US3634499A - Antifibrinolytic compounds - Google Patents

Antifibrinolytic compounds Download PDF

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Publication number
US3634499A
US3634499A US833161A US3634499DA US3634499A US 3634499 A US3634499 A US 3634499A US 833161 A US833161 A US 833161A US 3634499D A US3634499D A US 3634499DA US 3634499 A US3634499 A US 3634499A
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United States
Prior art keywords
ethanol
carboxylic acid
acid
compounds
nonane
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Expired - Lifetime
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US833161A
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English (en)
Inventor
Larry J Loeffler
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Merck and Co Inc
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Merck and Co Inc
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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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F21—LIGHTING
    • F21V—FUNCTIONAL FEATURES OR DETAILS OF LIGHTING DEVICES OR SYSTEMS THEREOF; STRUCTURAL COMBINATIONS OF LIGHTING DEVICES WITH OTHER ARTICLES, NOT OTHERWISE PROVIDED FOR
    • F21V23/00—Arrangement of electric circuit elements in or on lighting devices
    • F21V23/02—Arrangement of electric circuit elements in or on lighting devices the elements being transformers, impedances or power supply units, e.g. a transformer with a rectifier
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05B—ELECTRIC HEATING; ELECTRIC LIGHT SOURCES NOT OTHERWISE PROVIDED FOR; CIRCUIT ARRANGEMENTS FOR ELECTRIC LIGHT SOURCES, IN GENERAL
    • H05B41/00—Circuit arrangements or apparatus for igniting or operating discharge lamps
    • H05B41/02—Details

Definitions

  • n 1, 2 or 3 and in which X is either H or 0. More specifically also, 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.
  • fibrinolytic activity results from an overabundance of such activators.
  • plasmin fibrinolysin
  • activators in the blood and it would appear that excessive fibrinolytic activity results from an overabundance of such activators.
  • fibrinolytic state When too much plasmin is present, the clotting system of the blood becomes unbalanced, viable clots cannot be maintained, and hemorrhage may result. This situation is known as a fibrinolytic state.
  • Other enzyme systems i.e., the kallikreins, complement
  • anti-fibrinolytic agents i.e. drugs which will inhibit the activation of plasminogen to form plasmin.
  • anti-fibrinolytic 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 (eg see Nilssen, Acta Medica Scand, Suppl. 448, volume 180, 1966).
  • EACA epsilon aminocaproic acid
  • AMOHA trans-4-aminomethylcyclohexane carboxylic acid
  • -PAMBA 4-aminomethylbenzoic acid
  • the new compounds of my invention have the general structure in which n is 1, 2 or 3 and X is H or 0. They are thus 4-aminomethylbicyclo-[2.2.1]-heptane-1-carboxylic acid, 4-aminomethylbicyclo-[2.2.21-octane 1 carboxylic acid, 5 aminomethylbicyclo-[3.2.2]-nonane-1-carboxylic acid and the corresponding diketo compounds. Further modification of this molecular arrangement, such as substitution on the nitrogen or deletion of the -CH between the nitrogen and the ring, appears to destroy the activity.
  • the compound 4-aminomethylbicyclo-[2.2.2]-octane-1-carboxylic acid which shows at least 50 times the activity of EACA in vitro and is 8 times as active in vivo in dogs.
  • This compound has the further advantage of being well absorbed by oral administration; almost as well as when given intravenously.
  • the compounds of this invention are prepared by catalytic reduction of the corresponding 4-cyanobicycloheptane or octane or 5-cyanobicyclo-nonane-carboxylic acid.
  • the cyano compound is known [Roberts et al. J. Am. Chem. Soc. 637 (1953)] and [Wilcox et a1. Journal of Organic Chemistry, 33 877 (1968)].
  • the corresponding bicyclononane cyano acid is prepared in a similar synthetic route in which 1,3-dibromopropane is substituted for 1,2-dibromoethane in the second step.
  • the keto compounds are similarly prepared except that the keto groups are protected until the end as ethylene ketal derivatives.
  • the carboxylic esters are prepared by direct esterification of the amino acids such as by the use of alcoholic hydrogen chloride or thionyl chloride followed by alcohol.
  • the alkanoyl amino compounds are prepared by acylation of the amino acids.
  • esters and amides of this class of compounds are not themselves very active in vitro but the action of enzymes in vivo may 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.
  • the compounds of this invention can be used in 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) are readily usable, especially in injectable compositions.
  • EXAMPLE 1 4-aminomethylbicyclo- [2.2.2] -octane-1-carboxylic acid (A) Hydrochloride salt.To a solution of 2.80 g. (0.0156 mole) of 4-cyanobicyclo-[2.2.2]-octane-l-carboxylic acid (Roberts et al. JACS 1953, 75 637) in 100 ml. ethanol was added 5.0 ml. 6 N hydrochloric acid and 500 mg. platinum oxide. During hydrogenation on a Paar apparatus at room temperature and 40 lbs/in. pressure, the theoretical quantity of hydrogen was absorbed during the first half hour. After 2 hours, the hydrogenation was stopped and the reaction mixture filtered through sintered glass to remove the platinum catalyst.
  • EXAMPLE 2 Diethyl-6,8-dioxobicyclo-[3.2.2]-nonane-1,5- dicarboxylate To 250 ml. of 1,2-dimethoxyethane (freshly distilled over sodium hydride) in a dry atmosphere under nitrogen was added 25.0 g. of a 55.7% dispersion of sodium hydride in mineral oil (13.92 g. sodium hydride) (0.58 mole). To this was added in portions, over a half-hour period, with mechanical stirring, 73.8 g. (0.29 mole) finely powdered diethyl-1,4-cyclohexanedione 2,5-dicarboxylate [Org. Synth. 45, 25 (1966)].
  • Vapor phase chromatography of this material indicated the presence of a minor contaminant or less), not removable by distillation. However, the material obtained after one distillation proved of purity sufficient for use in the preparation of ethyl hydrogen bicyclo- [3.2.2]-nonane-1,5-dicarboxylate.
  • the chilled aqueous layer was acidified with 30 ml. of 6 N HCl, then extracted several times with ethyl acetate.
  • the combined ethyl acetate layers were washed with water, dried over magnesium sulfate, filtered, and the solvent stripped in vacuo, affording 38.4 g. of white powder, which was shown by thin layer chromatography to be a mixture of the desired mono acid with diacid (R s of 0.67 and 0.41 respectively on silica gel, employing 90:25:4 benzene-dioxane-acetic acid as the eluant). Passage of this material (66.5 g.) through a column of 500 g.
  • I claim: 1. A compound selected from the group consisting of 11' i 12- .i X '5. The compound of claim 1 in which X is O, and
  • n 2-6.
  • X is O
  • NH CH2C(CH2)nOC 0011 n 3.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Power Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US833161A 1969-06-13 1969-06-13 Antifibrinolytic compounds Expired - Lifetime US3634499A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US83316169A 1969-06-13 1969-06-13

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US3634499A true US3634499A (en) 1972-01-11

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US (1) US3634499A (en))
AT (1) AT298444B (en))
BE (1) BE741294A (en))
DE (1) DE1946067C3 (en))
FI (1) FI51344C (en))
FR (1) FR2052965B2 (en))
GB (1) GB1243321A (en))
IE (1) IE33852B1 (en))
NL (1) NL144264B (en))
SE (1) SE363502B (en))

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4331569A (en) * 1979-12-29 1982-05-25 Nippon Petrochemicals Co., Ltd. Substituted norbornanone acetals, process for preparing the same, and perfume compositions containing the same
US10202331B2 (en) 2014-11-03 2019-02-12 Thrombolytics, Llc Antifibrinolytic compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4331569A (en) * 1979-12-29 1982-05-25 Nippon Petrochemicals Co., Ltd. Substituted norbornanone acetals, process for preparing the same, and perfume compositions containing the same
US10202331B2 (en) 2014-11-03 2019-02-12 Thrombolytics, Llc Antifibrinolytic compounds

Also Published As

Publication number Publication date
IE33852B1 (en) 1974-11-27
FR2052965A2 (en)) 1971-04-16
DE1946067B2 (de) 1979-01-18
NL6914849A (en)) 1970-12-15
FI51344C (fi) 1976-12-10
AT298444B (de) 1972-05-10
FR2052965B2 (en)) 1973-06-08
BE741294A (en)) 1970-05-05
DE1946067A1 (de) 1970-12-23
NL144264B (nl) 1974-12-16
FI51344B (en)) 1976-08-31
DE1946067C3 (de) 1979-09-27
GB1243321A (en) 1971-08-18
SE363502B (en)) 1974-01-21

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