CA1036598A - Piperazino-pyrimidines used as a drug_ - Google Patents

Abstract

Compounds of general formula: (II) in which z represents an alkyl group having 1 to 4 carbon atoms, R1 represents a hydrogen atom or a methyl or ethyl group, and R2 represents a linear alkyl group having 3 to 6 atoms carbon, allyl, hydroxyethyl, cycloalkyl having 3 to 8 carbon atoms, benzyl or p-methoxyphenyl, the residue-NR1R2 can also represent a mortholino group. These compounds can be used as drugs for their action on the central nervous system. Process for the preparation of these compounds.

Description

103659 ~ 3 The present invention relates to new piperazino ~
pyrimidines which can be used as medicinals up to their pro- -~ c ~ preparation die.
In the patent application filed in Canada on August 15 1973 under number 178,905, the plaintiff has described new piperazino-pyrimidines, usable as drugs and responding to the general formula:
R

X ~ N ~ -Z
~ N ~
~ '.
Y (I) dan8 which R represents a methyl or methylthio group, X represents pré8ente A halogen atom or an alkoxy group having 1 to 5 carbon atoms, Y represents an aromatic radical, a group acylamino, or optionally amino amino, Z represents an ato-me d ~ hydrogen, a methyl, ethyl, hydroxy ~ thyle or phenyl group, -with the exception of 2-methylamino N-methylpiperazino-4 methylthio-5 6-chloro pyrimidine.
The present application relates to other compounds of the same type.
types which can also be used as medicines.
The components of the present request can be represented 8 understood by the general formula:

c ~ N3Z (II) ~ 2 l ~
in which Z represents an alkyl group having 1 to 4 atoms carbon, Rl represents a hydrogen atom or a methyl group ~ k. ' ~ '' ..
- 1 - q ~:. ,,, ~, "',:'', 1036598 ~
or ethyl, and R2 represents a linear alkyl group having 3 or 6 carbon atoms, allyl, hydroxyethyl, cycloalkyl poss ~ dant-3 to 8 carbon atoms, benzyl or p-methoxyphenyl, the rest -NRlR2 can also represent a morpholino group.
The compounds of formula (11) can be prepared as follows:
the process described in the patent application cited above, in using the corresponding HN l amines.

R2., The compounds described in the following examples have been prepared as in Example 1 of patent application number 178.905 but replacing the ethylamine with an equimolar amount of the a-corresponding HN ~ mine and possibly Nm ~ thylpiperazine by an equimolar amount of the corresponding N-alkyl-pip ~ razine-dante.
Example 1 AllYlamino-2 N-methYlPiperazino-4 chloro-6 methYlthio-5 ~ yrimidine This water-insoluble product is in the form of a colorless crystalline powder, soluble in alcohol and in ~
dilute hydrochloric acid. PF: 89-90C ~ Make ~ ne).
Analysis: C% H% N% Cl% S%
. .
Calculated ......... 49.76 6.37 22.32 11.32 10.27 Found .......... 49.73 6.35 22.30 ll, lO 10.20 ~ xample 2 N- ~ -hY-droxyethyl) amino-2 Nm ~ thYlPiPérazino-4 chloro-6 m ~ thylthio-5 pYr_midine Colorless, water-insoluble, soluble crystals in ethanol and in dilute hydrochloric acid. PF: 142C

Maquenne)

- 2 , ~ 03659 ~
Analysis: C% H% N% Cl% S%

Calculated .......... 45.35 6.3 22.04 11.18 10.08 Found ........... 45.34 6.80 22.25 11.33 10.15 Example 3 CYclohexylamino-2 N-methylpi ~ érazino-4 chloro-6 meth ~ l-thio-5 eyrimidine Colorless crystalline powder, insoluble in water, so-luble in ethanol and dilute hydrochloric acid.
PF: 129C (Kofler).
Analysis: C% H% N% Cl% S%

Calculated .......... 54.00 7.31 l9r69 10 ~ 00 9 ~ 00 Found ........... 54.27 7.16 19.90 9.80 8.99 `
Example ~ 4 n-PentYlam no-2_N-methYlPi ~ érazino-4 chloro-6 méthvl-thio-5 ~
Colorless crystalline powder, very soluble in etho-nol, insoluble in water, soluble in hydrochloric acid di-~ u ~. PF: 60C (Kofler).
Anaay ~ e: C / 0 H% N% Cl%

Calculation ~ .......... 52.40 7.56 20.37 10.33 Found ........... 52.56 7.68 20.50 9.94 Example ~ S n-hexYlamino-2 N-methYl ~ iPérazino-4 chloro-6_méthylt ~ O
-5 ~ yrimidine Colorless crystalline powder, very soluble in sol- ", ~, vant ~ and in particular dan9 ethanol, insoluble dan ~ water, soluble in dilute hydrochloric acid. PF: 67C (Kofler).
Anaayse C% H% N% Cl%

Calculation ~ .......... 53.76 7.83 19.58 9.94 Found ........... 53.79 7.58 19.93 9.89 Example ~ 6 BenzYlamino-2 N-methylpiperazino-4 methylthio-5_chloro-6 Pyrimidine ~:

_ 3 -. .

~ 036598 White crystalline product, soluble in water, little sol-luble in dilute hydrochloric acid, soluble in acid m ~ -diluted thanesulfonic. PF: 123C (K ~ fler) Analysis: c% ~ / O ~ / O
Calculated .... 56.12 6.05 19.26 Found ..... 56.08 5.99 19.33 Example 7 (N-methvl N-benzvlamino) chlorhvdrate -2 N-butYlpipé
razino-4 methylthio-5 chloro-6 pyrimidine White crystals, insoluble in water, soluble in dimethyl sulfoxide. PF: 180C (Kofler).
Analysis: C% ~ / O ~ / O
Calculated .... 55.25 6.84 15.34 Found ..... 55.25 6.48 15.21 Example 8 Morpholino-2 N-methvlPiperazino-4 chloro-6 methYlthio-5 PYrimidine ~ "
Colorless, water-insoluble, soluble crystals in ethanol, soluble in dilute hydrochloric acid.
PF: 102C.
Analysis: C% ~ / O ~ / O Cl% S%
Calculated .... 48.90 6.40 20.37 10.33 9.31 Found ..... 49.07 6.71 20.83 10.40 9.65 Example 9 ~ E ~ 2 Nn-butYlpiperazino - 4 methylthio-5 chloro- ^ ~
6 PYrimidine White crystals, insoluble in water, soluble in l ~ ethanol and in a dilute methanesulfonic acid solution.
PF: 70C.
Analysis: Ch ~ / O NP / o Calculated .... 52.90 7.31 18.15 Found ..... 52.95 7.36 18.39 Example 10 n-propYlamino-2 N? -Methylpiperazino-4 chloro-6 methyl-thio-5 pyrimidine Colorless, crystalline powder, soluble in ethanol, soluble in water, soluble in dilute hydrochloric acid.

: ".
S ~ * "?

~ .036S9g ~
PF: 120C (K ~ fler).

Analysis: C% ~ / O ~ / O C1%
____ ~ _ Calculated ..... 49.44 6.97 22.18 11.25 Found ...... 49.51 6.77 22.45 11.22 Example 11 n-butylamino-2 N-methvlpir, 4-erazino-6 chloro methylthio -5 pyrimidine Crystalline powder soluble in ethanol and acid dilute hydrochloric, insoluble in water. PF: 87C (Kafler) Analysis: C% ~ / O ~ / O Cl%
Calculated ..... 50.98 7.28 21.24 10.77 Found ...... 51.10 7.22 21.40 10.37 Example 12 Methoxy-4 ~ ph ~ nYlamino-2 N-methYlpiperazino-4 chloro-6 methYlthio-5 Pvrimidine Water-insoluble crystalline powder, soluble in dilute hydrochloric acid. PF: 144C (Kofler).
Analysis: C% H ~ / o ~ / O Cl% S%
____ __ Calculated ..... 53 ~ 75 5 ~ 80 18.44 9 ~ 35 8.43 Found. ~ .... 54.03 5.80 18.36 9.47 8.60 TOXICOLOGICAL PROPERTIES
The acute toxicities of the compounds according to the invention have been determined in CD 1 mice (Charles RIVER) by vo ~ es oral and intravenous. The LD 50s were calculated by the me-cumulative method of REED, JJ and MUENCH, H., Am. J. Hyg., 27, 493 (1938).
~ The LD 50 obtained are collated in the following table before:
Acute Product of Toxicity in 1 I mouse LD 50 ~ mg / kg) the ivvo example Approx. 46 200 2 89 approx. 600 ~ ~
. ~ '''': - '': '-:
89 sup. 900 , "" ,,, .. "
_ 5- ',' ~ 0365g8 Acute Product of Toxicity in Mice LD 50 (mg / kg) the ivvo example - ~~
.. ._. ._ __.
Approx. 4 87 600 _ sup. 900 ._. _ __ _ _ ._ 6 85 approx. 525 _ ._ ..
7 insoluble atox. 900 ~
_ _ ..
8,110 approx. 400 . ._. . . :, ' g insoluble approx. 600 ' . ... _ ~
approx. 200,.

11 98 approx. 225 .. ''. '' 12 83 approx. 495 . . . . .
The products according to the invention are not very toxic in 90uris via the venous and oral routes since their LD 50 are between 46 and 110 mg / kg iv and between 200 and plU8 900 ma / kg po PHARMACOLOGICAL PROPERTIES
1 - Anti-em ~ tiaue activity The anti-emetic properties of the compounds according to the have been demonstrated orally in dogs in the apomorphine vomiting test according to, CHEN ~ G. and -ENSOR ~ C. ~ J. Pharmacol exp. Therap., 98, 24 (1950).
The table below summarizes the results obtained:
. ....
, Product of Activi ~ é anti-em ~ tick in dogs:
example DE 50 in mg / kg po .. _, ' 1 0.80 ~ -f ; 2 0.85 - 4 1.90 - 6 - 5 ' :: -''! ', 103659 ~ 3 _ ._. ~
Product of anti-emetic activity in example dog ED 50 in mg / kg po ~
. . . . _ 6 approx. 2 7 1.50 8 sup. 5 9 sup. S: ':
0.16 11 approx. 3 The compound of Example 10 appears as the most strongly anti-emetic.
2 - Neuroleptic activity The neuroleptic effects of the compounds according to the invention have been demonstrated in the CD rat (Charles RIVER) by oral route in the catalepsy test according to COURVOISIER, S. ~
DUCROT, R. and JULOU, L. in Psychotropic Drugs, GARATTINI ~ S. and GHETTI, V. Edit.-ELSEVIER Publ. Co., AMSTERDAM, LONDON, NEW-YORK, PRINCETON, 1957, p. 373, as well as in the CD 1 mouse (Charles RIVER) orally in the traction test according to COURSOI-SIER, S., Quart. Rev. Psychiat. Neurol. 17, 25 (L956), on the one hand, and in the spontaneous motility test, on the other hand ~
The latter technique consists of accounting for ~;
movement of mice thanks to a floor with metal blades allowing to record the spontaneous activity of animals during the first 5 minutes following their introduction into the enclosure of measurement. The products are administered 60 minutes before the and we use 10 mice per dose. The results are ex-awarded in DE 50 which represents the dose of substance capable of reduce the average motility of animals treated by 50% compared to wearing to that of the control group having received only the vehicle;
ministration.
The table below summarizes the psycholeptic effects obtained: - ~

103659 ~ 3 Rat Mouse Product the example Catalepsy Traction Hypomotilit ~
DA SO (mg / kg) po DA 50 (mg / kg ~ po DE 50 (mg / kg) p.
.

2,300 _ 1o8 '

3,300 sup. 300 220 ~

4,400 210 80 ' 5sup. 300 sup. 300 70 7 _ _ 160 8 _ _ 10500 ~, ~ up. 300 I _ 1 20 The compound of Example 6 is shown to be the most active.
3 - Analqesic activity The analgesic properties of the products according to the invention have been demonstrated in CD 1 ~ Charles RIVER mice) in the test for painful abdominal torsions with phenylben-zoquinone according to SIEGMU ~ D, E., CADMUS, R and LU, G., Proc. Soc. Exp.
Biol. Med., 95, 729 (1957).
The table below summarizes the DA 50 obtained. Com-set from example 6 is the most active.

. . , ... _ _.
Product of Phenylbenzoquinone test in mice The example DA 50 in mg / kg po 1 greater than 100 2 greater than 100 3,100 4,100 r`:

'103659 ,.
Test Product ~ phenylbenzoquinone c ~ ez la mouse Example DA 50 in mg / kg po ...

7,400 8 greater than 100 9 55 ~, higher ~ 400 11,100 ~ greater than 35 4 - Antiserotonin activi ~ s The antiserotonin properties of the compounds according to the have been demonstrated orally in the CD rat (Charle ~ RIVER) in the technique of plantar edema with se-rotonin according to THEOBALD, W. and DOMENJOZ, R. Arzneimittel Forsch ~
8, 18 (1958) and in the CD 1 mouse (Charles RIVER) in the test "Head-twitch" according to CORNE, SJ, PICKERING ~ RW and WARNER ~ B.
T., Brit. J. Pharmacol, 20, 106 (1963). Antiseroto effects nines have also been studied intravenously in guinea pigs according to a method derived from KONZET, H. and ROSSLER, R. Arch. exp.
Pathol. Pharmakol, 195, 71 (1940) vis-à-vis the bronchospasm produced by serotonin. Finally, we investigated the effects in vitro serotonin spasm antagonists of the uterus isolated from spleen according to FANCHAMPS ~ A., DOEPFFNER, W., WEIDMAN, H. and CERLETTI ~ A., Schw. Med ~ Worsc ~, 90, 1040 (1960).
The following table summarizes the results obtained:

_ g _ '. '' "'': ~ '.', ', ~ 03659 ~
._ ... , _ ::
Isolated uterus guinea pig Rat p O ~ Spleen mouse . :
Edema product "Hea ~ -twitch" Broncho- Spasm with plantar serotonin spasm from e- to sero- sero-tonine tonine xample DA 50 in mg / kg DA 50 in mg / kg DE 50 in mg ~ g EC 50 in mgl, .... ._ _ ..
1 sup. at 100 20 0.01 0.02 2 _ sup. at 100 0.16 0.60 3 _ 67 0.30 0.05 4 9Up. at 300 25 0.05 0.05

5 approx. 300 55 0.18 0.02

6 _ 17 0.05 0.05

7 sup. at 400 127 _ _ 8sup. ~ 100 70 sup. ~ 0.1 0.18 9 _ 80 _ _ _ 10 0.05 0.05 11 3up. at 100 13 0.10 0.01 12 _ ~ 0.90 0.13 ~;

The compounds of Examples 10, 11, 1, 4 and 6 show the ~ strongest antiserotonin properties overall. ' 5 - ~ ics The spasmolytic properties of the compounds according to the have been demonstrated ~ using the MAGNUS technique, R.
Arch. Ges. Physiol., 102, 123 (1904) vis-à-vis ~ pasmes duo isolated rat denum caused either by acetylcholine for neuxotropic spasmolytics either by barium chloride for musculotropic spasmolytics.
The table below collates the results observed.
~, '' ~ ' - 10 - - ' 103659 ~ 3 ~
.. ~. . -. :,. . . - -Product of Spasmolytic Effe-ts on the Isolated Duodenum of Rat example (EC 50 in mg / l) Spasms ~ acetylchollne Chloride spasms barium ~ ~: ~
1 1.60 1.00 2 sup. ~ 10 sup. at 10 3 0.70 0.25 4 0.50 0.12 1.00 0.20 10.6 0.20 0.17

8 4.50 1.70

9.00 0.20 11 1.20 0.30 12 5.50 ~ _ The products according to the invention mainly exert e-musculotropic spasmolytic effects. The most effective are those of examples 4, 6, 5, 3 and 10.
THERAPEUTIC USE
The compounds according to the invention and their pharmaceu-can be used ~ in human therapy maine in the form of tablets, capsules, capsules ~ suppositories, ingestible or injectable solutions etc ... with the indications following: vomiting, nausea and migraines of all origins, digestive and other spasms, they can be used ~ also as psychotropic, analgesic, antiserotonin and spasmolytic ques.
They can be administered in single unit doses taken according to the forms and the compounds between 10 and 500 mg, se-lon a daily dosage between 50 and 2500 mg.

;,.:

Claims (2)

The realizations of the invention, about which a right exclusive ownership or lien is claimed, are defi-denied as follows: 1. Process for the preparation of the compounds of formula ge-neral:
(II) in which Z represents an alkyl group having 1 to 4 ato-carbon, R1 represents a hydrogen atom or a group methyl or ethyl, and R2 represents a linear alkyl group having 3 to 6 carbon atoms, allyl, hydroxyethyl, cyclo-alkyl having 3 to 8 carbon atoms, benzyl or p-methoxy-phenyl, the residue -NR1R2 can also represent a group morpholino characterized in that the trichloro- is reacted 2,4,6 pyrimidine of formula with an amine of formula in which R1 and R2 are as defined above, and does react the 4,6-dichloro pyrimidine derivative thus obtained with a pi-formula perazine in which Z is as defined above. 2. Compounds characterized in that they correspond to the formu-the general:

(II) in which Z represents an alkyl group having 1 to 4 ato-carbon, R1 represents a hydrogen atom or a group methyl or ethyl, and R2 represents a linear alkyl group having 3 to 6 carbon atoms, allyl, hydroxyethyl, cycloal-kyle having 3 to 8 carbon atoms, benzyl or p-methoxyphé
nyle, the remainder -NR1R2 can also represent a group morpholino, each time they are obtained by a process according to claim 1 or its obvious chemical equivalents.