LABDAN-DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS

Abstract: The present invention relates to novel labdanes, inter­ mediates and processes for the preparation thereof. The compounds have the ability to reduce elevated in­ traocular pressure and can, therefore, be used as medica­ ments.

Description: The present invention relates to labdanes. More particularly, the present invention relates to labdanes of formula I wherein (a) R₁ is hydrogen, a group of the formula R₂CO wherein R₂ is hydrogen or C₁-C₆-alkyl, or a group of the formula R₃R₄R₅Si wherein R₃, R₄ and R₅ are each independently C₁-C₆-alkyl; (b) R₆ and R₇ are each independently hydrogen, a group of the formula R₈CO wherein R₈ is C₁-C₆-alkyl, CH₃CHOH, HOCH₂CHOH, a group of the formula R 1⊘ O(CH₂)n wherein R 1⊘ is hydrogen or C₁-C₆-alkyl and n is 1, 2 or 3, or R₈ is a group of the formula R₁₁R₁₂NCHR₁₃ wherein R₁₁ is hydrogen, C₁-C₆-alkyl, a group of the formula a group of the formula or a group of the formula R₁₄CO wherein R₁₄ is hydrogen or C₁-C₆-alkyl; R₁₂ is hydrogen or C₁-C₆-alkyl; R₁₃ is hydrogen, C₁-C₆-alkyl, benzyl or a group of the formula CH₂OH; R₁₁ and R₁₂ taken together with the nitrogen atom to which they are attached form a group of the formula wherein X is CHR₁₅ wherein R₁₅ is hydrogen, c₁-C₆-alkyl or a group of the formula OR₁₆ wherein R₁₆ is hydrogen, C₁-C₆-alkyl or a group of the formula COR₁₇ wherein R₁₇ is C₁-C₆-alkyl and m is ⊘ or 1; a group of the formula NR₁₈ wherein R₁₈ is C₁-C₆-alkyl; and R₆ and R₇ taken together form a group of the formula CO or a group of the formula SO; (c) R₉ is hydrogen; (d) R₁ and R₉ taken together form a group of the formula CO, a group of the formula SO or a group of the formula CHNR₁₉R 2⊘ wherein R₁₉ and R 2⊘ are each independently C₁-C₆-alkyl; and R₁₉ and R 2⊘ taken together with the nitrogen atom to which they are attached form a group of the formula wherein X and m are as hereinbeforedescribed; with the provisos: (e) that R₆ is not hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl when R₇ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl, R₁ is hydrogen, R₂CO or R₃R₄R₅Si wherein R₃,R₄ and R₅ are as above, and R₉ is hydrogen; (f) that R₁ is not hydrogen or R₂CO when R₉ is hydrogen and R₆ and R₇ taken together are CO; (g) that R₁ and R₉ taken together are not CO or SO when R₆ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl, and R₇ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl; or when R₆ and R₇ taken together are CO or SO; the optical and geometric isomers thereof, or a pharmaceutically acceptable acid addition salt thereof, which are useful for reducing intraocular pressure, alone or in combination with inert adjuvants. Subgeneric to the labdanes of the present invention are compounds of formula I wherein (a) R₁ and R₉ are hydrogen and R₆ is a group of the formula R₈CO wherein R₈ is a group of the formula R₁₁R₁₂NCHR₁₃ wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedefined; (b) R₁ and R₉ are hydrogen and R₇ is a group of the formula R₈CO wherein R₈ is a group of the formula R₁₁R₁₂NCHR₁₃ wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedefined; (c) R₁ and R₉ are hydrogen and R₆ is R₈CO wherein R₈ is a group of the formula CH₃CHOC,HOCH₂CHOH, and a group of the formula R 1⊘ O(CH₂) n wherein R 1⊘ is hydrogen or C₁-C₆-alkyl and n is 1, 2 or 3; (d) R₁ and R₉ are hydrogen and R₇ is a group of the formula R₈CO wherein R₈ is a group of the formula CH₃CHOH,HOCH₂CHOH, and a group of the formula R₁₀O(CR₂) n wherein R₁₀ is hydrogen or C₁-C₆-alkyl and n is 1, 2 or 3; and (e) R₁ and R₉ taken together form a group of the formula CHNR₁₉R 2⊘ wherein R₁₉ and R 2⊘ are as hereinbeforedefined. As used through the specification and appended claims, the term "alkyl" refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 8 carbon atoms such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl, 2-octyl ; the term "alkanol" refers to a compound formed by a combination of an alkyl group and a hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and 2-propanol, 1,2-dimethylethanol, hexanol, octanol . The term "alkanoic acid" refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid ; the term "halogen" refers to a member of the family consisting of fluorine, chlorine, bromine or iodine. The term "alkanoyl" refers to the radical formed by removal of the hydroxyl function from an alkanoic acid. Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl. In the formulas presented herein the various substituents are Illustrated as joined to the labdane nucleus by one of two notations: a solid line (-) indicating a substituent which is in the β-orientation (i.e., above the plane of the molecule) and a broken line (---) indicating a substituent which is in the α-orientation (i.e., below the plane of the molecule). The formulas have all been drawn to show the compounds in their absolute stereochemical configuration. Inasmuch as the starting materials having a labdane nucleus are naturally occurring or are derived from naturally occurring materials, they, as well as the final products, have a labdane nucleus existing in the single absolute configuration depicted herein. The processes of the present invention, however, are intended to apply as well to the synthesis of labdanes of the racemic series. In addition to the optical centers of the labdane nucleus, the substituents thereon may also contain chiral centers contributing to the optical properties of the compounds of the present invention and providing a means for the resolution thereof by conventional methods, for example, by the use of optically active acids. A wavy line ( ~ ) connecting a group to a chiral center indicates that the stereochemistry of the center is unknown, i.e., the group may exist in any of the possible orientations. The present invention comprehends all optical isomers and reacemic forms of the compounds of the present invention where such compounds have chiral centers in addition to those of the labdane nucleus. The novel labdanes of the present invention are synthesized by the processes illustrated in Reaction Scheme A and B. To prepare a basic labdane 3 wherein R₇ is alkanoyl and R₁₉ and R 2⊘ are as hereinbeforedescribed, a 1α,9α-dihydroxylabdane 2 wherein R₇ is alkanoyl is condensed with a formamide dialkylacetal of formula 1⊘ wherein R₂₁ is alkyl and R₁₉ and R 2⊘ are as hereinbeforedescribed to provide a basic labdane 3 . The condensation is preferably performed in the absence of an added solvent, excess formamide dialkylacetal serving both as the reactant and solvent. A dipolar aprotic solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide or dimethylsulfoxide may be employed, however, as the reaction medium. The temperature at which the condensation is conducted is not critical. A condensation temperature within the range of about 25° to about 188°C is generally employed to assure a reasonable EP-A-0 116 713 relates to labdan derivatives having a formula according to formula I of the present invention, wherein R₁ may be H, R₉ may be H and R₆ and R₇ may be independently H or carboxylic acyl, to a process for their preparation and pharmaceutical compositions containing the same. The compounds and compositions exhibit particularly an antiallergic and/or bronchodilatory effect, but show also an intraocular pressure reducing activity. rate of reaction. A temperature of about 45° to about 65°C is preferred. To prepare a labdane of formula 4 wherein R₁₉ and R 2⊘ are as before and R₆ Is alkanoyl, a 7β-alkanoyloxy-6β-hydroxy-labdane 3 is rearranged to a 6β-alkanoyloxy-7β-hydroxylabdane 4 . The rearrangement is conveniently performed in an aqueous alkanol containing an alkali metal hydroxide. Among alkanols there may be mentioned methanol, ethanol, 1- and 2-propanol and t-butanol. Methanol is preferred. Among alkali metal hydroxides there may be included lithium, sodium and potassium hydroxide. Sodium hydroxide is preferred. While the rearrangement is preferably performed at about ambient temperature, it may be conducted at a reduced temperature within the range of about ⊘° to about 25°C, or at an elevated temperature of about 25° to 35°C. The rearrangement may preferably be effected, for example, by treating 3 with lithium 1,1,1,3,3,3-hexamethyldisilazide in an ethereal solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxy-ethane or bis-(2-methoxyethyl)ether at a reduced temperature of about ⊘°C. To furnish a basic labdane of formula 5 wherein R₁₉ and R 2⊘ are as above, a 6β-alkanoyloxy-7β-hydroxylabdane 4 is hydrolyzed to the 6β,7β-dihydroxylabdane 5 . The hydrolysis is carried out in an aqueous alkanol such as aqueous methanol, ethanol, 1- or 2-propanol or t-butanol, aqueous methanol being preferred, containing an alkali carbonate such as lithium, sodium or potassium carbonate, potassium carbonate being prefered, at a hydrolysis temperature within the range of about 1⊘° to about 75°C, a hydrolysis temperature of about 25°C being preferred. A 6β,7β-dihydroxylabdane of formula 5 may also be prepared by hydrolysis of a 7β-alkanoyloxy-6β-hydroxylabdane of formula 3 by means of the hereinbeforedescribed processes for the conversion of 4 to 5 . To introduce a 6β,7β-sulfite or 6β,7β-carbonate function into the basic labdane nucleus, i.e., to prepare a compound of formula 7 wherein X is SO or CO, respectively, a 6β,7β-dihydroxylabdane of formula 5 is treated with a compound of formula 11 . wherein Hal is bromo or chloro, preferably chloro, and Z is SO or CO in the presence of an organic base such as trimethyl- or triethylamine, pyridine, lutidine or collidine at a reduced temperature within the range of about -25° to about 25°C. The preferred organic base is pyridine and the preferred reaction temperature is about ⊘°C. To elaborate, a basic labdane characterized by the presence of aminoacyloxy and aminoacetal moieties, a 7β-hydroxylabdane 5 is esterified with an aminoacid of formula 12 . wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedescribed. The esterification is conveniently effected in a halocarbon such as dichloromethane or tirchloromethane in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a catalyst such as 4-(N,N-dimethylamino)pyridine at a reaction temperature within the range of about ⊘° to about 5⊘°C. Dichloromethane and dicyclohexylcarbodiimide are the preferred halocarbon and carbodiimide, respectively. A reaction temperature of about 25°C is also preferred. A hydrohalide of the aminoacid, for example, an aminoacid hydrochloride, may be employed in the process for the esterification of a 7β-hydroxylabdane. To construct a basic labdane characterized by an aminoacyloxy function at the 7β-position and a free hydroxy group at the 1α-position of the labdane nucleus, i.e., to synthesize a compound of formula 9 wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedefined, a 7β-alkanoyloxylabdane 2 is hydrolyzed under conventional conditions utilizing an alkali metal carbonate such as sodium carbonate in an aqueous alkanol such as methanol at a reaction temperature of about 25°C to the known 1α,6β,7β,9α-tetrahydroxy labdane 8 which is esterified with a compound of the formula 12 . wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedefined under reaction conditions substantially similar to those employed for the conversion of 5 to 6 described above. Alternatively, basic labdanes of formula 9 may be prepared by hydrolysis of the aminoacetal moiety of labdanes of formula 6 . The hydrolysis may be accomplished by treating an aminoacetal of formula 6 with an alkanoic acid such as acetic or propanoic acid, preferably acetic acid, in an aqueous alkanol such as methanol, ethanol or 1- or 2-propanol, preferably aqueous methanol, at a temperature within the range of about ⊘° to 5⊘°C, preferably at a temperature of about 25°C. Basic labdanes of formula 9 are also prepared by desilylation of a compound of formula 15 . The removal of the silyl group is achieved by, for example, treating the 1α-silyoxylabdane 5 with aqueous hydrogen fluoride in acetonitrile at a temperature of about 25°C. To gain entry into the labdane system having a basic moiety at the 7β-position and a silyloxy group at the 1α-position, i.e., to provide basic labdanes of formula 15 wherein R₃, R₄, R₅, R₁₁, R₁₂, and R₁₃ are as above, a 7β-alkanoyloxy-1α-hydroxylabdane 2 is silylated to a 7β-alkanoyloxy-1α-silyloxylabdane 13 which is hydrolyzed to a 7β-hydroxy-1α-silyloxylabdane 14 and converted to a basic labdane 15 . To effect the silylation, one treats a 1α-hydroxylabdane 2 with a N-(trialkylsilyl)-N-alkyltrifluoroacetamide of formula 16 wherein R₃, R₄ and R₅ are as above and R₂₃ is alkyl, preferably a trifluoroacetamide wherein R₂₃ is alkyl, most preferably N(t-butyldimethylsilyl)-N-methyltrifluoroacetamide, in a dipolar aprotic solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide or dimethylsulfoxide, preferably dimethylformamide, at a temperature within the range of about ⊘° to 75°C, preferably at a reaction temperature of about 25°C, to afford a compound of formula 13 . The hydrolysis is accomplished by treating a 7β-alkanoyloxy-1α-trialkylsilyloxylabdane 13 with an alkali metal carbonate in an aqueous alkanol. Included among alkali metal carbonates are lithium, sodium and potassium carbonate. Included among alkanols are methanol, ethanol, 1- and 2- propanol and t-butanol. Potassium carbonate and methanol are the preferred alkali metal carbonate and alkanol. While the reaction temperature is not narrowly critical, it is preferable to perform the hydrolysis at an elevated temperature within the range of about 6⊘° to about 1⊘⊘°C. A hydrolysis temperature of about 8⊘°C is most preferred. The introduction of the basic moiety at the 7β-position of the labdane nucleus, i.e., the conversion of a 7β-hydroxylabdane 14 to a 7β-aminoalkylcarbonyloxylabdane 15 is achieved by processes substantially similar to those employed for the conversion of 7β-hydroxylabdane 5 to 7β- aminoalkylcarbonyloxylabdane 6 . For example, one treats a 7α-hydroxylabdane 14 with an aminoacid 12 , free or as the hydrohalide salt, in a halo-carbon solvent such as dichloromethane in the presence of a catalyst such as 4-dimethylaminopyridine and a carbodiimide such as dicyclohexylcarbodiimide at about ambient temperature (ca. 25°C) to provide a compound of formula 15 . To synthesize a labdane having a 6β,7β-sulfite or 6β,7β-carbonate function and a 1α-hydroxy group, i.e., a compound of formula 17 wherein X is SO or CO, a 1α-silyloxylabdane of formula 14 is converted to a 1α-silyloxylabdane -6β,7β-sulfite or -carbonate of formula 16 by processes substantially similar to those employed for the conversion of a compound of formula 5 to a compound of formula 7 followed by desilylation by the process described above for the transformation of a 1α-silyloxylabdane 15 to a 1α-hydroxylabdane 9 . The labdane starting materials for the processes of the present invention, i.e., labdanes of formula 3 wherein R7 is hydrogen or a group of the formula R₈CO wherein R₈ is as hereinbeforedescribed, are described in U.S. patent 4,134,986, issued January 16, 1979 to B. S. Bajwa, et al., or may be prepared from compounds disclosed therein by conventional processes. The labdanes of the present invention are useful in the treatment of elevated intraocular pressure by virtue of their ability to reduce intraocular pressure as determined by the method described by J. Caprioli, et al., Invest. Ophthalmol. Vis. Sci., 25, 268 (1984). The results of the determination expressed as percent decrease of outflow pressure is presented in the Table. Intraocular pressure reduction is achieved when the present labdanes are administered to a subject requiring such treatment as an effective topical dose of a ⊘.⊘1 to 3.⊘% solution or suspension. A particularly effective amount is about 3 drops of a 1% preparation per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention. Compounds of the present invention are also useful for the treatment of hypertension, congestive heart failure, bronchial asthma and psoriasis. Compounds of the present invention include: (1) 1α-acetoxy-7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-6β,9α-dihydroxylabd-14-en-11-one. (2) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-6β-hydroxylabd-14-en-11-one 1α,9α sulfite. (3) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1,9-pyrrolidineformamide acetal. (4) 6β-[N-(t-butoxycarbonyl)aminoacetoxy]-8,13-epoxy-1α,7β, 9α-trihydroxylabd-14-en-11-one. (5) 8,13-epoxy-7β-formyloxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1,9 dimethylformamide acetal. (6) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α-formyloxy 6β,9α-dihydroxylabd-14-en-11-one. (7) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-6β-hydroxylabd-14-en-11-one 1α ,9α-carbonate. (8) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1,9 piperidineformamide acetal. (9) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1,9 morpholineformamide acetal. (1⊘) 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1,9 thiomopholineformamide acetal. (11) 8,13-epoxy-1α,9α-dihydroxylabd-14-en-one 1,9-dimethylformamide acetal 6β,7β-carbonate. (12) 7β-aminoacetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one. (13) 7β-(1-piperidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one. (14) 7β-(1-pyrrolidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one. (15) 7β-(4-morpholinoacetoxy)-8,13-epoxy-1α,6β,9α -trihydroxylabd-14-en-11-one. (16) 7β-(4-thiomopholinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one. (17) 8,13-epoxy-1α,6β,9α-trihydroxy-7β-(2-aminopropionyloxy)labd-14-en-11-one. (18) 8,13-epoxy-1α,6β,9α-trihydroxy-7β-(2-amino-3-phenylpropionyloxy)labd-14-en-11-one. Effective amounts of the compounds of the present invention may be administered to a subject by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, in some cases intravenously in the form of sterile solutions, or suspensions, and topically in the form of solutions, suspension or ointments, and by aerosol spray. The labdanes of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of increased solubility and the like. Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid and the like, salts of monobasic carboxylic acids such as, for example, acetic acid, propionic acid and the like, salts of dibasic carboxylic acids such as, for example, maleic acid, fumaric acid and the like, and salts of tribasic carboxylic acids such as, for example, citric acid and the like. Effective quantities of the compounds of the invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the aforesiad compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least ⊘.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 7⊘% of the weight of the unit. The amount of active compound in such composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between ⊘.1-3⊘ milligrams of the active compound. The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragancanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral or topical therapeutic administeration, the active compounds of the invention may be incorporated into a solution, suspension, ointment or cream. These preparations should contain at least ⊘.⊘1% of active compound, but may be varied between ⊘.5 and about 5% of the weight thereof. The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between ⊘.⊘1 to 1⊘ milligrams of active compound. The solutions or suspensions for topical or parenteral administration may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, proplyene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules or disposable syringes; the topical preparation may be enclosed in multiple dose vials or dropping bottles, made of glass or plastic. The following examples are for illustrative purposes only and are not to be construed as limiting the invention. All temperatures are given in degrees Centigrade. EXAMPLE 1 7β-Acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamide acetal 7β-Acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1⊘⊘ mg) was dissolved in 1 ml of dimethylformamide dimethylacetal. The mixture was stirred 1 hr at room temperature and overnight at 55° under nitrogen. The mixture was dissolved in ether, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The oil was dissolved in a minimum volume of dichloromethane and chromatographed using 1⊘ g of silica gel (23⊘-4⊘⊘ mesh). Eluent: 8 x 3 ml of dichloromethane, 8 x 3 ml of 3% methanol/dichloromethane and 8 x 3 ml of 5% methanol/dichloromethane. Evaporation of the solvent from appropriate fractions followed by drying at 6⊘° (1 mm) provided 9⊘ mg (79.1%) of product as an oil. EXAMPLE 2 6β-Acetoxy-8,13-epoxy-1α7β9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamide acetal A solution of 2⊘⊘ mg of 7β-acetoxy-8-13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 2 ml of dimethylformamide dimethylacetal was stirred at 35° overnight, under nitrogen, and allowed to cool to room temperature. To the mixture was added 1⊘ ml of an 2⊘% aqueous methanolic solution of sodium hydroxide. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed twice with water, saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration followed by evaportion of solvent provided an oil. The material was flash chromatographed using 2⊘ g of silica gel (0.07-0.037 mm; 230-400 mesh) (eluent: 50 x 15 ml of 30/70 ethyl acetate/hexane). Evaporation of the appropriate fractions followed by drying at 80° (1 mm) provided 81 mg (35.6%) of product, mp 173-175°. EXAMPLE 3 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamide acetal A solution of 225 mg of 7β-acetoxy-8,13-epoxy-1α,6β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamide acetal was stirred at room temperature under nitrogen for 5 hrs in 5 ml of saturated potassium carbonate solution in 2⊘% aqueous methanol. The solution was diluted with water and extracted twice with ether. The ether extracts were washed twice with water and dried over anhydrous sodium sulfate. Filtration followed by evaporation of the solvent provided an oil, which crystallized on standing. The crystals were dried at 113° (1 mm) to yield 192 mg (88.5%) of product, mp 136-144°. EXAMPLE 4 8,13-Epoxy-1α,9α-dihydroxylabd-14-en-11-one-1α,9α-dimethylformamide acetal-6β,7β-sulfite To a stirred solution of 2⊘⊘ mg of 8,13-epoxy-1α,6β,7β,9α-tetrahydroxyladb-14-en-11-one-1α,9α-dimethylformamide acetal in 2 ml of dry pyridine was added slowly, dropwise, a solution of ⊘.2 ml of thionyl chloride in 4 ml of dry pyridine. The mixture was stirred 15 min at ⊘°, poured into water, and extracted twice with ether. The extracts were washed twice with water, dried over anhydrous sodium sulfate and filtered. Concentration provided an oil. The material was dissolved in a minimum volume of 25% ethyl acetate/hexane and purified by flask chromatography on 25 g of silica gel (0.07-0.037 mm; 230-400 mesh) (eluent: 20 x 15 ml of 25 % ethyl acetate/hexane). Concentration of the appropriate fractions followed by drying at 40° (1 mm) provided 0.148 g (66.7%) of product, mp 157-162°. EXAMPLE 5 7β-[N-(t-Butoxycarbonyl)aminoacetoxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one To a mixture of 1⊘⊘ mg of 8,13-epoxy-1α,6β,7β,9α₋tetra-hydroxylabd-14-en-11-one, 34.1 mg of 4-dimethylaminopyridine and 47.6 mg of N- t -butoxycarbonylglycine dissolved in 5 ml of dichloromethane was added a solution of 61.6 mg of dicyclohexylcarbodiimide dissolved in 2 ml of dichloromethane. The mixture was stirred under nitrogen for 4 hr. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by flash chromatography on silica gel in hexane:ethyl acetate (3:1). The appropriate fractions were combined and evaporated to dryness under vacuum. The residue was crystallized from hexane, filtered and dried yielding 1⊘7.3 mg (75.2%) of product, mp 94-1⊘⊘°. EXAMPLE 6 7β-(N,N-Diethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1α,9α-dimethylformamide acetal To a mixture of 15⊘ mg of 8,13-epoxy-1α,6β,7β,9α-tetra-hydroxylabd-14-en-11-one dimethylformamide acetal, 59.4 mg of diethylglycine hydrochloride, 44.6 mg of 4-(N,N-dimethylamino)pyridine in 6 ml of dichloromethane was added 8⊘.5 mg of dicyclohexylcarbodiimide dissolved in 3 ml of dichloromethane. The mixture was stirred under nitrogen at ambient temperature overnight. The mixture was filtered and evaporated to dryness under vacuum. The residue was flash chromatographed in hexane:ethyl acetate (1:1). The appropriate fractions were combined and evaporated to dryness to yield 138.3 mg (72.8%) of product, mp 129-133°. EXAMPLE 7 7β-Acetoxy-1α-(t-butyldimethylsilyloxy)-6β,9α-dihydroxy-8,13-epoxylabd-14-en-11-one To a solution of 1.⊘⊘ g of 7β-aceotxy-8,13,epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in 5 ml of dimethylformamide was added, dropwise, 61⊘ ul of N-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide, and the reaction mixture was stirred for 1 hr. The mixture was allowed to stand at room temperature overnight, and was then diluted with 5 ml of one-half saturated brine and extracted with diethyl ether. The combined extracts were dried over anhydrous sodium sulfate, filtered and the filtrates were evaporated. The residue was flash chromatographed on a silica gel column using ethyl acetate-hexane (1:3) as the eluent. Evaporation of the appropriate fractions gave 1.24g (97.2%) of product. EXAMPLE 8 1α-(t-Butyldimethylsilyloxy)-8,13-epoxy-6β,7β,9α-trihydroxylabd-14-en-11-one A solution of 1.24 g of 7β-acetoxy-1α-(t-butyldimethylsilyloxy)-8,13-epoxy-6β,9α-dihydroxylabd-14-en-11-one, 4 ml of saturated potassium carbonate solution and 16 ml of methanol was heated at 8⊘° for 1 hr. The reaction mixture was cooled, diluted with saturated sodium chloride solution, and extracted with ether. The combined ether extracts were dried over anhydrous potassium carbonate, filtered, and the filtrate was evaporated. The residue was flash chromatographed on silica gel column using ethyl acetate-hexane (1:3) as the eluent. Evaporation of the appropriate fractions provided 646 mg (56.5%) of product. EXAMPLE 9 7β-(N,N-Dimethylaminoacetoxy)-8,13-epoxy-6β,9α-dihydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one hydrochloride 8,13-Epoxy-6β,7β,9α-trihydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one (1⊘⊘ mg) was dissolved in 4 ml of dichloromethane with 29.⊘ mg of dimethylglycine hydrochloride and 26.⊘ mg of 4-dimethylaminopyridine. To the above mixture was added 48 mg of N,N-dicyclohexylcarbodiimide dissolved in 1 ml of dichloromethane. The mixture was stirred at ambient temperature for 18 hr. The mixture was filtered through a cotton plug and the filtrate was evaporated to dryness. The residue was suspended in ether, filtered and evaporated to dryness. The residue was flash chromatographed on silica gel in hexane:ethyl acetate methanol (1⊘:1⊘:1). The appropriate fractions were combined and evaporated to dryness to provide 87.8 mg (74.7%) of product. The product was dissolved in ether and the hydrochloride precipitated, mp 227-228°. EXAMPLE 1⊘ 7β-(N,N-Diethylaminoacetoxy)-8,13-epoxy-6β,9α-dihydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one hydrochloride 8,13-Epoxy-6β,7β,9α-trihydroxy-1α-( t -butyldimethylsilyloxy)labd-14-en-11-one (5⊘ mg) was combined with 17.4 mg of N,N-diethylglycine hydrochloride and 13.1 mg of 4-(N,N-dimethyl amino)pyridine in 2 ml of dry dichloromethane. Dicylohexylcarbodiimide (24 mg) dissolved in 1 ml of dichloromethane was added to the above mixture in a sealed tube. The mixture was allowed to stand at ambient temperature overnight. The dicyclohexylurea was filtered off. After the filtrate was evaporated to dryness, the residue was suspended in ethyl acetate and filtered. The filtrate was flash chromatographed on silica gel in hexane:ethyl acetate (3:1). The appropriate fractions were combined and evaporated to dryness under vacuum. The residue was dissolved in ether, from which the product as the hydrochloride was precipitated, and yielded 32.7 mg of product, mp 2⊘⊘-21⊘°. EXAMPLE 11 7β-(N,N-Dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxy-labd-14-en-11-one hydrochloride 7β-(N,N-Dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one dimethylformamide acetal (1⊘3.1 mg) was dissolved in a mixture of 1.4 ml of methanol and 1.4 ml of 8⊘% acetic acid. The mixture was stirred at ambient temperature for 3 days after which it was evaporated to dryness. The residue was dissolved in ether and extracted several times with 5% sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was flash chromatographed on silica gel packed in hexane:ethyl acetate:methanone (1⊘:1⊘:1). The appropriate fractions evaporated to dryness. The residue was dissolved in ether and treated with ethereal hydrogen chloride to afford 28 mg (3⊘.5%) of product, mp 255-26⊘° (dec). EXAMPLE 12 7β-(N,N-Diethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one hydrochloride 7β-(N,N-diethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1,9-dimethylformamide acetal (84.1 mg) was dissolved in 2 ml of a mixture of methanol:acetic acid:water (1⊘:8:2) and allowed to stand overnight under nitrogen at ambient temperature. The mixture was basified with saturated aqueous sodium bicarbonate solution. The product was extracted into dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in ether and treated with ethereal hydrogen chloride. The ether suspension was evaporated and the residue was resuspended in ether. The solid was filtered and dried under vacuum at 8⊘° for 1 hr to yield 42.2 mg (52.⊘%) of product, mp 149-156° (dec). EXAMPLE 13 7β-(Methoxyacetoxy)8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (1⊘⊘ mg) was dissolved in 5 ml of dichloromethane together with 34.2 mg of 4-dimethylaminopyridine and 24.5 mg of methoxyacetic acid. To the above solution was added 61.7 mg of dicyclohexylcarbodiimide dissolved in 2 ml of dichloromethane, and the mixture was stirred overnight under an atmosphere of nitrogen. The mixture was filtered, evaporated to dryness and loaded onto a flash silica gel column packed in dichloromethane:methanol (1⊘:⊘.2). The appropriate fractions were combined and evaporated to dryness. Trituration of the residue with hexane provided 49.5 mg (41.4%) of product, mp 164-17⊘°. EXAMPLE 14 7β-[2-(N-t-Butoxycarbonyl)aminopropanoyloxy]-8,13-epoxy-1α,6β, 9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (1⊘⊘ mg) was stirred with 34.2 mg of 4-dimethylaminopyridine and 51.4 mg of N-t-butoxycarbonyl-L-alanine in 5 ml of dichloromethane. Dicyclohexylcarbodiimide (61.7 mg) dissolved in 2 ml of dichloromethane was added to the mixture and was allowed to stand overnight under nitrogen at ambient temperature. The mixture was diluted with ether, filtered and evaporated to dryness. The residue was flash chromatographed on silica gel packed in hexane:ethyl acetate (3:1). The appropriate fractions were combined and evaporated to dryness. Trituration of the residue with hexane provided 74.1 mg (5⊘.6%) of product, mp 117-122° (dec). EXAMPLE 15 7β-(N-Acetylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-one (1⊘⊘ mg) was stirred with 34.2 mg of 4-dimethylaminopyridine and 31.8 mg of N-acetylglycine in 5 ml of dichloromethane. Dicyclohexylcarbodiimide (61.7 mg) dissolved in 2 ml of dichloromethane was added to the solution and the resultant mixture was stirred under nitrogen at ambient temperature overnight. The mixture was filtered and evaporated to dryness. The residue was flash chromatographed on silica gel packed in hexane:ethyl acetate (1:1). The appropriate fractions were combined and evaporated to dryness. The residue was triturated with cyclohexane affording 26.6 mg (21.⊘%) of product, mp 1⊘6-11⊘°. EXAMPLE 16 7β-(4-Morpholinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one hydrochloride hydrate 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (1⊘⊘ mg) was dissolved in 5 ml of dichloromethane and stirred with 34.2 mg of 4-N,N-dimethylaminopyridine and 49.3 mg of (4-morpholino)acetic acid hydrochloride. Dicyclohexyl carbodiimide (61.7 mg) in 2 ml of dichloromethane was added to the mixture and was stirred under nitrogen overnight at ambient temperature. The mixture was diluted with ether and filtered. The filtrate was evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate (1:1) and eluted with hexane:ethyl acetate:methanol (1⊘:1⊘:1). The appropriate fractions were combined and evaporated. The residue was dissolved in ether and treated with ethereal hydrogen chloride to yield 55.5 mg (38.4%) of product, mp 165-175° (dec). EXAMPLE 17 7β-[N-(2-Nitrophenylsulfenyl)aminoacetoxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-trihydroxylabd-14-en-11-one (325 mg), 361.7 mg of N-(2-nitrophenylsulfenyl)glycine dicyclohexylammonium salt and 14⊘ mg of 4-N,N-dimethylaminopyridine hydrochloride were suspended in 25 ml of dichloromethane. After dissolution occurred, a solution of 273.3 mg of dicyclohexycarbodiimide in 5 ml of dichloromethane was added. The mixture was allowed to stand at ambient temperature overnight. The mixture was filtered and the filtrate was evaporated to dryness. The residue was flash chromatographed on silica gel in dichloromethane:methanol (1⊘:⊘.2). The appropriate fractions were combined and evaporated to dryness. The residue was crystallized from hexane:ether yielding, in two crops, 153.5 mg (3⊘.1%) of product, mp 1⊘4° (dec). EXAMPLE 18 8,13-Epoxy-9α-hydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one 6β,7β-sulfite 8,13-Epoxy -6β,7β,9α-trihydroxy-1α-(t-butyldimethylsilyloxy)labd-14-en-11-one (2⊘⊘ mg) was dissolved in 2.⊘ ml of pyridine together with 2⊘⊘ ml of thionyl chloride at 5°. After ⊘.5 hr, the mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate filtered and evaporated to dryness under vacuum. The residue was flash chromatographed (silica gel; hexane:ethyl acetate (3:1)). The appropriate fractions were combined and evaporated to dryness to give 122.2 mg of product, mp 1⊘7-1⊘9°. EXAMPLE 19 8,13-Epoxy-1α,9α-dihydroxylabd-14-en-11-one 6β,7β-sulfite 8,13-Epoxy-9α-hydroxy-1α(t-butyldimethylsilyloxy)-labd-14-en-11-one 6β,7β-sulfite (487.5 mg) was dissolved in 25 ml of acetonitrile and 4⊘% aqueous hydrofluoric acid (95:5) and stirred at ambient temperature for six hrs. The mixture was basified with saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous phase was extracted with ethyl acetate which was then combined with the organic phase. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was flash chromatographed on silica gel in hexane:ethyl acetate (3:1). The appropriate fractions were combined and evaporated to dryness to provide 208.7 mg (54.6%) of product, mp 186-193° (dec). EXAMPLE 2⊘ 8,13-Epoxy-1α,6β,9α-trihydroxy-7β-[2-(2-nitrophenylsulfenylamino) propionyloxy] labd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one was dissolved in 5⊘ ml of dry dichloromethane along with 863 mg of 2-(2-nitrophenylsulfenylamino)propionic acid, dicyclohexylammonium salt, 323 mg of 4-dimethylaminopyridine hydrochloride and 547 mg of dicyclohexylcarbodiimide. The mixture was stirred at ambient temperature under nitrogen overnight, after which it was diluted with ether and filtered. The filtrate was evaporated and the residue was dissolved in dichloromethane and flash chromatographed on silica gel packed with dichloromethane:methanol (1⊘:⊘.2). The appropriate fractions were combined and evaporated. The residue was crystallized from hexane:ether to give 627.6 mg (53%) of product, mp 2⊘9-216°. EXAMPLE 21 8,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-tetrahydrofuranoyloxy)-labd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (5⊘⊘ mg) was dissolved in 5⊘ ml of dry dichloromethane along with 157.6 mg of 2-tetrahydrofuroic acid, 174 mg of 4-dimethylaminopyridine and 42⊘ mg of dicyclohexylcarbodiimide. The mixture was stirred at ambient temperature under nitrogen overnight. The mixture was diluted with an equal volume of ether and was filtered. The filtrate was evaporated and the residue was flash chromatographed on silica gel in dichloromethane:methanol (1⊘:⊘.2). The appropriate fractions were combined, evaporated, and the residue was crystallized from cyclohexane to give 18⊘.5 mg (28.4%) of product, mp 162-165°. EXAMPLE 22 7β-(1-Piperidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxy and 14-en-11-one-1,9-dimethylformamide acetal 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-1,9-dimethylformamide acetal (75⊘ mg) was dissolved in 5⊘ ml of dichloromethane with 318.3 mg of 2-(1-piperidino)acetic acid hydrochloride, 228 mg of 4-dimethylaminopyridine and 4⊘2 mg of dicyclohexylcarbodiimide. The mixture was stirred for 36 hrs at ambient temperature under nitrogen, diluted with an equal volume of ether and filtered. The filtrate was evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate (1:1), after which the appropriate fractions were combined and evaporated. The residue was crystallized from hexane to give 286.5 mg (29.6%) of product, mp 15⊘-155° (dec). EXAMPLE 23 7β-(N,N-Dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 1,9-dimethylformamide acetal 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one dimethylformamide acetal (75⊘ mg) was dissolved in 5⊘ ml of dichloromethane and stirred at ambient temperature overnight, under nitrogen, along with N,N-dimethylglycine hydrochloride (247.5 mg), 4-dimethylaminopyridine (227.5 mg) and dicyclohexylcarbodiimide (4⊘2.4 mg). The mixture was diluted with an equal volume of ether, filtered and evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate:methanol (1⊘:2:1). The appropriate fractions were combined and evaporated. The resultant oil was dried under vacuum at 2⊘° to give 8⊘⊘ mg (89.⊘%) of product, mp 55-6⊘°. EXAMPLE 24 7β-(1-Piperidionacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one hydrochloride hemietherate 7β-(1-Piperidinoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamide acetal (259.5 mg) was dissolved in 5 ml of methanol and 5 ml of 8⊘% acetic acid. The mixture was stirred under nitrogen at ambient temperature overnight, evaporated, diluted with water, neutralized with sodium bicarbonate solution, and extracted with ether. The ether extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in anhydrous ether, from which the hydrochloride salt was precipitated by addition of etheral hydrogen chloride. The precipitate was filtered, washed with anhydrous ether and dried under vacuum at 11⊘° for 1 hr to afford 168.2 mg (62.6%) of product, mp 19⊘-194°. EXAMPLE 25 1α-(N-t-Butylaminoacetoxy)-6β,9α-dihydroxy-8,13-epoxy-7β-tetrahydrofurano-2-yloxy)-ladb-14-en-11-one hydrochloride hydrate 8,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-tetrahydrofuranoyloxy)-labd-14-en-11-one (2⊘⊘ mg) was dissolved in dry dichloromethane (2 ml) along with dimethylaniline (58.71 µl) with cooling to 5°. A solution of bromoacetyl bromide (49.1 µl) in dry dichloromethane (2 ml) was added dropwise over ⊘.5 hr to the solution. After 1 hr at 5°, the mixture was allowed to warm to ambient temperature and poured onto a mixture of ice and saturated aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate and the organic extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in dry dichloromethane (1 ml) and stirred under nitrogen. A solution of t-butylamine (91.2 µl) in ethyl acetate (2 ml) was added. The mixture was stirred at ambient temperature overnight, diluted with dichloromethane (1⊘ ml) and washed with water followed by saturated aqueous sodium bicarbonate solution. The dichloromethane layer was evaporated and the residue was flash chromatographed on silica gel in hexane:ethyl acetate:methanol (1⊘:1⊘:⊘.⊘1). The appropriate fractions were combined and evaporated. The residue was dissolved in anhydrous ether and treated with ethereal hydrogen chloride. The precipitate was filtered, washed with ether and dried under vacuum to give 1.22 mg (44.8%) of product, mp 165-17⊘°. EXAMPLE 26 6β,9α-Dihydroxy-8,13-epoxy-1α-(N-2-propylaminoacetoxy)-7β-tetrahydrofurano-2 yloxy)labd-14-en-11-one hydrochloride hydrate 8,13-Epoxy-7β-(2-tetrahydrofuranoyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one (4⊘⊘ mg) was combined with N,N-dimethylaniline (117.4 µl) in dry dichloromethane (4 ml at 5°C under nitrogen. A solution of bromoacetyl bromide (98.2 µl) in dry dichloromethane (4 ml) was added and the mixture was stirred at that temperature for 2 hr. The mixture was allowed to warm to ambient temperature and was quenched with ice/water. The mixture was extracted into ethyl acetate and the organic phase washed with dilute aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated. The residue gas dissolved in dry dichloromethane (2 ml). One ml of the resultant mixture was added to a solution of 2-propylamine (146.2 µl) in ethyl acetate (1 ml). The mixture was stirred under nitrogen at ambient temperature overnight. The mixture was washed with 1 ml of saturated aqueous sodium bicarbonate solution, the layers were separated, and the phase was flash chromatographed on silica/gel in hexane:ethyl acetate:methanol (1⊘:1⊘:⊘.1). The appropriate fractions were combined and evaporated. The residue was dissolved in anhydrous ether and treated with ethereal hydrogen chloride to provide 1⊘⊘ mg (37.5%) of product, mp 144-155°. EXAMPLE 27 6β,9α-Dihydroxy-8,13-epoxy-1α-(4-morpholinoacetoxy)-7β-(2-tetrahydrofurano-2-yloxy) labd-14-en-11-one hydrochloride hemihydrate 8,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-tetrahydrofuranoyloxy)labd-14-en-11-one (4⊘⊘ mg) was combined with N,N-dimethylaniline (117.4 µl) in dry dichloromethane (4 ml) at 5° under nitrogen. A solution of bromoacetyl bromide (98.2 µl) in dry dichloromethane (4 ml) was added and the mixture was stirred at 5° for 2 hr. The mixture was allowed to warm to ambient temperature, quenched with ice/water, and extracted into ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in dry dichloromethane (2 ml). One ml of the resultant mixture was added to a solution of morpholine (149.8 µl) in ethyl acetate (1 ml). The mixture was stirred under nitrogen at ambient temperature overnight. The mixture was extracted with saturated aqueous sodium bicarbonate solution (1 ml). The organic phase was flash chromatographed on silica gel in hexane:ethyl acetate (1:1). The appropriate fractions were combined and evaporated. The residue was dissolved in anhydrous ether and treated with ethereal hydrogen chloride to provide 11⊘ mg (4⊘.1%) of product, mp 15⊘-154°. EXAMPLE 28 8,13-Epoxy-7β-(2-methyltetrahydrofurano-2-yloxy)-1α,6β,9α-trihydroxy-labd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetahydroxylabd-14-en-11-one (5⊘⊘ mg) was combined with 4-dimethylaminopyridine (174.3 mg), 2-methyl-2-tetrahydofuroic acid (179.2 mg) and dicyclohexylcarbodiimide (3⊘8.3 mg) in of dichloromethane (5⊘ ml). The mixture was stirred at ambient temperature overnight under nitrogen. The mixture was diluted with an equal volume of ether, filtered and evaporated. The residue was flash chromatographed on silica gel in dichloromethane:methanol (1⊘;⊘.4). The appropriate fractions were combined, evaporated and the residue was crystallized from cyclohexane:ether to yield 354.6 mg (52.8%) of product, mp 154-164°. EXAMPLE 29 1α-(N-t-Butylaminoacetoxy)-6β,9α-dihydroxy-8,13-epoxy-7β-(2-methyltetrahydrofurano-2-yloxy)labd-14-en-11-one hydrochloride hydrate 8,13-Epoxy-1α,6β,9α-trihydroxy-7β-(2-methyltetrahydrofurano-2-yloxy) labd-14-en-11-one (164.⊘ mg) was dissolved in dichloromethane (2 ml) with N,N-dimethylaniline (44.3 mg) at ⊘°. A solution of bromoacetyl bromide (83.4 mg) in dichloromethane (2 ml) was added dropwise over 15 min. The mixture was stirred for 2 hr with gradual warming to room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane (1 ml) and stirred with a solution of t -butyl amine (1⊘⊘ mg) in ethyl acetate (2 ml) under nitrogen. The mixture was stirred at ambient temperature overnight, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated and evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate:methanol (1⊘:1⊘:⊘.1). The appropriate fractions were combined and evaporated. The residue was dissolved in anhydrous ether and created with ethereal hydrogen chloride to afford 65 mg (29.3%] of product, mp 156-161°. EXAMPLE 3⊘ 7β-(2,2-Dimethyl-1,3-dioxolano-4-yloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (5⊘⊘ mg) was dissolved in dichloromethane (5⊘ ml) and stirred with 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid potassium salt (25⊘ mg), 4-dimethylaminopyridine hydrochloride (215.6 mg) and dicyclohexylcarbodiimide (294.3 mg) overnight, at ambient temperture under nitrogen. The mixture was diluted with an equal volume of ether and filtered. The filtrate was evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate (3:1). The appropriate fractions were combined and evaporated to afford 35⊘.⊘ mg (5⊘.5%) of product, mp 1⊘⊘° (softening). EXAMPLE 31 7β-(2,3-Dihydroxypropionyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-7β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one (2⊘4 mg) was dissolved in a mixture of 8⊘% acetic acid (2 ml) and methanol (⊘.4 ml), under nitrogen, and the mixture was stirred at ambient temperature for 3 days. The mixture was evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate:methanol (1⊘:1⊘:⊘.⊘1). The appropriate fractions were combined and evaporated. The residue was crystallized from cyclohexane:ether to afford 85.⊘ mg (45.3%) of product, mp 162-178°. EXAMPLE 32 1α-(N-t-butylaminoacetoxy)-6β,9α-dihydroxy-7β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-8,11-expoxylabd-14-en-11-one 7β-(2,2-Dimethyl-1,3-dioxolano-4-yloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one (5⊘⊘ mg) was dissolved in dry dichloromethane (6 ml with N,N-dimethylaniline (137.6 µl) under nitrogen. The mixture was cooled to 5°. Bromoacetyl bromide (105.6 µl) dissolved in dry dichloromethane (6 ml) was added to the stirred solution and the mixture was allowed to stand for 2 hr with gradual warming to ambient temperature. The mixture was partitioned between ether and water. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dissolved in dichloromethane (5 ml) and stirred under nitrogen with t -butylamine (214.3 ml) dissolved in 1⊘ ml of ethyl acetate. The mixture was allowed to stand at ambient temperature overnight. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate:methanol (1⊘:1⊘:⊘.1). The appropriate fractions were combined and evaporated. The residue was dissolved in ether and treated with ethereal hydrogenchloride to afford 3⊘3.1 mg (45.2%) of product, mp 17⊘-176° (dec). EXAMPLE 33 8,11-Epoxy-7β-(pyroglytamoyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one 8,11-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (5⊘⊘ mg) was dissolved in dichloromethane (5⊘ ml) and stirred together with pyroglutamic acid (175.3 mg), 4-dimethylaminopyridine (174.3 mg) and dicyclohexylcarbodiimide (3⊘8.3 mg) overnight at ambient temperature, under nitrogen. The mixture was diluted with an equal volume of ether and filtered. The filtrate was evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate:methanol (1⊘:1⊘:1). The appropriate fractions were combined and evaporated. The residue was dissolved in ether and precipitated with hexane to afford 266.9 mg (41.⊘%) of product, mp 15⊘-16⊘°. EXAMPLE 34 8,13-Epoxy-7β-[N-(2-nitrophenylsulfenyl)prolyloxyl-1α,6β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-1α,6β,7β,9α-tetrahydrolabd-14-en-11-one (75⊘ mg) was combined with 4-(N,N-dimethylamino)pyridine hydrochloride (323 mg), N-(2-nitrophenylsulfenyl)proline dicyclohexyl ammonium salt (917.2 mg) end dicyclohexylcarbodiimide (5⊘5.⊘ mg) in dichloromethane (5⊘ ml). The mixture was stirred at ambient temperature under nitrogen overnight. The mixture was diluted with an equal volume of ether, filtered and evaporated. The residue was flash chromatographed on silica gel in dichloromethane:methanol (1⊘:⊘.2). The appropriate fractions were combined and evaporated to dryness. The residue was crystallized from hexane:ether to afford 88⊘.3 mg of product, mp 125-129°. EXAMPLE 35 8,13-Epoxy-7β-prolyloxylabd-14-en-11-one 8,13-Epoxy-7β-[N-(2-nitrophenylsulfenyl)prolyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one (48⊘ mg) was dissolved in ether (2⊘ ml). Saturated ethereal hydrogen chloride (2 ml) was added and the mixture was stirred for 15 min. The precipitate was filtered, washed with ether and dried at 8⊘° to yield 125 mg (31.⊘%) of product, mp 18⊘-195°. EXAMPLE 36 8,13-Epoxy-6-(tetrahydrofurano-2-yloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-7β-(tetrahydrofurano-2-yloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one (2⊘⊘ mg) was dissolved in dry tetrahydrofuran (5 ml) and maintained at 78°. Lithium bis(dimethylsilyl)amide (492.2 µl, 1M in tetrahydrofuran) was added and the mixture was warmed to ⊘°. The mixture was stirred for 3 hr after which additional lithium bis (trimethylsilyl)amide (2⊘⊘ µl, 1 M in tetrahydrofuran) was added. After a total time of 6 hr, (the reaction was flash chromatographed on silica gel in hexane:ethyl acetate:methanol (2:1:⊘.⊘1) to afford 68.⊘ mg (34.⊘%) of product, mp 1⊘⊘-115°. EXAMPLE 37 1α-(N-t-Butylaminoacetoxy)-7β,9α-dihydroxy-8,13-epoxy-6β-(tetrahydrofurano-2-yloxylabd)-14-en-11-one To a stirred solution of 8,13-epoxy-6β-(tetrahydrofurano-2-yloxy]-1α,7β,9α-trihydroxylabd-14-en-11-one (3⊘⊘ mg) in dry dichloromethane (3 ml) containing N,N-dimethylaniline (⊘.11 ml) in an ice bath, under nitrogen, was added dropwise a solution of bromoacetyl bromide (⊘.⊘75 ml) in dichloromethane (6 ml). The solution was stirred at ⊘° for 1 hr. The solution was poured into ice/water/ethyl acetate, extracted with ethyl acetate, washed with cold sodium bicarbonate solution, water and dried over anhydrous sodium sulfate Filtration followed by evaporation of solvent provided an oil which was dissolved in dichloromethane (3 ml) and added to a solution of t -butylamine (⊘.3 g) in ethyl acetate (3 ml). The mixture was stirred overnight, poured into ice/water/ethyl acetate. The layers were separated and the organic pahe was washed twice with water, saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration followed by evaporation of solvent provided an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride to provide 169 mg (41.4%] of product, mp 165-176°. EXAMPLE 38 8,13-Epoxy-6-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-1-7β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one (1.4 g) was dissolved in dry tetrahydrofuran (3⊘ ml) under nitrogen and cooled to 5°. Lithium bis(trimethylsilyl)amide (2.82 ml, 1 M in tetrahydrofuran) was added, with stirring. The mixture was allowed to stand for 2 hr at 5°C. The product was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in hexane:ethylacetate (3:1) and flash chromatographed on silica gel eluting with 8⊘⊘ ml of hexane:ethyl acetate (3:1) followed by 9⊘⊘ ml of hexane:ethyl acetate (2:1). The appropriate fractions were combined and evaporated. The residue was crystallized from hexane:ethyl acetate to provide 47⊘ mg (33.6%) of product, mp 11⊘-12⊘°. EXAMPLE 39 8,13-Epoxy-6-(2,3-dihydroxypropionyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-6β-(2,2-dimethyl-1,3-dioxolano-4-yloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one (399 mg) was dissolved in 8⊘% acetic acid (4.5 ml) and stirred with methanol (4.5 ml) at 5⊘° for 2 days, under nitrogen. The solvent was evaporated and the residue was partitioned between chloroform and saturated sodium bicarbonate solution. The chloroform extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was flash chromatographed on silica gel in dichloromethane:methanol (19:1). The appropriate fractions were combined, evaporated and the residue was dried under vacuum at 1⊘⊘° overnight to afford 91 mg (25.3%) of product, mp 225-235°. EXAMPLE 40 8,13-Epoxy-1α,6β,7β,9α-labd-14-en-11-one-6,7-carbonate 1,9-dimethylformamide acetal 8,13-Epoxy-1α,6β,7β,9α-labd-14-en-11-one 1,9-dimethylformamide acetal (1.⊘59 g) was heated under reflux in toluene (25 ml) containing N,N'-carbonyldiimidazole (⊘.5⊘ g) and triethylamine (⊘.55 ml). After 3 hr, the reaction mixture was evaporated and the residue was applied directly to a flash chromatograph. Elution with 5⊘% ethyl acetate-hexane gave ⊘.976 g (87%) of product after combination of the appropriate fractions. The analytical sample obtained by recrystallization from hexane had mp 138-14⊘°. EXAMPLE 41 8,13-Epoxy-6β-methoxyacetoxy-1α,7β,9α-labd-14-en-11-one To a stirred solution of ⊘.317 g of 8,l3-epoxy-7β-methoxyacetoxy-1α,6β,9α-labd-14-en-11-one in tetrahydrofuran (75 ml) was added 1 M lithium bis(trimethylsilyl)amide in hexanes (1.36 ml) in an ice bath. The solution was stirred 1 hr at ⊘°, poured into ice/water and extracted with ethyl acetete. The organic extracts were washed three times with water, once with saturated sodium, chloride solution and dried over anhydrous sodium sulfate. Filtration followed by evaporation of solvent provided an oil. The oil was dissolved in a minimum volume of 35% ethyl acetate/hexane and flush chromatographed on 2⊘⊘ g of silica gel. Evaporation of solvent from the appropriate fractions provided ⊘.147 g (46.4%) of product, mp 164-165°. EXAMPLE 42 7β-(1,2:3,4-Diisopropylidine-D-galacturonoyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one 8,13-Epoxy-(1α,6β,7β,9α-trihydroxylabd-14-en-11-one (5⊘⊘ mg), 1,2:3,4-diisopropylidine galacturonic acid (41⊘ mg), 4-dimethylaminopyridine (18⊘ mg) and dicyclohexylcarbodiimide (35 mg) were dissolved in dichloromethane (5⊘ ml) and stirred under nitrogen at ambient temperature overnight. The mixture was filtered and evaporated. The residue was triturated with ethyl acetate and filtered. The filtrate was evaporated and the residue was flash chromatographed on silica gel in dichloromethane:methanol (98:2). The appropriate fractions were combined and evaporated. The residue was crystallized from hexane:ether to afford 2⊘9 mg (24.6%) of product, mp 229-233°. EXAMPLE 43 7β-[3-Dimethylphosphinyl)propionyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one A solution of 8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one (6⊘⊘ mg), 2-carboxyethyldimethylphosphine oxide (3⊘⊘ mg), dimethylaminopyridine (2⊘ mg), dicyclohexylcarbodiimide (44⊘ mg) and dichloromethane (6⊘ ml) was stirred at room temperature for 16 hrs. The suspension was filtered and flash chromatographed (without being concentrated) on silica gel (eluent: 4% methanol/dichloromethane). Concentration of the appropriate fractions provided ⊘.559 g (68.7%) of product, mp 252-259°.

Claims: A compound of the formula wherein: (a) R₁ is hydrogen, a group of the formula R₂CO wherein R₂ is hydrogen or C₁-C₆-alkyl, or a group of the formula. R₃R₄R₅Si wherein R₃, R₄ and R₅ are each independently C₁-C₆-alkyl; (b) R₆ and R₇ are each independently hydrogen, a group of the formula R₈CO wherein R₈ is C₁-C₆-alkyl, CH₃CHOH, HOCH₂CHOH, a group of the formula R 1⊘ O(CH₂)n wherein R 1⊘ is hydrogen or C₁-C₆-alkyl and n is 1, 2 or 3, or R₈ is a group of the formula R₁₁R₁₂NCHR₁₃ wherein R₁₁ is hydrogen, C₁-C₆-alkyl , a group of the formula a group of the formula or a group of the formula R₁₄CO wherein R₁₄ is hydrogen or C₁-C₆-alkyl; R₁₂ is hydrogen or C₁-C₆-alkyl; R₁₃ is hydrogen, C₁-C₆-alkyl, benzyl or a group of the formula CH₂OH or R₁₁ and R₁₂ taken together with the nitrogen atom to which they are attached form a group of the formula wherein X is CHR₁₅ wherein R₁₅ is hydrogen, C₁-C₆-alkyl or a group of the formula OR₁₆ wherein R₁₆ is hydrogen, C₁-C₆-alkyl or a group of the formula COR₁₇ wherein R₁₇ is C₁-C₆-alkyl, and m is 0 or 1 or X is a group of the formula NR₁₈ wherein R₁₈ is C₁-C₆-alkyl or R₆ and R₇ taken together form a group of the formula CO or a group of the formula SO; (c) R₉ is hydrogen; or (d) R₁ and R₉ taken together form a group of the formula CO, a group of the formula SO or a group of the formula CHNR₁₉R₂₀ wherein R₁₉ and R₂₀ are each independently C₁-C₆-alkyl or R₁₉ and R₂₀ taken together with the nitrogen atom to which they are attached form a group of the formula wherein X and m are as hereinbeforedescribed; with the provisos: (e) that R₆ is not hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆alkyl, when R₇ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl, R₁ is hydrogen, R₂CO or R₃R₄R₅Si wherein R₃, R₄ and R₅ are as above, and R₉ is hydrogen; (f) that R₁ is not hydrogen or R₂CO,when R₉ is hydrogen and R₆ and R₇ taken together are CO; (g) that R₁ and R₉ taken together are not CO or SO, when R₆ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl, and R₇ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl; or when R₆ and R₇ taken together are CO or SO; the optical and geometric isomers thereof, or a pharmaceutically acceptable acid addition salt thereof. A compound according to claim 1 wherein R₁ and R₉ are hydrogen and R₆ is a group of the formula R₈CO wherein R₈ is a group of the formula R₁₁ , R₁₂NCHR₁₃ wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedescribed. A compound according to claim 1 wherein R₁ and R₉ are hydrogen and R₇ is a group of the formula R₈CO wherein R₈ is a group of the formula R₁₁R₁₂NCHR₁₃ wherein R₁₁, R₁₂ and R₁₃ are as hereinbeforedescribed. A compound according to claim 1 wherein R₁ and R₉ are hydrogen and R₆ is R₈CO wherein R₈ is a group of the formula CH₃CHOH, HOCH₂CHOH, group of the formula R 1⊘ O(CH₂) n wherein R 1⊘ is hydrogen or C₁-C₆-alkyl and n is 1, 2 or 3. A compound according to claim 1 wherein R₁ and R₉ are hydrogen and R₇ is a group of the formula R₈CO wherein R₈ is a group of the formula CH₃CHOH, HOCH₂CHOH, or a group of the formula R 1⊘ O(CH₂) n wherein R 1⊘ is hydrogen or C₁-C₆-alkyl and n is 1, 2 or 3. A compound according to claim 1 wherein R₁ and R₉ taken together form a group of the formula CHNR₁₉R 2⊘ wherein R₁₉ and R 2⊘ are as hereinbeforedefined. The compound of claim 3 which is 7β-[N,N-diethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamide acetal. The compound of claim 3 which is 7β-(N,N-dimethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one. The compound of claim 3 which is 7β-(N,N-diethylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one. The compound of claim 3 which is 7β-[2-(N-t-butoxycarbonyl)aminopropanoyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-one. The compound of claim 3 which is 7β-(N-acetylaminoacetoxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one. A compound of claim 4 which is 8,13-epoxy-1α,6β,9α-trihydroxy-7β-(2-tetrahydrofuranoyloxy)labd-14-en-11-one. A pharmaceutical composition which comprises as active ingredient a compound as defined in claim 1 in association with a pharmaceutically acceptable carrier. Use of a compound as defined in claim 1 for the preparation of a medicament useful in the treatment of elevated intraocular pressure. A process for the preparation of a compound of the formula 1 wherein: (a) R₁ is hydrogen, a group of the formula R₂CO wherein R₂ is hydrogen or C₁-C₆-alkyl, or a group of the formula R₃R₄R₅Si wherein R₃, R₄ and R₅ are each independently C₁-C₆-alkyl; (b) R₆ and R₇ are each independently hydrogen, a group of the formula R₈CO wherein R8 is C₁-C₆-alkyl, a group of the formula R 1⊘ O(CH₂) n wherein R 1⊘ is hydrogen orC₁-C₆-alkyl and n is 1, 2 or 3,or R₈ is a group of the formula R₁₁R₁₂NCHR₁₃ wherein R₁₁ is hydrogen, C₁-C₆-alkyl, a group of the formula a group of the formula or a group of the formula R₁₄CO wherein R₁₄ is hydrogen or C₁-C₆-alkyl; R₁₂ is hydrogen or C₁-C₆-alkyl; R₁₃ is hydrogen, C₁-C₆-alkyl, benzyl or a group of the formula CH₂OH, or R₁₁ and R₁₂ taken together with the nitrogen atom to which they are attached form a group of the formula wherein X is CHR₁₅ wherein R₁₅ is hydrogen, C₁-C₆-alkyl or a group of the formula OR₁₆ wherein R₁₆ is hydrogen, C₁-C₆-alkyl or a group of the formula COR₁₇ wherein R₁₇ is c₁-c₆-alkyl, and m is ⊘ or 1, or X is a group of the formula NR₁₈ wherein R₁₈ is C₁-C₆-alkyl, or R₆ and R₇ taken together form a group of the formula CO or a group of the formula so; (c) R₉ is hydrogen; (d) R₁ and R₉ taken together form a group of the formula CO, a group of the formula SO or a group of the formula CHNR₁₉R 2⊘ wherein R₁₉ and R 2⊘ are each independently C₁-C₆-alkyl; and R₁₉ and R 2⊘ taken together with the nitrogen atom to which they are attached form a group of the formula wherein X and m are as hereinbeforedescribed; with the provisos: (e) that R₆ is not hydrogen or R₈CO wherein R₈ is hydrogen. or C₁-C₆-alkyl when R₇ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl, R₁ is hydrogen, R₂CO or R₃R₄R₅Si wherein R₃, R₄ and R₅ are as above, and R₉ is hydrogen; (f) that R₁ is not hydrogen or R₂CO when R₉ is hydrogen and R₆ and R₇ taken together are CO; (g) that R₁ and R₉ taken together are not CO or SO when R₆ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl; and R₇ is hydrogen or R₈CO wherein R₈ is hydrogen or C₁-C₆-alkyl; or when R₆ and R₇ taken together are CO or SO; the optical and geometric isomers thereof, or a pharmaceutically acceptable acid addition salt thereof which comprises (a) condensing a compound of the formula 2 wherein R₇ is C₁-C₆-alkanoyl, with a formamid dialkylacetal of formula 10 wherein R₂₁ is C₁-C₆-alkyl and R₁₉ and R₂₀ are each independently C₁-C₆-alkyl, to provide a compound of the invention of the formula 3 wherein R₇, R₁₉ and R₂₀ are as hereinbefore defined, (b) optionally rearranging a compound of the formula 3 to obtain a compound of the invention of the formula 4 wherein R₆ is C₁-C₆-alkanoyl and R₁₉ and R₂₀ are independently C₁-C₆-alkyl, (c) optionally hydrolyzing a compound of the formula 3 or 4 to provide a compound of the invention of the formula 5 wherein R₁₉ and R₂₀ are independently C₁-C₆-alkyl, (d) optionally treating a compound of the formula 5 with a compound of the formula Hal-Z-Hal, wherein Hal is bromo or chloro and Z is SO or CO to provide a compound of the invention of the formula 7 wherein Z is SO or CO and R₁₉ and R₂₀ are independently C₁-C₆-alkyl, (e) optionally esterifying a compound of the formula 5 with an aminoacid of formula 12 wherein R₁₁, R₁₂ and R₁₃ are as defined above, to provide a comp ound of the invention of the formula 6 wherein R₁₉ and R₂₀ are independently C₁-C₆-alkyl, R₁₁ is hydrogen, C₁-C₆-alkyl, a group of the formula a group of the formula or a group of the formula R₁₄CO wherein R₁₄ is hydrogen or C₁-C₆-alkyl; R₁₂ is hydrogen or C₁-C₆-alkyl; R₁₃ is hydrogen, C₁-C₆-alkyl, benzyl or a group of the formula CH₂OH; R₁₁ and R₁₂ taken together with the nitrogen atom to which they are attached form a group of the formula wherein X is CHR₁₅ wherein R₁₅ is hydrogen, C₁-C₆-alkyl or a group of the formula OR₁₆ wherein R₁₆ is hydrogen, C₁-C₆-alkyl or a group of the formula COR₁₇ wherein R₁₇ is C₁-C₆-alkyl and m is ⊘ or 1; x is a group of the formula NR₁₈ wherein R₁₈ is C₁-C₆-alkyl, (f) optionally hydrolyzing a compound of the formula 6 or esterifying a compound of the formula 8 with a compound of the formula 12 wherein R₁₁, R₁₂ and R₁₃ are as hereinbefore defined, in a way described in step e) above to provide a compound of the invention of the formula 9 (g) optionally treating a compound of the formula 2 with a N-(trialkylsilyl)-N-alkyltrifluoroacetamide of formula 16 wherein R₃, R₄ and R₅ are as defined above and R₂₃ is alkyl, to provide a compound of the invention of the formula 13 wherein R₇ is C₁-C₆-alkanoyl, and R₃, R₄ and R₅ are each independently C₁-C₆-alkyl, (h) optionally hydrolyzing a compound of the formula 13 to provide a compound of the invention 14 wherein R₃, R₄ and R₅ are each independently C₁-C₆-alkyl, (j) optionally treating a compound of the formula 14 with an aminoacid of the formula to provide a compound of the invention of the formula 15 wherein R₃, R₄, R₅, R₁₁, R₁₂ and R₁₃ are as defined abov e, or (k) optionally treating a compound of the formula 14 with a compound of the formula Hal-Z-Hal, wherein Hal is bromo or chloro and Z is SO or CO to provide a compound of the invention of the formula 16 wherein R₃, R₄, R₅ and Z are as defined above, (l) optionally removing the silyl group in a compound of the formula 16 by treating it with aqueous hydrogen fluoride to provide a compound of the invention of the formula 17 wherein Z is as defined above, and (m) optionally removing the silyl group in a compound of the formula 15 to provide a compound of the invention of the formula 9 wherein R₁₁, R₁₂ and R₁₃ are as defined above.

Inventors: CHERILL, ROBERT J., KOSLEY, RAYMOND W., JR.
Applicants: HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED
Application year: 1986
Main classification: C07D311
IPC codes: A61K31, C07H7, C07D493, C07D407, A61P27, C07F9, A61P11, A61P9, C07D327, C07F7, C07D317, C07D311, C07D497, A61P3