Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
• • 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
  • C07J—STEROIDS
  • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/003—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring the S atom directly linked to a ring carbon atom of the cyclopenta(a)hydrophenanthrene skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals

Definitions

• the present invention relates to 14-deoxy-14a-cardenolide 3,8 -thioderivatives, a process for their preparation and pharmaceutical compositions containing same for the treatment of cardiovascular disorders such as heart failure and hypertension.
• the invention includes within its scope all the possible stereoisomers, in particular E and Z isomers, optical isomers and their mixtures and the metabolites and the metabolic precursors of the compounds of formula (I).
• E and Z isomers in particular E and Z isomers, optical isomers and their mixtures and the metabolites and the metabolic precursors of the compounds of formula (I).
• # is a single bond both the 5a and 5,8 isomers are encompassed within the scope of the present invention.
• compositions of (I) are salts which retain the biologically activity of the base and are derived from such known pharmacologically accetable acids such as e.g. hydrochloric, sulfuric, phosphoric, malic, tartaric, maleic, citric, methanesulfonic or benzoic acid.
• the alkyl and alkenyl groups may be branched or straight chain groups.
• the C2-C6 alkyl group is preferably a C2-C4 alkyl group, e.g. ethyl, propyl, isopropyl, butyl, sec-butyl.
• the C3-C6 alkenyl group is preferably a C3-C4 alkenyl group.
• the quaternary ammonium group is preferably a trimethylammonium- or a N-methylpyrrolidinium- or a N-methylpiperidinium- group.
• the OR1 group is preferably hydroxy, 2-aminoethoxy, 3-aminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 3-amino-2-hydroxypropoxy, 2,3-diaminopropoxy, 2-(1-pyrrolidinyl)ethoxy,3-(1-pyrrolidinyl)propoxy.
• the NR2R3 group is preferably amino, methylamino, ethylamino, propylamino, isopropylamino, allylami- no, propargylamino, dimethylamino, pyrrolidinyl, morpholino, piperazinyl, imidazolyl, guanidino, 2-aminoethylamino, 3-aminopropylamino, 2-(1-pyrrolidinyl)ethylamino, 3-(1-pyrrolidinyl)propylamino.
• the C(NH)NR4R5 group is preferably a primary amidino group.
• the NR6R7 is preferably amino, methylamino, ethylamino, propylamino, dimethylamino, pyrrolidinyl, morpholino, piperazinyl or imidazolyl.
• Preferred examples of specific compounds according to the present invention are:
• the invention furthermore provides a process for the preparation of said compounds (I), which comprises condensing the compounds having formula (II) where '" is as above defined with a compound of formula (III) where Y is an electron-withdrawing group, such as halogen, mesyloxy, or tosyloxy group, which confers electrophilic properties to the attached carbon atom, and R is as above defined, the hydroxy and amino groups, if any, present in R being protected, if necessary, with methods well known to those skilled in the art to give, after removal of the protective groups, if any, compounds of general formula (I) which may be converted into other compounds of formula (I) and optionally converting compounds (I) into pharmaceutically acceptable salts thereof and optionally separating a mixture of isomers into single isomers.
• Y is an electron-withdrawing group, such as halogen, mesyloxy, or tosyloxy group, which confers electrophilic properties to the attached carbon atom
• R is as above defined, the
• condensation reaction between (II) and (III) is best carried out in an inert aprotic solvent, such as tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxyde or in the neat (III) and in the presence of a strong base e.g. sodium or potassium hydride at a temperature ranging from -20 ° C to about 60 °C.
• an inert aprotic solvent such as tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxyde
• the purifications are best performed by flash-chromatography on silica gel.
• acetylthio derivatives (IV) are new and are obtained by reaction of the 3a-alcohols (V) with thiolacetic acid in the presence of a dialkyl azodicarboxylate and triphenylphosphine.
• the intermediate 3-oxo-14a-card-4,20(22)-dienolide (formula (VI) wherein --- is a double bond in position 4) is a known compound (Fritsch W. et al., Liebigs Ann. Chem. 1966, 699, 195).
• the 3-oxo-14a-card-5,20(22)-dienolide (formula (VI) wherein ---- is a double bond in position 5; see Prep. 12) is a new compound and is obtained by oxidation of the corresponding known 3,8-hydroxy derivative (Fritsch W. et al., Liebigs Ann. Chem. 1966, 699, 195) with morpholine-N-oxide in the presence of a perruthenate salt.
• the 3-oxo-5a,14a-card-20(22)-enolide (formula (VI) wherein ---- are single bonds and the hydrogen in position 5 is a; see Prep. 13) is a new compound and is obtained by oxidation of the corresponding known 3,8-hydroxy derivative (Kreiser W. and Vietnameser M., Liebigs Ann. Chem. 1972, 755, 1) with morpholine-N-oxide in the presence of a perruthenate salt.
• the compounds of general formula (III) are known compounds, generally commercially available or preparable from known compounds by known methods
• the 14-deoxy-14a-derivatives of digitoxigenin was expected from the literature data (Naidoo B.K., et al., J. Pharm. Sciences, 1974, 63, 1391) to be practically devoid of inotropic effect; however, unexpectedly, the thioderivatives (I), prepared according to the invention and their pharmaceutically acceptable salts are useful agents for the treatment of cardiovascular disorders such as heart failure and hypertension and have low toxicity. Moreover said compounds (I) show high affinity for the receptor site of the Na + ,K +- ATPase and behave as partial agonists on the enzymatic activity of the Na + ,K +- ATPase.
• DIGI aglycone digitoxigenin
• the solution was refluxed under nitrogen atmosphere for 3 hrs, then 5 ml of water were added and the resulting mixture extracted with methylene chloride. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure.
• the crude product was purified by flash-cromatography (Si0 2 ) using methylene chloride/methanol/30%ammonia solution 95/5/1 as eluant; the pure compound so obtained was dissolved in 2 ml of diethyl ether and a solution of 0.080 g of oxalic acid in 1 ml of diethyl ether was added to give 0.31 g of the title compound (I-a) as a white solid, mp 164-166 °C.
• the crude product was purified by flash-chromatography (Si0 2 ) using n-hexane/ethyl acetate 60/40 as eluant to give 0.30 g of 3 ⁇ -(2,3-epoxy)propylthio-5 ⁇ ,14 ⁇ -card-20(22)-enolide as a white pasty solid.
• Diisopropyl azodicarboxylate (7.7 ml) was added to a solution of 10.3 g of triphenylphosphine in 160 ml of tetrahydrofuran and the mixture was stirred for 30'. A white precipitate formed.
• a solution of 5.6 g of 3a-hydroxy-5 ⁇ ,14 ⁇ -card-20(22)-enolide and 2.8 ml of thiolacetic acid in 160 ml of tetrahydrofuran was added dropwise and the resulting mixture was stirred for 2 hrs at room temperature.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Engineering & Computer Science (AREA)
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• Pharmacology & Pharmacy (AREA)
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• Animal Behavior & Ethology (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Steroid Compounds (AREA)

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• 1992
  • 1992-07-01 DE DE4221538A patent/DE4221538C1/de not_active Expired - Fee Related
• 1993
  • 1993-06-16 EP EP93109611A patent/EP0576914A3/fr not_active Ceased
  • 1993-06-24 US US08/080,525 patent/US5489582A/en not_active Expired - Fee Related
  • 1993-06-30 JP JP5161311A patent/JPH0733795A/ja active Pending

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