US3928611A - Tris- and tetrakis- (1,2,3,4-tetrahydroisoquinoline) and -{8 3,4-dihydroisoquinoline{9 {0 compounds in inhibiting and dissolving blood clots - Google Patents

Tris- and tetrakis- (1,2,3,4-tetrahydroisoquinoline) and -{8 3,4-dihydroisoquinoline{9 {0 compounds in inhibiting and dissolving blood clots Download PDF

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US3928611A
US3928611A US336973A US33697373A US3928611A US 3928611 A US3928611 A US 3928611A US 336973 A US336973 A US 336973A US 33697373 A US33697373 A US 33697373A US 3928611 A US3928611 A US 3928611A
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tetrahydro
bis
ethyl
isoquinolinyl
compounds
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Parthasarathi Rajagapalan
Irwin J Pachter
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Bristol Myers Squibb Pharma Co
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ENDO LAB
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Priority to GB6184170A priority Critical patent/GB1334070A/en
Priority to CA101,945A priority patent/CA968802A/en
Priority to NL7100005A priority patent/NL7100005A/xx
Priority to BE761221A priority patent/BE761221A/xx
Priority to CH8571A priority patent/CH550798A/xx
Priority to FR7100182A priority patent/FR2081413B1/fr
Priority to DE19712100331 priority patent/DE2100331A1/de
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Priority to US336973A priority patent/US3928611A/en
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Priority to US05/723,336 priority patent/US4107165A/en
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Assigned to DU PONT MERCK PHARMACEUTICAL COMPANY reassignment DU PONT MERCK PHARMACEUTICAL COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: E.I. DU PONT DE NEMOURS AND COMPANY
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/305—Saturated compounds containing more than one carboxyl group containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/88—Unsaturated compounds containing keto groups containing halogen
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • Field of the Invention I v This invention relates to new compounds usefulfor inhibiting the formation vof,,blood clots, or dissolving blood clots after they have been formed, and more particularly to novel alkylenetris-and alkylenetetrakis- -[3,4-dihycally acceptable acid addition salts thereof 2.
  • currence 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 patency of the vessel. I I? Under normal conditions, the organism has low levels of activatof in the blood stream.
  • Fibrinolytic activity in vitro is manifested by many compounds such as the aromatic sulfonic acids, derivatives of salicylic acid, long chain fatty acids and halogenated unsaturated acids. Such compounds have not,
  • Fibrinolyticactivity in vivo can be induced by nicotinic acid, procaine, phenylbutazone, acetylcholine,
  • 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 -lytic activity.
  • Compounds of this type cannot be used when a substance is employed toeffect thrombolytic therapy, because in such instance the activity must be rapidly induced to be effective in dissolving clots.
  • Streptokinase a streptococcal protein
  • Streptokinase has been used for thrombolysis, but the side effects of pyrogenicity and anaphylactic reactions havelimitecl its use.
  • Bacte'rial pyroget'is have also been used to effect thrombolysis,"butthe severity and unpredictability of the pyrogenic reactions have negated their usefulness SUMMARY F rHE'l veNrioN.
  • the present;invention provides compounds which inhibit the formation of blood clots (-by inhibiting'platelet aggregation and/or, fibrin formation) oriidissolv'e such clots as they areformed (by fibrinolysisj-or after they .have been formed (by fibrinolysis): vSuch substances demonstrate activity .in mammals in-vivo, are highly potent, long-lasting, rapid in onset; readily prepared and suffer from none of the difficulties associated with materials of nautral origin.
  • a and B is each hydrogen or, taken together, represent an additional carbon to nitrogen bond
  • R and R represent hydrogen or lower alkyl
  • R R and R represent hydrogen, lower alkyl, halogen, hydroxy, lower alkoxy, lower alkenoxy, lower alkynoxy, lower acyloxy, aryloxy or phenyl lower alkoxy.
  • R and R or R and R may be linked to form a lower alkylenedioxy.
  • lower alkyl, alkoxy, etc. is meant such groups having from 1 to about 6 carbon atoms, except for lower" alkylenedioxy,
  • Z represents an organic radical having a valence of n, said radical being a hydrocarbon group that can contain up to four hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen, and wherein said radical can contain up to three substituents selected from the group consisting of amino, nitro, halo, hydroxy, lower alkyl, lower alkoxy, benzyloxy, trifluoromethyl, and a lower alkylenedioxy,
  • n the numbers 3 or 4.
  • compositions containing'such substances are also characterized by pharmaceutically acceptable acid addition salts of the compounds of the above general formula as well as compositions containing'such substances.
  • 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 lactate, tartrate, citrate, succinate, benzoate, acetate, p-toluenesulfonate and benzenesulfonate, and others-conventionally formed from acids conventionally used in the pharmaceutical art.
  • the alkylenetrisor alkylenetetrakis-[l,2,3,4-tetrahydroi'soquinoline] compounds within the above formula are useful as fibrinolytic agents in mammals. Such materials additionally possess the property of inhibiting platelet aggregation and may thus be utilized for inhibiting the formation of blood clots as well as for dissolving such clots as they may be formed or after they have been formed.
  • the alkylenetrisor alkylenetetrakis- [3,4-dihydroisoquinoline] compounds within the above formula are intermediates in the preparation of the corresponding tetrahydroisoquinoline compounds and, moreover possess the property of inhibiting platelet aggregation. Thus, both the tetrahydroisoquinoline and dihydroisoquinoline compounds within the above formula are useful for inhibiting the formation of blood clots.
  • the compounds of the invention are prepared by permitting selected triand tetracarboxylic acids or their derivatives (esters, and chlorides and the like) to react with appropriately substituted phenethylamines.
  • the triand tetraphenethylamides thus derived are cyclized through dehydration to the 3,4-dihydroisoquinoline compounds within the above formula, in accordance with the Bischler-Napieralski synthesis* with which those skilled in the art are familiar.
  • the cyclization is effected by reacting the amides with phosphorus oxychloride (POCI by itself or diluted with an equal amount of a suitable solvent, e.g., benzene or toluene.
  • POCI phosphorus oxychloride
  • the dihydroisoquinolines thus produced are thereafter converted to the l,2,3,4-tetrahydroisoquinoline compounds of the above formula by reduction.
  • the reduction step is carried out employing, for example, sodium borohydride in alcoholic solution or lithium aluminum hydride in tetrahydrofur.
  • Oxygenated functions are generally beneficial for maximum clot-dissolving activity and with one preferred aspect of this invention there is included in R R and R one or more lower alkoxy functions such as methoxy, isopropoxy, butoxy, or a methylenedioxy. These functions are most effective when situated at the 6 and 7 positions of the tetrahydroisoquinoline rings.
  • the Z variable represents, in most cases, the residue cases, the Z variable will contain from 5 to 18 carbon atoms.
  • the Z chain connecting the tetrahydroisoquinol and dihydroisoquinoline groups in the above formula may vary within wide limits with retention of potency. Activity is maximized, however, when the individual isoquinoline moieties are separated by chains of from three to ten carbon atoms.
  • the nature of Z is determined by the triand tetracarboxylic acids or their derivatives (esters, acid chlorides and the like) used in the synthesis of the compounds within the generic formula. Representative of acids which may be used in the preparation of biologically potent compounds of the above class are the following:
  • Tetrakis[ 1,2,3 ,4-tetrahydrol -'isoquinolinyl]alkanes wherein the alkane moiety has from 7 to 18 carbon atoms and wherein the tetrahydroisoquinoline moieties can be unsubstituted or. can contain lower alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy or hydroxy substituents.
  • These compounds can be produced by first reacting a 3-bromo-2-oxocyclohexanecarboxylic acid ester with a glycolic acid ester or thioglycolic acid ester to produce a 3-(carboxymethyl)oxy-(or thio)-2-oxocyclohexanecarboxylic acid di-ester. This latter compound is reacted with sodium hydroxide, water and ethanol to form a tri-ester 'of 2-(carboxymethyl)oxy-(or thio)-heptanedioic acid.
  • R, R and Z can be any of a wide variety of groups.
  • specific representative R and R groups include hydrogen, methyl,
  • R R and R groups are hydrogen, methoxy, ethoxy, butoxy, hexyloxy, methyl, ethyl, isopropyl, butyl, pentyl, hexyl, chloro, bromo, iodo, fluoro, allyloxy, Z-butenyloxy, 2-propynyloxy, acetoxy, phenoxy, benzyloxy, methylenedioxy, ethylenedioxy, trimethylenedioxy, hydroxy,
  • eties can be unsubstituted or can contain lower alkyl
  • 1,1',I"-(Nitrilotrialkylene)tris [l,2,3,4-tetrahydroisoquinolines], wherein each alkylene individually contains from 1 to 3 carbon atoms, and wherein the tetrahydroisoquinoline moieties can b e unsubstituted or can contain lower alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy, or hydroxy substituents.
  • 1,l'- ⁇ 3'[2-(1,2,3,4-tetrahydro- 6,7-dimethoxyl -isoquinolinyl)ethyl]heptamethylene ⁇ bis[1,2,3 ,4-tetrahydro-6,7-dimethoxyisoquinoline] trihydrochloride a compound within the above generic formula, was found to be effective in inducing fibrinolysis at 0.01 mg./kg. and at 10 mg./kg. (a 1000-fold difference in dose) without producing toxicity.
  • Certain representative compounds within the scope of the present invention have been tested for fibrinolytic activity by the whole blood clot lysis method, as modified from the procedure of Billimoria et al.
  • blood from rats given a fibrinolytic compound intraperitopeally is taken and diluted 1:10.
  • a standard amount is clotted with thrombin, incubated at 37C for four hours, and the amount of clot that has lysed is determined.
  • the ED dose of a compound is that amount, in mg/kg, which will cause the lysis of 50 percent of the clot under the above conditions.
  • compositions of this invention contain a compound of the above formula or a non toxic acid addition salt thereof together with a carrier.
  • the carrier may be either a solid or liquid and the 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 ethanol
  • compositions intended for parenteral administration must be sterile and this can be accomplished either by using sterile ingredients and carrying out the production under aseptic conditions or by sterilizing the final composition by one of the usual procedures such as millipore filtration. 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 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 intravenously, intramuscularly, intraperitoneally, or subcutaneously; by swallowing, in the cases of the solid and liquid preparations, by local application to the mucous membranes, in the case ofjellies, suppositories, tablets and the like; by inhalation of sprays or mists of the liquid preparations and the like.
  • the filtrate is stripped of the solvent under reduced pressure, the residue (1.1a) dissolved in 500 ml. of absolute ethan and treated with 13.5 g. of sodium borohydride, added in small portions, with vigorous stirring.
  • the mixture is then refluxed, protected from moisture, for 5 hours, cooled, and evaporated to dryness under reduced pressure.
  • the residue is treated with about a liter of water and extracted thrice with 800 ml. portions of benzene.
  • the combined benzene extracts are washed thoroughly with water, dried over anhydrous magnesium sulfate and filtered.
  • the residue obtained from the filtrate after removal of the solvent under reduced pressure is dissolved in minimum quantity of anhydrous benzene and the solution added, with agitation, to l l.
  • Pyrophoric nickel is prepared by washing commercial Rancy nickel several times in absolute ethanol, and then refluxing the centrifuged solids for three hours in absolute ethanol.
  • a mixture of 20 g. of this nickel and 2 g. of 1,1',1' ,l 3,5-tetrahydrothiopyrandiylidenetetraethylene)tetrakis[ l ,2,3,4-tetrahydro-6,7- dimethoxyisoquinoline] tetrahydrochloride is refluxed for two days in percent ethanol.
  • the mixture is centrifuged, the liquid decanted from the nickel, which -is washed twice with hot ethanol and once with water,
  • the combined ether extracts are tanediylidenetetraethylene)tetrakis[1,2,3,4-tetrahydried over anhydrous magnesium sulfate and filtered.
  • dro-6 ,7-isoquinolinediol isolated as its tetrahydrobro- The filtrate on evaporation to dryness under reduced 5 mide tetrahydrate, is obtained.
  • a mixture of 250 g. of sodium hydroxide, 200 m1. of water and 150 ml. of ethanol is heated at 50 for 30 minutes in an atmosphere of nitrogen and then treated with a solution of g. of the above ester in 50 ml. of
  • the intermediate 7.1a is purified in a manner very similar to that used to purify 1.1a, to yield (7.1a) 1,1- ⁇ -[2-(3,4-dihydro-6,7-dimethoxy-l-isoquinolinyl)ethyl]-2-phenylheptamethybis[ 3 ,4-dihydro-6,7-dimethoxyisoquinoline]trihydrochloride trihydrate a light yellow solid with a m.p. of 200-210 (dec.)
  • EXAMPLE 8 1,1'- ⁇ 2,2-DlMETHYL-5-[2-(l,2,3,4-TETRAHYDRO- 6,7-DIMETl-IOXY- l -ISOQUINOLINYL)ETHYL]- HEPTAMETHYLENE ⁇ -BIS[ l ,2,3,4-TETRAHYDRO- 6,7-DIMETHOXYISOQUINOLINE] TRIHYDROCHLORIDE TRIHYDRATE
  • EXAMPLE 9 1,1 - ⁇ 3-[2-( l ,2,3,4-TETRAHYDRO-l- ISOQUINOLINYL )-ETHYL]HEPTAME- THYLENE ⁇ BIS[ l ,2,3,4-TETRAHYDROISOQUINO- LINE] TRIHYDROCHLORIDE TRIHYDRATE Following the procedure outlined in Example'1,57 g.
  • EXAMPLE 12 1- ⁇ 3,3-BlS[2-(1,2,3,4-TETRAHYDRO-6,7-DIME- THOXY- l-lSOQUlNOLlNYL )ETHYL]PENTYL ⁇ -l ,2,3 ,4- TETRAHYDRO-6,7-D1METHOXYlSOQUlNOLINE TRIHYDROCHLORIDE TRIHYDRATE 4-(2-Carboxyethyl)-4-ethylheptanedioic acid trimethyl ester, b.p.
  • 167-175 0.5-0.8 mm. is prepared by the Wolff-Kischner reduction of 4-acety1-4-(2-carboxyethyl)heptanedioic acid followed by esterification of the product with methanol according to the method described in Example 3.
  • EXAMPLE 14 1,1 '- ⁇ 3-(p-CHLOROBENZYL)-3-[2-( 1 ,2,3,4-TET- RAHYDRO- 6,7-DlMETHOXY-1-1SOQU1NOL1NYL)ETHYL]- PENTAMETHYLENEl- BIS[ 1 ,2,3,4-TETRAHYDRO-6,7-D1METl-lOX- YISOQUINOLlNE] TRll-lYDROCHLORlDE 4-(2-Carboxyethyl) 4-(p-chlorobenzyl)heptanedioic' acid trimethyl ester, b.p.
  • 270280/0.9 mm. is prepared according to the method outlined in Example 3, starting with 4-chloroacetophenone, which is cyanoethylated to 3-(p-ch1orobenzoyl)-3-(2cyanoethyl)- l,S-pentanedicarbonitrile, m.p. l37. On hydro lysis, this trinitrile yields 4-(2-carboxyethyl)-4-(pchlorobenzoyl)heptanedioic acid, m.p. 225227, which is subjected to Wolff-Kishner reduction followed by esterification of the product.
  • EXAMPLE 20 Ingredients Mg/Tablet 1.1 3-[2-( l,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinyl)ethyllheptamethylene bis[1,2,- 3.4-tetrahydro-6,7-dimethoxyisoquinolinel trihydrochloride 25 Lactose USP (Spray dried) 170 Starch USP Magnesium stearate USP 1 Stearic acid USP Flavor q.s.
  • EXAMPLE 21 Ingredients Ampoule 1,1 ,1 ",1 -(1,5,lO,l4-tetradecanetetrayl)- tetrakis[ 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline] tetrahydrochloride 5g.
  • a and B is each hydrogen;
  • R and R individually represent hydrogen or lower alkyl, i R R and R represent hydrogen, lower alkyl, halo gen, V V I hydroxy, lower alkoxy, lower alkenoxy, lower al'-' kynoxy, acetaxy or butyloxy ph'enoxylyphenyl-lower alkoxy, or R and R or R and R may be linked to form methylenedioxy;
  • n 3; and v 2 represents a straight or branched alkanetriyl chain,
  • a composition for inhibiting the formation of and for dissolving blood clots in mammals which comprises, as the active ingredient, an effective amount for inhibiting the formation of and for dissolving blood clots in mammals of a compound of the formula wherein A and B is each hydrogen;
  • R and R individually represent hydrogen or lower alkyl
  • R R and R represent hydrogen, lower alkyl, halogen, hydroxy, lower alkoxy, lower alkenoxy, lower alkynoxy, acetoxy or butylroxy phenoxyl, phenyllower alkoxy, or R and R or R and R may be linked to form methylenedioxy;
  • n 3;
  • Z represents a straight or branched alkanetriyl chain
  • composition ofclaim 2 wherein the active ingredient is l,l"',l l ,4,7-heptanetriyl)tris[ 1 ,2,3,4- tetrahydro-6,7-dimethoxyisoquinoline].
  • composition of'claim 2 wherein the active ingredient is 1,] '- ⁇ 3-[2-( l,2,3,4-tetrahydro-6,7-dimethoxy-l- I l isoquinolinyl)ethyl]heptamethylene ⁇ bis[ l ,2,3,4-tetrahydro-6,ldimethoxyisoquinoline].
  • composition of claim 2 wherein the active ingredient is l,l 2,2-dimethyl-5-[2-( l ,2,3,4-tetrahydro-6,7- dimethoxy-l-isoquinolinyl)ethyl]heptamethylene ⁇ - bis[ 1 ,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline].
  • composition of claim 2 wherein the active ingredient is l,l ⁇ 3-[2-(7-benzyloxy-l,2,3,4-tetrahydro6-methoxy-l-isoquinolinyl)ethyl]heptamethylene ⁇ bis[7-benzyloxyl,2,3,4-tetrahydro-6-methoxyisoquinoline].
  • composition of claim 2 wherein the active ingredient is l ,l 3-nitro-3- [2-( l ,2,3,4-tetrahydrodimethoxy-I-isoquinolinyl)ethyl]pentamethyle ne ⁇ bis[ l ,2,3 ,4- tetrahydro-6,T-dimethoxyisoquinoline1.
  • composition of claim 2 wherein the active ingredient is 1,1'- ⁇ 3-[2-(l,2,3,4-tetrahydro-5,6- dimethyll -isoquinoliethyl]heptamethylene ⁇ bis[ 1 ,2,3,4-tetrahydro-5,6- dimethylisoquinoline].
  • composition of claim 2 wherein the active ingredient is l ,l '- ⁇ 3-[ 2-( 6-chloro-l ,2,3 ,4-tetrahydro-,

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US336973A 1970-01-06 1973-03-01 Tris- and tetrakis- (1,2,3,4-tetrahydroisoquinoline) and -{8 3,4-dihydroisoquinoline{9 {0 compounds in inhibiting and dissolving blood clots Expired - Lifetime US3928611A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
GB6184170A GB1334070A (en) 1970-01-06 1970-12-30 Tris- and tetrakis- 1,2,3,4-tetrahydroisoquinoline and -3,4- dihydroisoquinoline compounds
CA101,945A CA968802A (en) 1970-01-06 1971-01-04 Tris- and tetrakis-(1,2,3,4-tetrahydroisoquinoline) and - (3,4-dihydroisoquinoline) compounds
NL7100005A NL7100005A (enExample) 1970-01-06 1971-01-04
CH8571A CH550798A (de) 1970-01-06 1971-01-05 Verfahren zur herstellung von isochinolinderivaten.
BE761221A BE761221A (fr) 1970-01-06 1971-01-05 Composes de ter- et tetra-(1,2,3,4-tetra-hydroisoquinoline) et -(3,4-dihydro isoquinoline)
FR7100182A FR2081413B1 (enExample) 1970-01-06 1971-01-06
DE19712100331 DE2100331A1 (enExample) 1970-01-06 1971-06-05
US336973A US3928611A (en) 1970-01-06 1973-03-01 Tris- and tetrakis- (1,2,3,4-tetrahydroisoquinoline) and -{8 3,4-dihydroisoquinoline{9 {0 compounds in inhibiting and dissolving blood clots
US05/723,336 US4107165A (en) 1970-01-06 1976-09-15 Tris[tetrahydroisoquinoline] compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US102970A 1970-01-06 1970-01-06
US16534671A 1971-07-22 1971-07-22
US336973A US3928611A (en) 1970-01-06 1973-03-01 Tris- and tetrakis- (1,2,3,4-tetrahydroisoquinoline) and -{8 3,4-dihydroisoquinoline{9 {0 compounds in inhibiting and dissolving blood clots

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US16534671A Continuation 1970-01-06 1971-07-22

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US56143575A Division 1970-01-06 1975-03-25

Publications (1)

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US3928611A true US3928611A (en) 1975-12-23

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ID=27356801

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US336973A Expired - Lifetime US3928611A (en) 1970-01-06 1973-03-01 Tris- and tetrakis- (1,2,3,4-tetrahydroisoquinoline) and -{8 3,4-dihydroisoquinoline{9 {0 compounds in inhibiting and dissolving blood clots

Country Status (8)

Country Link
US (1) US3928611A (enExample)
BE (1) BE761221A (enExample)
CA (1) CA968802A (enExample)
CH (1) CH550798A (enExample)
DE (1) DE2100331A1 (enExample)
FR (1) FR2081413B1 (enExample)
GB (1) GB1334070A (enExample)
NL (1) NL7100005A (enExample)

Cited By (1)

* 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

Cited By (1)

* 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

Also Published As

Publication number Publication date
FR2081413A1 (enExample) 1971-12-03
BE761221A (fr) 1971-06-16
CA968802A (en) 1975-06-03
GB1334070A (en) 1973-10-17
NL7100005A (enExample) 1971-07-08
FR2081413B1 (enExample) 1975-04-18
CH550798A (de) 1974-06-28
DE2100331A1 (enExample) 1971-07-22

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