DE1811804A1 - Novel antihypertensive compounds and methods of making them - Google Patents

Description

New antihypertensive compounds and procedures on their division

The subject of the invention is new therapeutically effective in particular in the treatment of arterial hypertension. same mandelic acid extract fan length of the following poraels

CHOH -

in which R ₁ and Rj can be the same or different and each mean a waascrstoffato «, a hydroxyl group or an -O-alkyl group, in the latter lall the two oxygen atoms of R ₁ and R ₈ can be linked to one another via an alkylene group and R ₁ and R ₂ then mnwmn form an alkylene group and in which R, and R ^, which can be equal or different, stand for a hydrogen atom, an alkyl, aryl or alkylaryl group or a hydroxyl or -O-alkyl group as well Their accumulation cells formed with physiologically acceptable acids.

oas 3> 5 »-NÖI (0)

9098 48/1430

It was found that the compounds corresponding to the above formula act on the cardiovascular system and are of particular interest for the treatment of arterial hypertension.

The process for the preparation of the mandelic acid amidines of the The formula (I) given includes the following stages:

1) Reaction of an aliphatic lower alcohol with a candelic acid nitrile of the formula !:

-CHOH-CON

in which R ₁ and R _{2 have} the meaning already given, with formation of the corresponding imino ether β;

2) Implementation of this imino ester: either with gaseous ammonia (working regulation No. I) to produce a mandelic acid aryan of the formula I which is not substituted on the nitrogen (in which R.sup.1 and R.sup.4 are hydrogen atoms); or with an amine of the formula NHR ₅ R ^, In which R and R ^ denote an alkyl, aryl or arylalkyl group (ArIts regulation No. II) for the preparation of the corresponding nitrogen-substituted almond curamines of the formula I.

3) For the preparation of the mandelic acid & nidines of the formula I, in which one of the radicals fU or Rj ₁ «in« represents the hydroxyl group (mandelic acid aaidoxime), a MandslsMureamidln of the formula t , which is obtained by the above-mentioned process and is unsubstituted on the nitrogen, is reacted with »hydroxylamine ( Work precaution no. III).

Bs * Arbfiten about the industrial · staff management d «* Vtrverfahren could some« particularly * advantageous · JDurchfUhrurtt * -

909848/1439

"'■"',: BAD OR! G! ^S -'AL

^ ''. Ililllii'lfSPISS ^ iSi'K'ii ¹ : · :! ¹ !:;! ¹ ^ :;

1811604

-J-

welaen gafanden verdea * ma

a) Use of methanol as the preferred ellphetlseher Alcohol for making ds «Isdnoestere in the first Procedural stage.

Duroh dleaa Natasha »the following advantages can be achieved will be

1 · Verification daa duroh Xthanol gave reactive loaungssilttals or critical vasehvorgsngaaj

S. Education alas · Älnoaethyleetere, deasen phralkallaaha Bf ganscheften compared to the ethyl analogs aodlflslert aln4 un in particular has a higher density and consequently lighter ale daa latstera can be isolatedi aowie 3 · Legal change in the gas components

b) OanOgend curaaeltlge application of Mime in the tftssetung dar Aetna «it dan Xsdnoeetern in dar swelfcen far ·. Fahrensstttfe ·

■ j ·

Particularly advantageous goes to the invention in the manufacture of 3. "- Msthylsndloxy niprtsi eMuroa * UUna from one · 3" ^^ Methylendloaqr aanrtelsMurenltrll from "daa gttrah Usetsung of Plperonml sdt KalluBoyanid in wtlutsarigaai It. Milieu in Otsegenwart Catalyst and dilute aelsstture up to about pH * _t 0 bla 5 * 0 in a tight reaction apparatus was obtained 1st. Under these conditions, the leak-tightness of the apparatus and the change in the handling largely eliminate the risk of poisoning from the water-containing substance, and when using water-based sulphate as a catalyst, the reaction apparatus can be used with relatively small concentrations if there are frequent concentrations.

9098A8 / U39

BATH ORIGINAL

The following example is used to explain the invention: example 1 Production of 3,4-methylenedioxyHBandeleKurenltril,

A 20 l balloon with 2 nozzles is used as a device a Rttnrsystem with central pipe screw with adjustable Speed, a precision thermometer and an inlet funnel. The gas-tight device stands with the external environment only via a bubble counter, the output of which is connected to a hydrogen cyanide trap.

In this apparatus are introduced;

1600 g 95 # potassium cyanide (23.5 moles), > OOO g plperonal (20 moles) and 10 1 water.

The tightness of the apparatus is checked with the bubble counter, the balloon is cooled from the outside with ice water and stirred Dissolution of the cyanide, brings the piperonal into suspension and ensures temperature equalization within the device.

Then slowly add 400 cnr of a sodium bisulfite " solution of density 1.32 added. Finally, a semi-concentrated (about 6N) hydrochloric acid solution becomes very slowly while regulating the inflow rate in such a way that the temperature never exceeds 15 ° C. is added. the The addition of the hydrochloric acid is stopped when the pH of the reaction medium reaches 4.0 to 5.0.

The nitrile forms rather quickly in the form of oily light brown droplets that settle spontaneously when the stirrer is switched off. The oily layer is then sucked through Take off or with the help of a siphon and wash this in

909848/1439

• In · «Balloon« It is a ·· lower stutia with old stems drelael old water.

The obtained medium is brought into solution in chloroform and dried for 24 hours. According to Abdaapfon dos chloroform · la vacuua aan receives about 3800 β the raw products »of brown-orange color, which has a refractive index eel 20 ⁰ C of about 1.5 * 6.

Since · eo obtained Nitrll IMJt eloh sclbet not be distilled under veralndertea pressure as ee iu aldehyde and hydrogen cyanide · d • Kure dlssosllert. However, its purity makes it suitable for use as a starting material for various syntheses. Thus, by treating old anhydrous formalsic acid and alcohol with an ethereal solution, the corresponding zalno ester was obtained from an ossification so that the area of 1970 was "exogenously preserved to the greatest extent possible",

Example 2

Production of Nioht Substituted Aaldlnen (Arbelte regulation Mr X)

3,4-Wethylendloxy aandelalhiroaaldlnhydroohlorld

tNH

, HCl

Bins solution of 0.4 fetch jM-Wthylcndloay ssndelslurenltrll in 250 al water-free XthyUther and 40 al absolute Xthanol, the KBit · old dry gaseous chlorine · hydrogen acid is produced. Bach Sftttigen and Ifctfienlassen upper bsi about 10 hours 0 ⁰ C we "dee the ausgefUlt · Hydroonlorld 3> 4 W» thylendloaqr aandelstoirelainolthylesters filtered

• 09848 / U3

. BAD ORIGINAU

and old sweiiial 100 ml anhydrous washed ethyl ether.

The product obtained in this way is brewed in 300 ml of cold absolute ethanol and the solution is saturated with ^{gaseous ammonia at 0} ° C. After a few hours' rest, the crude 3,4-methylendloxy-commercial acid amldine hydrochloride is made up by adding 300 ml of anhydrous ethyl ether in the cold failed.

The product is purified by recrystallization from a mixture of ethanol and ethyl ether. Han receives the compound in the form of wave crystals "dl". Insoluble in water, methanol and ethanol, and insoluble in ethyl acetate, ethyl ether, petroleum ether and benzene. The Nomentansehmels * point bsw. 8ohnelsbeglnn the connection is 220 ⁰ C.

The yield of 3,4-methylenedioxy-almond-mureajiidin hydrochloride, depending on the nitrile used, is a total of 60 *.

OemMI of a more advantageous duration of the process according to the invention is used in the first stage Methanol instead of ethanol and forms the 3,4-methylenedioxyHsandelsäurelblnomethylester.

a) Production of the Xmlnoester »

The following substances are put into a 20 liter balloon *

6535 I crude nitrile according to Example 1, since "by addition of hydrocyanic acid to 6000 g Plperonal (40 moles) has been produced 1st »

14 1 anhydrous «chloroform and 1400 g anhydrous methanol (44 mol) ₄

" *- BATH

909848/1438

The balloon is equipped with an "agitation system", a central agitation system with adjustable speed, a preslion pressure meter and an "air conduction pipe," which are otherwise hermetically sealed A closed device is only available from the external view

User a bubble counter In connection, the output of which is old one Hydrogen chloride all in contact

The balloon is cooled from the outside in a water bath and the contents are stirred to equalize the temperature. Nan then lets dry gaseous form through the Oaselnleltungsrohr Hydrogen chloride streaks under control of the Durohsatse * In the catfish that everything is absorbed and the temperature of the ReactlonsBllleus remains below 25 ° C.

After introducing the theoretical amount of hydrochloric acid and who on the bubble counter there will be a departure from that begins »asu turns off the oss supply and stops the reaction.

The formed tadnoesterhydroohlorld lies in fore of small, dense, easy-to-separate crystals. Bs will saaaelt by filtration And old anhydrous · «Acetone HIs Sub the colorlessness of the Plltrata washed and dried la drying cabinet at about 55 ° C

About 7000 g of a slightly yellow, granular product without a defined Sohneispunktι this crude product is obtained used for the operations according to b)

b) Preparation of the amidine

In the 20 1 balloon described under a) from the outside is cooled with ice water »the following substances are given;

7000 g of the Xmlnoester obtained according to a) and 13 l of anhydrous ethanol.

For dispersion of the product and sua Ausgleloh the Temperatures are stirred, and asu then lets through the oasis

909848/1439

". ■■■ · i ·

BAD ORIGINAL!.

add gas-filled conduit to dry ammonia, under regulation of the Durohsatsea in such a way that all, «· . is absorbed and see the temperature of the Raaktionsrotlieus sets 20 ° C. One «divides the Aononiatc supply according to fixte» tion an excess of 20 to 3O # of the theoretical Quantity from «

Nan * beliflt the eo obtained suspension of the amidine hydro · » Chloride for 24 hours at ambient temperature and filtered and then wipes the formed Asldlnlvdroaliloridniedsrsolilag Filtered and wHcoht the precipitate with acetone until the Coloring in the tfaeohflCesigkeit is integrated »Bau rfiw teidln» hydroenlorld is in froakenschraiilc GetrcNslaeti «s let« in ■ gray curvy powder with «inei» Qmleht wm about% 9 $ ® € «This« product will be «doors 1 Utoicristals & lli · Slightly lured egg leaves and cleaned of animal charcoal while turning 7.

You lose 3950 g ^

in Fora by tte & 8nan «reiien Xrist» ll «n» - the »liobkeit in tfa®s # rb # i 20 ⁰ C in 4er öejptut of Si lies *

The dehaite of icnleierteis chlorine and of Stieketoff (protonetriiieli ia Maiiii «i'f? Titm Ferehloralliire etmi®s®i *) are always It> 0 + t $ (btcogen on the theoretical Itntg«) »

Yield · of crystallization is

the amonolysis de® lutte © «·!» «59jf». the
that for the synthesis tos nitrile
higher than

Example 3

ναι it Stiokatöff

(Work preselection Mr. 11}

909848 / U3S

Ν, Ν-DlKthylswideleMureamldlnhydroohlorld:

- C ¹

The compound is gemKft by adding 0.1 mol of the the working method described under work regulation no by allowing gaseous HCl to act on mandelic acid nitr11 mandelic acid imino-ethyl-ether hydrochloride obtained in the presence of ethanol to a solution of 0.3 moles of ethyl-alcohol in 150 ml of absolute ethanol and heating for two hours in the Water bath prepared under reflux.

After evaporation in vacuo, the residue is diluted with 100 ml Water taken up again and extracted with ethyl ether to remove excess diethylamine su. The aqueous solution is cut by adding caustic soda alkallson. The released basic Ν, Ν-Diethylmandeleäureamidin is with 3 x 50 ml of ethyl ether extracted. This ethereal solution is washed with water »dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.

The thus isolated "amidine (base; Pi 115 ⁰ C) is transformed by adding a solution of HCl in Xthylätner in da · hydrochloride. The precipitate obtained is isolated by filtration

The red N.M-diethylmandelic acid amide hydrochloride prepared in this way is crystallized from a mixture of Purified ethanol and ethyl ether.

$ 09848/141

BATH ORIGINAL

This product, with a yield of 35 %, is in the form of a fine white powder whose liorantai ^ melting point is 167 ° C and which is soluble in water, methanol and ethanol and insoluble in ethyl acetate, ethyl acetate and benzene.

Example * ·. Manufacture, of Aoldoxine ^ (Revetollimgfnrorscihrift Nrv -Ill)

Almond tureaaidcixis t

IV J '

W " Sf?

POr di · production dt · «« ·;

de «Ipslli 'd * r under

HiliifayilroelÜLoK'id «SOO si ifefäteiii 1 vwi '<: S *"ol; s satellite * -

ik 4,

teupemtur (·! »»

the mtkMm »ΙΑμαι» «Hu *, ·

Troelm · «tügjst ^ a ^ ffev. Ku 'fiiit' 7 ( ¹ ^ stA ** »» (n, r lf sucks dmi VisderseJEils ^ i * 0 · ™ rSit '«il # im- * *', _f , v» t * § », '

man NitheiMrS. w «» i 1 ^ V ¹ '"tf. ■ *

S 0 4 »0 4 9 <* ί ^1] S" ΠΛΓ \

1811604

Old connection obtained from a damming up of 901 in Pore vtMi crystals spread out, their Noaentaneolwelpunkt • is 164-165 ° C and that in acidified «sea, methanol» Ethanol and acetone, and soak in water and tiloether (ether sulfurlque) is insoluble

The MaMelsltureaaidoxiatiydroehlorld «that with the addition of one HCl solution in ethyl ether su an alcohol-topped solution Amldoxias ausfKUt, is a hygroscopic product.

The other compounds given as examples 5 to 15 according to the invention were prepared according to the three above-mentioned working procedures; the working procedure used for each of the compounds, the 3 as ₉ as which the compound is obtained, and its melting point are given below.

Beleplel 5 »Mand * lsJlur # j * ldi * j Regulation Kr. I (HCl; ft

Example 6: 1-Isopropylatfu ^ lsnuresftldlai No. II (HClJ Pt 209 ⁰ C)

Example 7: M-Phenyleandelsllureamidini regulation Mr * Π (HClj P: 128-1> 0 ⁰ C)

Beleplel 8: s-hydroxymandelic acid almond; Regulation no. T (HCli P * 204 ° C)

Example 9: N-18opropyl-e-hydroxyHBandelslturea * idin} Regulation No. XI (HCIj Ft 812-213 ° C)

Example lOs p-Hydrosgromndelsllursaaidiiii Regulation No. I

(HCIj P »215 ° C) Example 11t 3 # * - DihydroxyHMIidelsäureaidlni protocol

No. Z (HCIi Pi l? Fi ⁰ C)

BelspUl 12i N-

Pre-set Ar. Π (HCIi It 00β141 / 1411

'■■■■ "■ ,, ' *

BAD ORIQINAU

Example 15: 3.0% - di-methoxynandeleitureanidine; Regulation Mr. I (HCl; P: 205 ⁰ C)

example

amidine; Regulation No. II (HCl; Pi 212 ° C)

Example 15: NtN-Mäthyl - ^^ ethylendioxy-raandelsäureamidinj Regulation No. II (HClj Pi 160 ° C)

Example 16: N-Isopropyl-S ^ -methylendloxy-raendelsÄure -... araidinj Regulation No. -II (HCl % Fs ⁰

Toxicological and pharmacological tests of the compound according to example 2 »as described below, carried out with a sample prepared in the laboratory (Reference sample No. 1).

Investigation of the acute toxicity in snacks

Intravenous administration:

DL ₅₀ (iv) i 120 * 8.7 mgAg (104-158 ng / kg). Symptoms: Exophthalmiei ItyepniSe, immediate death * arch respiratory failure

Intramuscular administration:

DL ^ ₀ (i _t ia): Swiss 600. and, 100 © g / kg. Symptoms: tremors, convulsions, exophthalii, piloerectlon

(plloerectlon) «Ptosis * Reduced breathing

Administration through the stomach:
No mortality up to 1000 mg / kg.

Observation of animals naoh, Vemiireiohung ._νρη,., ^ 00.

of the product (im) t

Piloerection, ptosis, hypothermia (-53 ⁰ C) J da® product. «In« light tranq-ailllier ^ irteai; "S sattfeitt before death

909848/1439

by Blektroschook.

Examination of cardiovascular properties:

1) On the isolated rabbit heart with perfusion according to the Langendorf method

Three Isolated And By Berium Orid In Spastic Conditioned canal hearts were removed from a solution of the product to be investigated at a concentration of 10 and 100 mg / 1 flowed through. No significant effect was observed either on the coronary heart rate or on the ventricle amplitude and the heart rhythm.

2) On isolated guinea pig atrium

The bodies were in a (oarbogene) with Kohlendloxyd Locke-Flttssigkelt "ventilated" obtained at 30 ⁰ C in practice.

In two organs (atrium oordls dextran) this caused In doses of 1 * 2 to 12 yug / nl 'no change in product Amplitude and rhythm and did not result in any modification of the effects of Iaoprenaline and DMPP (apart from the Case in which the effect of isoprenaline increases on the amplitude 1st).

3) Leg arterial pressure of the anesthetized rat

The animals were anesthetized with urethane. The injections were performed through a jugular fixed catheter. Of the arterial pressure was eaten on the carotid artery.

In two batts, the product caused at 12 ng / kg

(iV; ie 1/10 of the JSL ^ o (* · ▼ ·) *** d * r mouse) a hypotenaive discharge and subsequently an increase in pressure of mean JM for three minutes.

"-: -j
00 * 848/143 *

ν '* ,, - \ BAO-pRlßlNAL

4) Leg arterial pressure of anesthetized rabbit

The rabbits were anesthetized with a chloralose-urethane mixture. At 12 mg / kg (ivj ie 1/10 of the DL ₅₀ (lv) in the mouse) the product caused:

a hypotension of 2j5Jf for 5 minutes 1

a reduction in the hypertensive effect of noradrenaline by &

no change in the effects of angiotenain (angloten sine) »Iaoprenalin and acetylcholine on the pressure.

5) With arterial pressure of the awakened latte a) Examination after application of brushes

The animals received aortic catheters, at least that Hours before the actual examination.

A) IntnMiakulMre misrepresentation - Had »it Noiwaldruelc

At 50 ng / kg the product feels four batteries dta Druok for mutli & al $ 19 (in average). © tee · »Maximen will be sewn Minutes reached * The Atugangedmielc provides nieli. naoti eto & 1/8 hour again (the hypotensive effect can be repressed).

B »i 300 bis / ksf + pemliwlerfc es tion den Diiiok imI fwt * ^ latt;«: ». ; l The Mlrkiaif bk * , k '^ i * 11 P' mvl-m tm rises aieBt * (

B) BwIfU *

vmssh de? f 'my. & ■ -

-μ.

at

StiÖSi, Ö .. "14 31

"» Y- j !!? · " ¹ !! 5 "-ili illlifi

1811604

- 15 -

a MOMontsnc slight hypotension that lasted 1 1/2 hours. Observed in a rat with hypertension «to an esterified one Hypotension that lasts for about three hours.

At 100 mg / kg and rats bit noraalea pressure will be at three No significant effect was observed in rats and a mean hypotension of 20Ji, which set in immediately and swel hours lasts and is more delayed with the beginning of the return after several hours with a festering rat.

Hypotension is observed in hypertensive rats of an average of 5 ** in two rats, which «wipe for 50 minutes and occurs one hour after the injection and lasts more than 6 hours.

At 500 mgAg, hypotension of an average of M% was observed in 2 rats with norealdruok, which occurs within 30 minutes and 1 hour and reaches a maximum after 3 to 4 hours. One of the rats shows an increase in leather after k hours, the other maintains the lower pressure and dies on the next few days.

At 1000 mg / k "observed" on in a rat with normal Pressure} 0 minutes after product administration, $ 6 pound hypotension lasting more than 6 hours; the animal 1st died the next vag

b) Examination during long-term treatment with buccal administration

5 rats received the product in one dose for a long time of 100 Bg / kg-day. their pressure was by a bloodless method Sat every day before administration of the product and every hour after administration and was the first fag for 6

■ ν ;; ■. < '·' 'T ;. "Ky- ■■ - ■

909841 / Uli

Hours and on the following days for 3 to 4 hours.

During the course of the first day of treatment, the pressure decreases Minutes after administration by 23 #; one observes a gradual rise again (after 6 hours the decrease in pressure is only £ 10). On the other days it was no pressure drop observed.

On the 5th day the animals received 50 mg / kg des'Produktes (i.p.); the pressure quickly dropped 24 # and came in for three hours returned to its original level after the injection.

6) At the arterial pressure of the anesthetized cat

The animals were anesthetized with Nembutal »One intravenous dose of 12 mg / kg (1/10 of the (l.v.) in the mouse) causes in a cat:

a hypotension of

a delayed increase in the hypertensive effects of

Angiotensins

no change in the hypotensive effects of isoprenaline; a decrease in response for more than 1 hour the membrane nlctltans when stimulating the preganglionic

Fiber of the throat Syrapathlous.

It is to be noted that the product is at 12 / Ug / ial at the preparation of the vas deferens (canal deferent) hypogastric tear Mervus the guinea pig's response to the traneaniral Stimulation (in 4 organs) not changed and that the response to stimulation of the preganglionic fiber of the nerve decreased (with 2 organs).

7) Cardiovascular Effects in the Anesthetized Dog

The dogs were given a mixture of pentobarbital 909848/1431

- 17 - and Chloraloae anesthetized.

With a deal of 12 ag / kg administered intravenously (1/10 of the DL ₅₀ (lv) in the case of the Mau), the product causes in the dog r

There was a change in arterial pressure, among other things, defending £ 17 more than 40 minutes;

no objection to satisfaction;

no change in the systemic pressure on the right Ventricle;

a decrease in the amplitude of the pulsations of the right Hersvorkaaner under increasing dea diaatoliachen Druokea and Alteration of the systolic druokea;

no change in the pressive effects of adrenaline and Iaoprenalln; and

a vein change and then a course increase (3 minutes) de Throughput of the feeoral artery.

With intravenous Perfualon of 30 ag / kg in 10 minutes causes the product with 2 frets:

a slight change in arterial pressures («9 and -19 *);

no change in the Hersfraquens;

practically no change in the Kardlaldurohsatsea (-12Jf at a · Bund);

a change in the Hersareelt et al. 19 * la MitUl; and

no change in the peripheral rear Bund and a Veraindenaig among other things 18 * with others.

909848 / Ual

BAD ORiGINAU

Subsequently, new experiments were carried out with a new sample carried out from the semi-industrial production of the product! This «sample deceives the speaker no. 2.

The following results were obtained: I) Acute toxicity in the mouse

No mortality when administered via the stomach up su a dose of 2 g / kg

ZZ) Compatibility of product no. 2 and effect on the arterial pressure in awakened round.

1) Intramuscular administration

At 40 BäßA «(1/20 of the m ~ _Q (iv *) in the mouse) is observed

ft) line very good «tolerance; nozwale behavior, no Sohaers at the injection ** UHe,

b) Am · weak hjrpotraslv · effect? before the injection the bridge is 126 maHg and di® flrequens 120 strokes / atai

30 minutes after the Hajektlon the pressure is Iö8 ηβ% and dl «Frequen * bei Uo Sehläg» a / »in;

90 «in after the ZnJefeUoit the pressure is 113 HMUg and dl · Frequen * 130 Soiaftg »A * ii *

3 hours "after" the 5 injection, the pressure is 112 HnHg and dl · separate «110 aebilgt / fine;

5 ituoden naoh dwr BM »Wii» the pressure is 108 amHg and di · fr ^ um »at 100

BAD OR'G ^ - 'AL

• a subsequent fag enters the Druok 124 bellows and the Frequency 110 8ohlage / aln.

2) Administration on buccal "He" · Bel 100 agAs monitored aant

a) Bine excellent tolerance and a noraalea

Behavior}

Ii) no effect on the arterial pressure and the

Before the administration, the Druok is 107 Mflg and the Frequens IJO bottom saw / min;

The Druok is included 50 minutes after administration HAg end the frequency at 130 lies / ainj

50 minutes after the administration, the Druok cheats "" Hg;

The Druok lies 2 1/2 hours after the administration vug and the prequens at 120 8ohlägen / nln; and

* The Druok is 100 hours after the administration

* ■ t ·

and the Frequens 120 soles / ain.

Zuaaaaenfaaaend can say that, "grounded, DA8 the erfindungageedUM product rom enraohten Bund at intraauakulärer and buccal Verabrelohung eehr is well tolerated. The agreed nypotenelve effect shows eioh above all with intreauakular Verabralohung *

Ingsaat the following results were obtained for the product

909848/143 &

BATH ORIGINAL

Toxicity led eggs mouse:

(i «« ·. ·) »wipe IiOO imcl il'l / < - τ (tadele «I j > Ϊ S / feg

Effect. ay; f _: '-mi m--}; _: «: Ί ^ ΑΐΚ1 JMMM.1

ί „ίΐίΙ s Uj it y · ■>':.<-l'rü . " } ■■: * ■ ^ :, << ^ λ - h'i'z ■: ί" - ^ ΐΐ ^ ί: 7

ί 1 1! V ΐί; « W, i% - i.!:; - :? '! a -; »f" .Ti '' S ίί ^ ίί ^ ίν? π> χ-Γ * ΐΤ ΙΤΛ'-Ί- &'■% ίΠιΓΛίτ? ^ it / "■ f

Bel iniuW ^ iBktiliii ^ r ^ ie ^ iim'-üimrms, ψ & ιι g'3> ice / kg

the | Jj, _{l | p (|} (1, na,}

e llii ^s kaßg i> el eier et'waelsSea latte Ik ¹ I tnjililift * " ¹ I ι ¹ · t, i 1 f] « Pf jij n 1 [j _ti V £ '

hypotensive Wirluuiß Ivi the first Iufiaaiiae, but seven after the further administrations in the awakened rat "

. With intravenous administration of 30 mg / kg to 10 minutes (1/4 of the DI ₅₀ in the mouse)

hypotension that is not due to a decrease in heart rate or peripheral dilation;

909 848/1439

Decrease in peripheral vascular resistance (resistance vasoulaire peripherique) and the work of the heart.

Cardiovascular effect in the awakened human

Moderate hypotensive effect at 40 mgAg (IM); no hypotensive effect at 100 mg / kg (buccal);

tolerance is in the awakened dog at I.m. and buccal administration good.

In addition, the effect on the heart was shown in the anesthetized Dog examined in the following way: An electrocardiogram with integration of the heart rate after slow perfusion was examined the compound by intravenous route at a dose of 15 mg / kg recorded. In this way, no change in the electrocardlographic curve was observed. The heart rate remained practically untouched.

The result of a clinical examination is described below, which was carried out in particular with the product according to Example 2 was carried out:

I) Bukkaie administration

The product according to Example 2 was administered orally to 10 people with hypertension at a dose of 300 mg per 24 hours; the total daily dose is taken in 3 qabs of each divided into a capsule with the following composition:

3 * 4 ~ methylenedioJty-mandelic acid amide hydrochloride ...... 100 mg

Lactose. _a ...... «, * .., ....... *, ... qsp 1 capsule

DSa examination mm? "Carried out in each coat sn patients who had been trd vmu? without four borders of any parameter «which

9098U / U39

BATH ORIGINAL

suitable would be »to modify the arterial pressure (Kost, Akti vity or other therapeutic treatment); dep arterial Initial pressure was on the three, the therapeutic exam previous days b & stimnit (between deai 7 "" fell ok "day of Hospital stay) and swap was the measurement with a ¥ aqueζ «apparatus according to the palpatory and auscultatory Method made; The mean outlet pressure is a mean out of 9 measurements »those made on these three preceding days became·

Under the conditions mentioned for the therapeutisch® Investigation proved particularly at the doses administered see the product as a hypotensive agent of constant and remarkable efficiency, t'ss complete and is tolerated without side reactions *

With 10 sick. (3 "with severe Bypertaitsioia" ad 7 with moderate hypertension. ©! *) A mean noise reduction of -60 mnHg in the sysfcGliselien pressure “nt! from ZZkQ ismHg bein diaafculischen pressure υ deviates, ΛΛ, a percentage success of 100 $ ί unet a percentage of good results of lOOi (if one as "good ^ rgobnie" a Brusicseokyng by > 40 MmHg with systolieches. Bracic or oils deletion of one referred to as the diastolic pressure value brought down to 100 BBBffg or diastolic pressure).

No Itevertrlglloiiiceife or S observed.

HJ Ihtr & muscular & r: - λ'ί ·: ^ w mv * ! fa- Since ti 3? ^! 9'Γ'3υ ^:! :? '"! §Ί» ϊ''| € Α · - ^Γ >7'ί --- Λδ (■: "■■: ■■■ - 3 from 5Q! K £ _t Ivi \ i.ii,; S '■. ■' ■ r .-. F ■ - ¹ ? ■ '/ ι ■' ■ 'P "', te Product) ■ '.-> I <£.' J ^■::. - al, β JO niimtmn) ^ d ΐ- -

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Effect without secondary effects.

The active ingredient was supplied in ampoules with 100 mg of product In 10 ml of physiological saline solution are used.

In general, it can be concluded that the medicament according to the invention under the stated test conditions and at the doses used, a remarkable constant hypotensive potency and excellent tolerability shows.

Indications for the administration of the invention Medicinal products are the following:

On the one hand, arterial hypertension regardless of severity and etiology; on the other hand, hemorrhagic or ischemic vascular complications of arterial hypertension (cerebral, coronal, visceral or of the extremities) favored or triggered by hypertension. ,

The drug can also be administered orally (with long-term treatment) or parenterally (with immediate or general treatment) will.

9098 ^ 8/1439

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Claims (1)

Claim 1 «New therapeutic in particular feel ύ®χ · Bsiumdlung ä® :." arteriollen Ilyporfconsicm uii / kaafr-e itettcIel & Mureßbköimnlinee ßer formula * n-CHOH in which R ₁ and Rg can mean the same or different "aä _t jevieil8 a hydrogen atom, a hydroxyl group or a.-O'-Altqrl". group, if in the latter case the two oxygen "· fetomes of R ₁ and Rg "Anything that can be linked to one another via an equilibrium group and R ₁ and Rg then together form an alitol-dioxy group and in which R and R, which can be the same or different * for a hydrogen atom, an alkyl", Ax ¹ JrI - or alkyrylaryl group or a hydroxyl group or a hydroxyl group as well as its addition salts formed with physiologically acceptable acids. 2. HandeleäureabkÜDWilingG according to claim I ₄ characterized by the formula CHOH-C CH. 909 8 48 / U3 BATH ORIGINAL in egg R. » and R ₁ , have the meanings given above. 3. 3 _} 4-Methylendloxymand8lsäureamidin and its acid addition salts as Mandölaäureabkömralllge according to claim 4, M, N "Dläfchylmandel8äurearaldin and its scure attachment salts as mandelaic acid derivatives according to claim 1. 5ο almond slureajnidoxini and its acid addition salts as Mandelaic acid bottle according to claim 1, 6. MandölsMurearaldln and its Smalmure addition salts ala commercial acid abktonlings according to claim I _n ? · H-Isopropylmandela acid araidin and its acidic acid salts as an almond slur mixture according to claim 1 0, N-Phenylmandelalureainidln and its acid addition salts as trading acid derivatives according to claim 1 * 9 · a-Hydroxymandelic acid aaldine and its acid addition salts as an almond acid kussuiling "according to claim 1. 10 * N-isopropyl-ra-hydroxymandel-Kureamidine and its acid additive seal zo as a hand isMureabköwmlInge according to claim 11. p-Hydroxyaandel8 * ureamldin and its SKureanlagerungsaalze sin MflndciflJiureabkUmmllngo according to Claim. 1 'V i "! JP ^ m Λνήι An.! ^ I ¹ Uf h BATH ORIGINAL 14. ^ i ^ -Diroethoxy-raandelalureaaildin and its acidification salts as mandelic acid packaging according to claim 1, 15 »NjH-Dlmethyl- ^ i ^ -mefchylendloxy-raandslsaurfiasiiidla and his Acid build-up gas salt © as mandelaic acid abbot, baby babies according to claim 1 « 16, NiN-diethyl- ^ i ^^ mathylendioxy-aiandiilsäureainidiri and its Säuroanlageningssaläse ala almond acid-kömralinge according to claim 1. 17 »M-Isoprop ^ l - ^. ^ - Biöthylöndloxy-almond acid aniidine and its as mandelic acid removable according to claim 1 l8. Pharamzeubisohe Zuaamroensotasungen, gekennaeiohnat duröh a content of at least one of the compounds according to claims 1 to IT. Process for the preparation of the mandelic acid abkönaalinge according to claim I _9, characterized in that: a) an alcohol with a mandaic acid nitrile of the formula: cam - c * n Ciif) uma®tzt au corresponding Imihoaistar; lind ® & gXBven läJt, -imirni B ^ wnd n _j} α in Waas «- stoff» ^ Ai ■ 9 008 A 3 / UiO BATH ORIGINAL »'" Ι iiiiit "";" ^: 'PB ='»; ■ c) possibly άηε r-tt nitrogen! not substituted; iei te Mandelfiaui> ci: tr.icUii der Fom? l I, with the R ₅ and H _{i {} hydrogen atoms Gindj. with hydroxyl ·: «■ '. . to: cntgprcehondon mandelic acid · "amldcxim converts, 20. The method according to claim 19 *, characterized in that one sur the production of the ji ^ -Metb ^ lendioxymandelSureaniidins of the formula I from a 3 # ^ methylenedioxymandel8 acid nitrile auaßeht ,, das dui ^ eli implementation of piperonal with fraliumoyanid in aqueous Hilieu in the presence of sodium bisulfite as Catalyst and dilute hydrochloric acid until pH 4.0 to 5.0 has been obtained * 21. The method according to claim 19 »characterized in that the imiiioester with ifethano3. will be produced. 909848 / U39 ORIGINAL BATHROOM