DE2338087A1 - NEW ALDONIC AMIDES AS MEDICINAL PRODUCTS - Google Patents

Description

Chemical works Mbert Aktiengesellschaft »Wiesbaden Patent application

New aldonic acid amides as pharmaceutical additions to patent (patent application P 23 21 752.9)

The main patent relates to new aldonic acid amides of the general formula I.

^ N-C- (CHOH) -CH, -X * f

• a * ^ f | η * ^ -

² O

in the

R _{1 is} an aliphatic radical with 4 to 7 carbon atoms in

normal or branched arrangement, which is optionally interrupted by an oxygen or sulfur atom and / or optionally carries a hydroxyl group, the oxygen or sulfur atom or the hydroxyl group having more is separated as a carbon atom from the nitrogen atom of the acid amide group,

R _{2 is} hydrogen or an aliphatic radical with 1 to 3 carbon atoms which is optionally substituted with a phosphiny group which in turn bears alkyl, hydroxyalkyl and / or alkoxyalkyl radicals with 1 to 3 carbon atoms in each alkyl or alkoxy component can be,

η is an integer from 3 to S and

X represents a hydroxyl group or hydrogen.

- 409883/1440. ,.

_ 2 -

The main patent also relates to a method of production of aldonic acid amides of the aforementioned formula I and medicaments, which by a content of compounds of the Formula I are marked.

It has now been found that such aldonic acid amides are also found of the aforementioned formula I are suitable as medicaments in which

»It 8-JO. preferably R- an aliphatic radical YmTt8 carbon atoms, in normal or branched arrangement, which is optionally interrupted by an oxygen or sulfur atom and / or optionally carries a hydroxyl group, for example the oxygen or sulfur atom or the hydroxyl group is separated from the nitrogen atom of the acid amide group by more than one carbon atom.

Rj , η and X have the meaning given above for the main patent.

The present application also relates to a process for the preparation of Mdonsäureamiden of the aforementioned formula I with the meaning given according to the invention for R ₁ , which is characterized in that aldonic acids or their derivatives, such as esters or lactones, with amines of the general formula II

^R 1

H-N

in which R _{1 has} the meaning given according to the invention (except n-octyl) and R> has the same meaning as given above for the medicament. Finally, the new AldonsXurearaide of the general formula I are also the subject of the invention, in which R. the meaning given according to the invention (other than n-octyl) and R-, η and X have the meaning given above for the main patent.

409883/1440

In principle, all routes known in carbohydrate chemistry for amide syntheses can be followed for the synthesis of the new aldonic acid amides. However, it is advantageous to use the arainolysis of the aldonic acid esters, it being possible to use, for example, the methyl or ethyl esters, but even better the easily accessible lactones of the corresponding aldonic acids, such as pentonic, hexonic, 6-deoxyhexonic and heptonic acids. The pentonic acids arabonic, ribonic and xylonic acids, the hexonic acids allonic, altronic, galactonic, gluconic, gulonic, idonic, mannonic and talonic acids and their 6-deoxy analogs are of importance for this purpose. From the series of heptonic acids, mention should be made of glycerogalactonic, glycerogulonic, glycerogluconic, glyceroidonic, glyceromannonic and glycerotalonic acid. The listed lactones are mostly used in the optically active forms, such as the L, D, LL, DL, DD form. However, the racemates can also be used in the same way. The amines converted into the claimed amides are, for example, 2-amino-n-octanef2,4- \ 5 $. [

Io \ trimethylpentane, -5-methylheptane, -6-methylheptane, -5-hydroxy-5- \ t = 'methylheptane. All the materials can be optionally used in their L / ³ "optically active form.

The reactants can be advantageous in the ratio 1: 1 to 1: 1.2 to react at temperatures between 10 and 80 ⁰ C. If a solvent is used, it is advantageous to use monohydric alcohols with 1 to 4 carbon atoms, such as methanol, ethanol, the propanols, n- and isobutanols and / or monoethers of diols with a total of 3 to 6 carbon atoms, such as ethylene glycol monomethyl ether , monoethyl ether or raonobutyl ether, and also dihydric alcohols with 2 to 6 carbon atoms, such as ethylene glycol, propane or butanediols or diethylene glycol; p-Dloxane can also be used, and to a certain extent also pyridine, quinoline and dimethylformamide, although with these basic reading agents conditions must be observed under which isomerization of the hydroxyl groups is avoided.

A09883 / 1AAO

The progress of the reaction can be followed with the aid of chromatographic analysis methods, for example thin-layer chromatography. So the timing of the full Easily determine implementation.

A large number of new AldonsHuramides can be prepared using the specified process, such as the compounds (see the formula table under the serial number)

1) D (+) - gluconic acid - (+) - (6-methyl) -heptyl- (2) -amide;

2) D (+) - GluconaSure - (-) - (6-methyl) -heptyl- (2) -a »id;

3) D (+) - gluconic acid (5-methyl) -heptyl-amide;

4) ρ (+) - gluconic acid-n-octyl- (2) -amide j

5) D (+) - gluconic acid (2,4,4-trimethyl) pentyl (2) amide;

6) D (+) - gluconic acid (5-hydroxy-5-methyl) -heptyl- (2) -amide j

⁺ ) The corresponding ribonic, galactonic and heptagluconic acid compounds can also be prepared, as are those of C 1 and C 3 amines. The structure of the substances produced according to the invention was determined determined in different ways, namely by melting point, elemental analysis, thin-layer chromatography and IR spectroscopy. In individual cases, the result was due to nuclear magnetic resonance or Mass spectrography corroborated. The Aldonsäureamld «are versatile due to their physical properties, since they have both a lipophilic and a hydrophilic moiety; in contrast to the unsubstituted amides the amides show good stability even in aqueous solutions. Solubility in water is achieved, for example, in d-gluconic acid amide of 1-amino-n * octane has a value of at least · «· 0.21 at 20 ° C.

The aldonic acid amides can be used as intermediates for dl · production of acyl compounds, phosphoric and boric acid esters as well Metal complexes, as well as auxiliary materials in electroplating Process as a mold release agent or lubricant in the plastics, in particular aminoplast molding compounds processing industry or al

+) 7) D (+) - gluconic acid-3- (h * xyloxy) -propylamide. - 5 -

409883 / U40

Intermediates for electrochemical reactions such as reductions or oxidations are used. Similar to the well-known lactic acid ethanol amld, they show solubilizing properties and due to the accumulation of hydroxyl groups has antistatic effects. Furthermore, they show good tolerance and low toxicity versatile pharmacological effects, of which in particular the analgesic, anti-inflammatory, vasodilator and breathable can be used for therapeutic applications. The very low toxicity offers advantages in the therapeutic application.

The stability of the compounds, which are usually obtained in crystalline form, allows the preparation of industrially usable preparations as well as the production of pharmaceutical preparations, e.g. for oral, parenteral and rectal administration.

The preparation of these preparations can be carried out according to the usual practice with the deletion of suitable further active ingredients and / or suitable ones compatible excipients such as starch, lactose, cellulose derivatives, stearic acid or its salts, solvents, dissolving agents, suppositories, chlorides, phosphates and carbonates, e.g. sodium bicarbonate, take place in a manner known per se Way to powders, tablets, dragees, capsules, suppositories, solutions or suspensions.

Examples

1) To a suspension of 17.81 g (0.1 mol) D (+) - gluconic acid-S-lactone in 55 nl of methanol at an initial temperature of 23 ° C. with stirring in the course of 20 minutes 12.92 g (0.1 mol) (+) - ^ - heptane dripped. The progress of the reaction can be followed with the aid of chromatographic and / or electrographic methods. The D (+) -gluconic acid - (+) - (6-methyl) -2-heptyl- (2) -araid (melting point 130 ° C) is isolated by concentrating the solvent and then

409883 / UAO

Crystals are filtered off. Yield 27.12g *. 85% of theory.

Instead of D (+) - GluconsMure - ^ - lactone, D (+) - Glucon-

acid-v-lactone can be used.

Examples 2-6

The connections according to & here were generated analogously

represents.

The compound according to Example 4 was found in the phenyl-p-quinone writhing test on the mouse according to Sigmund et al (Proc.Soc.exp.Biol. Med. 95_ (1957) 729) as having an analgesic effect. With a cheaper one Tolerance was found to be much higher therapeutic Index than for aminoph3nazon. The determined values are compiled in the following table:

Substance number,

_5o in rag / kg via QS

Phenyl-p-quinone test

LD ₅₀ (mouse)
in mg / kg per os

TI

(Phenylquinone test)

¹⁰ SO * »So

c «. 35

4ooo

> 4o to 80

Aminophenazon 27 eiafenin 42

1252
84o

46
2o

409883 / UAO

Formula table

running No.

structure

Scheel «- point ⁰ C

manufactured] after

Example Mr.

CH.

CH,

OH H OH OH

C-CH- (CH-KrCH-NH-C-C-C-C-C-CH-OH

²³ Ii III i

O H OH H H 130 *

CH,

CH,

OH H OH OH

H-C-CH- (CH -), - CH-NH-C - C - C - C -C-CH - OH

^{3 2 3} IIIII

0 H OH H H 159 ⁴

CH,

H, C-CH ₀ -CH- (CH-). -NH-C -3 2 2 A η

OH H

C -

OH OH

- C-CH-OH

I ²

H OH H H

CH,

OH H OH OH

H-C- (CH-) c-CH-NH-C -C-C-C-C-CH-OH

^{3 2 5} ι \ ι ι T

O H OH H H 161 '

CH, CH,

H, C-C-CH-C-NH-C

³ I ² I Ii

CH, CH, 0

OH H OH OH

I I I I

C - C -C - C - CH-OH

I Il I ■

H OH H H

131 '

CH,

CH.

OH H OH OH

I ^J I ° (III

H-C-C- (CH -), - CH-NH-C -C-C-C-C-CH-OH

³ I ^{2 3} · IIIII

OH O H OH H H

£ 1.

OH H OH OH

I I I I

H ₃ C- (CH ₂ ) ₅ -O- (CH ₂ ) ₃ -NH-CC -CCC-CHjOH

OH OH H H 122-126

409883 / U40

Claims (1)

Patents area 1. Medicines, characterized by a content of compounds the formula I. • ν NC- (CHOH) -CH - XI * α η ί ^R 2 0 X wherein R _{1 is} an aliphatic radical, R_ is hydrogen or an aliphatic radical with 1 to 3 carbon atoms, optionally with a phosphinyl group, which in turn carries alkyl, hydroxyalkyl and / or alkoxyalkyl radicals with 1 to 3 carbon atoms in each alkyl or mkoxy component , can be substituted, η is an integer from 3 to 5 and X is a hydroxyl group or hydrogen, according to patent (patent application P 23 21 7 52.9), characterized in that R .. is an aliphatic radical with 8 'carbon atoms in normal or branched The arrangement represents / ier is optionally interrupted by an oxygen or sulfur atom and / or optionally carries a hydroxyl group, the oxygen or sulfur atom or the hydroxyl group being separated from the nitrogen atom of the amide group by more than one carbon atom. 2. MdonsHureamide of the general formula I according to claim 1 and Claim 1 of the patent (patent application P 23 21 752. 9 \ characterized in that ¹ ^ ₂ , η and X have the meaning given in claim 1 and in claim 1 of the main patent and that R _{1 has} the meaning given in claim 1 with the exception of a] pj ·. Has hydrocarbon for it tes \ [in normal order. 3. Further development of the process for the production of Aldons suramides of the general formula I according to claim 2 of the Patent (patent application P 23 21 752.9), where one aldonic acids or their derivatives, such as esters or lactones, A09883 / UA0 OfUGiNAL INSPECTED with amines of the general formula II H-IT II characterized in reacting such Aroide of the general formula II in which R _1, R _2, η, and X have the meanings given in the claim of the present application. 4. Embodiment according to Claims 1 to 3, characterized in that R _{1 is} an aliphatic radical having 8 carbon atoms. June 18, 1973
Dr.KIr / Her 409883 / 1U0