DE1793706C3 - Process for the preparation of N- (2-diethylaminoethyl) -2-methoxy-3,4- or. -4,5-methylenedioxybenzamide and its pharmacologically non-toxic acid addition salts - Google Patents

Description

The subject of patent 15 IS 311 is N- (2-Di- Ethylaminoethyl) -2-melho \\ -5.4- or -4.5-methylenedioxybenzamide and their pharmacologically non-toxic acid addition salts.

The hardness now concerns a process for the production of N-12-diethvlaminoethyl) -2-meth- |> xy-3.4- or -4.5-methylenedioxyhenzamide and their pharmacology. < non-toxic acid addition additives. which is characterized by it. that in a known manner 2-methox \ -3.4- or -4.5-me- (liylendioxvbenzoic acid is reacted with an N-alkyl-5-phenylfc.onolium-3-sullonate and the product obtained is then reacted with 2-diethylanimoethylamine and if necessary, the benzamide obtained is converted into a fin pharmacologically non-toxic acid addition salt.

As a pharmacologically non-toxic acid addition SaI For example, the hydrochlorides are suitable. Hydrobromides. 1 Ivdroiodide. Phosphates. Sulfates. Curate. Tartrates. f.;. ctate. Acetates and Athanesulfonates as well Corresponding acid salts, which are very sparingly soluble in water, which slowly resorb in the organism! will.

The process products have valuable pharmacological properties and can be very effective antiemetics. Neurolepics. Psycholeptics and analgesics are used willow. In comparative studies Kurdish the effect of the N- (2-diethv lammoäthvli-ί - methoxy - 3.4 - mcthvlendiowbcnzamidhvdiochlofidsll) and the N - (2 - diethv laminoalhyll - 2 - mcth- f> \\ - 4.5 - methylendimv ben / amid Checked against two known connections.) The results obtained here are summarized below. where these are converted to the free bases.

1. Antiemetishe 1 -Properties

The antagonistic effect against Apomor- | »back was (hen and I nsor in" Journal Pharmacology and oil 1 \ peiimenial I herapeulics "l ^l.) For a 50. ¹ YN. Pp. 24h to 250. and by Due ι ο t («> and Decourt in · <('ompies 1 endues des seances de la Soeiete de Biologie et de scs liliales ··. 1951. 145. p. 350. 357. described Afterwards, the substances to be tested are administered subcutaneously or orally 30 or W) minutes before the administration of apomorphine (100 ^ g kg vii, and the substance is observed half an hour after the alkaloid inoculation The experiments described here were carried out with a group of four dogs, and Kieuz experiments were also carried out: two animals were used for comparison, the other two received the relevant dose of the S'jhsi.m / 1 week later the procedure was reversed and the number of breakouts per group before and after administration is determined. If the protection obtained is plotted logarithmically against the dose administered, 111 percent. A curve is obtained from which the effective dose DT ^ _{n of} the investigated n connections can be determined. Hs were those in the following labeile! specified wer'e found.

'labile antiemetic activity

Imn H) O vg kg apomorphine. at IJinnit

ViM Hindun d IM

I! Example 11 IS.5

II (example 2 | 240
N- (3-dimethylamine propylene! 1-500
3-dilorphenoihiazine I known 1

N- dieth vlaminoäth ν 1 2-meiho \\ - 2 (\ p
4-ammo-5-chlorobenzamide (known I

From this i a at Ie it follows that > lic antiemelische Activity of the \ 'connections of example I and 2 compared to the N- (3'-DimcthvlaniinopropvIi-3-chloiphenothiazm and partly also against the N-diethylau: .moäthvl-2-mclho \ v -4-amino-5-el.Ιοί benzamide is considerably better. To mention AuIVi the lsi, that the compounds I and 11 in (iegeiisat / for N ■ (3 '- Dime! Hy laniinopropv I) - 3 - chiorphenothiazm never Pai "kinsonschc with doses of any size Cause disturbances.

2. WiikuiiL! aiii das / entralnei vepsvsieiri

The antagonism to Iremoim at the Mouse was determined as follows: The analgesic Effect of Tremorm when administered internally; was determined as Tunklicin itei dose, from which the analgesic dose 100 can be calculated light The antagonistically acting product became miraperitoneal (I injected into groups of 10 mice with increasing doses, and at the same time tremor (7.5 mg kgl administered with the analgelisehen dose 100. Minutes later, the sensitivity of the lere was tested according to the Haffner method, which was carried out as follows is carried out: Ts becomes a painful one Stimulus is generated by attaching moor tweezers to the tail of a mouse. Usually veisucht the animal, see of it /> i left the inalgesic The effect is considered to have been brought about by everybody. which did not try to de Tweezers to remove. Not from the proposition Vi> n dependence on the I onai nhmiis the dose eihali man emc Knive, ai's tier graphisc'-i the effective anti-iemorin dose 50 (Dl ,,, I can be determined Here the 111 der labeile 2 / usamnu ns: eslellen I keep pjebnissc ei.

Table 2
/ Vnlhrcmorin aclivity

Vcibindiini! IN THE.,, (mi; kjLi I (example
Il {example 37.4
1.9 tsi- {3'-dim
3-ehlorplie
^ known) 40 mg kg
Effect of H) D.
12) ethylaminopropyl) -
nothiazine

(illll kl. ¹ 1 ρ. I

II (Example 1) 23.X

III (Example 2) 7.d
IN-13-dimethylaminopropyl) - 1.8
3-chlorophenothiazine (known)
¹ N-diethylaminoethyl-2-melhoxy- 7.3
4-amino-5-chlorobenzamide (known) Taeschler and Kerl el ti. The Journal of Physiokmy (New York). 1959. Ba. 51, pp. 873 to K78;

B ο i s i e r. Therapy. 1960. pp. 73 to 77: Bο ι s ι e r and Simon. 1 herapy. 19W. Vol. Ί «. Pp. 1257 to 1277.

Table 4
Catalan activity

Table 2 shows that the dose of N- (3-diflietin larninopropy!) -3-chlorophenothiazine required to produce a 50% effect is very much higher than the Dl-: _s "values of the compounds of Examples I. and 2. since with 40 mg of the known compound only an analgesic effect of H) "" is obtained.

In the following table 3 the values of the animescaline activities are given which naeli the Method by Chen and Bohner. described in »Archives Internationales de Pharmacodynamie ··. ! I960. Vol. 125, No. 1 and 2, p. 2. as well as by D e e g a 11 and Cook, "Journal of Pharmacology and L. Experitnental Therapeutics «. 1958. Vol. 122. p. 17a. were determined.

Table 3

Antimeskaiin-Akti vital i _S.

1 (example 1)
il (example 2)

N- (3'-DimethylaminopropyD-3-chlorophenoihia / in (known)

It can be seen from Table 3 that the benzamides I ! and II are better tolerated. in the (In contrast to N- (3'-Diinelhy] aminopropyl) -3-ehlorjphenothia / .in they do not have a dampening effect on the central nervous system. This is made possible by mescaline excited. a small dose of N- (3'-dimethvlaminopropyl | - 3-chlorophenothiazine neutralizes this activity. Soimil Connections I and 11 allow a more adaptable one Treatment.

They are also in their cataleptic activity Compounds of Examples I and 2 to the N- (V-Ditflethylaminopropyl) -. V-chlorophenothiazine superior |) he cataleptic effect was after tier in the The method described in the following literature references:

Tedeschi. Archives Internationales de Pharmacodynamie. 1959. Vol. 122. pp. 129 bis 143:

50 mg kg s. E. 50 mg kg s. C.

= ⁷ ma kü sc

v \ Ii -

Un υ

20 ",, 20" ,,

'. As is well known, it is of great importance that a drug should not have a catalysis effect. As can be seen from the numerical values in Table 4, with 50 mg of the compounds! and II only achieves an effect of 20 ", whereas an amount as small as only 7 mg of N- (3-Dinahvlaminopropyl) -3-chlorophenothiazine already causes an effect of 50".

The benzamides 1 and II generally have more favorable toxicity values than N- (3-dimethylaminopropyl-3-chlorophetiothiazine. as can be seen from Table 5.

Table 5

I (example 1)
Il (example 2)
N- (3-dimelhylaminopropyl) -

3-ehlorphenothiazine (known;

ΠU ₁ , (Wed

35

50 to 55

2.X

'P

99 to loo

170

199 to 21 N.

1S5

The experiments / own that the compounds I and Ii are effective antiemetics. The above incidents were also confirmed in the 1 lumanmedi / in, and the treatments gave under pharmacodynamic clinical conditions no indication of intolerance.

55, example 1

N- (2-diethylaminoethyl) -2-meth (i \\ - 3.4-metlivlendnixvhen / aniid

37.9 g (0.193 mol) of 2-methox> - 3.4-melln lendioxv- βο ben / oes' ure and 19.5 g (0.193 Moll 1 riälhylamin are dissolved in 400111I anhydrous acetonitrile. This solution is to a suspension of 4 ° g 10.193 mol 1 N- ^.: \ Thyl-5-plienylisoxoiium-3'-sulfonate in WK) ml of anhydrous acetonitrile cooled to 0 C was added. 6s and then the (dance 45 minutes at the usual "temperature." The reaction mixture is then cooled to 0 C and stirred with 45 e (). 38 d mol) of 2-diitlivlaminoiithvlamin

added, whereby the solid substance slowly dissolves. Stirring is continued for 4 hours at ordinary temperature, and then the mixture is allowed to stand overnight. The solution obtained is then concentrated to a small volume in vacuo and then with 50 ml of water. 0 ml of benzene and 20 ml of 10 η sodium hydroxide solution are added. The benzene layer is then separated off, washed with water, dried over sodium sulfate and then the benzene is distilled off in vacuo. 54.1 g of N- (2-diethylaminoethyl; -2-methoxy-3,4-methyiendioxybenzamide are obtained as an oily residue. The base is then dissolved in absolute alcohol and the solution with an excess of a solution of absolute alcohol which contains 10% gaseous hydrogen chloride The warm solution is then diluted with ether until crystallization occurs. The crystals are filtered off and washed on the filter with ether. 46.2 g of N- (2-diethylaminoethyl methoxy -. ^ - methylenedioxybenzamide hydrochloride! Yield: 73 " ,,,) obtained from F. Ki4 to 165 C.

Example 2

N- (2-diethvlanimoäthyl) -2-methoxv-4.5-methvlendio \\ benzamide

39.2 g (0.2 Moll 2-methoxy-4.5-methylenedioxy-benzoic acid are dissolved in a mixture of 200 ml of anhydrous acetonitrile and 20.5 g (0.2 Moll I riälhvlamin). This solution is stirred with a suspension of 50.5 g (0.2 Mt) I ) N-ethyl-5-pheiv. 1-isoxolium-3'-sulfonate in 400 ml of anhydrous acetonitrile was added.The mixture, cooled with the aid of a Lis bath, is stirred first for 1 hour and thinly for 2 hours at normal temperature 46 g (0.4 mol of 2-diethylaminoethylammine) are added to the cooled LÖMINU with stirring, then the whole is left to stand overnight at ordinary temperature and then concentrated in vacuo to a small volume separated, the benzene layer, this dried washed with water and dried over sodium sulphate, the benzene is now completely removed in vacuo to remain n ^ a pale yellow oil this is in _a; ml of water and 20 ml H) n-Naironlauge \ crselzi d..?. Dissolved absolute alcohol and mixed with an excess solution of absolute alcohol containing 15% of gaseous hydrogen chloride. The resulting wai never solution is then diluted with ether, the N- (2-diethylaminoethyl) -2-methoxy-4,5-methylenedioxide-benzamide hydrochloride precipitating. The compound is sucked off and washed with ether on the killer. One obtains 35.5 11 (63 '! <. | Of the hydrochloride from F. 213 to 215 C.

Claims (1)

Claim: Process for the preparation of N- (2-Diathylaminoäihyi) -2-incuioxy-3.4- or -4,5-yneth vier.-dioxybenzamide and of their pharmacologically non-toxic acid addition salts, thereby characterized in that one is known per se Way 2-methoxy-3.4- or -4.5-methy lendioxybenzoic acid with an N-alkyl-5-phenylisoxolium-3'-sulfonate reacted and the product obtained then with 2-DiethylaminoülhyIamin converts and, if necessary, the benzamide obtained converted into a pharmacologically non-toxic acid addition salt.