CS197709B1 - N-/beta-/6-purinylthio/butyl/ureas and method for the production thereof - Google Patents

Description

The invention relates to novel N- [S- (6-purinylthio) butyl] ureas of the formula I / ^R1

S (CH ₂ ) ₄ NH-CO-N <

I \ R ^{2 (I)} '

H in which R @ ¹ is hydrogen, C1 -C4 alkyl, C5 -C6 cycloalkyl, 2-hydroxy-. ethyl, carboxymethyl, ethoxycarbonylmethyl or 1-carboxy-2-phenyl-1-ethyl and R ² represents a hydrogen atom or a C 1 -C 2 alkyl group, or wherein R ¹ and R ² form together with the nitrogen to which they are present bonded, a six-membered heterocyclic ring containing 1 to 2 nitrogen atoms, which may optionally be further substituted by a phenyl, carboxymethyl or ethoxycarbonylmethyl group, and a process for their preparation.

The N- [S- (6-Purinylthio) butyl] ureas of formula I are antimetabolites of purine nucleic acid bases and exhibit a cancerostatic effect on experimental tumors of mice and rats. For example

N- [S- (6-purinylthio) butyl] urea (Formula I, R ¹ = R ² - H) extending at an oral dose of 100 mg / kg for the life of Wistar rats with Yoshida ascitic sarcoma 138%, respectively . at a dose of 200 mg / kg po to 171%, compared to the lifetime of the untreated control group (lifetime of this group = 100%). N- [3- (6-Purinylthio) butyl] -N '-ethylmočovina (Formula I, R ¹ = G2H5, R ² = H) showed 100 mg / kg beneficial therapeutic effects against 37 ascitickému sarcoma strain in mice H, where it reduced the tumor size to 63% compared to the untreated control group of animals and extended the lifespan of the treated animals to 113%. N- [8- (6-purinylthio) butyl] -N '- (carboxymethyl) urea (Formula I, R ¹ = CH ² COOH, R ² = H) was anti-cancerally active against Crocker sarcoma in mice at a dose of 200 mg / kg strain H (reduced the tumor size of the treated group of animals to 77% and prolonged their survival time to 126%) and to mammary adenocarcinoma in mice strain H (reduced the tumor size of the treated group of animals to 86% and prolonged their survival to 118%).

According to the invention, N- [3- (6-purinylthio) butylureas of the formula I can be prepared by the process of preparing S- (6-purinylthio) valeric acid azide II.

S (CH ₂ ) ₄ CON ₃ nA - ⁿ -

Η (Π), converts to S- (6-purinylthio) butyl isocyanate of formula III

S (CH ₂ ) ₄ NCO

OA

H (III), which is reacted with an amine of formula IV / ^R1

H N <(IV), R 2 wherein R ¹ and R ² are as defined above, and the obtained N- [S- (6-purinylthio) butyl] urea of formula I, wherein R ¹ and R ¹ and R ^{2 respectively} together, denotes an ethoxycarbonyl-containing radical, optionally saponified to the urea of formula I, in which R ¹ and R ¹ and R ² together, respectively, denotes a free carboxyl-containing radical.

The acid azide II converts to the S- (6-purinylthio) butyl isocyanate of formula III already at room temperature, but the reaction proceeds relatively slowly under these conditions. Suitably, the reaction is carried out at elevated temperature, preferably at 80 to 120 ° C, in a suitable inert solvent, for example in dioxane, dimethylformamide, dimethylsulfoxide or hexamethyltriophosphoric triamide. The reaction should be carried out with the exclusion of water and atmospheric humidity, since the isocyanate of formula II decomposes with water to cleave carbon dioxide to give 4- (6-purinylthio) butylamine, the presence of which in the reaction product impairs purification and decreases yields of the desired urea.

The reaction of the isocyanate of the formula II with the amine of the formula IV usually proceeds easily at room temperature, and is conveniently carried out in that the S- (6-purinylthio) butyl isocyanate of the formula II is not isolated reaction with at least 2 mol equivalents of the corresponding amine. The reaction time under these conditions ranges from 2 to 24 hours.

The saponification of the N- [S- (6-purinylthio) butyl] ureas of the general formula I in which R ¹ and R ¹ and R ² together, respectively, denotes an ethoxycarbonyl radical, for example in which R ¹ denotes a -CH ₂ COOC _{2 group} H ₅ or -CHCOOC ₂ H ₅ , or wherein R ¹ and R ²

CH ₂ C ₆ H ₅ together denotes the group -NN-CH ₂ COOC ₂ H ₅ , is carried out by treating said ester with at least 2 mol equivalents of an alkali metal hydroxide, for example sodium or potassium hydroxide, and liberating the acid from the obtained aqueous salt solution by acidifying it a strong acid, e.g. hydrochloric acid, to a pH of about 3.

The N- [8- (6-purinylthio) butyl] ureas of formula I can be isolated from the reaction mixture by conventional methods. A preferred method consists in distilling off the solvent, stirring the residue with dilute aqueous acid, for example dilute hydrochloric or acetic acid, and purifying the crude product thus obtained by crystallization or column chromatography.

The required S- (6-purinylthio) valeric acid azide of formula II can be prepared according to the Czechoslovak patent specification 128 123.

Further details of the process according to the invention will be apparent from the following non-limiting examples. The melting points of the compounds are determined on the Kofler block and are given, as with other temperature data, in ° C.

Examples

Example 1

N- [S- (6-Purinylthio) butyl] urea

A suspension of 2.77 g (0.01 mol) of dried S- (6-purinylthio) valeric acid azide in 60 ml of anhydrous dioxane was heated to reflux for 10 minutes with stirring, excluding air humidity and stirring. The isocyanate III solution obtained is cooled to 20-25 ° C and ammonia gas is introduced at this temperature for 2 hours. The reaction mixture is allowed to stand overnight at room temperature, then most of the dioxane is distilled off under reduced pressure and the residue is stirred with 25 ml of 0.1 N hydrochloric acid. The precipitated product (2.42 g, yield 82%) gave, after recrystallization from water, the desired product as colorless crystals of m.p. 190-193 °.

Example 2

N- [S- (6-Purinylthio) butyl] -N'-methylurea

To a dioxane solution of isocyanate III prepared as described in Example 1 of 2.77 g (0.01 mol) of azide II, at room temperature was added 8 ml of a 40% aqueous solution of methylamine (2.2 g, 0.07 mol) and the mixture was stirred for 2 hours. The volatiles were distilled off under reduced pressure and the residue was stirred with 25 ml of 0.1 N hydrochloric acid. The precipitate (2.16 g, yield 77%) was filtered off and recrystallized from water; m.p. 183 DEG-185 DEG.

Example 3

N- [S- (6-Purinylthio) butyl] -N'-ethylurea

To a dioxane solution of phocyanate III prepared as described in Example 1 from 2.77 g (0.01 mol) of azide II, at about 20 ° C, 2.25 g (0.05 mol) of ethylamine is added and the reaction mixture is allowed to stand. overnight at room temperature. The volatiles were distilled off under reduced pressure and the residue was stirred with 25 ml of 0.1 N hydrochloric acid. The title compound (2.32 g, 79% yield) after recrystallization from ethanol gave the desired product, mp 180-181 °.

In the same way, using the appropriate primary amines instead of ethylamine, the following ureas of the formula obecného are prepared, for example:

N- [8- (6-purinylthio) butyl] -N'-butylurea, m.p. 156-157 ° (from aqueous ethanol); N- [S- (6-purinylthio) butyl] -N'-cyclohexylurea, m.p. 202-203 ° (aqueous ethanol); N- [8- (6-purinylthio) butyl] -N '- (2-hydroxyethyl) urea, m.p. 168-170 ° (from aqueous acetone);

N- [8- (6-purinylthio) butyl] -N '- (ethoxycarbonylmethyl) urea, m.p. 180-181 ° (aqueous ethanol).

Example 4

N- [8- (6-Purinylthio) butyl] -N ', N'-diethylurea

Using the procedure described in Example 3, using 3.66 g (0.05 mol) of diethylamine instead of ethylamine gave the crude product (2.28 g, 71% yield) which was purified by silica gel column chromatography (23 g). eluting with chloroform / ethanol 9: 1.

The fractions containing the desired product were combined, the solvents were distilled off under reduced pressure, and the residue was recrystallized from aqueous ethanol. 142 DEG-143 DEG.

In the same way, using the appropriate secondary amines instead of diethylamine, the following ureas of formula I are prepared, for example:

N- [8- (6-purinylthio) butyl] -N ', N'-pentamethyleneurea, m.p. 197-198 ° (from aqueous ethanol);

N-phenyl-N '- {N- [S- (6-purinylthio) butyl] carbamoyl] piperazine, m.p. 163-165 ° (from ethanol-hexane);

N-ethoxycarbonylmethyl-N '- {N - [8- (6-purinylthip) butyl] -carbamoyl} piperazine, mp 111-113 ° (from acetone).

Example 5

N- [8- (6-Purinylthio) butyl] -N '- (carboxymethyl) urea m.p.

N- [8- (6-Purinylthio) _x butyl] -N '- (ethoxycarbonylmethyl) urea (3.52 g, 0.01 mol) was added with stirring at 20-25 ° into 1 N hydroxide solution sodium (20 mL, 0.02 mol) and after dissolution the reaction mixture was allowed to stand overnight at room temperature. The solution is decolorized with activated carbon, filtered, the filtrate is acidified with dilute hydrochloric acid (1: 1) to a pH of about 3 and the precipitated product is recrystallized from water; mp 205-209 °.

In the same manner, using the appropriate ethoxycarbonyl derivatives of ureas of formula I, for example, the following acids of formula I are prepared:

N-carboxymethyl-N '- {N' '- [8- (6-purinylthio) butyl] carbamoylpiperazine, monohydrate, 1.1. 176-179 ° (from water);

DL-N- {N4 [S- (6-purinylthio) butyl] carbamoyl} phenylalanine, m.p. 170-172 ° (from water).

Claims (11)

SUBJECT VYNALEZU 1. N- [S- (6-Purinylthio) butyl] ureas of formula I / ^R1 S (CH ₂ ) ₄ NH-CO-N < R ² N @ 1 N @ ¹ N @ NH in which R @ ¹ is hydrogen, C1 -C4 alkyl, C5 -C6 cycloalkyl, 2-hydroxyethyl, carboxymethyl, ethoxycarbonylmethyl or 1-carboxy-2-phenyl-1- ethyl and R ^{2 are} hydrogen or C 1 -C 2 alkyl, or wherein R ¹ and R ² are taken together with the ring to which they are attached to form a six-membered heterocyclic ring containing 1 to 2 nitrogen atoms, which may optionally be further substituted by phenyl, carboxymethyl or ethoxycarbonylmethyl. 2. N- [S- (6-Purinylthio) butyl] urea. 3. N- [8- (6-Purinylthio) butyl] -N'-ethylurea. 4. N- [8- (6-Purinylthio) butyl] -N '- (ethoxycarbonylmethyl) urea. 5. N- [S- (6-Purinylthio) butyl] -N '- (carboxymethyl) urea. 6. N- [S- (6-Purinylthio) butyl] -N ', N'-diethylurea. 7. A process for producing N- [8- (6-purinylthio) butyljmočovin above formula I wherein R ¹ and R ² have the above meanings, characterized in that the azide of S- (6-purinylthio) ester of the formula II S (CH ₂ ) ₄ CON ₃ I N || H converts the S- (6-purinylthio) isocyanate of formula ni (Π), S (CH ₂ ) ₄ NCO ₂ (III), m / ^z H which is reacted with an amine of formula IV HN / ^{R 1} , R ² (IV), wherein H ¹ and R ² are as defined above, and the obtained N- [S- (6-purinylthio) butyl] urea of formula I, wherein R ¹ and R ¹ and R 2 respectively ² together, denotes an ethoxycarbonyl-containing radical, optionally saponified to the urea of formula I, in which R ¹ and R ¹ and R ² together, respectively, denotes a free carboxyl-containing radical. 8. The process of claim 7, wherein the azide of formula II is converted to the isocyanate of formula III by heating to 80-120 [deg.] C. in an inert organic solvent. 9. The process of claim 8 wherein the inert solvent is dioxane, dimethylformamide, diethylsulfoxide or hexamethylphosphoric triamide. 10. The process of claim 7, wherein the isocyanate of formula III is reacted with at least 2 mol equivalents of the amine of formula IV at a temperature of 15 to 25 ° C without isolation in the environment in which it was prepared. 11. The method according to item 7, characterized in that a urea of the formula I wherein R ¹ or R ¹ and R ² together represent the radical containing ethoxycarbonyl, hydrolyzed to the urea of Formula I ,. wherein R ¹ and R ¹ and R ² together, respectively, denote a carboxyl group-containing residue by treatment with at least 2 moles of alkali metal hydroxide.