DE1670543C - Substituted 2 morpholino 4 piperazi no 6 amino s triazine - Google Patents

Description

The connection relates to substituted 2-morpholino-4-piperazino-6-amino-s-triazines of the general formula I.

NHR ¹

N N

'S /

CN H Ν — CR ²

(I)

in which R ^{1 stands} for a methyl or ethyl group and R ^{2 is} one of the radicals

-OCH ₃ , -OC ₂ H ₅

-CH ₁ -O-

is, and their salts.

These compounds have biological activity, in particular they are characterized by analgesic have anti-inflammatory efficacy.

The compounds according to the invention are prepared by in a manner known per se either

a) a tris-halogen-s-triazine in any order with morpholine and an amine of the universal

NH-R ¹ common formula II

H ₂ NR ¹ (II)

to a compound of the general formula IM NH-R "

(UI)

in the Hai door there is a halogen atom, it reacts with piperazine to form a compound of the general Formula IV

NH

(IV)

converts and the compound of general formula IV with either the methyl or ethyl ester a haloformic acid or phosgene and methanol or ethanol or with a phenoxyacetyl halide to form a compound of the general formula I or a compound of the general formula IV with a Halcgenessigsäi.iehalogcnid to a compound of the general formula V

/ -χ Ν

OH N- ¹ I

Y — n "

-N ^

NC-CH ₂ -HaI

(V)

implements and this with a connection of general Formula Vl

Mc - O

(Vl)

where Me stands for an alkali metal or hydrogen atom, to a compound of the general formula I. in which R _{2 is} a phenoxymethyl group., reacts or

b) a compound of the general formula III obtained with a compound of the general formula Formula VII

HN Il NCR ²

(VII)

implements

and optionally the compounds thus obtained converted into their salts.

When carrying out the process, one can advantageously proceed in such a way that the trishalo-s-triazine, preferably cyanuric chloride, ζ. Β. in an alcohol, preferably methanol, or suspended in a mixture of water and alcohol or of waiter and acetone and then adding equimolarc amounts of morpholine or the amine of the general formula II with cooling and neutralizing the acid liberated, which for example by an additive of alkali hydroxide can happen. The equimolecular amount of the other amine is then advantageously added without isolating the intermediate product and the acid released is again neutralized.

The compound of the general formula II formed is isolated and, preferably, in an alcohol Methanol, in the presence of at least equimolecular Amounts of piperazine (or of the Pipcraz derivative according to general formula VII) with back-

ss Il 11IJ heated. The acid released is neutralized either by an excess of piperazine or by adding an alkali metal hydroxide. After completion, the compound is isolated, for example dissolved in ethyl acetate, and equimolecular amounts of the haloformic acid ester are added to the solution. The acid released can in turn be neutralized by adding an alkali hydroxide. The procedure is analogous if one takes the place of the haloformic acid ester

Phosgene and methanol or ethanol are used.

For the conversion into the salts, the Acids commonly used in the manufacture of pharmaceuticals. Examples are sulfur,

Phosphorus, hydrogen halide, sulfamine, benzyl sulfone, p-toluenesulfone, maleic, furnar, amber, Tartaric, lactic, citric, ascorbic, cilycolic or salicylic acid.

example 1

a) 24 g (0.1 mol) of 2-morpholino-4-chloro-6-ethylamino-s-triazine are suspended in 100 ml of ethyl alcohol and 25.8 g (0.3 mol) of piperazine are added and M) minutes under reflux heated, whereby solution fails. After the alcohol has been distilled off, the residue is taken up in methylene chloride and washed several times with water. After the methylene chloride has been removed, the syrupy residue is stirred with ether, the 2-morpholino-4-piperazino-6-ethylamino-s-triazine chloride is dissolved and 10.6 g of triethylumin (0.105 mol) are added a solution of 11.4 g of C'hlorumeisensüureäthylester (0.105 mol) in 50 ml of methylene chloride is added dropwise and the temperature is kept at 20 "C. After working up as in Example Ib), 32 g of 2-morpholino-4-N'-carboathoxypiperazino 6-ethylamino-s-triazine

NHC ₁ H ₅

OHN

NH N-COCH ₅

W Il

NHCH

2 "5

OH ^N NL Jl ~ Ν 'Π NH

a. is crystallized. 22.5 g with a melting point of 110 tu, 112 " ¹ C are obtained, that is 77% of theory.

b) 29.3 g (0.1 f> '·.?!) 2-morpholino-4-piperazino- (■ ethylaminos-triazine are in KK) ml of methylene-4iilorid dissolved and 10.6 g 1 riethyuimin (0.105 mol) given. A solution of 9.9 g is added with stirring <methyl chloroformate (0.105 mol) was added dropwise within 30 minutes, the temperature is kept at 20 C. After standing overnight the I riälhylammoniumsalz is washed out with water, the solution is dried and concentrated. Is are 29g of 2-morpholino-4-N-carbomethoxypiperazino-6-ethylamino-s-triazine

NIIC ₂ II ₅

, NN
O Il N * ■ N Il N COCH,

obtained with m.p. 119 to 122 C ', that is 87.6 "i, the theory.

Example 3

a) 29.3 g (0.1 mol) of 2-morpholino-4-piperazino-6-ethylumino-s-triazine are dissolved in 100 ml of methylene chloride and, while stirring, 40 ml of a solution of 0.1 g of triethylamine (0.1 mol) in Methylene chloride was added dropwise within 45 minutes. After working up as in example I b) the crude product obtained is extracted with ether. whereby formed impurities are dissolved out will.

There are 29.4 g of 2-morpholino-4-N'-chloroacetylpiperazino-6-ethylamino-s-triazine (97%)

with melting point HX up to 120 C, that is X2.6 '\, the I theory.

Example 2

29.3 μ (0.1 mol) 2 - morpholino- 4 - pipora / inn- (i-iithylamiiio-s-tria / in are in KK) ml of methylene

35

40 NHC ₂ H,

N N

O H N --A,

Vi N-CCILC

/ i! ο

obtained with m.p. 152 to 156 C, that is 79.6 " _n of theory.

b) 36.9 g (0.1 mol) of the compound obtained are dissolved in an I ösiMig of 2.7 g of sodium (0.113 mol) and 10.6 g of phenol (0.113 mol) in 2 (K) ml of ethyl alcohol entered and heated with stirring for 90 minutes under RicklluB, the converted I ria / in- \ binding loosens and NaCI fails. On cooling, the product crystallizes out, which after filtering off is separated from the NaCl by washing with water. Ks become 36 μ 2-morpholmo-4 - N '- phcnoxyacetyl - pipera / ino - 6 - ethylammos-tria / in

NHC ₂ H ₅ NH NC - CH, - ()

with SchmD. 150 to 155 "C (97%) obtained, that is 84.3% of theory.

The connections

Pharmaceutical tests
NIICJIs

<■ ■ "'- ·. Ι

O Il N C

N D

Ii ■■■ · .. Ii

C N Il N -C-

(Λ)

NHCJIs

O H N-C

C -N

v \ urden on carrageenin edema of the hatle paw according to the method of Domcnjoz and IV ''! workers. Arch. Exp. Pharm. Pathol., 230, 235 (1957) tested for anti-inflammatory effects. The analgesic effect was tested with the miius tail test according to Illa "ffner. Dtsch. Med. Wschr., 55, 731 (1929). The oxicity test was carried out on the mouse after oral administration by determining the acute oxicility (FD ₅₀ in nig / kg ) after Miller im 'I ai η tcr, Proc. Soc. exper. Hiol. a. Med., 57, 261 (1944).

The fractions of the analgesic. Anti-inflammatory and toxicological experiments have been summarized in the table below and compared with known agricultural products:
I j

j fJiK-in '

I 1 iL-mniiinL 'm "u;
IIk-i '(I ιΐιμ kp in.ill

Akiiu-

D I) W

ΙΙϋΙΓιι.-ι ii-.l

i: i>, "in

iiiü \. L 'onil

Io

.in ili
I!> ..

l'heinlbiilazen ■
I'ldiimelacin \

<■ .your j

l'iienacetm. . . ■
Connection Λ,
Connection M '

■ / Kiin III · '· I

about 50
about KO

Xl
94

1Oi,

sth;

415

: 14

700

: 49

25th

4S0

2040

I! 05

7000

The 'labeile / Eigl. dall the connections Λ and H A stronger analogical Wii sound than phenylbutazone have ι: ήΙ equal or stronger (idemliemineiul like as iiidoinetacin. where abet iin lalle der Veibiniliing Λ additionally emc analj'etischc ^ 'itkuii)! aullritl.

Claims (1)

Patent claims: 1. Subscription 2-morpholino-4-pipcni / ino-6 - amino - s - triazines of the general formula I ONLY' N N (D O Il N C CN Il NCR ² Il NC-CII ₁ -O-V ' in the R 'for a meth \ l-
and R ^{2 is} one of the radicals (B) λ, τ ethyl group (H-T OCH .. CII ₁ O is. and their salts 2. Procedure for making connections according to claim I. characterized in that one either in a manner known per se a) an I ris-haioger.-s-lriazine in any order with morpholine and one! \ niiti of the general l-formula I i 11th N. IiIi to a ^ 'erbiniliinr. del allgenn-üi'-ii I mniel 111 Nile R ¹ O H N IaI ! Uli in the I'm al fm em! [· Ι! ·! T; eiialoiii
selzl. this with i'iperazin to one '
der alli. '. emei: ien I-Oi niel IN' 1 ) '■ Ν " converts and the compound of the general formula IV either with the Mciliyl- or Ethyl ester eini haloformic acid or phosgene and methanol or ethanol or with a Phcnoxyacctylhalogcnid to give a compound of the general formula I. or a compound of the general formula IV with an I li'.logcnessigsäure- halide to a compound of the general formula V. NIi-R ¹ N N O H H NC C-Il ₂ - (V) reacts and this with a compound of the general formula VI Me- (VI) where Me stands for an alkali metal or hydrogen atom, to form a compound of the general formula I. in which R _{2 is} a phenoxymethyl group, or b) a obtained compound of the general HN HN —C —R ² (VII) reacted and optionally converted the compounds obtained in this way into their salts.