IL31192A - Anti-fibrinolytic bicycloheptane,bicyclooctane and bicyclononane compounds - Google Patents

Description

and bicyclononane MERCK 29406 This Invention to new compounds capable of counteracting certain hemorrhagic ditions and other disorders resulting from a pathologioal fibrinolytic state in These are bicyclooctane and bicyclononane compounds of the structure II which a is 2 or 3 and each X is either or The invention also relates to pharmaceutical compositions for the prevention or treatmen of a pathological fibrinolytic state i suitable for the oral of from 1 to 20 and preferably 2 to 8 of body weight per day of the above compounds for varying periods of The dissolution of fibrin deposits in mammals is due to their lysis by the enzyme which is formed in the blood from also presen in the conversion plasminogen to is promoted activators in the blood and it appear that excessive fibrinolytic activity results from an abundance of such When too much plasmln is the system of the blood becomes clots cannot be and hemorrhage may situation is known as a fibrinolytic Other enzyme systems the may also be activated in an undesirable manner when such a An Interest has recently developed fibrlnolytio drugs which will inhibit the activation of plasminogen to form These fibrlnolytlc agents are believed to interfere with the tion of the activators of converting plasminogen to The clinical of such drugs include their tion to persons undergoing various kinds of surgery as and prostrate obstetrical hemorrhage and many other uses which have been suggested the literature see Acta Supp volume 1 1966 A standard against which newer ones are generally tested and compared is epsilon known as One deficiency agent has been the very high dosages some cases 3 6 grams or more every 4 to 6 diarrhea side effects such as nausea been two more potent agents have been namely carboxylic acid and acid reported to be more active than by both in vitro and in vivo tests see Anderssen 230 and et al Acta et Toxicol 65 both of which discuss This invention provides a class of aminomethyl acids which shows activities of 5 to 50 times that of in tests essentially the same as those know to correlate with clinical Their use thus constitutes an improved 3 The according to this invention are lic lic acid and the corresponding diketo Further modification of this moleoular such as substitution on the nitrogen or deletion of the between the nitrogen and the appears to destroy the Especially preferred the compound which shows at least 50 times the activity EACA Ln and is 8 times as active vivo in This compound has the further advantage being well absorbed by oral almost as well as when given The compounds of this invention are prepared by catalytic reduction of the corresponding heptane or octane or In the case of the bicycloheptane and bicyclooctane the cyano compound is known and Journal of Organic Chemistry corresponding bicyclononane cyano acid is prepared in a similar synthetic route in which is substituted for ethane in the second syntheses are described in the Plow The keto compounds are similarly prepared except that the keto groups are protected until the end as ethylene ketal The boxylic esters are prepared by direct esterification of the amino acids such as by the use of alcoholic hydrogen chloride or thionyl chloride followed by the alkanoyl amino compounds are prepared by acylation of the amino These esters and alkanoyl derivatives are to be considered as inoludod nf structural formulae and in tho appondod cla SHEET FLOW SHEET Equivalents R ethyl n 2 or 3 Reactions Claisen condensation with Reaction with NaH or other strong base followed by BR Reaction with HS presence of etherate in glacial acetic acid Reduction with Raney nickel Gentle saponification with a base such as NaOH in aqueous alcohol Reaction with triethylamine and chloroformic followed by ammonia to convert the anhydride to the amide Dehydration with in or pyridine Heat with base such as NaOH in aqueous alcohol Catalytic such as over Pt in aqueous alcoholic HCl solution Reaction with glycol in presence of toluene sulfonic acid in benzene Heating with acid The compounds of this invention are used in the method of this invention by either or intravenous although the oral route is The esters and of this class of compounds are not selves very active in but the action of enzymes in vivo may cause the slow liberation of the highly active amino thus providing a prolonged availability of the drug in the This is important because of the tendency of these drugs to be swiftly eliminated in the The compounds of this invention can be used in any pharmaceutically acceptable in the form of tablets or The pharmaceutically acceptable salts of the amino group such as the hydrobromide and of the carboxy group such as the alkali alkaline earth are readily especially in injectable The invention can be illustrated by the ing EXAMPLE 1 acid Hydrochloride salt To a solution of of acid et al JACS 1953 75 in 100 ethanol was added 6 hydrochloric acid and 500 platinum During hydrogenation on a Paar apparatus at room temperature and stopped and the reaction mixture filtered through sintered glass to remove the platinum Evaporation of the colorless filtrate in vacuo left a white solid which was reevaporated with three portions of ethanol to remove most of the excess hydrochloric Purification was accomplished by dissolution in 200 hot ethanol and reprecipitation with 750 absolute ethyl The white in sealed capillary at after air was obtained in Three recrystallizations from ethanol ether gave analytically pure which was dried at over phosphorous pentoxide for 18 hours at The product exhibited a single circular ninhydrin positive spot upon thin layer chromatography on silica gel with acetic Free Amino Acid A sample of analytically pure hydrochloride was dissolved in 2 distilled placed above a column of acetate wet and eluted with distilled Tests with hydrin indicated that all of the free amino acid was tained in the first few of The first 100 of when evaporated in vacuo afforded the free amino After one to three recrystallizations from the material or material dried at for 24 hours melted at with decomposition and some darkening and softening at for 24 hours at over raised the melting point to at EXAMPLE 2 late To 250 of tilled over sodium in a dry atmosphere under nitrogen was added of a dispersion of sodium hydride in mineral oil sodium To this was added in over a with mechanical finely powdered 2 Hydrogen was the mixture became slightly and a pink suspension After removal of 120 of by there was 370 After removal of most of the remaining dimethoxyethane by the mixture was stirred and heated at in an oil bath for 65 The solids were removed by washed with 3 x and diluted with 400 hexane washing with hexane and air drying left Guha Che 1392 Before use in the next synthetic the material was recrystaliized from ethanol and was dried overnight at in dicarbox and was added boron trifluoride The resultant mixture was stirred at room temperature with protection from moisture for three After the tion of 160 the mixture was extracted with 3 x 60 4 x 50 sodium then 3 x After drying over magnesium evaporation of the solven left a viscous Trituration with 70 of methanol and chilling afforded a white tion from then two recrystallizations from gave analytically pure material as Diethyl b A solution in 300 ethanol refluxed with 300 active Raney nickel catalyst for four After removal of the nickel catalyst by the ethanol was removed in vacuo and the product separated from the phase mixture with water by extraction into The combined ether layers were dried over anhydrous magnesium filtered and giving colorless liquid A repeat preparation gave the product in crude Vacuum distillation of crude material afforded colorless Two repeat distillations gave a sample for not removable by the material obtained after one distillation proved of purity sufficient for use in the preparation of ethyl hydrogen hydrogen box To a solution of clean sodium spheres in absolute ethanol was added distilled water and diethyl in one The mixture was stirred magnetically and refluxed for 20 hours under After removal of most of the ethanol in vacuo from the water was added to the Unsaponified diester was removed by extraction into 3 x 25 and ester was covered after drying and removal of the of the chilled aqueous layer with 8 N chloric acid gave a white which was extracted into 4 x 50 ethyl The combined ethyl acetate after afforded viscous solution in 100 chloroform and chilling enabled removal of unwanted the separation could not be cleanly and completely achieved in this as monitored by TLC Evaporation of the filtrate and chromatography over silica gel using form as the gave the mono acid while the diacid did not elute from the There was recovered a slightly oily solid which appeared homogenous by from hexane gave material Ethyl carbox In a dry nitrogen ethyl hydrogen late was dissolved in 60 dry A After cooling to was then over a 10 minute period ethyl chloro in 10 chloroform with keeping the temperature between and After stirring for an additional 15 minutes at ammonia gas was bubbled through the stirred mixture for 15 minutes with continued The was removed and the suspension allowed to stir for 17 hours After a thorough washing with N hydrochloric saturated sodium water and drying over magnesium removal of the chloroform in vacuo left a white which was shown to be homogenous by thin layer yield Three recrystallizations of a small sample from gave an analytical sample Ethyl To dissolved in 30 freshly distilled A molecular was added phosphorous The mixture was refluxed for 20 minutes with protection from moisture After removal of most of the excess solvent and phosphorous oxychloride by distillation in vacuo the red liquid residue was treated with cold saturated sodium evaporation of the pentane layer afforded a pale yellow The material was to be homogenous by thin layer possessed the expected absorptions in the infrared was saponified directly to the corresponding cyano acid without further ox acid To dissolved in 20 absolute ethanol added of sodium The mixture was refluxed for 2 then stirred night at After removal of the ethanol in the remaining solid was dissolved in 20 extracted with then acidified with hydrochloric acid and the product extracted into After washing and drying over magnesium removal of the ether afforded 790 white crude The material was shown to be homogeneous by thin layer The upon recrystallization from remained unchanged in melting and found to trap large quantities of solvent removed only on drying in vacuo at A small sample was recrystallized three times from benzene and after drying for analysis melted at acid hydrochloride To a solution of acid in 40 absolute ethanol was added 20 distilled 35 for 2 After removal of the catalyst by the filtrate was stripped in vacuo at then reevaporated several times with fresh portions of distilled A white solid in nearly quantitative Thin layer chromatography indicated one ninhydrin positive One recrystallization from afforded the pure 371 The sample was recrystallized three more times from et ether for without change in melting EXAMPLE 1 was prepared from the ing dioxo compound essentially as described by Holtz and 8δ To a solution of 2 in 9CC ethanol was added of N The mixture was stirred magnetically and refluxed under nitrogen for 22 After removal of most of the ethanol in 250 water was added and the mixture extracted with ethyl acetate for recovery of of the starting diester which could be The chilled aqueous layer was acidified with 30 of then extracted several times with ethyl The combined in affording of white which was shown by thin layer chromatography to be a mixture of the desired mono acid with diacid of and respectively in silica employing acetic acid as the Passage of this material through a column of 500 of silica employing chloroform and chloroform ethyl acetate as the eluant enabled clean separation of the mono and of the crude mono acid from the column from benzene afforded the pure in yield based upon unrecovered Several recrystallizations from ethanol gave an analytical To a solution of ethyl dicarboxylate in 500 dry chloroform was added triethyla ine To the chilled solution was added ethyl chloroformate over a maintaining the temperature at After the addition was stirring was continued at this temperature for an additional thirty With continued cooling in an ammonia gas was bubbled into the mixture for the mixture allowed to warm to room temperature with stirring After removal of the chloroform in addition of water and thorough extraction with ethyl acetate afforded nearly analytically pure amide 159 Three To a solution of of in 170 dry pyridine was added slowly 17 phosphorous ox The resulting solution was heated at for about 1 The volume was duced to about 30 by distillation in vacuo and the cooled residue added cautiously to about 300 saturated sodium bicarbonate containing Extraction with ethyl drying over magnesium filtering and stripping in vacuo left a yellow oil which solidified when from hexane afforded pure yield tion from hexane gave an analytical acid To dissolved in 50 ethanol was added sodium The mixture was refluxed for 6 hours under then left After removal of the ethanol in vacuo and the addition of starting material was recovered by ether Careful acidification of the cold aqueous layer produced an oil which quickly began to The product was collected either by filtration or extraction into ethyl After one recrystallization of the crude cyano acid based on unrecovered of pure product was Recrystallization from carboxylic acid To 590 mg aoid in 40 ml ethanol was added ml of hydrochloric acid and 100 mg platinium The compound was hydrogenated for 2 hours at filtered and then fluxed for 8 hours with 20 ml 6 hydrochloric After evaporation in vacuo and several times with small portions of the crude amino hydrochloride was dissolved in 5 water and through a column of acetate Evaporation of the effluent gave the crystalline Several reorystallizations from gave the amino acid for analysis The material appears to darken upon heating above exhibits the expected infrared absorptions 1610 1560 1450 1380 1270 1210 1140 780 560 350 and appears homogeneous upon thin layer chromatography on silica gel with butanolacetic It will be observed that the diketo compounds of 3 have been identified as having and configurations due to a lack of a plane of their mirror images are not EXAMPLE acid The above compound was prepared according to the cedure reported by Wilcox et al Journal of Organic Chemistry page 18 acid hydrochloride To 165 mg of acid dissolved in 20 ml ethanol was added 8 ml of ml of hydrochloric acid and 100 mg platinum The compound was hydrogenated on a Parr at 35 at room temperature for one After removal of the catalyst by filtration through sintered the filtrate was evaporated in vacuo at steam bath It was then washed three times with fresh 10 ml portions of A white solid 185 with an with The material appeared to be homogeneous by thin layer chromatography silica gel with Three from gave an analytical with EXAMPLE 5 Compounds are tested by measuring the effect of the inhibitor at various concentrations on the lyeie times of a fibrin clot with a constant concentration of streptokinase in The concentration of the inhibitor which increases the geometric mean lysis time by is Epsilon amino caproic acid is used as a standard and the relative potencies are with the following results 19 Compound Relative vitro Activity Reference Compound EACA Compounda acid acid lic acid aoid hydrochloride a y 30 Ihe Gomplimenls REINHOLD COHN AND PARTNERS PATENT ATTORNEYS 0 D 3 20 insufficientOCRQuality

Claims (1)

1. CLAIMS bicyclooctane and bicyclononane compounds the formula X X wherein each X stands for two hydrogen atoms or one oxygen atom and n is 2 or and their pharmaceutically acceptable acid and its acid and its carboxylic acid and it3 A process of preparing compounds of formula I in Claim which comprises catalytic reduction of a compound of the structure 21 Υ II which Y is or 0 and n is 2 or when Y is not heating with a mineral acid to free the Pharmaceutical comprising as an active agent a compound according to any of Claims 1 to For the Applicants AND PARTNERS insufficientOCRQuality