Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.

Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.

One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAID's act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.

Cyclosporin A (CsA), which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection

of transplanted organs. In 1993, FK-506 (Prograf) was approved by the US FDA for the prevention of rejection in liver transplantation.

CsA and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. In 1994, CsA was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis.

Though they are effective in fighting transplant rejection, CsA and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort.

Newer, safer drugs exhibiting less side effects are constantly being searched for in the field.

Four active components of Spachea correa were recently identified which inhibit thymidine uptake of T cells and are useful as immunosuppressive agents in animals, including man.

Formula 1 (a) b is a single bond and R is OAc Formula 1 (b) b is a double bond and R is OAc Formula 1 (c) b is a single bond and R is OH Formula 1 (d) b is a double bond and R is OH These compounds are useful as immunosuppressive agents in animals, including man. The present invention describes newly developed immunosuppressive compounds derived from the compounds described in Formulae l(a) through l(d) and which have the relative stereochemistry depicted above.

SUMMARY OF THE INVENTION This invention relates to a class of triterpene derivatives of the general structural Formula I are useful as immunosuppressives.

As an immunosuppressive, the compounds of this invention are useful in the treatment of autoimmune diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses. Also within the scope of this invention are pharmaceutical formulations comprising a compound of Formula I and a pharmaceutical carrier, as well as, pharmaceutical formulations comprising a compound of Formula I, a second immunosuppressive compound and a pharmaceutical carrier.

DETAILED DESCRIPTION OF THE INVENTION A. Scope of the Invention The present invention is related to compounds of formula I, including but not limited to those specified in the examples, which are useful in a mammalian subject for the treatment and prevention of the resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus,

posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne, Alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt- Koyanagi-Harada syndrome, sarcoidosis, etc.; pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases, Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Good-pasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis,

lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary's syndrome, Addison's disease, ischemia- reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, for example, thrombosis and cardiac infraction, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung- oxygen or drug, for example, paracort and bleomycins, lung cancer, pulmonary emphysema, cataracta, sclerosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, comeal alkali bum; dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C4 release; Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic" liver failure, augmention of chemotherapeutic effect, preventing or treating activity of cytomegalovirus infection, HCMV infection, and antiinflammatory activity; and treatment of immunodepression or a disorder involving immunodepression, including AIDS, cancer, senile dementia, trauma, chronic bacterial infection, and certain central nervous system disorders.

More particularly, this invention relates to compounds of the general structural Formula I:

or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein: a is: a single bond, or a double bond when R4 is absent; b is: a single bond, or a double bond; n is: 1 to 4; m is: 1 to 4; r is: 0 or 1; s is: 0 or 1; Xis: OorS; R1 and R2 are independently: a) H, or b) (C1-C6)-alkyl, wherein alkyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy vinyl, cyano, oxo, nitro, hydroxy, CHO, CO2H, COCl-C6-alkyl, CO2Cl-C6-alkyl, CONR1R2,NR1R2,NR1COC1-C6-alkyl, aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or

substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl -C6)-alkoxy, phenyl, phenoxy, cyano, nitro, hydroxy, CHO, CO2H, COC1-C6-alkyl, CO2C1-C6- alkyl, CONR1R2, NR1R2, NRlCOC1-C6-alkyl and any two of adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, heteroaryl, wherein heteroaryl is defined as a 5 or 6- membered ring substituted with one and two heteroatoms selected from 0, S, N, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COC l-C6-alkyl, C02Cl-C6-alkyl, CONR1 R2, NR1 R2, NR1COC1-C6-alkyl, any two adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or any two adjacent substituents can be joined together to form a benzo-fused ring; R3 is: a) -(C1-C6)-alkyl, alkyl as defined above; b) -(Cl -C6)-alkenyl, wherein alkenyl is unsubstituted or substituted with one, two or three substituents selected from from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COC 1 -C6-alkyl, CO2C 1 -C6-alkyl, CONR1R2, NR1R2, NRiCOCi-C6-alkyl, aryl as defined above, and heteroaryl as defined above; c) -(Cl -C6)-alkynyl, wherein alkynyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, C02H, COC 1 -C6-alkyl, C02Cl-C6-alkyl CONR1 R2, NR1R2, NR1COCl-C6-alkyl, aryl as defined above, and heteroaryl as defined above, d) -aryl, aryl as defined above, or e) -heteroaryl, heteroaryl as defined above; R4 is: a) absent and a is a double bond; b) -H, c) -OH, d) =O, e) -O[(C=O)Or]sC1-C10-alkyl, alkyl as defined above, f) -O[(C=O)Or]sC2-C10-alkenyl, as defined above, g) -O[(C=O)Or]SC2-C6-alkynyl, alkynyl as defined above, h) -O[(C=O)Or]s(C3-C7)-cycloalkyl, i) -O[(C=O)Or]saryl, aryl as defined above, j) -O[(C=O)Orjsheteroaryl, heteroaryl as defined above, k) -O(CH2)nO(CH2)mheteroaryl, heteroaryl as defined above, 1) -O(CH2)nO(CH2)maryl, aryl as defined above, m) -OC(=O)NR1 R2, n) -OSO2R3, or o) -NR1R2; R5a and R5b are independently: a) -H, b) -Br, -Cl, -F, -I, such that one and only one of R5a and R5b is -Br, -Cl, -F, -I, and the other is hydrogen, c) -OH, such that one and only one of R5a and R5b is -OH, and the other is hydrogen, d) -CN, e) -R3, or f) R5a and R5b taken together are =0;

R29a and R29b are independently: a) -H, b) Br, Cl, F, I, c) =0, d) -(CH2)s-O[(C=X)Or]sC1-C10-alkyl, alkyl as defined above, e) (CH2)s-O[(C=X)Orl sC2-C 1 O-alkenyl, alkenyl as defined above, f) -(CH2)s-O[(C=X)Or]sC2-C6-alkynyl, alkynyl as defined above, g) -(CH2)s-O[(C=X)Or] s(C3-C7)-cycloalkyl, h) -(CH2)5-O[(C=X)Orjsaryl, aryl as defined above, i) (CH2)s-O[(C=X)Orl sheteroaryl, heteroaryl as defined above, j) -(CH2)s-O(CH2)nO(CH2)mheteroaryl, heteroaryl as defined above, k) (CH2)s-O(CH2)nO(CH2)maryl, aryl as defined above, l) -(CH2)s-OC(=O)NR1R2, m) -(CH2)s-OSO2R3, n) -(C1-C6)-alkyl, alkyl as defined above, o) -(C2-C6)-alkenyl, alkenyl as defined above, or p) =CR1 R2, such that one and only one of R1 and R2 can be hydrogen.

An embodiment of the invention are the compounds of Formula I or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein: a is: a single bond; b is: a single bond; n is: 1 to 4; m is: 1 to 4; ris: or 1; sis: 0 or 1; X is: O or S; R1 and R2 are independently: a) H, or b) (C1-C6)-alkyl, wherein alkyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, vinyl, cyano, oxo, nitro, hydroxy,

CHO, CO2H, COCl-C6-alkyl, CO2C1-C6-alkyl, CONR1R2, NR1R2, NR1COC1-C6-alkyl, aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C 1 -C6)-alkoxy, phenyl, phenoxy, cyano, nitro, hydroxy, CHO, C02H, COCl-C6-alkyl, CO2C1-C6- alkyl, CONR1R2, NR1R2, NR1COCl-C6-alkyl and any two of adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, heteroaryl, wherein heteroaryl is defined as a 5 or 6- membered ring substituted with one and two heteroatoms selected from 0, S, N, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COC 1 -C6-alkyl, CO2C 1 -C6-alkyl, CONR1 R2, NR1R2, NR 1COC 1 -C6-alkyl, any two adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or any two adjacent substituents can be joined together to form a benzo-fused ring; R3 is: a) -(Ci-C6)-alkyl, alkyl as defined above; b) -(C1-C6)-alkenyl, wherein alkenyl is unsubstituted or substituted with one, two or three substituents selected from from the group consisting of: Br, Cl, F, I, (Ci-C6)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COC1-C6-alkyl, CO2C1-C6-alkyl, CONR1R2, NR1R2, NR1COC1-C6-alkyl, aryl as defined above, and heteroaryl as defined above;

c) -(C1-C6)-alkynyl, wherein alkynyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, C02H, COC1 -C6-alkyl, CO2Cl -C6-alkyl, CONR1 R2, NR1R2, NR1COC1-C6-alkyl, aryl as defined above, and heteroaryl as defined above, d) -aryl, aryl as defined above, or e) -heteroaryl, heteroaryl as defined above; R4is: a) absent and a is a double bond; b) -H, c) -OH, d) =O, e) -O[(C=O)Or]sC1-C10-alkyl, alkyl as defined above, f) -O[(C=O)Or]sC2-C10-alkenyl, as defined above, g) -O[(C=O)Or]sC2-C6-alkynyl, alkynyl as defined above, h) -O[(C=O)Or]s(C3-C7)-cycloalkyl, i) -O[(C=O)Orjsaryl, aryl as defined above, j) -O[(C=O)Or]sheteroaryl, heteroaryl as defined above, k) -O(CH2)nO(CH2)mheteroaryl, heteroaryl as defined above, 1) -O(CH2)nO(CH2)maryl, aryl as defined above, m) -OC(=O)NR1 R2, n) -oSO2R3 or o) -NR1R2; R5a and R5b are independently: a) -H, b) -F such that one and only one of R5a and R5b is -F and the other is hydrogen, c) -OH, such that one and only one of R5a and R5b is -OH, and the other is hydrogen, d) -CN, e) -R3, or f) R5a and R5b taken together are =0; R29a and R29b are independently: a) -H, b) Br, Cl, F, I, c) =0, d) -(CH2)s-O[(C=X)Orl sC l-C10-alkyl, alkyl as defined above, e) -(CH2)s-O [(C=X)Orl sC2-C 1 O-alkenyl, alkenyl as defined above, f) -(CH2)s-O[(C=X)Or]sC2-C6-alkynyl, alkynyl as defined above, g) -(CH2)s-O[(C=X)Orls(C3-C7)-cycloalkyl, h) -(CH2)s-O[(C=X)Orl saryl, aryl as defined above, i) -(CH2)5-O[(C=X)Orjsheteroaryl, heteroaryl as defined above, j) -(CH2)s-O(CH2)nO(CH2)mheteroaryl, heteroaryl as defined above, k) -(CH2)5-O(CH2)nO(CH2)maryl, aryl as defined above, 1) -(CH2)s-OC(=O)NR1R2, m) -(CH2)5-OSO2R3, n) -(Ci-C6)-alkyl, alkyl as defined above, o) -(C2-C6)-alkenyl, alkenyl as defined above, or p) =CR1 R2, such that one and only one of R1 and R2 can be hydrogen.

An embodiment of this embodiment are the compounds of structural Formula I or a pharmaceutically acceptable salt, crystal form or hydrate, wherein: R4 is:

a) -O[(C=O)Or]saryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, phenyl, phenoxy, cyano, nitro, hydroxy, CHO, C02H, COCl-C6-alkyl, CO2C1- C6-alkyl, CONR1 R2, NR1 R2, NR1 COC 1 -C6-alkyl and any two of adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or b) -O[(C=O)Orjsheteroaryl, wherein heteroaryl is defined as a 5 or 6-membered ring substituted with one and two heteroatoms selected from 0, S, N, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COC 1 -C6-alkyl, CO2C1-C6-alkyl, CONR1 R2, NR1 R2, NR1 COC 1 -C6-alkyl, any two adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or any two adjacent substituents can be joined together to form a benzo-fused ring.

A third embodiment of the invention are the compounds of Formula I or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein: a is: a single bond; bis: a double bond; n is: 1 to 4; m is: 1 to 4; r is: 0 or 1; s is: 0 or 1; X is: O or S; R1 and R2 are independently: a) H, or b) (C1-C6)-alkyl, wherein alkyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl-C6)-alkoxy, vinyl, cyano, oxo, nitro, hydroxy,

CHO, CO2H, COC 1 -C6-alkyl, CO2C 1 -C6-alkyl, CONR1R2, NR1R2, NR1COC1-C6-alkyl, aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl -C6)-alkoxy, phenyl, phenoxy, cyano, nitro, hydroxy, CHO, C02H, COCl-C6-alkyl, CO2C1-C6- alkyl, CONR1R2, NR1R2, NR1COC1-C6-alkyl and any two of adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, heteroaryl, wherein heteroaryl is defined as a 5 or 6- membered ring substituted with one and two heteroatoms selected from 0, S, N, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl -C6)-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COC l -C6-alkyl, CO2C 1 -C6-alkyl, CONR R2, NR1 R2, NR1 COC 1 -C6-alkyl, any two adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or any two adjacent substituents can be joined together to form a benzo-fused ring; R3 is: a) -(C1-C6)-alkyl, alkyl as defined above; b) -(Cl -C6)-alkenyl, wherein alkenyl is unsubstituted or substituted with one, two or three substituents selected from from the group consisting of: Br, Cl, F, I, (Cl -C6)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COC1-C6-alkyl,CO2C1-C6-alkyl, CONR1R2, NR1R2, NR1COCi-C6-alkyl, aryl as defined above, and heteroaryl as defined above;

c) -(Cl -C6)-alkynyl, wherein alkynyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl -C6)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COC1 -C6-alkyl, CO2Cl -C6-alkyl, CONR1R2, NR1R2, NR1C0C1-C6-alkyl, aryl as defined above, and heteroaryl as defined above, d) -aryl, aryl as defined above, or e) -heteroaryl, heteroaryl as defined above; R4is: a) absent and a is a double bond; b) -H, c) -OH, d) =O, e) -O[(C=O)Or]sC1-C10-alkyl, alkyl as defined above, f) -O[(C=O)Or]sC2-C10-alkenyl, as defined above, g) -O[(C=O)Or]sC2-C6-alkynyl, alkynyl as defined above, h) -O[(C=O)Or]s(C3-C7)-cycloalkyl, i) -O[(C=O)Orjsaryl, aryl as defined above, j) -O[(C=O)Or]sheteroaryl, heteroaryl as defined above, k) -O(CH2)nO(CH2)mheteroaryl, heteroaryl as defined above, 1) -O(CH2)nO(CH2)rnaryl, aryl as defined above, m) -OC(=O)NR1 R2, n) -oSo2R3 or o) -NR1R2; R5a and R5b are independently: a) -H, b) -F such that one and only one of R5a and R5b is -F and the other is hydrogen, c) -OH, such that one and only one of R5a and R5b is -OH, and the other is hydrogen, d) -CN, e) -R3, or f) R5a and R5b taken together are =0; R29a and R29b are independently: a) -H, b) Br, Cl, F, I, c) =0, d) -(CH2)s-O[(C=X)Or]sC1-C10-alkyl, alkyl as defined above, e) -(CH2)s-O[(C=X)Or]sC2-C10-alkenyl, alkenyl as defined above, f) (CH2)s-O[(C=X)Orl sC2-CG-alkynyl, alkynyl as defined above, g) -(CH2)s-O[(C=X)Or]s(C3-C7)-cycloalkyl, h) -(CH2)s-O[(C=X)Or]saryl, aryl as defined above, i) -(CH2)5-0[(C=X)Orlsheteroaryl, heteroaryl as defined above, j) -(CH2)5-O(CH2)nO(CH2)mheteroaryl, heteroaryl as defined above, k) -(CH2)5-O(CH2)nO(CH2)maryl, aryl as defined above, 1) -(CH2)S-OC(=O)NR1 R2, m) -(CH2)s-OSO2R3, n) -(C1-C6)-alkyl, alkyl as defined above, o) -(C2-C6)-alkenyl, alkenyl as defined above, or p) =CR1 R2, such that one and only one of R1 and R2 can be hydrogen.

An embodiment of the third embodiment are the compounds of structural Formula I or a pharmaceutically acceptable salt, crystal form or hydrate, wherein: R4is:

a) -O[(C=O)Orjsaryl, wherein aryl is defined as phenyl or naphthyl., unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl -C6)-alkoxy, phenyl, phenoxy, cyano, nitro, hydroxy, CHO, C02H, COC1-C6-alkyl, Co2Cl- C6-alkyl, CONR1R2, NR1R2, NR1COCl-C6-alkyl and any two of adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or b) -O[(C=O)Or]sheteroaryl, wherein heteroaryl is defined as a 5 or 6-membered ring substituted with one and two heteroatoms selected from 0, S, N, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C1-C6)-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COC 1 -C6-alkyl, CO2C 1 -C6-alkyl, CONR1 R2, NR 1R2, NR1 COCi -C6-alkyl, any two adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or any two adjacent substituents can be joined together to form a benzo-fused ring.

An embodiment of this invention are the compounds of Formula I or pharmaceutically acceptable salt, crystal form or hydrate, such as: 4,6,7,15,16 -pentakis(acetyloxy) -21,22-epoxy-i 8-hydroxy-22- <BR> <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4 ,6.,7,15,1 6-pentakis(acetyloxy)-2 1,22-epoxy-1,18 -dihydroxy-22- <BR> <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane;

4,6,7,15,1 6-pentakis (acetyloxy)-2 1,22-epoxy- oxy -22- <BR> <BR> <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-oxo-18-hydroxy -22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-ox o-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1,18,20-tris-hyd roxy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18,20-dihydroxy- 22- methoxycarbonyl[6α,7α15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-ox o-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> methoxymethyleneoxy-22-methoxycarbonyl- <BR> <BR> <BR> <BR> [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- ethoxymethyleneoxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane;

4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- octyloxymethyleneoxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- benzyloxymethyleneoxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; <BR> <BR> <BR> <BR> <BR> 4,6,7,15,1 6-pentakis(acetyloxy)-21 ,22-epoxy-l8-hydroxy-20- <BR> <BR> <BR> <BR> methoxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-<BR> <BR> <BR> <BR> 2,3 ,27,30-tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-et hoxy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> benzyloxy-22-methyoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-<BR> <BR> <BR> <BR> Friedo-2,3,27 ,30-tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> allyloxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-<BR> <BR> <BR> <BR> 2,3,27,30-tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-(3 - phenylpropyl)oxy-22-methoxycarbonyl-22- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4,6,7,15,1 6-pentakis(acetyloxy)-2 1,22-epoxy-18 -hydroxy-20-o:- phenoxythiocarbonyloxy-22-methoxycarbonyl-

[6α,7α,15 ,16 ,21 ,22 ]-D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- - phenoxythiocarbonyloxy-22-methoxycarbonyl[6α,7α,15 ,- 16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- 1 ,20-dioxo- 18- <BR> <BR> <BR> hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-oxo-20- ethylenedioxy-18-hydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-allkyl-18-hydr oxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-fluoro-18-hydr oxy- <BR> <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-fl uoro- <BR> <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,1 6-pentakis(acetyloxy)-21 ,22-epoxy- 1 -n-propyl- 18- <BR> <BR> <BR> hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane; <BR> <BR> <BR> <BR> <BR> <BR> <BR> 6,7,15,1 6-tetrakis(acetyloxy)-2 1,22-epoxy- 1 -oxo-4, 1 8-dihydroxy-22- <BR> <BR> <BR> <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane;

4-(2-bromobenzoyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21,22-ep oxy- 1-oxo-18-hydroxy-22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-4,18-dihydroxy-22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4-(2-bromobenzoyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21,22-ep oxy- 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane; 4-(2-benzyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21, 22- epoxy-18-hydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4-(2-bromobenzyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy )- 21,22-epoxy-18-hydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4-(2-napthylmethyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetylo xy)- 21,-22-epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,- 16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane; 4-(2-bromophenyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy )- 21,22-epoxy-18-hydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4-(phenethyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21 ,22- epoxy-18-hydroxy-22-methoxycarbonyl-

[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4-(2-thienyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21 ,22- epoxy- l 8-hydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4-(i-propyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21, 22- <BR> <BR> epoxy- 1 8-hydroxy-22-methoxycarbonyl- <BR> <BR> <BR> <BR> <BR> [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 4-(propargyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21 ,22- epoxy- 1 8-hydroxy-22-methoxycarbonyl- [60c,7a,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; <BR> <BR> <BR> <BR> <BR> <BR> 4-(allyloxycarbonyl)oxy-6 ,7, 15,1 6-tetrakis(acetyloxy)-2 1,22-epoxy-<BR> <BR> <BR> <BR> 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane; 4-(benzyloxymethyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21,22-e poxy- <BR> <BR> 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-<BR> <BR> <BR> <BR> <BR> Friedo-2,3,27 ,30-tetranor-24-oxaoleanane; 4-methoxy-6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-18-hydro xy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4-allyloxy-6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-18-hydr oxy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane;

4-benzyloxy-6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-18-hyd roxy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4-(2-bromobenzyloxy)-6,7,15,16-tetrakis(acetyloxy)-21,22-epo xy- 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane; 4-keto-6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-18-hydroxy- 22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-4(S),18-dihydroxy- 22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4(S)-6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-22 - methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane; 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-(2-oxoethyl)-1 8- hydroxy-20-hydroxymethyl-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane; 6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-4,18-dihydroxy-20- oxo- <BR> <BR> 22-methoxycarbonyl[6o:,7oc, 1513,1613,21 13,2213]D:A-Friedo-2,3 ,27,30- tetranor-24-oxaoleanane; and 4,6,7,15,1 6-pentakis(acetyloxy)- 1 -cyano-21,22-epoxy- 18 -hydroxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]-D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane.

The compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof.

In addition compounds with carbon-carbon double bonds may occur in Z- and E- forms with all isomeric forms of the compounds being included in the present invention.

As used herein, the term "alkyl" includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. "Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy.

"Alkanoyl" is intended to include those alkylcarbonyl groups of specified number of carbon atoms, which are exemplified by formyl, acetyl, propanoyl and butyryl; "alkanoyloxy" is intended to include those alkylcarbonyl groups of specified number of carbon atoms attached through an oxygen bridge, which are exemplified by formyloxy, acetoxy, propionoyloxy, and butyryloxy. "Alkenyl" is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched- configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethyl pentenyl, and the like, and includes E and Z forms, where applicable. "Halogen", as used herein, means fluoro, chloro, bromo and iodo.

The term "aryl" is defined as a phenyl or naphthyl ring which is optionally substituted with the substituents listed above at any available carbon atoms. The aryl may also be substituted with a fused 5-, 6-, or 7-membered ring containing one or two oxygens and the remaining ring atoms being carbon, the fused 5-, 6-, or 7-ring being selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.

The term "heteroaryl" as utilized herein is intended to include the following a 5 or 6-membered ring substituted with one or two heteroatoms selected from 0, S, N, and is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl -C6)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, C02H, COC 1 -C6-alkyl, CO2C 1 -C6-alkyl, CONR1R2, NR1R2, NR1COCl-C6-alkyl, any two adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring said ring containing 1 or 2 oxygen atoms and the remainder carbon atoms, or any two adjacent substituents can be joined together to form a benzo-fused ring. Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and pyrrolyl which are substituted or unsubstituted as defined above.

In the compounds of Formula I, the heteroaryl group may be optionally substituted with the substituents listed above at any available carbon atom or nitrogen atom (if present), but compounds bearing certain substitutents, directly substituted to a nitrogen may be relatively unstable and are not preferred. The heteroaryl may also be fused to a second 5-, 6-, or 7-membered ring containing one or two oxygens selected from the remaining ring atoms being carbon, selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.

Pharmaceutically acceptable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985).

It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydro-scopicity and solubility. As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts of an

organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylate and stearate. Similarly pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium (especially ammonium salts with secondary amines). Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium and ammonium salts. Also included within the scope of this invention are crystal forms, hydrates and solvates of the compounds of Formula I.

As seen in Reaction Scheme A, compound Ia [(4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-22- methyoxycarbonyl[60c,70c,15 ,16 ,21 13,2213]D:A-Freido-A-homo- 27,30-dinor-24-oxaoleana-1, 20(29)-dien-3-one] can be selectively hydrogenated at the C20(29) olefin to give the methyl analog. This conversion can be achieved by hydrogenation with tris(triphenylphosphine)rhodium(I)chloride (Wilkinson's catalyst) in THF at about 50 psi for approximately 24 hours.

REACTION SCHEME A As seen in Scheme B, the lactone group can be converted to a tetrahydrofuran (THF) analog in two steps. The lactone is first ozonized under standard conditions. Reductive workup with an agent such as sodium borohydride gives the lactol intermediate. The purified lactol intermediate is then reacted with triethylsilane and a Lewis acid such as borontrifluoride diethyl etherate to give the tetrahydrofuran (THF) analog.

REACTION SCHEME B The lactol hydroxy group can be replaced as demonstrated in Scheme C with a variety of substituents (reprsented as RSa). Reaction with allyltrimethyl silane and a Lewis acid such as boron trifluoride etherate (BF3 . OEt2) and dichloromethane gives the allyl analog (R5a = allyl R5b = H) which can be modified in a variety of ways that are known to the practioner. Alternatively, the lactol can be reacted with diethylaminosulfur trifluoride (DAST) in a basic solvent such as collidine to give the fluoro analog (R5 = F) which can be reacted with trisubstituted aluminum reagents such as triethyl aluminum to give the ethyl derivative, for example.

The lactol hydroxy group is oxidized to its lactone derivative by use of a variety of reagents. One that is particularly effective is pyridinium chlorochromate (PCC).

REACTION SCHEME C Compound Ia can be reacted with ozone under conditions described in Reaction Scheme B. These conditions also cleave the C20 olefin to give the keto lactol intermediate. This intermediate can be worked up under conditions described in Reaction Schemes B or C to give C20 hydroxy THF analogs. The C20 hydroxy derivative can then be oxidized to the C20 ketone under a variety of conditions. The Jones reagent (chromic acid and sulfuric acid in H20), pyridinium chlorochromate, or oxalyl chloride plus DMSO will achieve this conversion.

REACTION SCHEME D

The lactone group can be rearranged to substituted THF ethers under acidic or basic conditions. Stirring the lactone derivative in an alcoholic solvent such as methanol or ethanol with an acid such as H2SO4 or a base such as potassium carbonate (K2C03) gives the rearranged THF ester with the ester group corresponding to the alcohol selected as solvent. This reaction also causes the hydrolysis of the C4 acetate group which is reattached by stirring the hydroxy analog with acetic anhydride (Ac2O).

R5a-acetadehyde THF derivatives can be prepared by reacting the lactone starting material with reducing agents such as NaBH4 or LiEt3BH (Super hydride) in an alcoholic solvent.

RSa-ketone THF derivatives are prepared by reacting the lactone starting material with alkylmetal reagents such as methyl lithium in an aprotic solvent such as THF preferably at low temperatures such as -78°C.

The R5a ester, aldehyde and ketone groups of these THF analogs can be derivatized with a variety of procedures commonly known to practitioners.

The C20 olefin can be reduced to the methyl derivative by procedures described in Reaction Scheme A. It can also be oxidatively cleaved by reaction with osmium tetroxide (0304), preferably under catalytic conditions to give the diol. The diol is then cleaned with sodium meter periodate (NaIO4) to give the ketone.

REACTION SCHEME E Tetrahydrofuran derivatives ,variously modified at R5a and C20, can be selectively de-acetylated at C4 to give the corresponding alcohol by reaction with an aqueous solution of HCl (preferably 2M to 3M concentration) in THF at 450C. De-acetylation can also be achieved by reacting with CH3(Cl)Al[N(OCH3)CH3 (Weinreb reagent) in inert solvents such as THF, toluene or methylene chloride.

When R5a contains an ester group, the C4 acetate can be selectively removed using HCl in THF.

REACTION SCHEME F

The C4 hydroxy group can be oxidized to the corresponding ketone by a variety of oxidizing agents. The Jones reagent (chromic acid and sulfuric acid in H20), pyridinium chlorochromate, and oxalyl chloride plus DMSO all will achieve this conversion.

REACTION SCHEME G The C4 hydroxy group can also be dehydrated to give the olefin. Reaction of the alcohol with tris- phenoxymethylphosphonium iodide in hexamethylpho sphorous triamide (HMPT) at 75"C will achieve this conversion.

REACTION SCHEME H As depicted in Reaction Scheme I, esters at C4 can be prepared by reaction of a preformed carboxylic acid chloride with the C4 alcohol derivative (Reaction Scheme F) in a basic solvent such as pyridine. It should be understood that R4 is used to represent a portion of the R4 definition, e.g. R4 can be an alkyl carbonate which is depicted in the scheme as OC(=O)OR4' R4 representing the alkyl substituent. The acid chlorides, when not purchased, are prepared by stirring the carboxylic acids in reagents such as oxalyl chloride or thionyl chloride. Esters may also be prepared by reaction of the acid chloride and C4 alcohol with silver cyanide (AgCN) in an aprotic

solvent such as HMPA. C4 sulfonate derivatives are prepared in a similar manner by reaction with sulfonyl chlorides.

C4 carbonate and carbamate derivatives are prepared by first reacting the C4 alcohol derivative with carbonyldiimidazole (CDI) to obtain the imidazolecarbonyl intermediate which is then reacted with an alcohol or amine (R1 R2NH) to give the corresponding carbonate or carbamate derivatives.

C4 ether derivatives can also be prepared. The best procedure involves reacting an alcohol with trifluoromethanesulfonic anhydride (Tf2O, triflic anhydride) in the presence of a hindered base such as 2,6-di-t-butyl pyridine to obtain the preformed triflate in dichloromethane at reduced temperature, preferably -78°C. To this solution is added the triterpene alcohol, the reaction mixture is warmed to room temperature and stirring is continued until reaction is complete. Ethers may also be prepared by heating a mixture of triterpene C4 alcohol, the appropriate alkylhalide and an excess of silver oxide (Ag20) in an aprotic inert solvent such as DMF.

REACTION SCHEME I REACTION SCHEME I (CONT'D) R29a R29b CDI, R4,OH Me 0 r Rsa H CO2CH3 - - OAc R29aR29b c OAc Me 0 ThOAc H H OH CO2CH3 CH3 0 g<M OAc O oR4 - %0OcAc R29a R29b 6 Ac CH3 4 OH Me 0 H H wCO2CH3 *OAc OAc R4OH, To20, base 4e CH3 OR4,

Amines at C4 can be prepared from the C4 ketone described in Reaction Scheme G by reaction with an amine NHR1R2 in a variety of solvents with a reducing agent such as sodium cyanoborohydride.

REACTION SCHEME J THF derivatives containing a C20(29) olefin can be selectively hydrogenated across this double bond to give the methyl analog by procedures described in Reaction Scheme A.

REACTION SCHEME K When THF analogs contain a C20 olefin, it can be selectively converted to the corresponding ketone by sequential reaction with osmium tetroxide or ruthenium tetroxide and sodium periodate.

The C20 ketone can be conveniently reduced to its corresponding alcohol by using tetramethylammonium triacetoxyborohydride in a solvent such as THF at room temperature.

The C20 keto-THF and C20-hydroxy-THF derivatives can also be prepared by methods described in Reaction Scheme D.

REACTION SCHEME L

The C20-29 olefin can be converted to the C20 hydroxymethyl derivative. One procedure involves reaction with diborane in THF followed by oxidative workup with tri-N- methylamine-N-oxide (Me3NO).

The C20,C29 bis-alcohol can also be prepared by use of catalytic osmium tetroxide followed by oxidative workup with a reagent such as Me3NO.

REACTION SCHEME M The C20 ketone derivative can be reacted to produce olefins with a variety of well known olefination agents. A particularly useful reagent is the Horner-Emmons-type of olefination reagent [(RO)2P(O)CR'R"]. This produces a mixture of geometric isomers.

Alternatively, the C20 ketone can be reacted with nucleophiles (R29a'-M+) to give C20 substituted hydroxy derivatives. In general, Grignard reagents (R29a'MgBr) or alkyllithium reagents (R29a'Li) are utilized in aprotic solvents such as diethyl ether or THF.

It should be understood that R, R", R29a' and R29b are used to represent a portion of the R29a and R29b definitions, e.g.

R29a can be a substituted olefin which is depicted in the scheme as =CR R", R' and R" representing alkyl substituents.

REACTION SCHEME N Amines at C20 can be prepared from the C20 ketone by reaction with an amine R1R2NH in a variety of solvents with a reducing agent such as sodium cyanoborohydride.

REACTION SCHEME O The C20 hydroxy derivative (Reaction Scheme I) or the C20 hydroxymethyl derivative (Reaction Scheme J) can be converted to ether, ester, carbonate, carbamate, sulfonate and other related derivatives by procedures commonly practiced in the art and as described in Reaction Scheme I.

The C20 hydroxymethyl derivative may also be derivatized as a methanesulfonate ester or triflate ester by standard procedures. The methansulfinate or triflate can then be reacted with an amine NR1R2H to give amine derivatives.

REACTION SCHEME P REACTION SCHEME P (CONT) UTILITY The present invention is related to compounds of formula I, including but not limited to those specified in the examples, which are useful in a mammalian subject for the treatment and prevention of immunemediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, including xeno transplants, etc.; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile- onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, and the like; and further infectious diseases caused by pathogenic microorganisms. Further uses may include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis cornea, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.; pollen allergies, reversible obstructive airway disease, which includes condition such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis and the like; inflammation of mucous

and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases; intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related allergic diseases which have symptomatic manifestation remote from the gastrointestinal tract (e.g. migraine, rhinitis and eczema); renal diseases such as interstitial nephritis, Good- pasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fascitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen- mediated diseases, as for example organ injury such as ischemia- reperfusion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon preservation, transplantation or ischemic disease (for example, thrombosis and cardiac infraction): intestinal

diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation; renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency; pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali bum; dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C4 release; Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on. Furthermore, the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxin, viral hepatitis, shock, or anoxia), B-virus hepatitis, non-A/non-B hepatitis, cirrhosis (such as alcoholic cirrhosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on- chronic" liver failure (acute liver failure on chronic liver diseases), and moreover are useful for various diseases because of their useful activity such as augmention of chemotherapeutic effect, preventing or treating activity of cytomegalovirus infection, particularly HCMV infection, and antiinflammatory activity; and The compounds of the present invention may also be used in the treatment of immunodepression or a disorder involving immunodepression, such as AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock) chronic bacterial infection, and certain central nervous system disorders.

A method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kv 1.3 inhibition, comprising the administration, in an amount that is effective at inhibiting Kv 1.3, of a compound of Formula I. The method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kv 1.3 inhibition, wherein the condition is selected from the group consisting of: immunemediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, including xeno transplants, etc.; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile- onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, and the like; and further infectious diseases caused by pathogenic microorganisms. Further uses may include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.; pollen allergies, reversible obstructive airway disease, which includes condition such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway

hyper-responsiveness), bronchitis and the like; inflammation of mucous and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases; intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related allergic diseases which have symptomatic manifestation remote from the gastrointestinal tract (e.g. migraine, rhinitis and eczema); renal diseases such as interstitial nephritis, Good- pasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fascitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopreia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen- mediated diseases, as for example organ injury such as ischemia- reperfusion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon preservation, transplantation or ischemic

disease (for example, thrombosis and cardiac infraction): intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation; renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency; pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali bum; dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C4 release; Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on. Furthermore, the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxin, viral hepatitis, shock, or anoxia), B-virus hepatitis, non-A/non-B hepatitis, cirrhosis (such as alcoholic cirrhosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on- chronic" liver failure (acute liver failure on chronic liver diseases), and moreover are useful for various diseases because of their useful activity such as augmention of chemotherapeutic effect, preventing or treating activity of cytomegalovirus infection, particularly HCMV infection, and antiinflammatory activity; and immunodepression or a disorder involving immunodepression, such as AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock), chronic bacterial infection, and certain central nervous system disorders.

An embodiment of the invention is a method for the treatment of autoimmune diseases. Another embodiment of the invention

is a method for the prevention of rejection of foreign organ transplants comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAID's and corticosteroids act principally by blocking the effect or secretion of these mediators, but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immuno- suppressive agents are as likely to succumb from infection as they are from their autoimmune disease.

Cyclosporin A, which was approved by the US FDA in 1983, is currently the leading drug used to prevent rejection of transplanted organs. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Though cyclosporin A is effective in fighting transplant rejection, it is nephrotoxic and is known to cause several undesirable side effects including kidney failure, abnormal liver function and gastrointestinal discomfort.

Newer, safer drugs exhibiting fewer side effects are constantly being searched for in the field. The present invention provides for immunosuppressant agents which are inhibitors of a voltage dependent potassium channel, Kv1.3, that is found on human T-lymphocytes.

Potassium channels modulate a number of cellular events such as muscle contraction, neuro-endocrine secretion, frequency and duration of action potentials, electrolyte homeostasis, and resting membrane potential. These channels comprise a family of proteins that have been classified according to their biophysical and pharmacological characteristics. Inhibition of K+ channels, in their role as modulators of the plasma membrane potential in human T -lymphocytes, has been postulated to play a role in eliciting immunosuppressive responses. In

regulating membrane potential, K+ channels play a role in the regulation of intracellular Ca++ homeostasis, which has been found to be important in T-cell activation. The biochemical characterization of K+ channels is underdeveloped, due to the paucity of selective high affinity probes.

Functional voltage-gated K+ channels can exist as multimeric structures formed by the association of either identical or dissimilar subunits. This phenomena is thought to account for the wide diversity of K+ channels. However, subunit compositions of native K+ channels and the physiologic role that particular channels play are, in most cases, still unclear.

The Kv 1.3 channel is a voltage-gated potassium channel that is found in neurons, blood cells, osteoclasts and T-lymphocytes.

The Chandy and Cahalan laboratories proposed a hypothesis that blocking the Kv 1.3 channel would elicit an immunosuppressant response. (Chandy et al., J. Exp. Med. 160, 369, 1984; Decoursey et al., Nature, 307, 465, 1984). However, the K+ channel blockers employed in their studies were non-selective. Until research with the peptide margatoxin, a peptide found in scorpion venom, no specific inhibitor of the Kv 1.3 channel existed to test this hypothesis. Although a laboratory (Price et al., Proc. Natl. Acad. Sci. USA, 86, 10171, 1989) showed that charybdotoxin would block Kv 1.3 in human T cells, charybdotoxin was subsequently shown to inhibit four different K+ channels (Kv 1.3 and three distinct small conductance Ca++ activated K+ channels) in human T-lymphocytes, limiting the use of this toxin as a probe for the physiological role of Kv 1.3 (Leonard et al., Proc. Natl. Acad. Sci. USA, 89, 10094, 1992). Margatoxin, on the other hand, blocks only Kv1.3 in T-cells, and has immunosuppressant activity in both in vitro and in vivo models. (Lin et al., J. Exp. Med, 177, 637, 1993). Since the compounds of the embodiments of this invention produce blockade of Kv1.3, they will also inhibit T-cell activation.

Also within the scope of this invention is a method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kv 1.3 inhibition, comprising the administration of a

pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of Formula (I), in an amount that is effective at inhibiting Kv1.3.

Also within the scope of this invention is a combination therapy comprising a compound of formula I and one or more immunosuppressant agents. These immunosuppressant agents within the scope of this invention include, but are not limited to, LMUREK8 azathioprine sodium, brequinar sodium, SPANIDIN0 gusperimus trihydrochloride (also known as deoxyspergualin), mizoribine (also known as bredinin), CELLCEPT0 mycophenolate mofetil, NEURAL0 Cyclosporin A (also marketed as different formulation of Cyclosporin A under the trademark SANDIMMUNE), PROGRAFB tacrolimus (also known as FK-506) and RAPIMMUNE sirolimus (also known as rapamycin), leflunomide (also known as HWA-486), glucocortcoids, such as prednisolone and its derivatives, antibody therapies such as orthoclone (OKT3) and Zenapax and antithymyocyte globulins, such as thymoglobulins.

Using the methodologies described below, representative compounds of the invention were evaluated and found to exhibit IC50 values of at least <10 RM in any of the assays thereby demonstrating and confirming the utility of the compounds of the invention as Kv 1.3 inhibitors and immunosuppressants.

TCELLIL-2 ASSAY Peripheral blood mononuclear (MNC) cells from healthy donors were separated by density centrifugation with ficoll-hypaque (LSM, Organon Teknika, Durham, NC), followed by rosetted with neuraminidase treated sheep red blood cells (SRBC). After another centrifugation with leucocyte separation medium (LSM), the SRBC of the rosetted T cells were then lysed with ammonium chloride lysing buffer (GIBCO, Grand Island, NY). Such purified T cells were resuspended at 3 X 106/ ml in RPMI 1640 culture medium (GIBCO) supplemented with 10% fetal calf serum (Sigma, St. Louis, MO), 100 mM glutamine, 1 mM sodium pyruvate, 0.1 mM non-essential amino

acids, and 1 % penn-strep (GIBCO). The cell suspension was immediately distributed into 96 well round-bottom microculture plates (Costar) at 200 ,ul/well. The various dilutions of test compound were then added in triplicate wells at 25 Rl/well, incubated for 30 min at 37"C. Ionomycin (125 ng/ml), and PMA (1 or 5 ng/ml), were added to the appropriate wells. The culture plates were then incubated at 370C in a humidified atmosphere of 5% CO2 - 95% air for 18-24 hours. The supernatants were removed, and assayed for IL-2 with an IL-2 capture ELISA, using monoclonal anti-IL-2, and biotinylated goat anti-IL-2 antibodies (unconjugated antibodies purchased from R&D System, Minneapolis, MN). The ELISA was developed with streptavidin conjugated peroxidase (Zymed, San Francisco, CA) and substrate for peroxidase (Sigma). Mean OD and units of IL-2 of the replicate wells were calculated from standard curve, created with recombinant IL-2 (Collaborative Biomedical Products, Bedford, MA) and the results were expressed as concentration of compound required to inhibit IL-2 production of T cells by 50%.

T CELL PROLIFERATION ASSAY Peripheral blood mononuclear cells (MNC) from healthy donors were separated by density centrifugation with ficoll-hypaque (LSM, Organon Teknika, Durham, NC). After washing the MNC with complete media (RPMI 1640 medium with 5% fetal calf serum, 100 mM glutamine, 1 mM sodium pyruvate, 0.1 mM non-essential amino acid, and 1 % penn-strep, obtained from GIBCO, Grand Island, NY), they were then irradiated at 7500 RADS, and resuspended at 4-4.5 x 1 O6cells/ml in complete media. Another aliquot of MNC were rosetted with neuraminidase treated SRBC. After another centrifugation with LSM, the sheep red blood cells (SRBC) of these rosetted T cells were then lysed with ammonium chloride lysing buffer (GIBCO, Grand Island, NY). After washing 2X with complete media, these purified T cells were also resuspended at 2-2.5 x 1 OGcells/ml in complete media.

The various dilutions of the compound were added in triplicates at 50 ul/well of a 96 well flat-bottom microculture plate (Costar, Cambridge,

MA). T cell suspension was then immediately distributed into the wells at 100 ul/well. After incubating the cells with compound for 30 min. at 37"C in a humidified atmosphere of 5% C02 - 95% air, 20 ,ul/well of anti-CD3 (Ortho Diagnostic, NJ) at final conc. of 0.3 ng/ml was added, followed by 50 1ll of the irradiated MNC. The culture plates were then incubated at 370C in a humidified atmosphere of 5% C02 - 95% air for 72 hours. The proliferation of T lymphocytes was assessed by measurement of tritiated thymidine incorporation. During the last 18- 24 hrs. of culturing, the cells were pulse-labeled with 2 RCi/well of tritiated thymidine (NEN, Cambridge, MA). The cultures were harvested on glass fiber filters using a multiple sample harvester (MACH-II, Wallac,Gaithersburg, MD). Radioactivity of filter discs corresponding to individual wells was measured by standard liquid scintillation counting methods (Betaplate Scint Counter, Wallac). Mean counts per minute of replicate wells were calculated and the results were expressed as concentration of compound required to inhibit tritiated thymidine uptake of T cells by 50%.

KV1.3-RUBIDIUM EFFLUX ASSAY CHO cells transfected with Kv 1.3 channels at site densities of approximately 40,000 sites/cell are plated into 96 well culture plates and maintained in Iscove's Modified Dulbecco's Medium (IMDM, with L-Glutamine and HEPES, JRH Biosciences). Cells are incubated overnight with 86Rb+ (3 RCi/ml, Dupont-NEN) in the glutamine supplemented IMDM. After aspiration of the media, 100 ptl of Low K Buffer (in mM, 6.5 KCl, 125 NaCl, 1 CaCl2, 2 MgCl2, 10 HEPES, pH adjusted to 7.2 with NaOH) is added to each well followed by 100 ,ul test samples in Low K Buffer also containing 0.2% BSA and 2 mM ouabain.

Samples are tested at either 1 Fg/ml for routine screening or at a variety of concentrations encompassing at least 1/10 to 10 times the putative IC50 of test compound to determine potency. After a fixed preincubation time, which is usually 10 min, the samples are aspirated.

The Kv 1.3 channels are opened by depolarization of the cells with High K Buffer (final concentrations, in mM, 63.25 KCl, 68.25 NaCl, 1

CaCl2, 2 MgCl2, 10 HEPES, pH adjusted to 7.2 with NaOH) also containing test compounds. To measure 86Rb+ efflux through the channels, aliquots of 100 pl are taken from each well after a given time and added to plates containing 100 ,ul MicroScint-40 (Packard) for counting by liquid scintillation techniques. MicroScint-40 (100 lil) is then added to each well of the cell plate to determine the remaining 86Rb+ activity. The efflux counts are normalized for the total amount of 86Rb+ that was in the cells by adding the efflux counts to the cell plate counts. Activity is determined by % inhibition of the efflux window that is established using a saturating concentration of margatoxin (MgTX), a 39 amino acid peptide that is a potent blocker of Kv 1.3 channels (IC50 100 pM).

DOSAGE FORMS As an immunosuppressive, these compounds are useful in the treatment of autoimmune diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.

The compounds of this invention can be administered for the treatment of autoimmune diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm- blooded animal. For example, administration, can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal and parenteral. The term "parenteral" as used herein refers to modes of administration which include subcutaneous, intravenous, intramuscular, intraarticular injection or infusion, intrasternal and intraperitoneal.

The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.

They can be administered alone, but are generally administered with a

pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.

The dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Usually, a daily dosage of active ingredient compound will be from about 1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results. These dosages are the effective amounts for the treatment of autoimmune diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragees, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Other dosages forms that can also be used to administer the active ingredient as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet

from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene gycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

For administration by inhalation, the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulated with an appropriate weight percent solution or suspension of the compounds of Formula I in an appropriate ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the comeal and internal regions of the eye.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: CAPSULES A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

SOFT GELATIN CAPSULES A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

TABLETS A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

INJECTABLE A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.

SUSPENSION An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.

The same dosage forms can generally be used when the compounds of this invention are administered stepwise or in conjunction with another therapeutic agent. When drugs are administered in physical combination, the dosage form and administration route should be selected depending on the compatibility of the combined drugs. Thus the term coadministration is understood to include the administration of the two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the two active components.

The following examples illustrate the preparation of the compounds of Formula I and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

EXAMPLE 1 A Method Of Extracting The Compounds Of Formula 1 (a) and l(b) From Snachea correa Formula 1 (a) b is a single bond and R is OAc Formula 1 (b) b is a double bond and R is OAc

One gram of an ethanol extract of the roots of Spachea correa was partitioned between 100 ml of hexane (twice) and 100 ml of 90% aqueous methanol. After separation of the phases, the defatted methanol was concentrated down under vacuum to give an aqueous suspension. This was diluted out to 100 ml with water and extracted, with 100 ml of methylene chloride.

The bioactive methylene chloride extract was dried down to give 12 mg of residue. This was first fractionated by preparative thin layer chromatography (TLC) on a 20 cm by 20 cm E. Merck silica gel 60F254 plate of lmm thickness using methylene chloride-ethyl acetate 1:1 (v/v) as solvent, then by high performance liquid chromatography (HPLC) using a Zorbax RxC8$ 4.6 mm x 25 cm column, operated at 50"C and eluted with a 50 minute gradient of acetonitrile:water (1:1, v/v) to 100% acetonitrile, delivered at 1 ml/min, to afford 4 mg of compound l(a) and 1 mg of l(b).

Homogeneity of the preparations was ascertained in several TLC systems, such as E. Merck silica gel 60F254, methylene chloride-ethyl acetate 1:1, Rf l(a) 0.4, Rf l(b) 0.3; Whatman KC18, methanol-water 9:1, Rf l(a) 0.65, Rf l(b) 0.75 and by HPLC using a Zorbax RxC8 column, acetonitrile-water 3:2, k' l(a) 4.15, k' l(b) 3.30; and by NMR.

Mass spectra were recorded on JEOL SX-102A (electron impact, EI,903V) and JEOL HX110 (Fast Atom Bombardment, FAB) mass spectrometers. Exact mass measurements were performed at high resolution (HR-EI) using perfluorokerosene (PFK) as the internal standard. Trimethylsilyl derivatives were prepared with a 1:1 mixture of BSTFA-pyridine at room temperature The FAB spectrum was run in a matrix of dithiothreitol (20/80).

The compound of Formula l(a) runs underivatized by EI. The molecular ion is observed a m/z 788 and three successive loses of acetic acid are observed. The base peak is observed a m/z 334. The compound does not silylate. Scanning HR-EI indicated a

molecular formula of C40H52016. A table of the critical HR-EI data is given below.

Observed m/z Formula Assignment 788.3220 C40H52016 M+ 728.3040 C3 8H480 14 M-acetic acid 668.2834 C36H44012 M-2 x acetic acid 334.1417 C18H2206 base peak 13C NMR spectra were recorded for the compound of Formula l(a) in CD2Cl2 at 100 MHz on a Varian Unity 400 NMR spectrometer at 20"C. Chemical shifts are given in ppm relative to tetramethylsilane (TMS) at zero ppm using the solvent peak at 53.8 ppm as internal standard. The following data were observed: 15.0, 15..2, 16.8, 17.1, 20.7*, 20.9, 21.1, 21.6, 21.8, 22.2, 35.6, 40.8*, 42.1, 43.6, 45.1, 47.5, 49.3*, 53.5, 59.1, 62.6, 63.5, 66.1, 66.7*, 68.4*, 69.9, 73.9, 75.0, 75.6, 77.1*, 119.4, 123.7, 138.9, 143.0, 167.7, 169.2, 169.3*, 170.25, 170.31, 170.8, 171.3 ppm (where the * signifies the observation as broad resonances). The carbon count of 40 is in agreement with the molecular formula C40H520 16 derived by scanning HR EI-MS.

The 1H NMR spectra of compound of Formula(a) is provided as Figure 1. The spectra was recorded at 400 MHz in CD2Cl2 on a Varian Unity 400 NMR spectrometer at 250C.

Chemical shifts are in ppm relative to TMS at zero ppm using the solvent peak at 65.32 as the internal standard.

The mass spectra of the compound of Formula 1 (b) was obtained as above. The following results were obtained: Observed m/z Formula Assignment 786.3075 C40H50016 726.2886 C3gH46014 M-acetic acid 666.2651 C36H42012 M-2 x acetic acid

606.2451 C34H38010 M-3 x acetic acid 489.2099 C26H3309 base peak 471.1992 C26H3108 13C NMR spectra were recorded for the compound of Formulal(b) using the procedure described above. The following results were observed: 14.8, 14.9, 17.3, 20.8, 20.9, 21.3, 21.7, 21.8, 21.9, 27.1, 35.1, 40.6, 42.3, 45.4, 48.1, 50.4, 53.5, 54.1, 57.8, 63.7, 66.2, 67.8, 68.6, 71.4, 73.3, 73.8, 74.4, 119.5, 121.1, 124.3, 137.1, 138.9, 143.3, 167.6, 168.6, 169.3, 169.5, 169.9, 171.0, 171.7 ppm.

The carbon count of 40 is in agreement with the molecular formula C40H50016 derived by scanning HR EI-MS.

EXAMPLE 2 A Method Of Extracting The Compounds Of Formula l(c) And l(d) From Spachea Correa Formula l(c) b is a single bond and R is OH Formula 1 (d) b is a double bond and R is OH Analogs of the compounds of Formula 1 (a) and 1 (b) could be detected in the crude extract and fractions thereof when the process of Example 1 was carried out on a larger scale. Thus, 50 g of ethanol extract were partitioned as described in Example 1 using 900 ml of each solvent at each step.

Partial purification of the methylene chloride extract was achieved by column chromatography on E. Merck silica gel 60

(120 ml), eluting with a step gradient of ethyl acetate in methylene chloride. The step gradient was designed so that the column was washed first with 100% methylene chloride and then with methylene chloride- ethyl acetate mixtures of 9:1,8:2,3:2,2:1, 1:1, 1:2,2:8 and 1:9. Ultimately the column was washed with 100% ethyl acetate.

Fractions eluted with methylene chloride-ethyl acetate 3:2 were enriched in compound of Formula l(a) and 1(b). These were resolved by HPLC using a Zorbax RxC85 9 mm x 25 cm column, maintained at 50"C and eluted at 4 ml/min with acetonitrile-water 1:1 v/v. Three identical runs finally afforded 100 mg and 20 mg respectively of l(a) and l(b) after crystallization from methanol.

Later-eluting fractions from the silica gel column above were found to contain at least two related compounds based on UV spectra and color reactions on TLC plates. Material from the methylene chloride-ethyl actate 1:1 and 1:2 washings were combined and evaporated down. Separation was achieved on the same HPLC column as above, eluting with a 50 minute gradient of 30% to 50% acetonitrile in water. Two identical runs gave 6 mg of purified compound 1(c). Fractions containing the compound of Formula 1 (d) were again processed by HPLC (same column) using acetonitrile- water 3:7 delivered isocratically, to yield 2 mg of purified Formula 1(d).

The mass spectra of these compounds were recorded on a Finnigan TSQ700 mass spectrometer (electrospray ionization, ESI).

The samples were analyzed by LC/MS using a 2.1x150mm C8 column at 0.2ml/min. with a mobile phase of 45% acetonitrile/0.0lM aqueous ammonium acetate at 500C. Component 1 (d) had a retention time of 10.5 min. and a molecular weight of 744 which is observed a m/z: 745 (M+H), 762 (M+NH3), 786 (M + H + MeCN). Component l(c) has a retention time of 11.8 and a molecular weight of 746 which is observed at m/z: 747 (M+H), 764 (M+NH3) and 788 (M + H + MeCN).

The 13C NMR spectra obtained for the compound of Formula 1 (c) using the conditions previously described is as follows:

15.1 (2x), 16.9, 19.to, 20.8, 20.91, 20.94, 21.9, 22.3, 35.6, 40.6, 42.2, 43.9, 45.0, 47.7, 50.8, 53.5, 55.6, 61.8, 63.5, 66.0, 67.6 (2x), 69.8, 70.0, 73.9, 75.0, 75.6, 119.3, 123.7, 139.0, 144.4, 167.8, 169.2, 169.5, 170.1, 170.4, 171.4 ppm.

The carbon count of 38 is in agreement with the molecular formula C38H50016 derived by scanning HR EI-MS.

EXAMPLE 3 Separation Bv HPLC Compounds of this invention were characterized by the following behavior during HPLC separation on a Zorbax RxC8 4.6 mm x 25 cm column, maintained at 500C and eluted at 1 ml/min with acetonitrile-water 3:2 v/v): Compound 1(a): k' = 4.15; l(b): k'=3.30; l(c): k'=2.30; l(d): k'=2.10.

Analyses using this HPLC system can be used to quantify the compounds in the crude extract or other mixtures, by comparing the absorbance of HPLC peaks at a wavelength of 220 nm with that produced by injections of known (weighed) amounts of pure standards.

EXAMPLE 4 Additional Purification Procedure A simplified purification process allows for rapid fractionation of even larger amounts of crude extract and the preparation of gram amounts of the compounds of Formula 1 (a) and 1(b).

The ethanol extract is first dissolved at 20 grams per 150 ml in methanol. This solution is diluted with 150 ml of water and then extracted three times with methylene chloride using 150 ml of methylene chloride each time. The pooled methylene chloride extracts are evaporated down and fractionation proceeds by repeated column chromatography on silica gel. One employs methylene

chloride-methanol 97:3 in a first step; the mixed compounds of Formula l(a) and l(b) thus obtained are resolved by chromatographing on fresh silica gel eluted with methylene chloride- ethyl acetate 3:1. Volume of elution for the compound of Formula l(a) ranges from about 2 to about 3.5 column volumes of solvent; that for the compound of Formula l(b) is about 3 to about 4.5 column volumes. Finally, advantage is taken of the low solu- bility of these compounds, and, after total resolution by chromatography, the compounds of Formula l(a) and l(b) can be precipitated and or crystallized from concentrated methanol solutions.

EXAMPLE 5 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-A-homo-<BR> <BR> 27,30-dinor-24-oxaoleana-l-en-3-one A solution of 50 mg (63.7 Rmole) of 4, 6 ,7 ,15 ,16- Pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-22-methoxy- <BR> <BR> <BR> carbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-A-homo-27,30-dinor- 24-oxaoleana-1,20(29)-dien-3-one in 50 ml of dry THF was degassed under reduced pressure and saturated with nitrogen, the procedure being repeated several times. 25 mg of Wilkinson's catalyst [(PPh3)3RhCl] were added and the solution was degassed and saturated with hydrogen in the previously described manner. The

reaction vessel was then pressurized with H2 to 15 psi (latm) and shaken for 65h at 250C. After that time the solvent was removed under reduced pressure. The residue was dissolved in a small amount of ethyl acetate/hexanes (2:1) (ca. 1 mL) and filtered through 30g of silica gel eluting with 500 ml of ethyl acetate / hexanes (2: 1).

The first fractions, containing the Wilkinson-catalyst (approx. 50 mL) were discarded. The fractions containing the product were combined. After removing the solvent under reduced pressure the crude product was dried in vacuo and purified by HPLC to afford 20.8 mg (42%) of the title compound as a white solid. 1H NMR (CDCl3) 6 1.5 (d, 3H, J = 8.6 Hz, C29-H), 2.4 (m, 1H, C20-H).

Mass Spectrum (APCI): m/e 808.

EXAMPLE 6 <BR> <BR> <BR> <BR> <BR> <BR> <BR> 4,6,7,15,1 6-pentakis (acetyloxy)-21 ,22-epoxy-1 8-hydroxy-22- <BR> <BR> <BR> <BR> <BR> methoxycarbonyl[6cc,70c,15 ,16 ,21 13,2213]D:A-Friedo-2,3 ,27,30- tetranor-24-oxaoleanane

Step A: 4,6,7,15,1 6-pentakis(acetyloxy)-21 ,22-epoxy- 1,18- <BR> <BR> dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]-<BR> <BR> D:A-Friedo-2.3.27.30-tetranor-24-oxaoleanane 1 gm of 4,6,7,15,16-Pentakis(acetyloxy)-21,22-epoxy- 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-A-homo-27,30-dinor-24-oxaoleana-1-en-3-one(1.265 mmole) was dissolved in a mixture of 20ml of methanol and 20ml of dichloromethane. The solution was ozonized at 0°C for 1.5 hr (Welsbach-Ozonator, T-408, 90V, 0.5 S.L.P.M.) and purged with nitrogen for 15 min. Several small portions of sodium borohydride (500 mg total) were added and the mixture was stirred at room temperature for lh. To the reaction mixture was added 50 ml of 1N hydrochloric acid and 200 ml of dichloromethane and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride then was dried over MgSO4 and concentrated. The residue was filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to afford 343 mg of the title compound as a white solid; 1H NMR (CDCl3) 6 1.27 (d, 3H, J = 6.9 Hz, C29-H), 2.38 (m, 1H, C20-H), 3.34 (s, 1H, C21-H), 3.61, 4.09 (AB, 2H, J = 9.4 Hz, C24-H), 5.20 (m, 1H, C1-H); 13C NMR (CDCl3) 26.9 (C20), 53.1 (COOMe), 63.0 (C21), 69.9 (C24), 100.0 (C1); Mass Spectrum (APCI): m/e 784 (M+NH4).

Step B: 4,6,7,15,1 6-pentakis(acetyloxy)-2 1,22-epoxy- 1 8-hydroxy- 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane 10 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- <BR> <BR> <BR> 1,18-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.013 mmole) were dissolved in 2 ml of dichloromethane and 0.25ml of triethylsilane (2.0 mmole) and the reaction mixture was cooled to -780C. To this was added 0.25 ml of BF3oEt2 (1.58 mmole). After 1h, 5ml of aqueous sodium bicarbonate solution and 20ml of dichloromethane were added. The organic layer was separated and washed with saturated aqueous sodium chloride then was dried over MgSO4 and concentrated. The residue was filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to afford 7.5 mg (78%) of the title compound as a white solid; 1H NMR (CDCl3) 5 1.24 (d, 3H, J = 7.9 Hz, C29-H), 2.37 (m, 1H, C20-H), 3.32 (s, 1H, C21-H), 3.58, 3.84 (2Xm, 2X2H, C1-H + C24-H); 13C NMR (CDCl3) 5 27.0 (C20), 53.1 (COOMe), 63.1 (C21), 69.4, 70.2 (C1, C24); Mass Spectrum (APCI): m/e 768 (M+NH4).

EXAMPLE 6A (Alternate Method) 4,6,7,15,1 6-pentakis (acetyloxy)-2 1,22-epoxy- 1 8-hydroxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane 2 gm of 4,6,7,15,16-Pentakis(acetyloxy)-21,22-epoxy- 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-A-homo-27 ,30-dinor-24-oxaoleana- 1-en-3-one(2.53 mmole) were dissolved in a mixture of 40ml of methanol and 40ml of dichloromethane. The solution was ozonized at 0°C for 2 hr (Welsbach-Ozonator, T-408, 90V, 0.5 S.L.P.M.) and purged with nitrogen for 15 min. Several small portions of sodium borohydride (1.2 gm total) were added and the mixture was stirred at room temperature for 1.5 h. To the reaction mixture was added 50 ml of 1N hydrochloric acid and 200 ml of dichloromethane and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride then was dried over MgSO4 and concentrated. The crude reaction product was dissolved in 5 ml of dichloromethane and 2.5ml of triethylsilane at room temperature.

To this was added 2.5 ml of BF3oEt2 and the reaction was allowed to stir for 24 hr. To the reaction mixture was added aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated and washed with saturated aqueous sodium chloride then was dried over MgSO4 and concentrated to give approximately 2 gm of the title compound.

EXAMPLE 7 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-oxo-18-hydroxy -22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane To a solution of 15 mg of 4,6,7,15,16- pentakis(acetyloxy)-21,22-epoxy-1,18-dihydroxy-22- <BR> <BR> <BR> methoxycarbonyl-[6(x,7ct,15 ,16 ,21 13,2213]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane (0.07 mmole) (Step 6A) in 1.8 ml of dichloromethane was added 114 mg (0.526 mmole) of pyridinium chlorochromate, 288 mg (3.51 mmole) of sodium acetate and 57 mg of powdered 4 A molecular sieves. The reaction mixture was allowed to stir for 18 hr whereupon it was diluted with 10 ml of ethyl acetate, filtered through a small layer of Florisil and concentrated under vacuum. The crude product was purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to give 12.1 mg (80%) of the title compound. 1H NMR (CDCl3) 6 1.33 (d, 3H, J = 7.9 Hz, C29-H), 2.42 (m, 1H, C20-H), 3.36 (s, 1H, C21-H), 3.89, 4.55 (AB, 2H, J = 9.9 Hz, C24-H); 13C NMR (CDCl3) 6 27.1 (C20), 63.2 (C21), 175.8 (C 1); Mass Spectrum (APCI): m/e 782 (M+NH4).

EXAMPLE 8 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-ox o-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane Step A: 4,6,7,15,1 6-pentakis(acetyloxy)-2 1,22-epoxy- 1,1 8,20-tris- hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]-<BR> <BR> D:A-Friedo-2.3,27.30-tetranor-24-oxaoleanane 750 mg of 4,6,7,15,16-Pentakis(acetyloxy)-21,22-epoxy- 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-A-homo-27,30-dinor-24-oxaoleana- 1,20(29)-dien-3-one (0.95 mmole) were dissolved in a mixture of 20ml of methanol and 20ml of dichloromethane. The solution was ozonized at 0°C for 90 min (Welsbach-Ozonator, T-408, 90V, 0.5 S.L.P.M.) and purged with nitrogen for 15 min. Several small portions of sodium borohydride (250mg total) were added and the mixture was stirred at room temperature for 1h. The solution was diluted with 50ml of dichloromethane, 20ml of 1N hydrochloric acid was added and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride then was dried over MgSO4 and concentrated. The residue was filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to afford 209 mg (34%) of the title compound as a white solid; 1H NMR (CDCl3) 6 3.60 (s, 1H, C21-H), 3.63, 4.10 (AB, 2H, J = 9.4 Hz, C24-H), 4.31 (m, 1H, C20), 5.21 (m, 1H, C1-H); 13C NMR (CDCl3) 6 53.2 (COOMe), 100.1 (C1); Mass Spectrum (APCI): m/e 786 (M+NH4).

Step B: 4,6,7, 15,1 6-pentakis(acetyloxy)-2 1,22-epoxy-18,20- dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]- D :A-Friedo-2 3 27 *30-tetranor-24-oxaoleanane 50 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- 1,18,20-tris-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,- 2113,2213] -D: A-Friedo-2,3 ,27,30-tetranor-24-oxaoleanane (0.065 mmole) were dissolved in 2ml of dichloromethane. 0.25ml of triethylsilane (2.0 mmole) were added followed by 0.25ml of BF3*OEt2 (1.58 mmole). After lh, 5ml of aqueous sodium bicarbonate solution and 20ml of dichloromethane were added. The organic layer was separated and washed with saturated aqueous sodium chloride then was dried over MgSO4 and concentrated. The

residue was filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) using a mixture of 8:4:1 hexane: tbutylmethyl ether: acetonitrile to afford 39.5 mg (81%) of the title compound as a white solid; 1H NMR (CDCl3) 6 3.62 (s, 1H, C21-H), 3.60, 3.85 (AB, 2H, J = 9.4 Hz, C24-H), 3.60, 3.89 (2Xm, 2H, C1-H), 4.32 (m, 1H, C20- H); Mass Spectrum (APCI): m/e 770 (M+NH4).

Step C: 4,6,7,15,1 6-pentakis(acetyloxy)-2 1,22-epoxy- 1 8-hydroxy- 20-oxo-22-methoxycarbonyl [6a,7a, 15P,16P,21 13,2213]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane To a mixture of pyridinium chlorochromate (115 mg, 0.526 mmol), sodium acetate (788 mg, 3.51 mmol) and powdered 4A molecular sieves (57 mg) in 1.5 ml of dichloromethane at rt was added 20 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18,20- dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.027 mmol) dissolved in 1 ml of dichloromethane. The reaction mixture was stirred for 24 hr whereupon it was diluted with ethyl acetate (20 ml) and filtered through a thin pad of silica gel, eluting with ethyl acetate. The residue was then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to afford 15.5 mg (81%) of the title compound. 1H NMR (CDCl3) 52.41,2.83 (AB, 2H, J = 13.9 Hz, C19-H), 3.59, 3.84 (AB, 2H, J = 8.9 Hz, C24-H), 3.61, 3.86 (ABX, 2H, JAB = 8.9 Hz, JAX = 6.9Hz, JBX = 1.0 Hz, C1-H). 13C

NMR (CDC13) 6 201.1 (C20); Mass Spectrum (APCI): m/e 768 (M+NH4).

EXAMPLE 9 4,6,7,15,16-pentakis(acetyloxy)-21,22-epxoy-18-hydroxy-20- methoxymethyleneoxy-22-methoxycarbonyl [6α,7α,15 ,16 ,21 ,22 ]- D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 30 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- <BR> <BR> <BR> 18,20-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.04 mmole) were dissolved in 1 ml of dichloromethane. 0.5 ml of N,N- diisopropylethylamine were added, followed by 0.1 ml of chloromethyl methyl ether (1.3 mmole). The mixture was stirred at 25°C for 16h, then 50ml of dichloromethane were added. The solution was consecutively washed with 20 mL of 0.1 M hydrochloric acid and saturated aqueous sodium chloride then was dried over MgSO4 and concentrated. The residue was first filtered through a plug of silica gel and then purified by HPLC (Waters RCM, µ Porosil, 10 mm X 10 cm) using a mixture of 8:4:1 hexane- methyl tert-butyl ether-acetonitrile to afford 28 mg (88%) of the title compound as a white solid; 1H NMR (CDCl3) 6 3.39 (s, 3H, OMe), 4.65, 4.71 (AB, 2H, J = 6.9 Hz, OCH2O); 13C NMR (CDCl3) 6 55.7 (OMe), 96.6 (OCH2O); Mass Spectrum (APCI): m/e 814 (M+NH4).

The following examples were prepared using the above method: EXAMPLE 10 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- ethoxymethyleneoxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]- D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDCl3) 6 1.29 (t, 3H, J = 7.2 Hz, OCH2CH3), 3.55, 3.78 (ABX3, 2H, JAX = JBX =7.2Hz, JAB = 9.4Hz, OCH2CH3), 4.76, 4.78 (AB, 2H, J = 6.9 Hz, OCH2O). 13C NMR (CDCl3) 6 14.9 (OCH2CH3), 63.8 (OCH2CH3), 95.0 (OCH2O). Mass Spectrum (APCI): m/e 828 (M+NH4).

EXAMPLE 11 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> octyloxymethyleneoxy-22-methoxycarbonyl-[6α,7α,15 ,16 ,21 ,-<BR> <BR> 22131D :A-Friedo-2 3.2730-tetranor-24-oxaoleanane 1H NMR (CDCl3) 6 3.49, 3.70 (ABX2, 2H, JAX = JBX = 6.4 Hz, JAB = 9.4Hz, OCH2CH2), 4.74, 4.77 (AB, 2H, J = 6.9 Hz, OCH2O); 13C NMR (CDCl3) 6 94.6 (OCH20); Mass Spectrum (APCI): m/e 912 (M+NH4).

EXAMPLE 12 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> benzyloxymethyleneoxy-22-methoxycarbonyl-[6α,7α,15 ,16 ,21 ,-<BR> <BR> <BR> 2213 iD :A-Friedo-2 *3 327 30-tetranor-24-oxaoleanane

1H NMR (CDCl3) 6 4.59, 4.72 (AB, 2H, J = 11.9 Hz, OCH)Ph), 4.80 -4.82 (m, 2H, OCH20), 7.29 - 7.34 (m, 5H, ar); 13C NMR (CDCl3) 6 93.9 (OCH20), 127.8, 127.9, 128.4, 137.3. Mass Spectrum (APCI): m/e 890 (M+NH4).

EXAMPLE 13 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> methoxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane 30 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- <BR> <BR> 18,20-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.04 mmole) were dissolved in 0.5 ml of dimethyl formamide. 1 ml of methyliodide were added, followed by 100 mg of Ag2O. The mixture was stirred at 25°C for 16h under exclusion of light, then 10ml of dichloromethane were added. The solution was first filtered through a plug of silica gel and then purified by HPLC (Waters RCM, @ Porosil, 10 mm X 10 cm) using a mixture of 8:4:1 hexane-methyl tert-butyl ether-acetonitrile to afford 24 mg (78%) of the title compound as a white solid. 1H NMR (CDCl3) 5 3.45 (s, 3H, OMe).

Mass Spectrum (APCI): m/e 784 (M+NH4).

The following compounds were prepared by the above method, but the reaction mixture was heated to 500C for 16h: EXAMPLE 14 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-et hoxy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24 -oxaoleanane 1H NMR (CDCl3) 6 1.22 (t, 3H, J = 6.7 Hz, CH2CH3), 3.58 - 3.66 (m, 2H, OCH2CH3). Mass Spectrum (APCI): m/e 798 (M+NH4).

EXAMPLE 15 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> benzyloxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDCl3) 54.59,4.65 (AB, 2I4, J = 11.4Hz, OCH2Ph), 7.30 - 7.39 (m, 5H, Ph). Mass Spectrum (APCI): m/e 860 (M+NH4).

EXAMPLE 16 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- <BR> <BR> allyloxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane

1H NMR (CDCl3) 6 4.07 - 4.15 (m, 2H, OCH2),5.22 (dm, 1H, J = 10.4 Hz, =CH), 5.32 (dm, 1H, J = 16.8 Hz, =CH), 5.92 m, 1H, CH=CH2). Mass Spectrum (APCI): m/e 810 (M+NH4).

EXAMPLE 17 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-(3 - <BR> <BR> phenylpropyl)oxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDCl3) 6 2.71 (t, 2H, J = 7.7 Hz, OCH2), 3.50 - 3.69 (m, 4H, 2XCH2), 7.14 - 7.30 (m, 5H, Ph). Mass Spectrum (APCI): m/e 888 (M+NH4).

EXAMPLE 18 <BR> <BR> 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-α -<BR> <BR> phenoxythio-carbonyloxy-22-methoxycarbonyl-[6α,7α,15 ,16 ,-<BR> <BR> 210,22131 -D:A-Friedo-23 27.30-tetranor-24-oxaoleanane 20 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- <BR> <BR> 18,20-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.027 mmole) were dissolved in lml of dichloromethane. 0.05ml of pyridine, 0.lml of O-phenyl chlorothionoformat, and a catalytic amount of dimethylamino pyridine were added and the solution was stirred at room temperature for 14h. Then 25ml of dichloromethane were added and the solution was consecutively washed with an aquous solution of sodiumbicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to afford 12 mg (50%) of the title compound as a white solid. 1H NMR (CDCl3) 6 3.59, 3.81 (AB, 2H, J = 8.9 Hz, C24-H), 3.52, 3.85 (ABX, 2H, JAB = 8.9 Hz, JAX = 6.9 Hz, JBX = 1.0 Hz, C1-H), 3.87 (s, 1H, C21-H), 5.25 (m, 1H, C20-H), 7.11 (dm, 2H, J = 8.4 Hz), 7.35 (ddm, 1H, J1 = J2 = 7.2

Hz), 7.47 (ddm, 2H, Jl = J2 = 7.9 Hz). Mass Spectrum (APCI): m/e 906 (M+NH4).

Also obtained from the reaction mixture was 20% of a white solid identified as: 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- - phenoxy-thiocarbonyloxy-22-methoxycarbonyl[6α,7α,15 ,16 ,- 21 ,-22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDCl3) 6 3.60, 3.83 (AB, 2H, J = 8.9 Hz, C24-H), 3.59, 3.89 (ABX, 2H, JAB = 8.9 Hz, JAX = 6.9 Hz, JBX = 1.0 Hz, C1-H), 3.81 (s, 1H, C21-H), 5.24 (m, 1H, C20-H), 7.19 (dm, 2H, J = 7.9 Hz), 7.30 (ddm, 1H, J1 = J2 = 7.4 Hz), 7.44 (ddm, 2H, J1 = J2 = 7.9 Hz). Mass Spectrum (APCI): m/e 906 (M+NH4).

EXAMPLE 19 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1,20-dioxo-18- <BR> <BR> hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane The title compound was prepared from 4,6,7,15,16- pentakis(acetyloxy)-21,22-epoxy-1,18,20-trihydroxy-22-methox y- carbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor 24-oxaoleanane (Example 8, Step A) by procedures described in Example 8, Step C. 1H NMR (CDCl3) # 2.42, 2.82 (AB, 2H, J = 14.4 Hz, C19-H), 3.82 (s, 1H, C21-H), 3.86, 4.52 (AB, 2H, J = 9.9 Hz, C24-H), 4.01,4.28 (2Xm, 2X2H, OCH2CH2O); 13C NMR (CDCl3) 6 175.2 (C1), 200.3 (C20). Mass Spectrum (APCI): m/e 782 (M+NH4).

EXAMPLE 20 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-oxo-20- <BR> <BR> ethylenedioxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,- 21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane To a solution of 53 mg of 4,6,7,15,16- pentakis(acetyloxy)-2 1,22-epoxy- 1, 20-dioxo- 18 -hydroxy-22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,-16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane (0.07 mmole) in 2 ml of dichloromethane at -78°C was added 0.05 ml of bis-trimethylsilyloxyethane and 2 drops of trimethylsilyl triflate. The reaction was warmed to rt and stirred for 12 hr. The reaction was worked up and purified under conditions described in previous examples to give 8.5 mg of the title compound. 1H NMR (CDCl3) 6 3.52 (s, 1H, C21-H), 3.88, 4.56 (AB, 2H, J = 8.9 Hz, C24-H), 4.01, 4.28 (2Xm, 2X2H, OCH2CH20).

13C NMR (CDCl3) 6 105.4 (C20), 175.8 (Cl). Mass Spectrum (APCI): m/e 826 (M+NH4).

EXAMPLE 21 4,6,7,15,1 6-pentakis(acetyloxy)-21 ,22-epoxy- 1 -allyl- 18 -hydroxy-22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 50 mg of 4,6,7,15,16-pentakis(acetyloxy)- <BR> <BR> <BR> 21,22-epoxy-1,18-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,- 21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.065 mmole) dissolved in 1 ml of dichloromethane was cooled to OOC. To this was added 0.1 ml of allyltrimethylsilane (0.81 mmole) and 0.1 ml of boron trifluoride diethyletherate (0.63 mmole). The reaction mixture was stirred for 3 hr whereupon it was quenched with 10 ml of sat. sodium bicarbonate solution. The mixture was extracted with dichloromethane and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered through silica gel and evaporated in vacuo. The product was purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to give 48.5 mg (94%) of the title compound. 1H NMR (CDCl3) 52.21, 2.56 (2Xm, 2H, CH2), 2.39 (m, 1H, C20-H), 3.34 (s, 1H, C21-H), 3.50, 3.88 (AB, 2H, J = 9.9 Hz, C24-H), 5.07 (dd, 1H, J1 = 5.0 Hz, J2 = 1.0 Hz, CH), 5.10 (dd, 1H, J1 = 12.9 Hz, J2 = 1.0 Hz, CH), 5.78 (m, 1H, CH). Mass Spectrum (APCI): m/e 808 (M+NH4).

EXAMPLE 22 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-fluoro-18-hydr oxy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 .22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 50 mg of 4,6,7,15,16-pentakis(acetyloxy)- <BR> <BR> 21,22-epoxy-1,18-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,- 21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.065 mmole) in 2 ml of T11F and 0.1 ml of collidine was cooled to OOC.

To this was added 0.085 ml of diethylaminosulfur trifluoride (DAST) (0.64 mmole). The reaction mixture was stirred for 1 hr whereupon it was diluted with 25 ml of dichloromethane. The organic fraction was washed with sat. sodium bicarbonate solution, lN HCl solution (5x) and brine. It was then dried over sodium sulfate, filtered and evaporated in vacuo. The product was purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to give 35 mg of the title compound. 111 NMR (CDCl3) 62.41(m, 1H, C20-H), 3.37 (s, 1H, C21-H), 3.78, 4.33 (AB, 2H, J = 8.9 Hz, C24-H), 5.56 (m, 1H, C1-H). Mass Spectrum (APCI): m/e 786 (M+NH4).

EXAMPLE 23 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20-fl uoro- 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 50 mg of 4,6,7,15,16-pentakis(acetyloxy)- 21,22-epoxy-18,20-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,- 21 13,2213]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane in 1 ml of T11F was converted to the title compound by procedures described in Example 22. Mass Spectrum (APCI): m/e 772, 752 (M+NH4, M- HF+NH4).

EXAMPLE 24 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-n-propyl-18- <BR> <BR> hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane A solution of 12 mg of 4,6,7,15,16-pentakis(acetyloxy)- <BR> <BR> <BR> 21,22-epoxy-1-allyl-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,-<BR> <BR> <BR> <BR> <BR> 1613,21 13,2213]D:A-Friedo-2,3 ,27,30-tetranor-24-oxaoleanane (Example 21, 0.015 mmole) in 10 ml of ethyl acetate with a catalytic amount of 10% Pd/C was hydrogenated at 30 psi for 18 hr. The reaction mixture was filtered and purified using a Sep-Pak silica gel cartridge to give 9.8 mg of the title compound. 1H NMR (CDCl3) 6 0.97 (t, 3H, J = 7.2 Hz, CH3), 2.41 (m, 1H, C20-H), 3.35 (s, 1H, C21-H), 3.48, 3.86 (AB, 2H, J = 8.9 Hz, C24-H), 3.93 (m, 1H, Cl- H). Mass Spectrum (APCI): m/e 810 (M+NH4).

EXAMPLE 25 <BR> <BR> <BR> 6,7,15,1 6-tetrakis(acetyloxy)-2 1,22-epoxy- 1 -oxo-4, 1 8-dihydroxy-22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-<BR> <BR> tetranor-24-oxaoleanane 1.741 gm (17.8 mmole) of N,O-methylhydroxylamine hydrochloride was azeotropically dried with toluene (3 x 5 ml) and suspended in 11 ml of toluene. To this was added 9.0 ml of a 2.017 N solution of trimethylaluminum in toluene (18 role). This reaction mixture was stirred until gas evolution ceased. To a solution of 86.3 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- 1-oxo-18-hydroxy-22-methoxycarbonyl-[6α,7α,15 ,16 ,- 21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.11 mmole) in 1 ml of dichloromethane at 0°C was added 0.254 ml of the previously described solution (0.23 mmole) and the reaction was stirred overnight at rt. The reaction was then diluted with sat.

ammonium chloride solution. The organic fraction was filtered through celite, dried over sodium sulfate, filtered and evaporated in vacuo. The product was purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to give 62 mg (79%) of the title compound. 1H NMR (CDCl3) 6 2.42 (m, 1H, C20-H), 3.87, 4.25 (AB, 2H, J = 9.9 Hz, C24-H), 6.53 (d, 1H, J = 3.5 Hz, C21 -H); 4.27 (m, 1H, C4-H). Mass Spectrum (APCI): m/e 740 (M+NH4).

EXAMPLE 26 4-(2-bromobenzoyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21,22-ep oxy- <BR> <BR> 1-oxo-18-hydroxy-22-methoxycarbonyl-[6α,7α,15 ,16 ,21 ,22 ]-<BR> <BR> D:A-Friedo-23.27.30-tetranor-24-oxaoleanane To a solution of 14 mg of 6,7,15,16-tetrakis(acetyloxy)- 21,22-epoxy- 1 -oxo-4,1 8-dihydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane (0.019 mmole) in 0.5 ml of pyridine at rt was added 0.1 ml of 2-bromobenzoyl chloride (0.75 mmole). The reaction mixture was stirred for 18 hr at which time the reaction mixture was evaporated in vacuo. The residue was filtered through silica gel eluting with ethyl acetate : hexanes (4:1). The residue was then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to give 12.1 mg (80%) of the title compound. 1H NMR (CDCl3) 6 1.32 (d, 3H, J = 7.9 Hz, C29-H), 2.41 (m, 1H, C20-H), 3.39 (s, 1H, C21-H), 3.98,4.71 (AB, 2H, J = 9.4 Hz, C24-H), 5.75 (q, 1H, J = 5.9 Hz, C4-H), 7.36 (dt, 1H, J1 = 1.5 Hz, J2 = 7.4Hz), 7.41 (dt, 1H, J1 = 1.5 Hz, J2 = 7.4Hz), 7.69 (dd, 1H, J1 = 1.5 Hz, J2 = 7.4Hz), 7.78 (dd, 1H, J1 = 1.5 Hz, J2 = 7.4Hz).

Mass Spectrum (APCI): m/e 782 (M+NH4).

EXAMPLE 27 6,7,15,1 6-tetrakis(acetyloxy)-2 1 ,22-epoxy-4, 18 -dihydroxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane To a solution of 300 mg (0.400 mmole) of 4,6,7,15,16- pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-22-methoxycarbony l- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane 4.0 mL tetrahydrofuran was added 1.0 mL of a 2.0M aqueous HCl solution. The mixture was heated at 600C for 24 h, then was cooled to room temperature and partitioned between dichloromethane and brine. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by HPLC (Waters RCM, Nova-Pak silica, 25 mm X 10 cm) using a mixture of 2:1(6:3:1 hexane-methyl tert-butyl ether- acetonitrile: hexane) to afford 43 mg (65%) of the title compound as a white solid; 1H NMR (CDCl3) 6 4.41 (q, 1H, J = 6.0 Hz, C4-H).

Mass Spectrum (APCI): m/e 726 (M+NH4).

EXAMPLE 28 4-(2-bromobenzoyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21,22-ep xoy- 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane The title compound was prepared using the procedures described in Example 26. 1H NMR (CDCl3) 5 6.02 (q, 1H, J = 7.4 Hz), 7.75 (d of d, 1H, J = 7.5, 1.8 Hz), 7.68 (d of d, 1 H, J = 7.4, 1.1 Hz), 7.39 (t of d, 1 H, J = 7.4, 1.1 Hz), 7.36 (t of d, 1 H, J = 7.6, 1.8 Hz). Mass spectrum (APCI): m/e 908 (79Br, M+NH4) and 910(81Br, M+NH4).

EXAMPLE 29 <BR> <BR> <BR> 4-(2-benzyloxycarbonyl)oxy-6 ,7,15,1 6-tetrakis(acetyloxy)-2 1,22- <BR> <BR> epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]- D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane A solution of 14.1 mg (20 mmole) of 6,7,15,16- tetrakis(acetyloxy)-2 1,22-epoxy-4,18 -dihydroxy-22- <BR> <BR> <BR> methoxycarbonyl-[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane and 3.2 mg (60 mmole) of 1, 1 '-carbonyl diimidazole in 2 mL benzene was heated at 600C for 6 h. Then 200 RL (excess) of benzyl alcohol and 3 CLL triethyl amine were added and the solution was stirred at 600 C. After 18 h, mixture was filtered through silica gel using 30% acetone-hexane and the solvent was concentrated. The residue was purified by HPLC (Waters RCM, Nova pak silica, 8 mm X 10 cm) using a mixture of 2:1(5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane) to afford 12 mg (75%) of the title compound as a white solid. 1H NMR (CDCl3) 6 5.23 (s, 2H); 6 5.81 (q, 1H, J = 6.3 Hz, C4-H); 6 7.35-7.42 (m, 5H).

Mass Spectrum (APCI): m/e 860 (M+NH4).

The following examples were prepared using the above method: EXAMPLE 30 4-(2-bromobenzyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy )- <BR> <BR> 21,22-epxoy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,- 22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 111 NMR (CDCl3) 6 5.26, 5.36(dd ,AB 2H, J = 12 Hz), 6 5. 64 (q, 1H, J = 6. 4 Hz, C4-H); 6 7.24 (m,lH); 6 7.35 (m,lH); 6 7.44 (m,lH); 6 7.61 (m,lH). Mass Spectrum (APCI): m/e 938, 940 (M+NH4).

EXAMPLE 31 4-(2-naphthylmethyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyl oxy)- <BR> <BR> 21,22-epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,- 22 ]-D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 111 NMR (CDCl3) 6 5.70, 5.71(dd ,AB 2H, J = 12 Hz), 6 5. 61 (q, 1H, J = 6. 5 Hz C4-H); 6 7.46-8.05 (m,7H). Mass Spectrum (APCI): m/e 918 (M+NH4). Mass Spectrum (APCI): m/e 910 (M+NH4).

EXAMPLE 32 4-(2-bromophenyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy )- <BR> <BR> 21,22-epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,- 22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDCl3) 6 5.72 (q, 1H, J = 6.2 Hz, C4-H); 6 7.19 (m, 1H); # 7.27 (m, 1H); # 7.39 (m, 1H); # 7.65 (m, 1H). Mass Spectrum (APCI): m/e 924, 926 (M+NH4).

EXAMPLE 33 4-(phenethyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21 ,22- epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,- 22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDCl3) 6 3.02 (t, 2H, J = 7.0 Hz); 6 4.40 (t, 2H, J = 7.0 Hz); 6 5.47 (q, 1H, J = 6.2 Hz, C4-H); 6 7.23 - 7.33 (m, 5H). Mass Spectrum (APCI): m/e 874 (M+NH4).

EXAMPLE 34 4-(2-thienyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21 ,22- <BR> <BR> epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]- D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 111 NMR (CDCl3) 6 5.35, 5.39 (dd ,AB 2H, J = 12 Hz); 6 5.60 (q, 1H, J = 6.5 Hz, C4-H); 6 7.00 - 7.36(m, 3H). Mass Spectrum (APCI): m/e 866.

EXAMPLE 35 4-(i-propyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21, 22- <BR> <BR> epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]- D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDCl3) # 2.42 (m, 1H) ; # 5.58 (q, 1H, J = 6.0 Hz, C4- H). Mass Spectrum (APCI): m/e 826 (M+NH4).

EXAMPLE 36 4-(propargyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21 ,22- <BR> <BR> epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]- D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane 1H NMR (CDC13) â 2.55 (t,lH, J= 2.5Hz); 6 4.79 (d,2H, J= 2.5Hz) ;6 5.59 (q, 1H, J = 6.0 Hz, C4-H). Mass Spectrum (APCI): m/e 808 (M+NH4).

EXAMPLE 37 4-(allyloxycarbonyl)oxy-6,7,15,16-tetrakis(acetyloxy)-21,22- epoxy- 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane A solution of 20 mg of 6,7,15,16-tetrakis(acetyloxy)- 21,22-epoxy-4,18-dihydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]-D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane (28 mmole) and 25RL (300mmole) of pyridine in 1 ml methylene chloride were cooled to 0° and treated with 30 ,uL(280mmole) of allyl chloroformate and allowed to stir at 0° for 2 days. The reaction was partitioned between 20 ml ethyl ether and 10 ml water and separated. The aqueous layer was washed with 5 ml ether and the organic layers were combined. The combined organic layer was washed with 5 ml 2N H2S04 ,brine and dried over MgSO4 and concentrated. The residue was purified by HPLC (Waters RCM, Nova-pak silica, 8 mm X 10 cm) using a mixture of 3:1(5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane) to afford 6 mg (27%) of the title compound as a white solid. 1H NMR (CDCl3) 6 4.69 (m,2H,); 6 5.3 (m,lH); 65.39 (m,lH); 6 5.56 (q, 1H, J = 6.0 Hz, C4-H); 65.97 (m,lH). Mass Spectrum (APCI): m/e 810 (M+NH4).

EXAMPLE 38 4-(benzyloxymethyl)oxy)oxy-6,7,15,16-tetrakis(acetyloxy)-21, 22-epoxy- 1 8-hydroxy-22-methoxycarbonyl[6a,7a, 15P,16P,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane A solution of 20 mg (28 mmole) of 6,7,15,16- tetrakis(acetyloxy)-21,22-epoxy-4,18-dihydroxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane and 12FL (94mmole) of N,N dimethylaniline in 1 mL dichloromethane was treated with 12RL (87 mmole) benzylchloromethyl ether and the solution stirred overnight at room temperature. The solution was then treated with another 12µL each of N,N dimethylaniline and benzylchloromethyl ether and allowed to stir 6 hours at room temperature. The reaction was partitioned between 20 ml ethyl ether and 10 ml water and separated.

The aqueous layer was washed with 5 ml ether and the organic layers were combined. The combined organic layer was washed with 5 ml 2N H2S04 ,brine and dried over MgSO4 and concentrated. The residue was purified by HPLC (Waters RCM, Nova-pak silica, 8mm X 10 cm) using a mixture of 2:1(5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane) to afford 10 mg (43%) of the title compound as a white solid. 1H NMR (CDCl3) 6 4.46 (q, 1H, J = 6

Hz); 6 4.69, 4.71(dd ,AB 2H, J = 12 Hz), 4.85, 4.91 (dd, AB, 2H, J = 7 Hz), d 7.28-7.38 (m,5 H). Mass Spectrum (APCI): m/e 846 (M+NH4).

EXAMPLE 39 4-methoxy-6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-18-hydro xy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 14.2 mg (0.020 mmole) of 6,7,15,16- tetrakis(acetyloxy)-21,22-epoxy-4,18-dihydroxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane in 50 Rl of DMF was treated with 1 ml of methyl iodide and 50 mg Ag2O and allowed to stir for 2 days at 40°C. Filtered and washed residue with ether and concentrated. The residue was purified by HPLC (Waters RCM, Nova-pak silica, 8 mm X 10 cm) using a mixture of 2:1(5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane) to afford 4.3 mg (30%) of the title compound as a white solid. 1H NMR (CDCl3) 6 3.43 (s,3H, OMe); 6 3.93(q,1H J=5.8Hz, C4-H). Mass Spectrum (APCI): m/e 740 (M+NH4).

EXAMPLE 40 4-allyloxy-6,7,15,1 6-tetrakis(acetyloxy)-2 1,22-epoxy-l 1 8-hydroxy- <BR> <BR> 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 14.0mg (0.0198mmole) of 6,7,15,16- tetrakis(acetyloxy)-21,22-epoxy-4,18-dihydroxy-22- <BR> <BR> methoxycarbonyl-[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane in 50 1ll of DMF was treated with 1 ml of allyl bromide and 50 mg Ag20 and allowed to stir for 3 days at 50°C. Filtered and washed residue with ether and concentrated. The residue was purified by HPLC (Waters RCM, Nova-pak silica, 8 mm X 10 cm) using a mixture of 2:1(5:4:1 hexane-methyl tert-butyl ether-acetonitrile:-hexane) to afford 2.0 mg (14%) of the title compound as a white solid. 1H NMR (CDCl3) 6 3.95 (m,1H); 6 4.15 (q,lH, 6.2Hz, C4-H); 6 4.21 (m,lH); 6 5.28 (d,lH, 10.3 Hz); 65.36 (d,lH, 17.3Hz); 6 5.98 (m, 1H); 65.97 (m,lH). Mass Spectrum (APCI): m/e 766 (M+NH4).

EXAMPLE 41 4-benzyloxy-6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-18-hyd roxy- <BR> <BR> 22-methoxycarbonyl[6o:,7o:, 1513,1613,21 13,2213]D:A-Friedo-2,3 ,27,30- tetranor-24-oxaoleanane A solution of 15.1 mg (0.14mmoles) benzyl alcohol and 63 ,ul (0.285 mmoles) of 2,6 di t-butyl pyridine in 5 ml dichloromethane was cooled to -780C and treated with 23.5 Ill (0.14 mmoles) triflic anhydride and allowed to stir 45 minutes. To this was added 20 mg (0.028 mmoles) of 6,7,15,16-tetrakis(acetyloxy)-21,22- epoxy-4,18-dihydroxy-22-methoxycarbonyl- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane in 5 ml dichloromethane. The solution was allowed to warm to room temperature and immediatly partitioned between 20 ml ether and 10 ml water and separated. The aqueous layer was washed with 5 ml ethyl ether and the organic layers were combined.

The combined organic layer was washed with brine and dried over MgSO4 and concentrated. The residue was purified by HPLC (Waters RCM, Nova-pak silica, 25 mm X 10 cm) using a mixture of 2:1(5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane) to afford 18 mg (80%) of the title compound as a white solid. 1H NMR (CDCl3) 6 4.21 (q, 1H, J = 6 Hz C4-H); 6 4.50, 4.73(AB 2H, J = 12 Hz), d 7.31-7.43 (m,5 H). Mass Spectrum (APCI): m/e 816 (M+NH4).

EXAMPLE 42 4-(2-bromobenzyloxy)-6,7,15,16-tetrakis(acetyloxy)-21,22-epo xy- <BR> <BR> 18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane This example was prepared using the procedures described in Example 41.

1H NMR (CDCl3) 6 4.35 (q, 1H, J = 6 Hz, C4-H); 6 4.58, 4.74 (dd ,AB 2H, J = 12 Hz), d 7.20 (m,lH); 6 7.37 (m, 1H); 6 7.45 (d, 1H, 7.5 Hz); 6 7.59 (d,lH, 8Hz). Mass Spectrum (APCI): m/e 894,896 (M+NH4).

ff EXAMPLE 43 <BR> <BR> <BR> 4-keto-6 ,7,l5,l 6-tetrakis(acetyloxy)-2 1,22-epoxy- 1 8-hydroxy-22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 100 mg (0.134 mmole) of 6,7,15,16- <BR> <BR> <BR> tetrakis(acetyloxy)-2 1 ,22-epoxy-4, 1 8-dihydroxy-22- <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane in 2 ml acetone was treated with Jones reagent dropwise until brown color remains and TLC 30% acetone/ hexanes shows complete reaction. The reaction was partitioned between 30 ml ethyl ether and 10 ml water and separated. The aqueous layer was washed with 5 ml ether and the organic layers were combined. The combined organic layer was washed with 5 ml saturated NaHCO3, brine and dried over MgSO4 and concentrated.

The residue was purified by HPLC (Waters RCM, Nova-pak silica, 25mm X 10 cm) using a mixture of 3:2 (5:4:1 hexane-methyl tert- butyl ether-acetonitrile:hexane) to afford 98 mg (98%) of the title compound as a white solid. 13C NMR (CDCl3) 6 204.9 (C-4).

Mass Spectrum (APCI): m/e 724 (M+NH4).

EXAMPLE 44 6,7,15,1 6-tetrakis(acetyloxy)-2 1,22-epoxy-4(S),1 8-dihydroxy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 19 mg (0.50mmole) NaBH4 and 300 µl 1N ZnCl2 in 3ml ether was allowed to stir 15 minutes and to the solution was added 30 mg (.0.043mmole) of 4-keto-6,7,15,16- tetrakis-(acetyloxy)-21,22-epoxy-18-hydroxy-22-methxycarbony l- [6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane in 1 ml ether. allowed to stir for 3 hours at ambient temperature. Quenched reaction with 5 ml 1N HCl and partitioned with 20 ml of ethyl acetate.The aqueous layer was washed with 5 ml ethyl acetate and the organic layers were combined. The combined organic layer was washed with 5 ml saturated NaHCO3, brine and dried over NaSO4 and concentrated. The residue was purified by HPLC (Waters RCM, Nova-pak silica, 25 mm X 10 cm) using a mixture of 2:1(5:4:1 hexane-methyl tert-butyl ether- acetonitrile:hexane) to afford 25 mg (83%) of the title compound as a white solid. 1H NMR (CDCl3) 6 4.53 (q, 1H, J = 6.0 Hz, C4-H).

Mass Spectrum (APCI): m/e 726 (M+).

EXAMPLE 45 4(S)-6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- 18 -hydroxy-22- <BR> <BR> methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 14.2 mg of 6,7,15,16-tetrakis(acetyloxy)- <BR> <BR> <BR> 21,22-epoxy-4(S), 1 8-dihydroxy-22-methoxycarbonyl- <BR> <BR> <BR> <BR> <BR> <BR> <BR> [6α,7α,15 ,16 ,-21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24- oxaoleanane (20 mmole) and 20 RL (247 mmole) of pyridine in 1 ml methylene chloride were cooled to 0° and treated with 7 RL(100 mmole) of acetylchloride and allowed to stir at 0° for 4 hours. The reaction was partitioned between 15 ml ethyl acetate and 5 ml water and separated. The aqueous layer was washed with 5 ml ethyl acetate and the organic layers were combined. The combined organic layers were washed with 5 ml of 2N H2S04, brine and dried over MgSO4 and concentrated. The residue was purified by HPLC (Waters RCM, Nova-pak silica, 8 mm X 10 cm) using a mixture of 3:1(5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane) to afford 7 mg (47%) of the title compound as a white solid. 1H NMR (CDCl3) 6 1.93 (s, 3H), 5.74 (q, 1H, J = 6.0 Hz, C4-H).

EXAMPLE 46 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-1-(2-oxoethyl)-1 8- hydroxy-20-hydroxymethyl-2-methoxycarbonyl[6α,7α,15 ,16 ,- 21 ,22 ]D:A-Friedo-2,3,27,30-tetranor-24-oxaoleanane A solution of 4,6,7,15,16-Pentakis(acetyloxy)-21,22- <BR> <BR> <BR> epoxy-18-hydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]- D:A-Friedo-A-homo-27,30-dinor-24-oxaoleana-1,20(29)-dien-3-o ne (25.2 mg, 0.032 mmol)in 1.5 ml of THF was added BH3.THF (0.32 ml, 0.032 mmol) at 0°C and stirred 3h (0°C to rt). Then the solution was added NaOH (0.1 ml, 3N solution) and H202(98 ul, 0.96 mmol, 30 % solution) and heated to reflux for 2 h. The mixture was poured into brine and extracted with CH2Cl2, dried over MgSO4.

Volatile were removed by vacuum and the residue was purified by chromatography on silica gel using 66 % EtOAc-CH2Cl2 to afford 2.3 mg (9 %) of the title compound. 1H NMR (CDCl3) 6 9.81(t, 1H, J = 2.3 Hz), 4.56-4.59 (m, 1H), 3.04(ddd, 1H, J = 15.6, 9.2, 2.3 Hz), 2.51(ddd, 1 H, J = 15.5,4.3, 2.3 Hz). Mass spectrum (EI) m/e 831 (M+Na).

EXAMPLE 47 6,7,15,16-tetrakis(acetyloxy)-21,22-epoxy-4,18-dihydroxy-20- oxo- 22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane A solution of 4,6,7,15,16-pentakis(acetyloxy)-21,22- epoxy- 18-hydroxy-20-oxo-22-methoxycarbonyl [60c,7oc,15 1513,1613,- 21P,22P]D :A-Friedo-2,3 ,27,30-tetranor-24-oxaoleanane (75.6 mg, 0.10 mmol) in 4 ml of T11F was added 2 ml satd NaHCO3 and stirred at rt for 72 h. The mixture was poured into ether and washed with brine, dried with MgSO4. Volatiles were removed by vacuum and the residue was purified by HPLC (1 :4:5/Hexane: 7.7/7.0 ml/min) to afford 4.0 mg (6%) of the title compound. 1H NMR (CDCl3) 64.38 (q, 1H, J = 6.4 Hz). Mass spectrum (APCI) m/e 726 (M+NH4).

EXAMPLE 48 4,6,7,15,16-pentakis(acetyloxy)-1-cyano-21,22-epoxy-18-hydro xy-22- methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane 50 mg of 4,6,7,15,16-Pentakis(acetyloxy)-21,22-epoxy- 1,18-dihydroxy-22-methoxycarbonyl[6α,7α,15 ,16 ,21 ,22 ]D:A- Friedo-2,3,27,30-tetranor-24-oxaoleanane (0.065 mmole) and 35 mg of 2-nitrophenylselenocyanate (0.154 mmole) were dissolved in 0.5ml of tetrahydrofuran. 0.05 ml of tri-n-butylphosphine were added dropwise.

The resulting deep red solution was stirred for 2 h at room temperature.

0.5 ml of aq. hydrogenperoxide (30%) were added and the mixture stirred for 14 h. To the reaction mixture was added 20 ml of 1N hydrochloric acid and 20 ml of dichloromethane and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride then was dried over MgSO4 and concentrated. The residue was filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges) to afford 22.7 mg (0.029 mmole) of the title compound as a white solid. 1H NMR (CDCl3) 8 1.30 (d, 3H, J = 6.9 Hz, C29-H), 2.42 (m, 1H, C20-H), 3.36 (s, 1H, C21-H), 3.71, 3.89 (AB, 2H, J = 9.4 Hz, C24-H), 4.48 (d, 1H, J = 6.9 Hz, C1-H). 13C NMR (CDCl3) 67.8 (C1), 117.1 (CN). Mass Spectrum (APCI): m/e 793 (M+NH4).