Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid

Definitions

• This invention relates to a new antifibrinolytic compound and to a method of counteracting certain hemorrhagic conditions and other disorders resulting from a pathological fibrinolytic state in patients. More specifically, this invention relates to a new compound of the structure i u uca-@ coon wherein R is lower alkyl and the pharmaceutically acceptable salts thereof. More specifically, it relates to the prevention or treatment of a pathological fibrinolytic state in patients by the oral administration of from 1 to 20 and preferably 2 to 8 mg./kg. of body weight per day of the above compounds for varying periods of treatment.
• fibrin deposits in mammals is due to their lysis by the enzyme plasmin (fibrinolysin) which is formed in the blood from plasminogen, also present in the blood.
• plasmin fibrinogen
• This conversion from plasminogen to plasmin is promoted by activators in the blood and it would appear that excessive fibrinolytic activity results from an overabundance of such activators.
• activators in the blood and it would appear that excessive fibrinolytic activity results from an overabundance of such activators.
• the clotting system of the blood becomes unbalanced, viable clots cannot be maintained, and hemor rhage may result. This situation is known as a fibinolytic state.
• Other enzyme systems i.e., the kallikreins, complement
• antifibrinolytic agents i.e. drugs which will inhibit the activation of plasminogen to form plasmin.
• antifibrinolytic agents are believed to interfere with the function of the activators of converting plasminogen to plasmin.
• the clinical uses of such drugs include their administration to persons undergoing various kinds of surgery (such as heart-lung and prostate surgery), obstetrical hemorrhage problems, menorrhagia, and many other uses which have been suggested in the literature (e.g. see Nilssen, Acta Medica Scand. Suppl. 448, volume 180, 1966).
• EACA epsilon aminocaproic acid
• AMCHA trans-4-aminomethylcyclohexane carboxylic acid
• PAMBA 4-aminomethylbenzoic acid
• the new compound of my invention has the general wherein R is lower alkyl.
• the compound can be used as the racernate or either the d or 1 isomer.
• the pharmaceutically acceptable salts of the compound also show antifibrinolytic activity.
• the present invention also provides a process of preparing a compound of the structure which comprises the catalytic hydrogenation of a compound of the structure wherein R is lower alkyl.
• the hydrogenation is carried out under conventional conditions'generally in the presence of a catalyst such as platinum.
• the lower alkyl group R of 1 to 5 carbon atoms. is either methyl or ethyl.
• the compound is used in the method of this invention by either oral or intravenous administration, although the oral route is preferred.
• the esters and amides of this class compound are not themselves very active in vitro but the action of enzymes in vivo cause the slow liberation of the highly active amino acids, thus providing a prolonged availability of the drug in the body. This is important because of the tendency of these drugs to be swiftly eliminated in the urine.
• Such amides and esters are to be considered as being within the scope of the present invention since it is actually the present compound which produces the result within the body.
• the compound of this invention can be used in a composition comprising any pharmaceutically acceptable carrier, in the form of pills, tablets or capsules.
• pharmaceutically acceptable salts both of the amino group such as the hydrochloride, hydrobromide, sulfate, citrate, tartrate, etc.and of the carboxy group-such as the alkali metal, alkaline earth metal, etc., salts
• the pharmaceutically acceptable salts are readily usable, especially in injectable compositions.
• the invention can be illustrated by the cfollowing examples.
• the triester is hydrolyzed directly without purification by refluxing for 16 hours with a mixture of 25 ml. glacial acetic acid and 25 ml. concentrated hydrochloric acid. Evaporation leaves 1.83 g. (63% crude) of a white solid, which is chromatographed on silica gel (CHCl eluant) to remove a minor slower moving impurity. The chromatographed material is recrystallized from benzene-hexane, giving a white crystalline solid, M.P. 1655-168 C.
• the resulting crystalline solid is collected, washed with water and air-dried. Weight: 0.44 g. M.P. 242-245 C.
• the material is recrystallized from ethanol or ethyl acetate, M.P. 245247 C.
• EXAMPLE 2 The compound is tested in vitro by measuring the effect of the inhibitor at various concentrations on the lysis times of a fibrin clot with a constant concentration of streptokinase in plasminogen-rich plasma. The concentration of the inhibitor which increases the geometric mean lysis time by 50% is estimated. Epsilon amino caproic acid (EACA) is used as a standard and the relative potencies are obtained, with the following results:

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=25266213

Family Applications (1)

Country Status (10)

Cited By (4)

Family Cites Families (1)

• 1969
  • 1969-06-17 US US834138A patent/US3641128A/en not_active Expired - Lifetime
• 1970
  • 1970-05-25 NL NL7007536A patent/NL7007536A/xx not_active Application Discontinuation
  • 1970-06-02 IL IL34651A patent/IL34651A/xx unknown
  • 1970-06-12 ES ES380714A patent/ES380714A1/es not_active Expired
  • 1970-06-12 CH CH890670A patent/CH537366A/de not_active IP Right Cessation
  • 1970-06-15 GB GB1252248D patent/GB1252248A/en not_active Expired
  • 1970-06-16 FR FR7022081A patent/FR2052980B1/fr not_active Expired
  • 1970-06-16 BE BE752042D patent/BE752042A/fr unknown
  • 1970-06-16 DE DE2029756A patent/DE2029756C3/de not_active Expired
  • 1970-06-16 ZA ZA704088A patent/ZA704088B/xx unknown

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