DK146258B - METHOD OF ANALOGUE FOR THE PREPARATION OF 10- (3- (4- (P-FLUOROBENZOYL) PIPERIDINYL) PROPYL) PHENOTHIAZINES OR ACID ADDITION SALTS THEREOF - Google Patents

Description

1 & (19) DENMARK \ fig /

f (, 2) SUBMISSION WRITING, 146258 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No. 274076 (51) Int.CI.3: C 07 D 417/06 '(22) Date of filing: 18 | un 1976 (41) Aim. available: 28 Dec 1976 (44) Submitted: 15 Aug 1983 (86) International Application No :-(30) Priority: 27] un 1975 US 591216 (71) Applicant: A.H. 'ROBINS COMPANY INCORPORATED; Richmond, US.

(72) Inventor: William John 'Welstead Jr.; US, Robert Frederick 'Boswell Jr., - US.

(74) Plenipotentiary: The engineering firm Budde, Schou & Co_ (54) Analogous process for the preparation of 10- (3- (4- (p-fluorobenzoyl) piperidinyl) propyl) phenothiazines or acid addition salts thereof

The present invention relates to an analogous process for the preparation of novel 10- [3- (4- (p-fluorobenzoyl) piperidinyl] propyl] phenothiazines of the general formula wherein R is hydrogen, trifluoromethyl, acetyl or chlorine, or acid addition salts thereof .

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From the specification of Danish Patent No. 91,121, certain substituted carbamoyl-piperidinoalkylphenthiazine compounds (e.g. 2-acetyl-10- (3-4'-carbamoyl-piperidine-propyl) -phenthiazine) are known to have a sedative, antiemetic and analgesic effect. effect. Further, from the specification of Danish Patent No. 124,551, certain substituted alkyloxycarbonyloxyethyl (piperazino or piperidino-propyl) phenothiazine compounds having a sedative, neuroleptic and antiemetic effect are known. Further, from German Publication No. 1,930,818 certain 1-substituted 3- or 4-aroylpiperidine compounds, e.g. 1- (3- (p-acetyl-O-methoxyphenoxy) propyl] - and 1- [3- (p-fluorobenzoyl) propyl] -4- (p-fluorobenzoyl) piperidine, with soothing effect.

The compounds in question have a sedative effect. The sedative effect of the compounds of this invention is demonstrated by their ability to block lethal effects of d-amphetamine in pooled mice by testing according to the modified method of Burn and Hobbs, Arch. Intern. Pharmaco-dynes. 113: 290 (1958). For example, when 2-chloro-10β- [4- (p-fluorobenzoyl) piperidinyl] propyl} phenothiazine is administered intraperitoneally to mice, the compound has an ED 2 value of 0.72 mg / kg after 16 hours, indicating , that the compound has effective and long-lasting sedative effect. The ED₂ value of the aforementioned compound as well as other of the compounds of the invention are set forth in Table I.

Table I

The effects of different pre-treatment time intervals on the d-amphetamine lethality in mice

Protective EDgQ (95% confidence limits) mg / kg i.p.

1 hour 4 hours 8 hours 16 hours 4 0.17 (0.1-14) 0.53 (0.2-1.1) 0.19 (0.1-0.5) 0.72 (0.4 -1.3) 3 0.14 (0.06-0.3) 0.10 (0.05-0.22) 0.06 (0.03-0.13) 0.76 (0.6- 1.1) 1 0.94 (0.4-1.9) 0.35 (0.1-1.2) 0.27 (0.7-2.1) 12.1 (8-18) 2 1.44 (0.6-3.3) 3.5 (1.1-10.8) 1.4 (0.8-2.2) 1.89 (1.2-2.8)

The acute toxicity (LD50 value) of the compounds of Examples 1, 2, 3 and 4 is determined in mice. The values are given in Table II below.

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Table II

72 hours LD5Q value in mice pjVg # * LD50 confidence limits) mg / kg i.p.

4 248 (211-290) 3 287 (227-361) 1 330 (268-405) 2 317 (251-399)

The present compounds can be used in the form of acid addition salts which have better water solubility than the free bases. Suitable acid addition salts are derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric and organic acids such as acetic, citric, lactic, maleic, oxalic, fumaric and tartaric. The preferred acid addition salts are the hydrochlorides, maleates and fumarates. The acid addition salts are prepared by reacting the base compounds with the acid in question, one or both of the reactants being used in the form of a solution in ether, alcohol or acetone.

The compounds used to prepare the subject compounds are phenothiazine or 2-substituted commercially available or which can be prepared in known manner, and 1- (3-chloropropyl) -4- (4-fluorobenzoyl) piperidine. This compound is prepared by reacting 4- (p-fluorobenzoyl) piperidine with 3-chloropropanol in a lower alkanol solvent such as n-butanol with an acid acceptor to form 1- (3-hydroxypropyl) -4- (p-fluorobenzoyl) piperidine which, upon reaction with a reagent such as thionyl chloride, gives 1- (3-chloropropyl) -4- (p-fluorobenzoyl) piperidine.

4- (p-Fluorobenzoyl) piperidine can be prepared by the method described in DSA Patent No. 3,576,810.

The process according to the invention is characterized in that 1- (3-halogenopropyl) -4- (p-fluorobenzoyl) piperidine of formula 4

CH2CH2CH2X

wherein X represents halogen is reacted with a phenothiazine of the formula

H

wherein R is as defined above, or a metal salt thereof. The reaction is preferably carried out in the presence of a suitable solvent, e.g. benzene, toluene or xylene, as well as in the presence of an acid acceptor such as a strong inorganic base. The reaction is preferably carried out at elevated temperature, e.g. at the reflux temperature. In one embodiment of this process, the phenothiazine is metallized in a suitable solvent such as benzene, toluene or dimethylformamide using a conventional metallizing agent, e.g. sodium hydride or n-butyllithium at elevated temperature, e.g. 80-110 ° C and 1- (3-halogenopropyl) -4- (p-fluorobenzoyl) piperidine is reacted with the metallized phenothiazine.

The compounds prepared as above are isolated from the reaction mixture in a suitable manner, e.g. by distillation, chromatography, crystallization or by conversion to a suitable acid addition salt.

The process of the invention is further illustrated in the following Examples, in which Example A illustrates the preparation of an starting compound of formula (II) used in the following Examples 1-4.

Example A

4- (p-fluorobenzoyl) -1- (3-hydroxypropyl) piperidine

A mixture of 24.3 g (0.1 mole) of 4- (p-fluorobenzoyl) piperidine hydrochloride, 12.5 g (0.125 mole) of 3-chloropropanol and 42.0 g (0.5 mole) of sodium bicarbonate in 500 ml of n-butanol is stirred at reflux for 15 hours. Using thin layer chromatography, incomplete reaction is detected and an additional 3.0 g (0.025 mol) of 3-chloropropanol is added, and the reaction is continued for 3 hours. The reaction mixture is cooled and filtered, the filtrate is concentrated at reduced pressure and the residual oil is crystallized by trituration in isopropyl ether. 23 g (87%) of yellow-brown solid are obtained. 107-109 ° C.

2) 4- (p-Fluorobenzoyl) -1- (3-chloropropyl) piperidine 38.7 g (CV376 mol) of thionyl chloride is added dropwise to a stirred solution of 43.1 g (0.163 mol) of 4- (p-fluorobenzoyl) - 1- (3-hydroxypropyl) -piperidine in 400 ml of chloroform at room temperature. After the addition is complete, the reaction mixture is stirred at room temperature for an additional 16 hours. Then the mixture is cooled and 125 ml of 6 N sodium hydroxide solution are added dropwise. The chloroform solution is isolated, washed with water and dried over magnesium sulfate. Removal of the solvent gives 42.7 g of crude product (92% yield) which crystallizes on cooling. Recrystallization from isooctane gives 25.3 g of pure substance, m.p. 66.5 to 68.5 ° C.

Analysis for C ^H ^ gNOFCl: C% H% N%

Calculated 63.49 6.75 4.94

Found 63.49 6.86 4.81

Example 1 10- [3- [4- (p-Fluorobenzoyl) piperidinyl] propyl} phenothiazine fumarate hydrate -_ (1: 4)

A mixture of 4.9 g (0.025 mole) of phenothiazine, 7.5 g (0.0265 mole) of 1- (3-chloropropyl) -4- (p-fluorobenzoyl) piperidine and 8.4 g (0.15 mole) crushed potassium hydroxide beads are stirred in 200 ml of dry toluene under reflux for 20 hours. The cooled reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residual oil is subjected to thin layer chromatography and proves to be a mixture of the product and the reactants. Partial purification is achieved by dissolving the oil in ether and then adding ethereal hydrochloric acid to form the hydrochloride salt. However, the salt does not crystallize and is converted to the free base. The free base (4.5 g, 40.5% yield) is treated with 1 equivalent of fumaric acid to form the fumarate salt. Recrystallization of a mixture of methanol and isopropyl ether gives 4.7 g of a tan solid with m.p. 190-192 ° C.

Analysis for C29H39N20FS.C4H404.l / 4H2O: C% H% N%

Calculated 65.65 5.60 4.94

Found 65.82 5.60 4.93 6 146258

Example 2 2-Trifluoromethyl-10- {3- [4- (p-fluorobenzoyl) piperidinyl] propyl} phenothiazine fumarate

A mixture of 8.6 g (0.032 mole) of 2-trifluoromethylphenothiazine, 10.0 g (0.035 mole) of 1- (3-chloropropyl) -4- (p-fluorobenzoyl) piperidine and 11.2 g (0.2 mole) crushed potassium hydroxide beads are stirred in 300 ml of dry toluene under reflux for 20 hours. The cooled reaction mixture is filtered, the filtrate washed with water, dried over magnesium sulfate and concentrated to give 14.2 g of crude product (88% yield). The crude product is treated by excess fumaric acid in a mixture of methanol and isopropyl ether to give 20.5 g of the fumarate salt. Recrystallization of a mixture of isopropanol and isopropyl ether gives 12.2 g of fumarate salt with m.p. 158.5 to 161 ° C.

Analysis for C32H30N2®5SF4: C% H% N%

Calculated 60.94 4.80 4.44

Found 60.77 4.88 4.37

Example 3 2-Acetyl-10- [3- (4-p-fluorobenzoylpiperidinyl) propyl] phenothiazine difuma-rate sesquihydrate

A mixture of 7.7 g (0.032 mol) of 2-acetylphenothiazine, 10.0 g (0.0353 mol) of 1- (3-chloropropyl) -4- (p-fluorobenzoyl) piperidine and 14.0 g (0.25 mole) crushed potassium hydroxide beads are stirred in 300 ml of dry toluene under reflux for 24 hours. Thin layer chromatography shows incomplete reaction. To the reaction mixture is added an additional 10.0 g (0.0353 mol) of 1- (3-chloropropyl) -4- (p-fluorobenzoyl) piperidine in 75 ml of dry toluene and refluxed for a further 24 hours. The cooled reaction mixture is washed with water, dried over magnesium sulfate and concentrated to give 23.2 g of crude product. Chromatography on 400 g of magnesium silicate gives 6 g of crude product. The impurities are removed by molecular distillation to give the product as residue. The residue weighs 4.0 g (24.5% yield). The free base is treated with two equivalents of fumaric acid in methanol. The methanol is evaporated and the solid residue is recrystallized from a mixture of acetone and petroleum ether (30-60 ° C), m.p. 146-149 ° C.

Analysis for C ^H ^O ^S ^S C% H% N%

Calculated 59.43 5.39 3.75

Found 59.57 5.06 3.39 7 1Λ6258

Example 4 2-Chloro-10β - [4- (p-fluorobenzoyl) piperidinyl] propyl} phenothiazine hydrochloride hydrate (1: 4)

A mixture of 9.4 g (0.04 mole) of 2-chlorophenothiazine, 12.0 g (0.0425 mole) of 4- (p-fluorobenzoyl) -1- (3-chloropropyl) -piperidine and 14.0 g ( 0.25 mol) crushed potassium hydroxide beads in 300 ml of dry toluene are stirred and refluxed for 36 hours. After cooling, the toluene solution is isolated from the inorganic material by decantation and the toluene solution is concentrated to give 17.5 g of crude product. This is chromatographed on a column of 260 g of magnesium silicate to give 12.0 g of reasonably pure product (63% yield). Molecular distillation at 250 ° C gives 6.7 g of a yellow glassy substance. The oil is dissolved in ether and treated with ethereal hydrochloric acid to give a hygroscopic hydrochloride salt. The salt is triturated in boiling isopropyl ether and recrystallized from a mixture of isopropyl ether and chloroform. NMR and mass spectral analysis shows that the salt is solvated and dried at 120 ° C in a vacuum oven. The salt with m.p. 204-206 ° C is analyzed as the 1/4 hydrate.

Analysis for C27H28N2OFC12S · 1/4 1 0: C% H% N%

Calculated 62.13 5.31 5.37

Found 62.04 5.23 5.40