DE1493567B2 - Esters of alpha-alkylthyroxine derivatives and process for their preparation - Google Patents

Description

The present invention relates to esters of α-alkylthyroxines the general formula

HO

where R _{1 is} an alkyl radical having 1 to 6 carbon atoms, R _{2 is} an amino group or an acylamino group and R _{3 is} an alkyl radical having 1 to 6 carbon atoms or an aralkyl radical. denotes, where R _{3 is represented} by a group

R ₄

—N

in which R ₄ and R _{5 are} identical or different and are hydrogen atoms, lower alkyl radicals or, taken together with the nitrogen atom, a pyrrolidine, piperidine or morpholine radical, can be substituted, as well as their salts with organic or inorganic acids or bases.

In DT-PS 14 93 533 it was described that a-alkyl-thyroxine are able to lower the serum cholesterol level without increasing the basal metabolic rate. The absorption of the compounds mentioned there however, it is extremely low when administered orally. It has now been found that esters of the general Formula I are able to exert these beneficial effects even when administered orally. This finding is surprising because publications (e.g. by Clayton and Hems, J. Chem. Soc, Vol. 1 [1950], 840) it is known that the esterification of thyroxines is associated with a loss of activity. In contrast, the Esters of the general formula I equally in the case of oral and parenteral administration effective.

After oral administration of DL-u-methylthyroxine ethyl ester hydrochloride, this decreased in a dosage of ΙΟμΜοΙ per kilogram rat over 11 days the serum cholesterol level to 142 ± 12 mg / 100 ml compared to 270 ± 21 mg / 100 ml in the diet controls. Even when using 1000 times the concentration of the substance mentioned, none could Influence on oxygen consumption was determined. Similar beneficial effects can be achieved with other compounds of general formula I can be observed.

Compared to DL-u-methyl-thyroxine ethyl ester (reference substance = 100) the following were obtained for the esters of DL-a-methyl-thyroxine listed below Values:

Methyl: 100; ^ -Dimethylaminoethyl: 50 to 100; / ^ - diethylaminoethyl: 50 to 150; // - piperidinoethyl: 50 to 150; / i-morpholinoethyl: 50 to 100; // - pyrrolidinoethyl: 50 to 100.

The compounds of general formula I are prepared (method a) by adding an acid of general formula
YY

HO

CH, -C-COOH

(H)

wherein R ₁ and R _{2 have the} same meaning as in formula I, a salt of this acid or a reactive derivative, such as. B. a halide or anhydride of the acid of the general formula II, with a compound of the general formula

X Iv ₃

(HI)

wherein R _{3 has the} same meaning as in formula I and X is an oxy group, an esterified oxy group, a halogen atom or an oxy group whose hydrogen has been replaced by a metal atom, in the presence of acidic or basic esterification catalysts or by azeotropic removal of water to react. The reaction can be carried out using stoichiometric amounts of a

Carry out binding of the general formula II with a compound of the general formula III, but one of the components can also be used in excess. If neither the compound of the formula II is used as a salt with a base nor a compound of the formula III in which X is used for an oxy group in which the hydrogen has been replaced by a metal atom, acidic esterification catalysts are preferably used. In those cases in which an acid is released during the formation of a compound of the general formula I, it is expedient to work in the presence of basic substances to accelerate the reaction or to bind the acid. If water is released during the formation of the compound of the general formula I from a compound of the general formula II and a compound of the general formula III, the water formed can also be removed by means of azeotropic distillation.
The compounds of general formula I can also be prepared (method b) by adding a compound of general formula

HO

CH ₂ -C-COOH (IV)

wherein R ₁ and R _{2 have} the aforementioned meaning, a salt of this acid or a reactive derivative, such as. B. a halide or anhydride, with a compound of the general formula III in the aforementioned manner to a compound of the general formula

R ₁ O

CH ₂ -CC-OR ₃ (V)

wherein R ₁ to R _{3 have} the aforementioned meaning,

converts and in this with iodizing agents such. B. iodine / iodopotassium, N-iodoacetamide, N-iodosuccinimide or Chlorine iodine introduces two iodine atoms, if necessary in stages.

The compounds of the general formula V can be prepared by activating one Ester, preferably the p-tosyl ester, of a compound of the general formula

optionally at elevated temperature, to react and in the resulting compound of the general formula

NO ₂

R ₈ O

NO

HO

CH ₇ -CC-OR,

R ₁ O

I Il

CH ₂ -CC-OR ₃ (X)

(VI)

wherein R ₁ and R _{3 have} the aforementioned meaning, R _{6 represents} an acylamino group and R _{7 represents} a nitro group or an iodine atom, with a compound of the general formula

in which R ₁ , R ₃ and R ₆ to R _{8 have} the aforementioned meaning, exchanges the nitro group (s) for iodine according to methods known per se and _{splits off the radical R 8} in the manner described for the compound of general formula VIII, and optionally R _{6 is converted} into an amino group by methods known per se.

The compounds of the general formula V can also be prepared by one Compound of the general formula

R _S O-

OH

(VII)

HO

wherein R _{8 stands} for an aralkyl radical with a carbon atom in the aliphatic part, reacts in the presence of a solvent and / or an inorganic or organic base, preferably pyridine, optionally at an elevated temperature; in the resulting compound of the general formula

R ₁ O
CH ₂ -CC-OR ₃ (XI)

wherein R ₁ to R _{3 have} the aforementioned meaning, in a manner known per se with a compound of the general formula

NO,

R ₁ O

Γ ii

CH ₂ -CC-OR ₃ (VIII) R ₈ -O

At"

(XII)

where R ₁ , R ₃ and R ₆ to R _{8 have} the aforementioned meaning, the nitro group (s) are converted into diazonium group (s) by reduction - preferably catalytically in the presence of Raney nickel - and diazotization, and these are converted by the Sandmeyer method exchanged for iodine, the radical R ₈ hydrogenolytically - preferably in the presence of noble metal catalysts - removed by methods known per se and two iodine atoms optionally gradually introduced into the resulting compound of the general formula V, as described above, and optionally R ₆ into an amino group converted per se known method.

Correspondingly, compounds of the general formula I can be prepared by an activated ester, preferably the p-tosyl ester, of a compound of the general formula VI with a compound of the general formula

wherein R _{8 has} the aforementioned meaning and An stands for an anion, reacts in the presence of an alkaline substance, preferably a metal alcoholate, advantageously using an alcohol as a solvent, and brings the resulting compound of the general formula to reaction

L ν UK3 (Λ111)

wherein R ₁ to R ₃ and R _{8 have} the aforementioned meaning, is converted into a compound of the general formula V by hydrogenolytic cleavage of the radical R ₈ , which is then further converted to compounds of the general formula I, as described above.

You can finally prepare the compounds of general formula I (method c) by a compound of the general formula XI at pH values approaching the neutral point, preferably in the weakly alkaline range, with an acid of the formula

OH

(IX) HO

wherein R _{8 has} the aforementioned meaning, in the presence of a solvent and / or an inorganic or organic base, preferably pyridine,

CH ₇ -CO-COOH

(XIV)

condensed. The condensation takes place in itself

known manner, by adding a compound of the general formula XI in a buffer solution, such as z. B. an aqueous solution of borax and secondary sodium phosphate or citric acid and secondary sodium phosphate a weakly alkaline pH value, preferably pH 7.6 to 7.8 if necessary with the addition of a water-miscible organic solvent such as. B. one lower alkanol, dioxane, dimethylformamide, dimethylacetamide or ethylene glycol monoethyl ether dissolves and with an appropriate solution of an acid of the formula XIV all at once or in portions offset. You can stoichiometric amounts of compounds of the formula XI and XIV or one of the Use excess components. The condensation can also with the addition of a second Water immiscible phase, such as higher alcohols, chlorinated hydrocarbons, aliphatic or aromatic hydrocarbons. You can optionally in the presence of catalytically acting substances, such as B. organic peroxides or salts of divalent manganese, under anaerobic or aerobic conditions, e.g. B. with the introduction of oxygen for the duration of the Condensation, work at temperatures below 100 ° C.

If compounds of the general formula I are to be obtained in which R _{2 represents} an acylamino group, the compounds having a free amino group obtained by one of the above processes can be obtained by reaction with a reactive derivative of a carboxylic acid, such as. B. a carboxylic acid anhydride, halide or ester can be implemented in a manner known per se.

If desired, the compounds of general formula I can be added by adding a Convert base or an acid into the salt in question, which makes it optically more active when used Compounds for salt formation the corresponding salts of the isomeric forms are obtained, the can be split into the optically active components by methods known per se.

The following examples serve to further illustrate the invention. The melting and boiling point information are consistently uncorrected.

example 1

7.91 g of a-methylthyroxine are suspended in 150 ml of absolute ethanol. While warming, dry hydrogen chloride gas is passed in until it is saturated. The solvent is removed by distillation in vacuo. The residue is dissolved in 50% ethanol and neutralized with a 5% solution of sodium bicarbonate. This gives the ethyl ester of a-Methylthyroxins of melting point 156-157 ⁰ C after recrystallization from ethanol. Yield 6.05 g, that is 74% of theory.

Example 2

Analogously to Example 1, the methyl ester of α-methylthyroxine is obtained using methanol from melting point 123 to 125 ° C after recrystallization from methanol. Yield 85% of theory.

Example 3

2 g of a-methylthyroxine are added in portions to a ^{mixture, heated to 95 °} C., of 20 ml of benzyl alcohol and 5 g of polyphosphoric acid.

The clear solution is stirred at 95 ^° C. for 4 hours. It is allowed to cool, poured into 200 ml of water and extracted with ether. The ether solution is washed with 1 η ammonia solution, dried over sodium sulfate and concentrated in vacuo. After dissolving the residue in ethanol is obtained on addition of water, the benzyl ester of the a-Methylthyroxins a melting point of 178 to 18O ⁰ C after recrystallization from n-butanol.

Example 4

5.7 g of 3,5-diiodo-a-methylthyronine ethyl ester will be dissolved in a mixture of 60 ml of butylamine and 120 ml of ethanol. A solution is added dropwise 5.1 g of iodine in 50 ml of ethanol are added and the mixture is stirred for 1 hour. Then is under ice cooling neutralized with concentrated hydrochloric acid.

By adding a solution of sodium acetate in water gives the ethyl ester of a-Methylthyroxins of melting point 156-157 ⁰ C, in a yield of 83% of theory, identical to that obtained according to Example 1 product.

The 3,5-diiodo-a-methylthyronine ester used above as the starting product is obtained in the following way:

11.8 g of 3,5-diiodo-a-methylthyronine are in 240 ml suspended in absolute ethanol. The solution is saturated with dry hydrogen chloride while cooling with ice. With further introduction of dry hydrogen chloride is then several hours Heated to reflux temperature. The clear solution is concentrated to dryness in vacuo. The residue is dissolved in 50% ethanol and neutralized with 5% aqueous bicarbonate solution. Receives one the ethyl ester of 3,5-Dijod-a-methylthyronins from melting point 152 to 154 ° C in a Yield of 73% of theory.

Example 5

The procedure is as in Example 1 and obtained from the a-Äthylthyroxin the ethyl ester of melting point 138 to 140 ⁰ C in a yield of 72% of theory.

That used as the starting product above

α-Ethylthyroxine can be obtained in the following way:

35.6 g of lp-methoxyphenyl-butanone- (2), 19.5 g of potassium cyanide and 62.5 g of ammonium carbonate are suspended in 330 ml of 50% ethanol and ^{heated to 65 to 70 °} C. for 7 hours while stirring. On cooling, optionally after introducing carbon dioxide, the 5-ethyl-5- (4-methoxybenzyl) hydantoin crystallizes in the form of white crystals with a melting point of 191 ° to 193 ° C. after recrystallization from ethanol / water. Yield 90% of theory.

24.8 g of the above compound are heated to reflux temperature for 2 hours in 110 ml of 57% strength aqueous hydriodic acid. Upon cooling, there is obtained the 5-ethyl-5- (4-hydroxybenzyl) hydantoin of melting point 290-291 ⁰ C after recrystallization from ethanol. Yield 68% of theory.

23.4 g of the above compound are added in portions to 70 ml of a while stirring vigorously 35 to 37 ° C heated nitric acid with a density of 1.42. The mixture is stirred for 2 hours and dilute the solution with 2000 ml of ice water. The 5-ethyl-5- (3,5-dinitro-4-hydroxybenzyl) hydantoin falls in crystalline form. Melting point 236 to 238 ° C after recrystallization from ethanol. yield 70% of theory.

509 540/418

64.8 g of the above compound and 42 g of p-toluenesulfonic acid chloride are dissolved in 150 ml of pyridine Heated to reflux temperature for 10 minutes. After cooling, 62 g of 4-methoxyphenol, dissolved in 62 ml of pyridine, added and heated to reflux temperature for 1 hour. After cooling, the 5-ethyl-5 [3,5-dinitro-4 - (4'-methoxyphenoxy) -benzyl] -hydantoin is obtained by dilution with 6 times the volume of ice water from melting point 195 to 197 ° C after recrystallization from dilute acetic acid. Yield 93% of theory.

43.0 g of the above compound are in a mixture of 300 ml of methanol and 100 ml Dissolved tetrahydrofuran and hydrogenated with the addition of Raney nickel at normal pressure and room temperature. The catalyst is filtered off and the solvent is removed by distillation in vacuo.

Is obtained from the residue after recrystallization from Essigester / petroleum ether, the melting at 207-208 ⁰ C 5-ethyl-5- [3,5-diamino-4- (4'-methoxyphenoxy) benzyl] hydantoin in a yield of 77 , 5% of theory.

37.0 g of the above compound dissolved in 80 ml of glacial acetic acid are added dropwise to 40 ml concentrated sulfuric acid of 1O ⁰ C. This solution is added dropwise over the course of 2 to 3 hours to a ^{solution, cooled to -4 to -2 °} C., of 17.5 g of sodium nitrite in 175 ml of concentrated sulfuric acid and 200 ml of glacial acetic acid. The mixture is stirred for 1 hour at ⁰ ° C. and the solution is allowed to run rapidly with vigorous stirring to a mixture of 87 g of potassium iodide, 68.0 g of iodine, 10.0 g of urea, 1.3 l of water and 450 ml of chloroform. The mixture is stirred for 2 hours, the chloroform layer is separated off and the aqueous phase is extracted several times with chloroform. The combined chloroform extracts are washed with sodium bisulfite solution and then with water and dried over sodium sulfate. After filtration and removal of the solvent in vacuo, 5-ethyl-5- [3,5-diiodo-4- (4'-methoxyphenoxy) benzyl] hydantoin, which melts at 241 to 243 ° C., is obtained in a yield of 73% the theory.

59.2 g of the above compound are heated to reflux temperature for 1 hour with a mixture of 180 ml of hydriodic acid (d = 1.7) and 180 ml of glacial acetic acid. On cooling, 5-ethyl-5- [3,5-diiodo-4- (4'-hydroxyphenoxy) benzyl] hydantoin with a melting point of 313 ° to 316 ° C. is obtained after recrystallization from ethanol. Yield 93.7% of theory.

115.6 g of the above compound are in Dissolved 2200 ml of 2 η sodium hydroxide solution and heated to 140 ° C. in an autoclave for 100 hours.

It is then neutralized at the boiling point with 16% hydrochloric acid. The precipitate which separates out is filtered off with suction while it is still hot. It mainly consists of a-ethyl-3,5-diiodothyronine. On cooling, the a-ethyl-3-iodo-thyronine crystallizes from the filtrate. Both fractions are purified by dissolving in ethanol / concentrated hydrochloric acid and then precipitating the amino acid with saturated sodium acetate solution. This gives u-ethyl-3,5-diiodothyronine with a melting point of 285 to 288 ° C. with decomposition in a yield of 46.6% of theory and a-ethyl-3-iodothyronine with a melting point of 210 to 215 ° C. a yield of 39% of theory. The α-ethyl-3-iodo-thyronine solidifies with further heating between 220 and 240 ⁰ C and then melts again at 281 to 283 ° C with decomposition.

22.1 g of a-ethyl-3,5-diiodothyronine are dissolved in 130 ml of an aqueous 33% ethylamine solution and 86.5 ml of a 1.85 n-iodine-iodine potassium solution were added dropwise. The mixture is stirred for 1 hour and added with 16% hydrochloric acid up to a pH value of 5. The precipitated amino acid is filtered off, washed with water and dissolved in a mixture of ίο 250 ml of ethanol and 100 ml of 2N NaOH.

After clarifying with activated charcoal, a-ethylthyroxine is obtained by adding 2η-hydrochloric acid at pH 6 from a melting point of 236 to 238 ° C. in a yield of 60% of theory.

Example 6

The procedure is as in Example 1 and the ethyl ester of the melting point is obtained from the u-n-propyl-thyroxine 174 to 176 ° C in a yield of 57% of the Theory.

The u-n-propyl-thyroxine used above as the starting product is obtained analogously to that in the example 5 for the starting product via the following intermediate stages:

5 - η - propyl - 5 - (4 - methoxybenzyl) - hydantoin, melting point 244 to 245 ⁰ C from ethanol, yield 63% of theory, ■

5 - η - propyl - 5 - (4 - hydroxybenzyl) - hydantoin, melting point 286 to 288 ⁰ C from ethanol, yield 90% of theory,

5 - η - propyl - 5 - (3,5 - dinitro - 4 - hydroxybenzyl) hydantoin, melting point 212 to 213 ° C from glacial acetic acid, yield 74% of theory,
5-n-propyl-5- [3,5-dinitro-4- (4'-methoxyphenoxy) benzyl] hydantoin, melting point 196 to 198 ⁰ C from dilute acetic acid, yield 55% of theory,

5-n-propyl-5- [3,5-diamino-4- (4'-methoxyphenoxy) benzyl] hydantoin, Yield 96% of theory,

5-n-propyl-5- [3,5-diiodo-4- (4'-methoxyphenoxy) benzyl] hydantoin, melting point 247 to 248 ° C from methanol-ethylcellosolve,
5-n-propyl-5- [3,5-diiodo-4- (4'-hydroxyphenoxy) benzyl] hydantoin, melting point 298 to 299 ° C from ethanol, yield 80% of theory,
an-propyl-3,5-diiodothyronine, melting point 278 to 280 ° C, yield 58% of theory,
an-propyl-thyroxine, melting point 231 to 232 ° C., yield 46.5% of theory.

Example 7

The procedure is as in Example 1 and the ethyl ester of the melting point is obtained from (-H) -a-methyl-thyroxine 156 to 158 ° C in a yield of 84% of theory.

[«]? = + 10.0 ° (C = 5 in 1 N hydrochloric acid / 95% Ethanol 1: 2).

Example 8

The (-) - a-Methylthyroxinäthylester, melting point 156 to 158 "C in, is obtained analogously to Example 7 a yield of 78.3% of theory.

[«> = -12 ^i; (4% in glacial acetic acid).

Example 9

7.2 g of N-formyl-a-methyl-SS-diiodothyronine - ^ - diethylaminoethyl) ester hydrochloride are dissolved in 140 ml of absolute methanol and mixed with 40 ml of n-butylamine. 5.45 g of iodine, dissolved in 55 ml of absolute methanol, are slowly added dropwise with stirring, and the mixture is then stirred for 1 hour. Glacial acetic acid is added to pH 6. After addition of aqueous sodium acetate solution, the N-formyl-a-methylthyroxine - (/; - diiithylaminoethyl) ester is obtained in a yield of 89.4% of theory. The melting point is after recrystallisation from absolute ethanol 135 ^C C with decomposition.

The N-formyla-methyl-3,5-diiodo-thvronine - (/ * - diethylaminoutyl) ester hydrochloride used as the starting product can be obtained in the following way:

11.3 g of N-formyl - «- methyl-3,5-diiodothyronine suspended in 300 ml of absolute isopropanol, treated with 2.8 g / i-diethylaminoethyl chloride and Heated to reflux temperature for 4.5 hours. After cooling, the addition of absolute Ether the N-formyl-u-methyl ^ .S-diiodothyronine (p'-diethylaminoethyl) ester hydrochloride from melting point 115 to 120 ° C in a yield of 85.8% of theory.

Example 10

Analogously to Example 9, N-formyl-a-methyl-thyroxine-ß-pyrrolidinoethyl ester is obtained in a yield of 82.5%. After recrystallization from butanol / isopropanol, the melting point is 143 bis 145 ° C with decomposition.

The N-formylu-methyl-3,5-diiodo-thyronine- / i-pyrrolidinoethyl ester hydrochloride used as the starting product is obtained analogously to Example 9 from N-formyl-a-methyl-3,5-diiodothyronine and ß-pyrrolidinoethyl chloride. Yield 98% of theory, melting point after recrystallization from isopropanol 158 to 160 ° C with decomposition.

Example 11

Analogously to Example 9, the N-formyla-methyl-thyroxine - ^ '- morpholinoethylester is obtained in a yield of 73% of theory. After recrystallization from butanol / isopropanol, the melting point is 170 to 175 ° C with decomposition.

The melting point of the starting product, N-formyl-a-methyl ^ S-diiodothyronine- ^ morpholinoethyl ester hydrochloride is 165 to 168 ° C with decomposition.

Example 12

55

The procedure is as in Example 1 and the ethyl ester of the melting point is obtained from the a-n-pentyl-thyroxine 160 to 161 ° C after recrystallization from ethanol / water.

The u-n-pentyl-thyroxine used as the starting product above is obtained analogously to that in the example 5 for the starting product via the following intermediate stages:

5 - η - pentyl - 5 - (4 - methoxybenzyl) - hydantoin, melting point 203 to 205 ° C from ethanol / water. Yield 95% of theory,
5 - η - pentyl - 5 - (4 - hydroxybenzyl) - hydantoin.

Melting point 280 to 286 ^° C. from glacial acetic acid. Yield 80% of theory,

5-n-pentyl-5- (3,5-dinitro-4-hydroxybenzyl) hydantoin. Melting point 187 to 188 ^° C. from isopropanol / water. Yield 70.3% of theory, 5-n-pentyl-5- [3,5-dinitro-4- (methoxyphenoxy) benzyl] hydantoin. Melting point 193-195 ° C from methanol / water. Yield 86.2% of theory,

5-n-Pentyl-5- [3,5-diamino-4- (4'-methoxyphenoxy) benzyl] hydantoin. Melting point 189 to 190 ° C from methanol / water. Yield 89.4% the theory,

5-n-Pentyl-5- [3,5-diiodo-4- (4'-methoxyphenoxy) benzyl] hydantoin. Melting point 229 ° C from ethanol. Yield 93% of theory,
5-n-Pentyl-5- [3,5-diiodo-4- (4'-hydroxyphenoxy) benzyl] hydantoin. Melting point 235 ° C from glacial acetic acid. Yield 85.3% of theory,
an-pentyl-3,5-diiodothyronine, melting point 280 to 28 Γ C with decomposition, yield 79% of theory,

α-n-Pentylthyroxine, melting point 222-225 ° C with decomposition, yield 75.2% of theory.

Example 13

4.04 g of 3,5-diiodo-N-carbobenzoxy-a-methyl-thyronine- [2- (diethylamino) ethyl ester] hydrochloride are dissolved in 20 ml of glacial acetic acid, and 20 ml of 2N hydrobromic acid are added at 60 ° C. After 30 minutes one cools down. By adding ether, 3,5-diiodo-a-methyl-thyronine- [2- (diethylamino) ethyl ester] hydrobromide is obtained in the form of a hygroscopic precipitate. The precipitate is dissolved in 50 ml of absolute ethanol with 35 ml of n-butylamine and then added dropwise with a solution of 3.05 g of iodine in 35 ml of ethanol. Man lets react for some time and creates a by adding a 1: 1 mixture of glacial acetic acid and ethanol pH of 7 a. The addition of a 5% solution of sodium bicarbonate gives the α - methyl - thyroxine - 2 - (diethylamino) - ethyl ester in a yield of 4 g, that is 90% of theory.

The S ^ -diiodine-N-carbobenzoxy-a-methyl-thyronine-p-i-diethylamino) ethyl ester] hydrochloride used as the starting product above can be obtained in the following way:

11.06 g of 3,5-diiodo-a-methyl-thyronine-methyl ester and 5.52 g of potassium carbonate are suspended in 50 ml of absolute tetrahydrofuran and at 0 ° C 13.6 g of a 50% strength solution of carbobenzoxychloride in toluene were added dropwise. One lets

React for 1 hour and filter the undissolved material. The filtrate is concentrated to dryness in vacuo, the resulting oil is dissolved in a solution of 10 g of sodium hydroxide solution in 50 ml of methanol and 10 ml of water given and kept at room temperature for 20 hours. The solvent is removed in vacuo and the residue dissolved in water. By adding dilute hydrochloric acid to a pH of

2 to 3 is obtained 3,5-diiodo-N-carbobenzoxyu-methyl-thyronine melting point of 135 ⁰ C.

6.73 g of the above compound are dissolved in 40 ml of absolute isopropanol and 1.39 ml freshly distilled triethylamine added. 1.89 g of 2-diethylaminoethyl chloride hydrochloride are added and heated to reflux temperature for 5 hours with exclusion of moisture. Preserves when cooled

the 3,5-diiodo-N-carbobenzoxy-a-methyl-thyronine- [2- (diethylamino) ethyl ester] hydrochloride from melting point 177 to 178 ° C.

Example: 14

Proceed as in Example 13 and obtain from the 3,5 - Diiodo - N - carbobenzoxy - α - methyl - thyronine [2 - (N - piperidino) - ethyl ester] - hydrochloride den α - methylthyroxine - 2 - (N - piperidino) - ethyl ester in a yield of 85% of theory.

Example 15

6.57 g of 3,5-diiodo-N-benzoyl-α-methyl-thyronine methyl ester are dissolved in 100 ml of absolute methanol, and 50 ml of n-butylamine are added. A solution of 6.09 g of iodine in 70 ml of methanol is added dropwise. The reaction is allowed to continue for 2 hours at room temperature. Is obtained on the addition of methanolic hydrochloric acid to a-methyl-N-benzoyl-thyroxine-methylester of melting point 125 ⁰ C after recrystallization from methanol / water.

Claims (3)

Patent claims: 1. Esters of α-alkyl-thyroxine derivatives of the general formula ^R i 9 CH ₂ -CC-OR ₃ (I) in which R _{1 stands} for an alkyl radical with 1 to 6 carbon atoms, R _{2 stands for} an amino group or an acylamino group and R _{3 stands for} an alkyl radical with 1 to 6 carbon atoms or an aralkyl radical, where R _{3 is represented} by a group in which R ₄ and R _{5 are} identical or different and are hydrogen atoms, lower alkyl radicals or, taken together with the nitrogen atom, a pyrrolidine, piperidine or morpholine radical, can be substituted, as well as their salts with organic or inorganic acids or bases. 2. a-methyl-thyroxine-ethyl ester and its salts with organic or inorganic acids or bases. 3. Process for the preparation of compounds according to Claim 1 and salts of these compounds with organic or inorganic acids or bases, characterized in that one in a manner known per se a) a connection of the general formula HO 45 CH ₇ -C-COOH (H) wherein R ₁ and R _{2 have the} same meaning as in claim 1, a salt of this acid or a reactive derivative of the compound of the general formula II with a compound of the general formula X IVj (III) 60 wherein R _{3 has the} same meaning as in claim 1 and X is an oxy group, an esterified oxy group. a halogen atom or an oxy group, the hydrogen of which has been replaced by a metal atom, reacts in the presence of acidic or basic esterification catalysts or by azeotropic removal of water or b) a compound of the general formula
J HO CH ₇ -C-COOH (IV) wherein R ₁ and R _{2 have the} same meaning as in claim 1, a salt of this acid or a reactive derivative of the compound of the general formula IV with a compound of the general formula III in the presence of acidic or basic esterification catalysts or by azeotropic water removal to react and into the resulting compound of the general formula R ₁ O Γ ii CH ₇ -CC-OR, R ₇ (V) in which R ₁ to R _{3 have the} same meaning as in claim 1, with the aid of iodinating agents, introduces two iodine atoms, optionally in stages, and optionally _{acylates the amino group in the compounds of general formula I thus obtained in which R 2 is} an amino group and / or the compounds of the general formula I obtained in this way are converted into the corresponding salts with inorganic or organic bases or acids or
c) a compound of the general formula HO CH ₂ -CC-OR ₃ wherein R ₁ to R _{3 have the} same meaning as in claim 1, at a pH value approaching the neutral point, preferably in the weakly alkaline range, with an acid of the formula HO CH ₂ -CO-COOH (XIV) condensed and optionally in the compounds of general formula I thus obtained, in which R _{2 is} an amino group, acylated the amino group and / or the compounds of general formula I thus obtained are converted into the corresponding salts with inorganic or organic bases or acids.