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US2851458A - Diquaternary compounds and the manufacture thereof - Google Patents

Diquaternary compounds and the manufacture thereof Download PDF

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US2851458A
US2851458A US589365A US58936556A US2851458A US 2851458 A US2851458 A US 2851458A US 589365 A US589365 A US 589365A US 58936556 A US58936556 A US 58936556A US 2851458 A US2851458 A US 2851458A
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cyano
iodide
ammonium
methyl
trimethylethylene
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Billinghurst John Evlyn Warner
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SmithKline Beecham Corp
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Burroughs Wellcome Co USA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

Definitions

  • R and R are the same or different, and are each a cycloalkyl group (for example a cyclohexyl group) or a phenyl group which may carry one or more substituents, said substituents being halogen atoms (for example chlorine or bromine atoms), lower alkyl groups (for example a methyl group) or lower alkoxy groups (for example a methoxy group);
  • X is the group (CH or the group (CH,),.O.(CH n is an integer from two to ten;
  • N is a quaternary nitrogen atom carrying *two alkyl groups together having up to five carbon atoms, preferably two or three carbon atoms or which together form part of a pyrrolidino, piperidino or morpholino ring;
  • N+ is a quaternary nitrogen atom carrying at least one alkyl group having one to four carbon atoms and either carrying two further alkyl groups giving a total of up to nine carbon atoms
  • the intensity of the various autonomic actions of the examples described in this application varies with the chemical constitution of the example, the nature of the action and the animal species in which the action is measured. Many of the compounds described are considerably more active than known ganglion blocking agents such as hcxamethonium and pentolimum m inhib- 2,851,458 Patented Sept. 9, 1958 iting DMPP hypertension and preventing vagal bradycardia in cats and in inhibiting gastric secretion in fasted rats. They have the, additional advantage of a much longer duration of action.
  • the preferred compounds are the salts of N -(5-cyano- 5:5 diphenylpentyl)-N :N :N trimethylethylene-I-arnmonium-Z-morpholine, the salts of N -(6-cyano-6z6-diphenylhexyl -N N :N -trirnethylethlene-l-ammonium-2- morpholine, the salts of N -(6-cyano-6:6-diphenyl-3- oxahexyl)- N :N :N trimethylethylene-l-ammonium-2- morpholine, the salts of N -(3-cyano-3:3-diphenylpropyl)- N zN zN -trimethylethylene 1 ammonium-Z-morpholine and the salts of N -(5-cyano-5:S-diphenylpentyD- N :N :N trirnethyltrirnethylene 1
  • the present invention in one aspect, therefore, comprises compounds of the general Formula I.
  • compounds of the general Formula I are prepared by treating a suitable diamine of general Formula II with a quaternising agent, such as a lower alkyl halide or lower dialkyl sulphate.
  • a quaternising agent such as a lower alkyl halide or lower dialkyl sulphate.
  • N is a secondary or tertiary nitrogen atom and N is a primary, tertiary or quaternary nitrogen atom, the substituents provided by the quaternising agent, together with any substituents on N and N being such as will give the desired substitution in the compound of general Formula I.
  • N may be a tertiary nitrogen atom carrying one alkyl group having up to four carbon atoms and N may be a tertiary nitrogen atom carrying two alkyl groups having a total of from two to eight carbon atoms or may form part of a pyrrolidino, piperidino or morpholino ring, or N YN may be a piperazine ring in which N may carry an alkyl group having from one to three carbon atoms.
  • the quaternisation reactions may be carried out by allowing the di-tertiary amine to stand with or by heating it with a quaternising agent such as a lower alkyl halide, in a suitable solvent such as acetone or methanol.
  • a quaternising agent such as a lower alkyl halide
  • N is a secondary or a tertiary nitrogen atom and N is a tertiary nitrogen atom, may be synthesised by the following general route.
  • a small excess of aqueous caustic soda solution (40% by Weight) is added to N -2-chloroethyl-W-methyl-piperazine hydrochloride (36.1 g.), the liberated base is extracted with light petroleum (boiling point below 40), the extract is dried over anhydrous sodium sulphate, the solvent evaporated in vacuo and the residual oil is dissolved in dry benzene (40 cc.).
  • the benzene solution is added during 5 minutes to a suspension of sodamide (4.1 g.) in a solution of diphenylacetonitrile (19.9 g.) in dry benzene (100 cc.), and the mixture is stirred and boiled under a reflux condenser for 5 hours.
  • reaction mixture is cooled and treated successively with water (100 cc.) and an excess of dilute hydrochloric acid.
  • the aqueous phase is separated, an excess of ammonia solution is added, and the liberated base is extracted with hot ether.
  • the hot ether extract is immediately dried over anhydrous sodium sulphate and the solvent is evaporated.
  • the solid residue is crystallised from isopropanol to' give N -3-cyano-3:3-diphenylpropyl-N -methylpiperazine, melting point 104.
  • Example 2 A suspension of sodamide (10.2 g.; 0.26 mol.) in a solution of 1:4-dichlorobutane (30.5 g.; 0.24 mol.) in dry benzene (100 cc.) is stirred and boiled under a reflux condenser and a solution of diphenylacetonitrile (38.6 g.; 0.2 mol.) in dry benezene (300 cc.) is added during 3 hours. After a further V2 hour, the mixture is cooled, water (100 cc.) is added, the solution is filtered from some insoluble crystalline material, the benzene layer is separated and dried over anhydrous sodium sulphate, and the solvent is evaporated. The oily residue is distilled to give -5-chloro-l-cyano-1:l-diphenylpentane, boiling point 164-166/0.05 mm., and melting point 47.5-49, after crystallisation from ethanol.
  • the petroleum extract is washed with mater, dried over anhydrous sodium sulphate and fractionally distilled to give 5-(N-2- di-n-butylaminoethyl-N-methyl)amino 1 cyano-lzl-diphenylpentane, boiling point 2l2-213/0.07 mm., 11 1.5195.
  • melting point 175 with decomposition is obtained therefrom by the method of Example 1, with the modification that the quaternisation reaction solution is evaporated to dryness and the residue is crystallised from a mixture of ethanol and ethyl acetate.
  • Example 3 l-cyano-S-(N-methyl-N-2-piperidinoethyl)amino 1:1- diphenylpentane, boiling point 232-234/0.l5 mm., n 1.5410, is prepared from S-chloro-l-cyano-l:l-diphenylpentane and N-methyl-N-(Z-piperidinoethyl)amine by the method of Example 2, but using benezene as the reaction solvent.
  • Example 4 l-cyano-5-( N-methyl-N-Z-morpholinoethyl amino-l 1- diphenylpentane, boiling point 206 208/0.06 mm., n 1.5505, is prepared from 5-chloro-1-cyano-l:l-diphenylpentane and N-methyl-N-(2-morpholinoethyl)amine by the method of Example 3.
  • Dimethyl sulphate (1.1 ml.) is added to a solution of the ditertiary amino base (1.4 g.) in dry benzene (20 ml.). After 24 hours the mixture is filtered and the crystalline solid is recrystallised from ethanol to give Nl-(S-cyano-S:S-diphenylpentyl) N zN zN trimethylethylene-l-ammonium-Z-morpholinium di-methyl sulphate, melting at 173-175 A moderate excess of silver sulphate is added to a stirred solution of the di-iodide (10 g.) in aqueous ethanol (20% v./v.; ml.) boiling under a reflux condenser.
  • Example 5 chloro 1 cyano-l l-diphenylhexane, boiling point l74-l76/0.2 mm., and melting point 56, after crystallisation from ethanol, is prepared from diphenyl acetonitrile and 1:5-dichloropentane, by the method of Example 2.
  • l cyano 6 (N 2 diethylaminoethyl N methyl)- amino-lzl-diphenylhexane, boiling point 204206/0.15 mm., n 1.5310, is prepared from 6-chloro-l-cyano- 1:1 diphenylhexane and N (2 diethylaminoethyl)-N- methylamine by the method of Example 3.
  • Example 6 1 cyano 6 (N methyl N 2 pyrrolidinoethyl)- amino-1:l-diphenylhexane, boiling point 222-.223 /0.1 mm., n 1.5451, is prepared from 6-chloro-l-cyano- 1:1 diphenylhexane and N methyl N-(2-pyrrolidinoethl)amine by the method of Example 3.
  • N J (6 cyano 6:6 diphenylhexyl) N :N :N' trimethylethylene-l-ammonium-2-pyrrolidinium di-iodide monohydrate, melting point 105, after crystallisation from a mixture of methanol and ethyl acetate, is obtained therefrom by the method of Example 2.
  • Example 7 1 cyano 6 (N methyl N 2 morpholinoethyl)- amino-1sl-diphenylhexane,boiling point 228-230/0.1 mm., n 1.5450, is prepared by the method of Example 3. l
  • N (6 cyano 6:6 diphenylhexyl) N zN zN trimethylethylene 1 ammonium 2 morpholinium diiodide, melting point 208, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 1.
  • a solution of the di-iodide (5.0 g.) in aqueous methanol (250 cc.; 70% v./v.) is passed down a column (15 x 1.3 cm.) of Dowex 2 ion-exchange resin, in the hydroxyl form, and the column is subsequently washed with aqueous methanol (70% v./v.).
  • the efiluent is neutralise-d with dilute hydrochloric acid, the solvent is evaporated under reduced pressure and the residual gum is triturated with acetone to give a crystalline solid.
  • the solid is recrystallised from a mixture of ethanol and acetone to give N (6 cyano 6:6 diphenylhexyl)- 'N :N :N trimethylethylene 1 ammonium 2 morpholinium dichloride monohydrate, a hygroscopic substance, melting point 227, with decomposition.
  • Example 9 A solution of 6-chloro-1-cyano-1:1-diphenylhexane (6.0 g.) in an ethanolic solution of methylamine (30 g.; 33% w./w.) is heated at 100 in a sealed tube for 16 hours. The solution is concentrated to low volume and extracted with a mixture of dilute hydrochloric acid and ether. An excess of aqueous ammonia solution is added to the acid extract and the liberated base is extracted with ether. The ether extract is washed with a little water, .dried and evaporated. The residual oil is fractionally distilled to give 1-cyano-6-methylamino-l:l-diphenylhexane, boiling point 182-184/0.04 mm., n 1.5538.
  • N (6 cyano 6:6 diphenylhexyl) N zN zN trimethyl hexamethylene l ammonium 6 piperidinium di-iodide, melting point 176, with decomposition, after crystallisation from ethanol, is obtained therefrom by the method of Example 2.
  • Example 10 v 1 cyano 3 (N methyl N 2 piperidinoethyl)- amino-l:l-diphenylpropane, boiling point 214-215 /0.5 25 mm., n 1.5550, is prepared from 3-bromo-1-cyano-lz1- diphenylpropane and N methyl N-(2-piperidinoethyl)- amine by the method of Example 3, the period of boiling under a reflux condenser being extended to 16 hours.
  • N (3 cyano 3:3 diphenylpropyl)-N :N :N trimethylethylene 1 ammonium 2 piperidinium di-iodide, containing one and one-half molecules of water of crystallisation, melting point 135, with decomposition, after crystallisation from methanol, is obtained therefrom by the method of Example 1, the period of boiling under a reflux condenser being extended to 16 hours.
  • Example 11 1 cyano 3 (N methyl N 2 morpholinoethyl)- amino-1zl-diphenylpropane, boiling point 220-222/0.5 mm., is prepared by the method of Example 10, but with the use of ethanol as the reaction solvent.
  • Example 12 6O 7 mixture of ethanol and acetone, is prepared from the diiodide by the method of Example 11.
  • Example 13 N -cyano-5 :5 diphenylpentyl) N -methylpiperazine, boiling point 202203/0.06 mm. and melting point 68", is prepared from 5-chloro-1-cyano-1:l-diphenylpentlzane and N-methyl piperazine by the method of Example N -(5-cyano 5:5 diphenylpentyl) N zN zN trimethylpiperazinium di-iodide, melting at 197, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.'
  • Example 14 N -(5-eyano 5:5 diphenylpentyl) N zN diethyl- N -methylpiperazinium di-iodide, melting at 197, with decomposition, after. crystallisation from ethanol, is prepared from the ditertiaryamino base of Example vl3, by the method of Example 10, with the use of ethyl iodide and ethanol as the quaternising agent and solvent respectively.
  • Example 15 l-(cyano-S-(N 2 diethylaminoethyl N methyl)- amino-1z1-diphenylpentane, boiling point 212-213/0.3 mm., n 1.5380, is prepared by the method of Example l5.
  • Example 17 l-cyano-S-(N-ethyl N 2 diethylaminoethyDaminolzl-diphenylpentane, boiling point 196197/0.06 mm., n 1.5333, is prepared by the method of Example 15.
  • Example 18 N -(S-cyano 5:5 diphenylpentyl N :N :N :N :N pentaethylethylene 1:2 diammonium di-iodide, melting point 196", with decomposition, after crystallisation from a mixture of methanol and ethanol, is prepared from the ditertiaryamine base of Example 17, by the method of Example 14.
  • Example 19 l-cyano-S-(N-methyl N 2 pyrrolidinoethyl)aminolzl-diphenylpentane, boiling point 202-204/0.03 mm., n 1.5518, is prepared by the method of Example 15.
  • Example 20 N -(5-cyano-5:5-diphenylpentyl-N :N diethyl N methylethylene-l-ammonium-Z-pyrrolidinium di iodide, melting point 158, with decomposition, after crystallisationrfrom a mixture of methanol and ethanol, is prepared from the ditertiaryamino base of Example 19, by the method of Example 14.
  • Example 21 A solution of the ditertiaryamino base of Example 4 (2.4 g.) and n-propyl iodide (3 ml.) in n-propanol (8 ml.) is boiled under a reflux condenser for 24 hours. The solvent is evaporated and the residue is triturated with ether to give N -(5-cyano-5:S-diphenylpentyD-N methyl-N:N -di-n-propylethylene-l-amrnonium 2 morpholinium di-iodide, an amorphous solid, melting at 51-52.
  • Example 22 With the use of continual stirring, sodium (2.5 g.; 0.11 mol) is added in small portions, during 15 minutes, to liquid ammonia (500 ml.) to which a crystal of ferric nitrate has been added. The solution is stirred for a further 15 minutes and phenyl-p-tolyl acetonitrile (20.7 g.; 0.1 mol.) is then added during 20 minutes. After a further minutes, chloroiodobutane is added during 15 minutes and the solution is finally stirred for a further 5 hours. The ammonia is then allowed to evaporate; water (50 ml.) and ether.
  • Example 23 l-cyano-S-(N-methyl N 2 morpholinoethyl)amino- 1:1-di-(4-methylphenyl)pentane, boiling point 214216/ 0.08 mm., n 1.5508, is prepared by the method of Examlple 22.
  • Example 24 1:1-di-(4-chlorophenyl) 1 cyano-S-(N-methyl-N-Z- morpholinoethyl)aminopentane, boiling point 243-244/ 0.08 mm., u 1.5605, is prepared by the method of Example 22.
  • Example 25 l-cyano 5 (N-methyl-N-Z-morpholinoethyl)amino- 1:1-di-(4-methoxyphenyl)-pentane, boiling point 255- 257/0.05 mm., is prepared by the method of Example 22.
  • Example 26 S-chloro-l-cyano 1 cyclohexyl 1 phenylpentane, boiling point 169171'/0.3 mm., is prepared by the method of Example 2.
  • Example 27 l-cyano 7 (N-methyl-N-Z-piperidinoethyl)amino- 1:1-diphenylheptane, boiling point 228230/0.35 mm., n 1.5417, is prepared from 7-chloro-l-cyano-lz1-diphenylheptane and N-methyl-N-(2-piperidinoethyl)amine by the method of Example 12.
  • Example 28 l-cyano-8-(N-methyl-N-2-piperidinoethyl) amino-r l diphenyloctane, boiling point 238-240/0.07 mm., n 1.5369, is prepared from 8-bromo-l-cyano-1:l-diphenyloctane and N-methyl-N-(Z-piperidinoethyl)amine by the method of Example 12.
  • N 8 cyano-8 8-diphenyloctyl)-N :N :N -trimethylethylene-l-ammonium-Z-piperidinium di-iodide, melting point 155", with decomposition, after crystallisation from a mixture of methanol and ethyl acetate, is obtained therefrom by the method of Example 25
  • Example 29 l-cyano-5-(N 3 morpholinopropyDaminod:l-diphenylpentane, boiling at 233/0.8 mm., is prepared from S-chloro-l-cyano-l:l-diphenylpentane and 3-morpholinopropylamine by the method of Example 2, with the modification that the chloronitrile (0.02 mol.) is added dropwise to a stirred solution of the amine (0.04 mol.) in n-propanol, during a period of 2 hours.
  • N -(5-cyano-5 5 -diphenylpentyl N :N :N -trimethyltrimethylene-l-ammonium-3-morpholinium dichloride dihydrate, melting point 134, is obtained from the diiodide by the method of Example 11.
  • Example 30 N -(5-cyano-5 S-diphenylpentyl) N zN zN -triethyltrimethylene-l-ammonium-3-morpholinium di-iodide dihydrate, melting point 137", with decomposition, after crystallisation from ethanol, is prepared from the base of Example 29 by the method of that example, using ethyl iodide and ethanol as the quaternising agent and solvent respectively.
  • Example 31 A solution of l-cyano-l l-dip'henyl5-piperidinopentane (4.33 g.; 0.013 mol.) (prepared by the method of EX- ample 13) and 3-chloropropyltrimethylammonium bromide (2.64 g.; 0.012 mol.) (prepared from 1-bromo-3- chloropropane and trime'thylamine) in n-propanol (25* ml.) is boiled under a reflux condenser for 16 hours.
  • Example 32 A suspension of sodamide (8.6 g.; 0.22 mol.) in solution of p:p-dichlorodiethylether (71.5 g.; 0.5 mol.) in dry benzene (150 cc.) is stirred and boiled under a reflux condenser and a solution of diphenylacetonitrile (38.6 g.; 0.2 mol.) in dry benzene (300 cc.) is added during 3 hours. After a further half an hour, the mixture is cooled, water cc.) is added, the benzene layer is separated, dried over anhydrous sodium sulphate and the solvent is evaporated. The oily residue is distilled to give 6-chloro-1-cyano-d:l-diphenyl-4-oxahexane, boiling point 166169/0.1 mm.
  • a solution of the di-iodide (5.6 g.) in aqueous ethanol (200 cc.; 70% v./v.) is passed down a column (15 x 2 cm.) of a strong base ion-exchange resin, in the hydroxyl form, and the column is subsequently washed with aqueous ethanol (70% v./v.).
  • the eflluent is neutralised with dilute hydrochloric acid, the solvent is evaporated under reduced pressure and the residual gum is crystal lised from a mixture of ethanol and acetone to give N (6-cyano-6:6-diphenyl-3-oxahexyl)-N :N :N -trimethylethylene-l-ammonium-2-piperidiniurn dichloride monohydrate melting at -148".
  • N+ is a quaternary nitrogen atom selected from the class consisting of those containing two lower alkyl groups and those where the alkyl groups together form part of pyrrolidino, piperidino and morpholino groups
  • N+ is a quaternary nitrogen atom selected from the class consisting of those containing three lower alkyl groups, and those forming part of lower alkyl pyrrolidino, lower alkyl piperidino and lower alkyl morpholino groups
  • Y is an alkylene chain having from 2 to 10 carbon atoms
  • N+ YN+ is a piperazine ring in which N* is a quaternary nitrogen atom carrying a lower alkyl group and N+ is a quaternary nitrogen atom carrying two lower alkyl groups, the total number of carbon atoms in the alkyl groups not exceeding 6 and wherein A- is the anion of a therapeutically acceptable acid.

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Description

United States Patent DIQUATERNARY COMPOUNDS AND THE MANUFACTURE THEREOF Claims priority, application Great Britain June 8, 1 955 6 Claims. (Cl. 260-2475) The present invention relates to novel diquaternary compounds and to the manufacture thereof.
It has been found that compounds falling within the general Formula I have the property of blocking ganglion transmission when tested in experimental animals, for example, the cat.
In this formula, R and R are the same or different, and are each a cycloalkyl group (for example a cyclohexyl group) or a phenyl group which may carry one or more substituents, said substituents being halogen atoms (for example chlorine or bromine atoms), lower alkyl groups (for example a methyl group) or lower alkoxy groups (for example a methoxy group); X is the group (CH or the group (CH,),.O.(CH n is an integer from two to ten; N is a quaternary nitrogen atom carrying *two alkyl groups together having up to five carbon atoms, preferably two or three carbon atoms or which together form part of a pyrrolidino, piperidino or morpholino ring; N+ is a quaternary nitrogen atom carrying at least one alkyl group having one to four carbon atoms and either carrying two further alkyl groups giving a total of up to nine carbon atoms, preferably a total of three to six carbon atoms, or forming part of a pyrrolidino, piperidino or morpholino ring; Y is an alkylene chain having from two to ten carbon atoms, preferably two to six carbon atoms, or I-i+ ---YN+ may be a piperazine ring in which N is a quaternary nitrogen atom carrying one alkyl group having up to four carbon atoms and N+ is a quaternary nitrogen atom carrying two alkyl groups having a total of up to four carbon atoms, the total number of carbon atoms in the alkyl groups not exceeding six; and A is an anion of an inorganic or organic acid which may be, for example, halide or alkyl sulphate.
These compounds possess extremely powerful pharmacological properties resembling, but in many ways considerably greater than, those of known ganglion blocking agents such as hexamethonium and pentolinium. Thus, when injected into animals they lower the blood pressure and block the hypertensive action of the ganglion stimulating substance DMPP (N :N -dimethyl- N -phenylpiperazinium iodide), while increasing the hypertensive effects of adrenaline and noradrenaline. They strongly inhibit gastric secretion and bradycardia of vagal origin and cause mydriasis and yet have little effect on the peripheral actions of acetylcholine. In vitro they are powerful inhibitors of the peristaltic reflex of the isolated guinea-pig ileum but are only weak antagonists of locally applied acetylcholine.
The intensity of the various autonomic actions of the examples described in this application varies with the chemical constitution of the example, the nature of the action and the animal species in which the action is measured. Many of the compounds described are considerably more active than known ganglion blocking agents such as hcxamethonium and pentolimum m inhib- 2,851,458 Patented Sept. 9, 1958 iting DMPP hypertension and preventing vagal bradycardia in cats and in inhibiting gastric secretion in fasted rats. They have the, additional advantage of a much longer duration of action.
The preferred compounds are the salts of N -(5-cyano- 5:5 diphenylpentyl)-N :N :N trimethylethylene-I-arnmonium-Z-morpholine, the salts of N -(6-cyano-6z6-diphenylhexyl -N N :N -trirnethylethlene-l-ammonium-2- morpholine, the salts of N -(6-cyano-6:6-diphenyl-3- oxahexyl)- N :N :N trimethylethylene-l-ammonium-2- morpholine, the salts of N -(3-cyano-3:3-diphenylpropyl)- N zN zN -trimethylethylene 1 ammonium-Z-morpholine and the salts of N -(5-cyano-5:S-diphenylpentyD- N :N :N trirnethyltrirnethylene 1 ammonium-S-morpholine.
The present invention in one aspect, therefore, comprises compounds of the general Formula I.
These compounds may be prepared by any suitable synthetic route. According to the present invention in another aspect, compounds of the general Formula I are prepared by treating a suitable diamine of general Formula II with a quaternising agent, such as a lower alkyl halide or lower dialkyl sulphate.
In this formula, R R, X and Y have the meanings given above, N is a secondary or tertiary nitrogen atom and N is a primary, tertiary or quaternary nitrogen atom, the substituents provided by the quaternising agent, together with any substituents on N and N being such as will give the desired substitution in the compound of general Formula I. I
Thus, for example, N may be a tertiary nitrogen atom carrying one alkyl group having up to four carbon atoms and N may be a tertiary nitrogen atom carrying two alkyl groups having a total of from two to eight carbon atoms or may form part of a pyrrolidino, piperidino or morpholino ring, or N YN may be a piperazine ring in which N may carry an alkyl group having from one to three carbon atoms.
The quaternisation reactions may be carried out by allowing the di-tertiary amine to stand with or by heating it with a quaternising agent such as a lower alkyl halide, in a suitable solvent such as acetone or methanol.
Compounds of the general Formula II, where N is a secondary or a tertiary nitrogen atom and N is a tertiary nitrogen atom, may be synthesised by the following general route.
A substituted acetonitrile (III), for example diphenyl acetonitrile, is reacted with a polymethylene-azw-dihalide (IV) where Z is a halogen atom, forexample 1:5-
dichloropentane, in a suitable solvent, for example ben-- zene, in the presence of sodamide or another suitable reagent, to give the substance of general Formula V. This substance is reacted with a diamine of general Formula VI where N is a primary or secondary nitrogen atom, in a suitable solvent, for example ethanol, to give the required Compound 11.
Alternatively, for those compounds of Formula II in which X is the group (CH and which have a value of n equal to two or six to ten, the halogeno diamine of general Formula VII is reacted with the nitrile of Formula III by the method outlined above, to give a compound of Formula II Or for compounds of Formula II, where Y represents two or three or six to ten methylene groups, an aminonitrile of Formula VIII is reacted with the halogenoamine of Formula IX In .most of the examples given below the preparation of the iodide is described because generally the iodide is an easily crystallisable salt, but it will be understood that the methods described are also applicable to the preparation of other salts. Furthermore, one salt may be converted into any other salt by any suitable method.
The invention will now be described with reference to the following examples in which all temperatures are given in degrees centigrade.
' Example I A solution of N -2-hydroxyethyl-N -methylpiperazine (47 g.) in chloroform (50 cc.) is added during /2 hour to a solution of thionyl chloride (47 cc.) in 50 cc. chloroform, stirred and cooled in an ice-bath. The reaction mixture is'stirred at 50 for 3 hours, ether is added and the insoluble material is filtered and crystallised from methanol to give N -2-chloroethyl-N -methylpiperazine hydrochloride, melting at 297 with decomposition.
A small excess of aqueous caustic soda solution (40% by Weight) is added to N -2-chloroethyl-W-methyl-piperazine hydrochloride (36.1 g.), the liberated base is extracted with light petroleum (boiling point below 40), the extract is dried over anhydrous sodium sulphate, the solvent evaporated in vacuo and the residual oil is dissolved in dry benzene (40 cc.). The benzene solution is added during 5 minutes to a suspension of sodamide (4.1 g.) in a solution of diphenylacetonitrile (19.9 g.) in dry benzene (100 cc.), and the mixture is stirred and boiled under a reflux condenser for 5 hours. The reaction mixture is cooled and treated successively with water (100 cc.) and an excess of dilute hydrochloric acid. The aqueous phase is separated, an excess of ammonia solution is added, and the liberated base is extracted with hot ether. The hot ether extract is immediately dried over anhydrous sodium sulphate and the solvent is evaporated. The solid residue is crystallised from isopropanol to' give N -3-cyano-3:3-diphenylpropyl-N -methylpiperazine, melting point 104.
A solution of this base (1.0 g.) in methanol (5 cc.) and methyl iodide (1 cc.) is boiled under reflux condenser for 12 hours. The mixture is cooled and filtered and the crystalline product is recrystallised from aqueous methanol to give N -(3-cyano-3:3-diphenylpropyl)-N N zN -trimethylpiperazinium di-iodide, as cream rectangular prisms, melting point 215 with decomposition.
Example 2 A suspension of sodamide (10.2 g.; 0.26 mol.) in a solution of 1:4-dichlorobutane (30.5 g.; 0.24 mol.) in dry benzene (100 cc.) is stirred and boiled under a reflux condenser and a solution of diphenylacetonitrile (38.6 g.; 0.2 mol.) in dry benezene (300 cc.) is added during 3 hours. After a further V2 hour, the mixture is cooled, water (100 cc.) is added, the solution is filtered from some insoluble crystalline material, the benzene layer is separated and dried over anhydrous sodium sulphate, and the solvent is evaporated. The oily residue is distilled to give -5-chloro-l-cyano-1:l-diphenylpentane, boiling point 164-166/0.05 mm., and melting point 47.5-49, after crystallisation from ethanol.
A solution of S-chloro-l-cyano-l:I-diphenylpentane (5.7 g.; 0.02 mol.) and N-(Z-di-n-butylaminoethyl)-N- methylamine (7.5 g.; 0.04 mol.) in n-propanol (15 cc.) is boiled under a reflux condsenser for 9 hours. The solvent is evaporated under reduced pressure and the residue is extracted with a mixture of dilute hydrochloric acid and ether. An excess of aqueous ammonia is added to the acid extract and the liberated base is extracted with light petroleum (boiling point 60-80). The petroleum extract is washed with mater, dried over anhydrous sodium sulphate and fractionally distilled to give 5-(N-2- di-n-butylaminoethyl-N-methyl)amino 1 cyano-lzl-diphenylpentane, boiling point 2l2-213/0.07 mm., 11 1.5195.
N :N -di-n-butyl-N -(S-cyano 5 :5 diphenylpentyl)- N :N zN -trimethylethylene-l :Z-diammonium di-iodide, melting point 175 with decomposition is obtained therefrom by the method of Example 1, with the modification that the quaternisation reaction solution is evaporated to dryness and the residue is crystallised from a mixture of ethanol and ethyl acetate.
Example 3 l-cyano-S-(N-methyl-N-2-piperidinoethyl)amino 1:1- diphenylpentane, boiling point 232-234/0.l5 mm., n 1.5410, is prepared from S-chloro-l-cyano-l:l-diphenylpentane and N-methyl-N-(Z-piperidinoethyl)amine by the method of Example 2, but using benezene as the reaction solvent.
N -(5-cyano-5 S-diphenylpentyl) N :N zN -trimethylethylene-l-ammonium-Z-piperidinium di-iodide, melting point 212, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 1.
' Example 4 l-cyano-5-( N-methyl-N-Z-morpholinoethyl amino-l 1- diphenylpentane, boiling point 206 208/0.06 mm., n 1.5505, is prepared from 5-chloro-1-cyano-l:l-diphenylpentane and N-methyl-N-(2-morpholinoethyl)amine by the method of Example 3.
N -(5-cyano-5 :5-diphenylpentyl)-N :N :N trimethylethylene-l-ammonium-2-morpholinium di-iodide, melting point 211, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 1.
N -(5-cyano-5 :5-diphenyl)-I1 :N :N trimethylethylene-l-ammonium-Z-morpholinium dichloride monohydrate, melting point 238", with decomposition, after crystallisation from a mixture of methanol and acetone, is prepared by the method of Example 11.
Dimethyl sulphate (1.1 ml.) is added to a solution of the ditertiary amino base (1.4 g.) in dry benzene (20 ml.). After 24 hours the mixture is filtered and the crystalline solid is recrystallised from ethanol to give Nl-(S-cyano-S:S-diphenylpentyl) N zN zN trimethylethylene-l-ammonium-Z-morpholinium di-methyl sulphate, melting at 173-175 A moderate excess of silver sulphate is added to a stirred solution of the di-iodide (10 g.) in aqueous ethanol (20% v./v.; ml.) boiling under a reflux condenser. After one hour, the hot mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is crystallised from ethanol to give N -(5- cyano 5:5 diphenylpentyl) N :N :N trimethylethylene 1 ammonium-2-morpholinium sulphate, containing 9-12% of water of crystallisation and melting at 206-210 (decomp.).
Example 5 6 chloro 1 cyano-l l-diphenylhexane, boiling point l74-l76/0.2 mm., and melting point 56, after crystallisation from ethanol, is prepared from diphenyl acetonitrile and 1:5-dichloropentane, by the method of Example 2.
l cyano 6 (N 2 diethylaminoethyl N methyl)- amino-lzl-diphenylhexane, boiling point 204206/0.15 mm., n 1.5310, is prepared from 6-chloro-l-cyano- 1:1 diphenylhexane and N (2 diethylaminoethyl)-N- methylamine by the method of Example 3.
N (6 cyano 6:6 diphenylhexyl) NzN diethyl N :N :N trimethylethylene 1:2 diammoniumdi-iodide, melting point 202", with decomposition, after 1 crystallisation from methanol, is obtained therefrom by the method of Example 1.
Example 6 1 cyano 6 (N methyl N 2 pyrrolidinoethyl)- amino-1:l-diphenylhexane, boiling point 222-.223 /0.1 mm., n 1.5451, is prepared from 6-chloro-l-cyano- 1:1 diphenylhexane and N methyl N-(2-pyrrolidinoethl)amine by the method of Example 3.
N J (6 cyano 6:6 diphenylhexyl) N :N :N' trimethylethylene-l-ammonium-2-pyrrolidinium di-iodide monohydrate, melting point 105, after crystallisation from a mixture of methanol and ethyl acetate, is obtained therefrom by the method of Example 2.
Example 7 Example 8 1 cyano 6 (N methyl N 2 morpholinoethyl)- amino-1sl-diphenylhexane,boiling point 228-230/0.1 mm., n 1.5450, is prepared by the method of Example 3. l
N (6 cyano 6:6 diphenylhexyl) N zN zN trimethylethylene 1 ammonium 2 morpholinium diiodide, melting point 208, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 1.
A solution of the di-iodide (5.0 g.) in aqueous methanol (250 cc.; 70% v./v.) is passed down a column (15 x 1.3 cm.) of Dowex 2 ion-exchange resin, in the hydroxyl form, and the column is subsequently washed with aqueous methanol (70% v./v.). The efiluent is neutralise-d with dilute hydrochloric acid, the solvent is evaporated under reduced pressure and the residual gum is triturated with acetone to give a crystalline solid. The solid is recrystallised from a mixture of ethanol and acetone to give N (6 cyano 6:6 diphenylhexyl)- 'N :N :N trimethylethylene 1 ammonium 2 morpholinium dichloride monohydrate, a hygroscopic substance, melting point 227, with decomposition.
Example 9 A solution of 6-chloro-1-cyano-1:1-diphenylhexane (6.0 g.) in an ethanolic solution of methylamine (30 g.; 33% w./w.) is heated at 100 in a sealed tube for 16 hours. The solution is concentrated to low volume and extracted with a mixture of dilute hydrochloric acid and ether. An excess of aqueous ammonia solution is added to the acid extract and the liberated base is extracted with ether. The ether extract is washed with a little water, .dried and evaporated. The residual oil is fractionally distilled to give 1-cyano-6-methylamino-l:l-diphenylhexane, boiling point 182-184/0.04 mm., n 1.5538.
A solution of freshly prepared 1-bromo-6-piperidinohexane (2.0 g.) (prepared from 1:6-dibromohexane via 1-phenoxy-6-piperidinohexane by the method used, for example, by Marvel, Zartman and Bluthardt, Journal of the American Chemical Society," 1927, volume 49, page 2302), 1-cyano-6-methylamino-1 l-diphenylhexane (2.35 g.) and triethylamine (0.8 g.) in ethanol cc.) is
boiled under a reflux condenser for 3 hours. The solvent is evaporated, an excess of aqueous ammonia solution is added to the residue and the liberated base is extracted with ether. The ether extract is washed with water and dried over anhydrous sodium sulphate, and the solvent is evaporated. The residual oil is fractionally distilled to give l-cyano-S-(N-methyl-N-G-piperidinohexyl) amino- 1:1 diphenylhexane, boiling point 258- 260/0.08 mm., 11 1.5328.
N (6 cyano 6:6 diphenylhexyl) N zN zN trimethyl hexamethylene l ammonium 6 piperidinium di-iodide, melting point 176, with decomposition, after crystallisation from ethanol, is obtained therefrom by the method of Example 2.
Example 10 v 1 cyano 3 (N methyl N 2 piperidinoethyl)- amino-l:l-diphenylpropane, boiling point 214-215 /0.5 25 mm., n 1.5550, is prepared from 3-bromo-1-cyano-lz1- diphenylpropane and N methyl N-(2-piperidinoethyl)- amine by the method of Example 3, the period of boiling under a reflux condenser being extended to 16 hours.
N (3 cyano 3:3 diphenylpropyl)-N :N :N trimethylethylene 1 ammonium 2 piperidinium di-iodide, containing one and one-half molecules of water of crystallisation, melting point 135, with decomposition, after crystallisation from methanol, is obtained therefrom by the method of Example 1, the period of boiling under a reflux condenser being extended to 16 hours.
Example 11 1 cyano 3 (N methyl N 2 morpholinoethyl)- amino-1zl-diphenylpropane, boiling point 220-222/0.5 mm., is prepared by the method of Example 10, but with the use of ethanol as the reaction solvent.
N (3 cyano 3:3 diphenylpropyl)-N :N :N trimethylethylene 1 ammonium 2 morpholinium di-iodide, melting at 182, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
A solution of the di-iodide (2.9 g.) in methanol saturated with hydrogen chloride (15 ml.) is slowly evaporated on a steam-bath until no more iodide ions are present. The solution is then evaporated under reduced pressure and the residue is triturated with excess acetone to give a crystalline solid.' The solid is recrystallised from a mixture of methanol and acetone to give N (3 cyano 3:3 diphenylpropyl)-N :N :N -trimethylethylene 1 ammonium 2 morpholinium dichloride, a hygroscopic crystalline substance containing one and one-half molecules of water of crystallisation, -melting point 171, with decomposition.
Example 12 6O 7 mixture of ethanol and acetone, is prepared from the diiodide by the method of Example 11.
Example 13 N -cyano-5 :5 diphenylpentyl) N -methylpiperazine, boiling point 202203/0.06 mm. and melting point 68", is prepared from 5-chloro-1-cyano-1:l-diphenylpentlzane and N-methyl piperazine by the method of Example N -(5-cyano 5:5 diphenylpentyl) N zN zN trimethylpiperazinium di-iodide, melting at 197, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.'
Example 14 N -(5-eyano 5:5 diphenylpentyl) N zN diethyl- N -methylpiperazinium di-iodide, melting at 197, with decomposition, after. crystallisation from ethanol, is prepared from the ditertiaryamino base of Example vl3, by the method of Example 10, with the use of ethyl iodide and ethanol as the quaternising agent and solvent respectively.
Example 15 l-(cyano-S-(N 2 diethylaminoethyl N methyl)- amino-1z1-diphenylpentane, boiling point 212-213/0.3 mm., n 1.5380, is prepared by the method of Example l5.
N -(5-cyano 5 :5 diphenylpentyl) NzN diethyl- N :N :N -trimethylethylene-1:Z-diammonium di iodide, melting point 184, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
Example 17 l-cyano-S-(N-ethyl N 2 diethylaminoethyDaminolzl-diphenylpentane, boiling point 196197/0.06 mm., n 1.5333, is prepared by the method of Example 15.
N -(5-cyano5:S-diphenylpentyl) N :N :N triethyl- N :N -dimethylethylene-1:2-diammonium di-iodide, melting point 196, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
Example 18 N -(S-cyano 5:5 diphenylpentyl N :N :N :N :N pentaethylethylene 1:2 diammonium di-iodide, melting point 196", with decomposition, after crystallisation from a mixture of methanol and ethanol, is prepared from the ditertiaryamine base of Example 17, by the method of Example 14.
Example 19 l-cyano-S-(N-methyl N 2 pyrrolidinoethyl)aminolzl-diphenylpentane, boiling point 202-204/0.03 mm., n 1.5518, is prepared by the method of Example 15.
N -(5-cyano-5:S-diphenylpentyl) N :N :N trimethylethylene-1-ammonium-2-pyrrolidinium di-iodide, melting point 207, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
Example 20 N -(5-cyano-5:5-diphenylpentyl-N :N diethyl N methylethylene-l-ammonium-Z-pyrrolidinium di iodide, melting point 158, with decomposition, after crystallisationrfrom a mixture of methanol and ethanol, is prepared from the ditertiaryamino base of Example 19, by the method of Example 14.
Example 21 A solution of the ditertiaryamino base of Example 4 (2.4 g.) and n-propyl iodide (3 ml.) in n-propanol (8 ml.) is boiled under a reflux condenser for 24 hours. The solvent is evaporated and the residue is triturated with ether to give N -(5-cyano-5:S-diphenylpentyD-N methyl-N:N -di-n-propylethylene-l-amrnonium 2 morpholinium di-iodide, an amorphous solid, melting at 51-52.
Example 22 With the use of continual stirring, sodium (2.5 g.; 0.11 mol) is added in small portions, during 15 minutes, to liquid ammonia (500 ml.) to which a crystal of ferric nitrate has been added. The solution is stirred for a further 15 minutes and phenyl-p-tolyl acetonitrile (20.7 g.; 0.1 mol.) is then added during 20 minutes. After a further minutes, chloroiodobutane is added during 15 minutes and the solution is finally stirred for a further 5 hours. The ammonia is then allowed to evaporate; water (50 ml.) and ether. (250 ml.) is added to the residue and the ether extract is washed, dried over anhydrous sodium sulphate and evaporated. The residual oil is fractionally distilled to give 5-chloro-l-cyano-l-(4-methylphenyl)-lphenylpentane, boiling point 188-191/0.1 mm.
I-cyano-S-(N-methyl N 2 morpho1inoethyl)amino- 1-(4-methylpheny1) 1 phenylpentane, boiling point 22l222/0.04 mm., u 1.5510, is obtained therefrom by the method of Example 12.
N -[5-cyano-5-(4 methylphenyl) 5 phenylpentyl1- N :N :N=-trimethylethylene-1 7 ammonium 2 morpholinium di-iodide, melting point 211, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
Example 23 l-cyano-S-(N-methyl N 2 morpholinoethyl)amino- 1:1-di-(4-methylphenyl)pentane, boiling point 214216/ 0.08 mm., n 1.5508, is prepared by the method of Examlple 22.
N -[S-cyano 5:5 di (4 methyl)pentyl]-N :N :N trimethylethylene- 1 ammonium 2 morpholinium diiodide, melting point 215, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
Example 24 1:1-di-(4-chlorophenyl) 1 cyano-S-(N-methyl-N-Z- morpholinoethyl)aminopentane, boiling point 243-244/ 0.08 mm., u 1.5605, is prepared by the method of Example 22.
N -[5:5-di (4 chlorophenyl) 5 cyanopentyH- N 2N zN -trimethylethylene-l-ammonium 2 morpholinium di-iodide, melting point 205, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
Example 25 l-cyano 5 (N-methyl-N-Z-morpholinoethyl)amino- 1:1-di-(4-methoxyphenyl)-pentane, boiling point 255- 257/0.05 mm., is prepared by the method of Example 22.
N [5 cyano-5z5-di (4 methoxyphenyl)pentyl- N zN zN -trimethylethylene-l-ammonium 2 morpholinium di-iodide monohydrate, melting point 159, with decomposition, after crystallisation from a mixture of methanol and ethanol, is obtained therefrom by the method of Example 10, with the modification that ethyl acetate is added to the reaction solution to effect the initial crystallisation.
Example 26 S-chloro-l-cyano 1 cyclohexyl 1 phenylpentane, boiling point 169171'/0.3 mm., is prepared by the method of Example 2.
l-cyano-l-cyclohexyl (N-methyl-N-2-piperidinoethyl)-amino-1-phenylpentane, boiling point 228-229/ 0.35 mm., is obtained therefrom by the method of Example 10.
N (S-cyano 5 cyclohexyl 5 phenylpentyl)- N rN zN trimethylethylene 1 ammonium-Z-piperidinium di-iodide, melting point 235, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 10.
Example 27 l-cyano 7 (N-methyl-N-Z-piperidinoethyl)amino- 1:1-diphenylheptane, boiling point 228230/0.35 mm., n 1.5417, is prepared from 7-chloro-l-cyano-lz1-diphenylheptane and N-methyl-N-(2-piperidinoethyl)amine by the method of Example 12.
N -(7-cyano 7:7 diphenylheptyl) N zN zN -trimethylethylene l ammonium-Z-piperidinium di-iodide, melting point 172,'with decomposition, after crystallisation from a mixture of methanol and ethanol, is obtained therefrom by the method of Example 25.
Example 28 l-cyano-8-(N-methyl-N-2-piperidinoethyl) amino-r l diphenyloctane, boiling point 238-240/0.07 mm., n 1.5369, is prepared from 8-bromo-l-cyano-1:l-diphenyloctane and N-methyl-N-(Z-piperidinoethyl)amine by the method of Example 12.
N 8 cyano-8 8-diphenyloctyl)-N :N :N=-trimethylethylene-l-ammonium-Z-piperidinium di-iodide, melting point 155", with decomposition, after crystallisation from a mixture of methanol and ethyl acetate, is obtained therefrom by the method of Example 25 Example 29 l-cyano-5-(N 3 morpholinopropyDaminod:l-diphenylpentane, boiling at 233/0.8 mm., is prepared from S-chloro-l-cyano-l:l-diphenylpentane and 3-morpholinopropylamine by the method of Example 2, with the modification that the chloronitrile (0.02 mol.) is added dropwise to a stirred solution of the amine (0.04 mol.) in n-propanol, during a period of 2 hours.
A solution of the base (1.0 g.) and methyl iodide (2 ml.) in methanol (10 ml.) is boiled under a reflux condenser for 7 hours, in the presence of anhydrous sodium carbonate (2.5 g.). The reaction mixture is filtered and sufficient ethyl acetate is added to the filtrate to promote crystallisation. The crystalline product is filtered and recrystallised from methanol to give N -(5- cyano-5:5 -diphenylpentyl) N zN zN trimethyltrimethylene-l-ammonium-3-morpholinium di-iodide, containing one and one-half molecules of water of crystallisation, melting point 158, with decomposition.
N -(5-cyano-5 5 -diphenylpentyl N :N :N -trimethyltrimethylene-l-ammonium-3-morpholinium dichloride dihydrate, melting point 134, is obtained from the diiodide by the method of Example 11.
Example 30 N -(5-cyano-5 S-diphenylpentyl) N zN zN -triethyltrimethylene-l-ammonium-3-morpholinium di-iodide dihydrate, melting point 137", with decomposition, after crystallisation from ethanol, is prepared from the base of Example 29 by the method of that example, using ethyl iodide and ethanol as the quaternising agent and solvent respectively.
Example 31 A solution of l-cyano-l l-dip'henyl5-piperidinopentane (4.33 g.; 0.013 mol.) (prepared by the method of EX- ample 13) and 3-chloropropyltrimethylammonium bromide (2.64 g.; 0.012 mol.) (prepared from 1-bromo-3- chloropropane and trime'thylamine) in n-propanol (25* ml.) is boiled under a reflux condenser for 16 hours. The solvent is evaporated and the pasty residue is triturated with ether; the resulting solid is crystallised from a mixture of methanol and acetone to give N -(5-cyano 5:5 diphenylpentyl)-N=:N :N -trimethyltrimetbylene- 3-ammonium-1-piperidinium dibromide, melting point 268-269, with decomposition.
Example 32 A suspension of sodamide (8.6 g.; 0.22 mol.) in solution of p:p-dichlorodiethylether (71.5 g.; 0.5 mol.) in dry benzene (150 cc.) is stirred and boiled under a reflux condenser and a solution of diphenylacetonitrile (38.6 g.; 0.2 mol.) in dry benzene (300 cc.) is added during 3 hours. After a further half an hour, the mixture is cooled, water cc.) is added, the benzene layer is separated, dried over anhydrous sodium sulphate and the solvent is evaporated. The oily residue is distilled to give 6-chloro-1-cyano-d:l-diphenyl-4-oxahexane, boiling point 166169/0.1 mm.
A solution of 6-chloro-l-cyano-l:l-diphenyl-4-oxahexane (9.0 g.; 0.03 mol.) and N-methyl-N-(Z-piperidinoethyl)amine (8.5 g.; 0.06 mol.) in benzene (20 cc.) is boiled under a reflux condenser for 16 hours. The cooled solution is shaken with dilute hydrochloric acid and ether, and excess of aqueous ammonia solution is added to the acid extract and the liberated base is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulphate and the solvent is evaporated; the residual oil is fractionally distilled to give 1-cyano-6-(N methyI-N-Z-piperidinoethyl)amino 1:l-diphenyl-4-oxahexane, boiling point 240-241/0.5 mm., n 1.5474.
A solution of this base (5.0 g.) in methanol (25 cc.) and methyl iodide (10 cc.) is boiled under a reflux condenser for 20 hours. The solvent is evaporated and the residue is crystallised from ethanol. Recrystallisation from methanol gives N -(6-cyano-6:6-diphenyl-3-oxahexyD-NzN zN -trimethylethylene 1 ammonium-2- piperidinium di-iodide, melting at 183, with decomposition.
A solution of the di-iodide (5.6 g.) in aqueous ethanol (200 cc.; 70% v./v.) is passed down a column (15 x 2 cm.) of a strong base ion-exchange resin, in the hydroxyl form, and the column is subsequently washed with aqueous ethanol (70% v./v.). The eflluent is neutralised with dilute hydrochloric acid, the solvent is evaporated under reduced pressure and the residual gum is crystal lised from a mixture of ethanol and acetone to give N (6-cyano-6:6-diphenyl-3-oxahexyl)-N :N :N -trimethylethylene-l-ammonium-2-piperidiniurn dichloride monohydrate melting at -148".
Example 33 c XI I Y-I I-'2A wherein R and R are selected from the class consisting of the cyclohexyl, phenyl, lower alkyl and alkoxyphenyl -1 1 and halogenophenyl radicals, X-is selected from the class consisting of groups 'of the formulae: (0H,), and
( shl e):
wherein n is an integer of from 2 to 10, N+ is a quaternary nitrogen atom selected from the class consisting of those containing two lower alkyl groups and those where the alkyl groups together form part of pyrrolidino, piperidino and morpholino groups, N+ is a quaternary nitrogen atom selected from the class consisting of those containing three lower alkyl groups, and those forming part of lower alkyl pyrrolidino, lower alkyl piperidino and lower alkyl morpholino groups, Y is an alkylene chain having from 2 to 10 carbon atoms, and, wherein N+ YN+ is a piperazine ring in which N* is a quaternary nitrogen atom carrying a lower alkyl group and N+ is a quaternary nitrogen atom carrying two lower alkyl groups, the total number of carbon atoms in the alkyl groups not exceeding 6 and wherein A- is the anion of a therapeutically acceptable acid.
2. Therapeutically acceptable salts of N -(5-cyano-5:5-
diphenylpentyl)-N :N zN -trimethylethylene 1 ammm nium-Z-morpholine.
3. Therapeutically acceptable salts of N -(6-cyano-6z6- diphenylhexyl) N :N :N trimethylethylene 1 ammonium-Z-morpholine.
4. Therapeutically acceptable salts of N -.(6-cyano-6:6 diphenyl-Zl-oxahexyl)-N :N :N trimethylethylene-l-ammonium-Z-morpholine.
5. Therapeutically acceptable salts of N -(3-cyano-3z3- diphenylpropyl)-N :N :N trimethylethylene-l-ammonium-Z-morpholine.
6. Therapeutically acceptable salts of N -(5-cyano-5:5- diphenylpentyU-N :N :N -trimethyltrimethylene l am- 1 monium-B-morpholi ne. i
References Cited in the file of this patent UNITED STATES PATENTS 2,716,121 Denton Aug. 23, 1955 FOREIGN PATENTS 149,370 Austria Dec. 10, 1952

Claims (2)

1. COMPOUNDS OF THE GENERAL FORMULA:
2. THERAPEUTICALLY ACCEPTABLE SALTS OF N''-(5-CYANO-5:5DIPHENYLPHENTYL)-N1:N1:N2-TRIMETHYLETHYLENE - 1 - AMMONIUM-2-MORPHOLINE.
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US3028389A (en) * 1957-11-12 1962-04-03 Ravensberg G M B H Basic aralkyl nitriles and process for their preparation
US3403159A (en) * 1963-08-16 1968-09-24 Bellon Labor Sa Roger Phenylcyclohexylacetonitrile derivatives
US5739327A (en) * 1995-06-07 1998-04-14 The Clorox Company N-alkyl ammonium acetonitrile bleach activators
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US6010994A (en) * 1995-06-07 2000-01-04 The Clorox Company Liquid compositions containing N-alkyl ammonium acetonitrile salts
US6183665B1 (en) 1995-06-07 2001-02-06 The Clorox Company Granular N-alkyl ammonium acetonitrile compositions
US6235218B1 (en) 1995-06-07 2001-05-22 The Clorox Company Process for preparing N-alkyl ammonium acetonitrile compounds
US6764613B2 (en) 1995-06-07 2004-07-20 Mid-America Commercialization Corporation N-alkyl ammonium acetonitrile salts, methods therefor and compositions therewith
US9193689B2 (en) 2012-03-07 2015-11-24 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
US9611223B2 (en) 2013-09-11 2017-04-04 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2999096A (en) * 1957-05-23 1961-09-05 Endo Lab Cyanobenzhydryl ethers of amino alcohols
US3028389A (en) * 1957-11-12 1962-04-03 Ravensberg G M B H Basic aralkyl nitriles and process for their preparation
US3403159A (en) * 1963-08-16 1968-09-24 Bellon Labor Sa Roger Phenylcyclohexylacetonitrile derivatives
US5739327A (en) * 1995-06-07 1998-04-14 The Clorox Company N-alkyl ammonium acetonitrile bleach activators
US5741437A (en) * 1995-06-07 1998-04-21 The Clorox Company N-alkyl ammonium acetonitrile bleach activators
US5792218A (en) * 1995-06-07 1998-08-11 The Clorox Company N-alkyl ammonium acetonitrile activators in dense gas cleaning and method
US5814242A (en) * 1995-06-07 1998-09-29 The Clorox Company Mixed peroxygen activator compositions
US5877315A (en) * 1995-06-07 1999-03-02 The Clorox Company Dimeric N-Alkyl ammonium acetonitrile bleach activators
US5888419A (en) * 1995-06-07 1999-03-30 The Clorox Company Granular N-alkyl ammonium acetontrile compositions
US5959104A (en) * 1995-06-07 1999-09-28 The Clorox Company N-alkyl ammonium acetonitrile bleach activators
US5958289A (en) * 1995-06-07 1999-09-28 The Clorox Company N-alkyl ammonium acetonitrile bleach activators
US6010994A (en) * 1995-06-07 2000-01-04 The Clorox Company Liquid compositions containing N-alkyl ammonium acetonitrile salts
US6017464A (en) * 1995-06-07 2000-01-25 The Clorox Company Dimeric N-alkyl ammonium acetonitrile bleach activators
US6046150A (en) * 1995-06-07 2000-04-04 The Clorox Company Liquid compositions containing N-alkyl ammonium acetonitrile salts
US6183665B1 (en) 1995-06-07 2001-02-06 The Clorox Company Granular N-alkyl ammonium acetonitrile compositions
US6235218B1 (en) 1995-06-07 2001-05-22 The Clorox Company Process for preparing N-alkyl ammonium acetonitrile compounds
US6764613B2 (en) 1995-06-07 2004-07-20 Mid-America Commercialization Corporation N-alkyl ammonium acetonitrile salts, methods therefor and compositions therewith
US9193689B2 (en) 2012-03-07 2015-11-24 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
US9611223B2 (en) 2013-09-11 2017-04-04 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use

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