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Publication numberUS3641129 A
Publication typeGrant
Publication dateFeb 8, 1972
Filing dateJun 17, 1969
Priority dateJun 17, 1969
Also published asDE2029807A1, DE2029807B2, DE2029807C3
Publication numberUS 3641129 A, US 3641129A, US-A-3641129, US3641129 A, US3641129A
InventorsLarry J Loeffler
Original AssigneeMerck & Co Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Antifibrinolytic compounds
US 3641129 A
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Description  (OCR text may contain errors)

"United States Patent Oflice 3,641,129 Patented Feb. 8, 19 72 ABSTRACT OF THE DISCLOSURE The compound 4-aminomethylbicyclo-[2,2,2]-octanel-acetic acid and the pharmaceutically acceptable salts thereof are useful as antifibrinolytic compounds.

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 n ucu lu coon 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.

The dissolution of 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. 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. 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) may also be activated in an undesirable manner when such a state exists.

An interest has recently developed in antifibrinolytic agents, i.e. drugs which will inhibit the activation of plasminogen to form plasmin. These 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 heartlung and prostate surgery), obstetrical hemorrhage problems, menorrhagia, and many other uses which have been suggested in the literature (e.g. see Nilssen, Acta Medicia Scand. Suppl. 448, volume 180, 1966).

A standard antifibrinolytic agent, against which newer ones are generally tested and compared is epsilon aminocaproic acid, known as EACA. One deficiency of this agent has been the very high dosages needed; in some cases 3-6 grams or more every 4 to 6 hours. Also, side effects such as dizziness, nausea and diarrhea have been observed. More recently, two more potent agents have been described, namely trans-4-aminomethylcyclohexane carboxylic acid (AMCHA) and 4-aminomethylbenzoic acid (PAMBA). Each is reported to be more active than EACA by both in vitro and in vivo tests (eg see Ander- 'ssen et a1. Scand. J. Haemat. (1965) 2,230 and Melander et al. Acta Pharmacol. et Toxicol 22,340 (1965), both of which discuss AMCHA).

I have found a new aminomethyl bicyclic carboxylic acid which shows an activity of 10 times that of EACA in tests essentially the same as those known to correlate with clinical results. I have thus also found an improved antifibrinolytic method of therapeutic treatment requiring much smaller doses of the drug.

The new compound of my invention has the general structure ll NCH E cn cooa The pharmaceutically acceptable salts of the compound also show antifibrinolytic activity.

The present invention also provides a process of pre paring a compound of the structure which comprises hydrolyzing a compound of the structure wherein R is an organic radical containing of from 1 to about 10 carbon atoms. The hydrolysis is carried out under conventional conditions generally in the presence of an inorganic acid. In a preferred embodiment of the present invention, the R groups are either lower al-kyl or benzyl.

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. The pharmaceutically acceptable salts (both of the amino groupsuch as the hydrochloride, hydrobromide, sulfate, citrate, tartrate, etc.and of the carboxy groupsuch as the alkali metal, alkaline earth metal, etc., salts) are readily usable, especially in injectable compositions.

The invention can be illustrated by the following examples.

EXAMPLE 1 (A) 4 aminomethylbicyclo [2.2.2]-octane-l-carboxylic acid hydrochloride salt To a solution of 2.80 g. (0.0156 mole) of 4-cyanobicyclo-[2.2.2]-octane-l-carboxylic acid (Roberts et a1. LACS 1953 75, 637) in 100 ml. ethanol is added 5.0 ml. 6 N hydrochloric acid and 500 mg. platinum oxide. During hydrogenation on a Parr apparatus at room temperature and 40 lbs/in. pressure, the theoretical quantity of hydrogen is absorbed during the first half hour. After 2 hours, the hydrogenation is stopped and the reaction mixture filtered through sintered glass to remove the platinum catalyst. Evaporation of the clear, colorless filtrate in vacuo (30-40 C.) leaves a white solid which is reevaporated with three portions of ethanol to remove most of the excess hydrochloric acid. Purification is accomplished by dissolution in 200 m1. hot 95% ethanol and reprecipitation with 750 ml. absolute ethyl ether. The white solid, M.P. 318319 C. dec. (placed in sealed capillary at 250 C.) after air drying, is obtained in 90.5% yield. Three recrystallizations from 95% ethanol ether gives analytically pure material, M.P. 318-319 C. dec., which is dried at 110 C. over phosphorous pentoxide for 18 hours at 0.08 mm. Hg. The product exhibits a single circular ninhydrin positive spot (pink) upon thin layer chromatography on silica gel with 3:1:1 n-butanol, acetic acid, water, R =0.65.

(B) 4 benzamidomethylbicyclo-[2.2.2]-octane-1-ca1'boxylic acid To a solution of 1.03 g. (0.0047 mole) 4-aminomethylbicyclo [2.2.2] octane-l-carboxylic acid hydrochloride salt in 10 ml. water is added 4.7 m1. 2 N sodium hydroxide. With vigorous stirring at 0., there is added simultaneously and dropwise 0.66 g. (0.0047 mole) benzoyl chloride and 2.8 ml. 2 N sodium hydroxide. After stirring an additional 2 hours, it is extracted several times with ether and then acidified with 6 N hydrochloric acid. The product, M.P. 177-l80 C., is obtained in 89% yield. Recrystallization from benzene-acetonitrile gives analytically pure material, M.P. l79.5l81 C.

(C) 4 benzamidomethylbicyclo- [2.2.2] -octane-l-carboxylic acid chloride To a suspension of 3.38 g. (0.012 mole) 4-benzamidomethylbicyclo-[2.2.2]-octane-l-carboxylic acid in 10 ml. benzene is added 30 ml. thionyl chloride. The mixture is heated to reflux for 4 hours. After removal of the excess benzene and thionyl chloride in vacuo, the solid acid chloride is reevaporated several times with fresh benzene, then pumped in high vacuum over P 0 The solid product is used for reaction with diazomethane without further purification.

(D) 4 benzamidomethylbicyclo [2.2.2] -octanel-(3-diazo-acetone To a solution of 0.036 mole of diazomethane in 150 ml. ether at 0 to 5 C. is added over 2 hours a solution of the acid chloride prepared above. The solution is allowed to evaporate in a stream of dry nitrogen overnight. The resulting oily solid shows an intense band in the infrared at about 2100 cm." (diazo) and is free of the acid chloride absorption at 1725 cm.

(E) 4 benzamidomethylbicyclo [2.2.2]-octane-l-acetic acid A rearrangement is accomplished by the addition of small portions of the diazoketone (3.10 g., 0.010 mole) to 12 ml. of a mixture of collidine and benzyl alcohol at 170180 C. over a 5-10 minute period. After the addition of ether to the cooled mixture, it is extracted thoroughly with 3 N hydrochloric acid, then water, and finally dried over magnesium sulfate. After filtration and removal of the ether in vacuo, the excess benzyl alcohol is removed by distillation (75 /2 mm. Hg). This crude benzyl ester (3.35 g.) is saponified by stirring overnight in 12 ml. ethanol containing 4.3 ml. 2.0 N NAOH. Removal of the ethanol and acidification of the aqueous solution gives an oil which is extracted into ethyl acetate. The oil is purified by column chromatography on silica gel (benzen-ethyl acetate eluant) to give pure 4-benzamidomethylbicyclo- [2.2.2]-octane-l-acetic acid (700 mg. 23% yield). Because this material could not be obtained in crystalline form, it is hydrolyzed directly without further purification to the amino acid.

(F) 4 aminomethylbicyclo [2.2.2]-octane-1-acetic acid hydrochloride 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:

Compound: Relative in vitro activity (weight basis) (A) Reference compound: EACA 1.0 (B) New compound: 4 aminomethylbicyclo- [2.2.2]-octane-1-acetic acid Many other equivalent modifications of the invention would be apparent to those skilled in the art from a reading of the foregoing without a departure from the inventive concept.

I claim:

1. A compound selected from the group consisting of and the pharmaceutically acceptable salts thereof.

2. 4 aminomethylbicyclo-[2.2.2]-octane-1-acetic acid. 3. The pharmaceutically acceptable salts of the compound of claim 2.

References Cited UNITED STATES PATENTS 3,517,055 6/1970 Loeppler 260514 OTHER REFERENCES March, Advanced Organic Chem., pp. 309, 314, 1968.

LEWIS GO'ITS, Primary Examiner R. GERST, Assistant Examiner US. Cl. X.R.

260-14l, 471 A, 482 R, 501.11, 544 L; 424-319

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US6020370 *Feb 18, 1997Feb 1, 2000Warner-Lambert CompanyBridged cyclic amino acids as pharmaceutical agents
U.S. Classification562/500, 560/37, 560/118, 534/556, 562/867, 562/442
International ClassificationA61K31/185, A61K31/19, A61K31/195
Cooperative ClassificationA61K31/195, A61K31/19
European ClassificationA61K31/195, A61K31/19