WO1999020267A1 - Furanyl, tetracyclic triterpene derivatives with immunosuppressant activity - Google Patents

Furanyl, tetracyclic triterpene derivatives with immunosuppressant activity Download PDF

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Publication number
WO1999020267A1
WO1999020267A1 PCT/US1998/021592 US9821592W WO9920267A1 WO 1999020267 A1 WO1999020267 A1 WO 1999020267A1 US 9821592 W US9821592 W US 9821592W WO 9920267 A1 WO9920267 A1 WO 9920267A1
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WIPO (PCT)
Prior art keywords
lla
alkyl
hydroxy
triacetoxy
acetoxyethyl
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PCT/US1998/021592
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French (fr)
Inventor
Robert K. Baker
Jianming Bao
Frank Kayser
Shouwu Miao
William H. Parsons
Kathleen M. Rupprecht
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Merck & Co., Inc.
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Priority claimed from GBGB9807937.9A external-priority patent/GB9807937D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU10823/99A priority Critical patent/AU1082399A/en
Publication of WO1999020267A1 publication Critical patent/WO1999020267A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Immunoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as
  • the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
  • 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.
  • 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 which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs.
  • FK-506 Prograf
  • 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.
  • 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.
  • the present invention describes newly developed immunosuppressive compounds derived from the compounds described in Formulae 1(a) through 1(d) and which have the relative stereochemistry depicted above.
  • This invention relates to a class of triterpene derivatives of the general structural Formula I
  • 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.
  • pharmaceutical formulations comprising a compound of Formula I and a pharmaceutical carrier, as well as, pharmaceutical formulations comprising a compound of Formula I, and one or more immunosuppressive compounds and a pharmaceutical carrier.
  • 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 pemphigo
  • this invention relates to compounds of the general structural Formula I:
  • a and b are independently a single bond or a double bond, and represented by in the structure above;
  • r is: O or 1;
  • Rl and Rl ⁇ a are independently:
  • aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
  • heteroaryl is defined as an unsubstituted, monosubstituted, or disubstituted five or six membered aromatic heterocycle containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are selected from the group consisting of:
  • heterocyclyl wherein heterocyclyl is defined as a cyclic ;, non-aromatic moiety containing from 1 to 3 heteroatoms selected from the group consisting of O,
  • heterocyclyl wherein heterocyclyl is as defined above, and
  • aryl wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
  • R2 is:
  • aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of: (a') halo, as defined above, (b') hydroxy, (c') (C ⁇ -C 6 )-alkyl,
  • heteroaryl wherein heteroaryl is defined as an unsubstituted, monosubstituted, or disubstituted five or six membered aromatic heterocycle containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of:
  • heterocyclyl (s 1 ) fused benzo or pyridyl group, (s) heterocyclyl, wherein heterocyclyl is defined as a cyclic, non-aromatic moiety containing from 1 to 3 15 heteroatoms selected from the group consisting of O,
  • heterocycle being unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
  • heterocyclyl wherein heterocyclyl is as defined above; (4) (C2-Cio)-alkynyl, wherein alkynyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
  • R 4 and R ⁇ are independently: (1) hydrogen,
  • R 6 is:
  • R ' , R° and R ⁇ are independently selected from the group consisting of:
  • alkyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Ci-C ⁇ )-alkoxy, vinyl, cyano, oxo, nitro, hydroxy, CHO, CO2H, COCi-C6-alkyl, CO2C1-C6- alkyl, CONR R5, NR R5, NR COCl-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, (Ci-C ⁇ )-alkoxy, phenyl, phenoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COC1-C6- alkyl, CO2Ci-C6-alkyl
  • heteroaryl 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 O, S, N, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Ci-C ⁇ )-alkoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COCi-C ⁇ -alkyl, CO2Ci-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 subembodiment of the invention are compounds of structural Formula 1, wherein :
  • R3 is further defined as: (1) H, or
  • aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
  • heterocyclyl wherein heterocyclyl is as defined above;
  • heterocyclyl wherein heterocyclyl is as defined above;
  • R 4 and R ⁇ are further defined independently as:
  • R" is further defined as:
  • R , R8 and R ⁇ are further defined as independently selected from the group consisting of:
  • R and R are further defined as independently chosen from the group consisting of: (1) H, and
  • Ri is further defined as: (1) H,
  • R 4 and R ⁇ are further defined independently as: (1) hydrogen, (2) C r C 3 alkyl, or
  • R6 is further defined as: (1) hydrogen, (2) oxo and a is a single bond,
  • R ⁇ , R8 and R ⁇ are further defined as independently selected from the group consisting of:
  • R and R are further defined as independently chosen from the group consisting of:
  • RlOa an( j RlOb are f ur ther defined as H.
  • a most preferred embodiment is a compound selected from the group consisting of:
  • the compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof.
  • 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.
  • alkyl includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration.
  • 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.
  • 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.
  • Hydroogen as used herein, means fluoro, chloro, bromo and iodo.
  • 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.
  • heteroaryl as utilized herein, unless specifically defined otherwise, is intended to include the following: a 5 or 6- membered ring substituted with one, two or three heteroatoms selected from O, S, N, and is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl-C ⁇ )-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COCl-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.
  • 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 such as: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.
  • heterocyclyl as utilized herein, unless specifically defined otherwise, is intended to include a cyclic, non- aromatic substituents containing from 1 to 3 heteroatoms selected from the group consisting of O, N, and S, said heterocyclyl substituent being itself unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (C ⁇ -C6)-alkoxy, cyano, nitro, hydroxy, CHO, CO 2 H, COCi-C ⁇ -alkyl, CO2Ci-C6-alkyl, CONR ⁇ R 2 ,
  • NRURI 2 NRHCOCl-C6-alkyl.
  • Representative heterocyclyl substituents include, but are not limited to the following: piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, piperazinyl, pyrolidine-2- one, piperidine-2-one and the like.
  • Pharmaceutically acceptable salts include both the metallic
  • 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.
  • 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.
  • crystal forms, hydrates and solvates of the compounds of Formula I are crystal forms, hydrates and solvates of the compounds of Formula I.
  • the lactol product of Reaction Scheme A can be reacted with triethylsilane and a Lewis acid such as borontrifluoride diethyl etherate to give the tetrahydrofuran (THF) analog.
  • a Lewis acid such as borontrifluoride diethyl etherate
  • the lactol hydroxy group can be replaced as demonstrated in Scheme C with a variety of substituents (represented as R 10a ).
  • the hydroxy lactol derivaitve can be oxidized to its keto lactone derivative by use of a variety of reagents, including pyridinium chlorochromate (PCC).
  • PCC pyridinium chlorochromate
  • the lactone group of compound la can be rearranged to substituted THF esters under acidic or basic conditions (Reaction Scheme D).
  • 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 (K2CO3) 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 reesterified by stirring the hydroxy analog with acetic anhydride (Ac2 ⁇ ).
  • Rl-Oa-a-c-eta-de yde 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.
  • RlO a -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 C20 olefin can then be converted to the corresponding hydroxy derivative with ozone and reductive workup as described above.
  • Tetrahydrofuran derivatives 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 45°C. Deacetylation can also be achieved by reacting with CH3(Cl)Al[N(OCH3)CH3 (Weinreb reagent) in inert solvents such as THF, toluene or methyl ene chloride.
  • HCl preferably 2M to 3M concentration
  • Deacetylation can also be achieved by reacting with CH3(Cl)Al[N(OCH3)CH3 (Weinreb reagent) in inert solvents such as THF, toluene or methyl ene chloride.
  • 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 H2O
  • pyridinium chlorochromate pyridinium chlorochromate
  • oxalyl chloride plus DMSO all will achieve this conversion.
  • esters at C4 can be prepared by reaction of a preformed carboxylic acid chloride with the C4 alcohol derivative in a basic solvent such as pyridine.
  • 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.
  • AgCN silver cyanide
  • 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 carbonyl diimidazole (CDI) to obtain the imidazolecarbonyl intermediate which is then reacted with an alcohol or amine (R ⁇ R3 NH) to give the corresponding carbonate or carbamate derivatives.
  • CDI carbonyl diimidazole
  • R ⁇ R3 NH an alcohol or amine
  • C4 ether derivatives can also be prepared.
  • the best procedure involves reacting an alcohol with trifluoromethanesulfonic anhydride (Tf2 ⁇ , triflic anhydride) to obtain the preformed triflate in dichloromethane at reduced temperature, preferably -78°C.
  • Tf2 ⁇ trifluoromethanesulfonic anhydride
  • Ethers may also be prepared by heating a mixture of C4 alcohol, the appropriate alkylhalide and an excess of silver oxide (Ag2 ⁇ ) in an aprotic invert solvent such as THF.
  • Lactone la can be selectively de-acetylated at C4 to give the corresponding alcohol by reacting it with an aqueous solution of HCl (preferably 2M to 3M concentration) in THF. It can also be prepared by reaction with CH 3 (Cl)Al[N(OCH 3 )CH 3 (Weinreb reagent) in inert solvents such as THF, toluene or methylene chloride. The hydroxy product can be further derivatized according to procedures described in Reaction Schemes G and H. The lactone derivatives can then be converted to C20 keto THF derivatives according to Reaction Schemes A E.
  • 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 H2O
  • pyridinium chlorochromate pyridinium chlorochromate
  • oxalyl chloride plus DMSO all will achieve this conversion.
  • C4 amino derivatives can be prepared by reacting the C4 ketone with an amine NHR3R in a variety of solvents with a reducing agent such as sodium cyanoborohydride.
  • the lactone derivatives can then be converted to C20 keto THF derivatives according to Reaction Schemes A - E.
  • R ⁇ MgBr alkyllithium reagents
  • RJ-Li alkyllithium reagents
  • aprotic solvents such as diethyl ether or THF.
  • Allylsilane reagents also add to the C18 ketone. For instance, reaction with allyl trimethylsilane and titanium tetrachloride in THF or diethyl ether gives the allyl adduct.
  • R6 When R6 is OAc, it can be selectively hydrolyzed and derivatized using reaction schemes described above for the pentacyclic series.
  • the acetoxy group at position 15 can be selectively removed from the ketone precursor shown in excellent yield by refluxing in acetic acid with Zn powder.
  • the C18 ketone can then be derivatized according to methods described in Reaction scheme M.
  • the C15 hydroxy group can be oxidized to the corresponding ketone by a variety of oxidizing agents.
  • the Jones reagent chromic acid and sulfuric acid in H2O
  • pyridinium chlorochromate pyridinium chlorochromate
  • oxalyl chloride plus DMSO all will achieve this conversion.
  • 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 ossiu , skin, cornea, lung, pancreas, intestinum ***, 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, glomerulonephriti
  • 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
  • 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, ichthy
  • 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., 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.
  • 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 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 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.
  • 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
  • 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, ichthy
  • 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., 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.
  • 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 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.
  • AIDS 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 .
  • autoimmune or a rejection process 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.
  • 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.
  • the present invention provides for immunosuppressant agents which are inhibitors of a voltage dependent potassium channel, K v 1.3, 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 K v l.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 K v l-3 channel would elicit an immunosuppressant response. (Chandy et al, J. Exp. Med. 160, 369, 1984; Decoursey et al., Nature, 307, 465, 1984).
  • 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 K v 1.3 channel existed to test this hypothesis.
  • Margatoxin blocks only K v 1.3 in T- cells, and has immunosuppressant activity in both in vitro and in vivo models. (Lin et al., J. Exp. Med, 111, 637, 1993). Since the compounds of the embodiments of this invention produce blockade of K v 1.3, 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 K v 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 K v 1.3.
  • a combination therapy comprising a compound of formula I and one or more immunosuppressant agents.
  • immunosuppressant agents within the scope of this invention include, but are not limited to, IMUREK® azathioprine sodium, brequinar sodium, SPANIDIN® gusperimus trihydrochloride (also known as deoxyspergualin), mizoribine (also known as bredinin), CELLCEPT® mycophenolate mofetil, NEORAL® Cyclosporin A (also marketed as a different formulation of Cyclosporin A under the trademark SANDIMMUNE®), PROGRAF® tacrolimus
  • 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 .
  • T CELL IL-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
  • the culture plates were then incubated at 37°C 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).
  • MNC Peripheral blood mononuclear cells
  • LSM Organon Teknika, Durham, NC
  • 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
  • T lymphocytes were assessed by measurement of tritiated thymidine incorporation.
  • the cells were pulse-labeled with 2 ⁇ Ci/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 K v 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 86 Rb + (3 ⁇ Ci/ml, Dupont-NEN) in the glutamine supplemented IMDM.
  • IMDM Iscove's Modified Dulbecco's Medium
  • the K v 1.3 channels are opened by depolarization of the cells with High K Buffer (final concentrations, in mM, 63.25 KC1, 68.25 NaCl, 1 CaCl 2 , 2 MgCl 2 , 10 HEPES, pH adjusted to 7.2 with NaOH) also containing test compounds.
  • High K Buffer final concentrations, in mM, 63.25 KC1, 68.25 NaCl, 1 CaCl 2 , 2 MgCl 2 , 10 HEPES, pH adjusted to 7.2 with NaOH
  • To measure 86 Rb+ efflux through the channels aliquots of 100 ⁇ l are taken from each well after a given time and added to plates containing 100 ⁇ l MicroScint-40 (Packard) for counting by liquid scintillation techniques. MicroScint-40 (100 ⁇ l) is then added to each well of the cell plate to determine the remaining 86 Rb + activity.
  • 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.
  • administration can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal and parenteral.
  • parenteral 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • citric acid and its salts and sodium EDTA are also used.
  • 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.
  • 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.
  • MDI metered dose inhalation
  • 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 corneal 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.
  • a digestible oil such as soybean oil, cottonseed oil or olive oil
  • 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.
  • 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.
  • 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.
  • the dosage form and administration route should be selected depending on the compatibility of the combined drugs.
  • 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 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 6OF254 plate of 1mm thickness using methylene chloride-ethyl acetate 1:1 (v/v) as solvent, then by high performance liquid chromatography (HPLC) using a Zorbax RxCs 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 compound 1(a) and 1(b).
  • TLC preparative thin layer chromatography
  • HPLC high performance liquid chromatography
  • Mass spectra were recorded on JEOL SX-102A (electron impact, EI,903V) and JEOL HXllO (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 1(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 C40H52O16. A table of the critical HR-EI data is given below.
  • J-3-C NMR spectra were recorded for the compound of Formula 1(a) in CD2CI2 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.
  • TMS tetramethylsilane
  • 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.
  • 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.
  • the column was washed with 100% ethyl acetate.
  • Fractions eluted with methylene chloride-ethyl acetate 3:2 were enriched in compound of Formula 1(a) and 1(b).
  • Component 1(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).
  • Formula 1(c) using the conditions previously described is as follows: 15.1 (2x), 16.9, 19.8, 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.
  • 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 Kb).
  • 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.
  • Volume of elution for the compound of Formula 1(a) ranges from about 2 to about 3.5 column volumes of solvent; that for the compound of Formula 1(b) is about 3 to about 4.5 column volumes.
  • Step A 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-l,18,20-tris- hydroxy-22-methoxycarbonyl[6 ⁇ ,7 ⁇ ,15 ⁇ ,16 ⁇ ,21 ⁇ ,22 ⁇ ]-D:A- Friedo-2.3.27.30-tetranor-24-oxaoleanane
  • Step B 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18,20-dihydroxy- 22-methoxycarbonyl[6 ⁇ ,7 ⁇ ,15 ⁇ ,16 ⁇ ,21 ⁇ ,22 ⁇ ]-D:A-Friedo- 2.3.27.30-tetranor-24-oxaoleanane
  • Step C 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- oxo-22-methoxycarbonyl[6 ⁇ ,7 ⁇ ,15 ⁇ ,16 ⁇ ,21 ⁇ ,22 ⁇ ]D:A-Friedo- 2.3.27.30-tetranor-24-oxaoleanane
  • 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 the title compound.
  • the Grignard reagent is formed by adding the halide (benzyl chloride) in THF solution to an excess of magnesium in THF at room temperature under a nitrogen atmosphere and then refluxing for 1 hr.
  • iH NMR (CDCI3) 6 7.29-7.34 (m, 3H), 7.09 (d, 2H, J 7.1 Hz), 5.54 - 5.50
  • Step A Preparation of [3a-S-3a ⁇ ,3b ⁇ ,5a ⁇ ,9 ⁇ ,9a ⁇ ,10 ⁇ ,ll ⁇ ,lla ⁇ ]-lla- (l-R-acetoxyethyl)-6-(2-phenylacetylenyl)-6-hydroxy-9, 10,11- triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, 11.1 la-tetradecahydrophenanthro [ 1 ,2-c] furan
  • Step B Preparation of [3a-S-3a ⁇ ,3b ⁇ ,5a ⁇ ,9 ⁇ ,9a ⁇ ,10 ⁇ ,ll ⁇ ,lla ⁇ ]-lla- ( l-R-acetoxyethyl)-6-(2-phenethyl)-6-hydroxy-9, 10, 11- triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, 11.1 la-tetradecahydrophenanthro [ 1.2-c] furan
  • Step A Preparation of [3a-S-3a ⁇ ,3b ⁇ ,5a ⁇ ,9 ⁇ ,9a ⁇ ,10 ⁇ ,ll ,lla ]-lla- (l-R-acetoxyethyl)-6-oxo-9,10,ll-triacetoxy-3b,7,9a-trimethyl- l,3,3a,3b,4,5,5a,6,7,8, 9,9a,9b,10, ll,lla-hexa- decahydrophenanthro [1 ,2-c] furan
  • Step B Preparation of [3a-S-3a ⁇ ,3b ⁇ ,5a ⁇ ,9 ⁇ ,9a ⁇ ,10 ,ll ,lla ⁇ ]-lla-
  • Step C Preparation of [3a-S-3a ⁇ ,3b ⁇ ,5a ,9 ⁇ ,9a ⁇ ,10 ⁇ ,ll ,lla ]-lla-
  • Step A Preparation of 2-tetrahydropyranyloxyphenyl ethyl bromide
  • Step B The THP ether derivative of the title compound was prepared according to the procedures described in Example 7. The THP protecting group is removed as follows. To the THP ether derivative in 4 ml of methanol was added 10 mg TsOH and the mixture stirred at rt for 3.5 h. After removal of solvent, the reaction mixture is purified by HPLC.
  • Step B To a solution of [3a-S-3a ⁇ ,3b ⁇ ,5a ⁇ ,9 ⁇ ,9a ⁇ ,10 ⁇ ,ll ⁇ ,lla ⁇ ]-lla-
  • Wilkinson's catalyst [ (PPh3)3RhCl ] is added and the solution is degassed and saturated with hydrogen.
  • the reaction vessel is pressurized with H2 to 50 psi and hydrogenated on a Parr-apparatus at 25°C.
  • reaction is complete TLC, HPLC
  • the solvent is removed under reduced pressure.
  • the residue is first filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges).
  • the title compound is prepared by procedures described in Example 50.
  • the preparation 2-(2-ethylmercaptophenyl)- allyltrimethylsilane is as follows.
  • StepA Preparation of l-Ethylmercapto-2-bromobenzene
  • reaction mixture was stirred at 55-60 °C for 12 h and was poured into 200 ml of ether. It was washed with water (20 ml x 3), dried over MgSO4 and concentrated to afford l-ethylmercapto-2-bromobenzene as a colorless oil.
  • Step B Preparation of 2-(2-Ethylmercaptophenyl)- allyltrimethylsilane
  • a solution of the Grignard reagent of l-ethylmercapto-2- bromobenzene in tetrahydrofuran was prepared in the following way: 1.50 g (6.9 mmol) of l-ethylmercapto-2-bromobenzene were added to 218 mg (9.0 mmol) of magnesium in 8 ml of anhydrous tetrahydrofuran at room temperature under N2 and was heated to reflux for lh.
  • Example 50 The C6 sidechain is prepared as described below.
  • Step B Preparation of (R)-4-benzyl-3-[2-(2-ethylphenyl)ethyl]- oxazolidin-2-one
  • Step C Preparation of (R),(R)-4-Benzyl-3- [2-(2-ethyl-phenyl)-propyl] - oxazolidin-2-one

Abstract

The compounds of Formula (I) are useful as immunosuppressive agents.

Description

TITLE OF THE INVENTION
FURANYL, TETRACYCLIC TRITERPENE DERIVATIVES WITH
IMMUNOSUPPRESSANT ACTIVITY
BACKGROUND OF THE INVENTION
Immunoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as
Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves ophthalmopathy and asthma.
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.
is a single bond
is a double bond
is a single bond
is a double bond
Figure imgf000004_0001
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 1(a) through 1(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
Figure imgf000005_0001
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, and one or more immunosuppressive compounds 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 B_i-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, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn; 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:
Figure imgf000008_0001
or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein:
a and b are independently a single bond or a double bond, and represented by in the structure above;
Figure imgf000008_0002
r is: O or 1;
Figure imgf000008_0003
Rl and Rl^a are independently:
(1) H,
(2) =O, when R is absent or Rl0° is absent respectively, (3) (Cι-Ci-ø)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo, (b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Cι-C6)-S(O)n-,
(f) aryl-(Ci-C6)-alkyloxy, (g) cyano,
(h) nitro,
(i) vinyl,
(j) NR4R5,
(k) NR COCι-C6-alkyl, (1) CHO,
(m) CO2H,
(n) COCi-Cβ-alkyl,
(o) CO2Ci-C6-alkyl,
(p) CONR R5, (q) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy, (c') (Ci-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl, (e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl, (g') (Cl-C6)-alkyloxy, (h') (Ci-C6)-alkyl-S(O)n-,
(i') phenyl,
(j') phenoxy,
(k') cyano,
(D nitro,
(m') CO2H,
(n') COCi-Cβ-alkyl,
(o*) CO2Ci-C6-alkyl,
(P') CONR R5,
(q') NR4R5,
(r') NR4COCι-C6-alkyl,
(s') (Ci-C6)-alkenyloxy, and
(f) benzyloxy;
(r) heteroaryl, wherein heteroaryl is defined as an unsubstituted, monosubstituted, or disubstituted five or six membered aromatic heterocycle containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
(c') (Cι-C6)-alkyl,
(<T) (C l-C4)-perfluoroalkyl,
(e') (Cι-C6)-alkenyl,
(f) (Cl-C6)-alkynyl,
(g') (Cι-C6)-alkyloxy,
(h') (Ci-C6)-alkyl-S(O)n-,
(i') phenyl,
(j") phenoxy, (k') cyano,
(V) nitro,
(m') CO2H,
(n') COCi-C6-alkyl,
(o') CO2Ci-C6-alkyl,
(P') CONR4R5,
(q') NR R5,
(r') NR4COCι-C6-alkyl,
(s') fused benzo, and
10 (f) fused pyridyl group,
(s) heterocyclyl, wherein heterocyclyl is defined as a cyclic ;, non-aromatic moiety containing from 1 to 3 heteroatoms selected from the group consisting of O,
N, and S, said heterocycle being unsubstituted or
15 substituted with one, two or three substituents selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
(c') (Ci-C6)-alkyl,
20 (d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Cι-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy,
OX (Ci-C6)-alkyl-S(O)n-,
25 (i') phenyl,
(j') phenoxy,
(k') cyano,
(V) nitro,
(m') CO2H, (n') COCι-C6-alkyl,
(o') CO2Ci-C6-alkyl,
(p') CONR R5,
(q') NR4R5,
(r') NR4COCι-C6-alkyl, and
(s1) oxo,
(f) fused benzo, and
(u') fused pyridyl group;
(4) (C2-Cio)-alkenyl, wherein alkenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Ci-C6)-S(O)n-,
(f) phenyl-(C l-C6)-alkyloxy ,
(g) cyano,
(h) nitro,
(i) vinyl,
(j) NR4R5,
(k) NR COCι-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-Cβ-alkyl,
(o) CO2Ci-C6-alkyl,
(P) CONR R5,
(q) aryl, wherein aryl is as defined above, (r) heteroaryl, wherein heteroaryl is as defined above, and (s) heterocycle, wherein the heterocycle is as defined above, (5) (C2-Clo)-alkynyl, wherein alkynyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy, (c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Cι-C6)-S(O)n-,
(f) phenyl-(Ci-C6)-alkyloxy,
(g) cyano, (h) nitro,
(i) vinyl,
(j) NR R5,
(k) NR COCι-C6-alkyl,
(1) CHO, (m) CO2H,
(n) COCi-Cβ-alkyl, (o) CO2Ci-C6-alkyl,
(p) CONR R5,
(q) aryl, wherein aryl is as defined above, (r) heteroaryl, wherein heteroaryl is as defined above,
(s) heterocyclyl, wherein heterocyclyl is as defined above, and
(t) Si(R4)3, (6) an exo-methylene group, when R^ is absent or Rl^ is absent respectively; or
(7) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
(c') (Ci-C6)-alkyl,
(d') (C l-C4)-perfluoroalkyl,
(e') (Cι-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Cι-C6)-alkyloxy,
(h') (Ci-C6)-alkyl-S(O)n-,
(i') phenyl,
0") phenoxy,
(k') cyano, d') nitro,
(m') CO2H,
(n') COCl-Cβ-alkyl,
(o') CO2Ci-C6-alkyl,
(P') CONR R5,
(q*) NR R5,
(r') NR COCi-C6-alkyl,
(s') (Cι-Cβ)-alkenyloxy, and
(f) benzyloxy;
R2 is:
(1) H,
(2) absent when Rl is oxo, (3) absent when Rl is an exo-methylene group, or
(4) OH,
is:
(1) H, oi
(2) (Cl-Clθ)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Cι-C6)-S(O)n-,
(f) aryl-(Cι-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
0") NR4R5,
(k) NR4COCl-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-Cβ-alkyl,
(o) CO2Ci-C6-alkyl,
(P) CONR4R5,
(q) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of: (a') halo, as defined above, (b') hydroxy, (c') (Cι-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl, (g') (Ci-C6)-alkyloxy,
(h') (Cι-C6)-alkyl-S(O)n-,
(i') phenyl,
(j') phenoxy,
(k1) cyano, (D nitro,
(m') CO2H,
(n') COCl-C6-alkyl,
(o') CO2Cι-C6-alkyl,
(p') CONR4R5, (g') NR R5, and
(r') NR COCi-C6-alkyl, (r) heteroaryl, wherein heteroaryl is defined as an unsubstituted, monosubstituted, or disubstituted five or six membered aromatic heterocycle containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of:
(a1) halo, as defined above,
(b1) hydroxy, (c') (Cι-C6)-alkyl,
(d1) (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Cl-C6)-alkyloxy, (h') (Cι-C6)-alkyl-S(O)n-,
(i') phenyl,
(j') phenoxy,
(k1) cyano, 5 (D nitro,
(m') CO2H,
(n') COCi-C6-alkyl,
(o') CO2Cι-C6-alkyl,
(p') CONR4R5, 10 (q') NR R5,
(r') NR COCι-C6-alkyl, and
(s1) fused benzo or pyridyl group, (s) heterocyclyl, wherein heterocyclyl is defined as a cyclic, non-aromatic moiety containing from 1 to 3 15 heteroatoms selected from the group consisting of O,
N, and S, said heterocycle being unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
(a1) halo, as defined above, 20 (b1) hydroxy,
(c') (Cι-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl, 25 (g') (Cl-C6)-alkyloxy,
(h') (Cι-C6)-alkyl-S(O)n-,
(i') phenyl,
(j') phenoxy,
(k') cyano, (D nitro,
(m') CO2H,
(n') COCi-C6-alkyl,
(o') CO2Cl-C6-alkyl,
(p') CONR R5,
(q') NR R5,
(r') NR COCι-C6-alkyl, and
(s') oxo,
(f) fused benzo, and
(u') fused pyridyl group;
(t) Si(R4)3,
(3) (C2-Ciθ)-alkenyl, wherein alkenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Cι-C6)-S(O)n-, (f) phenyl-(Ci-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
(j) NR R5, (k) NR4COCi-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-Cβ-alkyl, (0) CO2Cι-C6-alkyl,
(p) CONR R5,
(q) aryl, wherein aryl is as defined above,
(r) heteroaryl, wherein heteroaryl is as defined above, and
(s) heterocyclyl, wherein heterocyclyl is as defined above; (4) (C2-Cio)-alkynyl, wherein alkynyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (Cl-C6)-alkyloxy,
(e) (Cι-C6)-S(O)n-, (f) phenyl-(Ci-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
0') NR4R5, (k) NR COCι-C6-alkyl,
(1) CHO, (m) CO2H,
(n) COCi-Cβ-alkyl, (o) CO2Cι-C6-alkyl, (p) CONR R5,
(q) aryl, wherein aryl is as defined above,
(r) heteroaryl, wherein heteroaryl is as defined above, and
(s) heterocyclyl, wherein heterocyclyl is as defined above; or (5) cyano;
R4 and R^ are independently: (1) hydrogen,
(2) C1-C6 alkyl, or
(3) aryl, wherein aryl is defined above,
R6 is:
(1) hydrogen,
(2) oxo and a is a single bond,
(3) O[(C=O)Or]sRH,
(4) O[(C=O)Or]saryl, aryl as defined above,
(5) O[(C-=O)Or]sheteroaryl, heteroaryl as defined above,
(6) OC(=O)NRHR12,
(7) NR R12, or
(8) absent, when a is a double bond;
R ' , R° and R^ are independently selected from the group consisting of:
(1) hydrogen,
(2) oxo,
(3) O[(C=O)Or]sRll,
(4) O[(C=O)Or]saryl, aryl as defined above,
(5) O[(C=O)Or]sheteroaryl, heteroaryl as defined above,
(6) OC(=O) NRnR12, and
(7) NRllRl2;
Figure imgf000020_0001
(1) H,
(2) absent when RlOa is oxo,
(3) an exo-methylene group, when R2 is absent or RlO*3 is absent respectively, or (4) OH; and
12 d R are independently chosen from the group consisting of:
(1) H, and
(2) (Cι-Cβ)-alkyl, wherein alkyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Ci-Cβ)-alkoxy, vinyl, cyano, oxo, nitro, hydroxy, CHO, CO2H, COCi-C6-alkyl, CO2C1-C6- alkyl, CONR R5, NR R5, NR COCl-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, (Ci-Cβ)-alkoxy, phenyl, phenoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COC1-C6- alkyl, CO2Ci-C6-alkyl, CONR R5, NR4R5, NR COCi-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 O, S, N, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Ci-Cρ)-alkoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COCi-Cβ-alkyl, CO2Ci-C6-alkyl,
CON R4R5, NR4R5, NR4COCι-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 subembodiment of the invention are compounds of structural Formula 1, wherein :
RlOa is further defined as: (1) H, (2) =O, when R10b is absent,
(3) (Ci-C4)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo, (b) hydroxy,
(c) oxo,
(d) (Ci-C3)-alkyloxy,
(e) CHO,
(g) CO(Ci-C3)-alkyl, (i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one or two of the substituents selected from the group consisting of:
(a1) halo, as defined above,
(b') hydroxy, (c') (Cι-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Cι-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Cι-C6)-alkyloxy, (h') (Cι-C6)-alkyl-S(O)n-, (i') phenyl,
(j') phenoxy,
(k1) cyano,
(1') nitro, (m') CO2H,
(n') COCι-C6-alkyl,
(<,') CO2Cι-C6-alkyl,
(p') CONR R5, (q') NR R5, (r') NR4COCι-C6-alkyl,
(s') (Ci-C6)-alkenyloxy, and (f) benzyloxy; (j) heteroaryl, wherein heteroaryl is defined as pyridyl or thienyl, (4) (C2-C4)~alkenyl, wherein alkenyl is unsubstituted or substituted with aryl, wherein aryl is as defined above;
(5) (C2-C3)-alkynyl, wherein alkynyl is unsubstituted or
substituted with phenyl or Si(R4)3, or
(6) an exo-methylene group, when Rl0° is absent.
Another subembodiment of the invention are the compounds of structural Formula I, wherein:
R3 is further defined as: (1) H, or
(2) (Ci-C3)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: (a) halo, wherein halo is fluoro, chloro, bromo, iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Cl-C6)-S(O)n-,
(f) aryl-(Ci-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
(j) NR4R5,
(k) NR4COCi-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-Cβ-alkyl,
(o) CO2Ci-C6-alkyl,
(P) CONR4R5,
(q) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
(a1) halo, as defined above,
(b') hydroxy,
(c') (Ci-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Cl-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy,
(h') (Cι-C6)-alkyl-S(O)n-,
(i1) phenyl,
(j1) phenoxy, (k1) cyano,
(1') nitro,
(m') CO2H,
(n') COCi-C6-alkyl,
(o') CO2Ci-C6-alkyl,
(p') CONR R5,
(g*) NR4R5, and
(r') NR COCι-C6-alkyl,
(r) Si(R )3,
(3) (C2-C3)-alkenyl, wherein alkenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Cl-C6)-S(O)n-,
(f) phenyl-(C i-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
(j) NR R5,
(k) NR COCι-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCl-Cβ-alkyl,
(o) CO2Ci-C6-alkyl,
(P) CONR R5,
(q) aryl, wherein aryl is as defined above, (r) heteroaryl, wherein heteroaryl is as defined above, and
(s) heterocyclyl, wherein heterocyclyl is as defined above;
(4) (C2-C3)-alkynyl, wherein alkynyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (Cι-C6)-S(O)n-,
(f) phenyl-(C i-C6)-alkyloxy ,
(g) cyano,
(h) nitro,
(i) vinyl,
(]' ) NR4R5,
(k) NR4COCl-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-Cβ-alkyl,
(o) CO2Ci-C6-alkyl,
(P) CONR R5,
(q) aryl, wherein aryl is as defined above,
(r) heteroaryl, wherein heteroaryl is as defined above, and
(s) heterocyclyl, wherein heterocyclyl is as defined above; or
(5) cyano; R4 and R^ are further defined independently as:
(1) hydrogen,
(2) CrC3 alkyl, or
(3) phenyl,
R" is further defined as:
(1) hydrogen,
(2) oxo and a is a single bond,
(3) O(C=O)RH, or (4) absent, when a is a double bond;
R , R8 and R^ are further defined as independently selected from the group consisting of:
(1) hydrogen, (2) oxo,
(3) O(C=O)R ; and
11 12
R and R are further defined as independently chosen from the group consisting of: (1) H, and
(2) (Cι-C3)-alkyl.
A preferred embodiment of the invention is wherein:
Ri is further defined as: (1) H,
2 . (2) =O, when R is absent, (3) (Ci-C8)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo, (b) hydroxy,
(c) oxo,
(d) (Ci-C3)-alkyloxy,
(e) CHO,
(g) CO(Cι-C3)-alkyl, (i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
(a1) halo, as defined above,
(b1) hydroxy, (c') (Ci-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Cι-C6)-alkyloxy, (h') (Cι-C6)-alkyl-S(O)n-,
(i1) phenyl,
(j1) phenoxy,
(k') cyano,
(1') nitro, (m') CO2H,
(n') COCl-C6-alkyl,
(o') CO2Cι-C6-alkyl,
(p') CONR R5, (q') NR R5, (!■') NR COCι-C6-alkyl, (s') (Ci-C6)-alkenyloxy, and (f) benzyloxy; (j) heteroaryl, wherein heteroaryl is defined as pyridyl or thienyl,
(4) (C2-C6)-alkenyl, wherein alkenyl is unsubstituted or substituted with aryl, wherein aryl is as defined above; and
(5) (C2-C3)-alkynyl, wherein alkynyl is unsubstituted or substituted with phenyl or Si(R4) , or
(6) an exo-methylene group, when R2 is absent; urther defined as:
(1) H, or
(2) (Ci-C3)-alkyl, wherein alkyl is unsubstituted or substituted
with phenyl or Si(R4)3
(3) (C2-C3)-alkenyl, wherein alkenyl is unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of: (a1) halo, as defined above,
(b') hydroxy, (c') (Cι-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl, (f) (Ci-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy,
(h') (Ci-C6)-alkyl-S(O)n-,
(i') phenyl,
(j') phenoxy, (k') cyano,
(D nitro,
(m') CO2H,
(n') COCi-Cβ-alkyl,
(o') CO2Ci-C6-alkyl,
(P') CONR4R5,
(q") NR4R5,
(r') NR4COCι-C6-alkyl,
(s') (Ci-C6)-alkenyloxy, and
(f) benzyloxy;
(4) cyano;
R4 and R^ are further defined independently as: (1) hydrogen, (2) CrC3 alkyl, or
(3) phenyl,
R6 is further defined as: (1) hydrogen, (2) oxo and a is a single bond,
(3) O(C=O)Rn, or
(4) absent, when a is a double bond;
R^, R8 and R^ are further defined as independently selected from the group consisting of:
(1) hydrogen,
(2) oxo, and
(3) O(C=O)Rn; and 11 12
R and R are further defined as independently chosen from the group consisting of:
(1) H, and (2) (Cl-C3)-alkyl.
Yet another preferred embodiment of the invention is wherein RlOa an(j RlOb are further defined as H. A most preferred embodiment is a compound selected from the group consisting of:
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-oxo- 9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,3b,4,5,5a,6,9,9a,9b,10, 11,11a- tetradecahydrophenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-benzyl-6- hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, 11 , 1 la-tetradecahydrophenanthro [ 1 ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-n-butyl-6- hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, 11 , 1 la-tetradecahydrophenanthro [l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6 -(3- phenyl-n-propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b, 4, 5, 5a, 6, 9, 9a, 9b, 10, ll,lla-tetradecahydrophenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,
3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydrophenanthro[l,2-c]furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,
3b, 4, 5, 5a, 6, 7, 8, 9, 9a, 9b, 10, ll,lla-hexadecahydrophenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,7, 8, 9, 9a, 9b, 10, 11,1 la-tetradecahydrophenanthro [l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, 11,1 la-tetradecahydrophenanthro [1,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2-n- butyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- allyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cjfuran;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- benzyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(but-3-en- l-yl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,
3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] -1 la-( l-R-acetoxyethyl)-6-(4- dimethyl-pent-3-en-l-yl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cjfuran;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- fluorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,6- difluorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(4- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3,4- dichlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cjfuran;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(4- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- trifluoromethylphenyl)ethyl)-6-hydroxy-9 , 10,11 -triacetoxy-3b ,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3- trifluoromethylphenyl)ethyl)-6-hydroxy-9, 10,1 l-triacetoxy-3b, 7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- naphth-2-ylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- naphth-l-ylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3- methoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(4- methoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,3- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3,4- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] fur an; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,5- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3,5- dimethoxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3,4- methylenedioxyphenyl)ethyl)-6-hydroxy-9, 10,1 l-triacetoxy-3b, 7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,3- methylenedioxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1 ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(4- dimethylaminophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1 ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2,2- diphenylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxy-5-methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1 ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(thien- 2-yl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,
3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,6- dimethoxylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenyl-propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b, 4, 5, 5a, 6, 9, 9a, 9b, 10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenyl-2-methylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- hydroxyphenylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(S)- phenylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenylprop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(R)- phenylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxyphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethylmercaptophenyl)prop-2-enyl)-6-hydroxy-9, 10,1 l-triacetoxy-3b, 7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1 , 2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethylphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methylmercaptophenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2-n- butylmercaptophenyl)prop-2-enyl)-6-hy droxy-9, 10,11 -triacetoxy-3b , 7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- vinylphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxye hyl)-6-(2-(S)-(2- ethylphenyl)propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan; and
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(S)-(-)- (2-methoxyphenyl)propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan.
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. "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, unless specifically defined otherwise, is intended to include the following: a 5 or 6- membered ring substituted with one, two or three heteroatoms selected from O, S, N, and is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cl-Cβ)-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COCl-C6-alkyl,
CO2Ci-C6-alkyl, CONRURI2, NR R12, NRHCOCi -Cβ-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 such as: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.
The term "heterocyclyl" as utilized herein, unless specifically defined otherwise, is intended to include a cyclic, non- aromatic substituents containing from 1 to 3 heteroatoms selected from the group consisting of O, N, and S, said heterocyclyl substituent being itself unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Cχ-C6)-alkoxy, cyano, nitro, hydroxy, CHO, CO2H, COCi-Cβ-alkyl, CO2Ci-C6-alkyl, CONRΪR2,
NRURI2, NRHCOCl-C6-alkyl. Representative heterocyclyl substituents include, but are not limited to the following: piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, piperazinyl, pyrolidine-2- one, piperidine-2-one and the like. 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.
REACTION SCHEME A
Figure imgf000042_0001
As seen in Reaction Scheme A, compound la [(4,6,7,15,16- pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-22-methyoxycarbonyl- [6α,7α,15β,16β,21β,22β]D:A-Friedo-A-homo-27,30-dinor-24-oxaoleana-l,
20(29)-dien-3-one] is ozonized under standard conditions. Reductive workup with an agent such as sodium borohydride gives the hydroxy lactol intermediate.
REACTION SCHEME B
Figure imgf000044_0001
As seen in Scheme B, the lactol product of Reaction Scheme A can be reacted with triethylsilane and a Lewis acid such as borontrifluoride diethyl etherate to give the tetrahydrofuran (THF) analog.
REACTION SCHEME C
Figure imgf000045_0001
The lactol hydroxy group can be replaced as demonstrated in Scheme C with a variety of substituents (represented as R10a).
Reaction with allyltrimethyl silane and a Lewis acid
such as boron trifluoride etherate (BF3 *OEt2) in dichloromethane
gives the allyl analog (R-lOa = allyl Rl0° = H) which can be modified in a variety of ways that are known to the practitioner. Alternatively, the lactol can be reacted with diethylaminosulfur trifluoride (DAST) in a basic solvent such as collidine to give the fluoro analog (Rl^a = F) which can be reacted with trisubstituted aluminum reagents such as triethyl aluminum to give the ethyl derivative, for example.
The hydroxy lactol derivaitve can be oxidized to its keto lactone derivative by use of a variety of reagents, including pyridinium chlorochromate (PCC).
REACTION SCHEME D
Figure imgf000047_0001
The lactone group of compound la can be rearranged to substituted THF esters under acidic or basic conditions (Reaction Scheme D). 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 (K2CO3) 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 reesterified by stirring the hydroxy analog with acetic anhydride (Ac2θ).
Rl-Oa-a-c-eta-de yde 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. RlOa-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 RlOa 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 then be converted to the corresponding hydroxy derivative with ozone and reductive workup as described above.
REACTION SCHEME E
Figure imgf000049_0001
In Reaction Scheme E, the C20 hydroxy group of the derivatized THF derivatives described in the preceeding Reaction Schemes can be oxidized to the corresponding ketone under a variety of conditions. The Jones reagent (chromic acid and sulfuric acid in H2O), pyridinium chlorochromate, or oxalyl chloride plus DMSO will achieve this conversion. REACTION SCHEME F
Figure imgf000050_0001
HCI/THF or
CH3(CI)AI[N(OCH3)CH3]
Figure imgf000050_0002
Tetrahydrofuran derivatives 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 45°C. Deacetylation can also be achieved by reacting with CH3(Cl)Al[N(OCH3)CH3 (Weinreb reagent) in inert solvents such as THF, toluene or methyl ene chloride. REACTION SCHEME G
Figure imgf000051_0001
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 H2O), pyridinium chlorochromate, and oxalyl chloride plus DMSO all will achieve this conversion.
REACTION SCHEME H
Figure imgf000052_0001
(PhO)3MePI HMPT, 75 °C
Figure imgf000052_0002
The C4 hydroxy group can be dehydrated to give the olefin. Reaction of the alcohol with tris-phenoxymethylphosphonium iodide in hexamethylphosphorous triamide (HMPT) at 75°C will achieve this conversion. REACTION SCHEME I
Figure imgf000053_0001
REACTION SCHEME I (CONT'D)
Figure imgf000054_0001
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 in a basic solvent such as pyridine. It should be understood that R^ is used to represent a portion of the R^ definition, e.g. R6 can be an alkyl carbonate which is depicted in the scheme as OC(=O)OR6 , Rβ 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 carbonyl diimidazole (CDI) to obtain the imidazolecarbonyl intermediate which is then reacted with an alcohol or amine (R^R3 NH) 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 (Tf2θ, triflic anhydride) to obtain the preformed triflate in dichloromethane at reduced temperature, preferably -78°C. To this solution is added the C4 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 C4 alcohol, the appropriate alkylhalide and an excess of silver oxide (Ag2θ) in an aprotic invert solvent such as THF.
The transformations described above can be first performed on compound la [(4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-
22-methyoxycarbonyl[6α,7α,15β,16β,21β,22β]D:A-Freido-A-homo-27,30- dinor-24-oxaoleana-l, 20(29)-dien-3-one]. Then the resultant derivatives can be converted to C20 keto THF derivatives as described above. REACTION SCHEME J
Figure imgf000056_0001
HCI/THF or
CH3(CI)AI[N(OCH3)CH3]
Figure imgf000056_0002
Lactone la can be selectively de-acetylated at C4 to give the corresponding alcohol by reacting it with an aqueous solution of HCl (preferably 2M to 3M concentration) in THF. It can also be prepared by reaction with CH3(Cl)Al[N(OCH3)CH3 (Weinreb reagent) in inert solvents such as THF, toluene or methylene chloride. The hydroxy product can be further derivatized according to procedures described in Reaction Schemes G and H. The lactone derivatives can then be converted to C20 keto THF derivatives according to Reaction Schemes A E.
The following 2 reaction schemes are incompatible with a C18 ketone group. They can be first performed on lactone la, which in turn can be converted to C20 keto THF derivatives.
REACTION SCHEME K
Figure imgf000057_0001
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 H2O), pyridinium chlorochromate, and oxalyl chloride plus DMSO all will achieve this conversion.
Figure imgf000058_0001
NHR3R3' NaCNBH3
Figure imgf000058_0002
C4 amino derivatives can be prepared by reacting the C4 ketone with an amine NHR3R in a variety of solvents with a reducing agent such as sodium cyanoborohydride. The lactone derivatives can then be converted to C20 keto THF derivatives according to Reaction Schemes A - E.
REACTION SCHEME L
Figure imgf000059_0001
LiCl
Δ
Figure imgf000059_0002
Reaction of the pentacyclic ketone with a metalhalide such as LiCl in a solvent such as DMF or DMSO at elevated temperatures such as 100 °C results in ring cleavage to obtain the tetracyclic enone depicted.
REACTION SCHEME M
Figure imgf000060_0001
Figure imgf000060_0002
The C18 ketone can be reacted with nucleophiles (Rl~M+) to give C18 substituted hydroxy derivatives. In general, Grignard reagents
(R^MgBr) or alkyllithium reagents (RJ-Li) are utilized in aprotic solvents such as diethyl ether or THF. Allylsilane reagents also add to the C18 ketone. For instance, reaction with allyl trimethylsilane and titanium tetrachloride in THF or diethyl ether gives the allyl adduct.
When R6 is OAc, it can be selectively hydrolyzed and derivatized using reaction schemes described above for the pentacyclic series. REACTION SCHEME N
Figure imgf000061_0001
Zn/HOAc
Figure imgf000061_0002
The acetoxy group at position 15 can be selectively removed from the ketone precursor shown in excellent yield by refluxing in acetic acid with Zn powder. The C18 ketone can then be derivatized according to methods described in Reaction scheme M.
REACTION SCHEME O
reflux
Figure imgf000062_0001
It was already shown in Reaction Scheme F that the acetate group at position 4 can be selectively removed. The acetate groups at positions 6, 7 and 15 can be removed by reaction with K2CO3 in refluxing methanol.
REACTION SCHEME P
Figure imgf000063_0001
Treatment of the hydroxy derivative from Reaction Scheme O gives the C15 and C7 hydroxy derivatives shown in this scheme. Similar reactions can be performed on this starting material. For instance, reaction with acetone with catalysis with PTSA (pαrα-toluene sulfonic acid) gives a mixture of acetonides, primarily at C6/C7 and C7/C15. Ester, carbamate and ether derivatives can be prepared using procedures described in Reaction Scheme I.
REACTION SCHEME Q
Figure imgf000064_0001
The C15 hydroxy group can be oxidized to the corresponding ketone by a variety of oxidizing agents. The Jones reagent (chromic acid and sulfuric acid in H2O), pyridinium chlorochromate, and oxalyl chloride plus DMSO all will achieve this conversion.
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 ossiu , 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 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 burn; 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 Kv1.3 inhibition, comprising the administration, in an amount that is effective at inhibiting Kv1.3, of a compound of Formula I. The method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kvl-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 burn; 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 Kvl.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 Kvl-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 Kv1.3 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 Kv1.3 in human T cells, charybdotoxin was subsequently shown to inhibit four different K+ channels (Kvl-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 Kv1.3 (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, 111, 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 Kv1.3 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, IMUREK® azathioprine sodium, brequinar sodium, SPANIDIN® gusperimus trihydrochloride (also known as deoxyspergualin), mizoribine (also known as bredinin), CELLCEPT® mycophenolate mofetil, NEORAL® Cyclosporin A (also marketed as a different formulation of Cyclosporin A under the trademark SANDIMMUNE®), PROGRAF® 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 μM in any of the assays thereby demonstrating and confirming the utility of the compounds of the invention as Kv1.3 inhibitors and immunosuppressants.
T CELL IL-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 IO6/ 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 μl/well. The various dilutions of test compound were then added in triplicate wells at 25 μl/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 37°C 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
106cells/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 lO^cells/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% CO2 - 95% air, 20 μl/well of anti-CD3 (Ortho Diagnostic, NJ) at final cone, of 0.3 ng/ml was added, followed by
50 μl of the irradiated MNC. The culture plates were then incubated at 37°C in a humidified atmosphere of 5% CO2 - 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 μCi/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 Kv1.3 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 μCi/ml, Dupont-NEN) in the glutamine supplemented IMDM. After aspiration of the media, 100 μl of Low K Buffer (in mM, 6.5 KC1, 125 NaCl, 1 CaCl2, 2 MgCl2, 10 HEPES, pH adjusted to 7.2 with NaOH) is added to each well followed by 100 μl test samples in Low K Buffer also containing 0.2% BSA and 2 mM ouabain. Samples are tested at either 1 μg/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 Kv1.3 channels are opened by depolarization of the cells with High K Buffer (final concentrations, in mM, 63.25 KC1, 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 μl are taken from each well after a given time and added to plates containing 100 μl MicroScint-40 (Packard) for counting by liquid scintillation techniques. MicroScint-40 (100 μl) 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 Kv1.3 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 corneal 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 1(b) From Spachea correa
single
double
Figure imgf000082_0001
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 6OF254 plate of 1mm thickness using methylene chloride-ethyl acetate 1:1 (v/v) as solvent, then by high performance liquid chromatography (HPLC) using a Zorbax RxCs 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 compound 1(a) and 1(b).
Homogeneity of the preparations was ascertained in several TLC systems, such as E. Merck silica gel 6OF254, methylene chloride-ethyl acetate 1:1, Rf 1(a) 0.4, Rf 1(b) 0.3; Whatman KC18, methanol-water 9:1, Rf 1(a) 0.65, Rf 1(b) 0.75 and by HPLC using a Zorbax RxCs column, acetonitrile-water 3:2, k' 1(a) 4.15, k' 1(b) 3.30; and by NMR.
Mass spectra were recorded on JEOL SX-102A (electron impact, EI,903V) and JEOL HXllO (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 1(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 C40H52O16. A table of the critical HR-EI data is given below.
Observed m/z Formula Assignment 788.3220 C40H52O16 M + 728.3040 C38-H48014 M-acetic acid 668.2834 C36H44θi2 M-2 x acetic acid 334.1417 C18H22O6 base peak
J-3-C NMR spectra were recorded for the compound of Formula 1(a) in CD2CI2 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 C40H52O16 derived by scanning HR EI-MS. The iH NMR spectra of compound of Formula(a) was recorded at 400 MHz in CD2CI2 on a Varian Unity 400 NMR spectrometer at 25°C. 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 C40H50O16 M + 726.2886 C38H46OI4 M-acetic acid
666.2651 C36H42O12 M-2 x acetic acid
606.2451 C34H38θio M-3 x acetic acid
489.2099 C26H33O9 base peak
471.1992 C26H31O8
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 C40H50OI6 derived by scanning HR EI-MS. EXAMPLE 2
A Method Of Extracting The Compounds Of Formula 1(c) And 1(d) From Spachea Correa
single
double
Figure imgf000085_0001
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 1(a) and 1(b). These were resolved by HPLC using a Zorbax RxCs 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 1(a) and 1(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 purified compound of 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 Cs column at 0.2ml/min. with a mobile phase of 45% acetonitrile/O.OlM aqueous ammonium acetate at 50°C. 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 1(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 13Q NMR spectra obtained for the compound of
Formula 1(c) using the conditions previously described is as follows: 15.1 (2x), 16.9, 19.8, 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 C38H50O16 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 RxCδ 4.6 mm x 25 cm column, maintained at 50°C and eluted at 1 ml/min with acetonitrile-water 3:2 v/v):
Compound 1(a): k' = 4.15; 1(b): k'=3.30; 1(c): k'=2.30; 1(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 Kb).
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 1(a) and 1(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 1(a) ranges from about 2 to about 3.5 column volumes of solvent; that for the compound of Formula 1(b) is about 3 to about 4.5 column volumes. Finally, advantage is taken of the low solubility of these compounds, and, after total resolution by chromatography, the compounds of Formula 1(a) and 1(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-20-oxo-22- methoxycarbonyl[6α,7α,15β,16β,21β,22β]D:A-Friedo-2,3,27,30- tetranor-24-oxaoleanane
Figure imgf000088_0001
Step A: 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-l,18,20-tris- hydroxy-22-methoxycarbonyl[6α,7α,15β,16β,21β,22β]-D:A- Friedo-2.3.27.30-tetranor-24-oxaoleanane
Figure imgf000089_0001
750 mg of 4,6,7,15,16-Pentakis(acetyloxy)-21,22-epoxy-18- hydroxy-22-methoxycarbonyl[6α,7α,15β,16β,21β, 22β]D:A-Friedo-A- homo-27,30-dinor-24-oxaoleana-l,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 lh. The solution was diluted with 50ml of dichloromethane, 20ml of IN 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 the title compound as a white solid. iH NMR (CDCI3) δ 3.60 (s, IH, C21-H), 3.63, 4.10 (AB, 2H, J = 9.4 Hz, C24-H), 4.31 (m, IH, C20), 5.21 (m, IH, Cl-H); 13C NMR (CDCI3) δ 53.2 (COOMe). 100.1 (Cl); Mass Spectrum (APCI): m/e 786 (M+NH4). Step B: 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18,20-dihydroxy- 22-methoxycarbonyl[6α,7α,15β,16β,21β,22β]-D:A-Friedo- 2.3.27.30-tetranor-24-oxaoleanane
Figure imgf000090_0001
50 mg of 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy- l,18,20-tris-hydroxy-22-methoxycarbonyl[6α,7α,15β,16β,-21β,22β]-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 the title compound as a white solid.
!H NMR (CDCI3) δ 3.62 (s, IH, C21-H), 3.60, 3.85 (AB, 2H, J = 9.4 Hz,
C24-H), 3.60, 3.89 (2Xm, 2H, Cl-H), 4.32 (m, IH, C20-H); Mass Spectrum (APCI): m/e 770 (M+NH4). Step C: 4,6,7,15,16-pentakis(acetyloxy)-21,22-epoxy-18-hydroxy-20- oxo-22-methoxycarbonyl[6α,7α,15β,16β,21β,22β]D:A-Friedo- 2.3.27.30-tetranor-24-oxaoleanane
Figure imgf000091_0001
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,15β,16β,21β,22β]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 the title compound. iH NMR (CDC13) δ 2.41, 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 = 6.9 Hz, JBX = 1.0 Hz, Cl-H).
13c NMR (CDC13) δ 201.1 (C20); Mass Spectrum (APCI): m/e 768 (M+NH4). EXAMPLE 6
[3a-S-3a ,3bβ,5a ,9β,9aβ,10 ,ll ,lla ]-lla-(l-R-acetoxyethyl)-6-oxo-
9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,3b,4,5,5a,6,9,9a,9b,10, 11,11a- tetradecahydrophenanthro[1.2-c] furan
Figure imgf000092_0001
A solution of 4,6, 7,15, 16-pentakis(acetyloxy)-21,22-epoxy-18- hydroxy-20-oxo-22-methoxycarbonyl[6α,7α,15β,16β,21β,22β]D:A-Friedo- 2,3,27,30-tetranor-24-oxaoleanane (Example 5) (219 mg, 0.29 mmol) and
LiCl (42.4 mg, 2.9 mmol) in 5.0 ml of DMSO was heated at 130 °C for 6 h and was poured into ether. The organic layer was washed with brine twice, dried with MgSO and filtered through a plug of silica gel. Upon removal of solvent, it was purified by HPLC to give the title compound. iH NMR (CDC13) δ 6.16 (s, IH), 5.72 (q, IH, J = 6.1 Hz), 5.54 (d of d, IH, J
= 6.4, 3.1 Hz), 5.50 (bs, IH), 5.27 (d, IH, J = 3.9 Hz), 3.90 (d, IH, J = 9.6 Hz), 3.82 (d, IH, J = 9.2 Hz), 3.64 (d, IH, J = 9.2 Hz), 3.58 (d of d, IH, J = 9.6, 7.1 Hz), 2.26 (d of d, IH, J = 12.2, 3.5 Hz), 2.10 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.77 (s, 3H), 1.25 (d, 3H, J = 6.4 Hz), 1.118 (s, 3H), 1.113 (s, 3H). Mass Spectrum (APCI): m/e 566 (M+NH4). EXAMPLE 7
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-benzyl-
6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,
3b.4.5.5a, 6.9, 9a.9b.10. ll,lla-tetradecahydrophenanthrofl.2-c]furan
Figure imgf000093_0001
The Grignard reagent is formed by adding the halide (benzyl chloride) in THF solution to an excess of magnesium in THF at room temperature under a nitrogen atmosphere and then refluxing for 1 hr. To a solution of the ketone from Example 6 (10 mg, 0.018 mmol) in 0.5 ml of THF was added benzylmagnesium chloride (0.12 ml, 1.0 M in ether) at rt. After 2 h, it was quenched with 3 drops of pH = 7 buffer and the wet solution was filtered through silica gel. Upon removal of the solvent the residue was purified by HPLC to give the title compound. iH NMR (CDCI3) 6 7.29-7.34 (m, 3H), 7.09 (d, 2H, J = 7.1 Hz), 5.54 - 5.50
(m, 2H), 5.24 (d, IH, J = 3.6 Hz), 5.19 (s, IH), 4.79 (s, IH), 3.86 (d, IH, J = 9.4 Hz), 3.82 (d, IH, J = 7.2 Hz), 3.57 - 3.61 (m, 2H), 3.12 (d, IH, J = 14.4 Hz), 2.88 (d, IH, J = 14.4 Hz), 2.05 (s, 3H), 1.99 (bs, 6H), 1.96 (bs, 6H), 1.25 (s, 3H), 1.20 (d, 3H, J = 6.1 Hz), 1.13 (s, 3H). Mass Spectrum (APCI): m/e 658 (M+NH4). EXAMPLE 8
[3a-S-3aα,3bβ,5aα,9β,9aβ,10 ,llα,llaα]-lla-(l-R-acetoxyethyl)-6-n-butyl-
6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydrophenan thro π.2-c] furan
Figure imgf000094_0001
The title compound was prepared as in Example 7. iH NMR (CDCI3) δ 5.71 (q, IH, J = 6.4 Hz), 5.59 (d of d, IH, J = 6.2, 4.2
Hz), 5.27 (d, IH, J = 3.9 Hz), 5.15 (bs, IH), 5.05 (bs, IH), 3.90 (d, IH, J = 9.4 Hz), 3.84 (d, IH, J = 9.0 Hz), 3.64 (d, IH, J = 9.0 Hz), 3.59 (d of d, IH, J = 9.4, 7.1 Hz), 2.10 (s, 3H), 2.03 (s, 3H), 2.01(s, 3H), 1.98 (s, 3H), 1.70 (s, 3H), 1.25 (s, 3H), 1.24 (d, 3H, J = 6.2 Hz), 1.15 (s, 3H), 0.93 (t, 3H, J = 7.3 Hz). Mass Spectrum (APCI): m/e 624 (M+NH4).
EXAMPLE 9
[3a-S-3aα,3bβ,5a ,9β,9aβ,10α,llα,lla ]-lla-(l-R-acetoxyethyl)-6 -(3- phenyl-n-propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0, ll.lla-tetradecahydrophenanthro[1.2-clfuran
Figure imgf000095_0001
The title compound was prepared by procedures described in Example 7. iH NMR (CDCI3) δ 7.28 (t, 2H, J = 7.8 Hz), 7.17 (t, IH, J = 7.0 Hz), 7.18 (d,
2H, J = 7.4 Hz), 5.68 (q, IH, J = 6.4 Hz), 5.57 (d of d, IH, J = 5.7, 3.9 Hz), 5.25 (d, IH, J = 3.7 Hz), 5.12 (bs, IH), 5.02 (bs, IH), 3.88 (d, IH, J = 9.2 Hz), 3.83 (d, IH, J = 9.2 Hz), 3.62 (d, IH, J = 9.2 Hz), 3.58 (d of d, IH, J = 9.2, 7.1 Hz), 2.53-2.65 (m, 2H), 2.10 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.58 (bs, 3H), 1.26 (s, 3H), 1.23 (d, 3H, J = 6.4 Hz), 1.21 (s, 3H), 1.12 (s, 3H). Mass Spectrum (APCI): m/e 686 (M+NH4)
EXAMPLE 10
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro [1.2-cl furan
Figure imgf000096_0001
Step A: Preparation of [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla- (l-R-acetoxyethyl)-6-(2-phenylacetylenyl)-6-hydroxy-9, 10,11- triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, 11.1 la-tetradecahydrophenanthro [ 1 ,2-c] furan
Figure imgf000096_0002
The title compound was prepared by procedures described in Example 7. iH NMR (CDCI3) δ 7.40-7.42 (m, 2H), 7.30-7.33 (m, 3H), 5.73 (q, IH, J = 6.4
Hz), 5.60 (d of d, IH, J = 6.2, 4.1 Hz), 5.29 (d, IH, J = 3.9 Hz), 5.23 (bs, IH), 5.19 (bs, IH), 3.92 (d, IH, J = 9.4 Hz), 3.83 (d, IH, J = 9.2 Hz), 3.64 (d, IH, J = 9.2 Hz), 3.59 (d of d, IH, J = 9.4, 7.1 Hz), 2.09 (s, 3H), 2.04 (s, 3H), 2.01(s, 3H), 2.00 (s, 3H), 1.98 (bs, 3H), 1.25 (s, 3H), 1.24 (d, 3H, J = 6.4 Hz), 1.18 (s, 3H). Mass Spectrum (APCI): m/e 668 (M+NH4).
Step B: Preparation of [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla- ( l-R-acetoxyethyl)-6-(2-phenethyl)-6-hydroxy-9, 10, 11- triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, 11.1 la-tetradecahydrophenanthro [ 1.2-c] furan
Figure imgf000097_0001
To a solution of the compound from Step A (4.3 mg, 0.07 mmol) in 5 ml of EtOAc was added 4 mg of palladium on carbon (10 %). The mixture in a Parr apparatus was pressurized with hydrogen to 50 PSI for 14 h. The solution was filtered through a plug of silica gel and dried to give the title compound. iH NMR (CDCI3) δ 7.30 (t, 2H, J = 7.5 Hz), 7.17-7.21 (m, 3H), 5.71 (q, IH, J = 6.2 Hz), 5.60 (d of d, IH, J = 5.9, 3.9 Hz), 5.27 (d, IH, J = 3.6 Hz), 5.25 (bs, IH), 5.10 (bs, IH), 3.89 (d, IH, J = 9.4 Hz), 3.84 (d, IH, J = 9.2 Hz), 3.64 (d, IH, J = 9.2 Hz), 3.59 (d of d, IH, J = 9.4, 7.1 Hz), 2.30-2.45 (m, 2H), 2.12 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.80 (bs, 3H), 1.26 (s, 3H), 1.25 (d, 3H, J = 6.4 Hz), 1.14 (s, 3H). Mass Spectrum (APCI): m/e 672 (M+NH4) EXAMPLE 11
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.7.8.9.9a.9b.l0. ll.lla-hexadecahvdrophenanthro[1.2-c]furan
Figure imgf000098_0001
Step A: Preparation of [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,ll ,lla ]-lla- (l-R-acetoxyethyl)-6-oxo-9,10,ll-triacetoxy-3b,7,9a-trimethyl- l,3,3a,3b,4,5,5a,6,7,8, 9,9a,9b,10, ll,lla-hexa- decahydrophenanthro [1 ,2-c] furan
Figure imgf000098_0002
To a solution of [3a-S-3aα,3bβ,5aα,9β,9aβ,10 ,ll ,llaα]-lla-
(l-R-acetoxyethyl)-6-oxo-9,10,ll-triacetoxy-3b,7,9a-trimethyl- l,3,3a,3b,4,5,5a,6,9,9a,9b,10, 11,1 la-tetradecahydrophenanthro [1,2- c]furan (Example 6) (10.0 mg, 0.018 mmol) in 5 ml of MeOH was added 2 mg of Palladium on carbon (10 %). The mixture in a Parr apparatus was pressurized with hydrogen to 50 psi for 14 h. The solution was filtered through a plug of silica gel and dried to give the title compound. iH NMR (CDCI3) δ 5.74 (q, IH, J = 6.2 Hz), 5.51 (d of d, IH, J = 6.1, 3.8
Hz), 5.24 (d, IH, J = 3.9 Hz), 5.07 (d of d, IH, J = 10.5, 5.3 Hz), 3.87 (d, IH, J = 9.6 Hz), 3.81 (d, IH, J = 9.2 Hz), 3.62 (d, IH, J = 9.2 Hz), 3.56 (d of d, IH, J = 9.3, 7.1Hz), 2.59- 2.49 (m, 2H), 2.22 (d of d, IH, J = 11.9, 2.3 Hz), 2.09 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.77 (s, 3H), 1.23 (d, 3H, J = 6.2 Hz), 1.12 (s, 3H), 1.06 (s, 3H), 0.94 (d, 3H, J = 5.9 Hz). Mass Spectrum (APCI): m/e 568 (M+NH4).
Step B: Preparation of [3a-S-3aα,3bβ,5aα,9β,9aβ,10 ,ll ,llaα]-lla-
( l-R-acetoxyethyl)-6-(2-phenylacetylenyl)-6-hydroxy-9, 10,11- triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,7, 8.9.9a.9b.10. ll.lla-hexadecahydrophenanthrofl.2-c1furan
Figure imgf000099_0001
The title compound was prepared according to procedures described in Example 7. iH NMR (CDCI3) δ 7.35 - 7.38 (m, 2H), 7.26 - 7.31 (m, 3H), 5.71 (q, IH, J =
6.4 Hz), 5.54 (d of d, IH, J = 6.2, 3.9 Hz), 5.24 (d, IH, J = 3.9 Hz), 4.67 (d of d, IH, J = 11.0, 4.8 Hz), 3.87 (d, IH, J = 9.6 Hz), 3.78 (d, IH, J = 9.2 Hz), 3.60 (d, IH, J = 9.2 Hz), 3.54 (d of d, IH, J = 9.6, 7.4 Hz), 2.06 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.91 (s, 3H), 1.26 (s, 3H), 1.20 (d, 3H, J = 6.4 Hz), 1.13 (s, 3H), 1.08 (d, 3H, J = 6.4 Hz)., Mass Spectrum (APCI): m/e 670
(M+NH4).
Step C: Preparation of [3a-S-3aα,3bβ,5a ,9β,9aβ,10α,ll ,lla ]-lla-
(l-R-acetoxyethyl)-6-(2-phenethyl)-6-hydroxy-9,10,ll- triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,7,8,
9.9a.9b.10. ll.lla-hexadecahydrophenanthro[1.2-clfuran
Figure imgf000100_0001
The title compound was prepared according to procedures described in Example 10, Step B. H NMR (CDC13) δ 7.28 (t, 2H, J = 7.8 Hz), 7.18 (t, IH, J = 7.3 Hz), 7.15 (d,
2H, J = 7.4 Hz), 5.71 (q, IH, J = 6.4 Hz), 5.57 (d of d, IH, J = 6.0, 3.9 Hz), 5.24 (d, IH, J = 3.9 Hz), 4.64 (d of d, IH, J = 10.5, 4.3 Hz), 3.87 (d, IH, J = 9.6 Hz), 3.81 (d, IH, J = 9.2 Hz), 3.61 (d, IH, J = 9.2 Hz), 3.56 (d of d, IH, J = 9.6, 7.1 Hz), 2.45 - 2.50 (m, IH), 2.34 - 2.39 (m, IH), 2.09 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.92 (s, 3H), 1.29 (s, 3H), 1.22 (d, 3H, J = 6.2 Hz), 1.13 (s, 3H), 0.88 (d, 3H, J = 6.4 Hz). Mass Spectrum (APCI): m/e 674 (M+NH4).
EXAMPLE 12
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,7,
8.9.9a.9b.10. 11.1 la-tetradecahydrophenanthro [1.2-cl furan
Figure imgf000101_0001
To a solution of [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-
(l-R-acetoxyethyl)-6-(2-phenethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,7,8,9,9a,9b,10, ll,lla-hexadecahydro phenanthro[l,2-c]furan (Example 11, 17 mg, 0.026 mmol) in 0.5 ml of pyridine was added SOCl2 (1 ml) and the solution was stirred at rt for 2 h. It was poured into 1 N H2SO4 and was extracted with ether. The organic layer was washed with aqueous NaHCO3 and water, dried with MgSO4 and filtered through a plug of silica gel and the residue was purified by HPLC to give the title compound. iH NMR (CDCI3) δ 7.29 (t, 2H, J = 7.6 Hz), 7.18 (d, 2H, J = 6.8 Hz), 7.14 (t,
IH, J = 7.3 Hz), 5.62 (q, IH, J = 6.3 Hz), 5.54 (d of d, IH, J = 6.4, 4.1 Hz), 5.50 (d, IH, J = 4.5 Hz), 4.72 (d of d, IH, J = 11.4, 3.4 Hz), 3.82 (d, 2H, J = 9.2 Hz), 3.62 (d, IH, J = 9.2 Hz), 3.56 (d of d, IH, J = 9.2, 7.1 Hz), 2.69 - 2.74 (m, IH), 2.56 - 2.62 (m, IH), 2.13 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.94 (s, 3H), 1.30 (s, 3H), 1.24 (d, 3H, J = 6.4 Hz), 1.20 (s, 3H), 1.09 (d, 3H, J = 6.9 Hz). Mass Spectrum (APCI): m/e 656 (M+NH4).
By procedures described in the preceeding examples, the following compounds can be prepared (Examples 13-47). EXAMPLE 13 [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydrophenanthro[l,2- cl furan
Figure imgf000102_0001
EXAMPLE 14
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000103_0001
EXAMPLE 15
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,ll ,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2-n- butyloxyphenyl)ethyl)-6-hydroxy-9, 10, 1 l-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000103_0002
EXAMPLE 16 [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- allyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000104_0001
EXAMPLE 17
[3a-S-3aα,3bβ,5a ,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- benzyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000105_0001
EXAMPLE 18
[3a-S-3a ,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(but-3- en-l-yl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro[1.2-c]furan
Figure imgf000105_0002
EXAMPLE 19 [3a-S-3a ,3bβ,5aα,9β,9aβ,10 ,ll ,llaα]-lla-(l-R-acetoxyethyl)-6-(4- dimethyl-pent-3-en-l-yl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000106_0001
EXAMPLE 20
[3a-S-3a ,3bβ,5aα,9β,9aβ,10 ,ll ,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- fluorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro[1.2-c]furan
Figure imgf000106_0002
EXAMPLE 21
[3a-S-3aα,3bβ,5a ,9β,9aβ,10α,llα,lla ]-lla-(l-R-acetoxyethyl)-6-(2-(2,6- difluorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan
Figure imgf000107_0001
EXAMPLE 22
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c] furan
Figure imgf000107_0002
EXAMPLE 23
[3a-S-3a ,3bβ,5aα,9β,9aβ,10 ,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[1.2-d furan
Figure imgf000108_0001
EXAMPLE 24 [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,lla ]-lla-(l-R-acetoxyethyl)-6-(2-(4- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [l,2-c]furan_
Figure imgf000109_0001
EXAMPLE 25
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3,4- dichlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000110_0001
EXAMPLE 26
[3a-S-3a ,3bβ,5aα,9β,9aβ,10α,llα,lla ]-lla-(l-R-acetoxyethyl)-6-(2-(2- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000110_0002
EXAMPLE 27
[3a-S-3a ,3bβ,5aα,9β,9aβ,10 ,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000111_0001
EXAMPLE 28
[3a-S-3a ,3bβ,5a ,9β,9aβ,10 ,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(4- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000112_0001
EXAMPLE 29
[3a-S-3a ,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- trifluoromethylphenyl)ethyl)-6-hydroxy-9, 10,1 l-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1.2-clfuran
Figure imgf000112_0002
EXAMPLE 30
[3a-S-3a ,3bβ,5a ,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3- trifluoromethylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1.2-clfuran
Figure imgf000113_0001
EXAMPLE 31 [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,lla ]-lla-(l-R-acetoxyethyl)-6-(2- naphth-2-ylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro [1.2-c]furan
Figure imgf000114_0001
EXAMPLE 32
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- naphth-l-ylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro[1.2-c]furan
Figure imgf000114_0002
EXAMPLE 33
[3a-S-3a ,3bβ,5aα,9β,9aβ,10 ,ll ,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3- methoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- cl furan
Figure imgf000115_0001
EXAMPLE 34
[3a-S-3aα,3bβ,5a ,9β,9aβ, 10a, 1 l , 1 laα] -1 la-( l-R-acetoxyethyl)-6-(2-(4- methoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000116_0001
EXAMPLE 35
[3a-S-3a ,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2,3- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000116_0002
EXAMPLE 36
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3,4- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000117_0001
EXAMPLE 37
[3a-S-3a ,3bβ,5aα,9β,9aβ,10 ,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2,5- dimethoxyphenyl)ethyl))-6-hydroxy-9, 10,1 l-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000118_0001
EXAMPLE 38
[3a-S-3a ,3bβ,5a ,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3,5- dimethoxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000118_0002
EXAMPLE 39
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(3,4- methylenedioxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1.2-clfuran
Figure imgf000119_0001
EXAMPLE 40 [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2,3- methylenedioxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1.2-c] furan
Figure imgf000120_0001
EXAMPLE 41
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(4- dimethylaminophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1.2-c] furan
Figure imgf000120_0002
EXAMPLE 42
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2,2- diphenylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro[1.2-dfuran
Figure imgf000121_0001
EXAMPLE 43
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxy-5-methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1.2-cl furan
Figure imgf000121_0002
EXAMPLE 44
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-
(thien-2-yl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro[1.2-c]furan
Figure imgf000122_0001
EXAMPLE 45
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2,6- dimethoxylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000122_0002
EXAMPLE 46
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- phenyl-propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro [1.2-clfuran
Figure imgf000123_0001
The title compound is isolated as a mixture of stereo isomers.
EXAMPLE 47
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- phenyl-2-methylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- cl furan
Figure imgf000124_0001
EXAMPLE 48
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- hydroxyphenylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan
Figure imgf000124_0002
Step A: Preparation of 2-tetrahydropyranyloxyphenyl ethyl bromide
Figure imgf000125_0001
Br
To a solution of 2-methoxyphenethyl alcohol (5.0 g, 32.6 mmol) in 40 ml of CH2CI2 was added dimethylaminopyridine (DMAP) (10 mg), Et3N (11.4 ml, 81.8 mmol) and MsCl (5.05 ml, 65.2 mmol) at 0
°C. After 1 h, the reaction mixture was poured into hexane and it was washed with aqueous NaHCO3 (2x), water and dried with MgSO4. Upon removal of the solvents, the residue was dissolved in 50 ml of acetone and LiBr (11.34 g, 130.6 mmol) was added. After the solution was heated at reflux for 16 h, it was poured into ether and washed with water, dried with MgSO4, filtered and dried to afford 2-methoxyphenethyl bromide.
To a solution of 2-methoxyphenethyl bromide (1.07g, 4.98 mmol) in 5 ml of CH2CI2 was added BBr3 (9.5 ml, 1.0 M in CH2CI2) at -78
°C and it was allowed to warm to rt over 1.5 h. The reaction mixture was poured into CH2CI2 and was washed with brine, dried to afford 2- hydroxy phenethyl bromide.
To a solution of 2-hydroxyphenethyl bromide (241 mg, 1.20 mmol) in 6 ml of CH2CI2 was added pyridinium p-toluene sulfonate
(PPTS, 10 mg) and dihydropyran. After 2 h, volatiles were removed and the residue was purified by flash column to afford the title compound. Step B: The THP ether derivative of the title compound was prepared according to the procedures described in Example 7. The THP protecting group is removed as follows. To the THP ether derivative in 4 ml of methanol was added 10 mg TsOH and the mixture stirred at rt for 3.5 h. After removal of solvent, the reaction mixture is purified by HPLC.
EXAMPLE 49
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(S)- phenylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydrophenanthro[1.2-c1furan
Figure imgf000126_0001
Step A: Preparation of R-(-)-2-phenylpropylbromide
Figure imgf000126_0002
Brx \ R-(-) To a solution of R-(-)-2-phenylpropionic acid (1.04 g, 6.9 mmol) in 30 ml of THF was added LAH (6.9 ml, 1.0 M in THF) at 0 °C. After stirring at rt for 14 h, the mixture was poured into 2 N HCl and the organic layer was washed with NaHCO3 and brine, dried with MgSO4 to give the corresponding alkanol which was converted to the bromide. The Grignard reagent was then prepared by the procedures described in Example 7 and reacted with the ketone to produce the title compound.
EXAMPLE 50 [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2- phenylprop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthrofl.2-c1furan
Figure imgf000127_0001
Step A: Preparation of 2-(phenyl)prop-2-enyltrimethylsilane
Figure imgf000127_0002
2 g of (2-bromoallyl)trimethylsilane (10.4 mmole) and 500 mg of tetrakis (triphenylphosphine) palladium (0.4 mmole) in 5ml of benzene were heated to 80°C until a homogenous solution resulted. The mixture was cooled to 40°C and 10ml of a 1M solution of phenylmagnesium chloride in THF were slowly added. The deep red reaction mixture was stirred at 40°C for 12h and poured into 20ml of water. Extraction with ethyl acetate, washing of the combined organic layers with aqueous sodium chloride then drying over MgSO4 gave an oil which was purified by silica gel chromatography with 19:1 hexanes- ethyl acetate to afford the title compound as a yellow oil. H NMR (CDCI3) δ 0.06 (s, 9H, SiMe3), 2.06 (s, 2H, CH2), 4.91 (s, IH, =CH2), 5.17 (s, IH, =CH2), 7.26 - 7.64 (m, 2H, ar-H), 7.18 - 7.25 (m, 2H, ar- H).
Step B: To a solution of [3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-
(l-R-acetoxyethyl)-6-oxo-9,10,ll-triacetoxy-3b,7,9a-trimethyl- l,3,3a,3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydrophenanthro[l,2- c]furan (Example 6) in CH2CI2 is added a solution of TiCl4 in CH2CI2 at - 78°C. The resulting suspension is stirred for 10 minutes then 0.2ml of 2- phenylprop-2-enyltrimethylsilane is added. Stirring is continued at -40°C until TLC control shows no remaining starting material. Water is then added, and the mixture is extracted with ethyl acetate The organic phase is washed with aqueous sodium chloride is then dried over MgSO4 and concentrated. The residue is first filtered through a plug of silica gel and then purified by HPLC.
EXAMPLE 51
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(R)- phenylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b.4.5.5a.6.9.9a.9b.l0. ll.lla-tetradecahydro phenanthro[1.2-c]furan
Figure imgf000129_0001
[3a-S-3aα,3bβ,5aα,9β,9aβ, lOα, 1 lα, 1 laα] -1 la-( 1-R- acetoxyethyl)-6-(2-phenylprop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy- 3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan (Example 49) is dissolved in dry THF. The solution is degassed under reduced pressure and saturated with nitrogen, the procedure being repeated several times. Wilkinson's catalyst [ (PPh3)3RhCl ] is added and the solution is degassed and saturated with hydrogen. The reaction vessel is pressurized with H2 to 50 psi and hydrogenated on a Parr-apparatus at 25°C. When reaction is complete (TLC, HPLC) the solvent is removed under reduced pressure. The residue is first filtered through a plug of silica gel and then purified by HPLC (Waters RCM, Prep Nova-Pak HR Silica, 2 25X100 mm cartridges).
EXAMPLE 52
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxyphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1.2-c] furan
Figure imgf000130_0001
The title compound is prepared by procedures described in Example 49. The preparation of 2-(2'-methoxyphenyl)prop-2- enyltrimethylsilane is as follows.
Figure imgf000130_0002
2 g of (2-bromoallyl)trimethylsilane (10.4 mmole) and 500mg of tetrakis (triphenylphosphine) palladium (0.4 mmole) in 5ml of benzene were heated to 80°C until a homogenous solution resulted. The mixture was cooled to 40°C and 10ml of a 1M solution of phenylmagnesium chloride in THF were slowly added. The deep red reaction mixture was stirred at 40°C for 12h and poured into 20ml of water. Extraction with ethyl acetate, washing of the combined organic layers with aqueous sodium chloride then drying over MgSO4 gave an oil which was purified by silica gel chromatography with 19:1 hexanes- ethyl acetate to afford the title compound as a yellow oil. iH NMR (CDCI3) δ 0.12 (s, 9H, SiMe3), 2.10 (s, 2H, CH2), 3.86 (s, 3H, OMe), 4.90 (s, IH, =CH2), 4.97 (s, IH, =CH2), 6.82 - 6.98 (m, 2H, ar-H), 7.18 - 7.25 (m, 2H, ar-H).
EXAMPLE 53
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethylmercaptophenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro π.2-c]furan
Figure imgf000131_0001
The title compound is prepared by procedures described in Example 50. The preparation 2-(2-ethylmercaptophenyl)- allyltrimethylsilane is as follows.
StepA: Preparation of l-Ethylmercapto-2-bromobenzene
Figure imgf000132_0001
Br
To a suspension of 1.00 g (5.3 mmol) of 2-bromo-benzenethiol and 1.47 g (10.6 mmol) of potassium carbonate in 15 ml of N,N- dimethylformamide was added 1.65 g (10.6 mmol) of iodoethane at 0 °C.
The reaction mixture was stirred at 55-60 °C for 12 h and was poured into 200 ml of ether. It was washed with water (20 ml x 3), dried over MgSO4 and concentrated to afford l-ethylmercapto-2-bromobenzene as a colorless oil.
Step B: Preparation of 2-(2-Ethylmercaptophenyl)- allyltrimethylsilane
Figure imgf000132_0002
A solution of the Grignard reagent of l-ethylmercapto-2- bromobenzene in tetrahydrofuran was prepared in the following way: 1.50 g (6.9 mmol) of l-ethylmercapto-2-bromobenzene were added to 218 mg (9.0 mmol) of magnesium in 8 ml of anhydrous tetrahydrofuran at room temperature under N2 and was heated to reflux for lh. Meanwhile, a solution of 1.20 g (6.2 mmol) of (2-bromoallyl)- trimethylsilane and 358 mg (0.31 mmol) of tetrakis(triphenylphosphine)- palladium in 6 ml of dry benzene was stirred at 80 °C under N2 for 30 min. Then it was cooled to 50 °C and to it was added the Grignard reagent described above. The reaction mixture was stirred at 40 °C for 3 h and was poured into 100 ml of ether. It was washed with water (20 ml x 2), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with hexane to give [2-(2- ethylmercaptophenyDallyl trimethylsilane as a colorless oil.
EXAMPLE 54 [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethylphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan
Figure imgf000133_0001
The title compound is prepared according to the procedures described in Example 50. EXAMPLE 55
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] - 1 la-(l-R-acetoxyethyl)-6-(2-(2- methylmercaptophenyl)prop-2-enyl)-6-hydroxy-9, 10,1 l-triacetoxy-3b, 7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1.2-clfuran
Figure imgf000134_0001
The title compound is prepared according to the procedures described in Example 50.
EXAMPLE 56
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2-n- butylmercaptophenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1.2-c] furan
Figure imgf000135_0001
The title compound is prepared in the same manner as Example 50.
EXAMPLE 57
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(2- vinylphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan
Figure imgf000135_0002
The title compound is prepared in the same manner as Example 49.
EXAMPLE 58
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(S)-(2- ethylphenyl)propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1.2-cl furan
Figure imgf000136_0001
The title compound is prepared in the same manner as
Example 50. The C6 sidechain is prepared as described below.
Step A: Preparation of (2-ethylphenyl)acetic acid
Figure imgf000136_0002
To a suspension of 8.53 g (350 mmoles) of magnesium in 270 mL in dry tetrahydrofuran was added 50 g (270 mmol) of l-bromo-2- ethylbenzene. The temperature was maintained at 50 °C during addition, then was heated under reflux. After 1 h, the solution was cooled to -78 °C under N2, and 54.42 g (324 mmoles) of allyl iodide was added dropwise. The mixture was allowed to warm to room temperature, stirred for an additional 2 h, then cooled to 0 °C. The reaction was quenched by addtition of 2M HCl and 500 mL of ether and the layers were separated. The organic layer was washed with 30 mL of saturated NaHCO3 solution and brine, dried over MgSO4, and concentrated. The oily residue was filtered through silica gel with 20% ethyl acetate-hexane and the eluate was concentrated to afford the crude l-allyl-2-ethylbenzeneas a colorless oil.
A solution of 54.05 g of the crude l-allyl-2-ethylbenzene in 500 mL of 1:1 CH2CI2-CH3OH was cooled to -78 "C. A stream of O3 was bubbled through the solution for 3 h, untill all of the starting material had disappeared. Then a stream of air was bubbled through the solution until the blue color had faded. A total of 25 mL of methyl sulfide was added and the solution was stirred at room temperature for 1 h. The solution was concentrated and dried under vacuum to afford (2- ethylphenyl) acetaldehyde as a colorless oil which was used directly in the next step. To a solution of the crude (2-ethylphenyl)acetaldehyde in 20 ml of EtOH was added a solution of 2.29 g (13.52 mmol) of AgNO3 in 7.5 ml of water and a solution of 2.08 g (37.2 mmol) of KOH in 13 ml of water at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and was filtered to remove the precipitated silverhydroxide. The filtrate was extracted with CH2CI2 (20 ml x 3) and the organic fractions were discarded. The aqueous layer was acidified with 6N HCl to PH = 1 and was extracted with CH2CI2 (50 ml x 3). The combined organic layers were dried over MgSO4 and concentrated to give 2-ethylphenylacetic acid. Step B: Preparation of (R)-4-benzyl-3-[2-(2-ethylphenyl)ethyl]- oxazolidin-2-one
Figure imgf000138_0001
To a stirred solution of 2.16 g (13.2 mmol) of (2- ethylphenyDacetic acid and 1.6 g (15.84 mmol) of triethylamine in 55 ml of anhydrous tetrahydrofuran was added 1.67 g (13.86 mmol) trimethylacetyl chloride at -78 °C under N2. After the resultant white suspension was stirred for 10 min. at -78 °C and 30 min. at 0 °C, it was recooled to -78 °C and a -78 °C solution of metallated oxazolidinone prepared by the addition of 8.67 ml (13,86 mmol, 1.6 M in hexane) of n- butyllithium to a -78 °C solution of 2.46 g (13.86 mmol) of (R)-(+)-4-benzyl- 2-oxazolidinone in 50 ml of anhydrous tetrahydrofuran was added via cannula. The reaction mixture was stirred at 0°C for an additional 30 min. and quenched by the addition of 50 ml of saturated aqueous ammonium chloride. The two layers were separated and the aqueous layer was extracted with CH2CI2 (50 ml x 3). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 6:1 hexane/ ethyl acetate to afford the title compound
Step C: Preparation of (R),(R)-4-Benzyl-3- [2-(2-ethyl-phenyl)-propyl] - oxazolidin-2-one
Figure imgf000139_0001
To a solution of 3.50 g (10.83 mmol) of (4R)-4-benzyl-3-[2-(2- ethyl-phenyl)-ethyl]-oxazolidin-2-one in 25 ml of tetrahydrofuran was added a solution of 13 ml (1.0 M, 13 mmol) of sodium bis(trimethyl- silyDamide at -78 °C under N2- After the reaction mixture was stirred at -78 oc for 30 min., 3.29 g (9.92 mmol) of iodomethane was added at -78
°C. The solution was stirred for 4 h and then quenched by the addition of 20 ml of aqueous saturated ammonium chloride solution. The two layers were separated and the aqueous was extracted with CH2CI2 (50 ml x 3).
The combined organic layers were dried over MgSO4 and concentrated.
The residue was purified by silica gel chromatography with 500:35 hexane/ ethyl acetate to afford the title compound. [α]D = -146 (c=1.55, CHCI3).
Step D: Preparation of (R)-2-(2-Ethylphenyl)-propanol
Figure imgf000139_0002
To a solution of 2.20 g (6.50 mmol) of (R),(R)-4-benzyl-3-[2-(2- ethyl-phenyl)-propyl]-oxazolidin-2-one in 20 ml of tetrahydrofuran was added 13 ml (1.0 M in THF, 13 mmol) of lithium aluminum hydride slowly at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then quenched by addition of 5 ml of water. The mixture was acidified with 2N HCl to PH = 1 and was extracted with CH2CI2 (50 ml x 3). The combined organic layers were dried MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10:1 hexane/ ethyl acetate to afford the title compound. [α]D = 5.6 (c=7.15, CHCI3).
Step E: Preparation of (R)-2-(2-Ethylphenyl)propylbromide
Figure imgf000140_0001
A solution of 0.93 g (6.20 mmol) of (R)-2-(2-ethylphenyl)- propanol in 40 ml of ether containing 2.60 g (9.92 mmol) of triphenylphosphine and 3.29 g (9.92 mmol) of carbon tetrabromide was stirred at room temperature for 3 h. It was filtered and concentrated. The residue was purified by silica gel chromatography with hexane to afford the title compound as a colorless oil (80%). [α]D = 19.1 (c=1.15, CHCI3).
EXAMPLE 59
[3a-S-3aα,3bβ,5aα,9β,9aβ,10α,llα,llaα]-lla-(l-R-acetoxyethyl)-6-(2-(S)-
(-)-(2-methoxyphenyl)propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro fl .2-cl furan
Figure imgf000141_0001
The title compound is prepared according to procedures described in Example 58.

Claims

WHAT IS CLAIMED IS:
1. A compound of structural Formula I:
Figure imgf000142_0001
or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein:
a and b are independently a single bond or a double bond, and represented by in the structure above;
Figure imgf000142_0002
Ri and Rl^a are independently: (1) H,
2 (2) =O, when R is absent or RlOb is absent respectively, (3) (Ci-Cio)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo, (b) hydroxy,
(c) oxo,
(d) (Cl-C6)-alkyloxy,
(e) (C╬╣-C6)-S(O)n-,
(f) aryl-(Cl-C6)-alkyloxy, (g) cyano,
(h) nitro, (i) vinyl,
(j) NR R5,
(k) NR4C0C╬╣-C6-alkyl, (1) CHO,
(m) CO2H,
(n) COCi-C6-alkyl,
(o) CO2C╬╣-C6-alkyl,
(p) CONR R5, (q) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
(a1) halo, as defined above,
(b') hydroxy, (c') (Ci-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (C╬╣-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy, (h') (C╬╣-C6)-alkyl-S(O)n-,
(i') phenyl,
0") phenoxy,
(k1) cyano, d') nitro,
(m') CO2H,
(n') COCi-C6-alkyl,
(o') CO2Ci-C6-alkyl,
(P') CONR4R5,
(q') NR4R5;
(r') NR4COCl-C6-alkyl,
(s') (Ci-C6)-alkenyloxy, and
(f) benzyloxy;
(r) heteroaryl, wherein heteroaryl is defined as an unsubstituted, monosubstituted, or disubstituted five or six membered aromatic heterocycle containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
(C) (C╬╣-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (C╬╣-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (C╬╣-C6)-alkyloxy,
(h') (C╬╣-C6)-alkyl-S(O)n-,
(i') phenyl,
(j') phenoxy, (k') cyano,
(V) nitro,
(m') CO2H,
(n1) COCi-C╬▓-alkyl,
(o') CO2Ci-C6-alkyl,
(P') CONR4R5,
(q') NR4R5,
(r') NR4COCi-C6-alkyl,
(s') fused benzo, and
10 (f) fused pyridyl group,
(s) heterocyclyl, wherein heterocyclyl is defined as a cyclic -,, non-aromatic moiety containing from 1 to 3 heteroatoms selected from the group consisting of O,
N, and S, said heterocycle being unsubstituted or
15 substituted with one, two or three substituents selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
(c') (Ci-C6)-alkyl,
20 (d') (C l-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Cl-C6)-alkyloxy,
(h1) (C╬╣-C6)-alkyl-S(O)n-,
25 (i') phenyl,
(j') phenoxy,
(k') cyano,
(D nitro,
(m') CO2H, (n*) COCi-C6-alkyl, (o') CO2Cl-C6-alkyl,
(p') CONR4R5, (q*) NR R5, (r1) NR4COC╬╣-C6-alkyl, and
(s1) oxo,
(f) fused benzo, and (u') fused pyridyl group; (4) (C2-Cio)-alkenyl, wherein alkenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo, (d) (C╬╣-C6)-alkyloxy,
(e) (Ci-C6)-S(O)n-,
(f) phenyl-(C╬╣-C6)-alkyloxy,
(g) cyano, (h) nitro, (i) vinyl,
(j) NR R5,
(k) NR4COCi-C6-alkyl,
(1) CHO,
(m) CO2H, (n) COCi-C╬▓-alkyl,
(o) CO2Ci-C6-alkyl,
(p) CONR R5,
(q) aryl, wherein aryl is as defined above, (r) heteroaryl, wherein heteroaryl is as defined above, and (s) heterocycle, wherein the heterocycle is as defined above, (5) (C2-Cio)-alkynyl, wherein alkynyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy, (c) oxo,
(d) (Cl-C6)-alkyloxy,
(e) (Ci-C6)-S(O)n-,
(f) phenyl-(Cl-C6)-alkyloxy,
(g) cyano, (h) nitro,
(i) vinyl,
(j) NR R5,
(k) NR COC╬╣-C6-alkyl,
(1) CHO, (m) CO2H,
(n) COCi-C6-alkyl,
(o) CO2C╬╣-C6-alkyl,
(p) CONR R5,
(q) aryl, wherein aryl is as defined above, (r) heteroaryl, wherein heteroaryl is as defined above,
(s) heterocyclyl, wherein heterocyclyl is as defined above, and
(t) Si(R )3, (6) an exo-methylene group, when R^ is absent or Rlob is absent respectively; or
(7) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
(C) (C╬╣-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy,
(h') (C╬╣-C6)-alkyl-S(O)n-,
(i') phenyl,
0") phenoxy,
(k') cyano, d') nitro,
(m') CO2H,
(n') COCi-C6-alkyl,
(o') CO2Ci-C6-alkyl,
(P') CONR4R5,
(q') NR4R5,
(r') NR4COCi-C6-alkyl,
(s') (C╬╣-C6)-alkenyloxy, and
(f) benzyloxy;
R2 is:
(1) H,
(2) absent when Ri is oxo, (3) absent when R is an exo-methylene group, or
(4) OH,
R3 is:
Figure imgf000149_0001
(2) (Cl-Cio)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, iodo,
(b) hydroxy,
(c) oxo,
(d) (Cl-C6)-alkyloxy,
(e) (C╬╣-C6)-S(O)n-,
(f) aryl-(Cl-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
(j) NR4R5,
(k) NR COC╬╣-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-C╬▓-alkyl,
(o) CO2Ci-C6-alkyl,
(P) CONR4R5,
(q) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of: (a') halo, as defined above, (b') hydroxy, (c') (C╬╣-C6)-alkyl, (d') (Cl-C4)-perfluoroalkyl,
(e') (C╬╣-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy, (h') (C╬╣-C6)-alkyl-S(O)n-,
(i') phenyl,
(j') phenoxy,
(k1) cyano,
(D nitro, (m') CO2H,
(n') COCi-C╬▓-alkyl,
(o') CO2Ci-C6-alkyl,
(p') CONR4R5,
(g1) NR4R5, and (r') NR4COC╬╣-C6-alkyl,
(r) heteroaryl, wherein heteroaryl is defined as an unsubstituted, monosubstituted, or disubstituted five or six membered aromatic heterocycle containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
(c') (Ci-C6)-alkyl, (d') (Cl-C4)-perfluoroalkyl,
(e1) (Ci-C6)-alkenyl,
(f) (C╬╣-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy,
(h') (C╬╣-C6)-alkyl-S(O)n-, (i') phenyl,
(j') phenoxy,
(k') cyano, d') nitro,
(m') CO2H,
(n') COCi-C╬▓-alkyl,
(o') CO2Ci-C6-alkyl,
(p') CONR4R5,
(q') NR R5,
10 (r') NR COC╬╣-C6-alkyl, and
(s') fused benzo or pyridyl group,
(s) heterocyclyl, wherein heterocyclyl is defined as a cyclic ;, non-aromatic moiety containing from 1 to 3 heteroatoms selected from the group consisting of O,
15 N, and S, said heterocycle being unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
(a') halo, as defined above,
(b') hydroxy,
20 (c') (Ci-C6)-alkyl,
(d1) (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (Ci-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy,
25 (h') (Ci-C6)-alkyl-S(O)n-,
(i') phenyl,
CT) phenoxy,
(k1) cyano,
(!') nitro, ( ') CO2H,
(n') COCl-C╬▓-alkyl,
(o') CO2Ci-C6-alkyl,
(p') CONR4R5,
(q') NR R5,
(r') NR4COC╬╣-C6-alkyl, and
(s') oxo,
(f) fused benzo, and
(u') fused pyridyl group; (t) Si(R4)3,
(3) (C2-Cio)-alkenyl, wherein alkenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo, (b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (C╬╣-C6)-S(O)n-,
(f) phenyl-(C╬╣-C6)-alkyloxy, (g) cyano,
(h) nitro, (i) vinyl,
(j) NR R5,
(k) NR COCi-C6-alkyl, (1) CHO,
(m) CO2H,
(n) COCi-C6-alkyl,
(o) CO2Ci-C6-alkyl, (p) CONR R5,
(q) aryl, wherein aryl is as defined above, (r) heteroaryl, wherein heteroaryl is as defined above, and (s) heterocyclyl, wherein heterocyclyl is as defined above;
(4) (C2-Cl╬╕)-alkynyl, wherein alkynyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo, (b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
Figure imgf000153_0001
(f) phenyl-(Ci-C6)-alkyloxy, (g) cyano,
(h) nitro,
(i) vinyl,
0') NR4R5,
(k) NR COCi-C6-alkyl, (1) CHO,
(m) CO2H,
(n) COCl-C╬▓-alkyl,
(o) CO Ci-C6-alkyl,
(p) CONR R5, (q) aryl, wherein aryl is as defined above,
(r) heteroaryl, wherein heteroaryl is as defined above, and (s) heterocyclyl, wherein heterocyclyl is as defined above; or (5) cyano;
R4 and R9 are independently:
(1) hydrogen,
(2) C1-C6 alkyl, or
(3) aryl, wherein aryl is defined above,
R6 is:
(1) hydrogen,
(2) oxo and a is a single bond,
(3) O[(C=O)Or]sRH,
(4) O[(C=O)Or]saryl, aryl as defined above,
(5) O[(C=O)Or]sheteroaryl, heteroaryl as defined above,
(6) OC(=O)NRllRl2,
(7) NRHR12, or
(8) absent, when a is a double bond;
R ' , R┬░ and R" are independently selected from the group consisting of:
(1) hydrogen,
(2) oxo,
(3) O[(C=O)Or]sRH,
(4) O[(C=O)Or]saryl> aryl as defined above,
(5) O[(C=O)Or]sheteroaryl, heteroaryl as defined above,
(6) OC(=O) NRHR12, and
(7) NRllRl2;
Figure imgf000154_0001
(1) H, (2) absent when Rl^a is oxo,
(3) an exo-methylene group, when R2 is absent or Rl0┬░ is absent respectively, or
(4) OH; and
12 d R are independently chosen from the group consisting of:
(1) H, and
(2) (Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: Br, Cl, F, I, (Ci-C╬▓)-alkoxy, vinyl, cyano, oxo, nitro, hydroxy, CHO, CO2H, COCi-C╬▓-alkyl, CO2C1-C6- alkyl, CONR4R5, NR R5, NR4COC╬╣-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, (Ci-C6)-alkoxy, phenyl, phenoxy, cyano, oxo, nitro, hydroxy, CHO, CO2H, COCi-C╬▓- alkyl, CO2Ci-C6-alkyl, CONR4R5, NR R5, NR4COC╬╣-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 O, 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, oxo, nitro, hydroxy, CHO, CO2H, COCi-C6-alkyl, CO2Ci-C6-alkyl, CON R R5, NR4R5, NR 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.
2. The compound of structural Formula I as recited in Claim 1, wherein :
RlO-a ^ further defined as:
(1) H,
(2) =O, when Rl┬░b is absent, (3) (Ci-C4)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy, (c) oxo,
(d) (Cl-C3)-alkyloxy,
(e) CHO,
(g) CO(Cl-C3)-alkyl,
(i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one or two of the substituents selected from the group consisting of:
(a1) halo, as defined above,
(b1) hydroxy,
(c') (Ci-C6)-alkyl, (d') (Cl-C4)-perfluoroalkyl,
(e') (Ci-C6)-alkenyl,
(f) (C╬╣-C6)-alkynyl,
(g1) (Ci-C6)-alkyloxy,
(h') (Ci-C6)-alkyl-S(O)n-, (i1) phenyl, (j') phenoxy,
(k') cyano,
(D nitro,
(m') CO2H, (n') COCi-C╬▓-alkyl,
(o') CO2Ci-C6-alkyl,
(p') CONR4R5, (q') NR R5, (r') NR COCi-C6-alkyl, (s') (Ci-C6)-alkenyloxy, and
(f) benzyloxy; (j) heteroaryl, wherein heteroaryl is defined as pyridyl or thienyl,
(4) (C2-C4)-alkenyl, wherein alkenyl is unsubstituted or substituted with aryl, wherein aryl is as defined above;
(5) (C2-C3)-alkynyl, wherein alkynyl is unsubstituted or substituted with phenyl or Si(R4) , or (6) an exo-methylene group, when Rl0┬░ is absent.
3. The compound of structural Formula I as recited in
Claim 2, wherein:
R is further defined as: (1) H, or (2) (Cl-C3)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, iodo,
(b) hydroxy, (c) oxo, (d) (C╬╣-C6)-alkyloxy,
(e) (Ci-C6)-S(O)n-,
(f) aryl-(C ╬╣-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
(j) NR R5,
(k) NR COC╬╣-C6-alkyl,
(1) CHO,
( ) CO2H,
(n) COCl-C6-alkyl,
(o) CO2Ci-C6-alkyl,
(P) CONR4R5,
(q) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of:
(a1) halo, as defined above,
(b1) hydroxy,
(c') (Ci-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (C╬╣-C6)-alkenyl,
(f) (C╬╣-C6)-alkynyl,
(g') (Ci-C6)-alkyloxy,
(h') (C╬╣-C6)-alkyl-S(O)n-,
(i1) phenyl,
(j1) phenoxy,
(k1) cyano,
(D nitro,
(m') CO2H, (n') COCl-C╬▓-alkyl,
(o') CO2Ci-C6-alkyl,
(p1) CONR R5,
(g') NR4R5, and (r') NR COC╬╣-C6-alkyl,
(r) Si(R4)3,
(3) (C2-C3)-alkenyl, wherein alkenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (C╬╣-C6)-alkyloxy,
(e) (Ci-C6)-S(O)n-, (f) phenyl-(Cl-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
(j) NR4R5, (k) NR4COC╬╣-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-C╬▓-alkyl,
(o) CO2Ci-C6-alkyl, (p) CONR R5,
(q) aryl, wherein aryl is as defined above, (r) heteroaryl, wherein heteroaryl is as defined above, and (s) heterocyclyl, wherein heterocyclyl is as defined above;
(4) (C2-C3)-alkynyl, wherein alkynyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C6)-alkyloxy,
(e) (C╬╣-C6)-S(O)n-, (f) phenyl-(Ci-C6)-alkyloxy,
(g) cyano,
(h) nitro,
(i) vinyl,
0') NR4R5, (k) NR COC╬╣-C6-alkyl,
(1) CHO,
(m) CO2H,
(n) COCi-C╬▓-alkyl,
(o) CO2Ci-C6-alkyl, (p) CONR4R5,
(q) aryl, wherein aryl is as defined above,
(r) heteroaryl, wherein heteroaryl is as defined above, and (s) heterocyclyl, wherein heterocyclyl is as defined above; or
(5) cyano;
Ro are further defined independently as: (1) hydrogen, (2) CrC3 alkyl, or
(3) phenyl,
R6 is further defined as: (1) hydrogen,
(2) oxo and a is a single bond,
(3) O(C=O)Rll, or
(4) absent when a is a double bond;
R^, R8 and R^ are further defined as independently selected from the group consisting of:
(1) hydrogen,
(2) oxo,
(3) O(C=O)Rll; and
11 12
R and R are further defined as independently chosen from the group consisting of:
(1) H, and
(2) (C╬╣-C3)-alkyl.
4. The compound of structural Formula I as recited in Claim 2, wherein:
Ri is further defined as: (1) H,
2
(2) =O, when R is absent,
(3) (C╬╣-C8)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: (a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) oxo,
(d) (Ci-C3)-alkyloxy, (e) CHO,
(g) CO(C╬╣-C3)-alkyl,
(i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of: (a') halo, as defined above,
(b1) hydroxy,
(c') (Ci-C6)-alkyl,
(d') (Cl-C4)-perfluoroalkyl,
(e') (Cl-C6)-alkenyl, (f) (Ci-C6)-alkynyl,
(g') (Cl-C6)-alkyloxy,
(h') (Ci-C6)-alkyl-S(O)n-,
(i1) phenyl,
(j') phenoxy, (k') cyano,
(D nitro,
(m') CO2H,
(n') COCi-C6-alkyl,
(o') CO2Ci-C6-alkyl, (p') CONR4R5,
(q*) NR R5,
(r') NR COCi-C6-alkyl,
(s') (Cl-C6)-alkenyloxy, and
(f) benzyloxy; (j) heteroaryl, wherein heteroaryl is defined as pyridyl or thienyl, (4) (C2-C6)-alkenyl, wherein alkenyl is unsubstituted or substituted with aryl, wherein aryl is as defined above; and (5) (C2-C3)-alkynyl, wherein alkynyl is unsubstituted or substituted with phenyl or Si(R4)3, or (6) an exo-methylene group, when R2 is absent;
urther defined as: (1) H, or
(2) (C╬╣-C3)-alkyl, wherein alkyl is unsubstituted or substituted
with phenyl or Si(R4)3
(3) (C2-C3)-alkenyl, wherein alkenyl is unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
(a') halo, as defined above,
(b1) hydroxy,
(c') (Ci-C6)-alkyl, (d') (Cl-C4)-perfluoroalkyl,
(e') (C╬╣-C6)-alkenyl,
(f) (C╬╣-C6)-alkynyl,
(g') (Cl-C6)-alkyloxy,
Qi') (C╬╣-C6)-alkyl-S(O)n-, (i1) phenyl,
(j') phenoxy,
(k1) cyano,
(l1) nitro,
(m') CO2H, (n') COCi-C╬▓-alkyl,
Co') CO2Ci-C6-alkyl,
(p') CONR R5,
(q') NR4R5,
(r') NR COC╬╣-C6-alkyl,
(s') (Cl-C6)-alkenyloxy, and
(f) benzyloxy;
(4) cyano;
R4 and R^ are further defined independently as:
(1) hydrogen,
(2) CrC3 alkyl, or
(3) phenyl,
R6 is further defined as:
(1) hydrogen,
(2) oxo and a is a single bond,
(3) O(C=O)Rll, or
(4) absent when a is a double bond;
R7, R8 and R^ are further defined as independently selected from the group consisting of:
(1) hydrogen,
(2) oxo, and (3) O(C=O)Rll; and
R11 and R12 are further defined as independently chosen from the group consisting of:
(1) H, and (2) (C╬╣-C3)-alkyl.
5. The compound of structural Formula I as recited in Claim 4, wherein RlOa and Rl^D are further defined as H.
6. A compound selected from the group consisting of:
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-oxo- 9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,3b,4,5,5a,6,9,9a,9b,10, 11,11a- tetradecahydrophenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-benzyl-6- hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10,
11 , 1 la-tetradecahydrophenanthro [1 ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-n-butyl-6- hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10,
11 , 1 la-tetradecahydrophenanthro [1,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6 -(3- phenyl-n-propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydrophenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,
3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydrophenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,7,8,9,9a,9b,10, ll,lla-hexadecahydrophenanthro[l,2-c]furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenethyl)-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,7,8, 9, 9a, 9b, 10, ll,lla-tetradecahydrophenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydrophenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2 - c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2-n- butyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- allyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2 - c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] -1 la-(l-R-acetoxyethyl)-6-(2-(2- benzyloxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan; [3a-S-3aa,3bb,5aa,9b,9ab, 10a, 11a, 1 laa] -1 la-( l-R-acetoxyethyl)-6-(but-3-en- l-yl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a,
3b,4, 5, 5a, 6, 9,9a, 9b, 10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(4- dimethyl-pent-3-en-l-yl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- fluorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] -1 la-( l-R-acetoxyethyl)-6-(2-(2,6- difluorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(4- chlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] -1 la-(l-R-acetoxyethyl)-6-(2-(3,4- dichlorophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a,l la, 1 laa] -1 la-(l-R-acetoxyethyl)-6-(2-(4- methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] -1 la-( l-R-acetoxyethyl)-6-(2-(2- trifluoromethylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3- trifluoromethylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- naphth-2-ylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- naphth-l-ylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa]- 1 la-( l-R-acetoxyethyl)-6-(2-(3- methoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa]- 1 la-( l-R-acetoxyethyl)-6-(2-(4- methoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2 - c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,3- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3,4- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,5- dimethoxyphenyl)ethyl))-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(3,5- dimethoxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2- c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 11a, 1 laa] -1 la-( l-R-acetoxyethyl)-6-(2-(3,4- methylenedioxyphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,3- methylenedioxyphenyl)ethyl)-6-hydroxy-9, 10,1 l-triacetoxy-3b, 7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(4- dimethylaminophenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trim ethyl- 1,3, 3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2,2- diphenylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxy-5-methylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] -1 la-( l-R-acetoxyethyl)-6-(2-(thien- 2-yl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2,6- dimethoxylphenyl)ethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenyl-propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenyl-2-methylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- hydroxyphenylethyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(S)- phenylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2- phenylprop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] - 1 la-( l-R-acetoxyethyl)-6-(2-(R)- phenylpropyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan; [3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methoxyphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [ 1 ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethylmercaptophenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1 ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- ethylphenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2 - c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- methylmercaptophenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro [1,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] -1 la-( l-R-acetoxyethyl)-6-(2-(2-n- butylmercaptophenyl)prop-2-enyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a- trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l ,2-c] furan;
[3a-S-3aa,3bb,5aa,9b,9ab,10a,lla,llaa]-lla-(l-R-acetoxyethyl)-6-(2-(2- vinylphenyl)prop-2-enyl)-6-hydroxy-9, 10, 1 l-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan; [3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] - 1 la-( l-R-acetoxyethyl)-6-(2-(S)-(2- ethylphenyl)propyl)-6-hydroxy-9,10,ll-triacetoxy-3b,7,9a-trimethyl-l,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2-c]furan; and
[3a-S-3aa,3bb,5aa,9b,9ab, 10a, 1 la, 1 laa] - 1 la-( l-R-acetoxyethyl)-6-(2-(S)-(-)- (2-methoxyphenyl)propyl)-6-hydroxy-9, 10, 1 l-triacetoxy-3b,7,9a-trimethyl- 1,3,3a, 3b,4,5,5a,6,9,9a,9b,10, ll,lla-tetradecahydro phenanthro[l,2- c] furan.
7. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kv1.3 inhibition, comprising the administration, in an amount that is effective at inhibiting Kv1.3, of a compound of Formula I, as recited in Claim 1.
8. The method of treating a condition in a mammal the treatment of which is effected or facilitated by Kv1.3 inhibition, as recited in Claim 7, wherein the condition is selected from the group consisting of: 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, vasculi tides, 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, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn; 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.
9. The method as recited in Claim 8, wherein the condition is an autoimmune disease.
10. A method of preventing or treating the resistance to transplantation or transplantation rejection of organs or tissues into a patient in need thereof, which comprises the administration of a therapeutically effective amount of a compound of Claim 1.
11. A method of suppressing the immune system in a subject in need thereof, which comprises the administration to the subject of an immune suppressing amount of a compound of Formula I, as recited in Claim 1.
12. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of Formula I, as recited in Claim 1 or a pharmaceutically acceptable crystal form or hydrate thereof.
13. The pharmaceutical formulation of Claim 12, comprising in addition, a second immunosuppressive agent comprising azathioprine, brequinar sodium, deoxyspergualin, mizaribine, mycophenolic acid morpholino ester, cyclosporin, FK-506 and rapamycin.
14. The method of Claim 11, comprising the coadministration of a second immunosuppressive agent.
15. A method of preventing or treating the resistance to transplantation or transplantation rejection of organs or tissues into a patient in need thereof, which comprises the administration of a compound of Claim 1.
16. A method of preventing or treating 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, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn; 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 which comprises the administration of a compound of Claim 1.
17. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kv1.3 inhibition, comprising the administration of a pharmaceutical formulation comprising a pharmaceutical carrier and a compound of Formula I, as recited in Claim 1, in an amount that is effective at inhibiting Kv1.3.
18. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by Kv1.3 inhibition, comprising the coadministration of a therapeutically effective amount of a compound of Formula I, as recited in Claim 1, with a second immunosuppressive agent.
PCT/US1998/021592 1997-10-17 1998-10-13 Furanyl, tetracyclic triterpene derivatives with immunosuppressant activity WO1999020267A1 (en)

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EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection
CN109985052A (en) * 2017-12-29 2019-07-09 上海蓝木化工有限公司 The new application of triterpene compound

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WO1998016532A1 (en) * 1996-10-16 1998-04-23 Merck & Co., Inc. Triterpene derivatives with immunosuppressant activity

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Publication number Priority date Publication date Assignee Title
WO1998016532A1 (en) * 1996-10-16 1998-04-23 Merck & Co., Inc. Triterpene derivatives with immunosuppressant activity

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection
CN109985052A (en) * 2017-12-29 2019-07-09 上海蓝木化工有限公司 The new application of triterpene compound

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