IL31191A - N-(halocinnamoyl)-piperidine and morpholine derivatives and their preparation - Google Patents

N-(halocinnamoyl)-piperidine and morpholine derivatives and their preparation

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IL31191A
IL31191A IL31191A IL3119168A IL31191A IL 31191 A IL31191 A IL 31191A IL 31191 A IL31191 A IL 31191A IL 3119168 A IL3119168 A IL 3119168A IL 31191 A IL31191 A IL 31191A
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formula
compound
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reaction
piperidine
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IL31191A
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Thomae Gmbh Dr K
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Priority claimed from AT1091167A external-priority patent/AT280283B/en
Priority claimed from AT1075668A external-priority patent/AT281822B/en
Priority claimed from AT1075568A external-priority patent/AT281821B/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
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Publication of IL31191A publication Critical patent/IL31191A/en

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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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/64—Acyl halides
    • C07C57/72—Acyl halides containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/224—Phosphorus triamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5352—Phosphoranes containing the structure P=C-
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

* *t* 1.3 ' 9-( » N 1 DKJ ' X 1 )- U Π 1 tVl Π N~(halooinnamoyl)-piperidine and morpholine derivatives and their preparation PR. KARL THOMAS GmbH G. 29562 The present invention relates to certain novel cinnamamides having valuable pharmacological properties, and in particular antiphlogistic and antipyretic actions and processes for the preparation thereof.
According to the. present invention there are provided compounds of the general formula in the 3- or 4-pos wherein represents a bromine atom or an iodine atom/ and R2 a piperidino, 4-hydroxyplperidino or morpholino group.
The preferred compounds according to the invention by virtue of their particularly valuable pharmacological properties are:- N-(4-bromocinnamoyl)piperidine ; N- (3-bromocinnamoyl)piperidine ; N-(4-iodocinnamoyl)piperidine j N~(4-iodocinnamoyl)morpholine and N- (4-bromocinnamoyl)-4-hydroxypiperldine.
The compounds according to the invention may, for example, be prepared 'according to one of the following processes : A. ) Reaction of a cinnamic acid derivative of formula, .. reactive group, e.g. a halogen atom or an alkoxy or acyloxy group) with an amine of formula, H - R2 III (wherein R2 is as defined above).
The reaction is performed with advantage in a solvent, for example water, ether, chloroform or benzene, and optionally in the presence of a tertiary amine or in presence of an excess of the amine of formula III or in the presence of an inorganic base, for example an alkali metal hydroxide or alkali metal carbonate, conveniently at temperatures between 0° and 160° C. A tertiary amine and/or the amine of formula III may also serve as solvent; alternatively the reaction may be performed in the absence of a solvent.
If X represents a hydroxy group or a free amino group, or a mono- or disubstituted amino group, the reaction temperature is desirably increased to 200° -250°C. ' If required, the reaction may be carried out in a pressure vessel.
The reaction may also be performed as follows ·.
A reactive derivative of a compound of formula II produced in situ, for example by means of carbonyl-diimidazole, thiocarbonyl-diimidazole or a carbodiimide is reacted with an amine of formula III, or a compound of formula II is reacted with a reactive derivative of an amine of formula III, optionally produced in situ, for example by means of phosphorus trichloride (Lit.: Liebigs Ann.Ghem. 580, 68 (1953)).
B.) Reacting a compound of formula IV, (wherein is as defined above) with a compound of formula, A - C - R« V 0 (wherein Rg is as defined above and A represents a (R^O) g P-CHg- group in which ^ represents a lower alkyl group, or a P=CH- group, in which ^ represents an aryl or alkyl group).
If A represents a (R^0)2 P-CH2-group, a compound of formula V is first converted with a base (e.g. an alkali metal hydride, alkali metal amide, . alkali metal alcoholate or an alkali metal into its carbanion preferably in a solvent such as dioxan, whereby the carbanion reacts with an aldehyde of formula IV, preferably at temperatures between 20 and 80° C to a cinnamamide of general formula I.
However, this reaction may also be performed with alkali metal bases in an aqueous solvent, for example with an alkali metal carbonate in an aqueous lower alcohol.
If A represents a (R4)^ P=CH-group, an ylide of formula V is reacted with an aldehyde of formula IV (Lit,: Organic Reactions, vol. 14, page 270 ff (1965)) optionall without previous isolation, conveniently in an anhydrous solvent, for example dioxan or benzene, and preferably at temperatures between 20 and 100° C, . 31191/2 The starting materials used for the processes A and B may for example be prepared according to known methods The compounds of formula II, for example, may advantage-ously be obtained by olefiniation (Lit. : Wadsworth · and Emmons, J. Amer. Chem. Soc. 83, 1733 (1961)).
The preparation of an ylide of formula V may be effepted by a known method for example by reaction of a triaryl or. trialkylphosphine with a corresponding a-haloacetamide and subsequent reaction with a strong base (Lit.: Organic Reaction, vol.14, page 270 ff (1965)).
The preparation of a compound of formula V .may, for example, be effected by a known method for example by reacting a trialkylphosphite with a corresponding ct-haloacetamide (Lit. Kosolapoff sOrganophosphorus Compounds, page 121 ff, publishers: J. Wiley, Inc.
New York 1950).
The new cinnamamides of general formula I ■produced according to the invention possess valuable pharmacological properties, especially show antiphlogistic and antipyretic activity. In the kaolin and the carrageenin oedema- test in the rat, the compounds, of general fprmula I are better ' " than phenylbutazone in therapeutic- scbpe-yr, ,, , 31191/2 Certain N,Hrdialkyl-cinnamamldes as well as N-cinhamoyl-morphoiine are known from a publication in Jour. Am. Chem Soc. 72 pp. 3885-6 (1950)· However, the only pharmacological activity attributed in that publica-tion to these known compounds was an analgesic activity.
According to a further feature of the present invention there! are provided pharmaceutical compositions comprising at least one of the compounds of the invention as herein defined in association with a pharmaceutical carrier or excipient. The compositions may be presented in a form suitablei'fbr; oral, rectal or parenteral administration. Thus, for example, compositions for oral administration may be solid or liquid and may take the form of granules, tablets, coated tablets, capsules, syrups, emulsions, suspensions or drops, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art. Thus, for example, suitable tabletting excipients include lactose, potato and soluble starches and magnesium stearate.
For parenteral administration, the carrier may be a sterile, parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil e.g. arachis oil, contained in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 200 to 600 mg, and especially 300 to 400 mg, of active ingredient. The daily dose for adults may for example be from 400 to 1200 mg, preferably 600 to 800 mg.
The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients:-Preparation of the Starting Materials A) 4-Bromocinnamoyl chloride 75.8 g (0.33 mol) of 4-bromocinnamic acid were suspended in chloroform and mixed with 119.0 g (1.0 mol) refluxed at boiling point for 10 hours and the solution was evaporated in vacuo. The remaining crude acid chloride of m.p. 107 - 108° C was obtained in quantitative yield. 33) ethylpiperidinocarbonylmethylphosphonate 624 g (5.8 mol) of triethylphosphite were added dropwise to 615 g (3.8 mol) of N-chloroacetylpiperidine at 100°C, ethyl chloride being liberated from the reaction mixture. The reaction mixture was then heated to 140° C for 2 hours. Distillation yielded 674 g (67% of theory) of the product of b.p. 136 - 137°C .05 mm Hg.
C) Piperidinocarbonylmethyltriphenylphosphonium chloride 64.6 g (0.40 mol) of N-chloroacetylpiperidine and 104.9 g (0.40 mol) of triphenylphosphine were dissolved in 600 ml of toluene- and heated with stirring at 70° C for 8 hours. The precipitated salt was filtered off, washed with ether and dried. 116.2 g (68 of theory) of m.p. 210 - 211°C were isolated. 33) Piperidlnocarbonylmethylenetriphenylphosphorane 58.1 g (0.14 mol) of piperidinocarbonylmethyl-triphenylphosphonium chloride were dissolved in water and dilute sodium hydroxide solution added at 0°C until the solution had an alkaline reaction. The ylide was filtered off, washed with water and dried in vacuo over ?2°5° Yield: 46.2 g (87 of theory), m.p. 174 - 179°C.
E) Trispiperidinophosphine An etherial solution of 11.0 g (0.08 mol) of phosphorustrichloride was added dropwise to a ether at 0°C. After reflux the mixture for 1 hour, the precipitated piperidine hydrochloride was filtered off. Evaporation of the filtrate in vacuo yielded the desired product as an almost colourless oil which solidifies quickly. Yield: 17.3 g (76 of theory).
F) 4-Bromocinnamic acid anhydride .0 g (0.11 mol) of 4-"bromocinnamic acid and 56.0 g (0.55 mol) of acetic acid anhydride were refluxed for 8 hours. The solution was then evaporated in vacuo and the residue was treated with hot acetone to remove unchanged 4-bromocinnamic acid. The undissolved anhydride was recrystallized from absolute tetrahydro-furan.
Yield: 6.6 g (28 of theory), m.p. 199-200°C.
Example 1 N- (4-Bromocinnamoyl ) piperidine A suspension of 30.0 g (0.12 mol) of 4-bromocinnamoyl chloride in absolute ether was slowly added at 20° C to a solution of 31.5 g (0.37 mol) of piperidine in absolute ether. The mixture was stirred for 3 hours at 20°C to complete the reaction water was added and the major amount of the product was filtered off. A further amount of product was isolated from the etherial phase.
The product was recrystallized from petroleum ether to give 23.9 g (68% of theory) of colourless crystals.
M.p. 134°C.
Example 2 N-(3-Bromocinnamoyl)piperidine From 3-bromocinnamoyl chloride and piperidine analogously to Example 1. Yield: 84 of theory, m.p.
Example 3 N- (3-Iodocinnamoyl)morpholine From 3-iodoclnnamoyl chloride and morpholine analogously to Example 1. Yield: 33% of theory, m.p. 100-101° C (from ethyl acetate).
Example 4 N- (4-Iodocinnamoyl) piperidine From 4-iodocinnamoyl chloride and piperidine analogously to Example 1. Yield: 83 of theory, m.p. 134 - 135°C (from methanol).
Example 5 N- (4-Bromocinnamoyl) piperidine A suspension of 6.5 g (0.015 mol) of 4-bromocinnamic anhydride in 200 ml of benzene was mixed at 20° C with 2.5 g (0.03 mol) of piperidine. The mixture was subsequently refluxed for 2 hours to give a clear solution. The solvent was removed in vacuo, the residue was taken up in ethyl acetate and dilute sodium hydroxide solution was added. The precipitate was filtered offy the filtrate evaporated in vacuo and the residue recrystal-lized from ethyl acetate.
Yield: 3.0 g (68% of theory), m.p. 134°C.
Example 6 N- (4-Bromocinnamoyl)piperidine 7.5. (0.029 mol) of ethyl 4-bromocinnamate and 2.7 g (0.032 mol) of piperidine were added to a solution of 0.75 g (0.032 mol) of sodium in ethanol. The reaction mixture was left for 2 days and then refluxed for 4 hours. After cooling, the solution was filtered and the filtrate evaporated in vacuo. The residue was mixed with water over sodium sulfate. The solvent was removed in vacuo. When recrystallized from ethyl acetate 1.0 g (12$ of theory) of colourless crystal of m.p. 134°C were obtained .
Example 7 N- (4-Bromocinnamoyl ) piperidine 8.9 g (0.035 mol) of N,N-dimethyl-4-bromocinnamamide and 16.0 g (0.19 mol) of piperidine in 200 ml of benzene were heated in an autoclave at 200° C for 16 hours. Column chromatography of the crude product on silicagel (benzene' acetone = 3 : 1) enables 0.3 g (3$ of theory) of N-(4-bromocinnamoyl)piperidine of m.p. 134°C to be isolated. Example 8 N~( -Bromocinnamoyl) piperidine A mixture of 11.3 g (0.05 mol) of 4-bromocinnamic acid and.4.3 g (0.05 mol) of piperidine was heated to 200° C for 5 hours. After cooling, it was mixed with 2N-sodium hydroxide solution, the precipitate was filtered off and dissolved in chloroform. The un-reacted 4-bromocinnamic acid was removed by washing the chloroform solution with 2N-sodium hydroxide solution. Prom the organic phase, 6.2 g (42 of theory) of colourless crystals of m.p. 134° C (from isopropanol) were obtained.
Example 9 N- (4-Bromocinnamoyl ) piperidine 2.75. g (0.02 mol) of phosphorus trichloride were dropped into an ice-cooled solution of 5.1 g (0.06 mol) of piperidine in 50 ml of dry pyridine. Stirring was continued for 30 minutes at room temperature, in portions and the mixture was heated to 50° C for 2½ hours. The solution was evaporated in vacuo, the residue dissolved in chloroform and the solution washed with water, dilute sodium hydroxide solution and dilute hydrochloric acid. The product obtained from the chloroform phase was recrystallized from isopropanol. Yield: 4.6 g (31 of theory) m.p. 134°C. Example 10 N- (4-Bromocinnamoyl)piperidine A solution of 7.2 g (0.06 mol) of thionyl chloride in chloroform was added dropwise to a solution at room temperature of 7.6 g (0.033 mol) of 4-bromoclnnamic acid and 6.4 g (0.075 mol) of piperidine in chloroform. The solution became clear after an exothermic reaction. The solution was left for 7 hours and then water added. The chloroform phase was separated, washed with dilute sodium hydroxide solution and with water, dried over sodium sulfate and evaporated in vacuo. The .residue was recrystallized from methanol and from ethyl acetate. Yield: 3.1 g (32 of theory), m.p. 134°C.
Example 11 N-(4-Iodocinnamoyl )morpholine .. 4.1 g (0.015 mol) of 4-iodocinnamic acid were suspended in chloroform and mixed dropwise with a solution of 3.7 g (0.021 mol) of thiocarbonyl-diimidazole in chloroform (prepared from thiophosgene and imidazole, lit.: Liebigs Ann. Chem... 657,98 (1962)). The mixture was heated to boiling for 6 hours and a solution of 2.2 g. (0.025 mol) of morpholine in chloroform then added dropwise and the resulting mixture stirred for 2 ffays dissolved in ethyl acetate. The solution was washed with dilute hydrochloric acid and dilute sodium hydroxide solution and dried over sodium sulfate. The ethyl acetate was evaporated in vacuo to leave a solid product which was re'crystallized several times from methanol. Yield: 1.8 g (35$ of theory), .p. 175-177°C. Example 12 N- (3-Bromocinnamoyl)piperidine acid and 1.9 g 0.022 mol of piperidine in. absolute dimethylformamide was mixed at 0°C with a solution of 4.5 g (0.022 mol) of dicyclohexylcarbodiimide in dimethylformamide. After leaving the mixture to stand over-night, it was heated for 8 hours at 40° C. The reaction mixture was poured into water and extracted with chloroform. The crude product obtained from the chloroform solution was purified by column chromatography on silica gel (benzene-acetone = 5 : 1). Yield: 0.4 g (7 of theory), m.p. 98 - 99°C.
Example 13 N- (4-Bromocinnamoyl ) iperidine .5 g of a 50 suspension of sodium hydride in mineral oil (0.114 mol of sodium hydride) were mixed slowly at 20°C with 30.0 g (0.114 mol) of diethyl piperidinocarbonyl ethyl-phosphonate . The mixture was heated to 70° C for 45 minutes to complete the carbanion formation. Asolution of 17.5- g (0.095 mol) of 4-bromobenzaldehyde in absolute dioxan was dropped into the solution at room temperature. After mixture was poured into water, the product extracted with ether or benzene and purified by recrystallization from methanol. 18.6 g (66 . of theory) of colourless crystals of m.p, 134°C were obtained.
Example 14 N- (4-Bromocinnamoyl ) morpholine From 4-bromobenzaldehyde and diethyl morpholino-carbonylmethylphosphonate analogously to Example 13» Yield: 70 · of theory, m.p. 142 - 144°C (from benzene-ether) „ Example 15 N- ( 5-Bromocinnamoyl ) morpholine From 3-bromobenzaldehyde and diethyl morpholino-carbonylmethylphosphonate analogously to Example 13.
Yield: 38% of theory, m.p. 80-81°C (from petroleum ether).
Example 16 N- (4-Bromocinnamoyl) lperidlne A mixture of 30.0 g (0.16 mol) of 4-bromobenzaldehyde 51.0 g (0.19 mol) of diethyl piperidinocarbonylmethyl-phosphonate and 34.0 g (0.25 mol) o potassium carbonate in 500 ml of 75% aqueous methanol was heated at boiling point for 5 hours. After cooling the reaction mixture, it was poured into water and the product was filtered off. The product was recrystallised from isopropanol. 43.1 g (90% of theory) of N- (4-bromocinnamoyl) piperidine were obtained as colourless crystals of m.p. 133-134° C.
Example 17 N- (4-1 odocinnamoyl )morpholine Yield: 64% of theory, m.p. 176 - 178°C (from methanol) Example 18 N-(4-Iodocinnamoyl)piperidine Prom 4-iodobenzaldehyde and diethyl piperidino-carbonylmethylphosphonate analogously to Example 16. Yield: 71 of theory, m.p. 134-135°C (from methanol). Example 19 N- (3-Iodocinnamoyl)morpholine From 3-iodobenzaldehyde and diethyl morpholino-carbonylmethylphosphonate analogously to Example 16. Yield: 40$ of theory, m.p. 100 - 101° C.
Example 20 N- (4-Bromocinnamoyl) pi'peridine A solution of 5.5 g (0.03 mol) of 4-bromobenzalde-hyde and 11.7 g (0.03 mol) of piperidinocarbonylmethyl enetriphenylphosphorane in 100 ml of absolute benzene was refluxed at boiling point, for 20 hours. After removal of the solvent in vacuo the triphenylphosphine oxide was separated from the product by extraction with a large quantity of low-boiling petroleum ether. The residue was recrystallized from methanol and yielded o3 g (60$ of theory) of the pure product, M.p. 134°C.
Example 21 N- (4-Iodocinnamoyl)piperidine 7o3 g (0.017 mol) of piperidinocarbonylmethyl-diphenylphosphonium chloride were added in portions to aosuspension of 1,95 g (0,017 mol) of potassium tert.- butoxide in absolute dioxan, A solution of 4.0 g (0.017 mol) of 4-iodobenzaldehyde in absolute cooling, it was poured into water and extracted with chloroform. The crude product obtained from the chloroform extract was recrystallized several times from isopropanol for purification. Yield: 3.2 g (57% of theory), m.p. 134 - 135°C.
Example 22 N-(4-Bromocinnamoyl) iperidine A suspension of 15.8 g (0.07 mol) of 4-bromocinnamic acid in absolute; toluene was mixed at 20°C with a solution of 4.5 g (0.016 mol) of trispiperidinophosphine in absolute toluene. The mixture was then heated to 100° C for 1½- hours. After evaporation of the solvent in vacuo, water was added to the residue and the product was extracted with ethyl acetate. Yield: 3.1 g ( 2 of theory), m.p. 134°C (from ethyl acetate). Example 23 N- (4-Iodocinnamoyl) iperidine From 4-iodobenzaldehyde and diethylpiperidino-carbonylmethylphosphonate analogously to Example 13. Yield: 5 of theory, m.p. 134 - 135°C.
Example 24 N-(4-Iodocinnamoyl)morpholine Prom 4-iodocinnamoylchloride and morpholine analogously to Example 1.
Yield: 80 of theory, m.p. 176 - 178°C.
Example 25 N-(3-Iodocinnamoyl) piperidine From 3-iodobenzaldehyde and diethylpiperidino-carbonylmethylphosphonate analogously to Example 16. Yield: 44 of theor m 10 - 110°C Example 26 N- (4-Bromocinnamoyl ) -4-hydroxypiperidine A solution of 28.0 g (0.115 mol) of 4-bromocinnamoyl chloride in chloroform was dropped slowly with stirring into a solution of 11.6 g (0.115 mol) of 4-hydroxypiperidine and 17.3 g (0.171 mol) of triethylamine in chloroform. After stirring for 3 hours at 20° C the reaction mixture was mixed with water and chloroform, the organic phase was separated and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue recrystallised from methanol. 29.0 g (82$ of theory) of colourless crystals of m,p. 160 - 162°C were obtained.
Example 27 N-(5-Bromocinnamoyl) -4-hydroxypiperidine From 3-hromocinnamoyl chloride and 4-hydroxypiperidine analogously to Example 26. Yield: 6$ of theory, m.p. 116 - 117°C (from ethyl acetate).
Example 28 N- (4-Iodocinnamoyl ) -4-hydroxypiperidine From 4-iodocinnamoyl chloride and 4-hydroxypiperidine analogously to Example 26. Yield: 5$ of theory, m.p. 176 - 177°C (from ethanol).
Example 29 N-(3-Iodocinnamoyl) -4-hydroxypiperidine From 3-iodocinnamoyl chloride and 4-hydroxypiperidine analogously to Example 26, Yield: 31.0$ of theory, m.p. 126 - 127°C (from ethylacetate ) .
Example 30 N- (4-Bromocinnamoyl) -4-hydroxypiperidine N-chloroacetyl-4-hydroxypiperidine and sodium diethylphosphite ] and 0.833 g (4.50 m mol) of 4-bromobenzaldehyde in 20 ml of dry dioxan were mixed with 0.482 g (4.30 m mol) of potassium tert.-butoxide. The reaction mixture was heated, with stirring, for two hours at 60° C. The brown solution was then cooled, diluted with 200 ml of water and extracted with chloroform. The crude product obtained from the chloroform extract by evaporation in vacuo was purified by colunr chromatography on silicagel (benzene :acetone=l :1) . When recrystallized from chloroform/acetone containing a small quantity of ether, 0.45 g (3 $ of theory) for colourless crystals of m.p. 159 - 161°C were obtained.
Example 31 N- (4-Bromocinnamoyl)--4-h.ydroxypiperidine A mixture of 0.8 g (4.3 m mol) of 4-bromobenzalde-hyde, 1.9 g (4.3 m mol) of 4-hydroxypiperidinocarbonyl-methyltriphenylphosphonium chloride (m.p. 57-59° C) [prepared from triphenylphosphine and N-chloracetyl- (4-hydroxypiperidine] and of 1.1 g (9.9 m mol) of potassium tert.-butoxide in 20 ml dry dimethylformamide was heated to 50° C for 14 hours. After cooling the reaction mixture it was poured into water and extrac-ted with chloroform. The crude product obtained from the chloroform extract by evaporation in vacuo was purified by column chromatography on silicagel (benzene acetone = 2 : 1). Yield: 0.4 g (30$ of theory), m.p. 159 - 161°C.
Example 32 Tablets with.300*00 nig, of N-(4-bromocinnamoyl)piperidine Composition: , 1 tablet contains: N-(4-bromocinnaoyl)piperidine 300 mg corn starch 30 mg polyvinylpyrrolidone 10 mg cellulose microcrystalline 50 mg Aerosil 5 mg magnesium stearate 5 mg 400 mg Preparation: The active ingredient mixed intensely with the corn starch, moistened with a 10 ethanolic solution of : he polyvinylpyrrolidone, granulated through a 1.5 mm mesh-size screen and dried at 40° C. The granulate was once more passed through the above screen and mixed with the remaining excipients. The mixture was pressed into tablets.
Weight of tablet: 400 mg Die : 11 mm Example 33 Dragees with 300 mg of N-(4-bromocinnamoyl)piperidine The tablets prepared according to Example 1 were coated with a shell according to a known process, the shell consisting essentially of talcum and sugar. The finished dragees were polished with beeswax.
Weight of dragee: 550.00 mg Example 34 Composition 1 suppository contains: N- (4-bromocinnamoyl)piperidine 400 mg suppository base (e.g. Witepsol 45) 1350 mg 1750 mg Preparation: The finely pulverized active ingredient was stirred into the molten suppository base cooled to 40°C by means of an immersion homogenizer„ The mass was poured at 38°C into slightly precooled moulds.
Weight of suppository: 1.75 g Example 35 Suppositories for children with 50 mg of N-(4-bromo-cinnamoyl)piperidine and 60 mg of 5- (l-cycloheptenyl) -5-ethyl-barbituric acid Composition 1 suppository contains: N-(4-bromocinnamoyl)piperidine 50 mg -(l-cycloheptenyl)-5-ethylbarbituric acid 60 mg suppository base (e.g. Witepsol W 45) 890 mg 1000 mg Prepara ion: Analogously to Example III.
Example 6 Tablets with 300 mg of N-(4-bromocinnamoyl) lperldine . 50 mg of caffeine. 25 mg of phenylethylbarbituric acid and 10 mg of codeine phosphate Comp£sition 1 tablet contains: N-(4-bromocinnamoyl)piperidin.e 300 mg potato starch 100 mg carboxymethylcellulose, low viscosity 7 mg cellulose macrocrystalline 103 mg magnesium stearate 5 600 mg Pre_paratio : The N-(4-Bromocinnamoyl)piperidine, caffeine, phenylethylbarbituric acid and potato starch were mixed and granulated with a 6^-aqueous solution of the carboxymethylcellulose through a 1.5 mm mesh-size screen. The granulate was dried at 40°C, rubbed once more through above screen and mixed with the codeine phosphate and the remaining excipients. Tablets were pressed out of the mixture.
Weight of. tablet: 600 mg Die: 13 mm, flat, with notch Example 37 Suspension with 200 mg of N- (4-bromocinnamoyl ) piperidine and 4 mg of N-cyclohexyl-N-methyl-(2-amino-3. -dibromo-benzyl) ammonium chloride per 5 ml Composition 100 ml of suspension comprise: N-( 4-bromocinnamoyl) piperidine 4.00 g N-cyclohexyl-N-methyl- ( 2-amino-3 , 5- dibromobenzyl) ammonium chloride 0.08 g citric acid 2.35 g sodium hydroxide 1.30 g dioctylsodiumsulfosuccinate (DONSS) 0.02 g benzoic acid 0.10 g sodium cyclamate 0.20 g sorbit 20.00 g glycerin 10.00 g red-cuttant aroma 0.10 g distilled water 74.45- g 115.50 g Preparation In approximately 15 of the indicated quantity of water are dissolved successively DONSS and the two finely pulverized active ingredients. The remaining water was heated- to 80° C and Veegum was suspended therein. Citric acid, sodium hydroxide, benzoic acid, sodium cyclamate, sorbit and polyvinylpyrrolidone were then dissolved in turn. The solution was cooled to room temperature and glycerin, red-cuttent aroma and the suspension of the active ingredient were stirred in.
The finished preparation was homogenized. ml of suspension contain 200 mg of N-(4-bromocinnarnoyl)piperldine and 4 mg of N-cyclohexyl-N-methyl-(2-amino-3.5- dibromo-benzyl) ammonium chloride.

Claims (44)

1. Compounds of the general formula wherein R-, represents a bromine atom or an iodine in the J=- or 4- osition atom/and ≥ a piperidino, 4-hydroxypiperidino or morpholino grq,up.
2. N-(4-Bromocinnamoyl)piperidine.
3. N- ( 3-Bromocinnamoyl) piperidine .
4. N-(4-Iodocinnamoyl)piperidine.
5. N- (4-Iodocinnamoyl ) morpholine .
6. . N-(4-Bromocinnamoyl)-4-hydroxypiperidine.
7. Compounds of the general formula I, as defined in claim 1, specifically as herein described with the exception of compounds as claimed in any of claims 2 to 6,
8. A process for the preparation of compounds of the general formula I, as defined in claim 1, in which a cinnamic acid derivative of formula (wherein ^ is as defined in claim 1 and X represents a hydroxy group, a free amino group or an amino group mono- or disubstituted by lower alkyl groups, or a reactive group) is reacted with an amine of formula
9. A process as claimed in claim 8 in which the reaction is effected in a solvent.
10. A process as claimed in claim 9 in which the said solvent comprises water, ether, chloroform, benzene or an excess of the amine of formula III.
11. A process as claimed in any of claims 8 to 10 in, which the reaction is effected in the presence of a tertiary amine, an excess of the amine of formula III or an inorganic base.
12. A process as claimed in claim 11 in which the said inorganic base comprises an alkali metal hydroxide or an alkali metal carbonate.
13. A process as claimed in any of claims 8 to 12 in which the reaction is effected at a temperature between 0 and 160°C.
14. A process as claimed in any of claims 8 to 13 wherein a cinnamic acid derivative of formula II is used in which X represents a halogen atom or an alkoxy or acyloxy group.
15. A process as claimed in any of claims 8 to 12 in which a cinnamic acid derivative of formula II is used in which X represents a hydroxy group or a free amino group and the reaction is effected at a temperature of from 200 to 250°C.
16. A process as claimed in any of claims 8 to 15 in which the cinnamic acid derivative of formula II or the amine of formula III is a compound formed in situ in the reaction medium.
17. A process for the preparation of compounds of the general formula I, as defined in claim 1, in which (wherein is as defined in claim 1) is reacted with a compound of formula 0 (wherein is as defined in claim 1 and A represents a represents a lower al , in which R4 represents an aryl or alkyl group),
18. A process as claimed in claim 17 in which a compound of formula V is used wherein A represents a group in which R, is an ethyl group.
19. A process as claimed in claim 17 in which a compound of formula V is used wherein A represents a (R4)^ P=CH- group in which R4 represents a phenyl or piperidino group.
20. A process as claimed in claim 17 or claim 18 in which a compound of formula V is used wherein A represents a group and the reaction is carried out in the presence of a base whereby the carbanion of the compound of formula V reacts with the compound of formula IV.
21. A process as claimed in claim 20 in which the said base comprises an alkali metal hydride, an alkali metal amide, a . -alkali metal alcoholate or an alkali metal,
22. A rocess as claimed in claim 20 or claim 21 in
23. solvent comprises dioxan or an aqueous solvent.
24. A process as claimed in claim 23 in which the said aqueous solvent is an aqueous lower alcohol.
25. A process as claimed in any of claims 20 to 24 in which the reaction is effected at a temperature between 20 and 80° C.
26. . A process as claimed in claim 17 or claim 19 in which a compound of formula ,'V is used wherein A represents a (R^)^P=CH- group and the compound of formula V is a compound formfeduiiiijsifou- in^$h£o¾eaction medium.
27. A process as claimed in any of claims 17 , 19 and 26 in which the reaction is effected in an anhydrous solvent.
28. A process as claimed in claim 27 in which the said solvent comprises dioxan or benzene.
29. 2 o A process as claimed in any of claims 17 , 19 and 26 to 28 in which the reaction is effected at a temperature between 20 and 100° C.
30. A process as claimed in claim 8 substantially as herein described.
31. A process as claimed in claim 8 substantially as herein described in any of Examples 1 to 12 , 22 , 24 and 26 to.29.
32. A process as claimed in claim 17 substantially as herein . described .
33. . A process as claimed in claim 17 substantially as herein described in any of Examples 13 to 21 , 23 , 25 , 30 and 31.
34. Compounds of the general formula I as defined in claim 1 wh n re ared b a rocess as claim d
35. Pharmaceutical compositions comprising at least one compound of formula I, as defined in claim 1, in association with a pharmaceutical carrier or excipient.
36. Compositions as claimed in claim 35 which contain a further active ingredient.
37. Compositions as claimed in claim 35 or claim 36 in a form suitable for oral, rectal or parenteral administration.
38. Compositions as claimed in claim 37 in the form of granules, tablets, coated tablets, capsules, syrups, emulsions, suspensions or drops.
39. Compositions as claimed in any of claims 35 to 38 in the form of dosage units.
40. Compositions as claimed in claim 39 in which each dosage unit contains from 200 to 600 mg of active ingredient.
41. Compositions as claimed in claim 40 in which each dosage unit contains from 300 to 400 mg of active ingredient.
42. Pharmaceutical compositions as claimed in claim 35 substantially as herein described.
43. Pharmaceutical compositions substantially as herein described in any of Examples 32 to 37.
44. N Eaoh and every novol oomp-oun , --pre-e-e^-a-, eompooition and method heroin diocloood.
IL31191A 1967-12-01 1968-12-01 N-(halocinnamoyl)-piperidine and morpholine derivatives and their preparation IL31191A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AT1091167A AT280283B (en) 1967-12-01 1967-12-01 Process for the preparation of new cinnamic acid amides
AT1075668A AT281822B (en) 1968-11-05 1968-11-05 Process for the production of new cinnamic acid amides
AT1075568A AT281821B (en) 1968-11-05 1968-11-05 Process for the production of new cinnamic acid amides

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IL31191A0 IL31191A0 (en) 1969-02-27
IL31191A true IL31191A (en) 1972-09-28

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ES (1) ES360959A1 (en)
FR (2) FR1593868A (en)
GB (1) GB1190680A (en)
IE (1) IE32544B1 (en)
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US4824842A (en) * 1985-02-14 1989-04-25 Kyowa Hakko Kogyo Kabushiki Kaisha Cinnamoyl piperidines and thiomorpholine and cerebral protection compositions
EP4277896A1 (en) * 2021-01-14 2023-11-22 B.G. Negev Technologies and Applications Ltd., at Ben-Gurion University Anti-quorum sensing, anti-biofilm, and inflammation attenuating compounds, compositions, and methods of using same

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BE724746A (en) 1969-05-29
FR8274M (en) 1970-11-02
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NL6816625A (en) 1969-06-03

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