either in the field or in storage. The 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A are applied for such uses as sprays, dusts, emulsions and the like either to the growing plants or the harvested crops. The techniques for applying the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A in this manner are known to those skilled in the agricultural arts. The exact dosage and frequency of administration depends on the particular 25- methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2- deoxoparaherquamide A used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the 25-methylene compounds (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethyl-2-deoxoparaherquamide A in the patient's blood and/or the patient's response to the particular condition being treated. DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims. I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Z j " or "R j " where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z j would represent a bivalent variable if attached to the formula CH 3 -C(-Z, _ )H. Groups R j and R- would represent monovalent variable substituents if attached to the formula C^-CH^- R j XR -H. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R j and R- are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, diese carbon atoms are designated as C j , where "i" is the integer corresponding to the carbon atom number. For example, C 6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term "Rg" represents a variable substituent (either monovalent or bivalent) at the C 6 position. Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" in general represents a bond between two atoms in the chain. Thus CH 3 -O-CH 2 -CH(R j )-CH 3 represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol "=" represents a double bond, e.g., CH 2 -C(R i )-O-CH 3 , and the symbol "≡" represents a triple bond, e.g., HC≡C-CH(R j )- CH 2 -CH 3 . Carbonyl groups are represented in either one of two ways: -CO- or - C(-O)-, with the former being preferred for simplicity. Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear fashion by N -C(CH 3 )-CH-CC1-CH«C H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-l-piperazinyl can be represented by -N*-(CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C*H 2 . A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, -C(X | )(X 2 )- the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X j ) which is "below" another substituent (X 2 ) will be identified as being in the alpha (α) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol "- - -" or "...". The corresponding substituent attached "above" (X 2 ) the other (X j ) is identified as being in the beta (β) configuration and is indicated by an unbroken line attachment to the carbon atom. When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable R; attached to a carbon atom as -C(-R j )- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents α-R j • and β-R j _ k - When a bivalent variable, R j , is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α-R j :β-R j _ k " or some variant thereof. In such a case both α-R j • and β- R j _ k are attached to the carbon atom to give -C(α-R i :)(β-R i . k )-. For example, when the bivalent variable R 6 , -C(-R 6 )- is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are α-R 6 _ | :β-Rg_ 2 , .... α-R 6 _ o : -R^_ j0 , etc, giving -C(α-R 6 _ j )(β-R 6 _ 2 )- -C(α-R 6 . 9 )(β-R 6.10 )-, etc. Likewise, for the bivalent variable R, , , -C(-R j j )-, two monovalent variable substituents are For a ring substituent for which separate α and β orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the α and β designations are omitted. Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -Cι(R:)H-C 2 (R )H- (C j and C 2 define arbitrarily a first and second carbon atom, respectively) R j and R j may be defined to be taken together to form (1) a second bond between C j and C 2 or (2) a bivalent group such as oxa (-O-) and die formula thereby describes an epoxide. When R j and R: are taken together to form a more complex entity, such as the group - X-Y-, then the orientation of the entity is such that C j in the above formula is bonded to X and C 2 is bonded to Y. Thus, by convention the designation "... R j and R: are taken together to form -CH 2 -CH -O-CO- ..." means a lactone in which the carbonyl is bonded to C 2 . However, when designated "... R j and R j are taken together to form - CO-O-CH 2 -CH 2 -the convention means a lactone in which the carbonyl is bonded to C, . The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "C j - C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C j -C 4 alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C 2 -C 4 alkoxycarbonyl describes a group CH 3 - (CH 2 ) n -O-CO- where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the "C j -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C, - C 3 )alkoxycarbonyl has the same meaning as C 2 -C alkoxycarbonyl because the "C j -C 3 " refers only to the carbon atom content of the alkoxy group. Similarly while both C 2 -C 6 alkoxyalkyl and (C j -C 3 )alkoxy(C j -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms. When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent. II. DEFINITIONS All temperatures are in degrees Centigrade. THF refers to tetrahydrofuran. DMSO refers to dimethylsulfoxide. LDA refers to lithium diisopropylamide. TEA refers to triethylamine. DMF refers to dimethylformamide. Saline refers to an aqueous saturated sodium chloride solution. Chromatography (column and flash chromatography) refers to purification separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give die desired compound(s). NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane. -φ refers to phenyl (C 6 H 5 ). MS refers to mass spectrometry expressed as m/e, m z or mass/charge unit. [M + H] + refers to the positive ion of a parent plus a hydrogen atom. El refers to electron impact. Cl refers to chemical ionization. FAB refers to fast atom bombardment. HRMS refers to high resolution mass spectrometry. Ether refers to diethyl ether. Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. When solvent pairs are used, die ratios of solvents used are volume/volume (v/v). When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt v). _ indicates that there are 2 possible orientations for the attached group, (1) α or β when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond. UC#### refers to the Upjohn Culture number abed. EXAMPLES Without further elaboration, it is believed diat one skilled in die art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of die invention and are to be construed as merely illustrative, and not limitations of die preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. PREPARATION 1 16-Iodo- 17 -cyanomarcfortine A as a mixture of diastereomers (Formula 5) Solid cyanogen iodide (11.7 g, 76.5 mmol) is added to a solution of marcfortine A (10.5 g, 22 mmol) in chloroform (150 mL) and the reaction mixture heated under reflux until all of the marcfortine A has been consumed (about 5 hr). The resulting mixture is cooled to 20-25°, diluted with methylene chloride (100 mL), washed with sat sodium bicarbonate and then washed with a solution of sodium sulfite. The organic phase is separated, dried over magnesium sulfate and concentrated to dryness. The resulting crude solid is subjected to chromatography (silica gel; ethyl acetate/hexane, 3/2) to give the title compound. PREPARATION 2 16, 17-Dehydro- 17-cyanomarcfortine A (Formula 6) 16-Iodo-17-cyanomarcfortine A (PREPARATION 1, 9.5 g, 15 mmol) is dissolved in methanol (150 mL), and aqueous potassium hydroxide (45%, 3 mL) is added. The reaction mixture is stirred at 20-25° for 2 hr. Water is added and the resulting precipitate collected by filtration, washed with water and dried overnight under reduced pressure to give the title compoound. PREPARATION 3 17-Ketomarcfortine A (Formula 7) Selenium dioxide (2.9 g, 26 mmol) is added to a solution of 16,17-dehydro-17- cyanomarcfortine A (PREPARATION 2, 6.0 g, 10 mmol) in 95% ethanol (100 mL) and die reaction mixture stirred at 20-25° for 2 hr. The reaction is quenched by adding saturated sodium bicarbonate (100 mL). The resulting mixture is extracted with methylene chloride (2 x 200 mL). The extracts are combined, dried (magnesium sulfate), and concentrated to give crude product. This material is purified by chromotography (silica gel; ethyl acetate) to give the title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 28 H 33 N 3 O 5 +H - 492.2498, measured - 492.2478. Alternatively, and more preferably, the title compound can be synthesized by using p-toluenesufonic acid. Thus, p-toluenesulfonic acid monohydrate (1 g) is added to a solution of 16,17-dehydro-17-cyanomarcfortine A (10 g) in 95% medianol (50 mL) and the reaction mixture stirred at 20-25° for 1 hr. Triethylamine (2 mL) is added to d e mixture and die solvent is evaporated. The residue is triturated with aqueous sodium carbonate solution (10%, 100 mL) and die solid is filter and dried to give the title compound as a solid (90% yield). PREPARATION 4 15,16-Dehydro-17-ketomarcfortine A (Formula 8) A solution of lithium diisopropylamide is prepared from a solution of n-butyl lidiium (1.6 M, 9.9 mL, 15.4 mmol) in hexane and diisopropylamine (2.2 mL, 15.7 mmol). This is diluted with anhydrous tetrahydrofuran (THF, 20 mL) and cooled to at - 78°. A solution of 17-ketomarcfortine A (PREPARATION 3, 2.0 g, 4.1 mmol) in anhydrous THF (20 mL) is added dropwise and the reaction mixture allowed to warm to -40° during 1 hr. The mixture is again cooled to -78° and treated dropwise widi phenyl selenium chloride (19 mg, 5.2 mmol) in THF (10 mL). After 5 min the reaction is quenched wid saturated sodium bicarbonate, extracted widi methylene chloride, dried (magnesium sulfate), and concentrated to give a solid which is used witiiout further purification. This material is dissolved in THF (150 mL) and treated wid hydrogen peroxide (30%, 1.5 mL) at 0°. The cooling bath is removed and die reaction mixture stirred for 30 min at 20-25°. The reaction is quenched by adding sodium hydroxide (1 N, 100 mL). The mixture is extracted with mediylene chloride (2 X 200 mL). The extracts are combined, dried (magnesium sulfate) and concentrated to give crude product. This material is purified by chromatography (silica gel; ediyl acetate) to give the title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 28 H 31 N 3 O 5 +H = 490.2342, measured - 490.2345. PREPARATION 5 14α-Hydroxy-15,16-dehydro-17-ketomarcfortine A (Formula 9a) Using Oxaziridine Chemistry A solution of potassium bis(trimethylsilyl)amide in toluene (0.5 M, 1 mL, 0.5 mmol) is added dropwise to a solution of 15,16-dehydro-17-ketomarcfortine A (PREPARATION 4, 66 mg, 0.14 mmol) in THF (2 mL) at -78°. The resulting mixture is allowed to warm to -40° during 1 hr. The reaction mixture is cooled to -78°, stirred 15 min and then treated by d e dropwise addition of a solution of 2-phenylsulfonyl-3- phenyloxaziridine (42 mg, 0.16 mmol) in THF (2 mL). The mixture is stirred 5 min after which the reaction is quenched by adding sodium bicarbonate. The mixture is extracted with methylene chloride (2 x 25 mL). The extracts are combined, dried (magnesium sulfate) and concentrated to give crude material. This is purified by preparative thin layer chromatography (silica gel; ediyl acetate) to give the title compound, HRMS (FAB, M Z [M+H]) calculated for C 2g H 31 N 3 O 6 +H = 506.2291, measured - 506.2280. 14,15-Dehydro-16-hydroxy-17-ketomarcfortine A (14 mg, 20%) is also obtained. PREPARATION 6 14α-Hydroxy-15,16-dehydro-17-ketomarcfortine A (Formula 9a), 15,16-dehydro-14,17-diketomarcfortine A (Formula 11) and 14,15- dehydro-16,17-diketomarcfortine A (Formula 24) Using Selenium Dioxide 15,16-Dehydro-17-ketomarcfortine A (PREPARATION 4, 1.29 g, 2.6 mmol) is dissolved in p-dioxane (30 mL) and treated with selenium dioxide (390 mg). The mixture is refluxed for 1 hr and die solvent evaporated under reduced pressure. The residue is triturated with methylene chloride (30 mL) and filtered. The filtrate is concentrated and die residue subjected to chromatography (silica gel; medianol/ethyl acetate, 1/20) to give 14α-hydroxy-15,16-dehydro-17-ketomarcfortine A (430 mg, 32%) as a solid. 15,16-Dehydro-14,17-diketomarcfortine A (Formula 1 1, 212 mg, 16%) and 14,15-dehydro-16,17-diketomarcfortine A (Formula 24, 106 mg, 8%) are also obtained from d e chromatography. PREPARATION 7 15,16-dehydro- 14, 17-diketomarcfortine A (Formula 11 ) 14α-Hydroxy-15,16-dehydro-17-ketomarcfortine A (PREPARATION 6, 60 mg, Formula 9a) is dissolved in mediylene chloride (10 mL) and treated widi manganese dioxide (60 mg). The mixture is stirred at 20-25° for 1 hr and concentrated. Preparative thin layer chromatography of the residue (silica gel; methylene chloride/ethyl acetate, 50/50) gives the title compound. PREPARATION 8 14α-hydroxymarcfortine A (Formula 10) 14α-Hydroxy-15,16-dehydro-17-ketomarcfortine A (PREPARATION 6, 20 mg, 0.040 mmol) is dissolved in THF (5 mL) and treated wid a solution of lithium aluminum hydride (1 M, 0.11 mL, 0.1 1 mmol) in THF at 0°. The mixture is stirred for 0.5 hr at 0° after which a solution of sodium bicarbonate (10%) is added. The mixture is extracted widi methylene chloride (2 x 10 mL). The extracts are combined, dried (magnesium sulfate) and the solvent removed under reduced pressure. Preparative thin layer chromatography (silica gel; methanol/ethyl acetate, 10/90) gives the title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 2g H 35 N 3 O 5 +H - 494.2655, measured = 494.2653. PREPARATION 9 14α-Hydroxy-17-ketomarcfortine A (Formula 12a) 14α-Hydroxy-15,16-dehydro-17-ketomarcfortine A (formula 9a, PREPARATION 6, 50 mg, 0.1 mmol) is dissolved in THF (5 mL) and treated wid a solution of lidiium triethylborohydride in THF (1 M, 0.7 mL) at -78°. The mixture is stirred for 0.5 hr at - 78°. The reaction is quenched by adding methanol (1 mL) and the mixture is concentrated. The resulting solid is subjected to chromatography (silica gel; methanol/methylene chloride, 1/20) to give die title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 2g H 33 N 3 O 6 + H - 508.2447, measured - 508.2437. PREPARATION 10 Preparation of 14α-hydroxy-17-ketomarcfortine A (Formula 12a) and 14β-hydroxy-17-ketomarcfortine A from 15,16-dehydro- 14,17-diketomarcfortine A (Formula 11) 15,16-Dehydro-14,17-diketomarcfortine A (Formula 11, PREPARATION 6, 470 mg, 0.93 mmol) is dissolved in THF and treated with a solution of lidiium borohydride in THF (1 M, 2 mL) at 20-25°. The mixture is stirred for 2 hr after which a solution of sodium bicarbonate (10%) is added. The mixture is extracted widi methylene chloride (2 x 20 mL). The extracts are combined, dried (magnesium sulfate) and die solvent evaporated. The residue contains a mixture of die two epimers which are readily separated by chromatography (silica gel; methanol ethyl acetate, 1/20) - 14α-hydroxy- 17-ketomarcfortine A (90 mg, 19%) and I4β-hydroxy-17-ketomarcfortine A (94 mg, 20%). PREPARATION 11 Preparation of 14α-hydroxymarcfortine A (Formula 10) from 14α- hydroxy-17-ketomarcfortine A (Formula 12a) 14α-Hydroxy-17-ketomarcfortine A (Formula 12a, PREPARATION 10, 413 mg, 0.81 mmol) is dissolved in THF (20 mL) and treated with a solution of borane THF complex in THF (1 M, 2.43 mL) at 0°. The mixture is stirred for 2.25 hr. The mixture is stirred for 0.5 hr after which medianol (3 mL) is added. After the solvent is evaporated, die residue is subjected to chromatography (silica gel; medianol/ethyl acetate, 1/16) to give the title compound. PREAPARATION 12 14,17-Diketomarcfortine A (Formula 13) A solution of oxalyl chloride (40 μL) in anhydrous methylene chloride (5 mL) is treated with dimediyl sulfoxide (45 μL) at -78°. The mixture is stirred for 1 hr at -78°. A solution of 14α-hydroxy-17-ketomarcfortine A (PREPARATION 11, 27 mg) in meuiylene chloride (2 mL) is added dropwise. The reaction mixture is stirred 20 min at -78°. Triethylamine (0.3 mL) is added to the reaction mixture which is allowed to warm to 20-25° during 20 min. The mixture is partitioned between sodium carbonate (10%, 10 mL) and med ylene chloride (10 mL). The organic layer is separated, dried (magnesium sulfate) and concentrated. The residue is subjected to chromatography (silica gel; methanol/methylene chloride, 1/20) to give the title compound, HRMS (FAB, M Z, [M+H]) calculated for C 2g H 31 N 3 O 6 + H - 506.2291, measured - 506.2280. PREPARATION 13 14α-Hydroxy-14β-methyl-17-ketomarcfortine A (Formula 14a) A solution of 14,17-Diketomarcfortine A (PREPARATION 12, 16 mg, 0.032 mmol) in methylene chloride (5 mL) at -78° is treated widi a solution of methylmagnesium bromide (3 M, 0.16 mL, 0.48 mmol) in ether at -78°. The resulting mixture is stirred for 0.5 hr at -78°. The reaction is quenched by adding sodium carbonate (10%, a few drops). The mixture is diluted widi methylene chloride (10 mL), dried (magnesium sulfate) and concentrated. The residue is subjected to chromatography (silica gel; methanol/methylene chloride, 1/20) to give 14α-hydroxy-14β-methyl-17-ketomarcfortine A (8 mg, 50%, R f - 0.25), HRMS (FAB, M/Z, [M+H]) calculated for C 29 H 35 N 3 O 6 + H - 522.2604, measured = 522.2620. Also obtained from the layer is 14β-hydroxy-14 -medιyl-17-ketomarcfortine A (1.2 mg, 7%, R f = 0.4), HRMS (FAB, M/Z, [M+H]) calculated for C 29 H 35 N 3 O 6 + H = 522.2604, measured - 522.2630. The 6: 1 ratio of products thus obtained is increased to greater than 50: 1 and the yield increased to 80% when THF is used as the reaction solvent in place of methylene chloride. PREPARATION 14 14α-hydroxy-14β-medιylmarcfortine A (Formula 15) A solution of 14α-hydroxy-14β-methyl-17-ketomarcfortine A (PREPARATION 13, 5mg, 0.01 mmol) in THF (5 mL) is treated with a solution of liuiium aluminum hydride (1M, 0.03 mL, 0.03 mmol) in THF at 0°. The mixture is stirred for 0.5 hr at 0° after which a solution of sodium bicarbonate (10%) is added. The mixture is extracted with methylene chloride (2 x 5 mL). The extracts are combined, dried (magnesium sulfate) and the solvent evaporated. Preparative TLC (silica gel; methanol methylene chloride, 1/20) gives the title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 29 H 37 N 3 O 5 + H - 508.2811 , measured = 508.2816. PREPARATION 15 14-Ketomarcfortine A (Formula 16) A solution of oxalyl chloride (150 μL) in anhydrous methylene chloride (20 mL) is treated with DMSO (170 μL) at -78°. The mixture is stirred for 1 hr at -78°. A solution of 14α-hydroxymarcfortine A (PREPARATION 1 1 , 1 10 mg) in methylene chloride (5 mL) is added dropwise. The reaction mixture is stirred 20 min at -78°. TEA (1 mL) is added to die reaction mixture which is allowed to warm to 20-25° during 20 min. The mixture is partitioned between sodium carbonate (10%, 20 mL) and mediylene chloride (20 mL). The organic layer is separated, dried (magnesium sulfate) and concentrated. The residue is subjected to chromatography (silica gel; medianol/methylene chloride, 1/25) to give the title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 2g H 33 N 3 O 5 + H - 492.2498, measured - 492.2510. PREPARATION 16 14β-Hydroxymarcfortine A (Formula 17) A solution of 14-ketomarcfortine A (PREPARATION 15, 10 mg) in methanol (2 mL) is treated widi sodium borohydride (5 mg) at 0°. The mixture is stirred for 0.5 hr at 0° after which a solution of sodium bicarbonate (10%) is added. The mixture is extracted widi mediylene chloride (2 x 10 mL). The extracts are combined, dried (magnesium sulfate) and die solvent evaporated. Preparative TLC (silica gel, medianol ediyl acetate, 1/16) gives die title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 2g H 35 N 3 O 5 + H - 494.2655, measured = 494.2653. PREPARATION 17 14α-Hydroxymarcfortine A N-oxide (Formula 18) A solution of 14α-hydroxymarcfortine A (PREPARATION 11, 15 mg) in mediylene chloride (3 mL) is treated widi m-chloroperoxybenzoic acid (15 mg) at 0°. After d e mixture is stirred for 0.5 hr at 0°, treated widi TEA (30 μL) and concentrated. Preparative TLC (silica gel; medianol/methylene chloride, 1/8) give die title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 2g H 35 N 3 O 6 + H - 510.2604, measured = 510.2615. PREPARATION 18 14α-Hydroxy- 14β-ethylmarcfortine A (Formula 19) A solution of 14-ketomarcfortine A (PREPARATION 15, 25 mg, 0.05 mmol) in THF (5 mL) at -78° is treated widi a solution of ethylmagnesium bromide (3 M, 0.15 mL, 0.45 mmol) in ether at -78°. The resulting mixture is stirred for 0.5 hr at -78°. The reaction mixture is allowed to warm to 20-25° during 20 min. The reaction is quenched by adding sodium carbonate (10%, a few drops). The mixture is diluted widi mediylene chloride (10 mL), dried (magnesium sulfate) and concentrated. The residue is subjected to chromatography (silica gel; medianol/methylene chloride, 1/20) to give the title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 30 H 39 N 3 O 5 + H - 522.2968, measured - 522.2983. PREPARATION 19 Preparation of 14β-methylmarcfortine A from 14α-hydroxy-14β- methylmarcfortine A A solution of potassium bis(trimethylsilyl)amide in toluene (0.5 M, 1 mL, 0.5 mmol) is added dropwise to a solution of 14α-hydroxy-14β-medιylmarcfortine A (Formula 15, PREPARATION 14, 66 mg, 0.14 mmol) in THF (2 mL) at -78°. The resulting mixture is allowed to warm to -40° during 1 hr. The reaction mixture is cooled -78°, stirred 15 min, and d en treated by die dropwise addition of a solution of phenylchloroduonoformate (0.094 mL, 0.7 mmol) in THF (2 mL). After 10 min the dry ice badi is removed. After further reaction for 3 hr, the reaction is quenched by adding sodium bicarbonate. The mixture is extracted widi meuiylene chloride (2 x 25 mL). The extracts are combined, dried (magnesium sulfate) and concentrated to give crude material. This is purified by preparative TLC (silica gel, ediyl acetate) to give 14α-O- phenoxyϋiiocarbonyl-14β-medιylmarcfortine A. To a solution of 14α-O-phenoxythiocarbonyl-14β-methylmarcfortine A (64 mg, 0.1 mmol) in toluene (5 mL) is added AIBN (2,2'-azabisisobutyonitrile, 3.3 mg) followed by addition of tributyltin hydride (54 μL, 0.2 mmol). The mixture is refluxed for 3 hr. After the solvent is evaporated, die residue is purified by preparative TLC (silica gel, ethyl acetate) to give 14β-methylmarcfortine A. PREPARATION 20 An Alternative Synthesis Of 17-ketomarcfortine A (Formula 7) To marcfortine A (65 g, 0.136 mol) and sodium bicarbonate (137 g, 1.63 mol) in tetrahydrofuran (THF, 2 L) and water (1.25 L) at reflux is added iodine (206 g, 0.81 mol) dropwise in THF (1.25 L) over a one hour period. (Alternatively, d e mixture can be stirred at 20-25° for 16 hours). After being allowed to slowly cool to 20-25° (2.5 hr), die reaction is quenched wiϋi saturated sodium tiiiosulfate (1.5 L) and extracted widi etiiyl acetate (2 X 1 L). The combined organic layers are washed with saturated sodium tiiiosulfate (1 L), dried (magnesium sulfate), filtered, evaporated and dried overnight in die vacuum oven (65°) to give 62 g of crude 17-ketomarcfortine A (Formula 7), NMR (300 MHz, CDC1 3 ) 7.68, 6.80, 6.70, 6.32, 4.90, 3.75, 3.23, 3.09, 2.80, 2.65, 2.49-2.21, 2.08, 1.98-1.45, 1.46, 1.44, 1.09 and 0.90 δ. Alternatively, iodine monochloride (IC1) can be used instead of iodine. PREPARATION 21 16-Dithiophenyl-17-ketomarcfortine A (Formula 20) The crude 17-ketomarcfortine A (PREPARATION 20, 5 g, 10.2 mmol) is added via a cannula in THF (150 mL) at -78° to an LDA solution which was prepared by adding π-butyllithium (1.6 M, 24.8 mL, 0.04 mol) dropwise to diisopropyl amine (5.7 mL, 0.041 mol) at O° in THF (100 mL). The reaction mixture is allowed to slowly warm to -50° over one hr. The resulting mixture is then treated widi phenyl disulfide (4.4 g, 0.02 mol). The reaction is immediately quenched with saturated sodium bicarbonate solution (100 mL) and extracted with methylene chloride (300 mL). The organic phase is dried (magnesium sulfate), concentrated (8 g) and chromatographed (silica gel, 120 g; ethyl acetate/hexane, 60/40) to give die the title compound, MS (FAB) - 708 (M + + H); NMR (300 MHz, CDC1 3 ) 7.74, 7.71, 7.64, 7.45-7.30, 6.81 , 6.72, 6.32, 4.91, 3.70, 3.16, 3.01, 2.75, 2.53, 2.35, 2.15-1.50, 1.47, 1.45, 1.06 and 0.82 δ. PREPARATION 22 16-Thiophenyl- 16-sulfoxyphenyl- 17-ketomarcfortine A (Formula 21) To 16-dithioρhenyl-17-ketomarcfortine A (PREPARATION 21, 10 g, 14 mmol) in methylene chloride (250 mL) at -78° under a nitrogen atmosphere is added m- chloroperoxybenzoic acid (64%, 4.2 g, 15.5 mmol) dropwise in methylene chloride (200 mL) for 15 min. The reaction is immediately quenched widi saturated sodium thiosulfate (200 mL), diluted widi saturated sodium bicarbonate (200 mL) and extracted into methylene chloride (200 mL). Drying (magnesium sulfate), followed by concentration under reduced pressure gives the title compound NMR (300 MHz, CDC1 3 ) 8.0-7.29, 6.80, 6.70, 6.31, 4.90, 3.68, 3.41, 3.14, 3.07, 2.82, 2.80-2.65, 2.16, 2.05-1.1, 1.47, 1.43, 0.96 and 0.83 δ. PREPARATION 23 16-Thiophenyl-15,16-dehydro-17-ketomarcfortine A (Formula 22) The crude 16-thiophenyl-16-sulfoxy phenyl- 17-ketomarcfortine A (Formula 21, PREPARATION 22, 11 g) is refluxed in toluene (250 mL) for 45 minutes, cooled to 20-25°, diluted with saturated sodium bicarbonate (300 mL) and extracted with ethyl acetate (300 mL). The organic layer is dried (magnesium sulfate) and concentrated to give the title compound, MS (FAB) = 598(M + + H); HRMS (M/Z, M + + H) C 34 H 35 N 3 O 5 S + H j , calculate -= 598.2376, observed - 598.2387; NMR (300 MHz, CDC1 3 ) 8.18, 7.55-7.45, 7.29-7.45, 6.83, 6.70, 6.34, 5.92, 4.91 , 3.87, 3.30, 3.21, 3.08, 2.80, 2.35, 2.10, 2.03, 1.78, 1.46, 1.44, 1.1 1 and 0.88 δ. PREPARATION 24 16-Sulfoxypheny 1- 15,16-dehydro- 17-ketomarcfortine A (Formula 23) To the crude 16-thiophenyl-15,16-dehydro-17-ketomarfortine A (Formula 22, PREPARATION 23, 10.6 g) in methylene chloride (300 mL) at -78° is added m- chloroperbenzoic acid (64%, 2.8 g) dropwise in methylene chloride (125 mL). The reaction is quenched widi saturated sodium diiosulfate (300 mL) and saturated sodium bicarbonate (300 mL), then extracted into mediylene chloride (300 mL). The organic layer is dried (magnesium sulfate), filtered and concentrated to give the title compound, NMR (300 MHz, CDC1 3 ) 7.75-7.3, 6.81, 6.75-6.6, 6.31, 4.90, 3.78-3.58, 3.22, 2.98, 2.88-2.45, 2.12-1.55, 1.46, 1.44, 1.12 and 0.88 δ. PREPARATION 25 14α-Hydroxy-15,16-dehydro-17-ketomarcfortine A (Formula 9a) To the crude 16-sulfoxyphenyl-15,16-dehydro-17-ketomarfortine A (Formula 23, PREPARATION 24, 13 g) in aqueous methanol (10/1, 300 mL) is added diethylamine (15 mL). After refluxing for 0.5 hr the reaction mixture is cooled to 20-25°, diluted wid water (450 mL), and extracted into methylene chloride (500 mL). Drying (magnesium sulfate), followed by concentration and chromatography (silica gel, 130 g; acetone/methylene chloride 30/70) the title compound. PREPARATION 26 14α-Hydroxy-14β-vinylmarcfortine A (Formula 30) A solution of 14-ketomarcfortine A (Formula 16, PREPARATION 15, 200 mg, 0.4 mmol) in THF (5 mL) at -78° is treated with a solution of vinylmagnesium bromide (1 M, 4.0 mL, 4 mmol) in THF at -78°. The resulting mixture is stirred for 2 hr at -78° and warmed to 20-25°. It is stirred at 20-25° for 2 hr. The reaction is quenched by adding sodium carbonate (10%, 3 mL). The mixture is diluted widi meuiylene chloride (30 mL), washed widi saturated ammonium chloride solution, dried (magnesium sulfate) and concentrated. The residue is subjected to chromatography (silica gel; hexane/acetone, 6/4) to give the title compound, NMR (300 MHz, CDC1 3 ) 7.86, 6.78 & 6.67, 6.32, 6.58, 5.43, 5.18, 4.89, 3.7, 3.11 , 2.95, 2.8-1.5, 1.44, 1.08 and 0.82 δ; MS (FAB, M/Z, [M + H]) - 520. PREPARATION 27 14α-Hydroxy-14β-methylmarcfortine A N-oxide (Formula 32) A solution of 14α-hydroxymarcfortine A (PREPARATION 11 , 30 mg) in methylene chloride (3 mL) is treated with m-chloroperoxybenzoic acid (20 mg) at 0°. After the mixture is stirred for 0.5 hR, then partitioned between aqueous sodium bicarbonate (5%, 10 mL) and methylene chloride (20 mL). The layers are separated and d e aqueous layer extracted with methylene chloride (10 mL). The combined organic extracts are dried wid magnesium sulfate, filtered, and evaporated under reduced pressure at 0°, treated with trietiiylamine (30 μL) and concentrated to produce the title compound, NMR (300 MHz, CD 3 OD) 6.91 & 6.70, 6.36, 4.91, 4.08 & 3.76, 3.5-3.1, 3.12, 2.8-1.6, 1.46 & 1.44, 1.50 and 0.93 (s, 3H) δ. PREPARATION 28 14α-Hydroxy-15α-methylmarcfortine A (Formula 35) 14α-Hydroxy-15α-methyl-17-ketomarcfortine A (PREPARATION 32, 90 mg, 0.18 mmol) is dissolved in THF (10 mL) and treated with borane dimediyl sulfide complex (12 M, 0.18 mL) at 0°. The mixture is stirred for 2 hr at 0°, dien methanol (0.4 mL) is added and stirred for an additional 1 hr. After die solvent is evaporated, die residue is subjected to chromatography (silica gel; acetone/methylene chloride, 30/70) to give the title compound, NMR (300 MHz, CDC1 3 ) 8.39, 6.79 & 6.70, 6.36, 4.91, 3.81, 3.67, 3.03, 3.1 1, 2.68 & 1.86, 2.7-1.2, 1.44, 1.02, 1.11 and 0.85 δ; HRMS (FAB, M/Z, [M+H]) calculated for C 29 H 37 N 3 O 5 + H = 508.2811, measured - 508.2840. PREPARATION 29 14,17-diketo-15α-methylmarcfortine A (Formula 36) A solution of oxalyl chloride (40 μL) in anhydrous meuiylene chloride (5 mL) is treated widi DMSO (45 μL) at -78°. The mixture is stirred for 1 hr at -78°. A solution of 14α-hydroxy-15α-methyl-17-ketomarcfortine A (PREPARATION 33, 27 mg) in methylene chloride (2 mL) is added dropwise. The reaction mixture is stirred 20 min at -78°. TEA (0.3 mL) is added to the reaction mixture which is allowed to warm to 20- 25° during 20 min. The mixture is partitioned between sodium carbonate (10%, 10 mL) and methylene chloride (10 mL). The organic layer is dried (magnesium sulfate) and concentrated. The residue is subjected to chromatography (silica gel; methanol methylene chloride, 1/20) to give the title compound, HRMS (FAB, M/Z, [M+H]) calculated for C 2g H 31 N 3 O 6 + H - 506.2291, measured - 506.2280. PREPARATION 30 14α-hydroxy-14β-methyl-15α-methyl-17-ketomarcfortine A (Formula 37) A solution of 14,17-Diketo-15α-methylmarcfortine A (PREPARATION 29, 25 mg, 0.05 mmol) in methylene chloride (5 mL) at -78° is treated widi a solution of mediylmagnesium bromide (3 M, 0.2 mL, 0.6 mmol) in ether at -78°. The resulting mixture is stirred for 0.5 hr at -78°. The reaction is quenched by adding sodium carbonate (10%, a few drops). The mixture is diluted with mediylene chloride (10 mL), dried (magnesium sulfate) and concentrated. The residue is subjected to chromatography (silica gel; methanol methylene chloride, 4/96) to give the title compound, NMR (300 MHz, CDC1 3 ) 8.13, 6.78, 6.70, 6.33, 4.91, 3.75, 3.16, 3.05, 2.78, 2.68-2.57, 2.42-2.0, 1.64, 1.45, 1.44, 1.11, 1.04 and 0.92 δ. PREPARATION 31 14α-hydroxy-14β-medιyl-15α-medιylmarcfortine A (Formula 38) 14α-Hydroxy-14β-methyl-15α-methyl-17-ketomarcfortine A (PREPARATION 30, 15 mg, 0.028 mmol) is dissolved in THF (10 mL) and treated with borane dimediyl sulfide complex (10 M, 0.02 mL) at 0°. The mixture is stirred for 2 hr at 0°, dien med anol (0.4 mL) is added and stirred for an additional 1 hr. After die solvent is evaporated, die residue is subjected to chromatography (silica gel; acetone/methylene chloride, 30/70) to give the title compound, NMR (300 MHz, CDC1 3 ) 7.82, 6.79, 6.67, 6.33, 4.90, 3.65, 3.09, 2.98, 2.69, 2.60-2.22, 2.06, 1.87, 1.85-1.75, 1.44, 1.43, 1.10, 0.94, and 0.86 δ. PREPARATION 32 14α-Hydroxy-15α-medιyl-17-ketomarcfortine A (Formula 34) A mixture of 14α-hydroxy-15,16-dehydro-17-ketomarcfortine A (Formula 9a, 300 mg) in THF (12 mL) is treated widi a solution of mediylmagnesium bromide (3 M, 1.0 mL, 5 equiv.) at 20-25°. The resulting mixture is refluxed for 1.5 hr dien cooled to 20- 25°. The reaction is quenched by adding saturated ammonium chloride (3 mL). The mixture is diluted widi mediylene chloride (30 mL), washed widi saturated ammonium chloride solution, dried over magnesium sulfate and concentrated. The concentrate is subjected to chromatography (silica gel; methanol/methylene chloride, 1/20) to give the title compound, NMR (300 MHz, CDC1 3 ) 7.90, 6.80 & 6.70, 6.32, 4.89, 4.36, 3.74, 3.20, 3.06, 2.78 & 2.10, 2.5-1.8, 1.46 & 1.44, 1.13, 1.12 and 0.88 δ. Alternatively, die title compound can be prepared by using lithium dimethyl cuprate reagent. To copper iodide (0.4 g, 0.002 mol) in THF at 0° is added metiiyl lithium (1.4 M, 9 mL, 0.013 mol) dropwise. The resulting mixture is stirred for 15 minuties then treated dropwise widi 14α-hydroxy-15,16-dehydro-17-ketomarcfortine A (Formula 9a, 0.5 g, 0.001 mol) in THF (12 mL) at 0°. Following 15 minutes of stirring the mixture is quenched widi saturated ammonium chloride (25 mL) and extracted into ethyl acetate (30 mL). The organic extract is dried over magnesium sulfate, filtered and concentrated to give crude material which is purified by a chromatotron (4mm plate; methanol/methylene chloride, 4/96) to give die tide compound. PREPARATION 33 14,17-Diketo-15α-methylmarcfortine A (Formula 36) A mixture of oxalyl chloride (40 μL) in anhydrous mediylene chloride (5 mL) is treated widi DMSO (45 μL) is formed at -78°. The mixture is stirred for 1 hr at -78°. A solution of 14α-hydroxy-15α-methyl-17-ketomarcfortine A (PREPARATION 33, 27 mg) in methylene chloride (2 mL) is added dropwise. The reaction mixture is stirred 20 min at -78°. Triediylamine (0.3 mL) is added to die reaction mixture which is allowed to warm to 20-25° during 20 min. The mixture is partitioned between sodium carbonate (10%, 10 mL) and mediylene chloride (10 mL). The phases are separated and die organic layer is dried over magnesium sulfate and concentrated. The concentrate is subjected to chromatography (silica gel; medianol methylene chloride, 1/20) to give the title compound, HRMS (FAB, M Z, [M+H]) calculated for C 2g H 31 N 3 O 6 + H = 506.2291 , measured = 506.2280. EXAMPLE 1 24,25,26,27,28-Pentanormarcfortine A (II) Marcfortine A (I, 8.5 g, 0.018 mol) is dissolved in formic acid (95% pure, 100 mL). The mixture is stirred at 20-25° for 16 hr. The volatile components are removed and die residue is redissolved in medianol (100 mL). The mixture is concentrated and d e residue is purified by chromatography (silica gel; methanol/mediylene chloride, 10/90) to give the title compound, selected NMR (300 MHz, CDC1 3 + CD 3 OD) 0.80, 1.09, 1.4-2.0, 2.2-2.8, 3.10, 3.87, 6.52 and 6.61 δ; MS (FAB, mlz, [M t H + ]) - 412. EXAMPLE 2 7-O-Prenyl-24,25,26,27,28-pentanormarcfortine A (III) To 4-bromo-2-methyl-2-butene (1.0 mL, 8.7 mmol) and potassium iodide (1.44 g, 8.7 mmol) which had been stirred in acetone (40 mL) for 5 min is added potassium carbonate (1.6 g, 11.7 mmol) followed by 24,25,26,27,28-pentanormarcfortine A (II, EXAMPLE 1, 1.2 g, 0.0029 mol) dropwise in acetone/water (10 mL/6 mL). The reaction mixture is stirred for 0.25 hr, quenched with a saturated solution of sodium sulfite (100 mL), and extracted into ediyl acetate (100 mL). The organic layer is dried over magnesum sulfate, filtered and concentrated under reduced pressure to give die title compound, NMR (400 MHz, CDC1 3 ) 7.90, 6.79, 6.57, 5.50, 4.49, 3.70, 3.10, 2.99, 2.66, 1.83, 2.55-2.5, 2.39, 2.29, 2.14, 1.95-1.30, 1.76, 1.61, 1.10 and 0.81 δ. EXAMPLE 3 7-O-(2 , ,3'-epoxy-3 l -methyl)butyl-24,25,26,27,28- pentanormarcfortine A (IV) To 7-prenyl-24,25,26,27,28-pentanormarcfortine A (III, EXAMPLE 3, 1.4 g, 2.9 mmol) in methylene chloride (30 mL) at 20-25° is added 3-chloroperbenzoic acid (2.4 g, 8.3 mmol) in one portion. Following 0.5 hr of stirring, sodium bisulfite (6 g, in 50 mL of water) is added and stirring is continued for 0.5 hr. The reaction is quenched with sodium bicarbonate (sat., 100 mL) and extracted into ethyl acetate (100 mL). The organic extract is separated and dried over magnesium sulfate, filtered and concentrated to give he title compound as a mixture of diastereomers which is used widiout any further purification, NMR (400 MHz, CDC1 3 ) 8.52, 8.44, 6.82, 6.59, 4.56-4.47, 3.92- 3.84, 3.69, 3.26-3.14, 3.1 1, 3.01 , 2.70-2.55, 3.39, 2.30, 2.15, 1.98-1.50, 1.41 , 1.40-1.20, 1.10, 0.82 and 0.81 δ. EXAMPLE 4 25-Hydroxy-24,25-dihydromarcfortine A (V) To 7-O-(2',3 l -epoxy-3'-methyl)-butyl-24,25,26,27,28-penta-nor-marcfortine A (IV, 1.2 g, 2.4 mmol) in THF (30 mL) at 20-25° under a nitrogen atmosphere is added tin (IV) chloride (0.2 mL) dropwise. After 0.25 hr of stirring the reaction is quenched with potassium fluoride (10% aqueous solution, 50 mL) and extracted into eti yl acetate (100 mL). The organic extract is separated and dried over magnesium sulfate, filtered and concentrated to give die title compound as a mixture of diastereomers which is used without any further purification. Selected NMR (400 MHz, CDC1 3 ) 8.17, 7.87, 6.80- 6.45, 4.40, 4.25, 4.05-3.90 and 3.15 δ. EXAMPLE 5 24,25-Dihydro-25-oxomarcfortine A (VI) To oxalyl chloride (0.045 mL) in methylene chloride (5 mL) at -78° is added DMSO (0.06 mL) slowly dropwise in mediylene chloride (1 mL). Following 0.25 hr of stirring at - 78°, 25-hydroxy-24,25-dihydromarcfortine A (V, EXAMPLE 4, 60 mg, 0.12 mmol) is added dropwise in mediylene chloride (1 mL). The reaction mixture is stirred for 0.25 hr, then quenched with TEA (0.25 mL) and stirred at 20-25° for 0.25 hr. The reaction mixture is partitioned between sodium bicarbonate (sat., 25 mL) and etiiyl acetate (25 mL). The organic extract is separated and dried over magnesium sulfate, filtered, concentrated and chromatographed (silica gel; methanol/metiiylene chloride (5/95) to give the title compound, NMR (400 MHz, CDC1 3 ) 7.45, 6.77, 6.64, 4.89, 3.70, 3.11, 3.02, 2.70, 1.85, 2.65, 2.40, 2.31, 2.15, 1.95-1.85, 1.80-1.0, 1.53, 1.51 , 1.13 and 0.85 δ; HRMS (FAB, M/Z [M+H]) calculated for C 2g H 35 N 3 O 5 +H - 494.2655, measured = 494.2662. EXAMPLE 6 24,25-Dihydro-25-methylenemarcfortine A (VU) To methyltriphenylphosphonium bromide (70 mg, 0.2 mmol) in ether (5 mL) at 20-25° is added n-butyllidiium (1.6 M in hexane, 0.13 mL, 0.2 mmol) dropwise. The resulting mixture is stirred for 5 min under a nitogen atmosphere at 20-25°, tiien treated dropwise with 24,25-dihydro-25-oxomarcfortine A (VI, EXAMPLE 5, 25 mg, 0.05 mmol) in THF (5 mL). The reaction mixture is stirred for 0.25 hr, quenched with water (25 mL) and extracted into etiiyl acetate (25 mL). The organic extract is separated and dried over magnesium sulfate, filtered, concentrated and chromatographed (silica gel; acetone/hexane, 40/60) to give the title compound, NMR (400 MHz, CDC1 3 ) 7.67, 6.72, 6.47, 5.24, 5.08, 4.90, 4.77, 3.60, 2.30, 3.04, 2.96, 2.60 & 1.78, 2.58-2.52, 2.23, 2.08, 1.88-1.20, 1.44 & 1.42 and 1.10 & 0.80 δ; HRMS (FAB, M/Z, [M+H]) calculated for C 29 H 37 N 3 O 4 +H ■= 492.2862, measured - 492.2858. EXAMPLE 7 24,25-Epoxymarcfortine A (VIII) A mixture of marcfortine A (I, 0.25 g, 0.5 mmol) and -chloroperbenzoic acid (60% pure, 0.4 g, 1.4 mmol) is stirred for 16 hr in methylene chloride (25 mL). The reaction mixture is treated widi sodium bisulfite (1.1 g in 15 mL water) stirred for 0.5 hr, quenched wid sodium bicarbonate (sat., 100 mL) and extracted into mediylene chloride (25 mL). The organic extract is dried over magnesium sulfate, filtered, concentrated and chromatographed (silica gel; acetone/metiiylene chloride, 40/60) to give die title compound as an inseparable mixture of diastereomers, selected NMR (400 MHz, CDC1 3 ) 8.01 & 7.86, 6.80 & 6.58, 5.36-5.30 & 3.00-2.97, 3.70, 3.12, 2.69 & 1.85 and 2.40 δ. EXAMPLE 8 24,25-dihydro-25-methyleneparaherquamide A (VU) Following the general procedure of EXAMPLES 1 -6 and making noncritical variations but starting with ppp A, die title compound is obtained. EXAMPLE 9 14α-Hydroxy-14β-metiιyl-24,25-dihydro-25-methylenemarcfortine A (VII) Following the general procedure of EXAMPLES 1-6 and making noncritical variations but starting with 14α-hydroxy-14β-medιylmarcfortine A, the title compound is obtained. EXAMPLE 10 14α-Hydroxy-15α-methyl-24,25-dihydro-25-medιylenemarcfortine A (VII) Following the general procedure of EXAMPLES 1 -6 and making noncritical variations but starting with 14α-hydroxy-15α-methylmarcfortine A, the title compound is obtained. EXAMPLE 11 24,25 -epoxyparaherquamide A (VIII) Following the general procedure of EXAMPLE 7 and making noncritical variations but starting with paraherquamide A, die title compound is obtained. EXAMPLE 12 14α-Hydroxy-14β-methyl-24,25-epoxymarcfortine A (VIII) Following die general procedure of EXAMPLE 7 and making noncritical variations but starting widi 14α-hydroxy-14β-methylmarcfortine A, the title compound is obtained. EXAMPLE 13 14α-Hydroxy-15α-methyl-24,25-epoxymarcfortine A (VIII) Following the general procedure of EXAMPLE 7 and making noncritical variations but starting widi 14α-hydroxy-15α-methylmarcfortine A, the title compound is obtained. EXAMPLE 14 N-(18a)-demethyl-2-deoxoparaherquamide A (method 1) Following die procedure set forth in International Publication WO92/00300, N- (18a)-demed ylparaherquamide A (50 mg, 0.1 mmol) is dissolved in etiiylene glycol dimediyl ether (glyme, 5 mL) and water (0.5 mL). This mixture is then treated widi lidiium borohydride (0.15 g, 6.9 mmol) and heated to reflux for 5 hr. The reaction mixture is quenched widi saline (25 mL) and extracted into etiiyl acetate. The organic phase is separated and dried over magnesium sulfate, filtered and concentrated. The concentrate is purified by silica gel chromatogaphy to give N-(18a)-demetiιyl-2- deoxoparaherquamide A. EXAMPLE 15 N-(18a)-demetiιyl-2-deoxoparaherquamide A (method 2) N-(18a)-demethyl-2-deoxoparaherquamide A can be prepared by starting with paraherquamide A and transforming it to 2-deoxoparaheraquamide A by the process set forth in WO97/03988. The 2-deoxoparaheraquamide A (10 mg) in in DMF (0.4 ml) is added to vigorously growing cultures (100 ml) of Cunninghamella echinulata subsp. elegans (UUC7602) or C. echinulata (UC7330) in 500 ml wide mouth flasks. Incubation is performed at 28° and shaking is continued for 1-3 days depending on die culture to give N-(18a)-demethyl-2-deoxoparaherquamide A. Isolation is achieved by diorough extraction with mediylene chloride, centrifugation and removal of solvents under reduced pressure. The residual material is analyzed by TLC and also by HPLC. Purification is achieved by various chromatographic techniques and structure confirmation is accomplished by NMR and MS. CHARTA 10 25 CHARTA - Continued 15 CϋΔE A - Continued (VI) 15 20 CHART B (I) 20 25

Claims: C IMS 1. 25-Methylene compounds of the formula (VII) where: (I) Marcfortine A (a) n is 1, (b) R 14 is Ri4 α :R 14β where R 14α is -H and R 14β is -H, (c) R 15 is R 15α :R 15β where R 15<χ is -H and R 15β is -H; (II) Paraherquamide A (a) n is 0, (b) R 14 is Rι α : χ 4β where R 1 α is -OH and R 14β is -CH 3 , (c) R 15 is Ri5 α -Ri5 β where R 15α is -H and R 15β is -H; (III) 14-hydroxy-14-alkyl Marcfortine A (a) n is 1, (b) R 14 is Rι α :R 1 where R 14(χ is -OH and R 14β is C r C 4 alkyl, (c) R 15 is R 15α :R 15β where R 15α is -H and R 15β is -H; (IV) 14-hydroxy-15-alkyl Marcfortine A (a) n is 1, (b) R 14 is Rι α :R 14β where R 14α is -OH and R 14β is -H, (c) R 15 is i5 α : χ5 β where . 15a is C j -C 4 alkyl and R 15β is -H and pharmaceutically acceptable salts thereof. 2. Methylene compounds of formula (VII) according to claim 1 where the pharmaceutically acceptable salts are salts selected from the group consisting of the acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH 3 -(CH 2 ) n -COOH where n is 0 thru 4, HOOC-(CH 2 )n-COOH where n is as defined above. 3. Methylene compounds of formula (VII) according to claim 1 where n j _ is 0. 4. Methylene compounds of formula (VII) according to claim 3 which is 24,25-dihydro-25-methyleneparaherquamide A. 5. Methylene compounds of formula (VII) according to claim 1 where n j is 1. 6. Methylene compounds of formula (VII) according to claim 5 which are selected from the group consisting of: 24,25-dihydro-25-methylenemarcfortine A, 14α-hydroxy- 14β-methyl-24,25-dihydro-25-methylenemarcfortine A and 14α-hydroxy-15α-methyl-24,25-dihydro-25-methylenemarcfortine A. 7. A methylene compound of formula (VII) according to claim 6 which is 24,25- dihydro-25-methylenemarcfortine A. 8. 24,25-Epoxy compounds of the formula (VIII) where: (I) Marcfortine A (a) n is 1, (b) R 14 is Rι 4α :Rι β where R 14(χ is -H and R 14β is -H, (c) R 15 is i5 α - i5β where R 15α is -H and R 15β is -H; (II) Paraherquamide A (a) n is 0, (b) R 14 is i4 α :Ri β where R 14α is -OH and R 14 β is -CH 3 , (c) R 15 is R 15α :R 15β where R 15α is -H and R 15β is -H; (III) 14-hydroxy-14-alkyl Marcfortine A (a) n is 1, (b) R 14 is Rι 4α :R 1 β where R 14α is -OH and R 14 β is C r C 4 alkyl, (c) R 15 is R 15α :R 15β where R 15α is -H and R 15β is -H; (TV) 14-hydroxy-15-alkyl Marcfortine A (a) n is 1, (b) R 14 is Rι α :Rι β where R 14α is -OH and R 14β is -H, (c) R 15 is Ri5 α : i5 where R 15α is C r C 4 alkyl and R 15β is -H and pharmaceutically acceptable salts thereof. 9. 24,25-Epoxy compounds of formula (VIII) according to claim 8 where the pharmaceutically acceptable salts are salts selected from the group consisting of the acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH 3 -(CH 2 ) n -COOH where n is 0 thru 4, HOOC-(CH 2 )n-COOH where n is as defined above. 10. 24,25-Epoxy compounds of formula (VIII) according to claim 8 where 1 is 0. 11. 24,25-Epoxy compounds of formula (VIII) according to claim 10 which is 24,25-epoxyparaherquamide A. 12. 24,25-Epoxy compounds of formula (VIII) according to claim 8 where n j is 1. 13. 24,25-Epoxy compounds of formula (VIII) according to claim 12 which are selected from the group consisting of: 24,25-epoxymarcfortine A, 14α-hydroxy-14β-methyl-24,25-epoxymarcfortine A and 14α-hydroxy- 15α-methyl-24,25-epoxymarcfortine A. 14. A 24,25-epoxy compound of formula (VII) according to claim 13 which is 24,25- epoxymarcfortine A. 15. N-(18a)-demethyl-2-deoxoparaherquamide A and pharmaceutically acceptable salts thereof.

Inventors: CLOTHIER MICHAEL F, LEE BYUNG H, CLOTHIER, MICHAEL, F., LEE, BYUNG, H.
Applicants: CLOTHIER MICHAEL F, LEE BYUNG H, UPJOHN CO, CLOTHIER, MICHAEL, F., LEE, BYUNG, H., PHARMACIA & UPJOHN COMPANY
Application year: 1997
Main classification: C07D491
IPC codes: A01N43, A61K31, A61P33, C07D491