Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals

Definitions

• R is loweralkyl, lowerhydroxyalkyl or lowerhaloalkyl, and R and R each are hydrogen or acyl or when taken together form an isopropylidene or a benzylidene moiety, and the pharmaceutically acceptable acid addition salts thereof.
• the compounds are useful as anti-anginal agents.
• Angina pectoris is a coronary syndrome characterized by a special type of paroxysmal sensation of pressing or strangling pain usually located behind the sternum or in the precordial region. The pain often radiates to the back of the left arm but may often radiate elsewhere. The attacks can vary greatly in severity and frequency.
• anginal pain rises from an imbalance in the heart between the supply of and the demand for oxygen.
• the pain is usually brought about by episodes of extreme emotional stress, exposure to cold, excitement or any other stressful situation.
• any sudden increase in cardiac work any decrease in coronary blood flow or any interference with oxygenation of the blood may cause an attack.
• anginal attacks can occur while the patient is sleeping. Therefore, anginal pain is not necessarily due to a decrease of blood flow but rather to an insufficiency of the flow in relation to the metabolic requirements or oxygen demands of the heart.
• nitroglycerin is probably the most widely used agent in managing acute attacks of angina; however, there has been a long standing need for a prophylactic agent which, when administered to patients with a history of, or who are susceptible to attacks of angina pectoris, will prevent or reduce the severity of future attacks.
• the present invention provides a novel class of compounds which are orally active, long-acting anti-anginal agents.
• the present invention relates to N -oxides of adenosine- 5-alkyl carboxylates, to therapeutic compositions containing such compounds as the active ingredient, to methods of making and using the compounds and to intermediates useful in the preparation of the compounds.
• the compounds of this invention are represented by the structural formula IIIH: M S 0 a l. IMO-('5 0 OR: OR;
• R is loweralkyl, lowerhydroxyalkyl or lowerhaloalkyl, and R and R each are hydrogen or acyl or when taken together form an isopropylidene or a benzylidene moiety, and the pharmaceutically acceptable acid addition salts thereof.
• the compounds are useful as antianginal agents. i
• loweralkyl refers to both straight and branched chain alkyl groups containing from 1 to 6 carbon atoms including methyl, ethyl, n-propyl, iso-propyl, n-butyl, dec-butyl, tert-butyl, n-pentyl, isopentyl, ne0-pentyl, nhexyl, and the like.
• halo refers to chloro, bromo, fluoro or iodo.
• lowerhydroxyalkyl and lowerhaloalkyl refer to the above defined C -C alkyl groups substituted with a hydroxy or a halo radical.
• pharmaceutically acceptable acid addition salts refers to salts prepared by reacting the ester with an organic or inorganic acid.
• Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate, napsylate and the like.
• acy refers to acetyl, propionyl, butyryl, and the like.
• Compounds of this invention wherein R and R are hydrogen are useful as anti-anginal agents at dosages of 0.025 to 30 mg./kg. of body weight daily.
• the compounds can be administered to angina pectoris patients by either oral or parenteral routes, however the oral route of administration is preferred. While the compounds can be administered in a single dose, it is preferred to administer them in divided dosages, i.e., three to four times daily.
• the anti-anginal activity of the compounds of this invention was first established using the method of Schoepke et al., Pharmacologz'st 8: 204 (1966).
• the compounds of this invention can be prepared by forming the N -oxide of 2',3-isopropylidene adenosine carboxylicacid, cleaving the 2',3'-isopropylidene group to obtain the N -oxide of adenosine-5-carboxylic acid, and reacting the acid with the appropriate alcohol (R OH) in the presence of, for example, thionyl chloride to obtain the desired product.
• R OH an appropriate alcohol
• the reaction is represented by the following reaction sequence.
• Example l.Adenosine-5-carboxylic acid-N -oxide A suspension of 2',3'-O-isopropylidene adenosine-5- carboxylic acid [Harmon et al., Chem. & Ind., 114 (1969)] (9.6 g., 0.03 mole) inv acetic acid (750 ml.) and H (100 ml. of 30% aqueous solution) was stirred at the room temperature. After 7 days, the reaction mixture was filtered to remove a small amount of suspended material (0.2 g.). The filtrate was cooled to 1015 C. and the excess of H 0 was destroyed by adding Pd/C (6 g.).
• Example 2 Adenosine-5 (ethyl) carb oxylate-N -oxide Thionyl chloride (2 ml.) was added dropwise to a suspension of adenosine-5'-carboxylic acid-N -oxide (1.8 g., 0.006 mole) in absolute ethanol (100 ml.) at 5-10 C. After 30 minutes at 510 C., the clear solution was stirred for 16 hours at the room temperature. At the end of this period, the mixture was kept at 50 C. for /2 hour, concentrated under reduced pressure to approximately 20 ml. and poured onto stirred ether (150 ml.). The precipitate was filtered and the residue was stirred with aqueous NaHCO (20 ml.) at 1015 C. and filtered to give 0.8 g. (45%) of the desired product, m.p.
• Adenosine-5 (chloroethyl)carboxylate N oxide using chloroethyl alcohol.
• Adenosine 5' (hydroxyethyl)carboxylate N -oxide using hydroxyethyl alcohol.
• Adenosine 5 (iso-butyl)carboxylate N oxide using iso-butyl alcohol.
• Adenosine 5' (isabutyl)carboxylate N oxide using iodomethyl alcohol.
• the compounds of this invention can be formulated into various pharmaceutical dosage forms such as tablets, capsules, pills and the like, for immediate or sustained release, by combining the active compound with suitable pharmaceutically acceptable carriers or diluents according to methods well known in the art.
• Such dosage forms may additionally include excipients, binders, fillers, flavoring and sweetening agents and other thereapeutically inert ingredients necessary in the formulation .of the desired pharmaceutical preparation.
• a compound in accordance with Claim 3 adenosine 5 (ethyl)carboxylate-N -oxide, or a pharmaceutically acceptable acid addition salt thereof.
• a compound represented by the formula 9 A compound in accordance with Claim 8, 2',3'-iso- NHI propylidene adenosine 5' carboxylic acid-N -oxide.
• JOHNNIE R. BROWN Primary Examiner US. (:1. X.R.
• R nd R each are hydrogen, acetyl, propionyl, or 424-430 butyryl, or when taken together form an isopropylidene or benzylidene moiety.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Saccharide Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (11)

Applications Claiming Priority (1)

Publications (1)

Family

ID=23134739

Family Applications (1)

Country Status (10)

• 1972
  • 1972-10-03 US US00294741A patent/US3830793A/en not_active Expired - Lifetime
• 1973
  • 1973-09-11 GB GB4274873A patent/GB1430778A/en not_active Expired
  • 1973-09-11 ZA ZA737242*A patent/ZA737242B/xx unknown
  • 1973-09-13 PH PH15016A patent/PH10069A/en unknown
  • 1973-09-13 AU AU60305/73A patent/AU476086B2/en not_active Expired
  • 1973-10-01 CA CA182,312A patent/CA1012141A/en not_active Expired
  • 1973-10-02 FR FR7335211A patent/FR2201101B1/fr not_active Expired
  • 1973-10-02 JP JP48110248A patent/JPS4970994A/ja active Pending
  • 1973-10-02 DE DE19732349503 patent/DE2349503A1/de active Pending
  • 1973-10-03 CH CH1411273A patent/CH586235A5/xx not_active IP Right Cessation

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