IL35902A - Tris-and tetrakis-(1,2,3,4-tetrahydroisoquinoline)and-(3,4-dihydroisoquinoline)compounds - Google Patents

Description

COMPOUNDS T AND AND 3 COMPOUNDS This invention relates to new compounds useful for inhibiting the formation of blood or dissolving blood clots after they have been and more particularly to novel alkylenetris and alkylenetetrakis 1 2 tetrahydro and and the pharmaceutically acceptable acid addition salts In the formation of a blood for example a a soluble plasma is converted to the insoluble protein As the fibrin is deposited it entraps blood cells within its meshwork to form a In the case of a the coagulum usually interferes with the flow through the blood The defense of the living organism against such occurrence is the plasma protein called plasminogen under certain can be activated by an whereby the plasminogen is converted to the Plasmin possesses the property of efficiently digesting and destroying fibrin The fibrinolysis results in dissolution of the in the case of a restores the patency of the Under normal the organism has low levels of in the blood It is believed that small amounts of plasminogen are constantly undergoing conversion to plasmin by the action of the from a quantitative the amount of activator normally present is insufficient to produce enough plasmin to lyse the relatively large amount of fibrin present activity is nanifcstcd by compounds such as the aromatic sulfonic derivatives of salicylic long chain fatty acids and halogcnated saturated Such compounds have been found to exhibit vivo fibrinolytic or thrombolytic Fibrinolytic activity in vivo can be induced by nicotin serotonin and the effect of these compounds is of of the order of Some sulphonylureas and steroids can induce an increase in fibrinolytic but a lag period of the order of hours precedes the slow increase lytic Compounds of this type cannot be used when a substance is employed to effect bolytic because in such instance the activity must be rapidly induced to be effective in dissolving a streptococcal has been used for but the side effects of pyrogenicity and reactions have limited its a protein isolated from human has also been used for thrombolysis but the difficulties involved in accumulating large supplies of the starting human and the great cost of preparing the substance has scribed its general and practical Bacterial pyrogens have also been used to effect but the severity and unpredictability of the pyrogenic reactions have negated their The present invention provides compounds which inhibit the formation of blood clots inhibiting platelet aggregation fibrin or dissolve such clots as they are formed or after they have been formed Such substances demonstrate Various of the compounds of this invention be to effect fibrinolysis of the clot in acute Many possess the further advantage oral activity and may be employed prophylactical ly to maintain increased fibrinolytic activity on a long term basis and thus diminish the incidence of new thrombotic Other objects and advantages of the compounds disclosed in the present methods of preparing them and compositions containing the same which are useful in preventing the formation of blood or in effecting high sustained levels of fibrinolytic activity in mammals without toxic even at substantially high dosage will be apparent from the detailed description of the preferred bodiments The novel compounds according to the invention are characterized by the following general A and is each hydrogen taken represent a single and represent hydrogen or lower substituents R and represent lower any adjacent of and R may be linked together to 3 5 form lower By the term is meant such groups having from 1 to about 6 carbon except for which refers to alkylenedioxy having up to 3 carbon Z is optionally substituted by alkyl wherein the alkylene alkyl substituents thereon may be interrupted by sulfur or nitrogen halobenzyl methyl methylenedloxy or cycloalkanediylidene or thio yrandiylidene n represents the numbers 3 or This invention is also characterized by pharmaceu cally acceptable acid addition salts of the compounds of the above general formula as well as compositions containing such The term acceptable addition includes such salts the mineral acid hydrobromide sulfate and and organic acid salts such as the toluenesulfonate and others conventionally formed acids ventionally used in the pharmaceutical The or alkylenetetrnkis 2 isoquinol compounds within the above formula are useful as fibrinolytic agents in Such materials additionally possess the property of inhibiting platelet aggregation and may thus be utilized for inhibiting the of blood clots as well as for dissolving such clots as they may be formed or after they have been The s or aki s i hydro i possess the property plntclct both the tctrahydroisoquinol nc and dihydroisoquinoline compounds within the above formula are useful for inhibiting the formation of blood The compounds of the invention are prepared by permitting selected and tetracarboxylic acids or their derivatives and chlorides and the to react with appropriately substituted phenethylamines The and thus derived are cyclized through dehydration to the compounds within the above in accordance with the with which those skilled in the art are The cyclization is effected by reacting the amides with phosphorus oxychloride by itself or diluted with an equal amount of a suitable benzene or The dihydroisoquinolines thus produced are thereafter converted to the 1 2 tetrahydroisoquinoline compounds of the above formula by The reduction step is carried out for sodium borohydride in alcoholic solution or lithium aluminum hydride in It will apparent from a consideration of the chemistry involved in making the products of this invention that their preparation results in the formation of mixtures of diastereoisomers It has been found that all such isomers display fibrinolytic or platelet aggregation inhibiting The for et Organic Reactions and 218 preceding formula therefore embraces all of the isomers arising during the synthesis of these The designation of the compounds of the by names and by formulas throughout the specification and shall be read to include all isomers and mixtures The preparation of any particular stereoisomer from a mixture of such isomers will be within the competence of one skilled in the A typical technique involves reacting the mixture of isomers of any given compound with a particular stereoisomer of an acid to form an isomeric mixture of acid addition These salts will have differing physical properties and can be separated by known Oxygenated functions are generally beneficial for maximum activity and with one preferred aspect of this invention there is included in and one or more lower alkoxy functions such as butoxy or methylenedioxy These functions are most effective when situated at the 6 7 positions of the tetrahydroisoquinoline The Z variable in most the residue after removal of the carboxy groups of the or tetracarboxylic acid that was used to produce the compound of the Representative types of organic groups that can be the Z variable include alkanetriyl having from 1 to 3 or nitrogen hetero phenylalkanetriyl benzylalkanetriyl and substituted alkanetetrayl having from 1 to 4 sulfur or nitrogen diylidenetetraethylene tetrahydrothiopyrandiy1 tetrahydropyrandiylidenetetraethylene and the In the Z variable can contain substituents such as the Z chain i tct rah i i and d inol i nc groups in the above may vary within wide limits with retention of Activity is when the individual i moieties are separated by chains of from three to ten carbon atom The nature of Z is determined by the and tctracarboxylic acids or their derivatives acid chlorides and the used in the synthesis of the compounds within the generic Representative of acids which may be used in the preparation of biologically potent compounds of the above class are the COOH COOH COOII CHA 4 COOII COOII COOII a 3 CH CH3 CH3 HO HO Certain compounds within the scope of the present invention have been tested for fibrinolytic by whole clot lysis as modified from the procedure of Billimoria et In this blood from rats given a fibrinolytic compound i is taken and diluted 1 10 A standard amount is clotted with incubated at for four and the amount of clot that has is The dose of a compound is that in which will cause the lysis of of the clot under the above These values for the various compounds tested are set forth in the following each of the compounds being identified by the number of the ensuing example in which its synthesis is As basis for the value of bisobrin 3 6 meso in this test is shown at the end of the FIBRINOLYTIC ACTIVITY OF COMPOUNDS OF THE INVENTION 0 0 Lancet 1959 EXAMPLE k Standard bisobrin dihydrochloride Another selection representative compounds within the scope of the present ing some in the previous have been tested for their ability to inhibit platelet Citrated whole blood from human who had not taken any medicine for the previous was centrifuged to obtain platelet rich On addition of ADP enosine to this platelet rich incubated with constant in an a gre optical density changes can be observed which are caused by platelet the extent platelet aggregation is determined for each sample blood Compounds to be were for five minutes prior to the addition of the The ED of a compound is in which reduces platelet aggregation by under the above conditi These values for the various compounds are in the table each of the compounds again being identified by name and by the number of the example in which its synthesis is As standard for the value of dipyridamole imido a clinically used coronary generally as being effective against platelet aggregation and experimental thrombosis is listed at the end of the PLATELET AGGREGATION INHIBITORY ACTIVITY OF COMPOUNDS OF THE INVENTION EXAMPLE ED 50 6 la la Didisheim Mayo EXAMPLE NO 9 6 dipyridamole The compositions of this invention contain n compound the above formula v i t dry filled d aqueous queous syru and the The compositions and in many cases do contain suitable coloring and flavoring Some examples of the carriers can be used in the preparation of the of the invention are gelatin sugars such as lactose and methyl cellulose and cellulose acetate magnesium vegetable oils such as peanut cottonseed sesame olive theo corn oil and oil of the liquid polyethylene propylene water and isotonic In preparing the compositions of the invention for maceutical the conventional practices and precautions are The compositions for parenteral administration must be sterile and this can be accomplished either by using sterile ingredients and carrying out the production under aseptic or by sterilizing the final composition by one of the usual procedures such as millipore Customary care should be exercised that no incompatible condition exists between the active component and the diluent preservative or flavoring agent or in the conditions employed preparation of the The compositions of the invention can be introduced into the by the or parenteral This can done by injecting the liquid preparations or by in the cases of the solid and li uid by local application in as appropriat Lf l 1 7 10XYI of 100 of the trimcthyl ester of nonancdioic acid and 210 of is stirred and heated at for 5 hours under an of cooled to about and dissolved in 1 of The solution is washed thrice with 800 portions of chloric then with dried over anhydrous magnesium sulfate and The filtrate is stripped of the solvent under reduced the residue dissolved in a minimum quantity of acetone and the solution is with to an excess of anhydrous ether cooled in dry The resulting triamide which separates is filtered and melts at after recrystallization A mixture of 100 of the amide and 400 of phosphorus diluted with an volume of anhydrous benzene is protected from for 5 and evaporated to under reduced The residue is carefully hydrolyzed with water and the clear solution thus obtained is extracted once with 500 of The chloroform extract is the aqueous layer is cooled and with aqueous sodium and then extracted thrice with 800 portions of The combined chloroform extracts are oughly washed with dried over anhydrous magnesium sulfate and The filtrate is stripped of the solvent under reduced the in 500 absolute ethanol and treated with of sodium added in small with vigorous The mixture is then protected from i for 5 and evaporated to dryness under insufficientOCRQuality

Claims (1)

1. A and B is each hydrogen or taken together represents a single and which may be the same or different are hydrogen or lower which may be the same or are lower lower lower phenyl lower or any adjacent pairs of the groups and may be joined together to form lower n is 3 or and Z is optionally substituted by alkyl wherein the alkylene and the alkyl substituents thereon may be interrupted by sulfur or nitrogen halobenzyl or or thiopyrandiylidene A according to claim wherein the alkane moiety has from to 18 carbon A tris according to claim wherein the alkane moiety has from 5 to 18 carbon A according to claim wherein the alkane moiety has from 7 to 18 carbon A according to claim wherein the alkane moiety has from 7 to 18 carbon pentamethylene A according to claim herein the benzyl group can be optionally substituted by up to three substituente on the benzene ring selected from i o halo and 3 A to claim 1 wherein benzyl group can be optionally substituted by up to three on the benzene ring selected from alk C amino 3 halo and A tetrakis according to claim 1 wherein the ring contains from to 8 carbon A tetrakis according to claim 1 wherein the aliphatic ring contains from to 8 carbon A tetrakis A tetraethylene A tetraethylene compound accordin to any of claims to wherein one or more of the tetrahydroisoquinoline or groups is substituted by at least one subetituent selected from C C benzyloxy and o l 11 4 6 1 2 2 4 6 7 ethyl 6 7 3 tetrakis 2 tetra tetrakis 6 ethyl penta bis tetrakis 7 tetrakis isoquinol bis 6 acid A salt 28 of a compound as claimed in any of Claims 1 to A pharmaceutical composition comprising one or more of the compounds as claimed in any of Claims 1 to together with an Alkylenetris and and compounds substantially as hereinbefore described and with reference to any of the Pharmaceutical preparation comprising alkylenetris and and compounds substantially as hereinbefore described and with reference to any of the insufficientOCRQuality