CS254631B1 - N- [4- (6-Purinylthio) butyl] -N-nitrosourea and the process for their preparation - Google Patents

Abstract

The solution relates to antineoplastically active N-/4-(6-purinylthio)butyl/N- -nitrosoureas of the general formula I H in which R denotes an alkyl group with 1 to 4 carbon atoms, a cyclohexyl or ethoxycarbonylmethyl group and 2 R denotes a hydrogen atom or an alkyl group with 1 to 4 carbon atoms and a method of their production by nitrosation of the corresponding ureas.

Description

The invention relates to N- / 4- (6-purinylthio) butyl / N nitrosomočivin of formula I (I), with (CH _{2) 4} N-CO-N; wherein R is a C 1 -C 4 alkyl, cyclohexyl or ethoxy2 carbonylmethyl group and R is a hydrogen atom or a C 1 -C 4 alkyl group, and a process for their preparation.

The compounds of the invention are novel cytostatics having both the character of alkylating agents and purine nucleic acid antimetabolites; contain, as carrier of the alkylating N-nitrosurea residue, a 4- (6-purinylthio) butyl group derived from an antineoplastically active 5- (6-purinylthio) valeric acid; U.S. Pat. 82 287).

According to the invention, N- [4- (6-purinylthio) butyl] -N-nitrosoureas of formula (I) are prepared by reacting the corresponding N- [4- (6-purinylthio) butyl] urea of formula (II).

S (CH ₂ ) 4 NHCO-N ₂ (II) in which nitrous.

and R ^Z have the above meanings, in a suitable environment brought into reaction with an acid

Suitably the nitrous acid is liberated directly in the reaction mixture by treatment with a mineral acid such as hydrochloric acid or an organic acid such as formic acid, acetic acid, a mixture of acetic acid and acecanhydride, an alkaline salt of nitrous acid such as sodium nitrite or a lower alkyl ester of the acid. nitrile, for example to butyl nitrite. The reaction is carried out at a temperature of 0 to 50 ° C, using at least 2 mol equivalents of alkali metal nitrite or alkyl nitrite. Mixtures of a lower alcohol such as methanol or ethanol with a mineral acid used to release nitrous acid from a salt or ester, or excess anhydrous lower aliphatic carboxylic acid, may be used as the medium.

Typically, the starting urea of formula II is dissolved in a mixture of ethanol with excess hydrochloric acid, a solution of 2 mol equivalents of sodium nitrite is added and the reaction mixture is heated to 50 ° C, or, more preferably, of the urea of formula II in a lower aliphatic carboxylic acid and at a temperature of 15 to 25 ° C are added 2 mol equivalents of solid sodium nitrite.

The N-nitrosoureas of formula (I) are isolated from the reaction mixtures by conventional methods, for example by diluting the reaction mixture with water, removing the material into a water-immiscible organic solvent, for example chloroform, and purifying the crude product by crystallization or column chromatography.

The necessary N- (4- (6-purinylthio) butyl) ureas of the general formula II can be prepared according to the Czechoslovak author's certificate 197 709. The N, N-dimethyl-,

N ', N-di-n-propyl- and N', N'-di-n-butyl-N- (4- (6-purinylthio) butyl) urea can be prepared in an analogous manner.

The N- (4- (6-Purinylthio) butyl) -N-nitrosoureas of formula (I) exhibited a cancerostatic effect when tested in experimental tumors of mice and rats, exhibiting either a survival of animals with experimental tumors or weight loss compared to control groups of animals. tumor, or a beneficial effect in both of these parameters.

For example, N- [4- (6-purinylthio) butyl] N-nitroso-N ' -cyclohexylurea (I = cyclo2-hexyl, R = hydrogen) extends the life span of Wistar rats when administered orally at 100 mg / kg. Yoshida's asiitiative sarcoma at 172% compared to the lifetime of the untreated control group (= 100 *).

N- [4- (6-Purinylthio) butyl] -N-nitroso-N ' -ethoxycarbonylmethyl urea (I, R < 4 > = ethoxycarbonyl-2-methyl, R = hydrogen) showed a dose of 200 mg / kg p.o. a beneficial therapeutic effect in Crocker sarcoma 180 in strain H mice, where it increased the lifespan of the treated animals to 138% compared to the untreated control group.

- 1 2

N- (4- (6-Purinylthio) butyl) -N-nitroso-N, N-diethylurea (I, R = R = ethyl) was effective against Yoshida ascitic sarcoma in Wistar rats (at a dose of 100 mg / kg after prolonged lifetime of treated animals to 156% and 200 mg / kg po to 220%) and to ascitic sarcoma 37 in H strain mice (at 100 mg / kg po reduced the tumor size of treated animals to 51%). In one of the two experiments, the compound was administered at a dose of 200 mg / kg after reducing tumor weight to 64%, at a dose of 100 mg / kg po to 73%, in both cases without extending the life of the test animals.

2

N- [4- (6-Purinylthio) butyl] -N-nitroso-N, N-dipropylurea (I, R = R = n-propyl) decreased at a dose of 200 mg / kg p.o. tumor weight S 37 to 68 ΐ while reducing survival time.

- - 12

N- [4- (6-Purinylthio) butyl] -N-nitroso-N, N-dibutylurea (I, R = R = n-butyl) decreased at a dose of 100 mg / kg p.o. tumor weight S 180 to 80 * while reducing survival time.

The process according to the invention is illustrated in more detail by 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- [4- (6-Purinylthio) butyl] -N-nitroso-N ' -methylurea

To a solution of 1.12 g (4 mmol) of N- [4- (6-purinylthio) butyl] -N'-methyl urea in a mixture of 40 ml of ethanol with 13.2 ml (6.6 mmol) of 0.5 N hydrochloric acid was added. 6 ml (0.006 mol) of 1 M sodium nitrite solution is added dropwise at 20-25 ° C with stirring. The reaction mixture was heated at 50 ° C for 6 hours, then allowed to stand overnight at room temperature and most of the ethanol was distilled off under reduced pressure (30 ° C bath). The residue was partitioned between water and chloroform, the combined organic extracts were washed with water, dried (Na 2 SO 4) and the solvent was distilled off under reduced pressure. The crude product (1.05 g, 85% yield), after recrystallization from ethanol / chloroform / hexane, gave N- [4- (6-purinylthio) butyl] -N-nitroso-N ' -methylurea in light yellow crystals of m.p. Mp 144-145 ° C.

Example 2

N- [4- (6-Purinylthio) butyl] -N-nitroso-N ' -cyclohexylurea

In the same manner as in Example 1, but using N- [4- (6-purinylthio) butyl] -N'-oxyclohexylurea as the starting material instead of N'-methylurea, the title compound was obtained, m.p. 94 DEG-96 DEG C. (from acetone / hexane).

Example 3

N- (4- (6-Purinylthio) butyl) -N-nitroso-N '- (ethoxycarbonylmethyl) urea

To a solution of 1.41 g (4 mmol) of N- [4- (6-purinylthio) butyl] -N ' - (ethoxycarbonylmethyl) urea in 4 ml of 98% formic acid is added under stirring at 15-20 [deg.] C. parts of 0.414 g (6 mmol) of triturated sodium nitrite. The reaction mixture is stirred at room temperature for 4 hours, then diluted with 40 ml of water, the product is taken up in chloroform and the chloroform extract is treated as described in Example 1. The crude product (1.50 g, practically 100%) is obtained after column chromatography. Silica gel (15 g), eluting with chloroform / ethanol 9: 1, pale yellow crystals of m.p. Mp 83-86 ° C (from acetone / hexane).

Example 4

N- (4- (6-Purinylthio) butyl) -N-nitroso-N ', N'-diethylurea

To a solution of 1.29 g (4 mmol) of N- [4- (6-purinylthio) butyl] -N ', Ν'-diethylurea in a mixture of 8 ml of acetic acid and 2 ml of acetic anhydride is stirred at 20-25 ° C, 0.414 g (6 mmol) of triturated sodium nitrite was added portionwise, the reaction mixture was stirred at the same temperature for 1 hour and then allowed to stand overnight at room temperature. After working up the reaction mixture as described in Example 3, the desired product is obtained in the form of yellowish crystals of m.p. 98-100 ° C (from ethanol to hexane).

Example 5

In the same manner as in Example 4, but using N- [4- (6-purinylthio) butyl] -N ', N'-dimethylurea, N- [4- (6-purinylthio) butyl] -N, N'-dipropylurea or N- (4- (6-purinylthio) butyl) -N ', Ν'-dibutylurea were prepared

N- [4- (6-purinylthio) butyl] -N-nitroso-N ', 4 ' -dimethylurea, m.p. 106-108 ° C;

N- [4- (6-purinylthio) butyl] -N-nitroso-N ', 4 ' -dipropylurea, m.p. 54-56 ° C (from ethanol to cyclohexane);

N- (4- (6-purinylthio) butyl) -N-nitroso-N ', N'-dibutylurea, m.p. 82 to 84 ° C (from ethanol to cyclohexane) ‘

Example 6

The N- (4- (6-purinylthio) butyl) -N ', Ν'-dialkylureas used as starting materials in Example 5, not yet described, were prepared as follows:

Suspension 13.87 g (0.05 mol) of dried 5- (6-purinylthio) valeric acid azide (Art.

AO 128 123) in 150 ml of anhydrous dioxane was heated to reflux for 10 minutes, excluding air humidity. The resulting 4- (6-purinylthio) butyl isocyanate solution was cooled to 20-25 ° C and, with stirring, a) 12.23 g (0.15 mol) of dimethylamine hydrochloride and 30.3 g (0.3 mol) were added with stirring. triethylamine, in case b) 15.2 g (0.15 mol) of dipropylamine, or in case c) 19.4 g (0.15 mol) of dibutylamine, and the mixture was allowed to stand overnight at room temperature.

The volatiles were distilled off under reduced pressure, the residue was taken up in a 9: 1 mixture of chloroform and ethanol and 0.1 M hydrochloric acid, the organic portion was dried (Na ₂ SO ₄ ) and the solvents were evaporated. The crude product was purified by chloroform / ethanol (9: 1) to elute and crystallize the residue obtained by distilling off the solvents from the combined uniform fractions.

It is obtained

a) N- [4- (6-purinylthio) butyl] -N ', 4'-dimethylurea, m.p. 99-101 ° C (from ethanol);

b) N- [4- (6-purinylthio) butyl] -N ', 4'-dipropylurea, m.p. 123 DEG-125 DEG C. (from a mixture of benzene and ethanol);

c) /- [4- (6-purinylthio) butyl] -N, N-dibutlyurea, m.p. 100 to 102 θθ (from benzene).

SUBJECT OF THE INVENTION

Claims (5)

SUBJECT OF THE INVENTION What is claimed is: 1. N-Z4- (6-Purinylthio) butyl / -N-nitrosoureas of the general formula I in which R1 represents a C1-C4 alkyl group, cyclohexyl or ethoxycarbonyl 2, a methyl group, and R represents a hydrogen atom or an alkyl group C 1 -C 4. 2. A process for the preparation of N- (4- (6-purinylthio) butyl) -N-nitrosoureas according to claim 1, characterized in that N- (4- (6-purinylthio) butyl) urea of the formula II is used. Wherein R and R are as defined above, react with nitrous acid in a suitable medium. 3. The process according to claim 2, wherein nitrous acid released in the reaction mixture by a mineral acid or a lower aliphatic carboxylic acid from an alkali metal nitrite or a lower alkyl nitrite is used. 4. The process according to claim 3, wherein the mineral acid is hydrochloric acid. 5. The process of claim 3 wherein the lower aliphatic carboxylic acid is formic acid, acetic acid, or a mixture of acetic acid and acetic acid.