JPS5849548B2 - Method for producing pyrimidine compound derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The applicant has filed French Patent No. 72, filed March 1, 1972.
No. 06981 describes 2-methylamino 4-N-methylpiperazino 5-methylthio 6chloropyrimidine, its production method and its action on the central nervous system.

The present invention is based on the general formula (wherein R is a methylthio group, X is a chlorine atom, 2 is a hydrogen atom, methyl, hydroxyethyl or phenyl group, and Y is an acylamino group, an unsubstituted amino group, a 2-methylamino 4-N having an alkylamino group, a methoxypropylamino group, an arylamino group, or a morpholino, piperidino, piperazino or 4-methyl-piperazino group having 1 to 4 atoms;
-Methylpiperazino 5-methylthio 6-chloro Intended for compounds other than pyrimidine.

Substituted amino groups include in particular alkylamino groups having 1 to 4 carbon atoms, such as methylamino, ethylamino, isopropylamine groups, arylamino groups of the first group, such as phenylamino, N-alkyl, N-7enylamino, hetero It represents a heterocyclic group in which the atom is nitrogen, such as a morpholino group, a piperidino group, a piperazino group, and a 4-methylpiperazino group.

Particular preference is given to compounds of formula (I) in which R is a methylthio group and X is a chlorine atom.

The compounds of the present invention combine a dichloropyrimidine of the formula 4 6 and a piperazine of the formula from 40 to 1 in the presence of an acid absorber.
reacted in an anhydrous medium at a temperature ranging up to 20 degrees C;
The product has the formula, optionally obtained by replacing the chlorine atom with an alkoxy group.

For conversion to alkoxy groups, sodium alcoholate is reacted in a dimethyl sulfoxide medium at temperatures around 100° C., or potassium is reacted with an excess of the corresponding alcohol at reflux temperature.

The compound of formula (n) in which Y represents a mono- or di-substituted amino group or a nitrogen-containing heterocyclic group has the formula 2, 4, 6
- Can be prepared by reacting trichloropyrimidine with the corresponding amine.

The isomers produced can be easily separated by operating in a water-methyl ethyl ketone mixture.

They may also be completely replaced and then separated.

If Y is an unsubstituted or monosubstituted amino group, it can be acylated in known manner, for example by the action of an acid anhydride or even an acid chloride in an aqueous or anhydrous medium.

This acylation can be carried out on the 2-amino 4-piperazinopyrimidine or before the chlorination of the 4,6-dionepyrimidine intermediate.

The products according to the invention have interesting pharmaceutical properties.

The following examples are illustrative and do not limit the invention; parts are by weight unless otherwise specified.

Example 1 2-ethylamino 4-N-methylpiperazino 6-chlor 5-methylthio pyrimidine (a) 2-ethylamino 4,6-dichlor 230 parts of 5-methylthiopyrimidine 740 parts of 2,4,6-trichlor 5-methylthiopyrimidine dissolved in methyl ethyl ketone of 6
Add 50 parts of ice and pour in 120 parts of a 38% diethylamine aqueous solution over 30 minutes while cooling the mixture so that the temperature does not exceed 5 degrees Celsius.

Next, 129.5 parts of a 31% solution of caustic soda was added at 20° C. for 1 hour.

After stirring for 6 hours, the desired isomer precipitated and 4-
Ethylamino 2,6-dichloro 5-methylthio pyrimidine remains in solution.

After cooling for 15 hours, the precipitate was collected and washed with methyl ethyl chloride.

73 parts of the desired product are obtained. Reconcile with ethanol.

Melting point is 147 degrees C0(b) 2-ethylamino 4-
N-methylpiperazino 6-chlor 5-methylthio
31.4 parts of the product of pyrimidine (a) are dissolved in 650 parts by volume of ethanol while warming to about 70°C.

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

The mixture was refluxed for 3 hours, cooled to minus 40 degrees Celsius, and the precipitate was collected and washed with water.

29 parts of the desired product are obtained.

Melting point: 101 degrees C. The hydrochloride salt is obtained by treatment with a calculated amount of hydrochloric acid in ethanol medium.

Analysis value example 2 2-isopropylamino 4-N-methyl-piperazino 6-chlor 5-methylthio pyrimidine 2(4)-6-dichlor 4(2)-isopropylamino 5-methylthio pyrimidine As in example 1, but Ethylamine is replaced by a corresponding amount of isoprobylamine.

The two isomers separate into an oil.

This mixture contains approximately 40% of the desired isomer.

(b) 2-isopropylamino 4 -N-,7'
-IF-Rubiperazino 6-chlor 5-methylthio pyrimidine 156 parts of the above isomer mixture and 18 parts of N-methylpiperazine
The mixture with 0 parts is heated in 1200 parts of alcohol for 3 hours and concentrated under reduced pressure.

The residue was taken up in ether (500 parts) and filtered.

Only the desired isomer is insoluble under these conditions.

Wash with water to remove N-methylpiperazine hydrochloride.

62 parts of the desired product are obtained.

Reconcile with ethanol.

Melting point is 145 to 146 degrees C. Analysis value C13H22N
As 5CIS, analytical amount: 315.5 (a) Example 3 2-tertiary monobutylamino 41N-methylpiperazino
5-Methylthio 6-chloropyrimidine Proceed as in Example 2, but using tertiary butylamine instead of isopropylamine.

The desired product is crystallized from ethanol.

Melting point: 157 degrees C. Analysis value C14H2, N, Cls and L
-'C, molecular weight 3 2 9.5?4 2-phenylamino 4-N-methylpiperazino 6-
Chlor 5-Methylthio Pyrimidine Proceed as in Example 1, but using aniline.

2-phenylamino 4-N-methylpiperazino 6-chloro 5-methylthio pyrimidine is obtained.

Analysis: Molecular weight as C16H2N5SCl: 386 Example 5 3-Methoxy 2-propylamino 4-N methylpiperazino 6-chloro 5-1 thyl f-o Pyrimidine Proceed as in Example 1, but using 3'-methoxyprobylamine, After distilling off methyl ethyl ketone, 3'
-Methoxy 2(4)-propylamino 4(2)・6-
Obtain dichlor 5-methylthio pyrimidine.

Contains 25% of target product. The distillation residue (1 part) was dissolved in concentrated hydrochloric acid (specific gravity - 1.19) < (5 parts by volume), and water (
2.2 parts).

Under these conditions, 3'-methoxy 2-propylamino 4,6-dichloro 5-methylthio pyrimidine precipitates, while the other isomer remains dissolved.

Melting point: 85 degrees C0 40 parts of 37-methoxy 2-propylamino 4 dissolved in 400 parts by volume of absolute ethanol
・6 dichlor 5-methylthiopyrimidine and 43 parts of N
- methylpiperazine and boiled under reflux for 3 hours.

Ethanol is distilled off under reduced pressure, and the distillation residue is taken up in 300 parts by volume of ether to remove N-methylpiperazine hydrochloride.

The precipitate is washed with 300 parts by volume of ether.

Seal the sediment and wash it. The residue after distilling off the ether is initially an oil, but soon crystallizes.

Reconsolidate in hexane and add 40 parts of 3'-methoxy 2propylamino 4-N-methylpiperazino 6-chlor 5
- Obtain methylthio pyrimidine.

Melting point: 80 degrees C.

Analysis value C14H240N5ClS Molecular weight 345.5
Example 6 2-amino 4-N-methylpiperazino 6chlor 5
-Methylthio pyrimidine hydrochloride Same as Example 1, but
Using ammonia instead of ethylamine, 2-amino
Obtain 4-N-methylpiperazino 6-chloro 5-methylthio pyrimidine.

Melting point is 191 to 192 degrees Analysis value of C0 monohydrochloride (molecular weight: 310) C1oH17N5SCl2 Example 7 4-N-phenylpiperazino 2-methylamino 6-chloro 5-methylthio Pyrimidine Same as Example 1, but 2 -Methylamino 4,6-dichlor 5
-Methylthio pyrimidine is reacted with N-phenylpiperazine to obtain 4-N-phenylpiperazino 2-methylamino 6-chloro (5-methylthio pyrimidine).

Melting point is 163 to 164 degrees C.

Analysis value As C16H2oN5SCl, molecular weight: 34
9.5 Example 8 2-Methylamino 4-N-(β-hydroxyethyl)
Hyherazino 6-chlor 5-methylthio pyrimidine Same as Example 7 but using N-(β-hydroxyethyl)piperazine to prepare 2-methylamino 4N(β-hydroxyethylpiperazino)6chlor 5-methylthio pyrimidine. sell.

Melting point 120 to 122 degrees C (from ethanol).

As analysis value C 1 2 H20 N50SC l,
Molecular weight: 317.5? Experimental value % 45.21 6.28 21.83
10.58 Example 9 2,4-bis(N-methylpiperazino) 6chlor 5
-Methylthio pyrimidine dihydrochloride 2,4,6-trichlor A mixture of 5-methylthio pyrimidine and excess N-methylpiperazine is heated to reflux for 3 hours.

2,4-bis(N-methylpiperazino) 6-chlor
Obtain 5-methylthiopyrimidine.

The melting point of hydrochloride is over 250 degrees C (decomposition).

Analysis value C15 H2N6SCl3.H20, molecular weight: 489.5 Example 10 2-Methylamino 4-piperazino 6-chloro 5-
Methylthiopyrimidine hydrochloride Anhydrous piperazine was added to 2-methylaminohydrochloride under the conditions described in Example 1.
4,6-dichlor 5-methylthio pi*? The desired product is obtained by reacting with rimidine.

Melting point: 250 degrees C or higher (decomposition).

Analysis value: C 1o Hl N=, SC 12 , molecular weight: 3 10 Example 11 2-piperidino 4 -N-methylpiperazino 5-methylthio 6-chlor Pyrimidine hydrochloride Proceed as in Example 1, but use piperidine instead of ethylamine. .

The desired product is reconsolidated from ethanol.

Melting point: 215 degrees C (decomposition). Analysis value C15H24N5S
Cl-HCl amount: 378.4, molecule? 12 N-methyl 2-N-phenylamino 4 -N-methylpiperazino 5-methylthio 6-chloro pyrimidine hydrochloride As in Example 1, using N-methylaniline instead of ethylamine.

The desired product is reconsolidated from ethanol.

Melting point is 220 degrees C (decomposition). Analysis value C1H22N5C
As IS-HC1, molecular weight: 400.4 Example 13 2-(N-methyl N-benzoyl)amino 4-N-methylpiperazino-6-chloro 5 methylthio pyrimidine hydrochloride 28 parts of 2-N-methylamino 4-N- Methylpiperazino-6-chloro5-methylthiopyrimidine 1
Dissolve in 50 parts by volume of tetrahydrofuran and add to 10.5 parts of triethylamine.

After 30 minutes, 13.7 parts of penzoyl chloride was added at room temperature, and the mixture was heated under reflux for 5 hours.

Separate the Seikai triethylamine hydrochloride, dilute the sap with water, and extract with ether.

The ether solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure.

The residue is taken up again in ether to remove a small amount of starting product.

Forms a monohydrochloride salt in ether, melting point approximately 210 degrees C0. Reconcretes from ethanol.

Analysis value C18H22N5ClSO-HC1 Molecular weight:
428.4 Example 14 (Reference example) 2-acetylamino 4-N-methylpiperazino 5-
Methyl 6-chloropyrimidine (a) 2-acetylamino 4,6-dioxo 5-methyl pyrimidine 80 parts of 2-amino 4-dioxo 5-methyl pyrimidine in a mixture of 500 parts by volume of acetic acid and 108 parts by volume of acetic anhydride. is refluxed for 8 hours.

Wash with ether and dry under reduced pressure to obtain 87 parts of the desired product.

(b) 2-acetylamino 4,6-dichlor 5
Methyl pyrimidine In a mixture containing 38 parts of 2-acetylamino 4,6-dichloro5-methyl pyrimidine and 46.5 parts of triethylamine in 255 parts of tetrahydrofuran,
At a temperature of 0° C., 108 parts of phosphorus oxychloride are added in small portions.

After stirring at room temperature for 6 hours, the reaction mixture was poured into ice water and extracted with chloroform.

The chloroform phase is washed with water, dried over sodium sulfate and concentrated to dryness.

The remaining solid matter is kneaded in absolute ethanol, filtered, and dried under reduced pressure.

Analysis value C7H7N3Cl20 (C) 2-acetylamino 4-N-methylpiperazino 5-methyl 6-chloro pyrimidine 10 in the presence of 4 parts of triethylamine and 4 parts of N-methylpiperazine
8.8 parts of 2-acetylamino 4,6-dichloro 5-methyl pyrimidine are dissolved in 0 parts by volume of tetrahydrofuran.

The reaction mixture is refluxed for 6 hours. The reaction mixture was poured into water, the insoluble matter was removed, and the mixture was reconsolidated with ethanol.

Melting point is 202 degrees C0 analysis value as C12H18N50Cl Example 15 2-N-diethylamino 4-N-methylpiperazino
5-Methylthio 6-chloro pyrimidine dihydrobromide Following the method of Example 1, but using diethylamine instead of ethylamine.

The desired product is isolated as the dihydrobromide salt.

Reconcile with ethanol.

Melting point is 248 degrees C (decomposition). Analysis value C,, H26N
As 50SC I Br 2, molecular weight: 509.8 Example 16 2-(N-methyl N-acetyl)amino 4-N-methylpiperazino 5-methylthio 6kuu,,pyrimidine 2-methylamino 4-N-methylpiperazino 5-methylthio 6 -Chlor Pyrimidine is refluxed in 60 parts of acetic anhydride for 2 hours.

Dissolve completely.

After removing excess reagent, the residue is treated with dilute caustic soda.

The separated oil is extracted with chloroform.

The solvent is removed under reduced pressure. Dissolve the colorless solid in ethanol.

Rather, use the monohydrochloride.

This material is reconsolidated from an acetone/ethanol mixture.

Melting point: 188 degrees C. Analysis value C13H2oN50SCl-
As HCl, molecular weight: 366.3 Example 17 (Reference example) 2-Methylamino 4-N-methylpiperazino 5-methylthio 6-methoxypyrimidine hydrochloride 100 parts by volume of dimethylsulfonate in the presence of 5.4 parts of sodium methylate 2-methylamino 4-
Dissolve 32 parts of N-methylpiperazino 5-methylthio 6-chloropyrimidine.

The temperature is maintained at 100 degrees C for 8 hours. Dilute with water, extract with chloroform, evaporate the solvent, and give the hydrochloride in absolute ethanol.

21 parts of product were obtained, which was reconsolidated from ethanol.

Melting point 245 degrees C0 (decomposition) Analysis value C12H2. As N5OS-HCl, molecular weight: 319.9 Example 18 (Reference example) 2-Methylamino 4-N-methylpiperazino 5-methylthio 6-propoxy 20 parts of pyrimidine hydrochloride 2-methylamino 4-N-methylpiperazino 5-methylthio 6- Chlor pyrimidine is dissolved in 130 parts by volume of n-propanol in the presence of 7 parts of granulated caustic potash.

The mixture is refluxed for 2 hours and then poured into water.

The oil that separates is extracted with ether.

The organic phase is washed with water, dried and evaporated.

The residue solidifies when taken up in petroleum ether.

Reconstitutes from petroleum ether. Melting point is 90 degrees co Analysis value As C14H2sNsOS, molecular weight: 3
11.5 Example 19 (Reference Example) 2-Methylamino 4 N-methylpiperazino 5 Methylthio 6-allyloxypyrimidine hydrochloride The same procedure as in Example 18, but using allyl alcohol, yields the above hydrochloride.

Melting point: 174 degrees C (decomposition).

Analysis value As C14H24N5SOCl Molecular weight: 3
45.9? 20 (Reference Example) 2-Methylamino 4-N-methylpiperazino 5-methylthio 6-β-monoethoxyethoxypyrimidine hydrochloride Proceed as in Example 18, but using β-ethoxyethanol.

Obtain the above hydrochloride. Melting point: 136 degrees C0 Analysis value: C 1 5 As H2N502S・HCI, molecular weight: 378 Toxicity The toxicity of the compound of the present invention was determined by oral and intravenous injection at CD 1
(Charles RIVER) Let's look into mice.

LD5o is J+J. REED and H. HUENC
H7! )' AITI. J. Hyg. ,2
7, 493 (1938).

The results are shown in the table below.

The test method for this LD5o is as follows.

Groups of CDI mice with the same number of animals are administered the compound to be treated.

This amount increases exponentially from one group to another.

Record the number of animals that died within 3 days.

Tests must be conducted at non-toxic and 100% lethal doses.

The number of dead animals obtained at a given dose is added to the number of dead animals obtained at a lower dose, and the number of live animals obtained at a given dose is added to the number of surviving animals obtained at a higher dose. .

For each dose, calculate the mortality rate from the cumulative number of dead and living animals using the following formula:

The toxicity of the product of the present invention is 33 to 124 m9/k when administered intravenously.
g and orally between 200 and 900 ■/ky
It is between the above and can be said to be almost non-toxic.

Pharmaceutical properties 1. Anti-emetic activity G. CHEN and C, ENSOR are J. Parma
col. exp. T herap,, 9 8
In the vomiting test using apomorphine, which was described in J.D., 24 (1950), apomorphine was administered orally to dogs.

The results obtained are shown in the table below.

The above test is conducted as follows.

Ten healthy dogs of both sexes are used for each study.

Five of them were orally administered a predetermined amount of the test compound solution.
The other five animals receive the same volume of solvent as a control.

Thirty minutes after administration of the above solution or vehicle, the dog was given apomorphine HClO. 1 mg/kg is injected subcutaneously and then observed for vomiting frequency for 30 minutes.

After 3 days of rest, the same group of animals is used again in the cross-over experiment.

The antiemetic activity of a compound is evaluated by its ability to suppress emesis or reduce the frequency of vomiting.
Expressed as % effective dose (ED5o) /kg.

The compounds of Examples 1016, 2, 8 and 1 have very strong anti-emetic effects.

2. Sedative effect The sedative effect of the compound of the present invention is expressed by C. D. Rat (Char
les RIVER) was investigated by oral administration.

Method, published by Elsevier (Amsterdam, London, New York, Flinstone), 1597, S.
Psych by GARATTINS and V, GHETTI
On page 373 of otropic Drugs, S. COUR
VOISIER. R. DUCROT and L. JULOU
The tonicity test described by Quart, Rev. P
sychiat. Neurol,, 17, 25
(1956) in S. CD1 by oral administration described by COURVOISIER (Charles RIV
ER) The results of a traction test on rats are also shown.

The results using the main compounds are shown in the table below.

This traction test was as follows.

, CD I (Charle
sRIVER) The mouse is suspended by its front legs on a horizontal wire.

All animals that fail to perform a turnover to contact the wire on at least one of the hind legs within 5 seconds are sedated.

Control animals undergo such turnover in less than 5 seconds.

The neuroleptic activity of a compound is 50%, which is a dose of the compound /ky that suppresses the pull reflex in 50% of treated mice.
Active dose (AD50) is expressed.

So 3. Sedative effect: The sedative effect of the animal according to the present invention was demonstrated in CDI mice (C
harles RIVER).

The method is described by E. SIEGMUND, R. CADMUS and Go. LU is Proc. Soc. Exp, Biol. M
ed. This is an abdominal torsion pain test using phenylbenzoquinone as described in J. Chem., 95, 729 (1957).

This test was performed for 2-phenyl-1,4-penzoquinone at 0.
0.02% aqueous solution to 0.02% aqueous solution. By 25 ml intraperitoneal injection,
CD I (Charles RIVER) causes a typical syndrome in male mice.

This syndrome is expressed by intermittent contractions of the abdomen, bending and rotation of the trunk, and extension of the hind legs.

Several non-toxic doses of the test compound are divided logarithmically and administered orally in the form of an aqueous solution to different groups of mice.

Forty-five minutes after compound administration, mice are injected intraperitoneally with 2-phenyl-1,4-penzoquinone.

One group of mice is simply injected with 2-phenyl 1,4-penzoquinone and serves as an untreated control group.

The effect of 2-phenyl-1,4-penzoquinone is observed within 5 minutes after injection.

A dose-response curve (a curve showing the rate of protected animals as a function of the dose of test compound) is plotted.

This curve shows the 50% active dose (AD,).

) is estimated. That is, the dose of compound ■/kg that suppresses the syndrome in 50% of treated mice.

The following table shows the AD5o obtained.

The compounds of Examples 5, 1 and 14 are also active.

4. Anti-serotonin activity The anti-serotonin activity of the compounds according to the present invention was determined by
eimittel Forsch, 8, 18, (19
58) W, THEOBALD and R, DOMENJO
CD1 rat (Charles RIVER) foot edema test with serotonin according to the method described by S. J. CORNE, R. W. PICKERING and B. T. WARNER h” J. Pharm
acol. , 20, 106 (1963),
We investigated this using a ``heat convulsion'' test using CDI mice (Charles RIVER).

Furthermore, anti-serotonin activity has been demonstrated by H. KONZET and R
．． ROSSLER is Arch. exp. Patho
l. Parmakol, 195, 71 (1
940) and the study on guinea pigs using intravenous administration as described in A. FANCHAMPS, W. DOEPFE
NER, H. WEIDMAN and A. CERLETT
I Schw, Med. Worsch. , 9 0
, 1940 (1960), an in vitro test was conducted on serotonin spasms in isolated rat uterus.

The results are shown in the table below.

The test method of Corn et al. is as follows.

This test is based on the characteristic head twitching that appears in mice after intraperitoneal injection of 5-hydroxytryptophan, a precursor of serotonin.

Several non-toxic doses of the test compound were administered to 10 CD
I (Charles RIVER) mice are dosed orally at time 1=0.

At time t-+60 minutes, 5-hydroxytryptophan 4
00m9/kg is injected intraperitoneally into mice.

At time 1 = +90 minutes, ie 30 minutes after 5-hydroxytryptophan administration, the mice are observed for 2 minutes for head twitching.

The antiserotonin of the test compound was 50% active dose (AD5
o), ie the dose of compound Tn9/kg which suppresses the head convulsions induced by 5-hydroxytryptophan in 50% of treated mice.

Anti-serotonin activity by the serotonin plantar edema test by Theobald et al. is measured as follows.

CD weighing 130-160v (CharlesRI
VER) Rats are used in the test.

Test compounds are administered orally to rats.

After 30 minutes, a serotonin solution containing 25 μl of 5-hydroxytryptamine per liter was added. Inject 1 ml into the heel of the left hind leg.

135 minutes after the 5-HT injection, the hind legs are amputated and weighed.

The degree of serotonin-induced plantar edema is calculated from the difference between the 5-HT treated left hind paw volume and the untreated right hind paw volume.

The antiserotonin activity of the test compound was determined by the 50% active dose (
AD50 ), i.e. the dose of the compound with a 50% reduction in the degree of plantar edema induced by serotonin ■/k
Represented by y.

Antiserotonin activity by the serotonin bronchospasm test of KONZET et al. is measured as follows.

Urethane 1. for guinea pigs weighing 40 M' or more. 5 P
Anesthetize by intraperitoneal injection of /kg.

The animal is then bisected and a pneumothorax is performed at five rib intervals.

A cannula is placed in the trachea and the animal's bronchus is placed against some resistance from the hydraulic ram with a breathing pump.

Artificially ventilate the animal. A constant volume of air, slightly higher than the animal's breathing capacity, is pumped into the bronchi at a physiological rhythm of about 70 breaths per minute.

Excess air passes through the hydraulic ram and its volume is measured by a manometer.

Fluctuations in bronchial volume (eg, reduction in bronchial volume due to bronchial constriction induced by convulsants) can be seen from corresponding fluctuations in excess air passing through the hydraulic ram.

An electrocardiogram will also be recorded throughout the test.

Antagonists, ie, compounds that cause bronchospasm (serotonin, histamine, acetylcholine), and the test compound are injected intravenously.

Injections are made through a catheter into the lateral condylar vein.

For bronchospasm, administer the antagonist at 0.0005 to 0. 0 0
Repeat every 3 or 4 minutes for 5 mtp/kg injections.

The antagonists are administered sequentially to avoid tachyphylaxis.

Test compounds are injected 1 minute before antagonist.

This injection of the antagonist can be repeated regularly until the inhibition phenomenon disappears before injecting another compound or another dose of the same compound.

The antiserotonin activity of the test compound was determined by the 50% active dose (E
D5o), i.e. the dose of the compound with a 50% reduction in the degree of serotonin-induced bronchospasm■
/kg.

Compounds of Examples 1, 5 and 6 show the highest anti-serotonin activity.

5. Spasmolytic activity R. MAGNUS is Ahch. Ges. P
Hysiol. 102, 123 (1904), the alleviating effect on neurotropic spasm induced by acetylcholine and myotropic spasm induced by barium chloride in the excised rabbit 12 denum was investigated.

The results are shown in the table below.

A piece of duodenum 3 crrL in length is taken from a rabbit that has been stunned and bled beforehand.

This duodenal piece was washed with Tyrode (NaC per 1 liter of water).
18P, KCI0.2g, CaC12 0.2P, Mg
Cl21 0ynq, MaHP04 5m9, NaHC
O3 1? and immediate burial solution containing glucose 1i) 5
01nl-containing tank.

This is maintained at 37°C and oxygen is added by gentle bubbling.

This duodenal piece is stretched with a weight of 21 mm and its movement is recorded.

Stabilize the organ by leaving it for about 30 minutes and add an acetylcholine solution containing 150 m9 of acetylcholine per liter of solution.
．． The spasm is induced by irrigation with 0.5 ml of barium chloride solution containing 5 ml or 5 liters of barium chloride per liter of solution.

After 4 minutes, the organs are washed several times and allowed to stand for 6 minutes.

The organ is exposed to acetylcholine or barium chloride every 10 minutes.

If the seizures produced are normal and stable, the test compound was administered at 0. Acetylcholine or barium chloride in the form of a 5 yd aqueous solution is introduced 1 minute after administration and left in contact with this organ for 3 minutes until the duodenum is irrigated.

The anticonvulsant activity of a compound is determined by the 50% effective concentration (EC5o
), i.e. 91.5■ per liter of acetylcholine in the tank
or by the concentration of compound /l which causes a 50% reduction in convulsions induced within 3 minutes by a concentration of 50 /l of barium chloride.

The products of the invention exhibit essentially antispasmodic activity of the promuscular type, the most effective being those of Examples 3, 2, 5 and 8.

Therapeutic Uses The compounds of the invention and acceptable salts may be used as compresses, capsules, gelatin formulations, suppositories, oral or injectable solutions,
Can be used for vomiting, migraines of all causes, gastrointestinal cramps, and more.

Additionally, it can be used as a psychotropic, sedative, antiserotonin and anticonvulsant.

Used as compresses, doulagies, gelatin preparations, Cassier suppositories, ampoules for injection, infusion solutions, in doses ranging from 50 to 2500 n9 per day, depending on the dosage form and the compound. sell.

Example 21 2-pendylamino-4-N-methylpiperazino-5-
Methylthio-6-chloropyrimidine white crystalline product, easily soluble in water, slightly soluble in dilute hydrochloric acid, easily soluble in dilute methanesulfonic acid.

Melting point: 123°c0 (Kδfler).

Analysis: Example 22 2-morpholino 4-N-methylpiperazino 6-chloro 5-methylpyrimidine.

Colorless crystal, insoluble in water, easily soluble in ethanol, easily soluble in dilute hydrochloric acid.

Melting point: 102°C. Analysis: Example 23 2 n-propylamino-4-N-methylpiperazino6 Chloro-5-methylthiopyrimidine colorless crystalline powder, easily soluble in ethanol, insoluble in water, easily soluble in dilute hydrochloric acid.

Melting point: 120°C (Kδfler). analysis Example 24 2-n-butylamino Jino-6-Chloro 5 7 4-N-methylpipera Methylthiopyrimidine Insoluble in crystalline powder, easily soluble in ethanol and dilute hydrochloric acid.

Melting point: 87°C (K3fler). analysis: water example 25 4′ methoxy 2 Phenylamino 4 N Methylpiperazino 6-chloro 5 Metinorechi Opyrimidine Crystalline powder, insoluble in water, 144°c (K6fler).

analysis: Easily soluble in dilute hydrochloric acid.

Claims (1)

[Claims] 1 General formula (wherein R is a methylthio group, X is a chlorine atom, Z is a hydrogen atom, methyl, hydroxyethyl or phenyl group, Y is an unsubstituted amino group, a carbon Atom 1~
Compounds having 4 alkylamino groups, methoxypropylamino groups, arylamino groups, or morpholino, piperidino, piperazino or 4-methyl-piperazino groups (with the proviso that 2-methylamino-4-N-
methylpiperazino-5-methylthio-6-chloropyrimidine) having the formula (wherein R and Y are as defined above).
Process for the preparation of the above compounds, characterized in that 6-dichloropyrimidine is reacted with piperazine having the formula, where Z is as defined above. 2 General formula (wherein R is a methylthio group, X is a chlorine atom, 2 is a hydrogen atom, methyl, hydroxyethyl or phenyl group, Y is an acylamino group or alkyl is in the preparation of a compound having the formula (wherein R is as defined above and Y is an unsubstituted amino group or an alkylamino group having 1 to 4 carbon atoms) 4,6-dichloropyrimidine having the group ) with a piperazine having the formula in which 2 is as defined above, and then acylating the compound obtained. , a method for producing the above compound.