DE1493567C3 - Esters of alpha-alkylthyroxine derivatives and process for their preparation - Google Patents

Description

The present invention relates to esters of «-alkyl- of the general formula thyroxine of the all common formula

J J

R ₁ O
CH ₂ -CCOR ₃ (I)

R,

CH ₂ -C-COOH

(H)

where 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

—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 α-AIkyI-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.

Thus, after oral administration of DL-α-methylthyroxine ethyl ester hydrochloride, a decrease 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 can be 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-u-methyl-thyroxine listed below Values:

Methyl: 100; // - dimethylaminoethyl: 50 to 100; /) '- diethylaminoethyl: 50 to 150; /> '- PiperidinoethyI: 50 to 150; // - Morpholinoethyl: 50 to 100; /; - Pyrrolidinoethyl: 50 to 100,

The connections of the general form! I are prepared (method a) by adding an acid ίο 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

XR 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

bond of the general formula II with a compound of the general formula III, but you can also use one of the components in Use excess. Preferably, if neither the compound of formula II is used as a salt with a base or a compound of the formula III in which X is an oxy group in which the hydrogen is replaced by a metal atom, are used, acidic esterification catalysts are 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 it the acid. Is in the formation of the compound of general formula I from a compound of general formula II and a compound of general formula III water free, so the resulting Water can also be removed by means of azeotropic distillation.

The compounds of general formula I can also be prepared (method b) by one is a compound of the general formula

CH ₂ -C-COOH (IV) R ₂

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

I Il

-CH ₂ -CC-OR ₃ (V)

J ^R 2

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

NO-

HO

CH ₇ -CC-OR,

(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

R «O-

-OH

(VII)

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

NO ₂

(VIII)

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

(IX)

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

wherein R _{8 has} the aforementioned meaning, in the presence of a solvent and / or an inorganic or organic base, preferably pyridine, NO,

R «0

^R > 9

CH ₂ -CC-OR ₃

wherein R ₁ , R ₃ and R _n 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

HO-f VCH ₂ -CC-OR ₃

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

R «-O

On"

(XII)

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

R ₁ 0

C-CrOR ₃ (XIII)

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

HO

CH ₇ -CO-COOH

PCIV)

condensed. The condensation takes place in itself

In a known manner, by adding a compound of the general formula XI in a buffer solution, such as. B. an aqueous solution of borax and secondary sodium phosphate or citric acid and eecondary sodium phosphate a weakly alkaline pH, preferably pH 7.6 to 7.8 optionally with the addition of a water-miscible organic solvent such. B. a liederen alkanol, dioxane, dimethylformamide, di-Tiethylacetamid or Äthylenglykolmonoäthyläther and mixed with a corresponding solution of an acid of the formula XIV all at once or in portions. You can use stoichiometric amounts of compounds of the formulas XI and XIV or one of the components in excess. The condensation can also take place 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 active substances, such as. As organic peroxides, or salts of divalent manganese, working under introduction of oxygen during the duration of the condensation, at temperatures below 100 ⁰ C, under anaerobic or aerobic conditions, for example.

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 in 150 ml of absolute Ethanol suspended. While warming, dry hydrogen chloride gas is passed in until it is saturated one. The solvent is removed by distillation in vacuo. The return starvation is in Dissolved 50% ethanol and neutralized with a 5% solution of sodium bicarbonate. Included the ethyl ester of a-methylthyroxine with a melting point of 156 ° to 157 ° C. is obtained after crystallization 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.

* 'B e i s ρ i e 1 3

2 g of a-methylthyroxine are added in portions to a mixture of 20 ml heated to 95 ° C Benzyl alcohol and 5 g of polyphosphoric acid were added.

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 over sodium sulfate dried and concentrated in vacuo. After the residue has been dissolved in ethanol, the addition is obtained of water, the benzyl ester of a-methylthyroxine from melting point 178 to 180 ° 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.

The ethyl ester of a-methylthyroxine is obtained by adding a solution of sodium acetate in water from melting point 156 to 157 ° C, in one Yield of 83% of theory, identical to the product obtained according to Example 1.

The 3,5-diiodo-u-methylthyronine ester used above as a 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 the ethyl ester of the melting point is obtained from the a-ethylthyroxine 138 to 140 ° 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. On cooling, 5-ethyl-5- (4-hydroxybenzyl) hydantoin with a melting point of 290 to 291 ° C. is obtained 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.

409 620/11

64.8 g of the above compound and 42 g of p-toluenesulfonic acid chloride are heated to reflux temperature in 150 ml of pyridine for 10 minutes. After cooling, 62 g of 4-methoxyphenol, dissolved in 62 ml of pyridine, are added and the mixture is heated at reflux temperature for 1 hour. After cooling, by dilution with 6 times the volume of ice-water containing 5 -AE thyl - 5 [3,5 - dinitro - 4- (A '- methoxy phenoxy) - benzyl] hydantoin of melting point 195-197 ⁰ 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 within 2 to 3 hours to a ^{solution, cooled to -4 to -2 0} 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. Upon cooling, there is obtained the 5-ethyl-5- [3,5-diiodo-4- (4'-hydroxyphenoxy) benzyl] hydantoin of melting point 313-316 ⁰ C after recrystallization from ethanol. Yield 93.7% of theory.

115.6 g of the above compound are dissolved in 2200 ml of 2η 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 falling precipitation is sucked off while it is still hot. It mainly consists of u-ethyl-3,5-diiodothyronine. Crystallized from the filtrate on cooling the u-ethyl-3-iodo-thyronine. Both fractions are concentrated by dissolving in ethanol / Hydrochloric acid and subsequent precipitation of the amino acid with saturated sodium acetate solution. The α-ethyl-3,5-diiodothyronine is thus obtained with a melting point of 285 to 288 ° C Decomposition in a yield of 46.6% of theory and the a-ethyl-3-iodo-thyronine melting point 210 to 215 "C in a yield of 39% of theory. The α-ethyl-3-iodo-thyronine solidifies with further Heat between 220 and 240 ° C and then melt again at 281 to 283 "C with decomposition.

22.1 g of u-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, u-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 a-n-propyl-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 - propyl - 5 - (4 - methoxybenzyl) - hydantoin, melting point 244 to 245 ° C from ethanol, yield 63% of theory,

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

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

5-n-PropyI-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,
un-propyl-3,5-diiodothyronine, melting point 278 to 280 ⁰ C, yield 58% of theory,
un-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 the -u-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 (-) -u-methylthyroxine ethyl ester is obtained analogously to Example 7. Melting point 156 to 158 "C in a yield of 78.3% of theory.
[«> = -12" (4% in glacial acetic acid).

Example 9

7.2 g of N-formyl - «- methyl-3,5-diiodothyronine (ß-diethylaminoethyl) ester hydrochloride are dissolved in 140 ml of absolute methanol and 40 ml of n-butylamine offset. 5.45 g of iodine, dissolved in 55 ml of absolute methanol, are slowly added dropwise with stirring and stirs for 1 hour. Glacial acetic acid is added to pH 6. After addition the N-formyl-α-methylthyroxine (/ j-diethylaminoethyl) ester is obtained from aqueous sodium acetate solution in a yield of 89.4% of theory. The melting point after recrystallization is from absolute ethanol 135 ° C with decomposition.

The N-formyla-methyl-3,5-diiodothyronine - (/; - diethylaminoethyl) ester hydrochloride used as the starting product 'is obtained in the following way:

11.3 g of N-formyl-a-methyl-3,5-diiodothyronine are suspended in 300 ml of absolute isopropanol, 2.8 g of diethylaminoethyl chloride are added and the mixture is refluxed for 4.5 hours. After cooling, by the addition of absolute ether, the N-formyl-u-methyl-S ^ -dijodthyiO-nin (p'-diethylaminoethyl) ester hydrochloride of melting point 115 to 120 ⁰ C in a yield of 85.8% of theory .

Example 10

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

The N-formylu-methyl ^ .S-diiodo-thyronine-ß-pyrrolidinoethyl ester hydrochloride used as the starting product is obtained analogously to Example 9 from N-formyl-α-methyl-3,5-diiodothyronine and ß-pyrrolidinoethyl chloride. Yield 98% of theory, melting point after recrystallization from isopropanol, 158 to 16O ⁰ 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-u-methyl-3,5-diiodothyronine - /:) - rnorpholinoethylester-hydrochloride is 165 to 168 ° C with decomposition.

Example 12

55

The procedure is as in Example 1 and obtained from the in-pentyl-thyroxine the ethyl ester of melting point 160-161 ⁰ 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) -benzylj-hydantoin. Melting point 235 ° C from glacial acetic acid. Yield 85.3% of theory,
an-pentyl-3,5-diiodothyronine, melting point 280 to 28TC 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 treated at 60 ° C. with 20 ml of 2N hydrobromic acid. After 30 minutes it is cooled 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, 35 ml of n-butylamine are added and a solution of 3.05 g of iodine in 35 ml of ethanol is then added dropwise. The mixture is left to react for some time and a pH of 7 is set by adding a 1: 1 mixture of glacial acetic acid and ethanol. By adding a 5% solution of sodium bicarbonate yields the a - methyl - thyroxine - 2 - (diethylamino) - ethyl ester g in a yield of 4 which are 90% of theory.

The S ^ -diiodo-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 one obtains the 3,5-diiodo-N-carbobenzoxya-methyl-thyronine of melting point 135 ° 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

to the 3,5-diiodo-N-carbobenzoxy-u-methyl-thyronin- [2- (diethylamino) ethyl ester] hydrochloride of melting point 177-178 ⁰ C.

Example 14

The procedure is as in Example 13 and from the 3,5-diiodine-N-carbobenzoxy-α-methyl-thyronine- [2 - (N - piperidino) - ethyl ester] - hydrochloride the 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 - «- methyl-thyronine methyl ester are dissolved in 100 ml of absolute methanol and mixed with 50 ml of n-butylamine. One gives A solution of 6.09 g of iodine in 70 ml of methanol is added dropwise. It is left at room temperature React for 2 hours. The addition of methanolic hydrochloric acid gives the methyl-N-benzoyl-thyroxine methyl ester melting point 125 ° C after recrystallization from methanol / water.

Claims (3)

Patent claims: i. Esters of -alkyl-thyroxine derivatives of the general formula R, O CH ₂ -CC-OR ₃ (I) IO 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 ■ R « HO- X-R, (III) 15th 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. ü-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 compound of the general formula 45 CH ₂ -C-COOH (ID 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 60 wherein R _{3 has the} same meaning as in claim 1 and X can be an oxy group, an esterified oxy group, a halogen atom or an oxy group whose hydrogen is replaced by a metal atom, in the presence of acidic or basic esterification catalysts or by azeotropic water removal to the reaction or b) a compound of the general formula
J HO R, 0- / VCH ₂ -C-COOH R, (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 HO 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 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.