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US3929887A - Alkylenepoly(aralkylamines) and the salts thereof - Google Patents

Alkylenepoly(aralkylamines) and the salts thereof Download PDF

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US3929887A
US3929887A US274486A US27448672A US3929887A US 3929887 A US3929887 A US 3929887A US 274486 A US274486 A US 274486A US 27448672 A US27448672 A US 27448672A US 3929887 A US3929887 A US 3929887A
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bis
dimethoxyphenyl
dihydrochloride
hours
acid
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Jr Leonard J Fliedner
Irwin J Pachter
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Bristol Myers Squibb Pharma Co
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ENDO LAB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/22—Tricarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings

Definitions

  • 260/544 M 260/558 R; 260/559 D; 260/566 A; 260/569; 260/592; 424/250; 424/251; 42 4/274; 424/276; 424/282; 424/316;
  • 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 patency of the vessel.
  • the organism Inder normal conditions, the organism has low levels of activator 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 insufficient to produce enough plasmin to lyse the relatively large amount of fibrin present in a clot such as a thrombus.
  • 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, however, been found to exhibit in vivo activity.
  • 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.
  • Some sulfonylureas 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 to effect 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 have limited its use.
  • 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 prevented general and practical use.
  • Bacterial pyrogens have also been used to effect thrombolysis, but the severity and unpredictability of the pyrogenic reactions have negated their usefulness.
  • compositions so active may be used to effect fibrinolysis of the clot in acute thrombosis. They may also be employed prophylactically to maintain increased fibrinolytic activity on a long term basis and thus diminish the incidence of new thrombotic episodes.
  • Ar is a substituted or unsubstituted, monocyclic or bicyclic, aromatic, hydroaromatic or heteroaromatic moiety, preferably phenyl, naphthyl, tetrahydronaphthyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, or indazolyl;
  • R is hydrogen, amino, lower alkyl, lower alkenyl
  • R is hydrogen, lower alkyl or Ar
  • Z is a hydrocarbon radical, straight or branched, saturated or unsaturated, which has a valence of x and comprises from 2 to 15 carbon atoms, one of which may be replaced by an oxygen, sulfur or nitrogen atom, and which may include polyvalent cyclic radicals such as arylene moieties (e.g., pphenylene), cycloalkanediylidene moieties (e.g. cyclopentanediylidene) and heterocyclediylidene moieties (e.g. pyrandiylidene or thiopyrandiylidene), or which radical may be substituted by halo, amino or nitro groups;
  • arylene moieties e.g., pphenylene
  • cycloalkanediylidene moieties e.g. cyclopentanediylidene
  • heterocyclediylidene moieties e.g. pyrandiyliden
  • n and n may each be 0, 1 or 2;
  • x is 2, 3 or 4.
  • the term pharmaceutically acceptable addition salts includes the inorganic mineral acid salts, e.g., the hydrochloride, hydrobromide, sulfate and phosphate; and organic acid salts such as the lactate, tartrate, citrate, maleate, succinate, benzoate, acetate, p-toluenesulfonate and benzenesulfonate, and others conventionally formed from acids and utilized in the pharmaceutical art.
  • the lower alkyl, alkenyl, or like groups are intended to include those moieties incorporating up to about 8 carbon atoms. 2.
  • the compounds utilized in accordance with the present invention may be prepared by several routes, including the various reaction schemes set forth at length on pages 4-16 of the aforesaid copending application Ser. No. 735,510 (which disclosure is incorporated by reference herein). It will be apparent from a consideration of such syntheses, including those described in detail below, that compounds of Formula A may be prepared in which the parenthetical moieties of the bis, tris, or tetrakis compounds thereof may be the same or different. Such mixed compounds may be deliberately prepared by sequentially reacting reagents incorporating the desired aromatic moieties. It is, however, not generally preferred to utilize such mixed compounds in the practice of the present invention, in view of the relative complexities which their syntheses necessarily involve.
  • the compounds of Formula A may be formed as mixtures of diastereoisomers. Both such isomeric mixtures and the individual isomers incorporated therein have been found to exhibit fibrinolytic activity. Accordingly, it is further intended that the designation of the compounds of Formula A, by name and formula throughout the present specification and claims, shall be construed to include all isomers and mixtures thereof.
  • the following reaction scheme illustrates a principal method by which many of the fibrinolytic agents of the present invention may be prepared.
  • the group Y may be hydrogen, lower alkyl or lower acyl:
  • the polyarylpolyone [Formula I] is taken up in a suitable organic solvent, for example, pyridine, or a lower alkanol such as ethanol or propanol, and treated with hydroxylamine or an O-lower alkyl hydroxylamine, suitably in the form ofa salt such as the hydrochloride.
  • a suitable organic solvent for example, pyridine, or a lower alkanol such as ethanol or propanol
  • the reaction is effected in the presence of a tertiary amine such as pyridine, or a basic salt such as sodium acetate.
  • the reaction may be carried out at temperatures ranging from ambient through solvent reflux temperature, i.e., from about 15 to 1 15C. It is preferred to carry out the reaction under reflux, for a period of from about 3 to 12 hours.
  • the polyoxime is acylated with an acyl halide or acid anhydride to form [11, Y lower acyl] prior to reduction to The reduction may be carried out either catalytically or chemically.
  • the polyoxime [II] is taken up in a suitable hydrogenation solvent, for example, an alkanoic acid such as acetic acid, and hydrogenated under moderate pressure, say from about 20 to psi., in the presence ofa catalyst such as platinum oxide.
  • the hydrogenated mixture is then taken up in an alkaline aqueous medium, and extracted with a suitable solvent. It is preferred to isolate the product [A'] in the form of the hydrochloride salt which may be readily obtained by passing gaseous hydrogen chloride through a dry solution of the polyamine in an organic solvent such as ether.
  • a compound [11] is the poly(O-alkylor O- acyl-oxime) it is preferred to carry out the reduction steps by chemical means for example, with a solution of diborane in tetrahydrofuran.
  • the oxime ether or ester is dissolved in a suitable solvent such as tetrahydrofuran, cooled to between about 0 and 5C, and the diborane solution added dropwise thereto.
  • the solution is allowed to warm to ambient temperature and allowed to stand for from about 12 hours to 2 days.
  • the excess solvent is then removed by evaporation in vacuo, and the residual complex decomposed by the addition of acid.
  • dilute hydrochloric acid at about 0 is added slowly, followed by refluxing for from about 1 to 2 hours.
  • the resulting solution is extracted with ether, the aqueous layer made alkaline, reextracted with a suitable solvent, dried, and the desired polyamine [A'] isolated by treatment with hydrogen chloride in the usual manner.
  • a starting diketone [1'] may be converted to a diamine [A"] in which Ar may be any of the groups specified hereinabove, and R is hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl or phenyllower alkyl, and may be the same or different.
  • ac'ompound of Formula [I'] is heated under reduced pressure to yield the desired compound with an ammonium formate R NH .HCO ⁇ .
  • the forof Formula [A"] which may then be purified in the mate utilized in this process may be ammonium forusual manner, most suitably in the form of the hydromate or a substituted ammonium formate, for example, chloride.
  • mate such as allylammonium formate, or hexenylami
  • the following reaction scheme illustrates a further monium formate; a lower cycloalkylammonium formethod by which the fibrinolytic agents of the present mate such. ascyclopropylammonium formate, cyinvention may be prepared.
  • the starting diketone [1"] is indicated as formate; a lower alkynylammonium formate such as being converted to diamine [A"] or diamine ]A"], propynylammonium formate, butynylammonium forboth within Formula A in which Ar and R may be any mate.
  • R is lower tuted anilinium unsubstituted aryl or aralkylammonium alkyl, lower alkenyl, lower cycloalkyl or phenyl-lower formate such as anilinum formate, benzylammonium alkyl:
  • the mixture is Grignard reagent of the formula R MgX to yield the then cooled and treated with water, suitably ice water, di(tertiary)carbinol [lV, R 9* H]; where in the final to yield the intermediate compound [III].
  • a suitable reducing agent such as sodium
  • the dicarbinol [IV] may be converted to the cormcthyl.
  • compound [III] is responding diamine [A"] by means of the Ritter reactaken up in a suitable ethereal solvent, reduced with tion with concentrated sulfuric acid and hydrogen cyalithium aluminum hydride, and the N,N-dimethylnide or acetonitrile.
  • This produce if desired, may be diaryldiamine is isolated, suitably as the hydrochloride, substituted at the amino position by acylation with acyl in the usual manner.
  • the intermediate [III] is not further purified but submit- As noted hereinabove, the further reaction schemes ted to hydrolysis. In the preferred mode of procedure, described in the aforesaid copending application Ser. the intermediate [III] is taken up in a mineral acid such No.
  • reaction mixschemes may also be employed in the synthesis of as concentrated hydrochloric acid and heated under the fibrinolytic agents of this invention. The use of such reflux for from about 1 to 3 hours.
  • the reaction mixschemes is exemplified in Examples 4 (coupling of two ture is then cooled, diluted with water', extracted with a aminoacetylenes), 5 (conversion of a diurethane to a suitable solvent and the aqueous layer concentrated disecondaryamine), 6 (condensation of 2 mols of an aromatic aldehyde with 1 mol of a,m-dinitroalkane followed by reduction of the resulting dinitrodiolefin), 11 and 12 (reduction of a dinitrile to a bis(methylamine)), 15 (condensation of a diketone with 2 mols of a primary amine followed by reduction of the resulting diimine), 16 (homologation of a diketone by means of the Reformatsky reaction to a diole
  • the compounds of Formula A induce immediate, Ionglasting fibrinolytic activity in mammals in need of such treatment.
  • a further advantage 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 over-dosage of other substances of great potency.
  • compounds of Formula A have been found effective in inducing fibrinolysis at 0.05 mg/kg. Indeed, it has been determined that the same compounds can be administered at levels of 100 mg/kg.
  • intravenous administration to rats the compounds have been found effective at 0.2 mg./kg. and also at 80 mg./kg.
  • Activity by the oral route in rats has been established at doses of from 1 to 300 mg/kg. ln dogs activity on intravenous administration at 0.2 mg./kg. and also at 60 mg/kg has been determined.
  • These dosage levels are illustrative and are not meant to limit the application of the invention. The clinician may find it advisable to adjust dosage in the light of individual recipient response.
  • 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 is taken and diluted 1:10.
  • a standard amount is clotted with thrombin, incubated at 37C for 4 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% of the clot under the above conditions.
  • ED values for the various compounds tested are set forth in the following table, each of the compounds being identified by name and by the number of the ensuing example in which its synthetis is described: Billimoria, J. D., Drysdale. .1., James, D.C.O., and Maclagan, N. F., The Lancet 11, 471 (1959).
  • nonanediamine dihydrochloride 9 1,6 bis( 3,4-dimethoxyphenyl )-N,N 1
  • the compound when administered orally to rats has been found to possess an ED of 7 mg./kg., and an LD of 400 mg./kg. It is of interest to note that the deaths at such very high doses are not due to the fibri nolytic effect of the drug,.but rather to neurological and respiratory depression.
  • compositions of the invention contain a compound of Formula A or a non-toxic acid addition salt thereof together with a pharmaceutically acceptable 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.
  • Examples of carriers which may be used in the compositions of the invention are 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, 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 propylene glycol
  • ethanol ethanol
  • agar water
  • compositions of the invention for pharmaceutical administration, conventional practices and precautions are used. Those compositions intended for parenteral administration must be sterile, either by the use of sterile ingredients and aseptic conditions of preparation, 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 any diluent preservative or flavoring agent utilized, or in the conditions employed in preparation of the compositions.
  • the fibrinolytically active compositions of the invention may be administered to mammals in need of such treatment by the oral, rectal, or parenteral routes. This may be achieved by injecting the liquid preparations intravenously, intramuscularly, intraperitoneally, or subcutaneously; by swallowing, in the case of the solid and liquid preparations; by local applications to the mucous membranes, in the case of jellies, suppositories, tablets and the like; by inhalation of sprays or mists of the liquid preparations; or the like.
  • Those compounds of Formula A which are preferred in the practice of the present invention are those in which the aromatic functions thereof are phenyl or substituted phenyl groups.
  • the preferred substituted phenyl moieties may be substituted by up to 3 substituents selected from the group consisting of lower alkyl, such as methyl, ethyl, propyl or butyl; hydroxy; halo, such as bromo or chloro; lower alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; amino, including di(lower alkyl)amino, such as dimethylamino; phenyllower alkoxy, such as benzyloxy, phenethyloxy; or aryloxy, such as phenoxy; or methylenedioxy.
  • lower alkoxy-substituted phenyl moieties e.g., p-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4-dipropoxyphenyl, and 3,4- dibutoxyphenyl, provide particularly beneficial fibrinolyticactivities and are, therefore, particularly desirable for the purposes of the present invention.
  • R on the amino moieties of the compounds of Formula A are hydrogen; amino; lower alkyl, such as methyl, ethyl, butyl, hexyl, octyl, or the like; lower alkenyl, such as allyl or butenyl; lower cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or phenyl-lower alkyl, which may if desired be substituted, such as benzyl, phenethyl, or methoxybenzyl.
  • R which, as noted above, may be the same or different in the respective moieties
  • R is hydrogen or an alkyl group having up to 4 carbon atoms
  • R substituent in each moiety is hydrogen
  • the R substituents of the fibrinolytic agents of Formula A may be hydrogen; lower alkyl, such as methyl, ethyl, propyl or butyl; or aryl, preferably phenyl or substituted phenyl, as described hereinabove. Those compounds which are not substituted, viz., those in which R is hydrogen, have however, been found to exhibit the maximum fibrinolytic activities.
  • the structure of the connecting chain Z linking the two, three of four aralkylamine moieties in the compounds of Formula A may be widely modified without diminution of fibrinolytic activity. It is preferred to employ as the Z moiety saturated or unsaturated open chain radicals, which may include polyvalent cyclic radicals, such as p-phenylene or cyclopentanediylidene, one carbon atom of which may, if desired, be substituted by an oxygen, sulfur, or nitrogen atom, such as oxydiethylene, thiodiethylene, methyliminodiethylene, pyrandiylidene or thiopyrandiylidene. Best results have, however, been obtained employing compounds wherein Z is a straight or branched hydrocarbon chain, incorporating from 4 to 10 carbon atoms when x is 2, and from 7 to 15 carbon atoms when x is 3 or 4.
  • the compounds of Formula A in which the integers m and n are l or 2 display the fibrinolytic activity of this invention.
  • the preferred embodiments of the invention comprise those compounds in which such moieties are directly bonded to the same carbon atom, i.e., those in which both m and n are 0.
  • Recrystallization from ethanol yields 1,6-bis-(3,4-dimethoxyphenyl)-1,6-hexanedione dioxime, m.p. 154.
  • the dioxime (5 g.) is dissolved in 150 ml. of acetic acid and shaken in a Parr bomb over 0.2 g. of platinum dioxide under hydrogen at 55 p.s.i. Hydrogen absorption ceases after about 3 hours.
  • the catalyst is removed by filtration and the solvent removed by distillation.
  • the syrupy residue is dissolved in water, and the resulting solution made alkaline.
  • the oil which separated is extracted with ether. Upon drying and treatment with gaseous hydrogen chloride the hydrochloride salt separates.
  • Recrystallization from methanol yields (1.1) 1,6- bis(3,4-dimethoxyphenyl 1 ,6-hexanediamine dihydrochloride, m.p. 283-285.
  • ethanol is removed in vacuo, the residue treated with water, and organic material extracted into ether. After washing several times with water, the ether layer is dried with potassium carbonate and the ether evaporated to give the 0,0- dimethyl dioxime of 1,6-di-2-thienyl-1,6-hexanedione.
  • the dioxime (13 g.) is refluxed for 15 minutes with 130 ml. of acetic anhydride. Upon cooling the bis(O- acetyl) derivative crystallizes, m.p. l52l53. A 14.5 g. sample of the latter compound is suspended in 300 ml. of tetrahydrofuran and 200 ml. of l M diborane solution added dropwise, keeping the temperature at 0 during the addition. The reaction mixture is allowed to 'warm to room temperature and stand for 17 hours. 200
  • the oily product is converted into 1,9-bis(3,4- dimethoxyphenyl)-l,9-nonanediamine dihydrochloride, which upon several recrystallizations from methanol-ethanol, melts at 287289.
  • EXAMPLE 8 1,9Bis( 3,4-dimethoxyphenyl)-l ,9-nonanediamine dihydrochloride An intimate mixture of l,9-bis(3,4-dimethoxyphenyl)-l,9-nonanedione (40 g.) and ammonium formate (100 g.) is heated, with stirring, at l65-l70 for 2 days, cooled to about 60 and treated with ice-water. The aqueous layer is decanted off and the semi-solid residue washed twice with water, treated with 80 ml. of concentrated hydrochloric acid and refluxed for 2 hours. The mixture is cooled and diluted with ca. 500 ml. of water, and twice extracted with chloroform.
  • N,N-dibutyl-1,8di-2-furyl-1,8-octanediamine dihydrochloride from butylammonium formate and 1,8-di-2-furyll ,8-octanediamine (8.3) N,N'-diallyl-l ,6-di-p-tolyl-l ,6-hexanediamine dihydrochloride, from allylammonium formate and 1,6-di-p-tolyl-1,6-hexanediamine (8.4) l,6-bis(p-chlorophenyl)-N,N-dicyclobutyl-l ,6- hexanediamine dihydrochloride, from cyclobutylammonium formate and l,6-bis( p-chlorophenyl )-1 ,6-hexanedione (8.5) N,N'-bis(p-methoxybenzyl)-1,8-d
  • aqueous layer is decanted and the semi-solid mass triturated several times with water and finally with a small quantity of methanol.
  • the mixture is then filtered and the solid recrystallized from methanol to yield N,N'-[l,6- bis(3,4-dimethoxyphenyl)- hexamethylene]diformamide, m.p. l-l62.
  • Lithium aluminum hydride (500 mg.) is added in one lot to a well-stirred hot suspension of the above diformamide (1.1 g.) in tetrahydrofuran (350 ml.) and the resulting mixture is refluxed for 3.5 hours. Excess hydride is decomposed in the usual manner, and the product obtained as a viscous oil. It is dissolved in ether and treated with gaseous hydrogen chloride. The obtained l,6-bis(3 ,4-dimethoxyphenyl)-N,N-dimethyl-1,6-hexanediamine dihydrochloride is filtered and crystallized from isopropanol and ether, m.p. 250252.
  • EXAMPLE 13 l ,6-Bis(p-methoxyphenyl)-1,6-hexanedihydrazine dihydrobromide
  • a solution of 10 g. of 1,6-dichloro-1,6-diphenylhexane in 100 ml. of ethanol is heated under reflux for 5 hours with 20 ml. of hydrazine hydrate.
  • the resulting mixture is concentrated, poured into water and made strongly basic.
  • the product separates and is purified as (13.1) 1,6-bis(p-methoxyphenyl l,6-hexanedihydrazine dihydrobromide.
  • EXAMPLE 14 3 ,3 -Thiobis[a-(3,4-dimethoxyphenyl )-propylamine] dihydrochloride
  • a mixture of 3',4'-dimethoxy-3-(dimethylamino)- propiophenone (32 g.) and thioacetamide (16.6 g.) are heated at l45-l50 for 15 minutes.
  • the resulting product is recrystallized from ethanol to yield 3,3"-thiobis[3',4-dimethoxypropiophenone], which, by the method of Example 2 is converted to the corresponding 0,0'-dimethyl dioxime, m.p. 94-97.
  • EXAMPLE 18 l ,6-Bis(3,4-dimethoxyphenyl)-3-methyl-1,6-hexanediamine dihydrochloride
  • l,6-bis(3,4-dimethoxyphenyl)-3methyl-1,-hexanedione, m.p. 83-86 prepared by means of an AlCl catalyzed Friedel-Crafts reaction of veratrole with the acid chloride of 3-methy1-1,6hexanedioic acid in tetrachloroethane, is converted to the corresponding dioxime, a glassy solid without a discrete m.p.
  • This dioxime (16 g.) is dissolved in 250 ml. acetic acid, and hydrogenated in a Parr apparatus at 50 p.s.i. using 1.6 g. of 10% palladium on charcoal as catalyst.
  • the resulting oil is converted to (18.1) l,6-bis( 3 ,4-dimethoxyphenyl )-3-methyl-l ,6- hexanediamine dihydrochloride, which, after recrystallization from isopropanolethyl acetate, melts at 238-240.
  • This dinitrile 14.6 g. is placed in a Soxhlet extractor over a slurry of LiAlH (3.0 g.) in tetrahydrofuran (250 ml.). The material is completely extracted from the thimble on refluxing for 67 hours, and after standing overnight, the reaction mixture is decomposed with 1 N NaOH and filtered. The filtrate is evaporated to dryness, taken up in benzene and extracted with 3 N l-lCl. The combined extracts are clarified by extraction with ether, basified with dilute ammonia, and the gum which separates is taken up in benzene.
  • the gummy precipitate is triturated with ethyl acetate and acetone, filtered, recrystallized from ethanol-acetone-ether, and dried in vacuo (0.03 mm.) over P 0 at room temperature for 20'hours to give (21.1) 4-[3-amino-3-(3 ,4- dimethoxyphenyl)propyl]-1 ,7-bis( 3 ,4-dimethoxyphenyl)-4-ethyl- 1,7-heptanediamine trihydrochloride, m.p. 168l73.
  • EXAMPLE 22 4-[ 3-Amino-3-( 3,4-dimethoxyphenyl)propyl]-l ,9- bis( 3 ,4-dimethoxyphenyl)-1,9-nonanediamine trihydrochloride A mixture of the trimethyl ester of 4-(2-carboxyethyl)nonanedioic acid (33.2 g.) and 10% aqueous sodium hydroxide (354 ml.) is refluxed gently for 17 hours, cooled in an ice-bath, and acidified with concentrated hydrochloric acid.
  • the mixture is then extracted continuously with ether for 24 hours, the extract dried over Na SO and evaporated in vacuo to dryness to yield 4-(2-carboxyethyl)-l,9-nonanedioic acid as a viscous oil.
  • the acid (19.5 g.) and freshyl distilled thionyl chloride (33 ml.) are mixed and stirred for 17 hours at room temperature.
  • Benzene is distilled invacuo from the organic phase and the residue is steam distilled to remove excess veratrole and the last traces of tetrachloroethane. The remaining water-insoluble oil is redissolved in benzene, dried over MgSO and the benzene distilled in vacuo.
  • This triketone (4.54 g.) is converted by the method of Example 19 to the corresponding 0,0,0"-trimethyl trioxime, which is isolated as a light yellow glass with an indefinite melting point below 100.
  • the light yellow solid residue is triturated with hexane, filtered, and after dissolving in dry tetrachloroethane (50 ml.), is added dropwise in one hour to a stirred suspension of veratrole (24.3 g.), aluminum chloride (25.6 g.), and dry tetracloroethane ml.) which is maintained at 0 by ice-bath cooling.
  • the reaction mixture is stirred at 0 for 2 hours, stored in a refrigerator (2-3) overnight, and then decomposed by carefully pouring onto a mixture of cracked ice (400 g.) and concentrated hydrochloric acid (20 ml.).
  • This latter product (12 g.) is dissolved in 100 ml. glacial acetic acid and hydrogenated in a Parr apparatus at 50 p.s.i. and 55 over 1.2 g. of 10% palladium on charcoal.
  • the catalyst is filtered and washed with water.
  • the residue remaining after evaporating the aqueous acetic acid in vacuo is dissolved in water, the solution made strongly basic with 10 N aqueous sodium hydroxide, and the mixture extracted with benzene. After washing the combined benzene extracts with water and drying, the benzene is evaporated in vacuo and the residue treated with ethanolic hydrogen chloride and ether.
  • EXAMPLE 25 3 ,5 -Tetrahydrothiopyrandiylidenetetrakis a-( 3 ,4- dimethoxyphenyl)propylamine] tetrahydrochloride Tetramethyl 3,5-tetrahydrothiopyrandiylidenetetrapropionate, whose synthesis from tetrahydro-4l-l-thiopyran-4-one is described in Example 3 of the aforesaid copending application Ser. No.
  • EXAM PLE 27 Pharmaceutical Formulations Compound formulations may be prepared incorporating any of the fibrinolytic compounds of the present invention as follows:
  • CAPSULES Ingredients mg./capsule active compound 200 lactose USP 100 magnesium stearate USP 3 Cab-O-Sil (amorphous silicon dioxide) 1.5
  • SUPPOSITORIES Ingredients active compound 200 mgJsuppository cocoa butter q.s.
  • SYRUP Ingredients active compound granulated sugar sodium benzoate 50 grams/liter 600 grams/liter 1 gram/liter flavor q.s. color q.s. deionized water q.s.
  • R is lower alkyl, phenyl or benzyl
  • R is hydrogen or lower alkyl
  • Z is alkylene of 7 to 15 carbon atoms and having a valence of x; and x is 3 or 4; and the acid addition salts thereof.

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Abstract

Novel alkylenepoly(aralkylamines) and related compounds, the pharmaceutically acceptable acid addition salts thereof and compositions containing such substances have been found to exhibit high sustained and useful levels of fibrinolytic acitivity in mammals.

Description

' United States Patent Flie dner, Jr. et al.
[ Dec. 30, 1975 [54] ALKYLENEPOLY(ARALKYLAMINES) AND THE SALTS THEREOF Inventors: Leonard J. Fliedner, Jr., Flushing;
Irwin J. Pachter, Woodbury, both of N.Y.
Endo Laboratories, Garden City, N.Y.
Filed: July 24, 1972 Appl. No.: 274,486
Related US. Application Data Continuation of Ser. No. 38,529, May 18, l970, which is a continuation-in-part of Ser. No. 735,510, June 10, l968, abandoned.
[73] Assignee:
[52] US. Cl. 260/570.5 P; 260/256.4 R; 260/268 R; 260/3l0 R; 260/310 C;
260/327 TH; 260/329 AM; ;260/347.7; 260/465 C; 260/465 H;
260/475 R; 260/50l.l 8;260/501.19;
260/544 M; 260/558 R; 260/559 D; 260/566 A; 260/569; 260/592; 424/250; 424/251; 42 4/274; 424/276; 424/282; 424/316;
424/330 [51] Int. Cl. C07C 87/20 [58] Field of Search 260/570.5 P
References Cited OTHER PUBLICATIONS Pailes et al., Monatoch, Vol. 84, pp. 585-591, (1953).
Primary ExaminerR. V. Hines 6 Claims, N0 Drawings ALKYLENEPOLY(ARALKYLAMINES) AND THE SALTS THEREOF CROSS REFERENCE TO OTHER APPLICATIONS BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to new compounds and pharmaceutical compositions capable of inducing increased fibrinolytic activity in mammals in need of such treatment.
2. The Prior Art In the formation of a blood clot, for example a thrombus, fibrinogen, a soluble plasma protein, is converted to the insoluble protein fibrin. As the fibrin is deposited it entraps blood cells within its meshwork to form a coagulum. In the case of a thrombus, the coagulum usually interferes with the flow of blood through a blood vessel.
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 patency of the vessel.
Inder normal conditions, the organism has low levels of activator 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 insufficient to produce enough plasmin to lyse the relatively large amount of fibrin present in a clot such as a thrombus.
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, however, been found to exhibit in vivo activity.
Fibrinolytic activity in vivo can be induced by nicotinic acid, procaine, phenylbutazone, acetylcholine, epinephrine, serotonin and histamine. However, the effect of these compounds is of short-lived duration, i.e., of the order of minutes.
Some sulfonylureas 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 to effect thrombolytic therapy, because in such instance the activity must be rapidly induced to be effective in dissolving clots.
Streptokinase, a streptococcal protein, has been used for thrombolysis, but the side effects of pyrogenicity and anaphylactic reactions have limited its use.
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 prevented general and practical use.
Bacterial pyrogens have also been used to effect thrombolysis, but the severity and unpredictability of the pyrogenic reactions have negated their usefulness.
It is a principal object of the present invention'to provide a class of fibrinolytically active materials which 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 natural origin. Compositions so active may be used to effect fibrinolysis of the clot in acute thrombosis. They may also be employed prophylactically to maintain increased fibrinolytic activity on a long term basis and thus diminish the incidence of new thrombotic episodes. 7
Other characteristics and advantages of the fibrinolytically active compounds hereof, the pharmaceutical compositions incorporating the same, and the methods of administering such materials to mammals to induce increased fibrinolysis therein, will be apparent from the following detailed description of various preferred embodiments thereof.
SUMMARY OF THE INVENTION 1. The Compounds The compounds which, in accordance with the present invention, have been found to be useful as fibrinolytic agents in mammals are those of the following general formula, and the pharmaceutically acceptable acid addition salts thereof:
Ar is a substituted or unsubstituted, monocyclic or bicyclic, aromatic, hydroaromatic or heteroaromatic moiety, preferably phenyl, naphthyl, tetrahydronaphthyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, or indazolyl;
R is hydrogen, amino, lower alkyl, lower alkenyl,
lower cycloalkyl, or'phenyl-lower alkyl;
R is hydrogen, lower alkyl or Ar;
Z is a hydrocarbon radical, straight or branched, saturated or unsaturated, which has a valence of x and comprises from 2 to 15 carbon atoms, one of which may be replaced by an oxygen, sulfur or nitrogen atom, and which may include polyvalent cyclic radicals such as arylene moieties (e.g., pphenylene), cycloalkanediylidene moieties (e.g. cyclopentanediylidene) and heterocyclediylidene moieties (e.g. pyrandiylidene or thiopyrandiylidene), or which radical may be substituted by halo, amino or nitro groups;
m and n may each be 0, 1 or 2; and
x is 2, 3 or 4.
As employed herein, the term pharmaceutically acceptable addition salts" includes the inorganic mineral acid salts, e.g., the hydrochloride, hydrobromide, sulfate and phosphate; and organic acid salts such as the lactate, tartrate, citrate, maleate, succinate, benzoate, acetate, p-toluenesulfonate and benzenesulfonate, and others conventionally formed from acids and utilized in the pharmaceutical art. As further used herein, the lower alkyl, alkenyl, or like groups are intended to include those moieties incorporating up to about 8 carbon atoms. 2. Syntheses of the Compounds The compounds utilized in accordance with the present invention may be prepared by several routes, including the various reaction schemes set forth at length on pages 4-16 of the aforesaid copending application Ser. No. 735,510 (which disclosure is incorporated by reference herein). It will be apparent from a consideration of such syntheses, including those described in detail below, that compounds of Formula A may be prepared in which the parenthetical moieties of the bis, tris, or tetrakis compounds thereof may be the same or different. Such mixed compounds may be deliberately prepared by sequentially reacting reagents incorporating the desired aromatic moieties. It is, however, not generally preferred to utilize such mixed compounds in the practice of the present invention, in view of the relative complexities which their syntheses necessarily involve. Nevertheless, it has been found that the mixed compounds, as well as those in which the parenthetical moieties are identical, possess fibrinolytic activity in accordance with the present invention. Accordingly, it is intended that the designation of the compounds of Formula A, by name and formula throughout the present specification and claims, shall be construed to include both those compounds in which the parenthetical moieties are the same or different.
It will also be appreciated that the compounds of Formula A may be formed as mixtures of diastereoisomers. Both such isomeric mixtures and the individual isomers incorporated therein have been found to exhibit fibrinolytic activity. Accordingly, it is further intended that the designation of the compounds of Formula A, by name and formula throughout the present specification and claims, shall be construed to include all isomers and mixtures thereof.
Most of those syntheses which may be employed in the preparation of the alkylenepoly(aralkylamine) fibrinolytic agents hereof utilize as their principal starting material the corresponding polyketone Polyketones of this general formula may be readily prepared from the corresponding poly(acylhalides) by the Friedel-Crafts reaction or by other conventional methods known in the art.
The following reaction scheme illustrates a principal method by which many of the fibrinolytic agents of the present invention may be prepared. In this scheme the group Y may be hydrogen, lower alkyl or lower acyl:
O NOY The polyarylpolyone [Formula I] is taken up in a suitable organic solvent, for example, pyridine, or a lower alkanol such as ethanol or propanol, and treated with hydroxylamine or an O-lower alkyl hydroxylamine, suitably in the form ofa salt such as the hydrochloride. Preferably, the reaction is effected in the presence of a tertiary amine such as pyridine, or a basic salt such as sodium acetate. The reaction may be carried out at temperatures ranging from ambient through solvent reflux temperature, i.e., from about 15 to 1 15C. It is preferred to carry out the reaction under reflux, for a period of from about 3 to 12 hours. Concentration of the reaction mixture and dilution with water yields the polyarylpolyone polyoxime or the ether derivative thereof [11] which is then reduced to the desired alkylenepoly(aralkylamine) [A']. Alternatively, the polyoxime is acylated with an acyl halide or acid anhydride to form [11, Y lower acyl] prior to reduction to The reduction may be carried out either catalytically or chemically. In the former mode, the polyoxime [II] is taken up in a suitable hydrogenation solvent, for example, an alkanoic acid such as acetic acid, and hydrogenated under moderate pressure, say from about 20 to psi., in the presence ofa catalyst such as platinum oxide. The hydrogenated mixture is then taken up in an alkaline aqueous medium, and extracted with a suitable solvent. It is preferred to isolate the product [A'] in the form of the hydrochloride salt which may be readily obtained by passing gaseous hydrogen chloride through a dry solution of the polyamine in an organic solvent such as ether.
Where a compound [11] is the poly(O-alkylor O- acyl-oxime) it is preferred to carry out the reduction steps by chemical means for example, with a solution of diborane in tetrahydrofuran. The oxime ether or ester is dissolved in a suitable solvent such as tetrahydrofuran, cooled to between about 0 and 5C, and the diborane solution added dropwise thereto. Upon completion of the addition the solution is allowed to warm to ambient temperature and allowed to stand for from about 12 hours to 2 days. The excess solvent is then removed by evaporation in vacuo, and the residual complex decomposed by the addition of acid. in the preferred mode of reaction, dilute hydrochloric acid at about 0 is added slowly, followed by refluxing for from about 1 to 2 hours. The resulting solution is extracted with ether, the aqueous layer made alkaline, reextracted with a suitable solvent, dried, and the desired polyamine [A'] isolated by treatment with hydrogen chloride in the usual manner.
The use of the preceding reaction scheme for the preparation of fibrinolytic agents in accordance with this invention is illustrated in Examples 1-3, 7, l4, l8, and 21-26 below.
In accordance with a further scheme indicated, for purposes of illustration, in connection with the synthesis of diamines within Formula A, a starting diketone [1'] may be converted to a diamine [A"] in which Ar may be any of the groups specified hereinabove, and R is hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl or phenyllower alkyl, and may be the same or different.
In this scheme ac'ompound of Formula [I'] is heated under reduced pressure to yield the desired compound with an ammonium formate R NH .HCO{. The forof Formula [A"] which may then be purified in the mate utilized in this process may be ammonium forusual manner, most suitably in the form of the hydromate or a substituted ammonium formate, for example, chloride.
a lower alkylammonium formate such as propylam- The preparation of variou s fibrinolytic agents by monium formate, butylammonium formate, or hexmeans of the above described reaction scheme is illusylammon-ium formate; a lower alkenylammonium fortrated in Examples 8-10 of the present specification.
mate such as allylammonium formate, or hexenylami The following reaction scheme illustrates a further monium formate; a lower cycloalkylammonium formethod by which the fibrinolytic agents of the present mate such. ascyclopropylammonium formate, cyinvention may be prepared. Again, for purposes of clobutylammonium formate or cyclohexylammonium illustration, the starting diketone [1"] is indicated as formate; a lower alkynylammonium formate such as being converted to diamine [A"] or diamine ]A"], propynylammonium formate, butynylammonium forboth within Formula A in which Ar and R may be any mate. or hexadiynylammonium formate; or a substiof the groups specified hereinabove, and R is lower tuted anilinium unsubstituted aryl or aralkylammonium alkyl, lower alkenyl, lower cycloalkyl or phenyl-lower formate such as anilinum formate, benzylammonium alkyl:
0 OH H HCN or CH3CN Ar--- 2 Ar- Z /conc. H 80 NHCH2R", O NH2 Ar Z UR'Q- -CI Ar-C Z 2)LiAlH 2 [AIM] [An] formate or p-methoxybenzylammonium,formate. In this scheme, where it is desired to obtain a final The reaction mixture is heated with agitation for product wherein R is other than hydrogen, a comfrom about 3 to 24 hours at a temperature of from pound of the Formula [I"] is treated with a suitable about 10 to 20 below its boiling point. The mixture is Grignard reagent of the formula R MgX to yield the then cooled and treated with water, suitably ice water, di(tertiary)carbinol [lV, R 9* H]; where in the final to yield the intermediate compound [III]. The N,N- product desired, R =H, the starting diketone [l"] is diformyldiaryldiamine [III] may; if desired, be purified. reduced with a suitable reducing agent such as sodium This course is desirable where the formamide [III] is in alcohol, sodium borohydride in alcohol, or lithium secondary in nature, (i.e. where R,=H) and it is desired aluminum hydride in ether or tetrahydrofuran. In either to produce a compound of Formula [A"] wherein R is case, the dicarbinol [IV] may be converted to the cormcthyl. Under these circumstances compound [III] is responding diamine [A"] by means of the Ritter reactaken up in a suitable ethereal solvent, reduced with tion with concentrated sulfuric acid and hydrogen cyalithium aluminum hydride, and the N,N-dimethylnide or acetonitrile. This produce, if desired, may be diaryldiamine is isolated, suitably as the hydrochloride, substituted at the amino position by acylation with acyl in the usual manner. halide such as propionyl chloride or cyclobutanecarbo- I-Iowevcr, where it is desired to produce either the nyl chloride, followed by reduction of the resulting unsubstituted diamine or a diamine of Formula [A] diamide with, for example, lithium aluminum hydride, wherein the R groups have values other than methyl to yield the substituted diamine [A]. the intermediate [III] is not further purified but submit- As noted hereinabove, the further reaction schemes ted to hydrolysis. In the preferred mode of procedure, described in the aforesaid copending application Ser. the intermediate [III] is taken up in a mineral acid such No. 735,510 may also be employed in the synthesis of as concentrated hydrochloric acid and heated under the fibrinolytic agents of this invention. The use of such reflux for from about 1 to 3 hours. The reaction mixschemes is exemplified in Examples 4 (coupling of two ture is then cooled, diluted with water', extracted with a aminoacetylenes), 5 (conversion of a diurethane to a suitable solvent and the aqueous layer concentrated disecondaryamine), 6 (condensation of 2 mols of an aromatic aldehyde with 1 mol of a,m-dinitroalkane followed by reduction of the resulting dinitrodiolefin), 11 and 12 (reduction of a dinitrile to a bis(methylamine)), 15 (condensation of a diketone with 2 mols of a primary amine followed by reduction of the resulting diimine), 16 (homologation of a diketone by means of the Reformatsky reaction to a diolefinic diester, reduction of the latter to the corresponding saturated diester, conversion of this product to a diamide and reduction of the latter), 17 (reduction of a diketone to the corre sponding diol, conversion of the latter to the corresponding dihalide, reaction of this product with an amine), 19 (condensation of 2 mols of a diarylacetonitrile with one mol of a polymethylenedihalide, followed by reduction of the resulting dinitrile) and 20 (degradation of a diamide by the Hofmann reaction) below. 3. Pharmaceutical Uses of the Compounds As indicated hereinabove it has been found, in accordance with the present invention, that the compounds of Formula A induce immediate, Ionglasting fibrinolytic activity in mammals in need of such treatment. A further advantage 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 over-dosage of other substances of great potency.
For example, by intraperitoneal administration to rats, compounds of Formula A have been found effective in inducing fibrinolysis at 0.05 mg/kg. Indeed, it has been determined that the same compounds can be administered at levels of 100 mg/kg. By intravenous administration to rats, the compounds have been found effective at 0.2 mg./kg. and also at 80 mg./kg. Activity by the oral route in rats has been established at doses of from 1 to 300 mg/kg. ln dogs activity on intravenous administration at 0.2 mg./kg. and also at 60 mg/kg has been determined. These dosage levels are illustrative and are not meant to limit the application of the invention. The clinician may find it advisable to adjust dosage in the light of individual recipient response.
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. In this method blood from rats given a fibrinolytic compound is taken and diluted 1:10. A standard amount is clotted with thrombin, incubated at 37C for 4 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% of the clot under the above conditions. ED values for the various compounds tested are set forth in the following table, each of the compounds being identified by name and by the number of the ensuing example in which its synthetis is described: Billimoria, J. D., Drysdale. .1., James, D.C.O., and Maclagan, N. F., The Lancet 11, 471 (1959).
FIBRINOLYTIC ACTIVITY OF COMPOUNDS OF THE INVENTION diamine dihydrochloride 3 1,6-bis( p-ch1oropheny1)- 1 ,-hexane- 6 diamine dihydrochloride 1,9-bis( 3 ,4-dimethoxyphenyl)-1,9- 2
nonanediamine dihydrochloride 9 1,6 bis( 3,4-dimethoxyphenyl )-N,N 1
dimethyl-1,6-hexanediamine dihydrochloride 1,9-bis( 3,4-dimethoxyphcny1 )-N,N 4
dimethyl-1,9-nonanediamine dihydrochloride 2.7-diphcny1-1,8-octanediamine di- 4 hydrochloride 2.2.8.8-tetraphenyl-1,9-nonanedi- 4 amine dihydrochloride 3.3 -thiob|s[a-( 3.4 dimethoxyphenyl)- propylamine] dihydrochloride 1,6-bis( 3.4-dimethoxyphenyl )-3 methyl- Lb-hexunediamine dihydrochloride 1 ,6-bis(3.4-diethoxypheny1)-1 ,o-hexanediziminc dihydrochloride 1.6-bis( 3.4-di ropoxyphenyl)1,o-hexune- 5 diaminc dihy rochlonde diamine dihydrochloride 1.7-bis( 3,4-dimcthoxyphcnyl l .7-hcptuncdiaminc dihydrochloride bis(cthylumine) dihydrochloride dihydrutc 2,2.8 8-tctrakis(3.4-dimcthoxypheny1)- 6 1.9-nonzmcdizuninc dihydrochloride 1.1.6,6-tctraphcnyll .(i-hcxuncdiuminc 4 dihydrochloride 4-cthyl-1.7-bis(3,4-dimcthoxyphcnyl)-1.7- heptuncdiuminc trihydrochloridc 0.09 )1,9-nonuncdiummc trihydrochlondc 4,7-hisl 3 -.imino-3-(3.4-dimcthoxyphenyl)- -continued FIBRINOLYTIC ACTIVITY OF COMPOUNDS OF THE INVENTION In order to determine the safety of these compounds, the LD (oral) of l,6-bis(3;4-dimethoxyphenyl)-l,6- hexanediamine dihydrochloride has been determined. The compound when administered orally to rats, has been found to possess an ED of 7 mg./kg., and an LD of 400 mg./kg. It is of interest to note that the deaths at such very high doses are not due to the fibri nolytic effect of the drug,.but rather to neurological and respiratory depression.
The compositions of the invention contain a compound of Formula A or a non-toxic acid addition salt thereof together with a pharmaceutically acceptable 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. Examples of carriers which may be used in the compositions of the invention are 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.
In preparing the compositions of the invention for pharmaceutical administration, conventional practices and precautions are used. Those compositions intended for parenteral administration must be sterile, either by the use of sterile ingredients and aseptic conditions of preparation, 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 any diluent preservative or flavoring agent utilized, or in the conditions employed in preparation of the compositions.
The fibrinolytically active compositions of the invention may be administered to mammals in need of such treatment by the oral, rectal, or parenteral routes. This may be achieved by injecting the liquid preparations intravenously, intramuscularly, intraperitoneally, or subcutaneously; by swallowing, in the case of the solid and liquid preparations; by local applications to the mucous membranes, in the case of jellies, suppositories, tablets and the like; by inhalation of sprays or mists of the liquid preparations; or the like.
PREFERRED EMBODIMENTS OF THE INVENTION Those compounds of Formula A which are preferred in the practice of the present invention are those in which the aromatic functions thereof are phenyl or substituted phenyl groups. The preferred substituted phenyl moieties may be substituted by up to 3 substituents selected from the group consisting of lower alkyl, such as methyl, ethyl, propyl or butyl; hydroxy; halo, such as bromo or chloro; lower alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; amino, including di(lower alkyl)amino, such as dimethylamino; phenyllower alkoxy, such as benzyloxy, phenethyloxy; or aryloxy, such as phenoxy; or methylenedioxy. It has further been found that lower alkoxy-substituted phenyl moieties, e.g., p-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4-dipropoxyphenyl, and 3,4- dibutoxyphenyl, provide particularly beneficial fibrinolyticactivities and are, therefore, particularly desirable for the purposes of the present invention.
Among the preferred substituents R on the amino moieties of the compounds of Formula A are hydrogen; amino; lower alkyl, such as methyl, ethyl, butyl, hexyl, octyl, or the like; lower alkenyl, such as allyl or butenyl; lower cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or phenyl-lower alkyl, which may if desired be substituted, such as benzyl, phenethyl, or methoxybenzyl. Especially preferred, however, are those compounds of Formula A in which R (which, as noted above, may be the same or different in the respective moieties) is hydrogen or an alkyl group having up to 4 carbon atoms, and most desirably those compounds in which the R substituent in each moiety is hydrogen.
As indicated hereinabove, the R substituents of the fibrinolytic agents of Formula A may be hydrogen; lower alkyl, such as methyl, ethyl, propyl or butyl; or aryl, preferably phenyl or substituted phenyl, as described hereinabove. Those compounds which are not substituted, viz., those in which R is hydrogen, have however, been found to exhibit the maximum fibrinolytic activities.
It has been found that the structure of the connecting chain Z linking the two, three of four aralkylamine moieties in the compounds of Formula A may be widely modified without diminution of fibrinolytic activity. It is preferred to employ as the Z moiety saturated or unsaturated open chain radicals, which may include polyvalent cyclic radicals, such as p-phenylene or cyclopentanediylidene, one carbon atom of which may, if desired, be substituted by an oxygen, sulfur, or nitrogen atom, such as oxydiethylene, thiodiethylene, methyliminodiethylene, pyrandiylidene or thiopyrandiylidene. Best results have, however, been obtained employing compounds wherein Z is a straight or branched hydrocarbon chain, incorporating from 4 to 10 carbon atoms when x is 2, and from 7 to 15 carbon atoms when x is 3 or 4.
The compounds of Formula A in which the integers m and n are l or 2 display the fibrinolytic activity of this invention. However, the preferred embodiments of the invention comprise those compounds in which such moieties are directly bonded to the same carbon atom, i.e., those in which both m and n are 0.
For a better understanding of the nature and objects EXAMPLE 1 1,6-Bis( 3 ,4dimethoxyphenyl)-1,6-hexanediamine dihydrochloride To a solution of 7.72 g. of l,6-bis(3,4-dimethoxyphenyl.)-l,6-hexanedione in 100 ml. of ethanol and 50 ml. of pyridine is added hydroxylamine hydrochloride (4.17 g.) and the reaction mixture refluxed for 12 hours with stirring. The solution is concentrated to 50 ml. Upon dilution with 50 ml. of water, the product separates and crystallizes upon scratching. Recrystallization from ethanol yields 1,6-bis-(3,4-dimethoxyphenyl)-1,6-hexanedione dioxime, m.p. 154. The dioxime (5 g.) is dissolved in 150 ml. of acetic acid and shaken in a Parr bomb over 0.2 g. of platinum dioxide under hydrogen at 55 p.s.i. Hydrogen absorption ceases after about 3 hours. The catalyst is removed by filtration and the solvent removed by distillation. The syrupy residue is dissolved in water, and the resulting solution made alkaline. The oil which separated is extracted with ether. Upon drying and treatment with gaseous hydrogen chloride the hydrochloride salt separates. Recrystallization from methanol yields (1.1) 1,6- bis(3,4-dimethoxyphenyl 1 ,6-hexanediamine dihydrochloride, m.p. 283-285.
In place of using 1,6-bis(3,4-dimethoxyphenyl)-1,6- hexanedione in the foregoing procedure there is used:
l,8-bis(3,4-dimethoxyphenyl)-1,8-octanedione,
1 ,12-bis(p-methoxyphenyl)-l ,l2-didecanedione,
2,2,1 1,1 l-tetramethyl-l ,12-diphenyl-l ,l 2-dodecanedione,
l,10-bis(2,3,4-trimethoxyphenyl)-l,lO-decanedione,
l,lO-bis(l-hydroxy-2-naphthyl)-1,10-decanedione,
l ,6-bis(4-methoxy-3-nitrophenyl)-1,6-hexanedione,
l,6-bis( 3 ,4-methylenedioxyphenyl)-l ,6-hexaned- 1one,
l,6-bis( 5 ,6,7,8-tetrahydro-2-naphthyl)-1,6-hexaned- 1one,
1,6-bis(p-ethoxyphenyl l ,6-hexanedione,
l,8-bis(p-dimethylaminophenyl l ,8-octanedione,
1,6-di-p-tolyl-l ,6-hexanedione,
1,6-bis(p-methoxyphenyl)-1,6-hexanedione 1-(o-hydroxyphenyl)-6-(p-methoxyphenyl )-l ,6-hexanedione,
1,6-bis(7-hydroxy-5-methyl-s-triazolo[ 1 ,5-a]pyrimidin-2-yl)-2,5-hexanedione, and
' 1-(p-methoxyphenyl)-7-(p-acetoxyphenyl)heptane- 1,5-dione, to yield:
1 ,8-bis( 3,4-dimethoxyphenyl)- 1 ,8-octanediamine dihydrochloride, m.p. 275280 (dec.) 1,12-bis(p-methoxyphenyl)-1,12-dodecanediamine dihydrochloride,
2,2,1 l,l l-tetramethyl-l l Z-diphenyll l 2-dodecanediamine dihydrochloride,
l ,10-bis(2,3,4-trimethoxyphenyl)-l lO-decanediamine dihydrochloride,
2,2-( l ,o-diaminohexamethylene)bis[ l-naphthol] dihydrochloride,
1 ,6-bis(3-amino-4-methoxyphenyl)-1, hexanediamine tetrahydrochloride,
l,6-bis(3,4-methylenedioxyphenyl)- l ,fi-hexanediamine dihydrochloride, m.p. 265267 l,6-bis(5,6,7,8-tetrahydro-2-naphthyl)-1,6-hexanediamine dihydrochloride,
.10) l,6-bis(p-ethoxyphenyl)-l ,6-hexanediamine dihydrochloride,
1,8-bis(p-dimethylaminophenyl)-l ,B-Qctanediamine tetrahydrochloride, 1,6-di-p-tolyl-1,fi-hexanediamine dihydrochloride 1,6-bis(p-methoxyphenyl)-l,-hexanediamine dihydrochloride,
m.p. 272274 o-[ l ,6-diamino-6-(p-methoxyphenyl )hexyllphenol dihydrochloride, 2,2'-(2,5-diaminohexamethylene)bis[S-methyl-s-triazolo- [l,5-a]pyrimidin-7ol] dihydrochloride, l-(p-methoxyphenyl)-7-(p-acetoxyphenyl)heptane-1,S-diamine dihydrochloride EXAMPLE 2 1,6-Di-2-thienyl-1,6-hexanediamine dihydrochloride A mixture of 1,6-di-2-thienyl-1,6-hexanedione (5.6 g.), pyridine (5 ml.), O-methyl hydroxylamine hydrochloride (5 g.) and ethanol (25 ml.) is heated at reflux for 3 hours. At the end of this time, ethanol is removed in vacuo, the residue treated with water, and organic material extracted into ether. After washing several times with water, the ether layer is dried with potassium carbonate and the ether evaporated to give the 0,0- dimethyl dioxime of 1,6-di-2-thienyl-1,6-hexanedione.
A solution of this oxime ether (5 g.) in ml. tetrahydrofuran is treated with a solution of 1 N diborane in tetrahydrofuran (60 ml.) at 0. The diborane solution is added dropwise with stirring. After the addition is complete, the solution is allowed to warm to room temperature and stand for 4 days. Excess tetrahydrofuran is removed in vacuo and the residue cautiously treated with 1 N HCl at 0 until frothing has subsided. The product is then heated at reflux with ml. of 1 N HCl for 1% hours. A clear solution results which is cooled, extracted with ether, and the aqueous layer basified with potassium hydroxide solution. The oil separates is extracted several times with ether, and the layers dried with potassium carbonate. The ether solution is treated with gaseous hydrogen chloride. A precipitate forms, which upon recrystallization with isopropanol-waterether yields (2.1) l,6-di-2-thienyl-l,o-hexanediamine dihydrochloride, m.p. 283-285 (dec.) [melting points 13 followed by (dec.) are decomposition points rather than melting point] In similar fashion, through use of the foregoing procedure but in place of 1,6-di-2-thienyl-1,6-hexanedione, there is used:
1,6-bis(4,5-dichloro-2-thienyl)-1,6-hexanedioi1e l,6-bis(p-bromophenyl)-1,6-hexanedione 1,6-diphenyl-3-hexene-l ,6-dione l ,6-dimesityl-2,4-hexadiene-1,6-dione 1,6dinaphthyl-2,4-hexadiyne-1,6-dione l ,10-di(pyrrol-2-yl)-1,10-decanedione 1, l -di-2-thienyl-1 ,1 O-decanedione 1,8-di-2-furyl-1 ,8-octanedione l,8-dipyrazinyl-2,7-octanedione 1,7-bis(6-methoxy-m-tolyl )-l ,7-heptanedione 1,7-bis(4,5-dichloro-2-thienyl )-1 ,7-heptanedione l ,6-bis( l,3,5-trimethylpyrazol-4-yl)-1,6 hexanedione 1,8-di-4-pyridyl-1,8-octanedione 1,8-di-3H-indazol-3-yl-l ,8-octanedione and 1,7-diphenyl-2,6-heptanedione, the following compounds are produced, all isolated as their dihydrochlorides (2.2) l,6-bis(4,5-dichl0ro-2-thienyl)- l ,6-hexanediamine A mixture of 1,6-bis(p-chlorophenyl)-1,6-hexanedione (20 g.), ethanol (200 ml.), pyridine (300 ml.), hydroxylamine hydrochloride (12.5 g.) and water (25 ml.) is refluxed for 17 hours. Thesolvents are removed in vacuo. The white crystalline residue, after washing with water and recrystallization from ethoxyethanol, yields the dioxime of the diketone, m.p. 230232.
The dioxime (13 g.) is refluxed for 15 minutes with 130 ml. of acetic anhydride. Upon cooling the bis(O- acetyl) derivative crystallizes, m.p. l52l53. A 14.5 g. sample of the latter compound is suspended in 300 ml. of tetrahydrofuran and 200 ml. of l M diborane solution added dropwise, keeping the temperature at 0 during the addition. The reaction mixture is allowed to 'warm to room temperature and stand for 17 hours. 200
ml. of 10% aqueous potassium hydroxide is then added. An oil separates, is dissolved in ethanol and treated with a saturated solution of hydrogen chloride in ethanol. Addition of ether causes precipitation of 1,6-bis(pchlorophenyl )-1 ,6-hexanediamine dihydrochloride, which is recrystallized from ethanolether, m.p. 303305.
EXAMPLE'4 2,7-Diphenyl-3,5-octadiyne;2,7-diamine dihydrochloride v A mixture of 16.4 g. 3-amino-3-ph enyl-l-butyne;63 ml. of 2 N hydrochloric'acid, 2.8 g. ofcuprous chloride,
14 8.4 g. of ammonium chloride and 100 ml. of water is warmed to 5055 and a current of air passed through the well-stirred solution for 4 hours. Pure oxygen is passed through for another 3 hours, whereupon the solution becomes brown, and a brown precipitate forms. Solids are filtered off, and the filtrate basified with aqueous ammonia. A brown oil separates which is taken up in ether, washed with water, and dried. Removal of solvent gives a dark oil which is dissolved in benzene and chromatographed over neutral alumina l. The eluates are evaporated, the residue taken up in ether and treated with dry hydrogen chloride gas. The
precipitated solid is filtered and recrystallized from ethanol-ethyl acetate to give a slightly off-white 2,7- diphenyl-3,5-octadiyne-2,7-diamine dihydrochloride m.p. 285-288 (dec.). A portion of the hydrochloride is converted to the free base, pale yellow needles, m.p. 90.593.0 after recrystallization from hexane;
EXAMPLE 5 Triethylamine (4.58 g.) and 50 ml. methylene chloride are added to l,6-diphenyl-l,6-hexanediamine (5.51 g.) and the resulting solution is added dropwise over the course of 1 /2 hours with vigorous stirring to a solution of ethyl chlorocarbonate (4.92 g.) in ml. methylene chloride, the temperature of the reaction mixture being kept at 23 during the addition. Within one-half hour a white solid appears. The suspension is stirred for 22 hours at room temperature, whereupon the obtained precipitate is filtered off and washed with methylene chloride to yield 1.5 g. of a white solid diurethane, m.p. 202-204.
The filtrate and washings are combined, washed with 5% hydrochloric acid and then with water. Drying and evaporation of the methylene chloride leaves a solid residue which is triturated with ether and filtered to give 4.5 g. of the crude second isomer (m.p. 149-160) of the di-urethane of theabove mentioned diamine.
The latter compound (8.12 g.) suspended in tetrahydrofuran is added to a suspension of lithium aluminum hydride (6.08 g.) in 400 ml. of ether and 400 ml. of tetrahydrofuran. After four hours under reflux the mixture is decomposed with aqueous sodium hydroxide, filtered and evaporated to dryness to give a syrup which is treated with 5% hydrochloric acid. The obtained aqueous solution, filtered of some insoluble material, is made strongly basic with sodium hydroxide. The liberated base is dissolved in ethanol and treated with an ethanolic solution saturated with gaseous hydrogen chloride. Addition of absolute ether precipitates N,N '-dimethyl-1,6-diphenyl-1,6-hexanediamine dihydrochloride, which recrystallizes from ethanol-ether, m.p. 276277.
EXAMPLE 6 1,8-bis( 3 ,4-dimethoxyphenyl )-2,7-octanediamine dihydrochloride A mixture of veratraldehyde (4.98 g.), 1,6-dinitrohexane (2.64 g.) and ammonium acetate (1.16 g.) in 20 ml. acetic acid is refluxed for 2 hours. Upon cooling, 1,8-bis(3,4- dimethoxyphenyl )-2,7-dinitrol ,7-octadione, m.p. 184-185 crystallizes. The latter is reduced with lithium aluminum hydride in tetrahydrofuran to yield (6.1)
l,8-bis(3,4-dimethoxyphenyl)-2,7-octanediamine dihydrochloride, m.p. 248250, after recrystallization from isopropanol.
By a similar process, 1,8-dinitrooctane and p-benzyloxybenzaldehyde are converted into (6.2) 1,10- bis(p-benzyloxyphenyl)-2,9-decanediamine dihydrochloride.
EXAMPLE 7 1,9-bis( 3 ,4-dimethoxyphenyl)-1,9-nonanediamine dihydrochloride A mixture of 1,9-bis(3,4-dimethoxyphenyl)-1,9- nonanedione (42.8 g.), hydroxylamine hydrochloride (27.8 g.) dissolved in 60 ml. of water, sodium acetate (32.8 g.) dissolved in 70 ml. of water and ethanol (350 ml.) are refluxed for 16 hours. The ethanol is evaporated in vacuo and the oily residue extracted with ether. The ether extracts are washed with water and dried. Evaporation of the solvent leaves a residue which, by trituration with ether and cooling with ice, gives a solid material. The latter, after recrystallization from ethanol, yields the dioxime of the above mentioned diketone, m.p. ll ll 13.
The obtained dioxime (22.9 g.), dissolved in 225 ml. acetic acid, is hydrogenated in a Parr apparatus at 45 p.s.i. using 2.29 g. of 10% palladium on charcoal as catalyst. The oily product is converted into 1,9-bis(3,4- dimethoxyphenyl)-l,9-nonanediamine dihydrochloride, which upon several recrystallizations from methanol-ethanol, melts at 287289.
EXAMPLE 8 1,9Bis( 3,4-dimethoxyphenyl)-l ,9-nonanediamine dihydrochloride An intimate mixture of l,9-bis(3,4-dimethoxyphenyl)-l,9-nonanedione (40 g.) and ammonium formate (100 g.) is heated, with stirring, at l65-l70 for 2 days, cooled to about 60 and treated with ice-water. The aqueous layer is decanted off and the semi-solid residue washed twice with water, treated with 80 ml. of concentrated hydrochloric acid and refluxed for 2 hours. The mixture is cooled and diluted with ca. 500 ml. of water, and twice extracted with chloroform. The chloroform layer is discarded and the aqueous layer concentrated to a small volume under reduced pressure, cooled and filtered. The solid is washed with a small quantity of water, dissolved in methanol and re-precipitated with absolute ether. The solid is filtered and dried to give (8.1) l,9-bis(3,4-dimethoxyphenyl)- l,9-nonanediamine dihydrochloride, m.p. 287289.
In like manner, the following compunds are synthesized in lieu of compound 8.1 when the indicated reactants are substituted for ammonium formate and 1,9- bis(3,4-dimethoxyphenyl)-l,9-nonanedione, respectively:
(8.2) N,N-dibutyl-1,8di-2-furyl-1,8-octanediamine dihydrochloride, from butylammonium formate and 1,8-di-2-furyll ,8-octanediamine (8.3) N,N'-diallyl-l ,6-di-p-tolyl-l ,6-hexanediamine dihydrochloride, from allylammonium formate and 1,6-di-p-tolyl-1,6-hexanediamine (8.4) l,6-bis(p-chlorophenyl)-N,N-dicyclobutyl-l ,6- hexanediamine dihydrochloride, from cyclobutylammonium formate and l,6-bis( p-chlorophenyl )-1 ,6-hexanedione (8.5) N,N'-bis(p-methoxybenzyl)-1,8-di-4-pyridyl-l ,8- octanediamine dihydrochloride, from p-methoxybenzylammonium formate and l,8-di-4-pyridyl-l,8- octanedione (8.6) l,9-bis(3,4-dimethoxyphenyl)-N,N'-di-2-propynyl-l,9-nonanediamine dihydrochloride, from 2- propynylammonium formate and l,9-bis(3,4-dimethoxyphenyl l ,9-nonanedione (8.7) N,N-dioctyl-l,10-di-2-thienyl-1,lO-decanediamine dihydrochloride,from octylammonium formate and l, l O-di-Z-thienyl-l l O-decanedione EXAMPLE 9 l,6-Bis(3,4-dimethoxyphenyl)-N,N'-Dimethyl-1,6- hexanediamine dihydrochloride An intimate mixture of 1,6-bis( 3,4-dimethoxyphenyl)-l ,6-hexanedione (20.5 g.) and ammonium formate (40 g.) is heated with stirring at 160l 70 for 24 hours, cooled and treated with water. The aqueous layer is decanted and the semi-solid mass triturated several times with water and finally with a small quantity of methanol. The mixture is then filtered and the solid recrystallized from methanol to yield N,N'-[l,6- bis(3,4-dimethoxyphenyl)- hexamethylene]diformamide, m.p. l-l62.
Lithium aluminum hydride (500 mg.) is added in one lot to a well-stirred hot suspension of the above diformamide (1.1 g.) in tetrahydrofuran (350 ml.) and the resulting mixture is refluxed for 3.5 hours. Excess hydride is decomposed in the usual manner, and the product obtained as a viscous oil. It is dissolved in ether and treated with gaseous hydrogen chloride. The obtained l,6-bis(3 ,4-dimethoxyphenyl)-N,N-dimethyl-1,6-hexanediamine dihydrochloride is filtered and crystallized from isopropanol and ether, m.p. 250252.
EXAMPLE l0 1,9-Bis( 3 ,4-dimethoxyphenyl )-N,N '-dimethyl-l ,9- nonanediamine dihydrochloride By the procedure of Example 9, l,9-bis(3,4-dimethoxyphenyl)-l,9-nonanedione is converted into 1,9- bis(3,4-dimethoxyphenyl)-N,N-dimethyl-l,9-nonanediamine dihydrochlor- EXAMPLE 1 l 2,7-Diphenyl-l ,8-octanediamine dihydrochloride 2,7-diphenyloctanedinitrile is prepared by treating a solution of 95 g. 1,6-dichloro-1,6-diphenylhexane in 450 ml. of dimethyl sulfoxide with 37 g. of sodium cyanide. The stirred mixture is heated on a steam bath overnight, cooled, poured into water and the product extracted several times with chloroform. The extracts are washed with water, dried, and solvent removed in vacuo to give 25 g. of crude product. This material is 60 purified by chromatography and then crystallized from vacuum, the residue taken up in ether and dried. Removel of solvent gives 6.0 g. of oil. This material is dissolved in methanol, and the solution treated with hydrogen chloride gas. Removal of solvent gives a solid, which is dried overnight in vacuo over phosphorus pentoxide. It is then treated with boiling acetonitrile and filtered to give 2,7-diphenyl-l,8-octanediamine dihydrochloride as a white cystalline solid, m.p. 241-245 (dec.).
EXAMPLE 12 2,2 ,8 ,8-Tetraphenyl-1 ,9-nonanediamine dihydrochloride 2,2,8,8-Tetraphenyl-l,9-nonanedinitrile g.) dissolved in 75 ml. of benzene is added to 225 ml. of an ammonia-saturated methanolic solution and reduced with Raney nickel and hydrogen at 55. The nickel is removed and the solution evaporated to dryness. The residue is taken up in methanol and treated with gaseous hydrogen chloride. Concentration yields the hydrochloride salt, which separates as a solid. Recrystallization from ethyl acetate yields 2,2,8,8-tetraphenyl-l,9- nonanediamine dihydrochloride, m.p. l74177.
EXAMPLE 13 l ,6-Bis(p-methoxyphenyl)-1,6-hexanedihydrazine dihydrobromide A solution of 10 g. of 1,6-dichloro-1,6-diphenylhexane in 100 ml. of ethanol is heated under reflux for 5 hours with 20 ml. of hydrazine hydrate. The resulting mixture is concentrated, poured into water and made strongly basic. The product separates and is purified as (13.1) 1,6-bis(p-methoxyphenyl l,6-hexanedihydrazine dihydrobromide.
In similar fashion, refluxing with isobutylamine in place of hydrazine produces (13.2) N,N'-diisobutyll ,6-bis(p-methoxyphenyl)-1,6-hexanediamine.
EXAMPLE 14 3 ,3 -Thiobis[a-(3,4-dimethoxyphenyl )-propylamine] dihydrochloride A mixture of 3',4'-dimethoxy-3-(dimethylamino)- propiophenone (32 g.) and thioacetamide (16.6 g.) are heated at l45-l50 for 15 minutes. The resulting product is recrystallized from ethanol to yield 3,3"-thiobis[3',4-dimethoxypropiophenone], which, by the method of Example 2 is converted to the corresponding 0,0'-dimethyl dioxime, m.p. 94-97. Without further purification, this crude dioxime (9.52 g.) is dissolved in 250 ml. tetrahydrofuran, 1 N diborane in tetrahydrofuran (90 ml.) is added at 0, and the mixture stirred at room temperature for 40 hours. Workup as in Example 2 gives (14.1) 3,3'-thiobis- [a-( 3 ,4-dimethoxyphenyl )propylamine] dihydrochloride, m.p. 229-23l.
By a similar series of steps, starting with the following ketones:
3 ,3 '-thiodipropiophenone 3,3"-oxybis[3',4'-dimethoxypropiophenone] 3 ,3 '-oxybis[4 '-hydroxy-3 -methoxypropiophenone] and l,4-bis( 3 ,4-dimethoxyphenyl)-2,3-dimethyl-1,4-
butanedione the following compounds are produced:
(14.2) 3,3'-thiobis[a-phenylpropylamine] dihydrochloride (14.3) 3,3-oxybis[a-( 3,4-dimethoxyphenyl)propylamine] dihydrochloride 14.4) 4,41 -oxybis(3-aminotrimethylene)diguiacol dihydrochloride 14.5) l,4-bis(3,4-dimethoxyphenyl)-2,3-dimethyll ,4-butanediamine dihydrochloride respectively.
A mixture of 3,4-dimethoxyacetophenone (16.2 g.), methylamine hydrochloride (5.2 g.) and paraformaldehyde (5 g.) is heated in 20 ml. carbon tetrachloride, at for 30 minutes, a second solution of the dimethoxyacetophenone (16.2 g.) in 25 ml. carbon tetrachloride is added over a 25 minute period, and the reaction mixture is maintained at 70 for a total of 2 hours. On cooling, a glassy product is obtained, which, after digestion with ethanol, yields 3,3"- methyliminobis[3,4-dimethoxypropiophenone], m.p. 177l78. By the procedure described above for the preparation of (14.1), the latter is converted, via the 0,0-dimethyl dioxime to (14.6) 3,3-diamino-3,3- bis(3,4-dimethoxyphenyl)-N-methyldipropylamine, isolated as the trihydrochloride monohydrate, m.p. 213-217.
In a similar reaction sequence, using in place of the bis[dimethoxyacetophenone] the following diketones: 3 ,3 -methyliminobis[4-methoxypropiophenone] 3,3"-methyliminobis[4-methylpropiophenone], or
3,3"-butyliminodipropiophenone the following compounds are produced:
( 14.7) 3 ,3 '-diamino-3 ,3 -bis( p-methoxyphenyl )-N-methyldipropylamine trihydrochloride,
3 ,3'-diamino-N-methyl-3,3'-di-p-tolyldipropylamine trihydrochloride, or
3,3 '-diamino-N-butyl-3,3'-diphenyldipropylamine trihydrochloride, respectively EXAMPLE 15 N,N '-dibutyl-l,9-di-2-thienyl-1,9-nonanediamine dihydrochloride EXAMPLE 16 N ,N '-dimethyl-3 ,8-diphenyl-1,IO-decanediamine dihydrochloride A solution of ethyl bromoacetate (167 g.) and 1,6- diphenyl-l ,6-hexanedione (160 g.) in a mixture of 200 ml. dry benzene and 100 ml. absolute ether is added dropwise to g. of powdered zinc at such a rate as to keep the resulting mixture gently refluxing. The refluxing is continued for 30 minutes, after which the mixture is treated with 6 N sulfuric acid. The resulting product, the diethyl ester of 3,8-diphenyl-2,8-decadienedioic acid, is catalytically reduced over platinum oxide to 3,8-diphenyldecanedioic acid diethyl ester, reacted with methylamine to the corresponding N,N-dimethyl diamide, and then reduced with lithium aluminum hydride, to give N,N-dimethyl-3,8-decanediamine, isolated as its dihydrochloride.
EXAMPLE 17 N,N'-diethyl-1 ,6-bis( 3 ,4-dimethoxyphenyl)-1,6-hexanediamine dihydrochloride 1,6-Bis(3,4-dimethoxyphenyl)hexane-1,6-dione, (45.4 gms.), partially dissolved in 500 ml. of tetrahydrofuran, is added to a cold suspension of lithium aluminum hydride in 150 ml. of tetrahydrofuran. When the addition is complete, the mixture is refluxed for 2 hours, and cooled. Excess of lithium aluminum hydride is decomposed. The resulting mixture is filtered and the residue washed thoroughly with hot ethanol. The combined filtrates are evaporated to dryness to give a residue which, upon trituration with water, yields 1,6- bis( 3 ,4-dimethoxyphenyl )hexane-l ,6-dio1 (m.p. l20125).
To a cooled solution of 19.5 gms. of this alcohol in 150 ml. benzene, thionyl chloride (14.2 gms.) is added dropwise and the solution is refluxed for 1 hour. It is then evaporated to dryness in vacuo, leaving a residue which, upon recrystallization from hexane benzene, yields l,6-bis( 3 ,4-dimethxyphenyl 1,6-dichlorohexane, m.p. 119-125.
The latter compound gms.) is dissolved in 200 ml. of ethylamine, the resulting solution heated at 100 overnight in a pressure vessel, and evaporated to dryness. The residue is recrystallized to yield N,N-diethyll,6-bis(3,4-dimethoxyphenyl)-1,6-hexanediamine dihydrochloride, m.p. 275.
EXAMPLE 18 l ,6-Bis(3,4-dimethoxyphenyl)-3-methyl-1,6-hexanediamine dihydrochloride By the process of Example 7, l,6-bis(3,4-dimethoxyphenyl)-3methyl-1,-hexanedione, m.p. 83-86, prepared by means of an AlCl catalyzed Friedel-Crafts reaction of veratrole with the acid chloride of 3-methy1-1,6hexanedioic acid in tetrachloroethane, is converted to the corresponding dioxime, a glassy solid without a discrete m.p. This dioxime (16 g.) is dissolved in 250 ml. acetic acid, and hydrogenated in a Parr apparatus at 50 p.s.i. using 1.6 g. of 10% palladium on charcoal as catalyst. The resulting oil is converted to (18.1) l,6-bis( 3 ,4-dimethoxyphenyl )-3-methyl-l ,6- hexanediamine dihydrochloride, which, after recrystallization from isopropanolethyl acetate, melts at 238-240.
In a similar fashion, using adipoyl chloride in place of the acid chloride of 3-methyl-1,6-hexanedioic acid, and instead of veratrole using 1,2-diethoxybenzene, 1,2- dipropoxy benzene or 1,2-dibutoxybenzene, 1,6-bis(3,- 4diethoxyphenyl)-1,6-hexanedione, m.p. l 138, 1 ,6-bis(3,4-dipropoxyphenyl)-1,6-hexanedione, m.p. 147149, or l,6-bis(3,4l47l,6-hexanedione, m.p. l26l28, are obtained, respectively. These diketones in turn are converted to their dioximes, melting respectively at 138142, ll46 and l26127, and on catalytic reduction followed by a workup similar to that employed in Example 7, the following are obtained:
chloride, m.p. 211212(dec.). respectively.
When, in the above procedure, pimeloyl chloride is reacted with veratrole, 1,7-bis(3,4-dimethoxyphenyl)- 1,7-heptanedione, m.p. 9495 is obtained, which, after conversion to its dioxime, a glassy solid without a discrete m.p., is catalytically reduced to (18.5) 1,7- bis( 3 ,4-dimethoxyphenyl)-1,7-heptanediamine, isolated as its dihydrochloride, m.p. 258259 (dec.). Using instead of the pimeloyl chloride the acid chloride of p-benzenediacetic acid, 2,2"-(pphenylene)bis[3,4-dimethoxyacetophenone], m.p. 180183, is obtained, which is converted in the same manner, via its dioxime, m.p. 198-200, to (18.6) a,a'-bis(3,4-dimethoxyphenyl)-p-benzenebis(ethylamine), isolated as its dihydrochloride dihydrate, m.p. 268-260.
EXAMPLE 19 2,2,7,7-Tetrakis( 3 ,4-dimethoxyphenyl )-l ,8-octanediamine To a solution of potassium (3.9 g.) and a trace of FeCl in liquid ammonia (250 ml.), bis(3,4-dimethoxyphenyl)acetonitrile (31.3 g.) is added, followed ten minutes later by dropwise addition of a solution of 1,4-dibromobutane (10.8 g.) in ether. After stirring the reaction mixture for another hour, the ammonia is allowed to evaporate and is replaced by ether (250 ml.), followed by ml. water. The remaining solid is filtered off, washed with methanol and ether, and recrystallized from toluene to yield white crystals of 2,2,7,7-tetrakis(3,4-dimethoxyphenyl)octanedinitrile, m.p. 190192.
This dinitrile 14.6 g.) is placed in a Soxhlet extractor over a slurry of LiAlH (3.0 g.) in tetrahydrofuran (250 ml.). The material is completely extracted from the thimble on refluxing for 67 hours, and after standing overnight, the reaction mixture is decomposed with 1 N NaOH and filtered. The filtrate is evaporated to dryness, taken up in benzene and extracted with 3 N l-lCl. The combined extracts are clarified by extraction with ether, basified with dilute ammonia, and the gum which separates is taken up in benzene. After drying over K CO the solution is evaporated to dryness, and the residual white solid is treated with a small quantity of warm benzene and filtered. After recrystallization from toluene and drying at 100 in vacuo (0.2 mm.), (19.1) 2,2,7,- 7-tetrakis( 3 ,4-dimethoxyphenyl)-1,8-octanediamine is obtained, m.p. 192l96.
By the same procedure, using in place of the 1,4- dibromobutane an equimolar amount of 1,5-dibromopentane, (19.2) 2,2,8,- 8-tetrakis( 3 ,4-dimethoxyphenyl)-1,9-nonanediamine is obtained, isolated as the dihydrochloride, m.p. 253256 (dec.).
To a mixture of p-methoxymandelonitrile (39.2 g.) and anisole (38.5 g.) ml. of 85% H SO (w/w) is added, the reaction mixture is stirred for 45 minutes and poured over ice. The crude product which separates is filtered, washed with water and then with methanol, and after recrystallization from glacial acetic acid the resulting bis(p-methoxyphenyl)acetonitrile melts at 147159. By the procedure described above for the preparation of (19.1), using an equimolar amount of bis(p-methoxyphenyl)acetonitrile in place of the bis(3,4-dimethoxyphenyl)acetonitrile, (19.3) 2,2,7,7- tetrakis(p-methoxyphenyl)-1,8-octanediamine dihydrochloride, m.p. 270272, is obtained.
EXAMPLE 20 1,1,6,6-Tetraphenyl-1,6-hexanediamine dihydrochloride To a solution of 2,2,7,7-tetraphenyloctanediamide (4.76 g.), m.p. 223225, prepared from 2,2,7,7-tetraphenyloctanedioic acid via the corresponding acid chloride, in 350 ml. dimethylformamide a freshly prepared and chilled solution of bromine (1.8 ml.) in
4.5 M NaOH (40 ml.) is added, and the reaction mixture is stirred at 0 for an additional hour. At the end of that time it is allowed to warm up to room temperature,
after which is kept in a water bath at 7080 for an- EXAMPLE 21 4-[3-Amino-3-(3,4-dimethoxypheny1)propyl]-1,7- bis(3,4-dimethoxyphenyl)-4-ethyl-1,7-heptanediamine trihydrochloride 4-(2-Carboxyethyl)-4-ethyl-l,7-heptanedioic acid, m.p. 160161 (83 g.), prepared by the Wolff-Kishner reduction of 4-acetyl-4-(2-carboxyethyl)heptanedioic acid, is refluxed in 104 ml. thionyl chloride for 3 hours, the reaction mixture is cooled, and the excess thionyl chloride evaporated in vacuo. The light yellow solid residue is triturated with hexane, filtered, and after dissolving in dry tetrachloroethane (320 ml.), added dropwise in 1.5 hours to a stirred suspension of veratrole (146 g.), aluminum chloride (153 g.), and dry tetrachloroethane (800 ml.) which is maintained at 0-2 by ice-bath cooling. The reaction mixture is stored for hours at 23 and then decomposed by carefully pouring onto cracked ice and a small amount of concentrated hydrochloric acid. The organic phase is separated, washed with water until neutral, and then most of the tetrachloroethane distilled in vacuo. The residue is dissolved in benzene, washed first with 10% aqueous potassium carbonate, then with water, and finally dried over MgSO Evaporation in vacuo leaves an orange oil which solidifies on trituration with hexane-ether. Purification by column chromatography (neutral alumina, Activity 1 elution with 3:1 chloroform benzene) yields 4-[3-(3,4-dimethoxvphenvl)-3- oxopropyl]-1,7-bis(3,4-dimethoxyphenyl)-4-ethyl- 1,7-heptanedione as a white powder, m.p. 53-57.
To a solution of this triketone (40 g.) in 1:1 ethanol: pyridine (400 ml.) is added methoxyamine hydrochloride (33 g.) and the reaction mixture is refluxed for eight hours. After evaporating most of the solvent in vacuo, the residue is triturated with hot water, cooled, filtered, and washed with water. After drying, the resulting 0,0',0-trimethyl trioxime melts at 4550.
A solution of this compound (35 g.) in 1200 ml. tetrahydrofuran is treated dropwise under nitrogen with a solution of diborane in tetrahydrofuran (1 M,
1,1,6,6-tetraphe 500 ml.) at 0 2. After the addition is complete, stirring under nitrogen is continued for 19 hours at room temperature. Excess tetrahydrofuran is removed in vacuo and the residue treated cautiously at 010 with 10% aqueous potassium hydroxide until frothing subsides. Additional aqueous alkali (total, 1600 ml.) is added, and the mixture is refluxed for 5 hours, cooled and extracted with four portions of benzene. After washing the combined benzene extracts with water and drying, the benzene is evaporated in vacuo and the residue treated with ethanolic hydrogen chloride and ether. The gummy precipitate is triturated with ethyl acetate and acetone, filtered, recrystallized from ethanol-acetone-ether, and dried in vacuo (0.03 mm.) over P 0 at room temperature for 20'hours to give (21.1) 4-[3-amino-3-(3 ,4- dimethoxyphenyl)propyl]-1 ,7-bis( 3 ,4-dimethoxyphenyl)-4-ethyl- 1,7-heptanediamine trihydrochloride, m.p. 168l73.
In the foregoing procedure, using in place of the veratrole: anisole, phenetole, xylene, 1,Z-methylenedioxybenzene, or 1,2-diphenoxybenzene there is obtained:
respectively.
EXAMPLE 22 4-[ 3-Amino-3-( 3,4-dimethoxyphenyl)propyl]-l ,9- bis( 3 ,4-dimethoxyphenyl)-1,9-nonanediamine trihydrochloride A mixture of the trimethyl ester of 4-(2-carboxyethyl)nonanedioic acid (33.2 g.) and 10% aqueous sodium hydroxide (354 ml.) is refluxed gently for 17 hours, cooled in an ice-bath, and acidified with concentrated hydrochloric acid. The mixture is then extracted continuously with ether for 24 hours, the extract dried over Na SO and evaporated in vacuo to dryness to yield 4-(2-carboxyethyl)-l,9-nonanedioic acid as a viscous oil. The acid (19.5 g.) and freshyl distilled thionyl chloride (33 ml.) are mixed and stirred for 17 hours at room temperature. Excess thionyl chloride is distilled in vacuo and the residue, after dissolving in dry tetrachloroethane (65 ml.), is added dropwise in 2.5 hours to a stirred suspension of veratrole (43.2 g.), aluminum chloride (35.9 g.), and dry tetrachloroethane ml.) which is maintained at 0-2 by cooling in an ice-bath. The reaction mixture is stored for 15 hours at 3 and then decomposed by carefully pouring onto cracked ice and a small amount of concentrated hydrochloric acid. The organic phase is separated, washed with water until neutral, and then most of the tetrachloroethane is distilled in vacuo. The residue is dissolved in benzene and washed successively with 10% aqueous potassium carbonate, 1 N sodium hydroxide,
and water. Benzene is distilled invacuo from the organic phase and the residue is steam distilled to remove excess veratrole and the last traces of tetrachloroethane. The remaining water-insoluble oil is redissolved in benzene, dried over MgSO and the benzene distilled in vacuo. Purification by column chromatography (neutral alumina, Activity 1; elution with 2:1 benzenezethyl acetate) yields 4-[3-(3,4-dimethoxyphe- -3-oxopropyl]-l ,9-bis(3 ,4-dimethoxyphenyl )-l ,9- nonanedione, as a pale, yellow glass, with an indefinite melting point below 100.
This triketone (4.54 g.) is converted by the method of Example 19 to the corresponding 0,0,0"-trimethyl trioxime, which is isolated as a light yellow glass with an indefinite melting point below 100.
A stirred solution of this latter compound (4.60 g.) in tetrahydrofuran (100 ml.) is treated dropwise, under nitrogen, with a solution of diborane in tetrahydrofuran (1 M, 60 ml.) at 2. After the addition is complete, stirring under nitrogen is continued for 24 hours at room temperature. Excess tetrahydrofuran is removed in vacuo and the residue treated cautiously at 0-10 with aqueous potassium hydroxide until frothing subsides. Additional aqueous alkali (total, 100 ml.) is added and the mixture refluxed for 2 hours, cooled, extracted with benzene, the benzene evaporated, and the oily residue treated with 10% aqueous hydrochloric acid. This mixture is refluxed gently for 2.5 hours, cooled, and the supernatant liquid, after decanting from some insoluble oil, is made strongly alkaline by addition of 40% aqueous sodium hydroxide. The oil which separates is extracted into benzene, and the benzene extract washed with saturated aqueous sodium chloride solution, dried over Na SO and evaporated in vacuo. The residue is treated with ethanolic hydrogen chloride solution, and then ether. The precipitate is filtered, recrystallized from ethanol-acetone-ether, and dried in vacuo (0.01 mm.) over P 0 at room temperature for hours to give (22.1) 4-[3-amino-3-(3,4- dimethoxyphenyl)propyl]- l,9-bis(3 ,4-dimethoxyphenyl)-1,9-nonanediamine trihydrochloride, m.p. l78-184.
In a similar manner, using instead of the veratrole:
l,2-diethoxybenzene,
1,2-dibutoxybenzene, or
1,2-bis( benzyloxy)benzene the following are obtained:
Reduction of the latter with hydrogen over 10% palladium on charcoal in water yields 4,4'-{l ,9-diamino-4-[ 3-amino3-(3.4-dihydroxyphenyl)- propyl]nonamethylene}dipyrocatecho1 trihydrochloride EXAMPLE 23 4,7-Bis[ 3-amino-( 3 ,4-dimethoxypheny1 )-propyl ]-1 ,10- bis( 3 ,4-dimethoxyphenyl l 1 O-decanediamine tetrahydrochloride A mixture of 4,7-bis(2-carboxyethyl)decanedioic acid (13.9 g.) and thionyl chloride (38 g.) is refluxed for 3 hours, cooled, and excess thionyl chloride distilled in vacuo. The light yellow solid residue is triturated with hexane, filtered, and after dissolving in dry tetrachloroethane (50 ml.), is added dropwise in one hour to a stirred suspension of veratrole (24.3 g.), aluminum chloride (25.6 g.), and dry tetracloroethane ml.) which is maintained at 0 by ice-bath cooling. The reaction mixture is stirred at 0 for 2 hours, stored in a refrigerator (2-3) overnight, and then decomposed by carefully pouring onto a mixture of cracked ice (400 g.) and concentrated hydrochloric acid (20 ml.). The organic phase is separated, washed with water until neutral, and the tetrachloroethane distilled in vacuo. The residue is dissolved in benzene (300 ml.), washed with 10% aqueous potassium carbonate and dried (K CO The yellow oil (30 g.) which remains after evaporating the benzene in vacuo is purified by column chromatography (neutral alumina, Activity 1; elution first with 2:1 benzene: chloroform, to remove minor impurities, then with 1:1 benzenezchloroform). Evaporating the eluates and triturating the residual oil with hexane gives the desired product, 4,7-bis[3-(3,4- dimethoxyphenyl)-3-oxopropy1]-1,10-bis(3,4-dimethoxyphenyl)-1,10-decanedione as a white amorphous powder, melting below 100.
To a solution of this tetraketone (11 g.) in 1:1 ethanol:pyridine (100 ml.), hydroxylamine hydrochloride (7.2 g.) is added and the mixture refluxed for 17 hours. After evaporating the ethanol and most of the pyridine in vacuo, the oily residue is treated with ethanol (20 ml.) and excess water. Scratching produces a solid, which after further trituration with water (100 ml.), is filtered, washed with water, and dried to give the tetraoxime of the above mentioned tetraketone as a white solid, mp. 8285.
This latter product (12 g.) is dissolved in 100 ml. glacial acetic acid and hydrogenated in a Parr apparatus at 50 p.s.i. and 55 over 1.2 g. of 10% palladium on charcoal. On addition of the stoichiometric amount of hydrogen, the catalyst is filtered and washed with water. The residue remaining after evaporating the aqueous acetic acid in vacuo is dissolved in water, the solution made strongly basic with 10 N aqueous sodium hydroxide, and the mixture extracted with benzene. After washing the combined benzene extracts with water and drying, the benzene is evaporated in vacuo and the residue treated with ethanolic hydrogen chloride and ether. The precipitate is filtered, recrystallized from isopropanol-ether and dried in vacuo at 0.01 mm. over P 0 at room temperature for 24 hours to give (23.1) 4,7-bis[3-amino-3-(3,4-dimethoxyphenyl)- propyl]-1,10-bis(3 ,4-dimethoXyphcnyl)-1,10- decanediamine tetrahydrochloride, m.p. 166168.
In the foregoing procedure, using in place of the veratrole:
benzene,
anisole,
l,2-diethoxybenzene. or
N, N-dimethylaniline there if obtained:
(23.2) 4,7-bis(3-amino3-phenylpropyl)- l ,l0-diphenyll .10-
decanediamine tetrahydrochloride,
(23.3) 4.7-bis[3-amino-3-(p-methoxyphenyl)l-l. l 0-bis(p-methoxyphenyl)- l l O-decanediamine tetrahydrochloride,
(23.4) 4,7 bisl3-amino-3-(3,4-diethoxyphcnyl)] l,l0-bis(3,4-
diethoxyphenyl)-l.lO-dccanediaminc tetrahydrochloridc. or
(23.5) 4.7-bis[3-amino-3 (p-dimcthylaminophenyl)]-l.lO-bis(pdimethylaminophcnyl 1 l O-decanediamine octahydrochloride.
respectively.
EXAMPLE 24 5,9-Bis(a-aminoveratryl)-1 l 3-bis( 3 ,4-dimethoxyphenyl)-1,13-tridecanediamine tetrahydrochloride Tetraethyl 1,4,8,1 l-undecanetetracarboxylate, prepared as described in Example 2 of the copending application filed in the name of Parthasarathi Rajagopa- Ian and Irwin J. Pachter, and entitled TRIS- AND TET- RAKIS-[1,2,3,4-TETRAl-IYDROISOQUINOLINE] COMPOUNDS AND THEIR USE AS FIBRINO- LYTIC COMPOSITIONS, application Ser. No. 1029 filed Jan. 6, 1970 (EN-047 is hydrolyzed to the corresponding tetracarboxylic acid, converted to the acid chloride, and reacted with veratrole in the presence of aluminum chloride, by the procedure of Example 21 to form 1 ,13-bis(3 ,4-dimethoxyphenyl )-5 ,9- diveratroyl-1,13-tridecanedione. Conversion of this tetraketone, via the 0,0',O,O'-tetramethyl tetraoxime, by reduction of the latter with dibrone in tetrahydrofuran. yields (24.1 5 ,9-bis(aaminoveratryl)-1,13-bis(3,4-dimethoxyphenyl)-1,1 3- tridecanediamine, which is isolated as its tetrahydrochloride.
By the same sequence of steps, starting with tetramethyl 1,5,10,14-tetradecanetetracarboxylate, prepared as described in Example of the said copending application, and tetramethyl 1,4,9,12-dodecanetetracarboxylate, described in Example 16 of that application, there are obtained (24.2) 6,1 l-bis(a-aminoveratryl)- 1,16-bis(3,4-dimethoxyphenyl)-l,14-hexadecanediamine, and (24.3) 5,10-bis(a-aminoveratryl)-1,14- bis(3,4-dimethoxyphenyl)-1,14-tetradecanediamine, both isolated as their tetrahydrochlorides.
EXAMPLE 25 3 ,5 -Tetrahydrothiopyrandiylidenetetrakis a-( 3 ,4- dimethoxyphenyl)propylamine] tetrahydrochloride Tetramethyl 3,5-tetrahydrothiopyrandiylidenetetrapropionate, whose synthesis from tetrahydro-4l-l-thiopyran-4-one is described in Example 3 of the aforesaid copending application Ser. No. 1029, is converted via 3,3",3"", 3"""-(3,5-tetrahydrothiopyrandiylidene)- tetrakis[3',4'-dimethoxypropiophenone], to (25.1) 3 ,5-tetrahydrothiopyrandiylidenetetrakis[a-(3 ,4-dimethoxyphenyl)-propylamine] tetrahydrochloride, by the method of Example 24. Reduction with pyrophoric nickel, prepared from commercial Raney nickel, of this compound in 70% aqueous alcohol yields (25.2) 4,6- bis[3-amino-3-(3,4-dimethoxyphenyl)propyl]-1,9- bis(3,4-dimethoxyphenyl)-4,6-dimethyl-1,9-nonanediamine, isolated as its tetrahydrochloride.
By the same sequence of steps outlined above for the preparation of Example 25.1, but starting with tetrahydro-4H-pyran-4-one in place of tetrahydro-4l-I-thiopyran-4-one, (25.3) 3,5-tetrahydropyrandiylidenetetrakis[a-( 3 ,4-dimethoxyphenyl )propylamine] tetrahydrochloride is obtained.
Similarly, starting with 1,3-cyclopentanediylidenetet' rapropionic acid, whose preparation is described in Example 4 of the copending application referred to above, (25.4) 1,3-cyclopentanediylidenetetrakis[a- (3,4-dimcthoxyphenyl)propylamine] tetrahydrochloride is obtained.
EXAMPLE 26 2-{ 2-Amino-2-( 3 ,4-dimethoxyphenyl)-ethyl]thio}- 1,7-bis( 3,4-dimethoxyphenyl )-l ,7-heptanediamine trihydrochloride bis(3,4-dimethoxyphenyl)-1,7-heptanediamine, isolated as its trihydrochloride.
By the same sequence of steps, the following acids (each followed in parentheses by the Example number in copending application Serial No. 1029 in which it is first described):
l,4,7-heptanetricarboxylic acid 4-benzyl-4-( 2-carboxyethyl)- heptanedioic .acid 4-(2-carboxyethyl )-4-( p-chlorobenzyl)heptanedioic acid (Example 19),
(Example 13), or
(Example 14) are converted to:
(26.2) S-(a-aminoveratryl l ,9-bis( 3,4-dimethoxyphenyl l ,9-
nonancdiamine trihydrochloride,
4-[ 3-amino-3-( 3,4-dimethoxyphenyl)propyl]-4-benzyll ,7- bis(3,4-dimethoxyphenyl)-1,7-heptanediamine trihydrochloride, or
4-[ 3-amino-3-( 3 ,4-dimethoxyphenyl)propyl)-4-( p-chlorobenzyl)-1,7bis(3,4-dimethoxyphenyl)'l,7-heptanediamine trihydrochloride,
respectively.
In a similar manner, starting with the following acids (some of which are obtained by alkaline hydrolysis from their trimethyl esters):
6-(2-carboxyethyl)-3-phenylnonanedioic acid,
6-(2-carboxyethyl)-3,3-dimethylnonanedioic acid,
nitrilotripropionic acid, or
4-(2-carboxyethyl)-4-nitroheptanedioic acid these compounds are obtained:
(26.5) 6-[3-amino-(3,4-dimethoxyphenyl)propyl]-1,9-bis(3,4-
dimethoxyphenyl)-3-phenyl-1,9-nonanediamine trihydrochloride,
6-[ 3-amino-3-( 3 ,4-dimethoxyphenyl)propyl1-1,9-bis(3 ,4- dimethoxyphenyl )-3 ,3-dimethyl- 1 ,9-nonanediamine trihydrochloride,
3 3'3 '-triamine-3 ,3 ,3 '-tris( 3,4-dimethoxyphenyl )tripropylamine tetrahydrochloride, or 4-[3-amino-3-(3,4-dimcthoxyphenyl)propyl1-l,7-bis(3 ,4- dimethoxyphenyl)-4-nitro-1,7-heptanediamine trihydrochloride,
respectively.
Reduction of this last mentioned triamine (26.8) with lithium aluminum hydride yields (26.9) 4-amino-4-[3- amino-3(3,4- dimethoxyphenyl)propyl ]-1 ,7-bis( 3 ,4-dimethoxyphenyl)-l ,7-heptanediamine, isolated as the tetrahydrochloride.
EXAM PLE 27 Pharmaceutical Formulations Compound formulations may be prepared incorporating any of the fibrinolytic compounds of the present invention as follows:
TABLETS Ingredients mg./tablet active corn ound lOO lactose US (spray dried or anhydrous) 250 starch USP 25 magnesium stearate USP 3 stearic acid USP 5 These ingredients are passed through a 60 mesh sieve, blended for 30 minutes and compressed directly into tablets on a suitable tablet press using a 12/32 inch biconcave, scored punch. Each tablet s prepared has a weight of 383 mg.
CAPSULES Ingredients mg./capsule active compound 200 lactose USP 100 magnesium stearate USP 3 Cab-O-Sil (amorphous silicon dioxide) 1.5
INJECTABLE SOLUTION Ingredients active compound 100 mgJampule pyrogen free water for injection ml./ampule manmtol N.F. to make the solution isotonic The compound is added to the water and the solution is made isotonic with mannitol. It is then filled into ampules under sterile conditions and the sealed am- 5 pules are autoclaved. Each ampule contains mg./ml. solution.
SUPPOSITORIES Ingredients active compound 200 mgJsuppository cocoa butter q.s.
SYRUP Ingredients active compound granulated sugar sodium benzoate 50 grams/liter 600 grams/liter 1 gram/liter flavor q.s. color q.s. deionized water q.s.
All ingredients are combined, dissolved in the deionized water, and made up to a volume of 1 liter.
Other alkylenepoly(aralkylamines) also have been found to exhibit fibrinolytic activity. Thus, the compound 6,6-hexamethylenebis[a-methylveratrylamine] dihydrochloride, m.p. 225228 possesses an ED determined as indicated hereinabove, of 4 mg./kg.
It will be understood that various changes may be made in the methods and compositions described hereinabove without departing from the scope of this invention. Accordingly, it is intended that the preceding specification should be construed as illustrative and not in a limiting manner.
We claim:
1. A compound of the formula R0 NH-iz,
wherein R is lower alkyl, phenyl or benzyl;
R is hydrogen or lower alkyl;
Z is alkylene of 7 to 15 carbon atoms and having a valence of x; and x is 3 or 4; and the acid addition salts thereof.
2. The compound of claim 1, wherein said compound is 4-[3-amino-3-(3,4-dimethoxyphenyl)propyl]-1,9- bis( 3 ,4-dimethoxyphenyl l ,9-nonanediamine.
3. The compoundof claim 1 wherein said compound is 4,7-bis[3-amino-3-(3,4-dimethoxyphenyl)propyl]- 1,10-bis(3,4-dimethoxyphenyl)-1,IO-decanediamine.
4. The compound of claim 1, wherein said compound is 4-[3-amino-3-(3,4-dimethoxyphenyl)propyl]-l,7-
0 -bis(3,4-dimethoxyphenyl)-4-ethyl-1,7-heptanediamine.
5. The compound of claim 1, wherein said compound is 4-{amino-3-[3 ,4-bis(benzyloxy)phenyl]propyl} -1 ,9- bis[ 3 ,4-bis(benzyloxy )phenyl l ,9-nonanediamine.
6. The compound of claim 1, wherein said compound is 4-[3-amino-3-(3 ,4-diphenoxyphenyl)propyl]-4- ethyl-l ,7-bis(3,4-diphenoxyphenyl)-1,7-heptanediamine.

Claims (6)

1. A COMPOUND OF THE FORMULA
2. The compound of claim 1, wherein said compound is 4-(3-amino-3-(3,4-dimethoxyphenyl)propyl)-1,9-bis(3,4-dimethoxyphenyl)-1,9 -nonanediamine.
3. The compound of claim 1 wherein said compound is 4,7-bis(3-amino-3-(3,4-dimethoxyphenyl)propyl)-1,10-bis(3,4-dimethoxyphenyl)-1,10-decanediamine.
4. The compound of claim 1, wherein said compound is 4-(3-amino-3-(3,4-dimethoxyphenyl)propyl)-1,7-bis(3,4-dimethoxyphenyl)-4 -ethyl-1,7-heptanediamine.
5. The compound of claim 1, wherein said compound is 4-(-amino-3-(3,4-bis(benzyloxy)phenyl)propyl)-1,9-bis(3,4 -bis(benzyloxy)phenyl)-1,9-nonanediamine.
6. The compound of claim 1, wherein said compound is 4-(3-amino-3-(3,4-diphenoxyphenyl)propyl)-4-ethyl-1,7-bis(3,4 -diphenoxyphenyl)-1,7-heptanediamine.
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EP0675196A2 (en) 1988-01-07 1995-10-04 Novo Nordisk A/S Mutated subtilisin genes
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273940A (en) * 1979-10-22 1981-06-16 Abbott Laboratories Bis-(2-benzylaminoethyl)-disulfides
EP0675196A2 (en) 1988-01-07 1995-10-04 Novo Nordisk A/S Mutated subtilisin genes
EP1555314A2 (en) 1989-06-26 2005-07-20 Novozymes A/S Enzymes and detergent compositions
JP2766728B2 (en) 1990-08-08 1998-06-18 ノージン・リミテツド Propylamine derivative
WO1998020115A1 (en) 1996-11-04 1998-05-14 Novo Nordisk A/S Subtilase variants and compositions
EP2278001A1 (en) 1996-11-04 2011-01-26 Novozymes A/S Protease variants and compositions
EP1803817A1 (en) 1998-12-18 2007-07-04 Novozymes A/S Subtilase enzymes of the I-S1 and I-S2 sub-groups having an additional amino acid residue in an active site loop region
WO2000037421A1 (en) * 1998-12-21 2000-06-29 Iraj Ghadiminejad Nephronin: a series of compounds for treatment of infectious diseases and cancer
EP1150939A4 (en) * 1998-12-21 2003-03-26 Iraj Ghadiminejad Nephronin: a series of compounds for treatment of infectious diseases and cancer
EP2333055A1 (en) 2000-10-13 2011-06-15 Novozymes A/S Subtilase variants
EP2360247A1 (en) 2000-10-13 2011-08-24 Novozymes A/S Subtilase variants

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