DD247014A1 - PROCESS FOR PREPARING N-ACYLATED 1-METHYLAMINO-1-DESOXY POLYOLE - Google Patents

Abstract

The aim of the method is to increase the number of potential anti-tumor preparations based on cytotoxic derivatives of amino polyols by providing effective and less toxic compounds of the general formula AcNCH2 (CHOH) n CH2OH. These are anhydrides of pN, N-bis (2-chloroethyl) aminophenylessigsaeure or b- (pN, N-bis (2-chloroethyl) -amino-phenyl) -N-acetyl-a-aminopropionsaeure with 1-methylamino-1 -deoxy-polyols reacted in a solvent and the final products then separated by crystallization or chromatography on silica gel.

Description

Κ ι 2 6 4 2 2

ONH

I c-CK ,,

η = 3 or 4, '"

characterized in that anhydrides of pN, N-bis (2-chloro-ethyl) -amino-phenylacetic acid or / 3- [pN, N-bis (2-chloroethyl) -amino-phenyl] -N-acetyl-a Amino-propionic acid reacted with 1-methylamino-i-deoxy-polyols in a solvent and the final products are then separated by crystallization or chromatography on silica gel.

Field of application of the invention

The invention relates to a process for preparing N-acylated 1-methylamino-1-deoxy-polyols of the general formula

Ac '.- H CH ₀ (CHOH) CH ₅ OH

in which mean or II: Ac » - C - CH C H N (CH CH C2 NH I: il 2 6 4 2 2 I O 0 Ac = -C- O

If η = 4, the following compounds fall under the general formula:

a) 1-Methylamino-i-deoxy-D-galactitol with Ac = I or II

b) l-methylamino-i-deoxy-D-glucitol with Ac = I or Il '

c) i-methylamino-1-deoxy-D-mannitol with Ac = I or II.

If η = 3, the following compound falls under the general formula:

d) 1-methylamino-i-deoxy-L-arabinite with Ac = I or II.

These new compounds are biologically active substances that can be used as antitumor preparations.

Characteristic of the known technical solutions

There are known compounds in which two 2-chloroethylamino groups are attached to deoxy-polyols in the 1- and 6-position via the stable C-N bond:

HC -NH-CHClCl ·

(CHOH) _{4 o} w - INFI - w HI ₀ WrI ₀ W J.

They are mainly used in the clinical treatment of systemic diseases of the blood (K. Schellai et al., "Drug treatment for tumorous diseases" Budapest, 1975, p 185).

Object of the invention

The aim of the process according to the invention is to expand the arsenal of potential antitumor preparations on the basis of cytotoxic derivatives of amino-polyols.

Explanation of the essence of the invention

This object is achieved by a process for the preparation of N-acylated 1-methylamino-1-deoxy-polyols of the general formula 1, in which Ac and η have the abovementioned meaning, according to the invention by reacting anhydrides of pN, N-bis (2) chloroethyl) -amino-phenylacetic acid or / 3-tp-N, N-bis (2-chloroethyl) -amino-phenyl] -N-acetyl-a-amino-propionic acid with 1-methylamino-1-deoxy-polyols in a solvent , such as Methylene chloride or acetonitrile, reacted and the

Final products are then by crystallization or chromatography on silica gel abgetre_njTt_wexden.

The reaction proceeds according to the following scheme:

Ac _o 0 + HN-CH _o (CHOH) CH ₀ OH CH ₃ ',

Ac-N-CH ₀ (CHOH) CH ₀ OH

"3

The anhydrides of corresponding acids are prepared in a known manner with dicyclohexyl-carbodiimide.

The structure of the novel compounds prepared according to the invention is confirmed by elemental analysis and IR spectroscopy (presence of a broad band of amides in the range of 1 620-1 650 cm ^-1 and absence of an absorption band of ester carbonyl groups in the region of 1750 cm ^-1 .) The compounds are colorless crystalline or amorphous Substances that are soluble in water and polar solvents.

Some physico-chemical properties of the cytotoxic derivatives of 1-methylamino-1-deoxypolyols are given in the table below.

Nr.d. 1-methylamino enamel 25 ° R _F (chloro- Out Verb. -1-deoxy-polyol Point [A] form-metha- prey [C] D nol9: 1) [%]   la -D-galactitol 103-109 -22 0.19 72.8 - Ib -D-glucitol 91-92 -19 0.23 71.2 ic D-mannitol 73-76 -2 0.21 73.4 id -L-arabinitol 110-111 -14 0.28 78.5 Ma -D-galactitol "89-92 -12.5 0.10 52.6 hb -D-glucitol 77-79 -7.3 0.40 49.2 hc D-mannitol 69-73 -3 0.56 65.2 Hd ° -L-arabinitol 78-81 -5 0.40 57.7

Examples

The preparation of the compounds of general formula 1 with Ac = I or Il is explained in more detail by the following examples.

Example 1:

1- [pN, N-bis- (2-chloro-ethyl) -amino-phenylacetyl] -1-methylamino-1-deoxy-D-galactitol (Ia) To give a solution of 5.5 g pN, N-bis ( 2-chloro-ethyl) -amino-phenylacetic acid in 50 ml of methylene chloride, a solution of dicyclohexyl-carbodiimide in 10 ml of methylene chloride at -5 ° C is added. After 3 hours, it is filtered, 1.9 g of 1-methylamino-i-deoxy-D-galactitol are added to the filtrate, followed by boiling for 10 hours and then cooling. The residue is filtered off and recrystallized from 50 ml of alcohol. This gives 3 g of compound Ia (72.8% of theory).

Melting point: 108 to 109 ° C;

[a] i ⁵ : -22 ⁰ C (AIkOhOl);

Found: C 50.04; H 6.72; N, 6.39; Cl 15,38;

calcd for: C ₁₉ H ₃₀ Cl ₂ N ₂ O ₆ : C, 50.27; H, 6.62; N 6.18; Cl 15,64

Analogously, the other compounds mentioned under formula 1 b-d are prepared with Ac = I.

Example 2:

1- / 3- [pN, N-bis (2-chloro-ethyl) -amino-phenyl] -N-acetyl-a-amino-propionyl-1-methylamino-1-deoxy-D-mannitol (lic) To a suspension of 6.94 g / 3- [pN, N-bis (2-chloroethyl) -aminophenyl] -N-acetyl-a-amino-propionic acid in 15O'ml acetonitrile is added dropwise, the solution of 2.3 g Dicyclohexyl-carbodiimide in 20 ml of acetonitrile at 0 ° C was added, stirred for 4 hours and

filtered. 1.95 g of 1-methylamino-1-deoxy-D-mannitol are added to the filtrate, the mixture is stirred at 50 ° C. for 4 hours and the solvent is distilled off. The residue is dissolved in 50 ml of a mixture of ethanol and chloroform (1: 4) and chromatographed on a column with silica gel. EIuiert is with a mixture of alcohol-chloroform 1:19 and the fractions with R _F 0.56 {silica gel; Methanol-chloroform 1: 9) in vacuo. The compound lic is obtained in the form of a colorless amorphous powder having a melting range of 69 to 73 ° C.

Yield: 3.42 g (65.2% of theory); [a] 1 ⁵ : -3 ° C (chloroform);

gel: C, 49.30; H 6.73; N 7.90; Cl 13.06; · '· -

calc. for C ₂₂ H ₃₅ Cl ₂ N ₃ O ₇ -V22H ₂ O :. C 49.50; H 6.75; N 7,8; Cl 13,32.

Analogously, the other mentioned under formula 1 compounds a, b and d are prepared with Ac = Il. In investigating the biological activity of the compounds of the present invention, they were found to be useful in various transplanted tumors such as sarcoma 37, sarcoma 180, adenocarcinoma 755, Lewis lung cancer, adenocarcinoma of the colon (strain AKATOL), plasmacytoma (strain MORS-406) and Lympholeukosis L-1210 have antitumor activity. In this case, organ-specific biological effects were found, depending on the structure of these compounds. The growth of these tumors is inhibited by 60 to 100%, single tumors are cured in 50 to 100% of the cases. The advantages of the new compounds with respect to their antitumor activity are particularly evident on the plasmacytoma MORS-406, where stable healing is ensured in 50 to 100% of the animals. By contrast, the best known cytotoxic compounds only prolong the life of the animals by 56 to 66%. L

In addition, the compounds of the invention I Bund Id even allow the cure of adenocarcinoma755 in 100 to 50% of the animals. ,

Another positive feature of the new compounds is their significantly lower toxicity. Thus, daily doses are 5 to 10 times higher than the best known cancer chemotherapeutic agents. They are thus suitable for clinical use.

Claims (1)

Invention claim: Process for the preparation of N-acylated 1-methylamino-1-deoxy-polyols of the general formula Ac - N - CH ₂ (CHOH) _n CH ₂ OH, in which mean i Ac-C-CH _O CH.N (CH _O CH Cl) ₅ or // * 4 * - ^ ^.