DE2342880A1 - PIPERAZINE-PYRIMIDINE, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE - Google Patents

Description

Attorney's file 24 299 2 ^, AU9. 1973

Be / ücxi

Produits Chiniiques Ugine iiuhlmann Paris / IT France

"Piperazine-pyriniidines, process for their preparation and inre use "

Inventor: Gerard Loiseau

Georges Mattioda Ben§ Millischer Pierre Obellianne

In French patent specification 72 O69Ö1, the applicant has 2-I.ίethylamino-4-N-methylpiperazino-5-methylthio-6-chloropyrimidine, a process for its production and its effect on the central nervous system are described.

The present invention relates to compounds of the general

(* Fußnqtßk German JPat registration P 2307536.7) 122 H -2-

4Ü9885 / U57

M13 73 »» 7143 JIi .... »« Oimi μμαιλπτΑΤΕΝΤ KUndiM TBEX OS M 5M IERG d Kyritdw .iwhpn Mldi 453100 PottadMcki MOndw «« 5343

my formula

(D,

wherein R is a methyl or!, ietnylthiogruppe, £ a lialogenatom or an alkoxy group having 1 to 5 Konlenatoffatomen, Y an acylamino or optionally substituted amino group Z, a hydrogen atom, a Letnyl-, Ätnyl-, tfydroxyätiiyl- or phenyl, except for the compound 2-I.:etnylamino-4-N-methylpiperazino-5-methylthio-6-chloropyrimidine.

Particularly mentioned as substituted amino groups are: alkylamino groups having 1 to 4 carbon atoms, for example !.! ethylamino, ethylamino, isopropylamino groups, Arylamino groups, for example phenylamino, II-alkyl-N-phenylamino groups, heterocyclic! tests in which the heteroatom is a nitrogen atom, for example corpnolino-, Piperidino, piperazino, 4-methylpiperazino groups.

The compounds of formula (I) in which R is a methylthio group and X is a chlorine atom are particularly preferred.

The compounds of the invention can be prepared by adding a 4,6-dichloropyrimidine of the formula

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23A2880

OI

(H)

ei.ic: .. Pioerazin. the j'oi'i

/ ν

(in)

in cine ::: wacserrrei r.eaium in G-egenv / kind of a üjiur u ^ rptio: 'i ^:.: ittelL; at a temperature between 40 and 12 ° C uuuetzt xi'i ^ ciXoe.ieaiall- da ^ OnIoratoM uea Proauict ^ the

j or ..iC j.
■ I il \ Eq \ ri-Z / T ι

(IV)

durcii ei.ie

replaced.

Dieae urn oil dung lc ami dui'cn the ^ iuwirlcoiv-: a jatriumalhonolat ^ in a Dimethylsulfoxidiaediuni at a tempera temperature of about 100 G or by the effect of a superior force dec ent.jOreciie.iden Alkoaols and Kaliu :: uiydroxids at reflux temperature causes grounding.

Compounds, or formula (II), in which i is a mono- or disuc- ijtituier-1: ^.:; i.ijrruppe or a utick ^ toffiialtiger neteros_

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23A2880

is, dadurcii can be made dal: man k, 4.bl ⁿ ri - chloropyrimidine of the formula

Ul

Cl

reacts with the corresponding amine. The separation of the isomers formed can easily work in a durcui / ater-Methylätiiylketongemisch achieved v / ground, ax v üiteruLi be separated at a later Üubstituierung / can.

In the event that; Y is a substituted nicnt Odei · mono-substituted amino group, it is möglicn to acylate the compounds of r'orrael (II) nacri known methods, for example, a durcn Säureanriydrid or better the action of a durcn Süurecnlorids in aqueous ¹ Odei anhydrous Ledium. This acylation can be carried out either at deia <^ - ii; nino-4-picerasinopyrimidiii or before the (chlorination of the 4.fc-ionpyriniidin intermediate) by means of the.

The products according to the invention have interesting pnar ::: uzeutisciie üi'igerLScriy.ften, especially as Leail-: a- ::: e.ite can be used with ./effect on the central nervous system.

The following examples, y / orin them .--, the parts on the G-ewicnt refer, e ^ unless £ otherwise stated, explain the riri charge, oruie to crinkle it.

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Chlorohydrate of 2-ethylamino-4-N-methylpiperazino-6-chloro-5-methylthiopyrimidine

a) 2-Ethylamino-4,6-dichloro-5-methyltniopyrimidine

230 parts of 2,4,6-trichloro-5-methylthiopyrimidine are dissolved in 740 parts of methyl ethyl ketone, 650 parts of ice are added and 120 parts of an aqueous, aqueous solution of oil are poured in, while cooling is carried out so that that the temperature does not exceed ό C. Are then added in the course of a LJtunde at 20 ⁰ C. 129.5 parts sodium hydroxide to over 31>"solution. The isomer sought precipitates out, while 4-ethylamino-2,6-dichloro-5-methylthiopyrimidine remains in solution. After cooling for 15 hours, the mixture is filtered and washed with diethyl ethyl ketone. Lan receives 73 parts of the sought product, which is recrystallized from ethanol; Melting point 147 C.

b) 2-Ethylamino-4-rT-methylpiperazino-6-chloro-5-methylthiopyrimidine

31.4 parts of the product obtained under a) is dissolved in 650 parts by volume of ethanol, to which mixture is heated to 7O ⁰ G. 40 parts of N-methylpiperazine are poured in over the course of 10 minutes, the reaction mixture is refluxed for 3 hours, cooled to -40 ° C., filtered and washed with water. 29 parts of the desired product are obtained and are recrystallized from ethanol; Melting point 101 ⁰ G. The hydrochloride is obtained by reaction with a calculated amount of hydrochloric acid in an ethanol medium.

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Analysis:

CH U Cl

calculated ; Ό 41.06 6.3ö 19.96 20.24 found / - 41.1d 6.30 19.6u 20.07

Example 2

2-isoprop, ylamino-4-N-methylpiperazino-6-chloro-5-methyltniopyrimidine

a) 2 (4) .6-dichloro-4 (2) -isopropylamino-5-methylthiop.yrimidine The procedure is as in Example 1, using a corresponding amount of isopropylamine instead of ethylamine. The two isomers formed are isolated in oily i? ^l orm. The mixture contains about 40 / ό of the sought isomer.

b) 2-Isopropylamino ^ -N-methylpiperazino-α-chloro ^ -methylthiopyrimidine

The mixture is refluxed for 3 hours and heated to 156 parts of a mixture of the two preceding isomers with 160 parts of 1-methylpiperazine in 1200 parts of alcohol and concentrated in vacuo. The residue is taken up in atom (500 parts) and separated by filtering. Only the isomer sought is insoluble under these conditions; ns is separated from the chlorohydrate dec N-diethylpiperazine by separating with water. Iuan receives 62 parts of the desired product, which is recrystallized from ethanol. (Melting point 145 Ms 146 ⁰ C).
Analysis for C ₁ ^ H ₂₂ H-ClS l.iolekulargewicht ι 315.5

C H II Cl S

calculated? 5 49.44 6.97 22.1d 11.25 10.14 found> i 49.46 6.97 22.16 11.33 10.14

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Example 3

2-t-Butylarnino-4 ~ ^ -iaethylpiperazin.o-b) -KietJi, yltnio ~ 6-cb.loropyrimidine

Lan works as in Example 2, but uses t-butylamine instead of isopropylamine. The sought product crystallizes in ethanol; Melting point 157 ⁰ C.

Analysis: 2Ur C ₁ -H ^ ₄ N ₁ -ClO molecular weight 329.5

C H H

calculates y «5ü, 9o 7.2d 21.24

found y ° 5ö, d2 7.27 21.19

Example 4 Chlorohydrate of 2-Pheiaylamino-4-N-methylpiperazino-6-chloro

5-methyltniopyrimiaine

I.ian works v / ie in example 1, but uses aniline, I.ian receives the Cnloruyirat of 2-Phenylamino-4-N-metnylpiperazino-6-cnlor - ^ -: aetnyltniopyrimidins.

Analysis for C ± 1 ^ .. I ¹ I ₁ -SCl Kolelcular weight: 366

C II H Cl

calculated ψ 49.74 5.44 1o, 13 1o, 39 found j ° 49.35 5, o9 17.96 1o, 49

Example 5

3 ^> -Iaethoxy-2-propylamino-4-H-methylpiperazino-6-chloro-5-met hy It iii opyr iinidine

I.ian works as in Example 1, but uses 3 '-metnoxypropylamine. I.ian receives after distilling off the I.lethyläthylketon the

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Mixture of the two isomers 3 * -iviethoxy-2 (4) -propylamino-4 (2) .6-diciilor-5-methylthiopyrimidine containing of the product you are looking for.

The undesired isomer is separated off by dissolving the distillation residue (1 part) in concentrated hydrochloric acid d = 1.19 (5 parts by volume) and dilute with water (2.2 parts). Under These conditions precipitate the 3-liethoxy-2-propylamino-4 .6-dichloro-5-methylthiopyrimidine off while the other isomer remains in solution; Melting point 65 C.

40 parts of 3 »-methoxy-2-propylamino-4,6-dichloro-5-methylthiopyrimidine are left under reflux for 3 hours in solution in 400 parts by volume of anhydrous ethanol and 43 parts of N-Iietnylpiperazin Cook. The ethanol is distilled off under vacuum, the distillation residue is taken up in 300 parts by volume of ether and removes the precipitated chlorohydrate from N-methylpiperazine by filtering. Wash the precipitate on the filter with 300 parts by volume of ether and then wash the filtrate by decanting. After distillation of the ether, the initially oily residue crystallizes. After recrystallization from hexane, 40 parts are obtained 3 * -Methoxy-2-propylamino-4-N-methylpiperazino-6-chloro-5-methy1-thiopyrimidine. Melting point 60?!.

Analysis for C ₁₄ H ₂₄ ONcClS molecular weight 345.5

C H N Cl

calculated fo 46.62 6.94 20.26 10.27

found ° A 46.62 7.34 kiü, 11 10.4ö

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Example 6

Hydrogen hydrate of 2-amino-4-N-methylpiperazino-6-chloro-5-nietjiylthiopyrimidine

In the same way as in Example 1, but using ammonia instead of atnylamine, 2-amino-4-: T-methylpiperazino-6-chloro-5-methylthiopyrimidine is prepared. melting point 191 to 192 ⁰ C (ethanol). Analysis of the I.Ionocnlorhydrate (Molgewicnt: 310) 0 ^ H ₁₇ NcSOl ₂

C H N Cl S

calculated 38.71 5.48 22.58 22.90 10.32 found f * 38.83 5.47 22.27 23.49 10.67

Example 7

4-N-phenylpiperazino-2-meth _ylamino-f 6-chloro-5-πlethyltnio pyrimidine

In the same way as in Example 1, but through. implementation of N-phenylpiperazine with 2-methylamino-4,6-dichloro-5-meth.ylthiopyrimidine, one provides 4-N-phenylpiperazino-2-methylaminoo-chloro-S-methylthiopyrimidine here. Melting point: 163 to 164 0,

Analysis for C ₁₆ H ₂₀ N ₅ SCl molecular weight: 349.5

C H N Cl S

calculated <f ° 54.93 5.72 20.02 10.15 9.15 found # 54.86 5.90 20.00 10.54 9.36

Example 8 2-methylthio-4-N- (β-hydroxyethyl) piperazino-6-chloro-5-methyl

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thiopyrimidine

In the same // iron as in Example 7, but using N- (β-hydroxyethyl) piperazine, 2-methylamino-4-N- (β-hydroxyethyl) piperazino-6-chloro-5-methyltniopyrimidine is prepared here. Melting point: 120 to 122 ⁰ G (ethanol). Analysis for G ₁₂ II ₂₀ N ₅ OSCl molecular weight: 317.5

C. 35 6th II N 04 10, Oo calculated 7 * 45, 21 6th , 30 22 63 10, 50 found yö 45, , 2d 21

Example 9

Dichlorohydrate of 2,4-bis (N-methylpiperazino) -6-chloro-5-methylthiopyrimidine

The mixture of 2,4,6-trichloro-5-methylthiopyrimidine with an excess of N-methyl piperazine is heated under reflux for 3 hours. One obtains 2,4-bis- (N-methylpiperazino) -6-chloro-5-methylthiopyrimidine, its hydrochloride has a melting point> 25O ⁰ C has (decay) ..
Analysis for G ₁₅ H ₂₇ NgSGl ₃ , H ₃ O molecular weight: 409.5

CHN Cl S ■ calculated $ 39.72 6.47 18.53 23.5 7.06 found j> 40.34 6.34 19.15 22.90 6.60

Example 10 Hydrochloride of 2-meth.ylamino-4-piperazino-6-chloro-5-fflethyl- ^

thiopyrimidine

By reacting anhydrous piperazine with 2-methylamino-

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4.6-dicnlor-5-methyltniopyrimidine under the conditions of Example 1 gives you the product you are looking for. Melting point

> 25O ⁰ C (decay).
Analysis for C _1n H ₁₇ Nf-SCl ₉ molecular weight: 310

C. , 71 5 H N 5ö Cl 90 3 , 32 calculated ή » 3ö , d8 5 , "4ö 22 44 22 94 10 , 88 found '/ » 38 , 56 22 22 10

Example 11

Chlorine hydrate of 2-piperidino-4-N-meth, ylpiperazino-5-methylthio-6-chloropyrimidine

The same procedure is used as in Example 1, but the piperidine is used instead of ethylamine. The product sought is recrystallized from ethanol. Melting point 215 C ((decay).
Analysis for C ₁₅ II ₂₄ N ₅ SCl, HCl molecular weight: 376.4

CHNS calculated ° jo 47.60 6.65 1ü, 50 8.45 found ^ΰ β> 47.60 7.01 1ö, 65 8.45

Example 12 Chlorohydrate of N - I.Iethyl-2 - I'J-phenylamino-4-N ~ methylpiperazino-

5-methylthio-6-chloropyrimidine

Iuan proceeds as in Example 1, but uses N-ethylaniline.

instead of itnylaniin. The product sought is recrystallized from ethanol. Melting point 22O ⁰ C (decomposition).

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analysis for U ₁₇ II ₂₂ N ₅ CIb ₁ , äCl 0 - H -iolirev / icht 50 4 Ou, 4 C. 9 5.75 Ii 35 calculates yi 51, 6.04 17, 0, 0 found / 0 50, 17, ö, 0

Example 13

Chlorohydrate of 2- (N-ke t nyl-II-benzoyl) -amino-4 -j-l-metny 1-piperazino-5-metnylthiopyrimidine

10.5 parts of triethylamine are added to 2½ parts of 2-N-I '.' Iethylamino-4-N-methylpiperazino-5-raetnylthiopyriniidin in solution in 150 parts by volume of tetrahydrofuran, and 13.7 parts are poured over the course of 2.0 minutes Partition benzoyl chloride at ambient temperature and then reflux for 5 hours. Lan separates the triethylamine chlorohydrate formed, dilutes the filtrate with water and extranates with ether. The respiratory solution is evaporated with water, then dried over sodium sulphate and evaporated in vacuo. The residue is taken up a second Iial with ether in order to separate off a small amount of the starting product in this way. Lan forms the monoclonal hydrate using ether; Melting point Λ / 210 ⁰ C after recrystallization in ethanol.
Analysis for C ₁ -H ₂₂ N ₅ GlSO, HCl molecular weight: 42d, 4

50 C. H 16 N calculated / j 50 , 46 5.41 15th , 34 found 7O , 20 5.33 , 93

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Example 14 2-Acetyl-nino-4-l'I-methylpiperazino-5-methyl-6-chloropyrimidine

a) 2-Acetylamino-4,6-dioxo-5-methylpyrimidine

30 parts of 2-amino-4,6-dioxo-5-methylpyrimidine are treated d hours of reflux in a mixture containing 500 parts by volume Contains acetic acid and 10 parts by volume of acetic anhydride. To Filtration, vials with ether and drying under vacuum obtained man d? Parts searched product.

b) 2-acetylamino-4,6-dichloro-5-methylpyrimidine

Gradually, while maintaining the temperature at 0 G, 10 ° parts of phosphorus oxychloride are introduced into the mixture which contains 30 parts of 2-acetylamino-4,6-dichloro-5-methylpyrimidine and 46.5 parts of triethylamine in 255 parts of tetrahydrofuran. After stirring for 6 hours at room temperature, the reaction mixture is poured into ice water and extracted with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and concentrated to dryness. The residual pesticide is triturated in absolute ethanol, filtered and dried under vacuum.
Analysis for

38 C. 3 H 1 9 N 32 Cl calculated f> 38 , 20 3 , 20 1 9 , 10 32 , 30 found /" , 60 , 70 , 05 , 0

c) 2-Acetylamino-4-N ^ -methylpiperazino-5-methyl ^ r6-chloropyrimidine 8.8 parts ^ -acetylamino ^ .o-dichloro-S-methylpyrimidine are dissolved

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in 100 parts by volume of tetrahydrofuran in the presence of 4 parts of triethylamine and 4 parts of N-I-ethylpiperazine. The mixture is kept under reflux for 6 hours, poured into water and the insoluble constituent is filtered off, which is recrystallized from ethanol. Melting point: 202 ⁰ G.

Analysis for 0 .. 'ή, J. \ _c OGl
12 1 ο 5

G H N Eq

calculated / o 50, dO 6.39 24.70 12.50 found> «50.52 6.53 24.64 12.20

Example 15 Dibromohydrate of 2-N-diethylamino-4-IJ-methylpiperazino-5-

methyltni 0-6-chloropyrimidine

The procedure is as in Example 1, but using diethylamine instead of ethylamine. The desired product is isolated in the form of the dibromohydrate. After recrystallization in ethanol nat it has a collapse point of 24o ° G (decay).

Analysis for C ₁ , Hp ^ IlVOSClBrp molecular weight: 509, ö

• _o 32 C. 5 H 13th ιί Br 35 calculated 32 , 97 5 , 14 14th , 73 31, 90 found / , 65 , 26 , Od 31,

Example 16

Hydrochloride of 2- (N-methyl-if-acetyl) -amino-4-N-meth.ylpipera zino-5-methylthio-6-chloropyrimidine

20 parts of 2-methylamino-4-N-methylpiperazino-5-methylthio-6-chloropyrimidine is kept in 60 parts of acetic anhydride 2

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Hours, at; reflux. The product dissolves completely. Remove the excess reactant and treat the residue with a dilute sodium hydroxide solution. The oil that separates. extraction is carried out with chloroform, the solvent is removed under vacuum and a white test is obtained, which dissolves in ethanol, causing the hydrochloride hydrate to form. This is crystallized in an acetone / ethanol mixture. Melting point: 1dö ° C. dialysis for U ₁ .; i. , N _n OSCl, HGl molecular weight: 366.3

I Jj <- ^ - s

U H N S

reached / O 42.6p 5.77 19.22 d, 75

found> 42.90 5.75 1d, 90 b, 35

Example 17 Calornydrate of 2-I, ietii.ylaraino-4-n-i> ietn, 7lpiTjera2ino-5-metnyl-

tnio-b-metnoxypyrimidine

32 parts of 2 - !. Ietnyla: r _l ino-4-Ii-metiiylpiperazino ~ 5-metnylthio cnlorpyrimidin-6-one dissolved in 100 parts by volume Dimetnylsulfoxid in the presence of 5.4 parts Natriummet hy lat I.lan brings the temperature. wänrend ό hours at 100 ⁰ C, diluted with / ater and extracted with Cnloroform, drives the solvent and forms the hydrochloride in absolute ethanol. I.lan receives 21 parts of product, which is recrystallized from ethanol. Melting point: 2-1 j ⁰ C (decay).

Analysis for C ₁₂ IL ^ N ₅ OS, HCl Liol weight: 319.9

CHN Cl (Cl ")

reached ■; - 45.10 6.33 21.90 11.10

found / j 44.06 6.52 21, ÖO 11.0

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Example 1d

Chlomydrate of 2-diethylamino ^ -N-methylpiperazino-5-methylthio-6 ~ propoxypyrimidine

2u parts of 2-IJethylamino-4-I ^ -methylpiperazino-5-methylthio-6-chloropyrimidine are dissolved in 130 parts by volume of n-propanol in the presence of 7 parts of potassium hydroxide in the form of tablets. The mixture is filtered under a Hückflui for 2 hours; and then pour it into water. The oil which separates out is extracted with ether, the organic phase is washed with water, dried and evaporated. The residue is taken up with petroleum ether by solidifying. i.Ian recrystallizes in petroleum ether. Transfer point: 90 0
Analysis for C ^ Hp ^ icOS Llolgewicnt: 311.5

C H IT ο

calculated <$> 53.9o, 09 22.4ö 10.29 found ψ 53.90 β, 35 22.44 10.17

Example 19

Chlorohydrate of 2-I.ieth., Ylamino-4-u-nxeth.ylpiperazino-S-inetxvltnio-o-allyloxyp.yrimidine

In the same way as in Example 10, but using νοια allyl alcohol, one obtains the above-mentioned chlorohydrate. Melting point: 174 ° C (disintegration).

Analysis e for C ₁₄ H ₂₄ Ii ₅ SOGl G 61 6th H liol weight: 345 , 9 4d, 32 7th , 99 N Eq calculated / 0 4d, , 11 20.24 10 , 24 found> 20.36 9 , 90 -17-

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Example 2ύ

Cilorhydrate of 2-L-ethylamino-4-H-methylpiperazino-5-methyltnio-6-ß-etho: c./etiioxypyrimidine

i.iaii works as in example 1d, but uses the ß-Ätnoxy ütnanol. The above hydrochloride is eaten. Melting point: 136 ⁰ C
Analysis for C ₁₅ Ii ₂₇ N ₅ O ₂ S, HCl molecular weight: 37Ö

ό 47 C. 7th H 1 d N ö S. calculated 47 , 70 7th , 16 1 8th , 52 Ö , 46 found ', , 96 , 25 , 62 , 60

Toxicological properties

The acute toxicity of the compounds of the invention was examined orally and intravenously in CD 1 mice (Cnarles HIVEH). The LD 50 were determined by the cumulative method of JJ REED and H. MUENCH, Am. J. Hyg., 27, 493 (193ο ¹ ) calculated,

The LD 50 obtained are given in the table below.

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- 1ö -

product

example

Acute toxicity in mice LD 5u mg / kg

Intravenous Oral

13 14 15 16 17 18 19 20

41 79 67

insoluble 56 33

124

Ö3

57 115 113

91 insoluble

123 insoluble

5ö 63 56 insoluble about 200 about 525 about 600 about 600 about 200 about 225 about 900 about 525 about 675 about 225 about 525 about 525 about 600 about 270 about 600 about 525 about 400 about 525 about 400 about 265

The products of the invention are not very toxic to mice, administered intravenously or orally, since their Li) 50 is between 33 and

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12 '', ~:. \: I / \ z £ intravenously and 200 and menr than 900 mg / kg'ρ.ο. lies.

Pharinakologiscne Properties 1. Activity against vomiting

The properties of the compounds according to the invention against hereditary recurrence can be found orally in dogs by the examination of vomiting caused by dui'Cii apomorphine according to CiDSN, G. and C. J. EiiuOii, Pnarmacöl. exp. Do rap., 9ö, 24, (19LiO) can be detected.

The table below summarizes the results obtained.

Product of activity against vomiting in dogs Examples DE 50 mg / kg p.o.

1 o, 35

2 0.12

5 1.7

6 0.11

ο 0.25

10 0.07

13 1.9

14 3.7 17 1.4 10 3.9 19 1.5

The compounds of Examples 10, 6, 2, 6 and 1 are

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gen vomiting to be most effective.

2. Neuroleptic activity

The neuroleptic. .Effects of the compounds after the animal invention may have had CD. (Cnarles HIViJiO oral in the catalepsy examination according to iJ.COUliVüLJIER, H. DUCnOT and L. JULOU in Psychotropic Drugs, S. GAHATTIiI and GiIETTI, V. Edit.- Elsevier Publ. Co., AI.ibTERDAI.i, LONDON, riiäV / YOHK, PHINCETON, 1957, page 373 and in the same, "/ also by the traction test at Hausen CD 1 (Charles iilVEIi) oral (COULI- ¹ · VOIüIEH), S. - Quart. Hev. Psychiat. Neurol., 17, 25 (1956).

The table below summarizes the results obtained based on the essential connections:

Product deΐ ·
Examples Frocks. l.iiiuse 1 catalepsy
DA 50: ng / kg po Traction
Du ^ -: ng / kg το. ο. 5 o5 over 35 L. 175 30th 10 100 over 100 75 -

3. Anaigetic activity

The analytical properties of the products of the invention can do the examination at Hausen CD 1 (Cnarles HIVJi :)

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of ^ Ciuaerziiai'ten abdominal torsions with pnenyl likewise-Ciiinon according to E. »jIUGiIUiID, II. CiU) LiUS and Go. LU - Proc. Soc. üxp. Biol. Med., 95, 729 (1957).

The table below summarizes the DA 50 values obtained. The compounds of Examples 5, 1 and 14 are most effective.

Product of
Examples

Investigations with phenylbenzoquinone ΪΊί-iusen dDA 50 mg / kg p.o.

35 65 35

150 65

100 35

300

100

4. Ant iserotoninactivities The antiserotonin activities of the compounds according to the invention can be determined by oral administration in rats CD (Charles RIVER) by the paw edema method with serotonin (V /. TiIaOBAIiD and R. DOLIENJOZ - Arzneimittel Forsch, 3, 1o, (1953 ) and in mice CD 1 (Charles RIVER) after

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234288G

Investigation of the "head, twit cn" nacii ü.J. GOIüTE, it.v /. and B.T. ", / ΛΗΙΐΈϊί, Brit. J. Pharmacol., 20, 106 (1963) will. Llan can still maintain the antiserotonal activity about the three-colored he piglet intravenously after a Method according to H.ICOIiZiJT and Ii. fiOSüLEIT - Aren. exp. Patnol. Pharmakol., 195, 71 (1940) and on the other hand in vitro via the serotonin pasnus of the isolated uterus of rats FAIiCHAIIPS, Δ., .7. DOEPFEIKi :, .1. .7UIDLjUi and A. CJÜtLüTTI ochw. Iled. V / orsch., 90, 1940 (1960).

The following table shows the results obtained:

Products of the examples

iiatten ρ.ο. Home p.o.

lueerscnwein- isolated chen i.V. uterus v.iiat

Testicular edema nit Üeroto-

nin DA

mg / kg

"He ad-t witch" Bronchos pas- dpasmus rait DA 50 rag / kg mus with seroserotonin

tone in

DE bO mg Ag GE ^l j0 mg / kg

3 4 5 6

12 13 16 17 19

160 - - 30th - - 300 - over 300 60 90 100 35 - 100 30th over 100 400 300 100 300 over 100 - 100

1.2

0, Oi

0.05 0.6

The compounds of Examples 1, 5 and 6 appear to be the most powerful

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'ote: i have antiserotonin characteristics

5. Aaauolytic Activity

Lic EpasMolyfcinciien properties of the connections were determined with the help of the method of H. ILMLiUo - Area. Gea. Pnysiol., 1Ü2, 123 (1904) on the spasms of the isolated duodenum of rabbits either provoked with acetylcnoline for nernotropic spas- :: iolytic .virlnuigen or with Jariui-icnlorid for muGculotrope u pacnoiyt is.

The table below summarizes the results obtained .

ünanmolytiEcne ./irkunjren on also iooled products \) uodenu. \ i from Kiaiincnen (GiJ 50 mg / l)

^ .iele :: o ~ eiiabout acetylciiloline versus barium chloride

1 !; . 1.6

2 -j 1.2

i, over 5 1.3

ο. 5 1.3

y over 10 3.6

11 2.5 ^, 2

12 3 ■ 2.2

13 4 2.6 15 5 4
Ιο over 5 2.1 1y over 5 3.1

The products of the invention appear to be essentially one

-24-409885 / U57

BATH ORIGINAL

molytic activity of the nucculotropic type eAiisuwcison, where the most effective are those of Examples 3, 2, 5 and c.

Therarieit is before use

The products of the invention and their pharmaceutically acceptable salts can be administered therapeutically to humans in the form of tablets, capsules, cheeses, suppositories, as ingestible or injectable solutions, etc., in the event of the following irritations: vomiting, excess cold and Lii ^ räric; any origin, digestive and other spasms; They can be used in the same way as psychotropic, anaigeticchc, spacinolytic agents and as antiserotonins.

You can use tablets, coated tablets, capsules, tiles, Suppositories, injectable ampoules, as drops, etc. in dosage units according to the forms and compounds between 10 and 500 mg with a daily dose of un; 1 between 50 and 2500 mg are used.

In summary, the present invention includes compounds of the general formula

R.
X

II

(D,

r.

409885 / U57

BATH ORIGINAL

wherein R is a methyl or methylthio group, X is a halogen atom or an alkoxy group having 1 to 5 carbon atoms, Y is an aromatic radical, an Aeylamikogruppe or a Amino group, which is optionally substituted, Z is a hydrogen atom, a methyl, ethyl, hydroxyethyl or With the exception of 2-methylamino-4-N-methylpiperazino, the phenyl group is 5-methylthio-6-chloropyrimidine.

Claims;

-25-

A09885 / 1457

Claims (4)

Patent claim 1 j compounds of the general formula wherein R is a methyl or methylthio group, X is a halogen atom or an alkoxy group having 1 to 5 carbon atoms, Y is an acylamino group or an amino group, optionally is substituted, Z is a hydrogen atom, a methyl, ethyl, hydroxyethyl or phenyl group, with the exception of 2-methylamino-4-N-methylpiperazino-5-methylthio-6-chlopyrimidine. 2. A method for the preparation of compounds according to claim 1, characterized in that one is a 4,6-dichloropyrimidine of the formula N N (II) with a piwerazin of the formula N-Z (III) -26- 409885/1457 in an anhydrous Iiedium in the presence of a acid absorbent unsetst at a temperature between 40 and 120 G and optionally the oxygen atom of the product obtained replaced by an alkoxy group. 3. Verfanren according to claim 2, characterized in g e that the 2-aminopyrimidines obtained are subjected to acylation. 4. Medicines, in particular to act on the central nervous system, characterized in that it is a compound according to claim 1 or a salt such a compound with a pharmaceutically acceptable one 3iiure included. 409885 / U57