JPS5946943B2 - Method for producing piperazinopyrimidine derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing piperazinopyrimidine.

In the applicant's pending patent application No. 42866 of 1973, biverazinopyrimidines are described with the general formula: (wherein R represents a methyl group or a methylthio group, and x is a halogen atom or represents an alkoxy group containing a carbon atom, Y represents an acylamino group or a substituted or unsubstituted amino group, z represents a hydrogen atom or a methyl group, an ethyl group, a hydroxyethyl group, or a phenyl group, provided that 2-methylamino-4-N -Methylpiberazino-5-methylthio-6-chloro-pyrimidine) is claimed.

The aforementioned applications also describe and claim methods of making and using these compounds. According to the invention, the general formula: (wherein Z represents a methyl group, R1 represents a hydrogen atom, and R2 represents a straight-chain alkyl group having 3 to 6 carbon atoms, an alkyl group, a cyclohexyl group or a benzyl group) represents the group,
and -NRlR2 residue can represent a morpholino group).

Compounds of formula (I[) having pharmacological action of interest can be prepared, for example, using the corresponding R, amine, as described in Japanese Patent Application No. 48-1.
It can be produced by the method described and claimed in Japanese Patent Application Laid-Open No. 50-25578.

, the compound described in the following example was prepared as described in Example 1 of 1973 Co-pending Application No. 42866, but the ethylamine was replaced with an equimolar amount of the corresponding H-N amine;
N-methylpiverazine was substituted, if necessary, with equimolar amounts of the corresponding N-alkylpiverazine.

For convenience, Example 1 described in Application No. 42866 of 1973 will be described below. 2-ethylamino-4-N-methyl-piberazino-6-chloro-5-methylthio-pyrimidine hydrochloride GIL) 2-ethylamino-4,6-dichloro-5-methylthiopyrimidine: 230 parts 2 ,4,6
-11chloro-5-methylthio-pyrimidine 740
of methyl ethyl ketone, add 650 parts of ice, and pour in 120 parts of a 38% ethylamine aqueous solution over 30 minutes while cooling the mixture so that the temperature does not exceed 5°C.

Then 129.5 parts of 31% aqueous sodium hydroxide solution are added over 1 hour at 20° C. and the mixture is stirred for 6 hours. This precipitates the desired isomer, 4-ethylamino-2,6
-dichloro-5-methylthio-pyrimidine remains in solution. After cooling for 15 hours, the product is filtered off and washed with methyl ethyl ketone.

73 parts of the desired product are obtained and recrystallized from ethanol.

M. p. l47℃. (b) 2-ethylamino-4-N
-Methylpiberazino-6-chloro-5-methylthiobi 11 sewing machine: 31.4 parts of the product prepared in (a) were added to 65
Dissolve in 0 parts by volume of ethanol while heating to 70°C.

40 parts of N-methylbiverazine are added over 10 minutes.

The mixture is refluxed for 3 hours and then cooled to -40°C.
Separate the product and wash with water. 29 parts of the desired product are obtained and recrystallized from ethanol.

M. p. lOl℃. The hydrochloride salt is obtained by acting the calculated amount of hydrochloric acid in an ethanol medium. Analysis: '1TT1T11A Example 1 2-Alylamino-4-N-methylpiberazino-6-chloro-5-methylthio-pyrimidine This water-insoluble product is a colorless crystalline powder that dissolves in alcohol and dilute hydrochloric acid.

M. p. 89-90-C (Makuenne). Example 2 2-N-(β-hydroxyethyl)amino-4-N-
Methylpiberazino-6-chloro-5-methyl; ruthiopyrimidine colorless crystals, insoluble in water, soluble in ethanol and dilute hydrochloric acid.

M. p. l42°C (Makuenne) Example 3 2-cyclohexylamino-4-N-methylpiverazino-6-chloro-5
-Methylthiopyrimi, colorless crystalline powder, insoluble in water, soluble in ethanol and dilute hydrochloric acid.

M. p. 129°C (Kofura) Example 42-n-bentylamino-4-N-methylbiverazino-6-chloro-5-methylthiopyrimidine Colorless crystalline powder, easily soluble in ethanol, insoluble in water, soluble in dilute hydrochloric acid.

M. p. 60°C (Kofura-1) Example 52-n-hexylamino-4-N-methylpiverazino-6-chloro-5
-Methylthiopyrimidine colorless crystalline powder, easily soluble in solvents, especially ethanol, insoluble in water, soluble in dilute hydrochloric acid, Mp. 67℃
(Kofler) Example 6 2-Benzylamino-4-N-methylpiverazino-5-methylthio-6-chloropromycin White crystals, soluble in water, sparingly soluble in dilute hydrochloric acid, soluble in dilute methanesulfonic acid.

M. p. l23℃ (Kofura-1) Example 7 (Reference example) 2 -
(N-Methyl N-benzyl)amino-4-N-butylpiverazino-5-methylthio-6-chloropyrimidine hydrochloride White crystals, insoluble in water, soluble in dimethyl sulfoxide.

M. p. Example 8 2-morpholino-4-N-methylpiverazino-6
-Chloro-5-methylthiopi-11 colorless crystals, insoluble in water, soluble in ethanol and dilute hydrochloric acid.

M. p. 1O2°C Example 9 (Reference example) 2-morpholino-4-N-n-butylpiverazino-1 5
-Methylthio-6-chloropyrimidine White crystals, insoluble in water, soluble in ethanol and dilute methanesulfonic acid solution.

M. p. 7O℃? 1 value...52.957.3618.
39 Example 102-n-Propylamino-4-N-Methylpiverazino-6-chloro-5-methylthiopyrimidine Colorless crystalline powder, soluble in ethanol, insoluble in water, soluble in dilute hydrochloric acid.

M. p. l2O℃ (Kofura-1) calculated value...49.44
6.9722.1811.25 Actual value...49.51
6.7722.4511.22 Example 112-n-Butylamino-4-N-methylpiverazino-6-chloro-5-methylthiopyrimidine crystalline powder, soluble in ethanol and dilute hydrochloric acid, insoluble in water.

M. p. 87 DEG C. (Kofura) Example 12 1-Methoxy-2-phenylamino-4-N-methylbiverazino-6-chloro-5-methylthiopyrimidine crystalline powder, insoluble in water, soluble in dilute hydrochloric acid.

M. p. Toxicity The acute toxicity of the compounds according to the invention was determined in CD1 (Charles River) mice by oral and intravenous injection.

The LD5O of each compound was determined by J. J. Reed and H. Mu
ench (Am. J. Hyg., l938, 27, 49
Calculated using the cumulative addition method in 3). The obtained LD5O is listed in the following table.

The product according to the invention has very low toxicity to mice;
LD5O value is 46-110 W/Kf when administered intravenously! between 200 and 900 Tfl/Kg for oral administration.

Pharmacological activity 1 Anti-emetic activity The anti-emetic properties of the compounds according to the invention have been demonstrated by G. Chen and C.
．． EnsOr(J.PharmacOl.Exp.Th
erap. , l95O, 98, 24. Apomorphine was administered orally to dogs in an vomiting test conducted by the authors.

The results obtained are listed in the table below. It is found that the compound of Example 10 has the highest anti-emetic effect.

2 Sedative effect The sedative effect of the compound according to the present invention is due to S. Garatti-
-Ni and V. Edited by Ghetti (Elsevier)
Publ. C.O. PsychOt (Amsterdam, London, New York, Princeton, 1957)
S. rOpicDrugs page 373. CourvOis
ier, R. DucrOt and L. CD (Charles River) by the tonic test described by JulOu.
on rats by oral administration, and on the other hand in a traction test (
TractjOntest) (S.CourvOisi
eLQuart. Rev. Psychiat. Neur
Ol. 1956, 17, 25), the spontaneous motility test (SpOntaneOusmOtility test)
st), by oral administration on CD1 (Charles River) mice.

The latter technique consists of recording the movements of the mouse by means of a floor of elongated metal strips that allow the natural activity of the animal to be recorded for the first 5 minutes after the animal has been introduced into the measurement chamber.

The product is administered 60 minutes before the test is conducted and 10 mice are used per dose. The results are expressed as ED5O, which represents the dose of substance capable of reducing the average motility of the treated animals by 50% compared to the test group receiving only the drug carrier. The sedative effects obtained are listed in the table below.

It is evident that the compound of Example 6 has some activity.
Analgesic effect The analgesic effect of the product according to the invention is due to E. Siegm-U
nd, R., Cadmus and G. Lu(PrOc.S
Oc. Exp. BlOl. Med. , l957.95,
In the abdominal torsion pain test with phenylbenzoquinone described by Charles River
) tested on mice.

The table below lists the AD5Os obtained.

The compound of Example 6 has a strong effect. 4 Anti-serotonin activity The anti-serotonin activity of the compounds according to the invention was determined by W. TheO
bald and R. DOmenjOz(Arzneim
it-1TelFOrsch. , l958, 8, l8)
Serotonin-induced foot edema test (SerOt) described by
OnePlantaredematechnique
e), oral administration and S. J. CORneR. W. P
iClOll-Ring, Hexagram and B. T. Warner
(Brit. J. PharmacOl., l963, 2
“Head twitch” (Headtw) described by
itch) using the CDl (CharlesRive) test.
r) Tested by oral administration on mice.

Furthermore, anti-serotonin effects have been shown in H. et al. on serotonin-induced bronchospasm. Konzet's death and R. R.O.
ssler(Arch: Exp. PathOl, Pha
An intravenous study was carried out on guinea pigs by a method derived from the method of rmakOl, 194O, 195, 7l). Finally A. Fanchamps, W. DOe
pffner, H. Weidman} and A. Cerl
etti (Schw. Med. WOvsch., l96
In vitro tests were carried out to discover the opposite effect on serotonin spasm on isolated female rat uteruses as described by O,lO4O).

The following table lists the results obtained. The compounds of Examples 10, 11, 1, 4 and 6 generally exhibit the highest anti-serotonin properties.

5. Convulsant-reducing activity The convulsant-reducing activity of the compound according to the present invention is determined by the R. Magnus (Areh.ges.
physlOl. , 19O4, 1O2, 123).

The results obtained are listed in the table below.

The products according to the invention exhibit antispasmodic activity essentially of the promuscular type.

Examples 4, 6, 5, 3, and 10 are most effective. Therapeutic uses The compounds according to the invention and their pharmaceutically acceptable salts can be used in human therapy, e.g. as tablets.
, capsules (LOzenges), gelatin-coated pills,
It can be used as a suppository, oral or injectable solution for the following conditions: vomiting, migraines of all causes, gastrointestinal spasms and other spasms.

Furthermore, it can also be used as a neurotropic agent, an analgesic, an antiserotonin agent, and a spasm alleviator. They can be used in daily doses of 10 mK to 500 m (in a single dose of 1) and 50 m7 to 2500 W, depending on the type and compound.

Example 13 Comparative Example Compound of the present invention and 2-methylamino-4 described in West German Patent Application No. 2307536
The results of comparison with -N-methylpiberazino-6-chloro-5-methylthio-pyrimidine (compound A) are as follows.

a) Toxic Compound A (7) LD5O was 30 mv/Kg, whereas the compound of the present invention was 46 m7/K (g or more), which clearly shows lower toxicity.

b) Antispasmodic activity In the Magnus test (a test that evaluates the effect of the compound on the excised duodenum of rats treated with acetylcholine or barium chloride), the EC5O of the neuroactive antispasmodic activity of the compound of the present invention was 0.20. ~9.
00m7/11 for antispasmodic activity of myotropic type 0.12
~1.7wa/! In contrast, Compound A had both types of activity of 10 m7/l or more, which shows that the antispasmodic activity of the compound of the present invention is clearly high.

The above points can be summarized in the following table.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, Z represents a methyl group, R_1 represents a hydrogen atom, R_2
represents a straight-chain alkyl group, allyl group, cyclohexyl group or benzyl group having 3 to 6 carbon atoms,
-NR_1R_2 residues may represent a morpholino group), 2,4,6-trichloro-5-methylthio-pyrimidine and the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 and R_2 are the same as defined above) to produce a general formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R_1 and R_2 are the same as defined above). It is characterized by reacting 4,6-dichloro-5-methylthio-pyrimidine with piperazine having the general formula: ▲Mathematical formula, chemical formula, table, etc.▼ (in the formula, Z is the same as defined above) ,
A method for producing the compound of general formula (II) above.