LV10430B - Method for preparation of pyridine-2,4-dicarbonic acid n,n'-bis(akoxyalkyl)-diamide and application thereof - Google Patents

Abstract

N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxylic acid diamides of the formula I <IMAGE> where R<1> is linear or branched C1-C4-alkanediyl, R<2> is unbranched C1-C4-alkyl or hydrogen and n is 1 or 2 and R<1'>, R<2'> and n' have the same meanings as R<1>, R<2> and n, where R<1> and R<1'>, R<2> and R<2'>, and n and n' are identical or different, and their physiologically acceptable salts with the exception of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)pyridine-2,4-dicarboxylic acid diamide. The compounds of the formula I inhibit prolin hydroxylase and lysin hydroxylase and are suitable as fibrosuppressants and immunosuppressants.

Description

LV 10430

Beschreibung N, Ν'-Bis (alkoxy-alkyl) -pyridine-2,4-dicarboxylic acid amide, Verfahren zu deren Herstellung sowie deren Verwendung

Verbindungen, die die Prolin- and Lysinhydroxylase inhibieren, bewerken eine sehr selective Hemmung der Kollagenbiosynthese durch Beeinflussung der collagenspezifischen Hydroxylierungsreaction. In deren Verlauf wird Protein-able glands Proline or Lysin durch die Enzyme Prolin-bzw. Lysinhydroxylase hydroxyl. Wird diese Reaction durch Inhibitoren unterbunden, that is, the functional functions of the collagen molecule, unterhydroxyl esters of the collagen molecule, das von den Zellen nur in geringer Menge in den extrazellulen jerden. The unhydrogenated Kollagen can be added to the Kollagenmatrix and the proteolytic chain. Als Folge dieser Effekte verringert sich insgesamt die Menge des extrazellular abgelagerten Collagen.

Especially, the Inhibitor, the Inhibitor of the Proline Hydroxylase Durch Inhibitor, the α, α'-Dipyridyl in the Hemmung der Clg-Biosynthesis of Macrophage (W.M.Tiller et al., FEBS Lett. 90: 1978, 218; Immunobiology 155). (1978, 47). Dadurch and I go to Ausfall-des klassischen Weges der Komplementaktivierung. Inhibitoren der Prolinhydroxylase wirken daher auch als Immunsuppressiva, z.B. bei Immunocomplex krankheiten.

In a first step, the effective gehemmt of pyridine-2,4- and -2,5-dicarbonsaure of pyrrolidine hydroxylase (K. Mayaja et al., Eur. J. Biochem. 138: 239-245 (1984)). Diese Verbindungen sin in der Zellkultur allerdings nur in sehr hohen Konzentrationen als Hemmstoffe Virksam (Tschank, G. et al., Biochem. J. 238, 625-633, 1987). 2

In accordance with DE-A 34 32 094, pyridine-2,4- and -2,5-dicarboxylic acid esters with 1-6 C-atoms are ester alkyl esters which are inhibited by proline and lysine hydroxylase.

The diesters of the diester have been added to the diethyl ester, the dairy system, and the organism has been concentrated, and the concentration has been confirmed in the case of the gaseous event.

DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 beschreben in ingemeiner Form ester / Amide, hoher alkyl ester of diester and diamide der Pyridine-2,4-und-2,5-dicarboxylic acid, die die Collagenbiosynthese im Tiermodell wirksam hemmen.

Thus, DE-A 37 03 959 unter anderem die Syntheses of N, N1 - Bis (2-methoxyethyl) -pyridine-2,4-dicarbonurea diamide (III) CONH-CH2-CH2-O-CH3

(III) und N, Ν'-Bis (3-isopropoxypropyl) -pyridine-2,4-dicarbonsaurediamide (IV)

CONH-CH2-CH2-CH2-0-CH

beschrieben. (IV) LV 10430 3

In patent applications P 38 26 471.4 and P 38 28 140.6 are added in the form of N, N'-Bis (2-methoxyethyl) -pyridine-2,4-dicarboxylic amide (III) vorgeschlagen.

DE-A 37 03 959 is intended for enteral resorption, which is a non-specific formulation, so that the bedding is best used, and the formulation is ready for use in the preparation of a dosage form.

I wurde nun gefunden, da8 Verbindungen der Formel I n

_CONH- (R 1 ') - (OR 2') n., N CONH- (R 1) - (OR 2) (I) worin R 1 lineares or C 1 -C 4 -alkanediyl, R 2 unverts C 1 -C 4 -Alkyl or Wasserstoff η 1 or 2, and R 2, R 2 and n 'are selected from R 1, R 2, and R 2, and R 2, and R 2, and R 2 and R 2, and R 1 and 2 are identical, or physically! ogisch vertragliche Salze, ausgenommen N, N'-Bis (2-methoxyethyl) -pyridine-2,4-dicarbonsaurediamide and N, N '- Bis (2-hydroxyethyl) -pyridine-2,4-dicarbone aurediamide, die oben genannte Aufgabe erfullen.

DE-A 37 03 959 Beschrieben Verbindungen N, N'-Bis (2-methoxyethyl) -pyridine-2,4-dicarbonyl-saurediamide and N, N'-Bis (3-isopropoxypropyl) -pyridine -2,4-dicarbonsaurediamides We have obtained the formula I for use in the preparation of pharmaceutical formulations and for the use of the enteric resorbierbarkeit auf. (I) 4

Weiterhin betrifft erfindung et Verfahren zur Herstellung von N, N'-Bis- (alkoxyalkyl) -pyridine-2,4-dicarbonsaurediamide der Formula I CONH- (R1). ^ (OR2).

CONH- (R1 ') - (OR2') n. n worin R ^ · lineares or C 1 -C 4 -alkanediyl, R 2 unverzweigtes C 1 -C 4 -alkyl or Wasserstoff η 1 oder 2 bedeutet und i f λ 1 Λ 0

Rx, R2 and n1 are optionally substituted in the presence of R, R6 and n are the same, R1 and R1, R2 and R2 and n are identical or identical, N, N'-Bis (2-methoxyethyl) -pyridine- 2,4-Dicarboxylic acid amide and N, N'-Bis (2-hydroxyethyl) -pyridine-2,4-dicarboxylic acid amide, pyridine-2,4-dicarboxylic acid halide with alkoxyalkylamine or hydroxylalkylamine.

The reaction is carried out on N, N-bis (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamide der Formula I CONH- (R 1) - (O 2 R 2) n.

N CONH- (R1 ') - (OR2') n. worin R ^ · lineares oder verzweigtes C ^ -C ^ -Alkandiyl, R * unverzweigtes C1-C ^ -Alkyl oder Wasserstoff η 1 oder 2 bedeutet und (I) 5 EN 10430 »» Ο 1 1? R, R · 6 and n in Diesel Bedeutungen with R, R · 6 and n in i 5 o · haben, wobei R · 1 · and R, R and R and n and n * identical to or dadurch gekennzeichnet ist , dafl man zunachst A) 1. Pyridine-2,4-dicarbonsaure with all halogen derivatives, and daB man 2 all 2 hydroxyalkylamine or alkoxyalkyl derivative of formula II 'H 2 N- (R 1) - (OR 2). n (II) h2n- (R1 ') - (0R2') n. (II ') worin

Rx and Rx linearly or alternatively C4 -C4 -alkyl, 1 &quot;) &quot; R * and Rx &lt; RTI ID = 0.0 &gt; linear &lt; / RTI &gt;

1 ifo 2 I RA * and Rx, R ^ und R &quot; 6, which are identical or unlike verses, wobei aber II and II ', in einem Losungsmittel lost und dafl man dann die gemaB 1. hergestellte Losung mit der. gemāfl 2. hergestellten Losung zur Reaction bring, or daB man B) das so erhaltene N, N'-Bis (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamide in die Bis (hydroxyalkyl) verbindung c) das gemaB A ) 1. hergestellte

Pyridine-2,4-dicarboxylic acid halide substituted or unsubstituted with benzyl alcohol Pyridine-2,4-dicarbone &amp; urea benzyl ester, benzyl ester selective in 2-position des Pyridine verse, gemfl Verfahrensvariante A) 1. A d) Saurehalogenide Formulations and Formulations of Formula A) 2. Hergestellten Formation of Formula II ', Wobeiin Pyridine-4-carbonsaurebenzyl ester-2-6 carboxylic acid derivative, and daBzene -Position hydrogenolysis of abscesses, freie Carbonsaar gemafl Verfahrensvariante A) 1. erneut in das Saurechlorid uberfiihrt, welch dann mit eema gemaB A) 2. hergestellten Losung unter Verstindung der Formine II versus winters. und daB me ggf. anschlieBend die erhaltene Verbindung der Formel I in ihr physiologisch vertragliches Salz uberfiihrt.

The demineralization of the Formula I is followed by the purification of pyridine-2,4-dicarboxylic acid in the presence of toluene suspensions and the addition of a halogenated solution. SOCI2 / versetzt. Mild anhydrous molar Menge an Pyridine-2,4-dicarboxylic acid is added 2-3 equivalents to halogenierungsmittels, equilibrated to 2.5 Aquivalent. The reaction mixture was stirred at 90-110 ° C, vortexed at 100 ° C, solanized, and the gas was removed from the reaction mixture. AnschlieBend is obtained from a lorzugsweise im Hochvacum (bis ca. 10'J Torr) at -10% yield, and the carboxylic acid halide weiter umgesetzt.

Mild anhydrous mole an pyridine-2,4-dicarboxylic acid is used and the 2-4-molar molar alkene alkylene or hydroxyalkylamine in toluene gelol is added to the base. . Das Carbonsaurehalides wird with dem Alkoxyalkylamine bzw. dem Hydroxylalkylamin zur Reaction gebracht. Dies geschieht bezorzugt poison man die Losung des genannten-alkylamine zu dem gelosten 7 EN 10430

Pyridine-2,4-dicarbonsaurehalide tropft. I am able to use a carbon monoxide, which is a carbon monoxide halogenide and a derivative of alkoxyalkylamine bzw. Hydroxyalkylamines zu tropfen. The temperature of the solvent was lowered to -5 ° C to + 5 ° C, and to 0 ° C. Die Reaktionsmischung laBt me dann nachreagieren poison me z.B. auf Raumtemperatur erwarmt und noch 2-5 Hours, unfiltered 3 Hours nachruhr. Das erhaltene Produkt wird anschlieBend angesauert, um uberschussiges Hydroxy-bzw. Alkoxyalkylamine vom gevninschten Produkt abututenen. Das Ansauern can be used with 0.2 molar Citronensaure erfolgen. The organization phase was completed and the Wasser gewaschen. AnschlieBend wird die organche Phase getrocknet -worms iiber Magnesium sulphate and schliefilich or Losungsmittel befreit. Beim Entfernen des Losungsmittels Wallpaper Product als weifler Festkorper oder als 01 an. For the preparation of N, N'-Bis (hydroxyalkyl) -pyridine-2/4-dicarboxylic acid diamides, bis (alkoxyalkyl) diamide, bis (methoxyalkyl) diamide, non-ferrous literfekrenen, beispiel. Boron tribromide, in das entsprechende Bis (hydroxyalkyl) diamid uberftihrt.

Unsymmetrisch substituierte Verbindungen der Formel I konneen folgendermaflen synthetisiert werden:

Umsetzung Pyridine-2,4-Dicarbonsaurehalide / Chloride, with Substituted or Unsubstituted Benzyl Alcohol

Pyridine-2,4-dicarbonsaurebenzyl ester, selective selective reverse-ester in 2-position (ZB in Gegenwart eines Coupling Catalyst, Acta Helv. 44, p. 637, 1963), Uberfur der Freien Saure in 2-position Saethalogen, Um. einer Verbindung der Formel (II ') z Pyridine-4-carboxylic acid benzyl ester-2-carbon monoxide, hydrogenolytic acid derivative 8

Benzylschutzgruppe (z.B. with I / Pd, p. Houben-Weyl Bd. IV / 1c (1980), p. 381-82) and an anhydrous salt in the 4 position des Pyridine in the diacid halide.

Das Saurehalogens can be obtained by Amin II in das gemischte Diamid (I) fiber (wound reaction).

Gegebenenfalls can die for product extraction or extraction or chromatography Chromatographie z.B. tiber Kieselgel erfolgen. The isolation of the product can be achieved by crystallization and germination of the salt by means of a physiologically stable salt solution. Als geeignete Sāuren kommen beispielsweise in Betracht:

Mineral salt, wie Chlorvrasserstoff- und

Bromwasserstoffsāure sowie Schwefel, Phosphor, Salpeter-oder Perchlorsāure or organische SāUren wie Ameisen-, Essig-, Propion-, Bernstein-, Glykol-, Milch-, Āpfel-,

Wein, Zitronene, Malein, Fumar, Phenylessig, Benzoe, Methanesulfone, Toluenesulfone, Oxal, 4-Aminobenzoeyl-Naphthalin-1,5-disulfone in Ascorbine Saw.

The formulation of Form I congeners and medicaments in the form of a pharmazeutischer Tragensen enthalten is welcomed. Die Verbindungen konnen als Heilmittel, z.B. in Form pharmazeutischer Prepare a finder, welche diese Verbindungen in a fungi mit einem fur die enterale, percutaneous or parenteral application, pharmazeutischen, organizer or anorganischen Traager, wie z.B. Wasser, Gummi arabicum, Gelatine, Milchzucker, Starka, Magnesium stearat, Talc, Pflanzliche Ole, Polyalkylene Glycol, Vaseline usw. enthalten. 9 LV 10430

Die pharmazeutischen Prāparate konnen in fester Form, z.B. als Tabletten, Dragees, Suppositories or Capsules; in halbfester Form, z.B. als Salben, oder in flussiger Form, z.B. als Losungen, Suspensionen or Emulsionen, vorliegen. Gegebenenfalls can be used for sterilization and / or enthalting Hilfsstoffe, Conservation, Stabiliserungs, Netz or Emulgiermittel, Salze zur Veranderung des osmotischen Drucks or Puffer. This connection is a noch andere therapeutisch wirksame Stoffe enthalten.

I wound up using the enteric resin formulation. The Resorbierbarkeit wurde an Viistarratten untersucht, denen die erfindungsgemāBen Verbindungen intragastral verabreicht wurden. Der Serumspiegel sank in den erstnung nach Verabreichung der Substanz ab und Steichen nach ca. 5 Stunden ein nur noch leicht abfallendes Plateau. The demos can be followed directly by the Serum Piegel Verabreichung der Substanzen laflt sich auf die gute Resorbierbarkeit der Substanzen schliefien.

Im folgenden ist die Erfindung anhand von Beispielen nāher erlautert.

Beispiel 1

Pyridine-2,4-dicarbonsaure-bis-N, N '- (methoxypropyl) amide 3 g of pyridine-2,4-dicarboxylic acid in 50 ml of toluene and 1 ml of DMF are added and 2.7 ml of thionyl chloride is added. I solange the extract, after changing the gasentwicklung mehr zu beobachten (ca. 2.5 h). I was treated with 5 ml of toluene abdistillate and treated with 4.6 ml of 3-methoxypropylamine and 5 ml of triethylamine zugetropft. After stirring at room temperature for 4 h, the reaction mixture was cooled with water and extracted with 4 x methylene chloride. Die vereinigten organischen 10

Phasen werden iiber Magnesiumsulfat getrocknet und eingedampft. The product was chromatographed on Kieselgel (Losungsmittel Ethylacetat). Yield: 4.3 g; 1 H-NMR (CDCl 3): δ = 1.6-2.3 (4H, m); 3.2-3.8 (14 H, m); 7.8-8.0 (1H, m); 8.3-8.5 (1H, * m); 8.6-8.8 (1H, m).

Beispiel 2

Pyridine-2,4-dicarboxylic acid-bis-N, N '- (ethoxypropyl) amide

Vorschrift siehe Beispiel 1; Amine Component Ethoxypropylamin,

Yield: 4.5 g, mp: 46-48 ° C. 1 H-NMR (CDCl 3): δ = 1.3 (6H, tr); 1.7-2.1 (4 H, m); 3.3 - 3.8 (12H, m); 7.8-8.0 (1H, m); 8.4 - 8.5 (1H, m); 8.5-8.8 (1H, m);

Beispiel 3

Pyridine-2,4-dicarboxylic acid bis-N, Ν '- (2-dimethoxyethyl) amide

Vorschrift tie Beispiel 1, Amine component 2-Dimethoxy-ethylamin,

Yield: 1.6 g (3 g of pyridine-2,4-dicarboxylic acid), 1 H-NMR (CDCl 3): δ = 3.4 (12H, s); 3.7 (4 H, m); 4.5 (2 H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m);

Beispiel 4

Pyridine-2,4-dicarbonsaureic-bis-N, N '- (2-methoxyisopropyl) amide

Vorschrift siehe Beispiel 1; Amine Component 2-Methoxyisopropylamine;

Yield: 3.3 g (3 g Pyridine-2,4-dicarboxylic acid), 1 H-NMR (CDCl 3): δ = 1.3 (6H, d); 3.2 (6H, s); 3.5 (4H, d); 4.4 (2 H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m); 11 LV 10430

Beispiel 5

Pyridine-2,4-dicarbonsaure-bis-N, N 1 - (2-ethoxyethyl) amide

Vorschrift siehe Beispiel 1; Amine component Ethoxyethylamine / Ausbeute: 7.8 g (10 g Pyridine-2/4-dicarboxylic acid),

Mp: 42-44 ° C 1 H-NMR (CDCl 3): δ = 1.2 (3H, tr); 3.3-3.8 (12H, qu. Und m); 7.9 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m);

Beispiel 6

Pyridine-2,4-dicarbonsaure-bis-N, N '- (3-hydroxy-ethyl) amide 0.5 g of Pyridine-2,4-dicarboxylic acid bis-N, N' - (3-methoxyethyl) amide are added. 10 ml of Dichloromethane gelost and at -78 ° C boron tribromide (11 ml, 1 molar solution of lung in Dichloromethane) were added. Nach beendeter Zugabe auf Rummemperatur kommen lāssen and 3 hours nachriihren. 100 ml of gels were refluxed in Bicarbonate-Losung silica gel and extracted 3 times with ethyl acetate. The magnesium sulfate is then extracted and the solvent is removed. Das Rohproduct was chromatographed on Kieselgel.

Yield: 0.45 g; 1 H-NMR (CDCl 3): δ = 1.5-2.2 (4H, m); 3.4 (4 H, m); 3.6 (4 H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m);

Beispiel 7a

Pyridine-2,4-dicarboxylic acid dibenzyl ester 30 g of Pyridine-2,4-dicarboxylic acid dibenzyl ester are added in 1 ml with 30 ml of Thionyl chloride and 43,8 g of benzyl alcohol. The Das Product is a clear crystalline diisopropylether.

Yield: 42.1 g Schmelzpunkt 63-65 ° C 12

Beispiel 7b

Pyridine-2-carbonsaure-4-carbonsaurebenzylester

40 g of Pyridine-2,4-dicarbonsauredibenzyl ester in Beispiel 7a werden zeiner suspension are 27.8 g of Kupfer-II-nitrate in 700 ml of methanol. I have a meal for hours at the Riickflufl gekocht und nach dem Abkuhlen vom Kupferkomplex abfiltriert. The complex is mixed in a Dioxane suspension and Schv / efelkohlenstoff unit. The cuprous sulfide is filtered off and the organic phase is dried. Das Produkt wird mit Petrolether verruhrt. Yield: 25.3 g of Schmelzpoint 113-115 ° C

Beispiel 7c

Pyridine-2- (3-methoxypropyl) -carbonsaureamide-4-carboxylic acid benzyl ester 3.9 g Pyridine-2-carbonsaure-4-carbonsaurebenzyl ester with Beispiel 7b analogue Beispiel 1 ml 1.2 ml Thionyl chloride in das Saurechlorid Isomeric acid and 3-Methoxypropamine zum Amid umgesetzt. The product was chromatographed on a silica gel with ethyl acetate / ethyl acetate (1: 1).

Yield: 4.3 g 01

Beispiel 7d

Pyridine-4-carbonsaure-2- (3-methoxypropyl) -carbonsauramide (4.3 g) is stirred in 100 ml of Dioxane gel and 500 mg of Palladium / Kohl (10%). Nach beendigung der Viasserstoff aufnahme wird vom Catalyst abgesaugt und vom Losungsmittel abgezogen.

Yield: 3.5 g Schmelzpunkt 124-126 ° C 13 LV 10430

Beispiel 7e

Pyridine-4-carbonsaure- (2-methoxyethyl) -2-carbonsaure- (3-methoxypropyl) diamide

Entsprechend Beispiel 1 werden 1.8 g of Verbindung are treated with Beispiel 7d with 0.6 ml of Thionyl chloride in das Saurechloride uberfuhrt and anschlieflend with 2-Methoxyethylamine umgesetzt. The product was chromatographed on silica gel with dichloromethane / methanol (20: 1). Yield: 1.0 g 1 H-NMR (CDCl 3): δ = 1.9-2.0 (2H, qui); 3.4 (6H, s); 3.5-3.7 (8 H, m); 6.9 (1H, s, br); 8.0 (1H, dd); 8.4 (1H, s, br); 8.5 (1H, s); 8.7 (1H, d);

Beispiel 8

Pyridine-2-carbonsaure- (2-methoxyethyl) - 4-carbonsaure- (3-methoxypropyl) -diamide

The analogue of Beispielen 7a-e is obtained by verbindung gemaB Beispiel 8 hergestellt, for the induction of reaction of Beispiel 7c 2-Methoxyethylamine and of reaction of Beispiel 7e 3-Methoxypropylamine.

Melting point: 69-72 ° C. 1 H-NMR (CDCl 3): δ = 1.9 - 2.0 (2H, qui); 3.4 (3H, s); 3.45 (3 H, s); 3.6-3.7 (8 H, m); 7.4 (1H, br); 7.9 (1H, dd); 8.3 (1H, br); 8.4 (1H, d); 8.7 (1H, d);

Beispiel 9

Enterale Resorbierbarkeit

Weibliche Wistarratten von ca. 150 g Korpergewicht erhalten 50 mg / kg der zu untersuchenden Substanz mittels Schlundsonde intragastral verabreicht. Es werden nach 5; 10; 15; 30; 60; 120; 180 and 240 Minute jeweils 4 P.atten 14 narcotic and viber die Vein Cava entblutet. The Blut is used for centrifuging and verifying the ether with a demum serum extractor. Nach Verdampfen des Ethers wird der Rückstand in 100 ml Fliefimittel aufgenommen. The FlieBmittel was treated with 0.05 M Phosphorsaure and Acetonitrile (4: 1).

Von Dieser Probe Weld 50 μl in a HPLC-Sun Injector. The detection was carried out at 200 nm with UV retention and 2.2 min. Die Ergebnisse sind in der Tabelle 1 documentary.

Table 1: Serumspiegel der erfindungsgemaBen

Verbindungen aus den Beispielen 1-3 nach Gabe von 50 mg / kg p.o.

Zeit (Min). Substanz Ear Beispiel 1 x SD Substanz Ear Beispiel 2 x SD Substanz Ear Beispiel 3 x SD 5 45.3 + 15.4 51.4 + 11.2 8.9 + 3.1 10 49.8 + 3.6 39.2 + 4.0 11.5 + 0.6 15 39.9 + 11.0 29.4 ± 6.7 14.7 + 1.9 30 28.1 ± 3.2 15.2 ± 5.6 10.7 ± 1.9 60 9.4 + 5.5 1.4 ± 1.0 11.3 1.5 120 0.3 + 0.3 &lt; NWG 5.5 ± 0.9 180 &lt; NWG &lt; NWG - 2.9 ± 0.5 240 &lt; MWG &lt; NWG N 1.7 ± 0.4 x = Mittelwert aus 4 Messungen SD = Standardabweichung &lt; NWG = unterhalb der Nachweisgrenze 15 EN 10430

Beispiel 10

Pharmakologische Wirksamkeit

Zum Nachvereis Effectively Hemmung der Proline- and Lysinhydroxylase Duration of the Erfindungsgemafenen by Hydroxyproline Concentration in Der Leber and Die 7s- (IV) -Collagen-Concentrationen im Serum (a) Unbehandelten Ratten (Controlled) wurde (CCl ^ -Controlle) c) Ratten, denen zunāchst CCl ^ und anschliefiend eine erfindungsgemāfie Verbindung verbreicht wurae gemessen (diese Testmethe Wird Beschrieben von Rouiller, C., Rouiller, Vol. 2, S. 335-476, New York, Academique Press, 1964). * Die Wirkstarke der erfindungsgemāfien Verbindungen als prozentuale Hemmung der Leber-Hydroxyproline- and Serum-7s- (IV) -Collagenous Syntheses for Gabe im Vergleich zu Kontrolltieren, denen nur

Tetrachlorkohlenstoff verabreicht wurde (CCl ^ -Kontrolle), bestimmt. Die Ergebnisse sind in Table 2 aufgefiihrt. DE-A 37 03 959 (N, N 1 - Bis (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid amide and N, N'-Bis (3-isopropoxypropyl) - pyridine-2,4-dicarboxylic acid amide) ebenfalls mit aufgefiihrt. Uberraschenderweise zeigen die erfindungsgemafien Verbindungen sogar schon nach oraler Verabreichung eine bessere VJirksamkeit, als die i.p. verabreichte Verbindung aus Beispiel 2 der DE-A 37 03 959. 16

Table 2:

Substance is prepared in the form of a dose of Leber-Hydroxy-proline% Hemmungl 7s- (IV) -Serum-Kollagen% Hemmungl Verabreichung 1 2x2 mg 62 28 p.o. 2x10 mg 90 67 p.o. 2 2x2 mg 25 2 p.o. 2x10 mg 60 35 p.o. 2 (ear 2x25 mg 55 48 i.p. DE-A 3703959) 3 (ear 2x25 mg 49 11 p.o. DE-A 3703959)

Claims (17)

EN 10430 INVENTION FORMULA. A process for the preparation of N, N '-bis (alkoxyalkyl) -diamides of pyridine-2,4-dicarboxylic acid of the formula; (I): N CONH- (R 1) - (OR 1) n CONH- (R 1 ') - (OR 1') ni (I) wherein R 1 is a linear or branched C 1 -C 4 -alkanediyl, R 1 is a non-branched C 1 -C 4 -alkyl or hydrogen, n = 1 or 2, R1, R1, n 'have the same meanings as R1, R1 and n wherein R1 and R1, R1 and R1' as well as n and n 'may be the same or different except for pyridine-2,4-dicarboxylic acid N , N '-bis (2-methoxyethyl) -diamide and N, N' -bis (2-hydroxyethyl) -diamide, characterized in that the pyridine-2,4-dicarboxylic acid halide is reacted with alkoxyalkylamine or hydroxyalkylamine. (I) 1 Process for the preparation of N, N '-bis (alkoxyalkyl) -diamides of pyridine-2,4-dicarboxylic acid of formula (I): wherein R 1 is linear or branched C 1 -C 4 -alkanediyl, R 2 is unbranched C 1 -C 4 alkyl or hydrogen, n = 1 or 2, R 1, R 2, n 'have the same meanings as R 1, R 2 and n, wherein R 1 and R 1, R 2 and R 2 as well as n and n' can be the same or different a) mixing 1. pyridine-2,4-dicarboxylic acid with at least two equivalents of a halogenating agent and 2. at least two equivalents of hydroxyalkylamine or alkoxyalkylamine of formula (II) or (ΙΓ) H2N-R1 (OR2) n (II). ) H 2 N-R 1 '(OR 2') n '(ΙΓ) wherein R 1 and R 1 are linear or branched C 1 -C 4 alkanediyl, R 2 and R 2' are unbranched C 1 -C 4 alkyl or hydrogen, n = 1 or 2, R 1 and R 1, R 2 and R 2, and n and n 'are the same or different, but compounds (II) and (tomēr) different, however, are dissolved in a solvent prepared according to a-1 to which or (b) converting the N, N'-bis (alkoxyalkyl) diamide of the pyridine-2,4-dicarboxylic acid thus obtained into a bis (hydroxyalkyl) compound; or (c) the pyridine-2, 4-dicarboxylic acid halide obtained in (a-1) is reacted with a substituted or unsubstituted benzyl alcohol to form a benzyl ester of pyridine-2,4-dicarboxylic acid; the benzyl esters are selectively saponified at position 2 of the pyridine and re-converted into the halide according to variant a-1, then mixed with the solution of compound (ΙΓ) obtained according to a-2 to give pyridine-2, 4-dicarboxylic acid 4 - benzyl ester α-2-amide; 2 EN 10430 then hydrolytically cleaves the benzyl protecting group in position 4, re-converts the free carboxylic acid according to a-1 to the halide and mixes the latter with a solution of compound (II) prepared in accordance with a-2 to give an unsymmetrically substituted compound of formula ) which, if appropriate, is converted into physiologically acceptable salt. 3. A process according to claim 1 or 2, wherein R1 and R1, R2 and R2 as well as n and n 'have the same meanings, depending on the conditions of formula (I). The process according to claim 1 or 2, wherein in the formula (I) the substituents R 1 - OR 2 n and - R 1 and - (OR 2) n 'are different. A process according to claim 1 or 2, wherein R 1 in formula (I) represents a linear or branched (C 1 -C 6) alkyl group or hydrogen. 6. A process according to claim 1 or 2, wherein the compound of the formula: CONH-CH2-CH2-CH2-O-CH3 is obtained. as well as its physiologically acceptable salts. 7. A process according to claim 1 or 2, wherein the compound of the formula: conh-ch2-ch2-ch2-o-c2h5 is obtained. as well as its physiologically acceptable islands. 3 8. A process according to claim 1 or claim 2, wherein the compound is of the formula: conh-ch2-ch O-CHr O-CH- ^ COO NH-CH7-CH · 'N ^ O-CH3 O-CH3 as well as its physiologically acceptable salts. 9. A process as claimed in claim 1 or 2, wherein the compound of the formula: CHo i 0 conh-ch-ch2-och3 is obtained. conh-ch-ch2-och3 CH as well as its physiologically acceptable salts. 10. A process according to claim 1 or 2, wherein the compound is of the formula: CONH-CH2-CH2-0-C2H5 I k · Λ. conh-ch2-ch2-o-c2h5 as well as its physiologically acceptable salts. 4 LV 10430 The process according to claim 1 or 2, wherein the compound of the formula: CONH-CH2-CH2-CH2-OH - C0NH-CH9-CH7-CH2-0H N ά Δ as art and its physiologically acceptable salts. 12. A process according to claim 1 or 2, wherein the compound is of the formula: CONH-CH2-CH2-OCH3 CONH- (CH2) 3-OCH3 and its physiologically acceptable salts. 13. A process according to claim 1 or 2, wherein the compound of the formula is obtained: conh (ch2) 3och3 conh (ch2) 2 ° ch3 and its physiologically acceptable salts. A pharmaceutical preparation comprising a compound of formula (I) obtainable by the process of claims 1-13 and / or one of its physiologically acceptable salts with a suitable pharmaceutical carrier (base). 5 Use of a compound of formula (I) obtainable by the method of I-13 and / or its physiologically acceptable salts for effect on the biosynthesis of collagen and collagen-like substances or on Clq-biosynthesis. Use of a compound of formula (I) obtainable by the process of any one of claims 1 to 13 and / or physiologically acceptable salts thereof for the treatment of collagen and collagen-like substances in the treatment of biosynthesis and disorders of Clq-biosynthesis. 17. A process for the preparation of a medicament useful for effecting the biosynthesis of collagen and collagen-like substances, as well as the Clq-biosynthesis, characterized in that the medicament comprises the compound of the formula I, which can be obtained by the process according to claim 1. -13, and / or a physiologically acceptable salt thereof. 6th