Method of preparation of derivatives benzamidic pyrrolidine and piperidin.

The present invention relates to a method of preparing compounds of the formula:

wherein denotes a radical perfluoraliyle, 0_{the m}F_{2m + 1} , wherein m is 1 - 3, n is 1 - 3, the £equals 1 or 2, Q is a carbon-to-nitrogen, a methylene group

- HC₂ - methylmethylene or - CH2 (CH2 ^) - and R and R * 1 * hydrogène or represent a methyl or ethyl group.

The method of the invention also provides

the pharmaceutically acceptable salts of the compounds of formula I pharmaceutical compounds and their salts can be incorporated into pharmaceutical compositions. The method of the invention also provides novel intermediate compounds. The compounds I and their pharmaceutically acceptable salts are endowed of pharmaceutical anti-arrhythmic activity.

Some benzoic acid amides on the aromatic ring substituents 1, 1 a-dihydroperfluoralkoxy have been described in the Patent of the United States of America ît° 3,719 687.

The novel compounds produced by the process of the present invention differ, by their structure, that which has been described in the aforementioned Patent, in that:

1) The nitrogen atom of the benzamido group is attached through a methylene group or a carbon-to-nitrogen to a carbon atom of the pyrrolidine ring or piperidine J.

2) These compounds may be secondary amines

or tertiary j and

3) In the obtained compounds according to the present invention, the number of carbon atoms by attaching the nitrogen atom of the benzamido group to a pyrrolidine or piperidine is at most equal to 1 or 0. Similarly, the compounds of the method of I^I invention have advantageously and in most not a Centre⁸ asymmetry (it is to say asymmetric atom carbon)"

Examples of advantageous compounds that the method of 1 Η·η..

and attaches allows one⁸ obtaining include compounds in which Q is %

1) a carbon-to-nitrogen in position 3 of the pyrrolidine ring or piperidine J or

2) a methylene group or binding methylmethylene, attached to position 2 at pyrrolidine ring or piperidine " these compounds are advantageous because they typically have a very large excellent anti-arrhythmic, as demonstrated the comparative experiments performed on animals. Some of them also have few side effects as compared to previous compounds. Certain salts of these free bases also have low side effects®

the compounds of formula I wherein n is 2_S

Rç is trifluoromethyl and 1^{the R} orientation of groups dihydroperfluoréthoxy is in 2.5, are also examples of beneficial compounds.

The obtained compounds according to I^O invention which have

at least one asymmetric carbon atom, namely the carbon atom of the pyrrolidine ring or piperidine to which the group Q is attached, can be split into optically active enantiomorphs by known methods in practice. In addition other centers of asymmetry may exist, when Q is an alky group or when R * is iméthylène methyl or ethyl. All of these optical isomers are within the scope of the method of the present invention.

The compounds I can be used in the form of

acid addition salts of pharmaceutically acceptable_has especially soluble salts of acetic acid, hydrochloric, sulfuric or phosphoric acid. Other salts include those formed with acids hromhydric, tallow recirculating ball bearings, methane-tallow onic, benzene-suifonic, ethanedisulfonic acid, citric, maleic, oxalic, succinic, malic, fumaric and tartric. also employed are quaternary ammonium salts of d * pharmaceutically acceptable, for example salts of alkyl iodides and bromides.

The antiarrhythmically active compounds obtained by the method of the invention is manifested by the ability to inhibit ventricular fibrillation by chloroform in mice, as evidenced by the test method described in detail by jj.w "Lawson's in" j-. Hyg. With exp. Therap." 16 0:22 -31, 1968.

Advantageous examples of compounds of formula I have potent anti-arrhythmic activity in benzamides include (databases) that correspond to the hydrochlorides examples 8.9 and benzamides examples 13 and 14, 26, 27 and 28, as well as the pharmaceutically acceptable salts of these seven compounds.

In clinical practice, the compounds produced by the method of the present invention are normally administered as anti-arrhythmic agents orally or by injection in the form of pharmaceutical preparations which contain the active ingredient in the form of the free base or of one of the salts conventionally acceptable therapeutically, for example the hydrochloride or acetate, in combination with a pharmaceutically acceptable pharmaceutical. The carrier may be a solid diluent, semi-solid or liquid or capsule that can be ingested "

The preparations for parenteral administration by injection advantageously consist in an aqueous solution, generally salt, a water-soluble salt of d *, pharmaceutically acceptable pharmaceutical, of the active substance also containing, if necessary, a stabilizing agent and/or a buffer, for example sodium acetate.

Further, some of the compounds obtained by the method of the present invention are capable of producing local anesthesia, for example by topical application or by injection.

Local anesthetic activity can be observed in the corneal reflex test that uses rabbits as test animals. This test method was described by was E.P. Luduena and J. 0. Hoppe, in " the j. Hyg. The ex. Therap." 1 04:40, 1952.

The method of the invention, for the preparation of compounds I other than those where Q is a carbon-to-nitrogen at position 2 of the heterocyclic ring, comprises reacting a compound of formula:

- Φ

(wherein Z is a halogen, preferably chlorine, or a group 1.1-to-dihydroperfluoralkoxy in to c ^, and R_F. and n have the definitions given above) with an aminomethyl - or - aminopyrrolidine or piperidine of formula:

hr₂ kΩ

•NR¹

R

THE III

(wherein Q, and R, wherein R ' and £have the definitions given above, except Q which the n * is not a carbon-to-nitrogen whem^O it is in position 2).

The reaction is conducted in an inert solvent such as benzene, glyme, toluene or 1 * diethyl ether " preferably, R is not a hydrogen atom. It is known to use an acid acceptor such as a tertiary amine when Z is halogen. When Z is 1.1 to-dihydroperfluoralkoxy, the reaction is typically conducted by heating at reflux of the reactants in the absence or in the presence of an inert solvent such as glyme, the product is isolated.

A variant of the method. of the invention, interest in general, but providing a particular interest for the preparation of compounds wherein Q is a carbon-to-nitrogen in position 2_S comprises reacting an amino - or faâre amino methylpyrrole or an amino - or àmino-to-methylpyridine with a compound of formula II, and then selectively reduces or pyrrole substituted pyridine derivative (VI) resulting, according to the scheme:

wherein Ω, Z., Q_{the R} w, it and R ' have the definitions given above (Z being or a halogen, or a group 1.1-to-dihydroperfluoralkoxy and Q being a carbon-to-nitrogen, methylene or methylmethylene) provided however that when the second reactant is a substituted pyridine (the c * is to say when the JD equals 2), R is not present in this compound nor in the compound intermediate IV (the valences of the nitrogen atom are all met in the conjugated ring). The pyridines and intermediate (VI) pyrroles obtained by this variant of the invention are preceded by novel.

The intermediate compounds (VI) are prepared under reaction conditions identical to those used in the direct process described above, as that. Z is halogen or a group 1.1-to-dih.ydroperfluoralkoxy. They are then subjected to selective catalytic reduction, in corresponding derivatives of piperidine and pyrrolidine derivatives, of formula i. the catalyst which was most advantageous for the catalytic reduction is platinum oxide. The reduction is generally carried out under acid conditions, for example in acetic acid as solvent in the presence of hydrogen chloride.

The compounds of formula II can be prepared conveniently - from the corresponding acids (it is to say

compounds of formula II, wherein Z is OH), these acids being known in practice (see for example the Patent of the United States of America № 3,655 720. The compounds in which Z is a halogen, for example chlorine, can be prepared by heating to reflux acids with excess thionyl halide (chloride) in the presence of a small amount of dimethylformamide. The excess thionyl halide is then evacuated by distillation. The compounds of formula II, wherein Z is a group 1.1-to-dihydroperfluoralkoxy have been described in the Patent of the United States of America mentioned and ¥2, 3 can be prepared by reaction of polyhydroxy aromatic hydrocarbons hydroxyet ^ acids with alkylating agents of the formula V₃ S0₂ 0CIH₂R_F.

in the presence of sodium bicarbonate, potassium bicarbonate or other metal bicarbonate in an inert solvent as such ' acetone. The aromatic ester substituted obtained can then be 1.1 to-dihydroperfluoralkoxy hydrolyzed to the free acid (compounds of formula II wherein Z is OH)_C.

The compounds of formula III and IIIA are generally known in practice or can be prepared conveniently by known methods. Thus, compounds may be prepared III from compounds corresponding-IIIA, by catalytic reduction. Further, certain compounds of types III and IIIa can be prepared by reduction of the corresponding oximes which are themselves obtained from the corresponding aldehydes, by reaction with hydroxylamine hydrochloride.

In the following examples, all temperatures were expressed in degrees Celsius. Examples 1 to 7 relate to the preparation of intermediate compounds and other examples are working examples illustrating the method of the imentiomExample 1

Added dropwise in 40 min, 40 grams (0.10 moles) of 2.5 bis (2, 2, 2 a-trifluoroethoxy) benzoate 2, 2, 2 a-trifluoroethyl to a solution of 21.6 grams (0.20 moles) in 200 ml of 2 a-aminomethylpyridine diglyme, and the resultant mixture is stirred at about 25^0 for about 60 hours, heated and maintained at the reflux temperature for about one hour. Then, evaporation of the mixture to dry, is the triturate with water and filtering the resultant material. The solid material properly rinsed with water, dried in the vacuum furnace and thereafter 5:3 to recrystallize in a mixture of cyclohexane and carbon tetrachloride after treatment with decolorizing charcoal. the product obtained after drying proper is the 2.5 bis (2, 2, 2 a-trifluoroethoxy) - the n - (2 a-pyridylmethyl) benzamide derivatives, white solid substance melts at 102 - 104^I C..

This product is converted into a hydrochloride in diethyl ether by reacting with a solution of hydrogen chloride in ether leads. By recrystallization of the product in a mixture of isopropanol and ether dietbylic after treatment with decolorizing charcoal, there is obtained a purely white salt melts at 190 to-1932c.

Example 2

Is added dropwise a solution of 20.2 grams (0,060 mol) chloride 2.5 bis (2, 2, 2 a-trifluoroethoxy) benzoyl and 100 ml of diglyme to a solution of 5.64 grams (0,060 moles)

of 3-aminopyridine derivatives, 12.1 grams (0.12 moles) of triethylamine and 100 ml of diglyme. The solution is stirred and heated to reflux for about 40 hours, and then evaporate chassepie glyme-and the other volatile components. Is added an excess of solution to 10 the I sodium hydroxide and continuing evaporate the solution to drive off the triethylamine. The solid precipitate is separated by filtration, washed with water and dried carefully to the vacuum oven. , namely 2.5 bis (2, 2, 2 a-trifluoroethoxy)~- the n - (3 a-pyridyI) benzamide derivatives, is treated with decolorizing charcoal, then recrystallized in a mixture of isopropanol

and carbon tetrachloride; fine white needles are obtained melting at 114 - 117² 0. The analysis of the product shows that it crystallizes with a half mole of carbon tetrachloride per mole of compound.

Clo hr lo NR the I

Calculated pour ° 16^H 12WV ' ^ " V.⁴² '² 2.6 6.0

Found ii 42.1 2.6 6.0

Examples of novel intermediate compounds of formula TI, prepared from esters of acid 2.5 bis -.

(2.2,2 a-trlfluoréthoxy) benzoic acid or acyl halides according to the methods of examples 1 and 2_{the R} are provided in Table I according to:

TABLE I

Number of melting point 1¹ example compound f2c)

5

4

5

6

7

2.5 the bis - (2, 2, 2 a-trifluoroethoxy) of n - (2 a-pyridyI) benzamide hydrochloride (isolated in

the hydrochloride)

2.5 - the bis - (2,2,2 a-trifluoroethoxy) - n-(3 a-pyridylinéthyl) - benzamide derivatives (isolated

as the hydrochloride

2.5 the bis - (2, 2, 2 a-trifluoroethoxy) - n-benzamide derivatives (4 a-pyridyI) (isolated as

the form of the hydrochloride)

2.5a (2,2,2 a-trifluoroethoxy) - n-•- [(6-methyl 2 a-pyridyI) - méthylJbenza

mide

2.5 - di (2, 2, 2 a-trifluoroethoxy) s at the R n [1 - (2 a-pyridyI) - ethyl] benzamide derivatives

166 - 1792 181 - 188

164, 5 - 166, 5 113 - 114, 5

98 - 100, 5 The following example illustrates the reduction of intermediate compounds of fomnule 17 to form compounds of formula I by the method of the invention.

Example 8

Is agitated by shaking in a Parr hydrogenation apparatus, at a temperature of about 252c, for about four hours, 3, 9g (0.01 moles) of 2.5 bis - (2, 2, 2 a-trifluoroethoxy) - n-(3 a-pyhidyl) - benzamide derivatives, 2.4 ml (0.02 moles) of hydrogen chloride solution (8.4 n in isopropanol), 0.2 g of platinum oxide and 100 ml of acetic acid. Mixture is filtered and the filtrate is concentrated by evaporation under vacuum. Allowed to recrystallize the residue in a mixture of ethanol and isopropanol after treatment with decolorizing charcoal. Hydrochloride 2.5 bis (2, 2, 2 a-trifluoroethoxy) - the n - (3-piperidyl) - benzamide derivatives obtained as white needle-shaped bottom to 224 and 225sc.

The compounds of examples 9 à - 14, which are shown on the table II, are obtained according to the method of which there general description is given. in GJs * example 8:

TABLE II

Number of melting point (20) the example product

9 Hydrochloride 2.5 bis (2, 2, 2 -

trifluoro ethoxy) - n-- (2 a-pipéri -

dylméthyl) benzamide derivatives

10 Hydrochloride 2.5 bis - (2, 2, 2 a-trifluoroethoxy) - the n - (2-piperidyl) -

benzamide derivatives, hydrated form to

3/4 HR₂ 0

11 Hydrochloride 2.5 bis (2, 2, 2 a-trifluoroethoxy) - the n - (3-piperidyl -

methods for the hly) - amid Enz's b-I

12 Hydrochloride 2.5 bis (2, 2, 2 -

rifluor T-ethoxy) - n-- (4 a-pipéridyü) -

benzamide derivatives

13 Hydrochloride 2.5 bis (2, 2, 2 -

iFFT luor e T-hoxy) - n-K 6-methyl 2-piperidyl) methyl] benzamide derivatives

14 2.5 bis (2, 2, 2 a-trifluoroethoxy) the n~[1 - (2-piperidyl) - ethyl] Ben -

zamide

Example 15

Added dropwise in 25 min, under nitrogen atmosphere, 10.0 grams (0.0249 moles) of 2.5 bis - (2, 2, 2 a-trifluoréthoxÿ) benzoate to 28.4 g of 2, 2, 2 a-trifluoroethyl (0,249 moles) of 2 a-aminomethylpiperidine after three hours ., 50 ml of benzene is added and the mixture is stirred for about 40 hours to 45³ C. then focuses the vacuum. The residue solidifies after cooling; it is steam distilled and separated by filtration and then extracted into dichloromethane, washed with a saturated solution of sodium chloride, and the organic phase is dried over anhydrous magnesium sulfate. Magnesium sulfate is separated by filtration

and the solution in dichloromethane is added, with stirring, of four milliliters of solution of hydrogen chloride in isopropanol n-8.4. After two hours, the mixture is cooled. to about 02c and the crude product is collected by filtration, washed with diethyl ether and vacuum oven dried. After treatment with decolorizing charcoal and then recrystallization in a mixture of equal volumes of isopropanol and methanol, hydrochloride 2.5 bis - (2, 2, 2 a-trifluoroethoxy) - n 228 and 229 glassy consistency, acceptable scanning

189 - 191, 5 193.5 - 195 215 - 222

95 - 97, 5 (2 a-piperidylmethyl) benzaip.de as the product melts at 228 - 22920.

Example 16

In roughly following the procedure of example 15 * 1, with the exception that 1 * on replaces. the benzene by glyme and that the amine is added to the ester, prepared hydrochloride 2.5 bis (2, 2, 2 a-trifluoroethoxy) - the n - (4 a-pipéridylm.éthyl) benzamide hydrochloride melts at σ ^ 179 - 180.

The compounds of examples 17 - 24 (which are shown on the following table) are obtained by the process of example 8 or example 15.

TABLE III

of 2, 2, 2 a-trifluoroethyl and 2 - (1-aminoethyl) piperidine using the procedure illustrated in the example 15" is obtained as by-product the 2.5 bis - (2, 2, 2 a-trifluoroethoxy) - n-[I - (2-piperidyl) ethyl] benzamide as white needles melting at 95 - 97⁹ C..

Example 26■•

Reacting the 2.5 bis (2, 2, 2 a-trifluoréthoxj) - an IIR (2 a-piperidylmethyl) benzamide of the Clark Eschweiler reaction. The product is obtained as 2.5 bis (2, 2, 2 trifluoroethoxy~) O - [(l-methyl-2-piperidyl) methyl] benzamide derivatives, in the form of a white solid substance melts at 99 - 10250.

Example 27

Reacting the i-ethyl-2 a-aminomethylpiperidine

with the 2.5 bis (2, 2, 2 a-trifluoroethoxy) benzoate - 2, 2, 2 a-trifluoroethyl in glyme following the procedure of the example 15j to obtain the 2.5 bis (2, 2, 2 a-trifluoroethoxy) of n - [(1 ethyl 2-piperidyl) - 2methyl] benzamide derivatives in the form of

the free base, in color ivory needles, melts at 95 to-972c.

Example 28

By following the synthesis method shown in the example 15, is reacted 1 ethyl 2 a-aminométhylpyrrolidine and 2.5 bis (2, 2, 2 a-trifluoroethoxy) benzoate 2, 2, 2 a-trifluoroethyl, obtain the 2.5 bis (2, 2, 2 a-trifluoroethoxy) - M M - [(L-ethyl 2 a-pyrrolidyl) methyl] benzamide derivatives, in the form of a white solid substance melts at 78 - 8050.

Example 29

10 Ml of isopropanol is used for dissolving 2.07 grams (0,005 moles) of 2.5 bis - (2, 2, 2 a-trifluoroethoxy) - TI - (2 a-piperidylmethyl) - benzamide and adding a solution of one equivalent of acetic acid in 1 ml of isopropanol. Is obtained upon cooling a solid product is separated off by filtration.

After recrystallization of the product in isopropanol, obtained the desired acetate melts at 145 - 147² 0.

Table VI illustrates various pharmaceutically acceptable salts of 2 2.5 bis (2, 2, 2 a-trifluoroethoxy) - n-(2 a-piperidylmethyl) benzamide derivatives of the invention. The synthesis method that has been used is that of the example 29 *

TABLE 17

Number solubility ' melting point the example acid in water (in a SC)

hot

Example 59

Is heated to 56 - 57^O C. for about 90 minutes in a sealed tube, a mixture of 2.7 grams (0.0063 moles) of 2.5 bis (2, 2, 2 a-trifluoroethoxy) - the n - [(l-methyl-2-piperidyl) methyl] benzamide derivatives and finely divided 6 ml methyl iodide. The mixture is extracted methanol and methanolic extracts are concentrated to obtain crystalline solid that fact, recrystallize in 50 ml of ethyl acetate and about 2 ml of isopropanol, by performing processing at decolorizing charcoal.

By drying the resultant, obtained iodide 2 thereof [2.5 bis (2, 2, 2 a-trifluoroethoxy) benzamidométhyl] above 1.1 to-dimethylpiperidinium in the form of a solid substance blanchçïondant to 170 - 172, 520. Example 40

Following the procedure of example 39, reacting the 2.5 bis - (2, 2, 2 a-trifluoroethoxy) - hence he - [(L-ethyl 2-piperidyl) methyl-] 1enzamide with methyl iodide, to obtain iodide 2 thereof [2.5 bis - (2, 2, 2 a-trifluoroethoxy) benzamidométhyl] and 1 ethyl 1 a-méthylpipéridinium as a white solid substance melts at 162 - 16550.

the appearance "medicament" compounds of formula I obtained according to the invention has not been mentioned that to illustrate one possible application of such compounds, and of course that the present invention encompasses only the appearance "industrial preparation" of compounds of the invention.