DE1912581C3 - Thienyl (2) acetamides7 Process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

in which, when R ^{1 is} cyclohexyl or phenyl, R ^{2 is} thienyl (2) and when R ^{1 is} thienyl (2), R ^{2 is} cyclohexyl-phenyl or thienyl - (2) radical and M represents an alkali metal or a monovalent, anionic metallic radical, in an N, N-disubstituted 2-hydroxy-thienyl- (2) -acetamide of the general formula

R ¹

CH ₅ -CH ₁ -N

C - CON

R ² OH

converts, in which R, R ¹ , R ² , A and B have the meanings given above and at least one of the substituents R ¹ and R ^{2 is} a thienyl (2) radical, and optionally this compound with a methyl, ethyl Reacts, benzyl or propargyl halide or ester.

4. Pharmaceutical compositions consisting of at least one compound according to Claim 1 and usual carriers and auxiliaries.

The invention relates to thienyl (2) acetamides of the general formula I:

OH

Ar

N - CH ₂
R.

CH, - N

\ Z B

45 in which Ar represents a phenyl, thienyl (2) or cyclohexyl radical, R represents a hydrogen atom or the methyl or phenyl radical, A and B, which can be the same or different, each individually a methyl, ethyl or phenethyl radical or together a tetramelhylene, pentamethylene radical or the group - C, H ₄ - OC ₂ H ₄ - and Z is the free electron pair on the nitrogen atom or the group ¹⁵¹ CH ₂ R ¹ X, where R 'is a hydrogen atom or the methyl, Phenyl or ethynyl radical and X represents an anion of a therapeutically acceptable anoi ganischen acid.

The new thienylacetamides of the general formula I have a significant antispasmodic effect, superior to that of N-butylscopolamine is.

Among the compounds of general formula 1 is the methobromide of 2-phenyl-2r * -thienyl-2-hydroxy-N - (/; - pyrrolidinoiithyl) -N-methylacctamide Of particular note.

The preparation process of the compounds of general formula I, which is also the subject of present invention, is thereby uekennzeich-

net that a glyoxylic acid derivative of the general formula can be used in a manner known per se

R ¹ - COCOZ

in which R ¹ denotes a cyclohexyl, phenyl or thienyl (2) radical and Z denotes a hydroxyl group or a group from which a hydroxyl group can be obtained by hydrolysis, with an N, N'-substituted ethylenediamine of the general formula / ^

CH, -N

CH, - NH - R

condensed in which the substituents A and B, which can be the same or different, each individually represent a methyl, ethyl or phenethyl radical or together a tetramethylene, pentamethylene radical or the group - C ₂ H ₄ - OC ₂ H ₄ - and R represents a hydrogen atom or the methyl or phenyl radical, to an N, N-disubstituted glyoxamide of the general formula a

2. The condensation between the R ¹ -glyoxylic acid and the substituted ethylenediamine is carried out in the presence of a dehydrating agent and in particular a dialkyl or dicycloalkylcarbodiimide;

3. The functional derivative of R ¹ -glyoxylic acid is an acid halide;

4. The condensation between the R'-glyoxylic acid amide and the organometallic derivative

ίο is in a linear or cyclic ether and carried out in particular in ethyl ether and tetrahydrofuran;

5. The organometallic reagent is a lithium derivative or an organomagnesium halide or an organozinc salt;

6. The formation of the quaternary ammonium compound takes place in a solvent such as acetone.

CH ₂ -CH ₂ -N

R ¹ - COCO - N

in which the substituents R ¹ , R, A and B have the abovementioned meanings, this compound is condensed with an organometallic reagent of the general formula

R ² M

in which, when R ^{1 is} a cyclohexyl or phenyl radical, R ^{2 is} a thicnyl (2) radical, and when R ^{1 is} a thieny! (2) radical, R ^{2 is} a cyclohexyl, phenyl radical or fh; enyl- (2) radical and M represents an alkali metal or a monovalent, anionic metallic radical, in a Ν, Ν-disubstituted 2-hydroxythienyl- (2) -acetamide of the general formula

The following examples illustrate the invention.

example 1

Methobromide des 2-phenyl-2'-thienyl-2-hydroxy-N - (^ - pyrrolidino-ethyl)

Level a

N - (/ (- Pyrrolidino-ethyl) -N-methyl-H-thienylglyoxamide

To a solution of 63.9 g of a-Thienylglyoxylsäurechlorid in 450 cm ³ of benzene, a solution of 46.9 g N - pyrrolidino - N '- methyl - ethylenediamine in 450 cn! ³ benzene and keeps the temperature at 20 ⁰ C; the mixture is left to stand for a night, the hydrochloride formed is filtered off with suction, taken up in water, made alkaline with a dilute potassium carbonate solution and extracted with ether; the organic phase is evaporated and the oil residue is distilled; 69 g of N - (/ I-pyrrolidino-ethyl) -N-methyl- (i-thienyl-glyoxamide are obtained in the form of a clear yellow oil which distilled over at 192 "C / 2 mm, yield: 71%.

R ¹

C - CON

R ² OH

CH ₂ CH ₁ -N

converts, in which R, R ¹ , R ² , A and B have the above meanings and at least one of the substituents R ¹ and R ^{2 is} a thicnyl (2) radical, and optionally this compound with a methyl, ethyl , Benzyl or propargyl halide or ester.

The method can be characterized, inter alia, by the following embodiments:

1. The condensation between a functional derivative of R ¹ -glyoxylic acid and the substituted ethylenediamine is carried out in an organic solvent, preferably an aromatic hydrocarbon or a linear or cyclic ether;

Analysis: C ₁₃ H ₁₈ N ₂ O ₂ S = 266.35.

Calculated ... N 10.51%;
found .... N 10.65%.

IR spectrum:
Presence of C - O at 1650 cm " ¹ .

The hydrochloride of N - ((- pyrrolidino -älhyl) -N-methyl-u-lhienyl-glyoxamides is in form of colorless crystals, which are soluble in water and melts at 170 ⁰ C.

Analysis:
Calculated
found .

N 9.25, Cl 11.71%:
N 9.31, Cl 11.69%.

The N - (// - pyrrolidino-ethyl) -N-methyl - «- thienylglyoxamide can also be obtained in the following ways:

Dissolve 41.2 g Dicyclohcxylcarbodiimid in 300 cm "acetone, the solution is cooled to 0" C, and added a solution of 31,3g added u-thienyl-glyoxylic acid in 150cm * acetone, keeping the temperature below +5 ⁰ C; the mixture is stirred for 10 minutes and a solution of 12.8 g of N-pyrrolidine-N'-methyl-ethylenediamine in 100 cm 'of acetone is added, the temperature being maintained between + 5 ° C. and + 10 ° C.; one filtered and

evaporates the solvent under reduced pressure; the residue is taken up in ether, the ether phase is washed with a: dilute sodium carbonate solution, then with water, dried, the ether is evaporated and the oil residue is distilled; the N - (β - pyrrolidino - ethyl) - N - methyl - «- thieny 1-glyoxamide is obtained, which distills at 216 to 218 ° C / 6 mm Hg. The hydrochloride melts at 170 ° C.

Level B.

2-phenyl-2- (fz-thienyl) -2-hydroxy-N - (// - pyrrolidinoethyl) -N-methyl-acetamide

An ethereal solution of 0.05 mol of phenyimagnesium bromide is added to a solution of 12 g of N - (/ y-pyrrolidino-ethyl) -N-methyl-a-thienyl) -glyoxamide in 66 cm ^{3 of ether and the mixture is refluxed for 30 minutes;} crushed ice is poured into a mixture of hydrochloric acid, the precipitate is filtered off and soaked in water; it is made alkaline with a dilute sodium carbonate solution and the precipitate is filtered off with suction. 2-phenyl-2'-thienyl-2-hydroxy-N - (/ y-pyrro] idino-ethyl) -N-methyl-acetamide is obtained in the form of colorless crystals, melting point 134 ° C. (yield: 55%).

Analysis: C ₁₉ H ₂₄ N ₂ O ₂ S = 344.46.

Calculated ... N 8.13%;
found .... N 8.23%.

IR spectrum: carbon tetrachloride.

Presence of OH at 3350cm ', presence of C = O at 1650era " ¹ .

2-Phenyl-2 - (/ - thienyl-2-hydroxy-N - (/ f-pyrrolidino-ethyl) -N-methyl-acetamide can be characterized as a hydrochloride. For this purpose, 3.65 g of the just obtained are suspended Base in 50 cm ^{3 of} ethanol and adds 6.2 cm ^{3 of} an alcoholic, 1,7N hydrochloric acid solution; after evaporation of the solvent in vacuo, the hydrochloride of 2-Phe.iyl-2'-thienyl-2-hydroxy- U crystallizes - (Jl- pyrrolidino-ethyl) - N - methyl - acetamide, and melts at 190 ° C (yield: 75%).

Analysis: C ₁₉ H ₂₄ N ₂ O ₂ S • HCl = 380.93.

Calculated:

C 59.90, H 6.61, N 7.35, S 8.43, Cl 9.31%; found:

C 60.2, H 6.6, N 7.4, S 8.4, Cl 9.4%.

Level C

Methobromide of 2-phenyl-2'-thienyl-2-hydroxy-N - (/ 9-pyrrolidino-ethyl) -N-methyl-acetamide

4.9 g of 2-phenyl-2a-thienyl-2-hydroxy-N - (ß - pyrrolidino - ethyl) - N - methyl - acetamide are dissolved in 400 cm ^{3 of} acetone, 25 cm ^{3 of} a solution containing 62% methyl bromide is added in acetone, added and left to stand for one night; the crystals formed are filtered off with suction and, after recrystallization from isopropanol, the sought product is obtained, which melts at 202 ° C. (yield: 77%). The product is in the form of colorless crystals that are soluble in water.

Analysis: C ₂₀ H ₂₇ BrN ₂ O ₂ S = 439.42. Calculated:

C 54.66, H 6.19, Br 18.19, N 6.38, S 7.30%; found :

C 54.5, H 6.2, Br 18.0, N 6.0, S 7.2%.

"-Thienyl-glyoxylic acid can be obtained according to US Pat. No. 3,220,655; the corresponding acid chloride is based on u-thienyl-glyoxylic acid obtained by chlorination by known methods.

Example 2

2-phenyl-2'-thienyl-2-hydroxy- methobromide

N- (N'-methyl-N'-phenälhyI-aminoethyl) -

N-methyl-acetamids

Level a

Hydrochloride of N- (N'-Methvl-N'-phi-niithylaminoethyl) -N-nicthylphenyl-glyoxamide

A solution of 27.3 g of N.N'-dimethyl-N'-phenylethyl-ethylenediamine is poured in 55 ecm benzene

Cooling in a solution of 24 g of phenylglyoxylic acid chloride in 200ecm benzene; an "oil is formed which slowly crystallizes; one accommodates 1 hour Reflux and sucks off the hydrochloride formed, which is taken up in ethyl acetate and from isopropanol

recrystallized; the hydrochloride of N- (N'-methyl-N'-phenethyl-aminoethyl) -N-niethylphenyl-glyoxamide is obtained in the form of colorless crystals Ji .; at 155 C melt (yield: 60%).

Analysis: C ₂₀ H ₂₄ N ₂ O ₂ • HCl = 360.87.
Calculated .. N 7.76. Cl 9.82%;
found .... N 7.88-7.65, Cl 9.87%

IR spectrum:
Bands at 1650 and 1675 cm "'.

Level B.

2-phenyl-2i-thienyl-2-hydroxy-N- (N'-methyl-N'-phenethyl-aminoethyl) -N-methyl-acetamide

49.76 g of the hydrochloride obtained above are suspended in 180 cm ^{3 of} water, made alkaline by adding a 10% strength potassium carbonate solution, the mixture is treated with ether, the ether phases are dried over sodium sulfate, filtered and distilled to dryness; 43.95 g of N- (N'-methyl-N'-phenethyl-aminoethyl) -N-methylphenyl-glyoxamide are obtained, which is used as it is in the subsequent synthesis.

The 43.95 g of the base obtained above are dissolved in 250 cm ^{3 of} ether, this solution is poured into an ether solution containing 0.178 mol of thienyl (2) magnesium bromide and refluxed for 15 minutes; it is poured onto a hydrochloric acid / ice mixture and the insoluble hydrochloride formed is filtered off with suction and suspended in water; it is made alkaline by adding a dilute sodium carbonate solution and extracted with ether; after evaporation of the solvent and recrystallization from isopropyl ether, 2-phenyl-2a-thienyl-2-hydroxy-N- (N'-methyl-N'-phenethyl-aminoethyl) -N-methylacetamide is obtained in the form of colorless crystals, which at Melting at 96 ° C.

Analysis: C ₂₄ H ₂₈ N ₂ O ₂ S = 408.54.

Calculated ... N6.85%;
found N 6.89%.

<r

IR spectrum:

Presence of - OH at 3400cm " ¹ ,
Presence of O = O at 1650 cm " ¹ .

The 2 - phenyl -2utienyl - 2 - hydroxy - N - (N '- methyl - N' - phenethyl - aminoethyl) - N - methyl - acetamide can be characterized as a hydrochloride. For this purpose, 46.25 g of the base obtained above are dissolved in 300 cm ^{3 of} ethanol and an alcoholic solution of gaseous hydrochloric acid is added in a stoichiometric amount; the solvent is evaporated and the residue is treated with boiling methyl ethyl ketone; After recrystallization from methyl ethyl ketone, the hydrochloride of 2-phenyl-2'-thienyl-2-hydroxy-N- (N'-methyl-N'-phenethyl-aminoethyl) -N-methyl-acetamide with a melting point of 158 ° is obtained C.

Analysis: C ₂₄ H ₂₈ N ₂ O ₂ S • HCl = 445.

Calculated:

C 64.77, H 6.57, N 6.29, S 7.20, Cl 7.95%;
found:

C 64.9, H 6.7, N 6.3, S 7.4, Cl 8.3%.

Level C

Methobromide of 2-phenyl-2'-thienyl-2-hydroxy-N- (N'-methyl-N'-phenethyl-aminoethyl) -

N-methyl-acetamides

The procedure is as in stage C of Example 1; Starting from 2-phenyl-2a-thienyl-2-hydroxy-N- (N'-methyl-N'-phenethyl-aminoethyl) -N-methyl-acetamide and methyl bromide, the methobromide of 2-phenyl-2'-thienyl is obtained - 2 - hydroxy - N - (N '- methyl-N' - phenethyl - aminoethyl) - N - methyl - acetamides, which ^{melts at 204 0} C (yield: 63%).

Analysis: C ₂₅ H ₃₁ BrN ₂ O ₂ S = 503.49.

Calculated ... N 5.56. Br 15.87%;

found .... N 5.57-5.61, Br 15.64-15.59%.

Example 3

Methobromide of 2,2-di- «- thienyl-2-hydroxy-N - (/ I-pyrrolidino-ethyl) -N-methyl-acetamide

Level a

2,2-Di - «- thienyl-2-hydroxy-N - (/ <- pyrrolidino-ethyl) -N-methyl-acetamide

The procedure is as in stage B of Example 1; outgoing of 43 g of N - (/ i-pyrrolidino-etfayl) -N-methylo-thienyl-glyoxamide (obtained after stage A of Example 1) and 0.21 mol of a-thienylmagnesium bromide, dissolved in ether, obtained after recrystallization from isopropanol, then from ethyl acetate, the 2,2-di- «- thienyl - 2 - hydroxy - N - (/ f - pyrrolidino - ethyl) - N - methyl - acetamide in the form of colorless crystals which melt at 129 ° C (yield: 31%).

Analysis: C ₁₇ H ₂₂ N ₂ O ₂ S ₂ = 350.50.

Calculated ... C 58.25, H 6.33, N 7.99, S 18.30 ° · ,,; found .... C 58.6, H 6.1, N 7.7. S 18.0%.

IR spectrum: carbon tetrachloride.

Presence of - OH at 3350 cm " ¹ .
Presence of CO at 1650 cm " ¹ .

Level B.

Methobromide of 2,2-di-u-thienyl-2-hydroxy-N - (/ f-pyrrolidino-ethyl) -N-methyl-acetamide

The procedure is as in stage C of Example 1; by the action of methyl bromide on the in stage A Base prepared above in acetone, the methobromide des is obtained after recrystallization from ethanol 2,2-Di - «- thienyl-2-hydroxy-N - (/ f-pyrrolidino-ethyl) -N-methyl-acetamides, which melts at 198 ° C (yield: 79%). The product is in the form of colorless crystals, soluble in water.

Analysis: C ₁₈ H ₂₅ BrN ₂ O ₂ S ₂ = 445.44.

Calculated ... N 6.28, Br 17.94%;

found .... N 6.35-6.37, Br 17.91-18.0%.

Example 4

Methobromide of 2-phenyl-2 </ - thienyl-2-hydroxy-N- (N ', N'-dimethyl-aminoethyl) -N-phenyl-acetamide

Level a

N- (N ', N' -dimethyl-aminoethylJ-N-phenyl-phenylglyoxamides

A solution of 43.68 g of N-phenyl-N ', N'-dimethyl-ethylenediamine is added in 315 cm of benzene to a benzene solution of 45 g of phenylglyoxylic acid chloride, keeping the temperature below 25 ° C; the mixture is stirred for 40 minutes and what is formed is sucked Hydrochloride. After recrystallization from isopropanol and then from ethanol, the hydrochloride is present in the form of colorless crystals which melt at 203 ° C. (yield: 56%).

The hydrochloride is dissolved in water and made alkaline with the aid of a dilute sodium carbonate solution and extracted with ether; after evaporation of the solvent, the N- (N. ', N'-dimethyl - aminoethyl) - N - phenyl, phenyl - glyoxamide in the form of colorless crystals. Melting point at 9Γ C.

Analysis: C ₁₈ H ₂₀ N ₂ O ₂ = 296.36.

Calculated
found .

.. N 9.45%;

.. N 9.44-9.45%.

Level B.

2-phenyl-2'-thienyl-2-hydroxy-N- (N ', N' -dimethylaminoethyl) -N-phenyl-acetamide

The procedure is as in stage B of Example 2, an ethereal solution of 37.6 g of the just obtained Base with an ethereal solution containing 0.17Mol «-thienylmagnesium bromide contains, implements; after acid hydrolysis and recrystallization from cyclohexane one obtains the 2-phenyl-2u-thienyl-2-hydroxy-N- (N ', N '- dimethyl - aminoethyl) - N - phenyl - acetamide. Melting point at 92 ° C (yield: 67%).

Analysis: C ₂₂ H ₂₄ N ₂ O ₂ S = 380.49.
Calculated ... N 7.36%;
found .... N 7.35 -7.40%.

2-Phenyl-2.i-thienyl-2-hydroxy-N- (N'.N'-dimethyl -aminoethyl) - N -phenyl-acetamide can be characterized as a hydrochloride:

An alcoholic solution is added to an alcoholic solution of 20 g of the base obtained above gaseous hydrochloric acid added in stoichiometric amount; a precipitate forms.

which is suctioned off and recrystallized from ethanol; the hydrochloride of 2-phenyl-2 (i - thienyl - 2 - hydroxy -N- (Ν ', Ν' - dimethyl - aminoethyl) -N-phenyl-acetamides, Melting point 251 to 252 ° C (yield: 83%).

Analysis: C ₂₂ H ₂₄ N ₂ O ₂ S • HCl = 416.96. Calculated ... N 6.71, Cl 8.50%; found .... N 6.8-6.84, Cl 8.45-8.56%.

IO

Level C

Methobromide of 2-PhenyI-2'-thienyI-2-hydroxy-N- (N ', N'-dimethyl-aminoethyl) -N-phenyl-acetamide

The procedure is as in stage C of Example 1; outgoing of 2-phenyl-2i / -thienyl-2-hydroxy-N- (N ', N'-dimethyl - aminoethyl) - N - phenyl - acetamide and methyl bromide, the methobromide des is obtained 2- phenyl-2 (/ - thienyl -2-hydroxy- N- (N ', N'-dimethylaminoethyl) - N - phenyl - acetamides, melting point at 264 ° C.

The following compounds are prepared according to the procedure described in the preceding examples from:

Methobromide of 2-phenyl-2 «-ihienyl-2-hydroxy - N - (Ν ', Ν' - dimethyl - aminoethyl). N-methyl-acetamides; 228 ° C

Methobromide des 2-phenyl-2 "-'ihienyl-2-hydroxy-N- (fi -morpholinoethyl) -N-methylacetamides; F. 226 ° C,

2-phenyl-2'-thienyl-2-hydroxy methobromide -N - (Ν ', Ν'- diethyl aminoethyl) - N-methyl-acetamides; 177 ° C

Methobromide des 2 - phenyl - 2 «- ihienyl - 2 - hydroxy- N - (// - piperidinoethyl) - N -methyl-acetamides; Mp 218 ° C

Methobromide des 2 - cyclohexyl - 2 "- thienyl-

2-hydroxy-N - (/; - pyrrolidinoethyl) -N-methylacetamides; 196 ° C

Propargyl bromide of 2-phenyl-2'-thienyl-2-hyaroxy -N- (li- pyrrolidinoethyl) - N - methylacetamides; M.p. 180 ^° C

Benzyl chloride of 2-phenyl-2-thienyl-2-hydroxy-N- Qt -pyrrolidinoethyl) -N-methylacetamide; M.p. 235 ° C

Methobromide des 2-phenyl -2 "- thienyl -2-hy- 2S; Μ? ' ■ ^dieth ^ ^m -. Hy ^y i) - acel-

Ethyiodide of 2-phenyl-2'-thienyl-2-hydroxy- Fl "" ^{0 dinOethyl) Nmelhyltid}

Claims (3)

Patent claims: 1. Thienyl (2) acetamides of the general formula 1 OH Ar CN-CH ₂ -CH ₂ -N OR ZB in which Ar represents a phenyl, thienyl (2) or cyclohexyl radical, R represents a hydrogen atom or the methyl or phenyl radical, A and B, which can be the same or different, individually each represent a methyl, ethyl or phenethyl radical or together represent a tetramethylene, pentamethylene radical or the group -C ₂ H ₄ - OC ₂ H ₄ - and Z is the lone pair of electrons on the nitrogen atom or the group " ¹ CH ₂ R ¹ X, where R 'is a hydrogen atom or methyl -, phenyl or ethynyl radical and X represents an anion of a therapeutically acceptable inorganic acid. 2. Methobromide of 2 - phenyl - 2, t - thienyl - 2 - hydroxy - N - (/>'- pyrrolidino - ethyl) - N - methylacetamide. 3. Process for the preparation of the thienyl (2) acetamides according to claim 1, characterized in that that in a known manner, a glyoxylic acid derivative of the general formula R ¹ -COCOZ 35 in which R ¹ denotes a cyclohexyl, phenyl or thienyl (2) radical and Z denotes a hydroxyl group or a group from which a hydroxyl group can be obtained by hydrolysis, with an N ₁ N '-substituted ethylenediamine of the general formula CH, -N CH, NH-R in which the substituents A and B, which can be identical or different, each individually represent a methyl. Ethyl or phenethyl radical or together a tetramethylene, pentamethylene radical or the group C ₂ H ₄ - OC ₂ H ₄ - and R represents a hydrogen atom or the methyl or phenyl radical, to an N, N-disubstituted glyoxamide general formula CH ₂ -CH ₂ -N 60 R ¹ - COCO - N in which the substituents R ¹ , R, A and B have the abovementioned meanings, this compound is condensed with an organometallic reagent of the general formula R ² M