Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D497/10—Spiro-condensed systems

Definitions

• the present invention relates to carbamoyloxylabdanes. More particularly, the present invention relates to carbamoyloxylabdanes of the formula 1
• R 1 is hydrogen or a group of the formula R 2 R 3 N(CH 2 ) r C wherein R 2 and R 3 are independently hydrogen or loweralkyl of 1 to 6 carbon atoms and r is 0 or 1; and R 2 and R 3 taken together with the nitrogen atom to which they are attached form a group of the formula
• X is O, S, a group of the formula NR 19 wherein R19 is loweralkyl of 1 to 6 carbon atoms or a group of the formula CHR 4 wherein R 4 is hydrogen, loweralkyl of 1 to 6 carbon atoms or a group of the formula OR 5 wherein R 5 is hydrogen, loweralkyl of 1 to 6 carbon atoms or a group of the formula CR 10 wherein R 10 is loweralkyl of 1 to 6 carbon atoms and n is 0 or 1;
• R 9 is hydrogen
• R 6 and R 7 are independently hydrogen, a group of I the formula CR 20 wherein R 20 is hydrogen or loweralkyl of 1 to ⁇ carbon atoms, or a group of the formula R 13 R 14 NC wherein R 13 is hydrogen, loweralkyl of 1 to 6 carbon atoms, hydroxyloweralkyl of 2 to 6 carbon atoms, loweralkoxyloweralkyl having 1 to 6 carbon atoms in the alkoxy group and 2 to 6 carbon atoms in the alkyl group, a group of the formula HOCH 2 CH(OH)CH 2 ; R 14 is hydrogen, hydroxyl, loweralkoxy of 1 to 6 carbon atoms, loweralkyl of 1 to 6 carbon atoms, hydroxyloweralkyl of 2 to 6 carbon atoms, loweralkoxyloweralkyl of 1 to 6 carbon atoms in the alkoxy group and 2 to 6 carbon atoms in the alkyl group, loweralkanoyl of 2 to 6 carbon atoms, loweralkano
• R 21 and R 22 areas above, a group of the formula OCR 24 wherein R 24 is hydrogen, loweralkyl of 1 to 6 carbon atoms, lowercycloalkyl of 3 to 6 carbon atoms, loweralkenyl of 2 to 6 carbon atoms, haloloweralkenyl of 2 to 6 carbon atoms, loweralkanoylloweralkyl of 2 to 6 carbon atoms in the alkanoyl group and 1 to 6 carbon atoms in the alkyl group, loweralkoxyloweralkyl of 1 to 6 carbon atoms in each group, loweralkoxycarbonylloweralkyl of 1 to 6 carbon atoms in each group, loweralkylamino of 1 to 6 carbon atoms, lowerdialkylamino of 2 to 6 carbon atoms, a group of the formula OCR 24 wherein R 24 is hydrogen, loweralkyl of 1 to 6 carbon atoms, lowercycloalkyl of 3 to 6 carbon atoms, loweralkenyl of 2 to 6
• X and n are as above, a group of the formula (CH 2 ) u N(R 25 )COR 26 , wherein u is 1, 2 or 3 and R 25 and R 26 are independently hydrogen or loweralkyl of 1 to 6 carbon atoms, agroup of the formula (CH 2 ) 2 PR 27 R 28 ' wherein R 27 and
• R 28 ' are loweralkyl of 1 to 6 carbon atoms, with the provisos:
• R 1 is hydrogen and R 7 is a group of the formula
• R 1 is hydrogen and R 6 is a group of the formula
• R 1 is a group of the formula R 2 R 3 N(CH 2 ) r C wherein R 2 , R 3 , and r are as above, and R 6 and R 7 are hydrogen;
• R 1 and R 9 taken together form a group of the formula CHNR 11 R 12 wherein R 11 and R 12 are as above and R 6 or
• R 7 is a group of the formula R 13 R 14 N C wherein R 13 and R 14 are as above;
• R 1 is hydrogen, R 6 is hydrogen, R 13 is hydrogen and R 14 is loweralkyl of 1 to 6 carbon atoms;
• R 6 is a group of the formula R 13 R 14 NC wherein R 13 and R 1 4 are as above and R 7 is a group of the formula CR 20 wherein R 20 is as above; and (g) R 7 is a group of the formula R 13 R 14 N C wherein R 13
• R 14 are as above and R 6 is a group of the formula R 20 C wherein R 20 is as above.
• R 13 is hydrogen and R 14 is a group of the formula
• R 24 is loweralkyl of 1 to 6 carbon atoms or a group of the formula
• n and X are as above.
• 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, and the like;
• alkenyl refers to a straight or branched chain hydrocarbon radical containing unsaturation in the form of a single carbon to carbon double bond and having from 2 to 8 carbon atoms such as propenyl, 2-butenyl, 2-methyl-2-butenyl, 3-hexenyl, 3-ethyl-2-pentenyl, 3-methyl-3-heptenyl, octenyl, and the like;
• alkynyl refers to a straight or branched chain hydrocarbon radical containing unsaturation in the form of a single carbon to
• cycloalkyl refers to a saturated hydrocarbon group possessing at least one carbocyclic ring, the ring containing from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclyheptyl, cyclooctyl, and the like;
• alkoxy refers to a monovalent substituent which consists of an alkyl group linked through an ether oxygen and having its free valence bond from the ether oxygen such as methoxy, ethoxy, propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, 3-methylpentoxy,
• alkanoyl refers to the radical formed by removal of the hydroxyl function from an alkanoic acid.
• alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, and the like.
• 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 and the like.
• 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,
• halogen refers to a member of the family consisting of fluorine, chlorine, bromine or iodine.
• lower as applied to any of the aforementioned groups refers to a group having a carbon skeleton containing up to and including 6 carbon atoms.
• 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.
• ( ⁇ ) 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 racemic forms of the compounds of the present invention where such compounds have chiral centers in addition to those of the labdane nucleus.
• novel labdanes of the present invention are synthesized by the processes illustrated in Reaction Schemes A and B.
• the carbamoylation is accomplished by treating a 6 ⁇ ,7 ⁇ -dihydroxylabdane 2 with 1,1'-carbonyldiimidazole 8
• R 13 and R 14 are as above, neat, in an alkyl alkanoate, halocarbon or a mixture of a halocarbon and an alkanol to yield 4.
• alkyl alkanoates there may be mentioned methyl acetate, ethyl acetate, methyl propionate, ethyl propionate and the like. Ethyl acetate is preferred.
• halocarbons there may be mentioned dichloromethane, trichloromethane and the like. Dichloromethane is preferred.
• alkanols there may be mentioned methanol, ethanol, 2-propanol and the like. Methanol is preferred and mixtures of dichloromethane and methanol are also preferred.
• the temperature at which the carbamoylation is performed is not narrowly critical, it is preferred to carry out the reaction at a temperature between about 0oC to about 50°C, most preferrably at a temperature of about 25°C.
• the intermediate imidazolocarbonyloxylabdane 9 may be isolated by workup of the reaction mixture prior to the addition of amine 10 by methods well-known in the art.
• the intermediate labdane 9 may be isolated by chromatography on a suitable column (e.g, silica gel) with an appropriate eluent such as hexane/ethyl acetate.
• the hydrolysis is achieved by contacting a 7 ⁇ -carbamoyloxylabdaneformamide acetal 3 with aqueous alkanol, or with an aqueous alkanoic acid in alkanol, or a mineral acid in aqueous alkanol.
• aqueous alkanoic acids are aqueous formic acid, aqueous acetic acid, aqueous propionic acid and the like.
• mineral acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like.
• alkanols are methanol, ethanol, 2-propanol and the like.
• a reaction medium consisting of about 80% aqueous acetic acid and methanol or aqueous methanol is preferred.
• the hydrolysis proceeds readily at a temperature within the range of about 0°C to about 50°C in 80% aqueous acetic acid, and above 40oC to 90°C in aqueous methanol.
• the preferred hydrolysis temperatures in aqueous acetic acid and aqueous methanol are about 25° and 65°C, respectively.
• the carbamoylation of a 6 ⁇ ,7 ⁇ -dihydroxylabdaneformamide acetal 2 is e f fected by treating such a labdane 2 wi th a base, for example, an alkali metal bis(trialkylsilyl)amide of formula 11
• R 13 is as hereinbeforedescribed or a carbamoyl halide of formula 13
• alkali metal bis(trialkylsilyl)amides include lithium, sodium or potassium bis(trimethylsilyl)- or bis(triethylsilyl) amides and the like.
• ethereal solvents are diethyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran and the like.
• a reaction medium consisting of lithium bis(trimethyl) silylamide and tetrahydrofuran is preferred.
• the formation of the alkali metal alkoxide is performed at a temperature within the non-critical range of about -25°C to about 50oC, preferably at a temperature of about 0oC to about 25°C.
• the condensation of an alkali metal alkoxide of2 with either an isocyanate 12 or a carbamoyl halide 13 is performed at a temperature of about 0 C to about the reflux temperature of the reaction medium, preferrably at about
• a 7 ⁇ -carbamoylabdane of formula 4 is rearranged by means of an alkali metal alkoxide in an alkanol or ethereal solvent, alone or combination, at a temperature within the range of about 0°c to about 50°C, a temperature of about 25°C being preferred.
• Suitable alkali metal alkoxides include lithium, sodium and potassium 2-propoxides, lithium, sodium and potassium 2,2-dimethyiethoxides and the like.
• Suitable alkanols include 2-propanol, 2,2-dimethylethanol and the like.
• Suitable ethereal solvents include diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like. Potassium 2,2-dimethylethoxide and a combination of 2,2-dimethylethanol and tetrahydrofuran is the preferred rearrangement medium.
• a carbamoyloxy-6 ⁇ ,7 ⁇ ,9 ⁇ -trihydroxylabdane of formula 7 8,13-epoxy-1 ⁇ ,6 ⁇ ,7 ⁇ ,9 ⁇ -tetrahydroxylabd- 14-en-11-one 6, the synthesis of which is described in U. S. Patent 4,134,986, issued Janury 16, 1979 to B. S.
• Bajwa, et al. is contacted with 1,1'-carbonyldiimidazole 8 in an ethereal solvent such as tetrahydrofuran followed by an amine 10 wherein R 13 and R 14 are R 2 and R 3 , respectively, under conditions substantially similar to those employed for the conversion of 6 ⁇ ,7 ⁇ -dihydroxylabdane-1 ⁇ ,9 ⁇ -formamide acetal 2 to a 7 ⁇ -carbamoyloxylabdane 3, as hereinbeforedescribed.
• de Souza, et al., Medicinal Research Reviews, 3, 201 (1983), may be treated with 1,1'-carbonyldiimidazole 8 followed by an amine of formula 10, or an alkoxide of 13 may be condensed with an isocyanate 12 or carbamoyl halide 13 , all steps being performed by processes substantially similar to those describedherein for the related conversion of 7 ⁇ -hydroxylabdane 2 to 7-carbamoyloxylabdane 3.
• R 1 4 are hydrogen is converted to a 7 ⁇ -aminocarbonylo ⁇ y-
• R 26 is alkyl to a 7 ⁇ -(N-alkanoylaminocarbonyloxy)-1 ⁇ ,9 ⁇ -dihydroxylabdane-1 ⁇ ,9 ⁇ -sulfite 17. See Reaction Scheme C.
• the introduction of the 1 ⁇ ,9 ⁇ -sulfite is accomplished by treating a 1 ⁇ ,9 ⁇ -dihydroxylabdane 4 with thionyl chloride 8 in the presence of pyridine or a tertiary amine and an inert solvent.
• pyridine or a tertiary amine and an inert solvent.
• tertiary amines there may be mentioned trialkylamines such as trimethylamine, triethylamine, tripropylamine and the like, and heteroaromatic amines such as pyridine, picoline, lutidine, collidine and the like. Trialkylamines are preferred. Triethylamine is most preferred.
• halocarbons such as dichloromethane, trichloromethane, 1,1- and 1,2-dichloroethane and the like.
• Dichloromethane is preferred.
• reaction temperature at which the sulfite introduction is performed is not critical, it is preferred to conduct the reaction at a temperature of about 10o to about 40°C, a reaction temperature of about 25oC being most preferred.
• the condensation is effected by contacting a 7 ⁇ -(aminocarbonyloxy)labdane 17 with an anhydride 19 in the presence of a mineral acid or a sulfonic acid.
• mineral acids include sulfuric acid, nitric acid, hydrochloric acid and the like.
• sulfonic acids include methanesulfonic acid, hexanesulfonic acid, p-toluenesulfonic acid and the like.
• Mineral acids are preferred. Sulfuric acid is most preferred.
• the condensation is preferably performed at about 25oC. Reduced or elevated temperature, however, in the range of about 10°c to about 40°C may be employed.
• a 7 ⁇ -(N-aikanoylamin ⁇ carbonyloxy) function and a 1 ⁇ ,9 ⁇ -dihydroxy moiety i.e., a compound of formula 18
• a 7 ⁇ -(N-alkanoylaminocarbonyloxy)-1 ⁇ ,6 ⁇ ,9 ⁇ -trihydroxy- labd-14-en-11-one 17-1,9-carbonate is subjected to hydrolytic processes.
• Hydrolysis for example, is achieved by contacting a 1 ⁇ ,9 ⁇ -carbonate 17 with water in an appropriate solvent such as pyridine, picoline, lutidine, collidine and the like, pyridine being preferred.
• the hydrolysis is generally conducted at the reflux temperature of the reaction medium.
• a labdane of formula 21 wherein R 2 ,R 3 ,R 13 , R 14 , and r are as hereinbeforedefined a 7 ⁇ -carbamoyloxy-1 ⁇ -hydroxylabdane 4 is acylated to a 1 ⁇ -haloacetoxy-7 ⁇ -carbamoyloxylabdane 20 which is aminated to 21. See Reaction Scheme D.
• r is 1 and Hal is chloro, bromo or iodo is conducted in the presence of a dialkylaniline such as dimethylaniline, diethylaniline and the like in a halocarbon such as dichloromethane, trichloromethane, 1,1- or 1,2-dichloroethane, 1,1- or 1,2-dichloroethylene and the like at a reaction temperature from about 0 to about 50oC. Dimethylaniline and dichloromethane is the preferred reaction medium. A temperature within the range from about
• 1 -haloalkylcarbonyloxylabdane 20 is isolated by conventional work-up of the reaction mixture, e.g., extraction and evaporation.
• the amination is accomplished by contacting a 1 ⁇ -haloalkylcarbonyloxylabdane 20 with an alkylamine of formula 23 R 2 R 3 NH
• R 2 and R 3 are as hereinbeforedisclosed in an alkyl alkanoate at a temperature from about 5° to about 55°C, a reaction temperature of about 25°C being preferred. Included among alkyl alkanoates are methyl acetate, ethyl acetate, methyl propionate, ethyl propionate and the like. Ethyl acetate is the preferred alkyl alkanoate.
• R 18 is as hereinbeforedefined in the presence of 1,1'-carbonyldiimidazole 8 in a halocarbon such as dichloromethane, trichloromethane, 1,1- or 1,2-dichloroethane, 1,1- or 1,2-dichloroethylene and the like, or an alkyl alkanoate such as methyl acetate, ethyl acetate, methyl propionate, ethyl propionate and the like at a reaction temperature within the range of about 5 to about 50°c
• the preferred solvents are dichloromethane and ethyl acetate.
• An ethereal cosolvent e.g.
• tetrahydrofuran dioxane, diethyl ether, dimethoxyethane and the like may be employed when a halocarbon is used as the reaction medium.
• Tetrahydrofuran is the preferred cosolvent.
• the preferred reaction temperature is about 25°C.
• an amino acid 2 6 in the form of its hydrohalide salt i.e., an amino acid wherein R 18 is characteri zed by the presence of a basic amine function
• an acid acceptor such as, for example, a trialkylamine is also employed in the reaction medium. Included among trialkylamines are trimethylamine, triethylamine, tripropylamine and the like. Triethylamine is the preferred acid acceptor.
• R 28 is dialkylaminoalkyl and R 29 is alkyl
• R 28 is dialkylaminoalkyl and R 29 is alkyl
• An acid acceptor e.g., a 4-dialkylaminopyridine such as 4-dimethylamnopyridine is utilized when a hydrohalide salt of carbodiimide 27 is employed as a the condensing agent.
• a 7 ⁇ -(N-acyloxyaminocarbonyloxy)- labdane 25 is prepared from a 7 ⁇ -(N-hydroxyaminocarbonyl- oxy)labdane 24 by the mixed anhydride method.
• R 1 and, R 13 are hydrogen with the mixed anhydride of acrylic acid or methylacylic acid and 2,2-dimethylpropionic acid of formulas 28 or 28a
• a 7 ⁇ -(N-carbamoylaminocarbonyloxy)labdane for example, a labdane of formula 25 wherein R 24 is dialkylamino, more particularly dimethylamino, is elaborated by the carbamoyl halide method.
• R 24 is dialkylamino, more particularly dimethylamino
• R 30 and R 31 are alkyl and Hal is chloro, bromo or iodo, more particularly N,N-dimethylcarbamoyl chloride, i.e., a compound of formula 29 wherein R30 and R 31 are dimethyl and Hal is chloro, in a halocarbon such as, for example, dichloromethane, and an acid acceptor such as, for example, triethylamine, provides a 7-substituted labdane wherein R 24 is N,N-dialkyl, more particularly, N,N-dimethyl.
• a halocarbon such as, for example, dichloromethane
• an acid acceptor such as, for example, triethylamine
• an appropriate secondary carbinol for example, a compound of formula 30 wherein R 1 and R 9 taken together form a group of the formula CHNR 11 R 12 wherein R 1 and R 10 are as hereinbeforedefined is oxidized by the oxalyl chloride-dimethylsulfoxide complex in the presence of an acid acceptor such as triethylamine at a reduced temperature within the range of about -60° to about -50°C to afford a 7 ⁇ -[N-(2-oxopropyl)aminocarbonyloxy]labdane 31 wherein R 1 and R 9 are as above.
• the 1 ⁇ 9 ⁇ -dimethylformamide acetal protecting group is cleaved by hydrolysis processes hereinbeforedescribed to provide the 1 ⁇ 9b-dihydroxylabdane substituted at the 7 ⁇ -position by the aforesaid carbonyloxy group, i.e., a compound of formula 31 wherein R 1 and R 9 are hydrogen.
• a labdane-formamide acetal 32 (R 1 and R 9 taken together form a group of the formula CHNR 2 R 3 where R 2 and R 3 are alkyl) is acylated with diimidazole 8 in the presence of an amine 10 to provide a 6 ⁇ -aminocarbonyloxylabdanedialkylformamide acetal 34 (R 1 and R 9 form a group of the formula CHNR 2 R 3 wherein R 2 and R 3 are alkyl) which is hydrolyzed to a 6 ⁇ -aminocarbonyloxy- 1 ⁇ ,7 ⁇ ,9 ⁇ -trihydroxylabane 34 wherein R 1 and R 9 are hydrogen.
• the acylation is carried out by treating 32 with diimidazole 8 in a halocarbon such as, e,g., dichloromethane. trichloromethane,
• 1,2-dichloroethane, 1,1- or 1,2-dichloroethylene and the like an alkyl alkanoate such as, e.g., methyl acetate, ethyl acetate, ethyl propionate and the like, or an ethereal solvent such as, e.g. tetrahydrofuran, dioxane, diethyl ether and the like, in the presence of a tertiary amine such as e.g., a trialkylamine (i.e., trimethylamine, triethylamine, tripropylamine, lutidine, collidine or the like, or a heteroaromatic amine such as, e.g.
• a tertiary amine such as e.g., a trialkylamine (i.e., trimethylamine, triethylamine, tripropylamine, lutidine, collidine or the like, or a heteroaromatic amine
• reaction temperature of from about 0°C to the reflux temperature of the solvent system.
• the preferred solvent is a halocarbon, dichloromethane being most preferred.
• the preferred reaction temperature is about 25°c
• the initial stage of the conversion of 32 to 34 i.e., the treatment of 32 with diimidazole 8. in the presence of a tertiary amine is allowed to proceed for an extended period of time, preferably for about 12 to about 36 hours, most preferably for about 24 hours.
• the intermediate 6 ⁇ ,7 ⁇ -dihydroxylabdane-6 ⁇ ,7 ⁇ -carbonate 33 is isolated and, in turn, treated with amine 10 to form 6 ⁇ -carbamoyloxylabadane 34 or the conversion may be conducted in situ, preferably in situ.
• a 6 ⁇ -carbamoyloxy-7 ⁇ -hydroxylabdane 3 4 (wherein R 1 and R 9 together are CHNR 11 R 12 wherein R 11 and R 12 are alkyl) may be acylated to a 7 ⁇ -alkanoyloxy-6 ⁇ -carbamoyllabdane 35 (wherein R 1 and R 9 together are CHNR 11 R 12 wherein R 11 and
• R 12 are alkyl) by, for example, an alkanoic acid anhydride
• acetic acid anhydride 19 such as acetic acid anhydride 19 (wherein R 26 is methyl) in an alkanoic acid such as acetic acid 26 (wherein R 18 is methyl) in the presence of a tertiary amine such as 4-dimethylamnopyridine to provide a
• a 6 ⁇ -alkanoyloxy-7 ⁇ -hydroxylabdane 37 (wherein R 1 and R 9 taken together are CHNR 11 R 12 wherein R 1 1 and R 12 are alkyl), the preparation of which is described in U. S. Patent Application Serial No. 849,053, now U. S. Patent 4,639,443, granted January 27, 1987, may be carbamoylated to a 6 ⁇ -alkanoyloxy-7 ⁇ -carbamoyloxy labdane 38 (wherein R 1 and R 9 are as above) by, for example, the procedure hereinbeforedescribed for the conversion 2 to 3..
• the 1 ⁇ 9 ⁇ -dihydroxy-1 ⁇ ,9 ⁇ -dialkylformamide acetal group of 7 ⁇ -alkoxy-6 ⁇ -carbamoyloxylabdane 35 (wherein R 1 and R 9 together are CHNR 11 R 12 wherein R 11 and R 12 are alkyl) may be cleaved to the corresponding 1 ⁇ ,9 ⁇ -dihydroxy derivatives 35 and 36 (wherein R 1 and R 9 are hydrogen) (see Reaction Schemes E and F).
• a reduced hydrolysis temperature of about 25oc may be employed.
• the carbamoyloxylabdanes of the present invention are useful in the treatment of glaucoma by virtue of their ability to reduce elevated intraocular pressure in a glaucomatous subject 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 Table I.
• Intraocular pressure reduction is achieved when the present carbamoyloxylabdanes are administered to a subject requiring such treatment as an effective topical dose of a 0.01 to 3.0% solution or suspension.
• a particularly effective amount is about 3 drops of a 0.25% 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.
• the carbamoyloxylabdanes of the present invention are also useful in the treatment of cardiac failure by virtue of their ability to elicit a positive ionotropic effect as evidenced by an increase in contractile force in an isolated guinea pig atria assay, the electrically-driven guinea pig left atrium assay, which is performed as follows:
• guinea pigs weighing 200-300 grams are stunned with a blow to the back of the head.
• the heart is rapidly removed and placed in a petri dish containing Krebs solution.
• the ventricle is separated from the atria, the atria are sectioned into the right and left atria and double-0 silk ligatures are tied to the apex of the left atrium.
• the atrium is fixed to a pair of platinum plate electrodes and suspended in a 20-ml tissue bath containing Kreb's solution aerated with 95% oxygen-5% carbon dioxide at 37oc.
• One end of the atrium is fixed to a hook in the electrode and the other end is connected .to a Grass FT03 force displacement transducer.
• the atrium is stimulated at 3 Hz, 0.5 msec duration at supramaximal voltage (constant current) via a Grass S88 stimulator and constant current unit.
• Force of contraction is continuously displaced on a Gould recorder.
• Test drug is prepared as in section A and is added to the tissue baths in the same fashion. Change in contractile force from baseline is determined for each concentration, and the change in contractile force (g) is plotted against accumulated drug concentration (ug/ml).
• the activity of the test drug i.e., the increase in contractile force (g) from the stabilized force expressed the percentage change at a given concentration is determined graphically, as is the
• ED 50 -value i.e., the extrapolated dose (ug/ml) which increases the contractile force by 50% over the stablized rate.
• Cardiac failure treatment is achieved when the present carbamoyloxylabdanes are administered to a subject requiring such treatment as an effective oral, parenteral or intravenous dose of 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight 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.
• Compounds of the present invention include:
• the carbamoyloxylabdanes of the present invention are also useful in the treatment of hypertension, congestive heart failure, bronchial asthma and psoriasis.
• 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, suspensions or ointments and by aerosol spray.
• 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.
• the aforesaid 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 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% 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 0.1-30 milligrams of the active compound.
• the tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as micro-crystalline cellulose, gum tragacanth 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.
• a binder such as micro-crystalline cellulose, gum tragacanth 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
• a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermin
• dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
• 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.
• the active compounds of the invention may be incorporated into a solution, suspension, ointment or cream. These preparations should contain at least 0.01% of active compound, but may be varied between 0.1 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 or topical dosage unit contains between 0.01 to 10 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, propylene 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 ethylenediaminetetra- acetic acid; buffers such as acetates, citrates or phophates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene 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 ethylenediaminet
• the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience or crystallization, 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, carboxysuccinic acid, citric acid and the like.
• 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
• salts of tribasic carboxylic acids such as, for example, carboxysuccinic acid, citric acid and the like.
• 1,1'-carbonyldiimidazole was stirred at ambient temperature overnight. Anhydrous ammonia was bubbled into the mixture for 1 min and the mixture was stirred at ambient temperature for 48 to 72 hr in a sealed vessel. The mixture was filtered and evaporated. The residue was flash chromatographed on silica gel in hexane:ethyl acetate (1:1). The appropriate fractions were combined and evaporated. The residue was recrystallized from hexane:ether to afford 148 mg (26.9%) of product, mp 98-122°.
• EXAMPLE 2 8,13-Epoxy-7 ⁇ -(N-methylaminocarbonyloxy)-1 ⁇ ,6 ⁇ , 9 ⁇ - trihydroxylabd-14-en-11-one-1,9-dimethylformamide acetal
• 23 1 of a 1 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran was added to the mixture and the mixture was stirred at ambient temperature under nitrogen overnight.
• 1,1'-carbonyldiimidazole was stirred at ambient temperature under nitrogen over the weekend. Morpholine (500 ml) was added and the mixture was stirred at ambient temperature for 24 hr. The mixture was diluted with 100 ml of ethyl acetate and washed with 0.01 N hydrochloric acid until the aqueous washings remained acidic. The organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was flash chromatographed. on silica gel in hexaneiethyl acetate (1:1). The appropriate fractions were combined and evaporated to yield 180 mg (27.3%) of product, mp 75-100°. ANALYSIS:
• 1,1'-carbonyldiimidazole was stirred at ambient temperature under nitrogen for 48 to 72 hr.
• 4-Hydroxypiperidine (505 mg) was added and the mixture was stirred at ambient temperature for 24 hr.
• the mixture was diluted with 100 ml of ethyl acetate and washed with 0.01 N hydrochloric acid until the aqueous washings remained acidic.
• the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhyd.rous sodium sulfate, filtered and evaporated.
• the residue was flash chromatographed on silica gel in hexane:ethyl acetate (1:2). The appropriate fractions were combined and evaporated to yield 342.5 mg
• EXAMPLE 5 8,13-Epoxy-7 ⁇ -(2-hydroxyethylaminocarbonyloxy)-1 ⁇ ,6 ⁇ , 9 ⁇ - trihydroxylabd-14-en-11-one-1,9-dimethylformamide acetal
• 1,9-dimethylformamide acetal 500 mg was dissolved in 10 ml of dichloromethane together with 202.5 mg of 1,1'-carbonyldiimidazole under nitrogen. The mixture was stirred at ambient temperature overnight. Hydroxylamine hydrochloride (1.6 g) was dissolved in 25 ml of methanol together with a single crystal of phenophthalein. Sufficient 25% sodium methoxide in methanol was added to turn the color of the solution pink. The sodium chloride was allowed to settle. An aliquot of 6 ml of the hydroxylamine solution in methanol was added to the original solution and the mixture was. stirred for 1 hr.
• reaction mixture was allowed to cool to room temperature, water (20 ml) was added and the mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed. The residue was chromatographed on silica gel. The column was eluted with hexane:ethyl acetate :methanol (1:1:0.1). The appropriate fractions were collected and the solvent was removed to give 1.3 g (81%) of product, mp 188°.
• the mixture was poured into 50 ml of saturated sodium bicarbonate solution/ice, and the mixture was diluted with 50 ml of methylene chloride, washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate, and filtered. The solvent was removed and the residue was dissolved in 20 ml of methylene chloride. A solution of 1.4 g of t-butylamine in 20 ml ethyl acetate was added and the resulting mixture was stirred overnight under nitrogen. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate.
• 1,9-dimethylformamide acetal in 5 ml of methylene chloride was added 15 ml of 1-methylpiperazine.
• the mixture was stirred 16 hrs under a nitrogen atmosphere.
• the mixture was diluted with methylene chloride and extracted with 0.01N hydrochloride acid until the washings were neutral.
• the organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated.
• the residue was chromatographed on silica gel, eluting with 10% methanol/dichloromethane . The appropriate fractions were collected and the solvent was evaporated to give 2.56 g
• reaction mixture was washed with 0.01N hydrochloric acid (2 x 20 ml), saturated sodium bicarbonate solution, and water.
• the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to provide
• the o rganic phase was dried over anhyd rous sod ium sul fate , f il tered and the fil trate was evapo rated .
• the residue was d issolved in ether and ethereal hyd rogen chlor ide was added to provide 230 mg (53%) of product , mp
• reaction mixture was poured into ice/ethyl acetate/water, extracted twice with ethyl acetate, washed with cold 5% hydrochloric acid until the washings were acidic, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated.
• To a stirred solution of the residue in 50 ml of dry pyridine at 0° was added dropwise a solution of 12.5 ml of 20% phosgene in toluene. The mixture was stirred at ice bath temperature for 0.5 hr and at room temperature for 0.5 hr.
• reaction mixture was then poured into ice/water/ethyl acetate, extracted twice with ethyl acetate, washed with cold 5% hydrochloric acid until acidic, washed with saturated sodium chloride solution, dried over anhydrous sodum sulfate, filtered and concentrated.
• the residue was dissolved in a minimum volume of ethyl acetate and flash chromatographed on silica gel, eluting with 30% ethyl acetate/hexane followed by 40% ethyl acetate/hexanes. Concentration of the appropriate fractions provided 4.19 g (79.2%) of product.
• Several milligrams of the material was recrystallized from ethyl acetate/cyclohexane to provide the analytical product having mp 137-141 .

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