CS209847B2 - Method of making the derivatives of the benzamid containing the pyrrlidine or piperidine nucleus - Google Patents

Description

The invention relates to a process for the preparation of benzamide derivatives containing a pyrrolidine or piperidine core of the formula I

(0 where

R1 represents a perfluoroalkyl radical having 1 to 3 carbon atoms, n represents 1 to 3, p represents 1 or 2,

Q represents a carbon-nitrogen bond, a methylene group or a methylmethylene group and each of the substituents

R and R‘ are hydrogen, methyl or ethyl, as well as pharmaceutically acceptable salts thereof.

A perfluoroalkyl radical indicating a group

Rt has the formula

CmFm + 1, where m is 1 to 3.

The methylene group is represented by the formula —CH2 — and the methylmethylene group is represented by the formula —CH (CH3) -.

The invention also provides pharmaceutical compositions comprising the above compounds and novel intermediates useful in the process of the invention. The compounds obtainable by the process of the invention and their pharmaceutically acceptable salts are effective against cardiac arrhythmias. The invention also provides processes for preparing some of the novel intermediates.

U.S. Pat. No. 3,719,687 discloses certain benzoic acid amides substituted on the aromatic ring with 1,1-dihydroperfluoroalkoxy substituents. The novel compounds prepared by the process of the invention differ structurally from those described in the above-mentioned US patent in that:

1. the benzamide nitrogen atom is bonded to the carbon atom of the pyrrolidine or piperidine ring via a methylene group or a direct nitrogen-carbon bond;

2. These compounds may be either secondary or tertiary amines; and

3. In the compounds obtained by the process of the invention, the benzamide nitrogen atom is bonded to the pyrrolidine. or a piperidine ring via only one (carbon atom or directly without carbon atom).

The compounds obtainable by the process of the invention preferably have and in most cases an asymmetric carbon atom.

Preferred compounds obtained by the process of the invention are those compounds of formula I wherein Q is 1. a nitrogen-carbon bond pointing to the 3-position of the pyrrolidine or piperidine ring, or. .2. a methylene or methylmethylene linking group bonded to the 2-position of the pyrrolidine or piperidine ring. These compounds are advantageous because they generally have a greater antiarrhythmic effect, as found in animal experiments. Some of them have also been found to exhibit lower side effects compared to known respective compounds. Also, some salts of these free bases have lower side effects.

Also preferred are compounds of formula I obtainable by the process of the invention wherein n is 2, R _f is trifluoromethyl and the dihydroperfluoroethoxy groups are attached at the positions

2. and 3.

The compounds obtainable by the process according to the invention and which have at least one asymmetric carbon, i.e. the carbon atom of the pyrrolidine or piperidine ring to which the group Q is bonded, can be separated into the optically active enantiomers (antipodes) by known methods. In addition, other asymmetric centers are possible, for example when Q represents an alkylmethylene group or R R represents a methyl or ethyl group. All such optically active isomers are within the scope of the invention.

The compounds obtained by the process according to the invention can be used directly or in the form of pharmaceutically acceptable acid addition salts, in particular as soluble salts of acetic, hydrochloric, sulfuric or phosphoric acids, other such salts include combinations with hydrobromic, sulphonic acid, ; methanesulfonic, benzenesulfonic, vamdisulfophic, lemon, maleic, oxalic, amber, cider, fumaric and tartaric. Pharmaceutically acceptable quaternary ammonium salts can also be used, for example alkyl iodide and bromide salts.

The anti-arrhythmic activity of these compounds is demonstrated by their ability to block chloroform-induced ventricular fibrillation in mice, as demonstrated by the test described in detail by J. W. Lawson in J. Pharmacol. Exp. Therap. 160, 22-31, 1968.

Preferred compounds which can be obtained by the process according to the invention and which have a high antiarrhythmic activity are the benzamide compounds, bases corresponding to the hydride salts of Examples 1, 2 and 6, respectively, of the compound ¹ compounds. from example 7,

19, 20 and 2.1 as pharmacologically. suitable salts of the seven compounds.

In clinical practice, the compounds which can be obtained by the method of the invention are usually administered as antiarrhythmic agents orally or by injection in the form of pharmaceutical preparations containing the active ingredient as the free base or as a conventional therapeutically acceptable salt, for example. acetate or; hydrochloride in association with a pharmaceutically acceptable carrier. The carrier can be a solid, a pasty substance or a solid. liquid or digestible capsule.

For parenteral use by injection, the preparations preferably contain an aqueous, usually saline, solution of a water-soluble, pharmaceutically acceptable salt of the active ingredient and optionally also a stabilizer and / or buffer, for example sodium acetate.

In addition, some of the compounds obtainable by the process of the invention; characterized by a local anesthetic effect, for example by local or injection injection. • Local anesthetic effectiveness is tested by a reflex test on the cornea of rabbits as test animals. This experimental method is described by F. P. Luduena. and J.O. epeppern v. J. Pharmacol. Exp. Therap., 104, 40

1952.

The compounds of the invention may be prepared by reduction of a compound of the general formula

IIIA

(III A) where

Q, p, R and R R are as defined above, with hydrogen in the presence of a catalyst and the resulting compound of formula III

where

Q, p, R a ^; R &apos; have the above-mentioned height, reacted with a compound of formula II <5

(ID where

Z is chlorine or 1,1-dihydroperfluoroalkoxy having 1 to 4 carbon atoms;

Rf- and n are as defined above.

The reaction is carried out in an inert solvent such as benzene, monomethylglyoxime, toluene or diethyl ether. Preferably R is not hydrogen. When Z is halogen, po; an acid acceptor, for example a tertiary amine, is usually used. When Z is 1,1-dihydroperfluoroalkoxy, the reaction is usually carried out by heating the reactants under reflux without a solvent or with an inert solvent such as mo. nomethylglyoxime, followed by isolation of the intermediate.

A preferred catalyst for catalytic hydrogen reduction is platinum oxide. The reduction is usually carried out under acidic conditions, for example in acetic acid as solvent in the presence of hydrogen chloride.

The compounds of the formula II can advantageously be prepared from the corresponding acids (i.e., the compounds of the formula II in which Z is OH), which acids are known (for example from U.S. Pat. No. 3,655,728). Compounds of formula II in which Z is halogen, for example chlorine, can be prepared by refluxing the corresponding acids with an excess of a thionyl halide, for example thionyl chloride, in the presence of a small amount of dimethylformamide. The excess thionyl halide is then removed by distillation.

Compounds of formula II wherein Z is 1,1-dihydroperfluoroalkoxy are described in U.S. Pat.

655,728, and the reaction of hydroxy and polyhydroxy aromatic acids with alkylating agents of formula V can be obtained

UF, SO OCll R · (V) where

R _f is as defined above, in the presence of bicarbonate; sodium, potassium bicarbonate: or other metal bicarbonate in. an inert solvent such as acetone. The resulting 1,1-dihydroperfluoroalkoxy-substituted aromatic ester can then be hydrolyzed to the free acid (a compound of formula II wherein Z is hydroxyl).

Compounds of Formulas III. a.IIIA are known or can be conveniently prepared by known methods. It is expedient to start from the corresponding oximes, which are prepared from the corresponding aldehydes by reaction with hydroxylamine hydride.

In the examples below, all temperature data are expressed in degrees Celsius.

He did

A mixture of 3.9 g (0.01 mol) of 2,5-bis (2,2,2-trifluoroethoxy) -4- (3-pyridyl) benzamide, 8.4 N hydrogen chloride in 2.4 ml (0.02 mol) of isopropyl alcohol 0.2 g of platinum oxide and 100 ml of acetic acid are shaken in a Parr hydrogenator at about 25 DEG C. for 4 hours, then the mixture is filtered and the filtrate is concentrated by evaporation under reduced pressure. ethanol and isopropyl alcohol to give 2,5-bis (2,2,2-trifluoroethoxy) -N- (3-piperidyl) benzamide hydrochloride as white needles, m.p. 224-225 ° C.

The compounds of Examples 2 to 7 in Table 1 were prepared according to the procedure described in Example 1.

TABLE 1

Example number Compound Melting point 2 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide hydrochloride 228 to 229 3 3/4 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidyl) benzamide hydrochloride hydrate glassy product with acceptable analysis 4 2,5-bis (2,2,2-trifluoroethoxy) -N- (3-piperidylmethyl) benzanide hydrochloride 189-191.5 5 2,5-bis (2,2,2-trifluoroethoxy) -N- (4-piperidyl) benzamide hydrochloride 193.5 to 195 6 2,5-bis (2,2,2-trifluoroethoxy) -N- [(6-methyl-2-piperidyl) methyl] benzamide hydrochloride 215 to 222 7 2,5-bis (2,2,2-trifluoroethoxy) -N- [1- (2-piperidinyl) ethyl] benzamide 95 to 97.5

Example 8

In a nitrogen atmosphere, 10 g (0.0249 mol) of 2,2,2-trifluoroethyl- [2,5-bis (2,2,6-bis (2,2,6-bis (2,2,6-bis (2,2,6-dihydro-propyl) -benzyl] -piperidine)] was added dropwise over 25 minutes to 28.4 g (0.249 mol). 2-Trifluoroethoxy) benzoate]. After 3 hours, 50 ml of benzene are added and the mixture is stirred at 45 ^DEG C. for 40 hours. The mixture was then evaporated under reduced pressure. After cooling, the residue solidified, distilled with steam, separated by filtration and extracted with dichloromethane, washed with saturated sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. The magnesium sulphate was filtered off and 8.4 ml of hydrogen chloride in 4 ml of isopropanol was added with stirring to the dichloromethane solution. After 2 hours the mixture was cooled to about 0 ° C and the crude product was collected by filtration, washed with diethyl ether and dried in a vacuum oven. After decolourisation with activated carbon and recrystallization from a mixture of equal volumes of isopropyl alcohol and methanol, 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide hydrochloride is obtained as a product, m.p. 228 DEG-229 DEG. C.

Example 9

The procedure is as in Example 8 except that monomethylglyoxime is used instead of benzene and the amine is added to the ester; the resulting product is the hydrochloride

179 DEG-180 DEG C. 2,5-bis (2,2,2-trifluoroethoxy) -N- (4-piperidylmethyl) benzamide.

Using the procedure of Example 1 or 8, the compounds of Examples 10 to 17 are shown in Table 2.

TABLE 2

Example number Compound

3- (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide hydrochloride 3,4-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide hydrochloride 2,4 , 6-tri (2,2,2-trifluoroethoxy)

N- (2-piperidylmethyl) benzamide 2- (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide hydrochloride 3,5-bis (2,2,2-trifluoroethoxy) -N - (2-piperidylmethyl) benzamide hydrochloride 2,4-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl} benzamide 2,3-bis (2,2,2-trifluoroethoxy) -N - (2-piperidylmethyl) benzamide 2,6-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide hydrochloride

Melting point

107.5 to 109

157.5 to 159.5

264-265

196 to 197.5

202 to 204

271 to 272

199 to 201

266-268

Example 18

Using 2,2,2-trifluoroethyl [2,5-bis (2,2,2-trifluoroethoxy) benzoate] and 2- (1-aminoethyl) piperidine as starting materials, the product was obtained as in Example 8, yielding 2.5 bis (2,2,2-trifluoroethoxy) -N-piperidyl) ethylbenzamide as white needles, m.p. 95-97 ° C.

Example 19

2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide was reacted according to the Eschweiler-Clark reaction to give 2,5-bis (2,2,2-trifluoroethoxy) N - [(1-methyl-2-piperidyl) methyl] benzamide as a white solid, m.p. 99-102 ° C.

Example 20

Following the procedure of Example 8, the aminomethylpyrrolidine was reacted with 1-ethyl-2-aminomethylpiperidine to react with 2,2,2-trifluoroethyl [2,5-bis (2,2,2-trifluoroethoxy) benzoate]. in monomethylglyoxime to give the free base, 2,5-bis' (2,2,2-trifluoroethoxy) -N - [(1-ethyl-2-piperldyl) methyl] benzamide, as cream-white needles, m.p. Mp 95-97 ° C.

Example 21

Following the procedure of Example 8, 1-ethyl-2-aminomethylpyrrolidine was reacted with 2,2,2-trifluoroethyl [2,5-bis (2,2,2-trifluoroethoxy) benzoate] to give 2,5-bis (2 2,2-trifluoroethoxy) -N - [(1-ethyl-2-pyrrolidinyl) methyl] benzamide as a white solid, m.p. 78-80 ° C.

Example 22

2.07 g (0.005 mol) of 2,5-bis (2,2,2-trifluoroethoxy) -N1 (2-piperidylmethyl) benzamide are dissolved in 10 ml of isopropyl alcohol and a solution of 1 equivalent of acetic acid in 1 ml of isopropyl- Cooling gave a solid which was collected by filtration, and the product was recrystallized from isopropanol to give the acetate salt, m.p. 145-147 ° C.

A series of pharmaceutically acceptable salts of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide, as set forth in Table 3, were prepared as described in Example 22.

TABLE 3

Example number Acid

Solubility Melting point (° C) in hot water

‘23 24 25 HzSOl HsPOd CH = CH 26 HOOC COOH CH3SO3H 27 Mar: HCOOH 28 29 COOH CH ₃ (CH 2) 14 COOH 30 CH3CH2COOH 31 CH2CH2COOH COOH

> 2% 100 ALIGN! > 5% 210 > 5% 122 to 124 > 10% 115 to 121 > 10% 171 to 172 insoluble - insoluble _ > 10% -. > 5% -

Example 32

In a sealed tube, a mixture of 2.7 g (0.0063 mol) of finely powdered 2,5-bis (2,2,2-trifluoroethoxy) -N - [(1 - methyl-2-piperidyl) methylbenzamide and 6 ml of methyl iodide. The mixture was then extracted with methanol. The methanolic extracts are concentrated to give a crystalline solid which is recrystallized from 50 ml of ethyl acetate and about 2 ml of isopropanol after decolourisation with activated carbon. The resulting product is dried. There was thus obtained 2- (2,5-bis (2,2,2-trifluoroethoxy) benzamidomethyl] -1,1-dimethylpiperidinium iodide in the form of a residue.

Claims (1)

m.p. 172.5 ° C. Example 33 Using the procedure of Example 32, 2,5-bis (2,2,2-trifluoroethoxy) -N - [(1-ethyl-2-piperidyl) methyl] benzamide was treated with methyl iodide to give 2- [2, 5-bis (2,2,2-trifluoroethoxy) benzamidomethyl] -1-ethyl-L-methylpiperidiniumjodid as a white solid, mp 162-165 C. ^Q OF THE INVENTION CLAIMS 1. A process for the preparation of benzamide derivatives containing a pyrrolidine or piperidine core of formula (I) Q is a nitrogen-carbon bond, a methylene or methylmethylene group, and each of R and R‘ is hydrogen, methyl or ethyl, and pharmaceutically acceptable salts thereof, of a compound of formula II wherein: R _f is C 1 -C 3 perfluoroalkyl, n is 1 to 3, p is 1 or 2, wherein Z is chlorine or 1,1-dihydroperfluoroalkoxy having 1 to 4 carbon atoms, R _f and _n are as defined above, and compounds of formula IIIA ^R (III) wherein Q, p, R, and R‘ are as defined above, characterized in that the compound of formula (IIIA) is reduced with hydrogen in the presence of a catalyst and the resulting compound of formula (III): Q, p, R and R 'are as defined above, reacted with a compound of formula (II), and optionally forming a basic compound of formula (I) with an acid or base to form the corresponding pharmaceutically acceptable addition salt of a compound of formula AND.