US3560620A - Induction of fibrinolysis - Google Patents

Induction of fibrinolysis Download PDF

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Publication number
US3560620A
US3560620A US571195A US3560620DA US3560620A US 3560620 A US3560620 A US 3560620A US 571195 A US571195 A US 571195A US 3560620D A US3560620D A US 3560620DA US 3560620 A US3560620 A US 3560620A
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compounds
formula
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tetrahydro
compound
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Joseph M Schor
Nathan Weiner
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ENDO LABORATORIES Inc
EIDP Inc
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ENDO LAB
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Assigned to E.I. DU PONT DE NEMOURS AND COMPANY reassignment E.I. DU PONT DE NEMOURS AND COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ENDO LABORATORIES, INC., A CORP. OF DEL.
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • This invention relates to means for inducing fibrinolytic activity in mammals. More particularly, it is directed to effecting high, sustained, useful levels of fibrinolytic activity in mammals by the action of alkylenebis [1,2,3,4-tetrohydroisoquinoline] compounds of the following Formula A, or pharmaceutically acceptable acid addition salts thereof, and to compositions containing such substances Formula A wherein:
  • pharmaceutically acceptable addition salt includes such salts as: the mineral acid salts, e.g., the hydrochloride, hydrobromide, sulfate and phosphate; and organic acid salts such as the succinate, benzoate, acetate, p-toluene-sulfonate and benzenesulfonate, and others formed from acids conventionally used in the pharmaceutical art.
  • mineral acid salts e.g., the hydrochloride, hydrobromide, sulfate and phosphate
  • organic acid salts such as the succinate, benzoate, acetate, p-toluene-sulfonate and benzenesulfonate, and others formed from acids conventionally used in the pharmaceutical art.
  • athrombus for example, athrombus, fibrinogen, a soluble plasma protein
  • fibrinogen for example, fibrinogen
  • a soluble plasma protein is converted to the insoluble protein fibrin.
  • fibrin As the fibrin is deposited it entraps blood cells within its meshwork to form a coagulum.
  • the coagulum In the case of a thrombus, the coagulum usually interferes with the flow of blood through the vessel.
  • Plasmin The defense of the living organism against such occurrence is the plasma protein called plasminogen which, under certain conditions, can be activated by an activator whereby the plasminogen is converted to the protein, plasmin. Plasmin possesses the property of efficiently digesting and destroying fibrin (fibrinolysis). The fibrinolysis results in dissolution of the clot; and in the case of a thrombus, restores the potency of the vessel.
  • the organism Under normal conditions, the organism has low levels of acitvator in the blood stream. It is believed that small amounts of plasminogen are constantly undergoing conversion to plasmin by the action of the activator. However, from a quantitative viewpoint the amount of activator normally present is insuflicient to produce enough plasmin to lyse the relatively large amount of fibrin present in a clot such as a thrombus.
  • the compounds of foregoing Formula A have the property of stimulating the production and/or release of relatively large quantities of activator activity into the blood stream. In essence, those compounds induce increased levels of activator which, in turn, produce high levels of plasmin within the clot and this results in dissolution thereof.
  • the compounds of Formula A can be used to dissolve fibrin wherever it is deposited in the organism, independent of the cause of such deposition.
  • Fibrinolytic activity in vitro is manifested by many compounds such as the aromatic sulfonic acids, derivatives of salicyclic acid, long chain fatty acids and halogenated unsaturated acids.
  • the compounds of the present invention are active in vivo.
  • Fibrinolytic activity in vivo can be induced by nicotinic acid, procaine, phenylbutazone, acetylcholine, epinephrine, serotonin and histamine.
  • the effect of these compounds is of short-lived duration, i.e., of the order of minutes.
  • the compounds of Formula A in contrast thereto, can induce prolonged fibrinolytic activity, i.e., of the order of hours.
  • Some sulphonylureas and steroids can induce an increase in fibrinolytic activity, but a lag period of the order of hours precedes the slow increase in lyti cactivity.
  • Compounds of this type cannot be used when a substance is employed to effect thrombolytic therapy, because in such instance the activity must be rapidly induced to be effectice in dissolving clots.
  • the compounds of Formula A in contrast thereto, are highly effective for such use because they induce maximal lytic activity within minutes after administration.
  • Streptokinase a streptococcal protein
  • Streptokinase has been used for thrombolysis, but the side effects of pyrogenicity and anaphylactic reactions have limited its use.
  • compounds of Formula A are free of these side reactions.
  • Urokinase a protein isolated from human urine, has also been used for thrombolysis but the difficulties involved in accumulating large supplies of the starting material, human urine, and the great cost of preparing the substance have proscribed its general and practical utility.
  • Bacterial pyrogens have also been used to effect thrombolysis, but the severity and unpredictability of the pyrogenic reactions have negated their usefulness.
  • the compounds of Formula A are not pyrogenic.
  • fibrinolytic compounds of Formula A are the first synthetic substances which demonstrate activity in mammals in vivo, are highly potent, long-lasting, rapid in onset, readily prepared and suffer from none of the difiiculties associated with materials of natural origin.
  • the compounds of Formula A may be used to effect fibrinolysis of the clot in acute thrombosis. They may also be employed prophylactically to maintain increased fibrinolytic activity or a long term basis and thus diminish the icidence of new thrombotic episodes.
  • alkylenebis [1,2,3,4-tetrahydroisoquinoline] compounds and their acid addition salts present in the compositions of the invention when used in accordance with this invention, possess a high degree of activity and consequently only small amounts are required to produce fibrinolytic effects in mammals. At these dose levels, side effects are generally negligible.
  • Oxygenated functions are generally beneficial for maximum fibrinolytic activity and with one preferred aspect of this invention there is included in R and R one or more lower alkoxy functions such as methoxy, isopropoxy, butoxy or methylenedioxy. These functions are most effective when situated at the 6 and 7 positions of the tetrahydroisoquinoline ring systems.
  • alk The alkylene chain, designated as alk, may vary within wide limits with retention of fibrinolytic potency. Activity is maximized, however, when the tetrahydroisoquinoline rings are separated by chains of from three to ten carbon atoms. Examples of such chains are 2-propyltrimethylene, tetramethylene, 1,8-diethyloctamethylene and decamethylene.
  • R R R and R in preferred compounds, represent hydrogen or alkyl groups of not more than four carbon atoms. Most preferred are those compounds in which R R R and R are hydrogen or methyl.
  • the compounds of Formula A are all either known or, in view of their structures, are readily prepared by methods frequently described in the literature. Generally speaking, their preparation comprises the interaction of an appropriately substituted phenylethylamine with a dicarboxyalkane, whereof the bridge between the carboxyl moieties corresponds to the length of the alkylene chain desired.
  • the bis-phenylethylamide thus derived is then cyclized through dehydration to an alkylene-bis-[3,4-dihydroisoquinoline].
  • the latter is then converted into a compound of Formula A through reduction to the corresponding alkylenebis l,2,3,4-tetrahydroisoquinoline].
  • an outstanding feature of the compounds of Formula A is their relative lack of toxicity. Although they are active at very low dose levels, it is possible to exceed minimum effective levels by wide margins without encountering serious adverse reactions. This permits the compounds to be used without concern about undesirable side effects, as are so frequently encountered upon inadvertent overdosage of other substances of great potency.
  • compounds of Formula A were found to be effective in inducing fibrinolysis at 0.05 mg./kg. It was found, indeed, that the same compounds could be administered at levels of 100 mg./kg. By intravenous administration to rats, the compounds were effective at 0.05 ing/kg. and also at 80 mg./kg.
  • compositions of the invention contain an alkylenebis-[1,2,3,4-tetrahydroisoquinoline] having Formula A or a non-toxic acid addition salt thereof together with a carrier.
  • the carrier may be either a solid or liquid and the compositions can be in the form of tablets, liquidfilled capsules, dry filled capsules, dragees, pills, aqueous solutions, non-aqueous solutions, jellies, suppositories, syrups, suspensions, sprays, powders and the like.
  • the compositions can, and in many cases, do contain suitable preservatives, coloring and flavoring agents.
  • Some examples of the carriers which can be used in the preparation of the products of the invention are gelatin capsules, sugars such as lactose and sucrose; cellulose, methyl cellulose and cellulose acetate phthalate; gelatin; talc; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; liquid petrolatum, polyethylene glycol; glycerine; sorbitol; propylene glycol; ethanol; agar; water and isotonic saline.
  • sugars such as lactose and sucrose
  • gelatin talc
  • magnesium stearate vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma
  • liquid petrolatum polyethylene glycol
  • glycerine sorbitol
  • propylene glycol propylene glycol
  • compositions intended for parenteral administration must be sterile and this can be accomplished either by using sterile ingredients and carrying out the production under asceptic conditions or by sterilizing the final composition by one of the usual procedures such as millipore filitration. Customary care should be exercised that no incompatible condition exists between the active component and the diulent preservative or flavoring agent or in the conditions employed in preparation of the compositions.
  • compositions of the invention can be introduced into the mammal by the oral, rectal, or parenteral route. This can be done by injecting the liquid preparations intraveneously, intramuscularly, intraperitoneally, or subcutaneously; by swallowing, in the cases of the solid and liquid preparations, by local application to the mucous membrances, in the case of jellies, suppositories, tablets and the like; by inhalation of sprays or mists of the liquid preparations and the like.
  • EXAMPLE 1 1, l '-tetramethylenebis[ l,2,3,4-tetrahydroisoquinoline] dihydrochloride A mixture of 35.2 g. of adipic acid di(2-phenylethyl) amide, M.P. 184l85, and 176 g. of polyphosphoric acid was heated at 190193 for 1.25 hours. After cooling to the mixture was poured onto ice along with 20 ml. of concentrated hydrochloric acid. After washing with chloroform and benzene, the aqueous layer was made strongly alkaline with aqueous sodium hydroxide, extracted with benzene, and the benzene solution washed with water, dried, and purified by passage through an alumina column.
  • EXAMPLE 2 1,1-hexamethylenebis 1,2,3,4-tetrahydroisoquinoline] dihydrochloride
  • a mixture of 38 g. of suberic acid di-(Z-phenylethyl) amide, M.P. 165-166, and 300 g. of polyphosphoric acid was heated at 240 for 1.5 hours. After cooling to 100- it was poured into 500 ml. of ice water containing ml. of concentrated hydrochloric acid. After washing with benzene, the aqueous phase was made basic and extracted several times with benzene. Concentration product 1,1- hexamethylenebis[3,4-dihydroisoquinoline], M.P. 9092 after recrystallization from acetonitrile.
  • the dihydro compound (17 g.) was dissolved in hot dioxane (2 liters) and treated dropwise with 6.4 g. of sodium borohydride in 200 ml. of ethanol. After the exothermic reaction subsided, the mixture was heated under reflux for an additional 3 hours and concentrated. The mixture of diasterioisomers (5.1) melted at 175-190.
  • EXAMPLE 1O 1,1'-tetramethylenebis[1,2,3,4-tetrahydro-6,7,8-trimethoxyisoquinoline] dihydrochloride
  • EXAMPLE 13 Ingredients: Ampoule l,1-tetramethylenebis[1,2,3 ,4-tetrahydro-6,7- dimethoxyisoquinoline] dihydrochloride, isomer B mg Pyrogen free water for injection ml 25 Mannitol N.F. To make the solution isotonic.
  • the compound is added to the water and the solution made isotonic with mannitol.
  • the resulting pH is 5.5.
  • the solution is filled into ampoules under sterile conditions and the sealed ampoule is autoclaved.
  • the ampoule contains 5 ml. of the 5 mg./ml. solution.
  • dimethoxy-3-methylisoquinoline] dihydrochloride mg 25 Pyrogen free water for injection ml 25 Dextrose N.F. To make the solution isotonic.
  • the compound is added to the water and the solution made isotonic with dextrose.
  • the resulting pH is 5.5.
  • the solution is filled into ampoules under sterile conditions and the sealed ampoule is autoclaved.
  • the ampoule contains 5 ml. of the 5 mg./ml. solution.
  • EXAMPLE 15 Ingredients: Ampoule 1,1 -decamethylenebis 1,2,3 ,4-tetrahydro-6,7- dimethoxyisoquinoline] dihydrochloride dihydrate mg 25 Pyrogen free water for injection ml 25 Fructose N.F. To make the solution isotonic.
  • the compound is added to the water and the solution made isotonic with fructose.
  • the resulting pH is 5 .5
  • the solution is filled into ampoules under sterile conditions and the sealed ampoule is autoclaved.
  • the ampoule contains 5 ml. of the 5 mg./ml. solution.
  • EXAMPLE 16 Ingredients: Per ampoule 1,1-tetramethylenebis[1,2,3,4-tetrahydro-6- methoxyisoquinoline] mg 25 Peanut oil ml 5 Benzyl alcohol mg 5 The compound is dissolved in the peanut oil containing the benzyl alcohol. The ampoules are filled under sterile conditions. Each ampoule contains 5 ml. of 5 mg. of the compound/ml.
  • EXAMPLE 17 Ingredients: Mg,/suppository 1,l-hexamethylenebis[7-chloro-1,2,3,4-tetrahydroisoquinoline] 200 Cocoa butter c- Q.s.
  • the compound and cocoa butter are combined, mixed thoroughly and formed into two gram suppositories.
  • EXAMPLE 18 Ingredients Mg./ suppository 1,1'-hexamethylenebis[1,2,3 ,4-tetrahydroisoquinoline], isomer B 200 Oil of theobroma Q.s.
  • the compound and oil of theobroma are combined, mixed thoroughly and formed into two gram suppositories.
  • Method of treating a mammal to induce an increase in fibrinolytic activity in a mammal in need of such treatment which comprises administering to said mammal a fibrinolytically effective amount of a compound of the following Formula A or a pharmaceutically acceptable addition salt thereof:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US571195A 1966-08-09 1966-08-09 Induction of fibrinolysis Expired - Lifetime US3560620A (en)

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US57119566A 1966-08-09 1966-08-09

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US (1) US3560620A (de)
AT (1) AT278010B (de)
CH (1) CH478123A (de)
DE (1) DE1670633A1 (de)
FR (1) FR6600M (de)
GB (1) GB1178187A (de)
GR (1) GR35206B (de)
LU (1) LU54282A1 (de)
NL (1) NL6710907A (de)
SE (1) SE324568B (de)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3884925A (en) * 1972-06-19 1975-05-20 Sulco Basel Ag Diisoquinolyl-dipyridyl-butanes, their salts and their manufacturing process
US4009170A (en) * 1970-08-10 1977-02-22 Sterling Drug Inc. 1-Ethoxy-3,4-dihydroisoquindines
US4107165A (en) * 1970-01-06 1978-08-15 Endo Laboratories Tris[tetrahydroisoquinoline] compounds
EP0804734B1 (de) * 1994-05-13 2005-05-04 Miltenyi Biotec GmbH An protein gebundene sterile und pyrogenfreie säulen zum binden und entfernen von substanzen aus blut

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107165A (en) * 1970-01-06 1978-08-15 Endo Laboratories Tris[tetrahydroisoquinoline] compounds
US4009170A (en) * 1970-08-10 1977-02-22 Sterling Drug Inc. 1-Ethoxy-3,4-dihydroisoquindines
US3884925A (en) * 1972-06-19 1975-05-20 Sulco Basel Ag Diisoquinolyl-dipyridyl-butanes, their salts and their manufacturing process
EP0804734B1 (de) * 1994-05-13 2005-05-04 Miltenyi Biotec GmbH An protein gebundene sterile und pyrogenfreie säulen zum binden und entfernen von substanzen aus blut

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GB1178187A (en) 1970-01-21
CH478123A (fr) 1969-09-15
SE324568B (de) 1970-06-08
AT278010B (de) 1970-01-26
NL6710907A (de) 1968-02-12
DE1670633A1 (de) 1971-02-11
GR35206B (el) 1968-08-27
LU54282A1 (de) 1969-06-10
FR6600M (de) 1969-01-06

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