DE1915795C3 - N- (3,4,5-trimethoxycinnamoyl) -N'- (carbonylmethyl) -piperazine derivatives and their acid addition salts, processes for their preparation and medicaments containing these compounds - Google Patents

Description

H ₃ CO

OCH,

H ₃ CO

CH = CH - CO - Hal

^CH = ^CH ~ ^CO Π

OCH ₃

IO

- CH ₂ - CO - R

CO - R

in which R is an ethylamino, propylamine or isopropylamino group or a pyrrolidino, morpholino or hexamethyleneimino radical, and their acid addition salts.

2. Process for the preparation of the compounds according to claim 1, characterized in that a 3,4,5-Triitnethoxycinnamoylhalogenid is used in a manner known per se of the general formula II in which R is an ethylamino, propylamino or isopropylamino group or a pyrrolidino, morpholino or hexamethyleneimino radical, and their Acid addition salts.

The invention also relates to a process for the preparation of the compounds according to the invention, which is characterized in that a 3,4,5-trimethoxycinnamoyl halide is used in a manner known per se of the general formula II

15 OCH ₃

CH = CH - CO - shark

OCH ₃

OCH ₃

in which Hai denotes a halogen atom, with a (II) piperazine derivative of the general formula III

in which Hai denotes a halogen atom, with a piperazine derivative of the general formula TII HN N-CH ₇ -CO-R

(III)

H-N

N-CH ₂ -CO-R

(HI)

in which R has the meaning given in claim 1, in the presence of an acid-binding compound reacts and the compound of general formula I obtained in this way, if appropriate, in itself converted into an acid addition salt in a known manner with an acid.

3. Medicament, consisting of at least one compound according to claim 1 and at least a customary pharmacologically acceptable carrier and / or diluent.

The invention relates to new N- (3,4,5-trimethoxycinnamoyl) - N '- (carbonylmethyl) - piperazine rivals and their acid addition salts, a process for their preparation and containing these compounds Drug.

The invention relates to N- (3,4,5-trimethoxycinnamoyl) - N '- (carbonylmethyl) - piperazinderiin where R has the meaning given above, in Reacts the presence of an alkaline (acid-binding) compound, and the compound thus obtained dei general formula I, optionally in a manner known per se, with an acid into an acid addition salt convicted.

The reaction is carried out in an organic solvent. The obtained in the implementation Compound is obtained in a manner known per se, for example by evaporating the solvent and recrystallization. The 3,4,5-trimethoxycinnamoyl halide is preferably used in the process according to the invention 3,4,5-Trimethoxycinnamoylchlorid used, wöbe one works in benzene or acetone at the boiling temperature of the solvent and as an alkaline compound Sodium carbonate or sodium bicarbonate

5o used.

The compounds of the invention have valuable coronary dilating, hypotensive, cardiotropic vasodilating and diuretic properties. The invention therefore further relates to medicaments, di < of at least one compound according to the invention and at least one customary, pharmacologically ver Compatible carrier and / or diluent.

The compounds according to the invention are used in humans in doses between 100 and 750 mg per day with conventional carriers and / or diluents administered according to the pharmaceutical dosage forms used to be chosen.

The example and the experiments illustrate the invention.

example

N- (3,4,5-trimelhoxycinnamoyl) -N '- (pyrrolidino-

carbonylmethyl) piperazine and its maleate

(Connection no. 1)

20 g of N- (pyrrolidinocarbonylmethyl) piperazine are dissolved in 350 ml of anhydrous benzene, and 12 g of sodium bicarbonate are added. Then, the 3,4,5-Trimethoxycinnamoylchlorid is progressively added to the mixture, the temperature is increased to 40 ⁰ C. The mixture is then refluxed for 1 hour. After cooling down, a

aqueous sodium carbonate solution is added, and the mixture thus obtained is stirred for a few more minutes. After decanting and concentrating the Ber.zolphasc, the crude product is obtained, which in a mixture of methyl ethyl ketone and heptane is recrystallized. The yield is 65%.

Analysis:

Calculated ... C 63.29, H 7.48, N 10.07%; found .... C 63.18, H 7.51, N 10.04%.

The acetone solution of this base treated with the equivalent of maleic acid gives the maleate, which in anhydrous alcohol is recrystallized. F. = 135 ° C.

Analysis:

Calculated ... C 58.52, H 6.61, N 7.88; found .... C 58.43, H 6.72, N 7.90.

The compounds listed in Table I below are prepared according to the procedure of above example.

Table I.

OCH,

H ₃ CO- / V-CH = CH-CO-N N-CH ₂ -CO-R

OCH ₃

Verb.
No. R. H shape Molecular formula Molecular weight F.
("C) 2 /
—N
'\ base
Hydrochloride C ₂₀ H ₁₉ N ₃ O ₅
C ₂₀ H ₃₀ ClN ₃ O ₅ 391.46
427.92 174
200

C ₂ H ₅

—N

C ₃ H ₇ (n)

base
Maleate C ₂₁ H ₃₁ N ₃ O ₅
C ₂₅ H ₃₅ N ₃ O ₉

405.48
521.54

160 114

- N

C ₃ H ₇ (JSO)

base
Maleate C ₂₁ H ₃₁ N ₃ O ₅
C ₂₅ H ₃₅ N ₃ O ₉

405.48
521.55

175 152

-N

base C ₂ -VH ₃₅ N ₃ O ₅ 445.54 115 Maleate C ₂₁₁ H ₃₉ N ₃ O ₉ 561.62 163 base Q ₂ H ₃₁ N ₃ O ₆ 433.49 144 Maleate C ₂₀₁ H ₃₅ N ₃ O ₁₀ 549.56 186

(Continuation)

Verb. 'Form
No.

base
Hydrochloride

base
Maleate

base
Maleate

base
Maleate

base
Maleate

ber.
f-

ber.
found

ber.
found

ber.
found

ber.
found

ber.
found

ber.
found

ber.
found

ber.
found

ber.
found

Elemental analysis C

61.36 61.43

56.13 56.23

62.20 62.40

57.57 57.37

62.20 62.40

57.57 57.71

64.69 64.54

59.88 59.71

60.95 60.89

56.82 57.02 7.47
7.49

7.07
7.07

7.71
7.71

6.76
6.76

7.71
7.66

6.76
6.85

7.92
7.91

7.00
7.14

7.21
7.21

6.42
6.51

Cl

8.29
8.39

10.74 10.94

9.82 9.61

10.36 10.37

8.06 8.03

10.36 10.31

8.06 8.09

9.43 9.34

7.48 7.38

9.69 9.56

7.65 7.62

Testing of the compounds according to the invention in animal experiments

Coronary dilating properties

Coronary circulation is at the coronary vein sinus been examined in the dog. The compounds of the invention call upon administration intravenous perfusion an increase in the coronary venous sinus flow and a decrease in the Cardiac oxygen consumption, accompanied by a beneficial effect on cardiac metabolism. Besides that one observes a reduction in the work of the heart and the heart rhythm.

The results obtained with some of the compounds of the invention are shown below Table II compiled.

Table II Appointment increase reduction Verb. No. was enough of the coronary of the heart-sour dose flow slofl consumption (mg / kg) (%) (%) 25th 100 50 1
Maleate 4th 6.5 50 40 Maleate (while (while more than more than 2 hours) 2 hours)

Verb. No.

Maleate
6th
Maleate

Administer! e
dose

(mg / kg)

Increase in coronary flow

Reduction of cardiac oxygen consumption

10

25th

50
70

40 30

Hypotensive properties

The compound No. 4 is effective when administered intravenously at a dose of 12 mg / kg to the anesthetized Cats experience a 50% decrease in arterial pressure for 30 to 60 minutes. The connection No. 4 also calls when administered orally to non-anesthetized rats at a dose of mg / kg resulted in a 20% decrease in systolic pressure.

Effect on the heart

Apart from the above-mentioned reduction in cardiac work and heart rhythm via the Compounds according to the invention have an anti-arrhythmic effect, which at the electrical with increasing Frequency stimulated isolated guinea pig ventricle appears.

Vasodilating effect

The compounds of the invention have vasodilating properties with respect to the peripheral Circulation manifested by an increase in thigh artery flow in the dog to step. The measurement is carried out by a rotameter introduced into the articular path. The dose that increases the flow by 50%, is generally 125 ^ for intra-arterial injection

Diuretic activity

The compounds according to the invention increase the urine excretion and the excretion of chloride and sodium ions in the non-anesthetized rat table considerable.

toxicity

The toxicity of the compounds according to the invention is low. The LD ₅₀ in the mouse is 150 to 800 mg / kg for intravenous administration and 1 to 5 g / kg for oral administration, depending on the tested compound.

In the comparative experiments below, compounds No. 1 and 4 according to the invention were used known compounds compared.

denal administration an increase in the coronary artery flow and an increase in the oxygen content! coronary venous blood, d. H. a decrease in dei amount of oxygen consumed by the myocardium ■■

a) Intravenous administration

The results obtained with compounds nos. 1 and 4 and with many of the aforementioned comparative compounds are compiled in Table III below, in which the lethal dose for 50% of animals when the compounds are administered intravenously (LD ₅₀ iv) is given is.

Connection

I. Animal experiments

Compounds Nos. 1 and 4 of the present invention were tested for their vasodilatory effects with the compounds listed below that are recognized to be effective in the same field compared:

Comparison connection A (see FR-PS BSM 2280):

N-butyl-2- (diiodo-3,5-0-N-diethylaminoethoxy-4-benzoyl) -3-benzofuran hydrochloride.

Comparative compound B (Schaper et at., J. Pharmacol. Exptl. Therap., Vol. 152 [1966], p. 152):

1- [4,4-Di (4-fluorophenyl) butyl] -4 - [(2,6-dimethylanilinocarbonyl) methyl] piperazine.

Comparison compound C (cf. Rote Liste 1965, p. 875): 2,6-bis- (diethanolamino) -4,8-dipiperidinopyrimido (5.4 ~ d) -pyrimidine.

Comparison compound D (see BE-PS b 21 327):

3 - (/ I-diethylaminoethyl) -4-methylcoumarin-7-oxy-acetic acid ethyl ester.

Comparative compound E (see Red List 1965, p. 1044):

N- [3'-Phenylpropyl- (2 ')] -1, l-diphenylpropyl- (3) -amine.

Comparative compound F (cf. R. C h a r 1 i e r, Acta cardiologica, Suppl. 7 [1959], pp. 1 to 60):

(2-Ethyl-3-benzofuranyl) - (4-hydroxy-3,5-diiodophenyl) ketone.

Vasodilatory effects
on the coronary circulation

The compounds according to the invention No. 1 and 4 call independently of intravenous or intraduo-

30th

35

LD ₅₀ iV, effect on the coronary vein sinus at administer effect Oxygen mg / kg anesthetized dog was enough on blood enrich- M3US administer Dose/ flow tion was enough Lethal dose dose (%) (%) 4/100 + 60 + 120 (mg / kg) 0.5 / 100 + 125 + 110 617 25th 5/100 + 40 + 55 475 2.5 6/100 + 55 + 100 180 10 1/100 + 110 + 100 25th 1.5 150 1.5

16/100 +120 +75

It can be seen from Table III that compound no. 1 in an _{amount corresponding to 4% of the LD 50} has an effect on the coronary vein sinus flow rate and on oxygen enrichment which the effect of an amount corresponding to _{6% of the LD 50 of the comparison compound} B essentially corresponds. In an amount corresponding to only 1% of the LD ₅₀ , comparison compound C has an increased effect on the blood flow compared with compound no. 1 with a somewhat lower effect with regard to oxygen enrichment. The comparison compound C, however, causes unpleasant side effects such as headache, dizziness and gastrointestinal disorders, while the compound

No. 1 is free from such adverse effects.

As can be seen from Table III, compound no. 4 is superior to all comparison compounds, since none of the comparison compounds has such a good effect at such a low ratio of administered dose / LD ₅₀ .

b) Duodenal administration

Those with the compounds No. 1 and 4 and with vie The results obtained with the aforementioned comparative compounds are shown in Table IV below compiled.

Table IV

connection

Effect on the coronary circulation in
anesthetized mouth

dose
(mg / kg)

50

3.5
50
20th
50
50

effect on
Blood flow

+ 55

+ 55

ineffective
ineffective
+ 45
ineffective

Effect on oxygen enrichment

+ 100
+ 100

ineffective ineffective + 100
ineffective

From Table IV it can be seen that, with the exception of comparative compound C, none of the comparative compounds have an intraduodenal effect on the coronary circulation. The effect of the comparison compound C almost corresponds to the effect of the compound at the same administered dose No. 1, the toxicity of compound No. 1 being considerably lower than that of the comparative compound C (see the toxicity values in Table III). Compound no. 1 is thus advantageously different also from the comparison compound C.

Connection no. 4 calls at a much lower number Dose and at the same time a significantly lower toxicity a better effect than the comparison compound C.

Vasodilating effect on the body's circulation

The vasodilating effect was demonstrated on the femoral artery in the anesthetized dog when administered intravenously Administration of the compounds examined. The ones with connections 1 and 4 and with two The results achieved by the abovementioned comparison compounds are compiled in Table V below.

Table V

Connect LD ₅₀ iv Effect on the flow administered the manure Femoral artery Dose / lethal administer dose we was enough kung dose 0.02 / 100 (mg / kg) (Fg / ltg) 0.02 / 100 (%) 1 617 125 0.08 / 100 + 50 4th 475 100 0.34 / 100 + 65 C. 150 125 + 70 F. 72 250 +40

It can be seen from Table V that none of the comparison compounds has an effect comparable to that of compounds No. 1 and 4 _{with such a small fraction (0.02%) of the LD 50.}

Antihypertensive properties

In addition to the vasodilating effect on the coronary and body circulation, the compound has No. 4 also has antihypertensive properties. An orally administered dose of 50 mg / kg is sufficient for one The rat hypertonicized by renal ligation and contralateral nephrectomy, to its normal Restore arterial pressure. Comparative Compounds A, B, C, D and F are in this field ineffective.

II. Experiments on the isolated guinea pig heart

The compounds nos. 1 and 4 according to the invention were also compared with that from FR-PS 13 97 193 1-propionyl-2,4,6-trimethylpiperazine known as coronary dilatant (Comparison compound G) compared. The experiments were carried out on the isolated guinea pig heart accomplished. The results are shown in Table VI below.

Table Vl

Connection concentration

Increase in

coronary

flow

Change in frequency and amplitude of heartbeats

1 2.5

20th

20 zero

75 to 100 slight decrease, <25%

80 no notice

change

In another experiment on the isolated guinea pig heart, For compound no. 1 at a concentration of 2.5 μ ^ ηιΐ a 68% Increase in coronary flow is maintained.

The toxicities of Compounds Nos. 1 and 4 of the present invention and Comparative Compound G are compiled in Table VII below.

Table VII

connection

LDj ₁ , intraperitoneally
(mg / kg)

1 1175

4 705

G 500

Clinical trials

Compound No. 1 was used to treat patients suffering from peripheral circulatory insufficiency of the legs and brain. Compound No. 4 has been used to treat patients with coronary insufficiency. It was found that these compounds are extremely effective in the aforementioned fields of application with complete compatibility. Compounds nos. 1 and 4 were also used with success in those cases in which no improvement could be achieved with commercially available preparations.
The above studies show that the compounds according to the invention are extremely valuable medicaments because of their advantageous effects on the circulatory system.

Claims (1)

Patent claims: 1. N-ßAS-trimethoxycinnamoyO-N'-carbonylmethyl) - piperazine derivatives of the general formula IH ₃ CO vdte of the general formula I.
OCH ₃