NO131172B - - Google Patents

Description

Analogy method in the production of

therapeutically active piperidine or tetra-hydropyridine derivatives.

The present invention relates to an analogous process for the production of new heterocyclic compounds, more specifically 1-carbamoyl-4-(m-trifluoromethylphenyl)-piperidines and 1-carbamoyl-4-(m-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines, which is covered by the following structural formula:

where

R"'' is hydrogen, lower alkyl with 1-4 carbon atoms, phenyl or halophenyl1,

m is 0 or 1, and when m is 0, the dashed line means a double bond.

These ...compounds are produced by a compound of the general formula

where m has the meaning as stated above, is reacted with R 2NCO where

2 1

R has the same meaning as R. except hydrogen and for the preparation of compounds of the general formula I, where R means hydrogen, the compound of the general formula II is reacted with H^NCONHNO,, (nitrourea).

1-carbamoyl-4-phenylpiperidines have been previously described. It has been shown by those skilled in the art that 1-carbamoyl-4-phenylpiperidine [R.T. Brittain et al., J. Pharm. Pharmac. 20, 456

(1963)] exhibit excellent antitussive properties but had none

effect as an anticonvulsant against convulsions caused by pentylenetetrazol, and showed only a weak anticonvulsant effect against convulsions caused by maximal electroshocks. It has now been found that if the phenyl ring in 1-carbamoyl-4-phenylpiperidines contains a trifluoromethyl group in the meta position, the compounds produced are particularly useful as anticonvulsants, providing excellent protection against convulsions caused by maximal electric shocks as well as a significant protection against convulsions induced by pentylenetetrazol. When mice were induced to convulse using the supramaximal electroshock technique of Toman, J.E.P. et al., J. Neurophysiol. 9, 47

(1946), anticonvulsant protection was obtained when the compounds were given intraperitoneally at doses of 10-200 mg/kg, preferably at a dose of 10-100 mg/kg. The compounds also provided significant protection against convulsions in mice caused by pentylenetetrazol when the compounds were administered intraperitoneally at doses of 2.5 - 200 mg/kg, preferably at doses of 40 - 80 mg/kg. The investigation method used was according to Swinyard et al., J. Pharm. Exptl. Therapy. 100, 319 (1952).

Pharmacological data for the preferred compounds of the present invention are shown below in Table I. The ED..Q values were determined using the method of Litchfield and Wilcoxin, J. Pharm. Exptl. Therap., 96, 99 (1949).

Although the main effect of the new compounds is anticonvulsant activity, some of the compounds have also shown muscle relaxant properties. The preferred compounds according to the present invention which exhibit both of the aforementioned pharmacological activities are those indicated in Examples 1, 2 and 4. The muscle relaxant properties were demonstrated in cats using the "flexor-reflex" technique according to Carroll, M N et al., Arch. Int. Pharmacodyry. CXXX, Nos. 3-4, 280 (1961). when the compounds were given intravenously at doses of 5-100 mg/kg, preferably at doses of 5-50 mg/kg.

It is therefore an aim of the present invention to provide a method for preparing new 1-carbamoyl-4-m-trifluoromethylphenylpiperidines and 1-carbamoyl-4-m-trifluoromethylphenyl-1,2,3,6-tetrahydropyridines which are useful as anticonvulsants and musk lichen patching agents.

In the definition of the symbols in formula I and where they otherwise appear in the description or in the claims, the terms used have the following meaning: "lower-alkyl" includes radicals with straight and branched chains of up to 4 carbon atoms, such as e.g. following groups: methyl, ethyl, propyl, butyl, isopropyl and isobutyl.

The new compounds according to the present invention are produced by a process which is shown in the following reaction scheme:

where R and m have the meaning as previously defined.

The exchange reaction is usually carried out at or above room temperature in a dry, non-reactive solvent such as e.g. benzene, toluene, xylene, ethanol, chloroform etc. If nitrourea is one of the reactants, the reaction is preferably carried out at reflux temperature. The new compounds of formula I are isolated from the reaction mixture by filtration and evaporation of the solvent. The residue, which is usually a solid, is purified by recrystallization from a suitable solvent.

The starting materials of formula II can be prepared by the following reaction sequence:

where X is halogen. It must be understood that the compounds of formulas II-a and IL-b are examples that are not included in the general formula II.

The starting materials of formula II are prepared from 1-benzyl-4-piperidione (III).

One. ether solution of 1-benzyl-4-piperidine is added to a stirred ether solution of m-trifluoromethylphenylmagnesium bromide, and 1-benzyl-4-(m-trifluoromethylphenyl)-4-piperidinol (IV) is obtained there. Hydrogenolysis of IV in a suitable solvent such as e.g. lower alkanol at a temperature of 20 - 80°C, with hydrogen under a pressure of 2-3 atm. in the presence of a noble metal catalyst, preferably palladium-on-charcoal gives 4-(m-trifluoromethylphenyl)-4-piperidinol (V). The piperidinol V formed is carefully refluxed, preferably in a dilute inorganic acid, for a period of 3-24 hours. The thereby formed 4-(m-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine (II-b) is filtered from the reaction mixture after it has been made alkaline by using a suitable solvent, e.g. chloroform. The solvent is evaporated, and the impure product is purified by distillation. Catalytic reduction of 4-(-m-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (II-b) gives 4-(m-trifluoromethylphenyl)piperidine (II-a). As shown in the reaction scheme above, 4-(m_trifluoromethylphenyl)piperidine (II-a) can be prepared directly from IV if the hydrogenolysis is carried out in an acidic environment.

Forward ti 1li ng of the intermediate product

Forward tilling I

4-( m -trifluoromethylphenyl)- 1, 2, 3, 6- tetrahydropyridine hydrochloride

A solution of 15 g (0.0535 mol) of 4-(m-trifluoromethylphenyl)-4-piperidinol hydrochloride in 75 ml of 6N hydrochloric acid was refluxed for 3 hours, the solution cooled and neutralized with 3N sodium hydroxide and then extracted several times down chloroform. The combined extracts were dried and concentrated to an oil (13.4 g). The resulting free base was converted to the hydrochloride salt, which was recrystallized from isopropanol, and 11.8 g of the hydrochloride salt (84% yield) with a melting point of 204 - 206°C were obtained. An analytical sample recrystallized from isopropanol melted at 205 - 207°C.

Analysis: calculated for C, „H-, 0C1F.-,N: C 54.65: H 4.97: N '5.31

found : C 54.37; H 5.04; N 5.60

Forward position II

4-(m-trifluoromethylphenyl)piperidine

A mixture of 17.7 g (0.78 mol) 4-(m-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 250 ml of 95% ethanol containing 10 g of palladium-on-charcoal catalyst was shaken with hydrogen at 3 atm. at 70°C until 1 equivalent of hydrogen was absorbed. The cooled suspension was filtered and concentrated. The remaining oil was distilled under reduced pressure, and the fraction boiling at 60-63°C/ 0.07 mmHg was collected; the oil weighed 15.2 g (86% yield).

Example 1

1-carbamoyl-4-(m-trifluoromethylphenyl)piperidine

A mixture of 5.0 g (0.022 mol) 4-(m-trifluoromethylphenyl)-piperidine, 2.6 g (0.025 mol) nitrourea and 100 ml 95% ethanol was heated to 55-65°C until gas evolution ceased. The reaction mixture was then refluxed for 15 minutes, filtered and concentrated. The crude crystalline residue was recrystallized from ethyl acetate to give 3.1 g (53% yield) of a white crystalline material, m.p. 131.5 - 133°C.

Analysis: calculated for c13H15N2OF3: c 57>35> H 5>555 N 10.29

found : C 57.43; H 5.53; N 10,19

Example 2

1-ethylcarbamoyl-4-(m-trifluoromethylphenyl)piperidine

To a stirred solution of 3.0 g (0.013 mol) 4-(m-trifluoromethylphenyl)piperidine in 100 ml dry benzene was slowly added a solution of 1.1 g (0.015 mol) ethyl isocyanate in 25 ml dry benzene . After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature, after which the solvent was evaporated. The residual oil which crystallized by trituration with isooctane was recrystallized from a mixture of isooctane and isopropyl ether to give 3.3 g (77% yield) of a product melting at 96-95°C.

Analysis: calculated for <c>15H19<N>2<O>F3: C 59.99; H 6.38; N 9.33

found : C 60.18; H 6.42; N 9.33

Example 3

1-phenylearbamoyl-4-(m-trifluoromethylphenyl)piperidine

To a stirred solution of 2.0 g (0.009 mol) 4-(m-trifluoromethylphenyl) piperidine in 100 ml dry benzene was slowly added a solution of 1.1 g (0.009 mol) phenyl isocyanate in 25 ml dry benzene. After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature, after which the solvent was evaporated. The residual oil which crystallized on standing was recrystallized from a mixture of isopropyl ether and benzene to give 1.9 g (61% yield) of white crystals; sm.p. 129 - 131°C.

Analysis: calculated for C19<H>19<F>>3<N>2<0:> C 65>51' H 5>505 N 8'°4

found : C 65.72; H 5.50; N 8.06

Example 4

1-(m-chlorophenyl)-4-(m-trifluoromethylphenyl)piperidine

To a stirred solution of 2.0 g (0.009 mol) of 4-(m-trifluoromethylphenyl)piperidine in 100 ml of dry benzene was slowly added a solution of 1.5 g (0.010 mol) of m-chlorophenyl isocyanate. After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature, after which the solvent was evaporated. The remaining oil which recrystallized on cooling was recrystallized from a mixture of isopropyl ether and benzene. The obtained white crystals weighed 2.5 g (75% yield); sm.p. 156 - 157.5°C.

Analysis: calculated for H18C1F3N20: C 59.61; H 4.74; N 7.32

found : C 59.46; H 4.72; N 7.15

Example 5

l- carbamoyl- 4-( m- trifluoromethylphenyl)- l, 2, 3, 6- tetrahydropyridine

A mixture of 5.0 g (0.022 mol) 4-(m-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 2.4 g (0.022 mol) nitrourea and 50 ml 95% ethanol was heated to 55 - 60°C until gas evolution ceases. The mixture was refluxed for 15 minutes, filtered, and the solvent evaporated. The residual oil which crystallized on standing was recrystallized from ethyl acetate to give 2.2 g (37% yield) of white crystals; sm.p. 145 - 147°C.

Analysis: calculated for c13H13<N>2OF3: C 57>77; H 4.85; N 10.37

found : C 57.71; H 4.79; N 10.29

Example 6

1- phenylcarbamoyl- 4-( m- trifluoromethylphenyl)- 1, 2, 3, 6- tetrahydropyridine

To a stirred solution of 3.0 g (0.015 mol) 4-(m-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine in 100 ml dry benzene was slowly added a solution of 1.8 g (0.015 mol) phenyl isocyanate in 25 ml of dry benzene. After the addition was complete, the mixture was stirred for 1 hour at room temperature, after which the solvent was evaporated. The remaining oil which crystallized by trituration with isopropyl ether was recrystallized from a mixture of isopropyl ether and benzene. The obtained white crystals weighed 3.9; sm.p.

113 - 114°C.

Analysis: calculated for ClgH17N2OF3: C 65.89; H 4.95; N 8.09

found : C 66.12; H 4.93; N 8.06

The useful new compounds according to the invention, especially 1-carbamoyl-4-(m-trifluoromethylphenyl)piperidine, can be administered orally, parenterally or injected, and where the amount of the active ingredient per unit dose is 5 - 50 mg.

Claims (4)

1. Analogy method for the preparation of a therapeutically active compound of the general formula: where: R"*" is hydrogen, lower alkyl with 1 - h carbon atoms, phenyl or halo-phenyl, m is 0 or 1, and when m is 0, the dashed line represents one double bond, characterized in that a compound of the general formula 20 where tn has the meaning as indicated above, is reacted with R NCO where R has the same meaning as R<1> except hydrogen. and for the preparation of compounds of the general formula I where R1 means hydrogen , the compound of the general formula II is reacted with H„N OOiMH.NO (nitrourea). 2. Analogous process according to claim 1 for the production of 1-carbamoyl-4-(m-trifluoromethylphenyl)piperidine, characterized in that 4-[m-trifluoromethylphenyl)piperidine is reacted with nitrourea. 3. An analogous process according to claim 1 in the preparation of 1-ethylcarbamoyl-4-(m-trifluoromethylphenyl)piperidine, characterized in that 4-(vn-trifluoromethylphenyl)piperidine is reacted with e thy lisocyana t. 4. Analogous method according to claim 1 in the production of 1-(m-chlorophenylcarbamoyl)-4-(m-1rifluoromethylphenyl)piperidine, characterized in that 4-(m-trifluoromethylphenyl)piperidine is reacted with chlorophenyl isocyanate.