DE2055813C3

DE2055813C3 - Orally active agent against hypotension

Info

Publication number: DE2055813C3
Application number: DE19702055813
Authority: DE
Inventors: Josef Dr.; Voigt Hans Dr. med; 1000 Berlin Klosa
Original assignee: Dr.med. Hans Voigt, Pharmazeutische Fabrik GmbH, 1000 Berlin
Filing date: 1970-11-13
Publication date: 1977-07-07

Description

Dosis in Blutdruck- Dauer in Minuten Mit Zusatz von 2 mg/kg AN 1Dose in blood pressure duration in minutes With the addition of 2 mg / kg AN 1

mg/kg i.v. steigerung in mm/Hg Blutdrucksteigerung Dauer in Minutenmg / kg i.v. increase in mm / Hg increase in blood pressure duration in minutes

in mm/Hgin mm / Hg

1,01.0 00 00 1010 20 — 3020-30 4040 — 60- 60 5,05.0 20-20- 5 —5 - 40 — 6040-60 140140 — 160- 160 -30-30

Ärztliche Kontrollversuche
VersuchsanordnungMedical control attempts
Experimental set-up

20 Patienten im Alter von 30 — 60 Jahren mit ortho- 55 Die Versuchsdauer betrug 14 Tage (=2 Wochen),20 patients aged 30 - 60 years with ortho- 55 The duration of the experiment was 14 days (= 2 weeks),

statischen Regulationsstörungen wurden in 4 Gruppen Zur Objektivierung des Behandlungserfolges wurdeStatic regulation disturbances were divided into 4 groups to objectify the success of the treatment

zu je 5 Patienten unterteilt: die Blutdruckmessung durchgeführt, da mit der Normalisierung eines erniedrigten Blutdruckes auch einedivided into 5 patients each: the blood pressure measurement carried out, since normalization a low blood pressure also one

Gruppe A = Placebogruppe Normalisierung der orthostatischen Regulationsstö-Group A = placebo group normalization of orthostatic regulatory disturbances

Gruppe B = Behandlung mit Dragees zu 50 mg 60 rung einhergeht.Group B = treatment with coated tablets of 50 mg 60 mg.

Heptaminolhydrochlorid Die Blutdruckmessung erfolgte an 4 aufeinander-Heptaminol hydrochloride The blood pressure was measured on 4 consecutive

Gruppe C = Behandlung mit Dragees zu 5 mg folgenden Tagen vor Beginn der Medikation (Ver-Group C = treatment with coated tablets of 5 mg the following days before the start of the medication

«- Phenyl -«- (1 - methyl - 2 - phe- suchsmonat März 1972). Hieraus wurden die Mittel-"- Phenyl -" - (1 - methyl - 2 - phenyl month March 1972). From this the central

nyl)-äthylaminoacetonitril werte ermittelt. Die Medikation erfolgte dann zwi-nyl) ethylaminoacetonitrile values determined. The medication was then carried out between

Gruppe D = erfindungsgemäße Kombination aus 65 sehen 8 und 9 Uhr morgens in Dosen zu je 2 Dragees.Group D = inventive combination of 65 see 8 and 9 o'clock in the morning in doses of 2 coated tablets each.

50 mg Heptaminolhydrochlorid und Die Blutdruckmessungen wurden zwischen 13 und50 mg heptaminol hydrochloride and The blood pressure measurements were between 13 and

5 mg Ä-Phenyl-a-(l-methyl-2-phe- 14 Uhr durchgeführt. Die erhaltenen Mittelwerte sind5 mg of-phenyl-a- (1-methyl-2-phe-2 p.m. The mean values obtained are

nyl)-äthylamino-acetonitril in der nachfolgenden Tabelle aufgeführt:nyl) -äthylamino-acetonitrile listed in the table below:

Gruppe Blutdruck in mm Hg vor der BehandlungGroup blood pressure in mm Hg before treatment

systolisch diastolischsystolic diastolic

Blutdruck in mm Hg nach Behandlung
systolisch diastolischBlood pressure in mm Hg after treatment
systolic diastolic

AA. 108,3108.3 65,265.2 110,1110.1 63,963.9 BB. 110,5110.5 66,466.4 114,2114.2 65,365.3 CC. 109,1109.1 68,368.3 112,4112.4 68,568.5 DD. 108,7108.7 66,566.5 123,8123.8 66,366.3

Die erfindungsgemäße Kombination zeigte also im Mittel einen systolischen Blutdruckanstieg von 108,7 auf 123,8 mm Hg. Das entspricht im Mittel einer Zunahme von 15,1 mm Hg. Dagegen zeigte die Medikation mit den einzelnen Wirkstoffen für sich allein (B und C) sich praktisch wirkungslos in der angegebenen Dosierung. Auffallend ist die durch D gegebene Gleichmäßigkeit der Blutdrucksteigerung.The combination according to the invention thus showed an average systolic blood pressure increase of 108.7 to 123.8 mm Hg. This corresponds to an average increase of 15.1 mm Hg. In contrast, the medication showed with the individual active ingredients on their own (B and C) practically ineffective in the specified Dosage. The uniformity of the increase in blood pressure given by D is striking.

Demnach ist das überraschende, unerwartete und unvorhergehene der Erfindung, daßAccordingly, what is surprising, unexpected and unforeseen of the invention is that

1. durch Kombination des a-Phenyl-oc-(l-methyl-2-phenyl)-äthylaminoacetonitrils mit dem sympathikomimetischen Amin 6-Amino-2-methylheptanol-(2)-HCl eine langanhaltende Normalisierung des erniedrigten Blutdruckes eintritt.1. by combining a-phenyl-oc- (l-methyl-2-phenyl) ethylaminoacetonitrile with the sympathomimetic amine 6-amino-2-methylheptanol- (2) -HCl a long-lasting normalization of the lowered blood pressure occurs.

2. zur Erzielung eines solchen Effektes nur 10 bis 60 % zweckmäßig und 50 % der normalen Einzeldosis der einzelnen Wirkstoffe notwendig sind und daß gerade bei diesen Dosen ein solcher vorteilhafter Effekt gegeben wird.2. to achieve such an effect only 10 to 60% is appropriate and 50% of the normal single dose of the individual active ingredients are necessary and that such doses are more advantageous Effect is given.

Aus den Ergebnissen ist ersichtlich, daßIt can be seen from the results that

1. «- Phenyl - α - (1 - methyl - 2 - phenyl) - äthylaminoacetonitril die blutdriucksteigernde Wirkung des sympathikomimetischen Amins überzeugend zu steigern vermag,1. «- Phenyl - α - (1 - methyl - 2 - phenyl) - ethylaminoacetonitrile the blood pressure-increasing effect of the sympathomimetic amine is convincing able to increase

2. die nur flüchtige blutdrucksteigernde Wirkung des 6-Amino-2-methyl-heptanol-(2) durch a-Phenyla-(lmethyl - 2 - phenyl) - äthylaminoacetonitril bis zu 20mal verlängert wird.2. the only volatile blood pressure-increasing effect of 6-amino-2-methyl-heptanol- (2) by a-phenyla- (imethyl - 2 - phenyl) - ethylaminoacetonitrile is extended up to 20 times.

6-Amino-2-methylheptanol-(2)-hydrocMorid wirkt in Dosen zu 50 mg beim Menschen nicht blutdruck-6-Amino-2-methylheptanol- (2) -hydrocMorid works in doses of 50 mg in humans not blood pressure

X5 steigernd. Werden aber 5 mg a-Phenyl-a-(l-methyl-2-phenyJ)-äthylaminoacetonitril zugesetzt, also eine Dosis, die nicht einmal leistungssteigernd wirkt und auch keine blutdrucksteigernden Eigenschaften besitzt, so wird ein niedriger Blutdruck gesteigert und denX5 increasing. But 5 mg of a-phenyl-a- (l-methyl-2-phenyJ) ethylaminoacetonitrile added, i.e. a dose that does not even increase performance and does not have any antihypertensive properties, so a low blood pressure is increased and the

ganzen Tag hindurch auf gleicher Höhe gehalten, ohne daß dieser Blutdruck selbst bei erhöhter Dosis in eine krankhafte Steigerung des Blutdruckes übergeht.Maintained at the same level throughout the day without this blood pressure falling into one, even with a higher dose pathological increase in blood pressure passes over.

Es ist also das Wesen der Erfindung, durch Zusatz oder/unci Kombination von a-Phenyl-«-(l-methyl-It is therefore the essence of the invention, through the addition or / or combination of a-phenyl- «- (l-methyl-

2$ 2-phenyl)-äthyIamino-acetonitril zu 6-Amino-2-methyl-heptanol-(2) eine Normalisierung des erniedrigten Blutdruckes mit langer und gleichmäßiger Wirkung zu erhalten.
Die geringe Dosis macht folglich auch die neuen Arzneimittel ungiftiger und bekömmlicher. 2 $ 2-phenyl) -äthyIamino-acetonitrile to 6-amino-2-methyl-heptanol- (2) to obtain a normalization of the lowered blood pressure with a long and steady effect.
The low dose consequently also makes the new drugs less toxic and easier to digest.

3535

example

6-Amino-2-methylheptanol-(2)-hydrochlorid 50 mg6-Amino-2-methylheptanol- (2) hydrochloride 50 mg

<x-Phcnyl-£x-(l-methyl-2-phenyl)-äthylamino-acetonitril 5 mg<x-Phcnyl- £ x- (1-methyl-2-phenyl) -ethylamino-acetonitrile 5 mg

Beide Bestandteile werden gemischt und in Kapseln gefüllt.Both ingredients are mixed and filled into capsules.

Claims

1 2 *'1 2 * '

kings at the same level. This observation is patent claim: surprising and so far in the same sense by none

Substance or combination known.

Means in the form of tablets, coated tablets or. Accordingly, the invention relates to a means in

Capsules against hypotension, characterized by 5 form of tablets, coated tablets or capsules against a content of a mixture of 10 parts by weight of hypotension, characterized by a content of 6-Amino-2-methylheptanol- (2) -hydrochloride and a mixture of 10 parts by weight of 6-amino-2-methyl-1 Part by weight of a-phenyl-a- (l-methyl-2-phenyl) -ethyl-heptanol- (2) and 1 part by weight of a-phenyl- «- (l-methylamino-acetonitrile. 2-phenyl) ethylaminoacetonitrile.

ίο If the blood pressure increasing effect of _______ norephedrine, ephedrine and the like by a-phenyl-

a- (1-methyl-2-phenyl) -äthylaminoacetonitril is favorably influenced, these bodies have the disadvantage as catecholamine derivatives that these in the organism

It is known that only a few chemical substances are metabolized in mescaline bodies, so that undesired side effects which are orally effective to increase blood pressure arise unpunched. That is with are. These include norephedrine, ephedrine, 6-amino-2-methyl-heptanol- (2) -hydrochloride not the 1- (4-hydroxyphenyl) -2-methylaminoethanol, 1- (m-Hy- case. Accordingly, the case according to the invention was found Komdroxyphenyl) -2-ethy] aminoethanol _> m-hydroxyphe- binination in all data of the use as am günnyl- (l) -ethanol- (l) -ainine- (2) and 2-aminoheptanol. 20 th.

It is known that the hypertensive effect of a - phenyl - α - (1 - methyl - 2 - phenyl) - ethyl - ami-

These compounds only last for a short time, even volatilely. It lasts after the peroral administration of the aforementioned pressure-increasing effect. It has a performance-enhancing substance the effects taken in relatively high doses, which are pharmacowerden about caffeine have to, hardly more than 3 hours. One had 25 logically similar.

is already trying to reduce the blood pressure-increasing effect. A table should show the results of the blood pressure

These sympathomimetics are led by various types of pressure increase. The blood pressure Preparation, such as retardation, addition of Kollidon was carried out on the cat in urethane chloralose anesthesia, etc., to extend. The results are modestly true. In the experiments, care was taken that and are by no means therapeutically satisfactory. 30 the initial pressure was between 80 and 100 mm Hg.

The surprising observation has now been made. The experiments were carried out once with the well-known blood test that simultaneous administration of a-Phe- pressure-increasing body 6-amino-2-methylheptanyl- «- (l-methyl-2-pheriyl) -ethylamino- acetonitrile, carried out with nol- (2) -HCl alone, then together with the blood pressure-increasing 6-amino-2-methylhepta- «- phenyl - α - (i - methyl - κ - phenyl) - ethy) - aminonol- (2) -hydrochloride with considerable, around 50% acetonitrile, which orally does not only increase the blood pressure, the substance is administered orally to the animals 20 minutes lower dose than the one previously mentioned therapeutically before the start of the intravenous administered substance. The results represent the same evenly, without Schwan mean values from 5 tests each.