US2601308A - Anticoagulant, amide of 3, 3'-carboxy-methylene bis - Google Patents

Anticoagulant, amide of 3, 3'-carboxy-methylene bis Download PDF

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Publication number
US2601308A
US2601308A US166070A US16607050A US2601308A US 2601308 A US2601308 A US 2601308A US 166070 A US166070 A US 166070A US 16607050 A US16607050 A US 16607050A US 2601308 A US2601308 A US 2601308A
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Prior art keywords
hydroxycoumarin
amide
carboxymethylenebis
amides
action
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Expired - Lifetime
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US166070A
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English (en)
Inventor
Joseph J Lovas
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SPECIFIE PHARMACEUTICALS Inc
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SPECIFIE PHARMACEUTICALS Inc
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Priority to US166070A priority patent/US2601308A/en
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Publication of US2601308A publication Critical patent/US2601308A/en
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    • 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
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
    • C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
    • C07D311/48—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring with two such benzopyran radicals linked together by a carbon chain

Definitions

  • the compound 3,3'-methylenebis (-hydroxycoumarin) is well known under the trade name Dicoumarol, and has been investigated extensively. It is an anti-coagulant for oral use, but has two important disadvantages. The first is that the onset of the anti-coagulant action is delayed after oral administration usually for some 12 to 48 hours. This delay is undesirable in conditions requiring immediate effective treatment. The second disadvantage is the persistent and protracted anti-coagulant effect in the body after withholding administration of the drug. In many cases dangerously low prothrombin levels persist to such an extent as to require special measures such as blood transfusion or high dosages of vitamin K to restore the prothrombin level to normal in order to avoid the danger of hemorrhage after the therapy has been accomplished.
  • esters are indicated as having the same general anti-coagulant properties as 3,3- methylenebis (4-hydroxycoumarin) namely prophylaxis and treatment in blood circulatory and vascular disturbances, including thrombosis, embolism, phlebitis, Buergers disease, etc.
  • the amides of 3,3'-carboxymethylenebis (4-hydroxycoumarin) do not possess the disadvantages of 3,3'-meth.ylenebis (4-hydroxycoumarin) or the slower acting esters thereof. More particularly, said amides accomplish a rapid lowering of prothrombin to any desired level, depending upon the dosage administered. While the reason for this has not been established, it appears likely that the amides may be more rapidly absorbed. Thus the onset of the action is very rapid after administration of the amides. The amides also have a less protracted effect and are accompanied by a rapid normalization of the prothrombin level when the drug is withheld, thereby minimizing dangers due to hemorrhage. While the exact reason for this advantage also is not known, it appears likely that this may be due to quicker elimination of the amides from the bloodstream.
  • novel compounds of m invention have the following general formula, where R and R are hydrogen or a hydrocarbon radical preferably having not more than 5 carbon atoms, such as ethyl, propylene, butyl, amyl, etc.
  • the amides may be made in accordance with the invention by reacting an ester of 3,3'-carboxymethylenebis (4-hydroxycoumarin) with an ammoniacal compound, i.e., ammonia or an amine as described hereinafter.
  • the amides may be prepared by reacting a lactone of 3,3'-carboxymethy1enebis l-hydroxycoumarin) with the ammoniacal compound as described in copending application, Serial No. 142,936, filed February '7, 1950, and also described more particularly hereinafter.
  • the lactone of 3,3-carboxymethylenebis (4-hydroxycoumarin) may be made by reacting the above carboxy compound with a dehydrating agent such as. an acid halide or an acid anhydride.
  • a dehydrating agent such as. an acid halide or an acid anhydride.
  • This amide may be. compared, with 3, 3f-meth ylenebis l-hydroxycoumarin)...
  • This latter compound according to Patent No. 2,345,635, and its manufacturer under the. name Dicoumarol, decreases the prothrombin concentration of the blood, The compound is intended for the pro: phylaxis and treatment of intravascular clotting; in postoperative, post-traumatic and postinfectious thrombophlebitis; pulmonary embolism;
  • The. fiirst is the delayed onset (l to 2 days ⁇ of the anti-coagulant action, and the long time necessary to reach the maximum effect (8 to 5 days). This delay is undesirable in conditions requiring immediate effective treatment.
  • the second disadvantage. is. the persistent and protracted. anti-coagulant effect. inthe body after discontinuing; the administration. of; the drug (2 to 10 days). For this reason. strict precautions are to be taken in order; to avoidsevere and dangerous action.
  • the effects. are, cumulative and over-dosage may cause severe hemorrhage. In many cases. dangerous prothrombin levels persist after; use of 3,3'-meth-ylenebis.-(4-hydroxyccumarin); to. such an extent.
  • the amides do not. possess the disadvantages of the 3,3-methylenebis-(4-hydroxycoumarin). In contrast with the slow onset, the long time to reach the maximum effect and persistentafter eifects, the amides, accomplish a more rapid de- 7 crease of the prothrombin concentration of the.
  • ester is then converted to the corresponding ethyl amide following the customary procedures for conversion with ethyl amine as follows:
  • ethyl ester is refluxed for 8 hours with 5 parts of a 70% solution of ethyl amine.
  • the solution is acidified to a pH of 3-4 and the precipitate i filtered off. This precipitate is then recrystallized from acetone.
  • the ethyl amide of 3,3-carboxymethylenebis (4-hydroxycoumarin) is a white crystalline solid. When the solid is finely ground it melts at 203 to 204 C. with decomposition. It has been observed that when a melting point is taken of the crystalline material before grinding, it melts as high as 215 to 216 C. with decomposition. It is soluble in sodium carbonate and bases of the same or greater strength, insoluble in dilute mineral acids and insoluble in water. It i intended for oral administration, and for this rea- Butylamide of 3,3- m 1 Action carboxymethylenebisyene (4 hydroxycoumarm) (4-hydroxycoumarm) Onset of action 6 hours in all cases 24 to 48 hours. Maximum action Mo 15 hours inama- 3 to 5 days.
  • Example IV The diethylamide of 3,3-carboxymethylenebis (4-hydroxycoumarin) was prepared by dissolving 2 grams of the lactone (made with acetic anhydride in accordance with Example I) in a solution of 5 cc. of diethylamine and 5 cc. of water.
  • Percent Normal Prothmmbin Tjme- 40 Other amides may be prepared in accordance with my invention as indicated generally here- 1m 4 1 7 1 9 1mm in, and have the same uses as 3,3'-methylenebis- (4-hydroxycoumarin), but with the advantages d f I Percent Percent Percegt Percengs 0f quicker onset of the effect and a less protrac- Eth lami e 0 3,3 -car- 20 60 0 bofiymethylenebis tlve action as explained herein. i fi l ah 40 10 5 r I clalm' 3, -me yene is yo droxycoumarin) 1.
  • amides may be made following the same general procedure and using ammonia or the corresponding amine.
  • other amides may be prepared by reacting ammonia, butyl amine, amyl amine, diethyl amine, etc., with the ethyl ester or other esters as the starting material.
  • Ezrample III The butylamide of 3,3'-carboxymethylenebis (l-hydroxycoumarin) was prepared by dissolving 5 grams of the lactone (made with thionyl chloride in accordance with Example I) in a solution of 25 cc. of butyl amine and 25 cc. of water, and permitted to stand at room temperature. An excess of hydrochloric acid was then added, and the oily precipitate crystallized on standing. The precipitate was filtered, washed with water, dried at room temperature and recrystallized from acetone. The yield was 4.45 grams having a melting point of 202 C. with decomposition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US166070A 1950-06-03 1950-06-03 Anticoagulant, amide of 3, 3'-carboxy-methylene bis Expired - Lifetime US2601308A (en)

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BE496764D BE496764A (en)) 1950-06-03
US166070A US2601308A (en) 1950-06-03 1950-06-03 Anticoagulant, amide of 3, 3'-carboxy-methylene bis

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2810730A (en) * 1948-12-30 1957-10-22 Fucik Karel Process for making esters of bis(4-hydroxycoumarin-3-yl) acetic acid
US2811534A (en) * 1949-12-31 1957-10-29 Spofa Vereinigte Pharma Werke Method of manufacture of the biologically active coumarine derivatives
US2899358A (en) * 1959-08-11 Process
US3264323A (en) * 1963-12-17 1966-08-02 Warner Lambert Pharmaceutical Coumarin derivative

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB580084A (en) * 1941-10-11 1946-08-27 Wisconsin Alumni Res Found Anti-coagulant bis(4-hydroxycoumarins) and process for making the same
US2482510A (en) * 1944-03-18 1949-09-20 Spojene Farmaceuticke Zd Y Nar Derivatives of the benzotetronic acid and processes for manufacturing same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB580084A (en) * 1941-10-11 1946-08-27 Wisconsin Alumni Res Found Anti-coagulant bis(4-hydroxycoumarins) and process for making the same
US2482510A (en) * 1944-03-18 1949-09-20 Spojene Farmaceuticke Zd Y Nar Derivatives of the benzotetronic acid and processes for manufacturing same

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899358A (en) * 1959-08-11 Process
US2810730A (en) * 1948-12-30 1957-10-22 Fucik Karel Process for making esters of bis(4-hydroxycoumarin-3-yl) acetic acid
US2811534A (en) * 1949-12-31 1957-10-29 Spofa Vereinigte Pharma Werke Method of manufacture of the biologically active coumarine derivatives
US3264323A (en) * 1963-12-17 1966-08-02 Warner Lambert Pharmaceutical Coumarin derivative

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