IE44487B1 - 10-(w-(benzoylpiperidinyl)alkyl)phenothiazines - Google Patents

10-(w-(benzoylpiperidinyl)alkyl)phenothiazines

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Publication number
IE44487B1
IE44487B1 IE1357/76A IE135776A IE44487B1 IE 44487 B1 IE44487 B1 IE 44487B1 IE 1357/76 A IE1357/76 A IE 1357/76A IE 135776 A IE135776 A IE 135776A IE 44487 B1 IE44487 B1 IE 44487B1
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Ireland
Prior art keywords
compounds
formula
phenothiazine
fluorobenzoyl
compound
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IE1357/76A
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IE44487L (en
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Robins Co Inc A H
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Application filed by Robins Co Inc A H filed Critical Robins Co Inc A H
Publication of IE44487L publication Critical patent/IE44487L/en
Publication of IE44487B1 publication Critical patent/IE44487B1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic 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
    • C07D211/08Heterocyclic 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30Heterocyclic 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32Heterocyclic 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

. The. present Invention relates to 10 -[ω - (benzoylpiperidinyl) alkylJ phenothiazines, to a process for preparing them, to compositions containing them, and to a method of using the compounds and the compositions.
The compounds of the present invention have the general Formula I: wherein: R represents hydrogen, chloro, bromo, trifluoromethyl, lower alkoxy, acetyl sulphamoyl or dimethylsulphamoyl; R^· represents hydrogen, chloro, bromo, fluoro, trifluoromethyl, lower alkyl or lower alkoxy; and Π is 2,3 or 4.
Preferably nis 3 and R^ is fluoro, preferably in the para position on the benzoyl group and the p-fluorobenzoyl group is at the 4 position on the piperidinyl group.
The invention also embraces acid addition salts, more particularly non-toxic pharmaceutically acceptable acid addition salts, of compounds of Formula 1, and the term compounds of the invention as used hereinafter includes such salts unless the context implies otherwise.
The compounds of the invention are generally characterized by pharmacological activity, particularly tranquillizing activity, and are particularly useful in inducing an anti-anxiety effect in a living animal body.
The tranquillizing activity of the compounds of the invention was demonstrated by their ability to block the lethal effects of d-amphetamine in aggregated mice when tested according to a modified procedure of Burn and Hobbs, Arch, Intern, Pharmacodyn. 113: 290 (1958).
For example, when 2 - chloro - 10 - C3 - (4 - fluorobenzoylpiperidinyl)propylH phenothiazine was administered I.P. in rats the compound had an Εϋ^θ of 0.72 mg/kg after 16 hours, indicating the compound had effective and long lasting tranquillizing properties. The values of the foregoing compound and additional compounds as described in some of the Examples of this specification are summarized in Table 1.
TABLE 1 Effects of different pretreatment time intervals on d-amphetamine lethality in mice____________Protective ED5Q (95% confidence limits) mg/kg IP Example No. lhr. 4hr. 8hrs. 16hrs. 0.19(0.1-0.5) 0.72(0.4-13) 0.17(0.1-0.4) 0.53(0.2-1.1) 0.14(0.06-0.3) 0.10(0.05-0.22) 0.06(0.03-0.13)0.76(0.6-11) 1.27(0.7-2.1) 12.1(8-18) 0.94(0.4-1.9) 0.35(0.1-1.2) 1.44(0.6-3.3) 3.5(1.1-10.8) 1.4(0.8-2.2) 1.89(1.2-23) The acute toxicities (LD^q,s) of the compounds of Examples 1,4,6 and 7 were determined in mice and are summarized in Table XI. 0 4 8 7 TABLE II hour LD^'s in Mice Example No. LF-^ M«utss' mij.-ke IS' 7 248 (211-290) 5 6 287 (227-361) 1 330 (268-405) 4 317 (251—399) In the definition of the symbols in Formula I and where they appear elsewhere in the specification the following terms have the meanings specified.
The term lower-alkyl means straight or branched chain radicals of up to 8 carbon atoms inclusive and is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl and octyl.
The term lower-alkoxy has the formula —O-loweralkyl.
The compounds of the invention are preferably employed in the form of non-toxic pharmaceutically acceptable acid addition salts. Such salts have improved water solubility over the free base. Although the non-toxic salts are preferred, any salt may be prepared for use as a chemical intermediate, as in the preparation of another acid addition salt suitable for administration to an animal body for the desired physiolgical effect thereof. Appropriate pharmaceutically acceptable acid addition salts are those derived from inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric, and organic acids such as acetic, citric, lactic, maleic, oxalic, fumaric and tartaric. The preferred addition salts are the hydrochloride, maleate, citrate, fumarate and oxalate. The acid addition salts can be conventionally prepared by reaction of the basic compounds with the appropriate acid, either or both of which may be in the form of ether, alcohol or acetone solutions.
The starting materials used in preparing the compounds of the invention may be phenothiazine and 2-substituted phenothiazines, which are commercially available or which can be prepared by known procedures described in the chemical literature, and 1- (ω- haloalkyl) - 4 - (2 or 3) - benzoylpiperidines. The latter compounds may be prepared by reacting 4 - (2 or 3) - benzoylpiperidines with ω - haloalkanols in a lower alkanol solvent such as n-butanol with an acid acceptor to give 1 - (ω- hydroxyalkyl, - 4 - (2 or 3) - benzoylpiperidines which on reaction with a reagent such as thionyl chloride give the - ( ω- haloalkyl) - 4 - (2 or 3) - benzoylpiperidine.
The 4 - (2 or 3) - benzoylpiperidines are known compounds. They can be prepared according to methods disclosed in (J.S. Patent Specification No. 3,576,810.
The compounds of the invention may be prepared by reacting a 1 - ( ω - haloalkyl) - 4 - (2 or 3) benzoylpiperidine of the formula; <3 448? Formula II wherein and n are as defined and are preferably fluoro in the para position, and 3, respectively, and X is halo, e.g. chloro, bromo or iodo, preferably chloro, with a phenothiazine of the formula Formula III wherein R is as defined. The reaction is preferably carried out in the presence of an aprotic solvent, for example, benzene, toluene or xylene, and in the presence of an acid acceptor such as a strong inorganic base. The reaction is preferably carried out at an elevated temperature, for example, reflux temperature. In a variation of the foregoing procedure the phenothiazine is metallated in a suitable solvent such as benzene, toluene or dimethylformamide using a conventional metallating agent, for example, sodium hydride or n-butyllithium, and at an elevated temperature in the range from 80 to 130°C e.g. 80—110°C, and.the 1 - (ω - haloalkyl) - 4 - (2 or 3)benzoylpiperidine is reacted with the metallated phenothiazine. - 6 Alternately, the compounds of tiie invention may be prepared by the following method.
A 10-(u)-haloalkyl)phenothiazine of the formula (0Η2)ηΧ Formula IV wherein R and n are as defined and X is chloro, bromo or iodo, but preferably chloro, is reacted with a benzoylpiperidine of the formula wherein R1 is as defined, in an aprotic solvent, e.g., benzene, xylene or toluene, preferably at elevated temperature, e.g., 80-1(30 C. in the presence of an acid acceptor such as a strong inorganic base.
The compounds prepared by the foregoing procedures may be isolated from the reaction mixture by suitable techniques , for example, distillation, chromatography, crystallization or by conversion to a suitable acid addition salt. - 7 ·, <34487 The following preparations illustrate the preparation of intermediates. The following Examples illustrate the preparation of compounds of the invention.
Preparation 1 4-(p-Fluorobengoyl)-1-(3-hydroxypropyl)piperidine.
A mixture of 24.3 g. (0.1 mole) of 4-(p-fluorobenzayl)pipetidine hydrochloride, 12.5 9· (0.135 molo) of 3-chloropropanol and 48.0 g. (0.5 mole) of sodium bicarbonate in 500 ml, of n-butanol was stirred at reflux for 15 hours. An additional 3-0 g. {Ο.Ο25 mole) of 3-chloropropanol was added after thin layer chromatography showed incomplete reaction and the reaction was continued for 3 hours. The cooled reaction mixture was filtered, the filtrate concentrated at reduced pressure and the residual oil crystallised by trituration in isopropyl ether. The o tan solid weighed 33 g. (87^) and melted at 107-109 C. Recryatalli2ation from bensene-isooctane gave 17.7 S· ©£ material melting at 111-112%.
Preparation S 4-(p-FluorobeH2oyl)-1-(3-chloropropyl)piperidine.
Thionyl chloride (38.7 g·, 0.376 mole) was added dropwise to a stirring solution of 4-(p-fluorobanzoyl)-1-(3-hydroxypropyl) piperidine (43.1 g., 0.153 mole) in 400 ml. chloroform at room . temperature. After the addition was complete the reaction mixture was stirred at room temperature an additional 16 hours.
The mixture was then chilled and 135 ml. 6n sodium hydroxide solution was added dropwise. The chloroform solution was separated, washed with water, and dried aver magnesium sulfate. Removal of the solvent gave 43.7 g· crude product (92jJ yield) which crystallised on cooling. Recrystallization from iaooctane gave 25,3 g. pure product, m.p, 66.5-68.5%, - 8 Analysis: Calculated for CisHie)NCI--C1 : C’,65.49; II.6-79: n,4.04 Found : C.03.49; 11,6.85; N,4.8l Preparation 3 2-Bromo~10-( 3-chloropropyl)phenothiazine.
A solution of 2-bromophenothiazine (41-72 <3-, 0.05 mole) in 200 ml. of dry toluene was added to a stirred solution of 9-6 g. (0.15 mole) of n-butyllithium in 100 ral. of dry toluene. , 0 The stirred solution was warmed for about 2.0 hours at 45~5θ C. and then 31-5 9· (0.20 mole) of bromopropylchloride in 50 ml. of dry toluene was added. The mixture was refluxed for 15 hours.
The cooled reaction mixture was washed with water, dried over sodium sulfate and the dried solution concentrated at reduced pressure. The residual oil was distilled to give the product, 2-bromo-10~(3-chloropropyl)phenothiazine. - 9 444®? Example 1 1O-C3-(4-(p-Fluorobenzoyl)piperidinyl)propyljphenothiazine Fumarate Hydrate (1:4).
A mixture of phenothiazine (1).9 g., 0.025 mole), 1-(3chloropropyl)-4-(p-fluorobenzoyl)piperidine (7-5 9-, 0.0265 »ols) and crushed potassium hydroxide pellets (8.4 g., 0.15 mole) was stirred in 200 ml. dry toluene at reflux for 20 hours. The cooled reaction mixture was filtered and the filtrate concentrated at reduced pressure. The residual oil was shown to be a mixture of product and reactants by thin layer chromatography analysis.
Partial purification was achieved by dissolving the oil in ether and treating with ethereal hydrogen chloride solution to form the hydrochloride salt. The salt would not recrystallize, however, and was converted to the free base. The free base (4-5 g·, 40.5^ yield) was treated with one equivalent of fumaric acid to form the fumarate salt. Recrystallization from methanol0 isopropyl ether yielded 4-7 g. tan solid, m.p. 190-192 c.
Analysis: Calculated for CagH3gNa0FS.C4H404.1/4 HsO: 0,65.65,- H,5.60; N,4.94 Found c,65-82,- H,5.60; N,4.93 Example 2 When, in the procedure of Example 1, 1-(3-chloropropyl)4-(p-fluovobensoyl)piperidine is replaced by an equal molar amount of: 1-(3-chloropropyl)-4-(p-chlorobenzoyl)piperidine, l-(3-chloropropyl)-4-(p-bromobenzoyl)piperidine, 1-(3-chloropropyl)-4-(m-fluorobenzoyl)piperidine, 1-( 3-chloropropyl)-4-(m-trifluoromethylbenzoyl)piperidine, there are obtained, -C3-(4-(p-chlorobenzoyl)piperidinyl)propyl]phenothiazine, -Q3-(4-(p-bromobenzoyl)piperidinyl)propyljphenothiazine, -^3-(4-(m~fluorobenzoyl)piperidinyl)propyl]phenothiazine, -L3-(4-(m-trifluoromethylbenzoyl)piperidinyl)propyl]phenothiazine, 5 respectively.
Example 3 When, in the procedure of Example 1, phenothiazine is replaced by an equimolar amount of: 2-sulfamoylphenothiazine, or 2-dimethylsulfamoylphenothiazine, there are obtained, 2-su1famoyl-10-(3-(4-(p-f luorobenzoyl)piperidinyl)propyl]phenoth iazine, and 2-dimethylsulfamoyl-10-[3-( 4-(p-fluorobenzoyl)piperidinyl)propyl] phenothiazine.
Example 4 2-Trifluoromethyl-lO-r3-( 4-(p-fluorobenzoyl)piperidinyl) propyljphenothiazine Fumarate.
SO A mixture of 2-trifluoromethylphenothiazine (8.6 g.> 0.032 mole), 1-(3-chloropropyl)-4-(p-fluorobenzoyl)piperidine (10.0 g-, 0.035 mole), and crushed potassium hydroxide pellets (11.2 g., 0.2 mole) was stirred in 300 ml. dry toluene at reflux for 20 hours. The cooled reaction mixture was filtered, the filtrate washed with water, dried over magnesium sulfate, and concentrated to give 14.2 g. crude product (88$ yield). The crude product was treated with excess fumaric acid in methanol- 11 isopropyl ether to give 20.5 g. fumarate salt.
Recrystallisation from isopropanol-isopropyl ether gave 12.2 g. fumarate salt, m.p. 158.5-161°C.
Analysis: Calculated for 833¾¾¾¾5 C,S0.94; H,4.8O; 11,4.44 Found : C,60.77; H,4.88; N,4.37 Example 5 When, in the procedure of Example 4, 1-(3-chloropropyl)4-(p-fluorobenzoyl) piperidine is replaced by an equal molar amount of: 1-(2-chloroethyl)-4-(p-fluorobenzoyl)piperidine, 1-(2-ohloroethyl)-4-(p-chlorobensoyl)piperidine, 1-(z-chioroetnylj-4-(m-trirluorometnylbensoyl)piperidine, 1-(4-chlorobutyl)-4-(p-fluorobenzoyl)piperidine, and 1- (4-chlorobutyl) -4-(p-bromobenzoy1)piperidine, there are obtained, 2- trifluoromethyl-10-C2-(4-(p-fluorobenzoyl)piperidinyl)ethyl] phenothiazine, 2-trifluoromethyl-10-C2-(4-(p-chlorobenzoyl,piperidinyl)ethyl] phenothiaz ine, 2-trifluoromethyl-lO-C2-(4-(m-trifluoromethylbenzoyl)piperidinyl) ethylUphenothiazine, 2-trifluoromethyl-10-C4-(4-(p-fluorobenzoyl)piperidinyl)butyl] phenothiazine, and 2-trifluoromethyl-10-E4-(4-(p-bromobenzoyl)piperidinyl)butyl] phenothiaz ine, respectively. 444 87 Example 6 2-Acetyl-10-[ 3-( 4»(p-fluorobenzoyl) piperidinyl)propyl] phenothiazine Difumarate Sesquihydrate.
A mixture of 2-acetylphenothiazine (7-7 g-, 0.0J2 mole), 1-(3-chloropropyl)-4-(p-fluorobenzoyl)piperidine (10.0 g., 0.0355 mole) and crushed potassium hydroxide pallets (14.0 g., 0.25 mole) was stirred in 300 ml. dry toluene at reflux for 24 hours. Thin layer chromatography showed incomplete reaction. An additional 10.0 g. (0.0355 mole) of l-(3-chloropropyl)-4~(pfluorobenzoyl)piperidine in 75 ml. dry toluene was added to the reaction mixture and reflux continued for an additional 24 hours. The cooled reaction mixture was washed with water, dried over magnesium sulfate and concentrated to give 23.2 g. crude product. Chromatography on 400 g. magnesium silicate gave 6 g. of impure product. Impurities were removed by molecular distillation, leaving the product as the residue. The residue weighed 4.0 g. (24,5$ yield). The free base was treated with two equivalents of fumaric acid in methanol. The methanol was evaporated and the solid residue recrystallized from acetone-petroleum ether (30-60°c.); m.p. l46-l49°c.
Analysis: Calculated for C74HeqN40a3SaFa: C,59-43; H,5-59: N,3-75 Found : C,59-57: H,5-O6j H,3-59 Example 7 2-Chloro-10-r3-(4- (p-fluorobenzoyl)piperidinyl)propylH phenothiazine Hydrochloride Hydrate (1:4). · · A raixture of 2-chlorophenothiazine (9-4 g., 0.04 mole), 4-(p-fluorobenzoyl)-1-( 3-chloropropyl)-piperidine (12.0 g., - 15 4 0.0425 vole) and «rushed potassium hydroxide pellets (l4.0 g., 0.2%i πκΛε) in ;j00 ml. dry toluene was stirred ond refluxed for 56 hour :. After cooling, the toluen:.· solution was decanted away fr >m the inorganic material and concentrated to give 17-5 y. crude product. This was chromatographed on a 250 g. magnesium silicate column to give 32.0 g. of fairly pure product (63/ yield). Molecular distillation at 250 C. gave 6-7 g. of yellow glass. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give a hygroscopic hydrochloride salt.
The salt was triturated in boiling isopropyl ether and was recrystullized from isopropyl ether-chloroform. The salt which was shown by nuclear magnetic resonance and mass spectral analysis to be solvated was dried at 120°C. in a vacuum oven.
The salt, m.p. 204-206 C., analyzed as a 1/4 hydrate.
Analysis: Calculated for CayHasNsOFClaS · 1/4 IfeO: c, 62.13: H, 5-51; n,5-37 Found C, 62.04; H, 5-25? N,5'Jl0 Example 8 2-Bromo-10-r 5-(4-(p-fluorobenzoyl)piperidinyl)propylj phenothiazine Hydrochloride. Λ stirred mixture of 8.86 g. (0.025 mole) of 2-bromo-lO(3-chloropropyl)phenothiazine, 5-^-θ 0· (0-0?5 mole) of 4-(p£luoro!>enzoyl)piperidine and 10 g. of potassium carbonate in 100 ml of dry dimethylformamide was heated at 9θ-1θθ°Ι1· f°r 24 hours.
The cooled reaction mixture was filtered, the dimethylformamide removed at reduced pressure and the residue mixed with dry ether and th'· ether mixture filtered to remove solids. The dry ether solution was treated with ethereal hydrogen chloride to give the 2-bromo-l0-[3-( 4-(p-fluorobenzoyl)piperidinyl)propylIphenothiazine hydrochloride. - 14 44487 Effective quantities of any of the foregoing pharmacologically active compounds of the invention may be administered to a living animal body for therapeutic purposes according to usual modes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, tablets and capsules in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions.
For the parenteral administration the carrier or excipient may be a sterile, parenterally acceptable liquid; e.g. water or a parenterally acceptable oil; e.g. arachis oil contained in ampoules.
Although very small quantities of the compounds of the invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually from two milligrams or above, and preferably 5, 10, 25 milligrams or even higher such as up to 500 milligrams in certain instances, depending, of course upon the emergency of the situation and the particular result desired. Five to 25 milligrams appears optimum per unit dose. Daily dosages should preferably range from 4 to 100 mg. The active ingredients of the invention may be combined with other pharmacologically active agents as stated above. It is only necessary that the active ingredient constitute an effective amount; i.e. such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time.
Thus, according to another aspect of the invention a method for inducing tranquillization in a mammal (other 'than man) comprises administering to the mammal a transquillizing effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. The compound or salt may be administered together with a pharmaceutically acceptable carrier therefor, and usually in an amount in the range from 1 to 500 milligrams. - 15a — The following forma tations are representative for all of the pharmacologically afire compounds of this invention.
Formulations (l) Capsules Capsules of 2 -3·, 5 mg., 10 mg., and 25 mg. of active ingredient per capsule a c prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.
Typical blend for e icapsulation Per capsule, mg, jq Active ingredient, ;s salt 2 Lactose 259 Starch 126 Magnesium stearate 4 Total 391 5 mg. per Capau1« 10 mg. per Capsul0 25 mg. per Capsule Active ingredient, as salt 5 10 25 Lactose 250 240 225 Starch 126 126 126 20 Magnesium stearate 4 6 8 Τ'- eal 385 382 384 In each case, uniformly blend the selected active ingredient with lactose, starch, and magnesium stearate and encapsulate the blend. - 16 (2) A typical formulation for ci tablet containing 5-0 mg. of active ingredient par tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate.
Per Tablet, mg. 1. Active ingredient 5-0 2. Corn starch 15-0 3- Corn starch (paste) 12.0 4. Lactose 35-0 5- Dicalcium phosphate 132.0 6. Calcium stearate 2.0 Total 201.0 Uniformly blend 1, 2, 4 and 5· Prepare 3 as a 10 per cent paste in water. Granulate the blend with starch paste lr, and pass the wet mass through an eight mesh screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and compressed. (3) Injectable - 2^ sterile solution Per cc Active ingredient rag. 20 Preservative, e.g. chlorobutanol, wt./vol. percent 0<5 Water for injection g.s Prepare solution, clarify by filtration, fill into vials, seal and autoclave.

Claims (22)

1. CLAIMS:1. Compounds having the formula wherein: 4448-7 CQCr R represents hydrogen, chloro, bromo, trifluoromethyl, lower alkoxy, acetyl, sulphamoyl or dimethylsulphamoyl: R^represents hydrogen, chloro, bromo, fluoro, trifluoromethyl, lower alkoxy or lower alkyl; and n is 2, 3 or 4.
2. Compounds having the formula: jW o' wherein R is as defined in Claim 1.
3. Compornds having the formula: 15 wherein R is as defined in Claim 1,
4. 10-(3-^4-(g-Fluorobenzoyl)piperidinylDpropyl) phenothiazine. 18 4448?
5. 2-Chloro-10-(3-Q4-(g-fluorobenzoyl) piperidinylUpropyl)phenothiazine.
6. 2-Trifluoromethy1-10-(3-C4-(p-fluorobenzoyl) piperidinyljpropyl -phenothiazine. 5
7. 2-Acetyl-10-(3-Cp-fluorobenzoyl) piperidinylJpropyl)phenothiazine.
8. A process for the preparation of compounds as claimed in Claim 1 which comprises heating in an aprotic solvent at an elevated temperature and in the presence 10 of a strong inorganic base a 1 - (ω - haloalkyl) - 4 (2 or 3) - benzoylpiperidine of the formula: wherein R 1 and n are as defined in Claim 1 and X is chloro, bromo or iodo, with a phenothiazine of the formulas 01¼ 15 wherein R is as defined in Claim 1.
9. A process for the preparation of compounds having the formula: 19 4 4487;' 4 wherein R represents hydrogen, trifluoromethyl, acetyl or chloro, which comprises reacting a 1 - Q - halopropyl) - 4 - (£ _ fluorobenzoyi)piperidine having the formula: wherein X is halo, with a phenothiazine having the formula: FORMULA IIJ wherein R is as defined in Claim 1.
10. A process as claimed in Claim 8 or Claim 9 which 10 comprises converting the product compound into an acid addition salt thereof.
11. A process as claimed in Claim 8, substantially as described in any of the Examples.
12. A process as claimed in Claim 9, substantially 15 as described in any of Examples 1,3,4,6 or 7.
13. A process as claimed in Claim 10, substantially as described in any of Examples 1,4, 6 or 7.
14. Compounds as claimed in Claim 1 which have been prepared by a process as claimed in any of Claims 8,9, 11 or 40®? 12.
15. Acid addition salts of compounds as claimed in Claim 14 which have been prepared by a process as claimed in Claim 10 or Claim 13. 5
16. Pharmaceutically acceptable acid addition salts of compounds as claimed in any of Claims 1 to 7 or 14.
17. A pharmaceutical composition useful for its tranquillizing properties comprising a compound as claimed in any of Claims 1 to 7 or 14, or a pharmaceutically 10 acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.
18. A composition as claimed in Claim 17 in unit dosage form wherein the said compound or salt is present in an amount in the range from 5 to 500 milligrams. 15
19. A method for inducing tranquillization in a mammal (other than man) comprising administering to the mammal a tranquillizing effective amount of a compound as claimed in any of Claims 1 to 7 or 14, or a pharmaceutically acceptable acid addition salt thereof.
20. 20. A method as claimed in Claim 19 wherein the said compound or salt is administered together with a pharmaceutically acceptable carrier therefor.
21. A method as claimed in Claim 19 or Claim 20 wherein the said compound or salt is administered in an amount in the
22. 25 range from 1 to 500 milligrams.
IE1357/76A 1975-06-27 1976-06-22 10-(w-(benzoylpiperidinyl)alkyl)phenothiazines IE44487B1 (en)

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BR (1) BR7604100A (en)
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BE843281A (en) 1976-10-18
ZA763813B (en) 1977-05-25
BR7604100A (en) 1977-07-26
NZ181291A (en) 1978-06-20
DK146258B (en) 1983-08-15
AU503576B2 (en) 1979-09-13
IE44487L (en) 1976-12-27
AU1489076A (en) 1977-12-22
DK146258C (en) 1984-01-23

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