DE1919852A1 - 3beta-Diaethylaminoaethoxy-20-keto-delta? -Pregnane and process for its preparation - Google Patents

Description

. DR. ELISABETH JUNG ₁ DR. VOLKER VOSSIUS, DIPL-ING. GERHARD COLDEWEY

Patent attorneys 10 1000

MÖNCHEN 23 SIEGfSSTRASSE 26 · TELEPHONE 34 50 67 TELEGRAM ADDRESS: "> INVENTV MÖNCHEN TELEX 5-29686

U ₀ ZoS E 277 (ho / Vo / iä),. April 18, 1969

TH-D-IO ■■ - ■. · ■■ - ■■

JEAH-MARIE GASTAUD
Monaco

5 6

"30 ° diethylaminoethoxy ~ 20-kebo« A -pregnan and procedure to

its manufacture "
Priority: April 19, 1968, United Kingdom, Hr ₃ 18 537

The invention relates to the 3ß-diethylaininoethoxy ~ 20-keto-A 'pregnan of the formula ^ j qq »CH,

⁰ ^ - (CH ₂ ), - O -

and its salts with pharmacologically acceptable acids »The Salts can be derived from inorganic acids, such as hydrogen halide acids, sulfuric acid or nitric acid, or organic acids such as acetic acid, tartaric acid, citric acid, maleic acid or succinic acid.

The invention also relates to a process for the preparation of the 3ß-diethylaminoethoxy-20-keto-A '-pregnane "which is characterized is that you get the 20-keto group of pregnenolone

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tluroh KefcoJ.ys "l-JiiUig ^ .. ■ i> l _I ot) i ;; ier _f t _a -.hiyriy.i; £; do // j. · -Ketal, with aminoiv £ hylchlü3.Md in Gi ^ iuniit .eine * .-. Jlaea, - kDndetißier ^ beasi-ViOlILs- die.: i} uL!; u / w. yeo? biiiünag ,, tkiirch.rTJ ^ stzving niit ainer ,, organic or, arg ^ rlachen acid into the <SaXz overflows ₉ : ^ ₁ * _{/ r} ;

The example explains the invention _o

Bapiel. .. _; · _{; Λ} - - _; ,; .-...

Method A) '' "'"' ■■■ '■ - - -: -;:. ■ ·; ■ .:

1 part of pragxienolone in 60 vol% eilane / iensol is mixed with 2 parts by volume of ethylene glycol and 0.2 parts of p-toluenesulfonic acid. 20 parts by volume of benzene are molten, and the mixture is boiled for 10 hours under reflux in a water separator. Then another 0.02 part of p-toluene sulfonic acid is added and the mixture is again for 5 hours boiled under reflux and then allowed to cool. The glycol solution is decanted, the Benaollösuns concentrated to 12 parts by volume and 0.5 parts by volume of pyridine added . to 10 ° C the crystals are centrifuged off, washed with water GeV / waste and dried "P _0164-165 ° C; yield 75 7 ° of theory (in the first crystallization).

Method B> : - - ■■ - -.;. r: -., .- ■ .. ■ .. ".:>;■." ■■ - ■ -v.4. ■ - .. ·. , ^ jj ^ i 1 part of preghenolone is mixed with 3 VcI "^ parts, Methyläthyldiöxolan,. f (MED), 2 · Vol. parts of ethylene glycol / and: 0, · oil parts sulfonic acid was added and the mixture was easily pressure (inner temperature 75 to 80 ⁰ C) for about 5 hours "deetilliert.

2.5 / mol. Of distillate is collected and another 1 vol.

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Part of MED to, distilled untoj. ' the same conditions about 2 hours and receives 1 VoL-'feil distillate. Dae distillate overnight in a refrigerator to crystallize gelassen.Die crystals are centrifuged off and aunächst with cold methanol containing 0.5 i> pyridine contains and then washed with water and dried destillierrteni. Fo 163 to 164 ° C; Yield £ 80 of theory.

Condensation with ß ~ .Oiät.frylominoethylchlorid

1 part of the above product _s 1 part of butyl lithium in hexane and 12 Volo' parts of toluene for 4 hours under reflux boiled Thereupon, 1.6 parts of ß-Diathylaminoäthylchlorid in toluene (about 25 ^ 5 weight solution, based on the Ohlorhydrat) was added «The addition takes place in 3 portions at an interval of 24 hours. The mixture is boiled for 30 hours under reflux and then evaporated under reduced pressure to dryness The residue is Eweimal with 20 VoI "portions of petroleum ether (bp. 30 to 50 C) and anschlieasend extracted with 2 parts by volume _o petroleum ether. The extracts are combined and the solvent is distilled off under reduced pressure. By oily residue is aufgenoramen Vfcsser in 20 Yole parts and three times subjected to steam distillation (rotary piston - temperature of the water bath "50 ⁰ C) ₀ From the residue, water is distilled off, the residue taken up in 3 VoI, parts by acetone and crystallize in the refrigerator gelaeseno The crystals are centrifuged off and again in

2-YOl. Ieilen acetone umkris tallieiert ₀ P. 93 bie 95 ° C (Kofler); Auto yield $ 38 of theory.

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"™ 4 ** ·

Entketalisierim & and manufacture of the Ghlorhydrats 1 part of the above product is added with 4 VoI "portions of a solution of equal parts of water and acetic acid and 6 hours at room temperature stirred The Reaktionsgesaisch is made with 2 η Katronlauge under cooling alkaline and then twice with 10 VoI _c -Share ether extracted. The ether extract is dried over sodium sulfate and then distilled. The residue is taken up in 10 parts by volume of dry ether and, while stirring and cooling, precipitated with the calculated amount of hydrochloric acid in ether. The hydrochloric acid is centrifuged off and recrystallized from ethyl acetate.

Yield $ 25> of theory; P, 182-184 ⁰ C (Kofler). The new compound obtained is distinguished from the other steroids by a number of pharmacological properties that make them AU8 _r for human therapy especially valuable. The most characteristic pharmacological properties of the compound according to the invention and their possible uses in therapy are explained below.

Pharmacological properties
1) toxicity

a) acute toxicity

Test method: The LD ^ Q value is determined by the graphic method of Miller and Tainter on the mouse in eubcutaneous and oral administration certain

Subcutaneous oral

₀ 180 mg / kg 240 mg / kg

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When administered orally to rats and dogs in one dose of 50 and 100 mg / kg over three months there is no histological analysis or hematological abnormality or weight gain established"

The local anesthetic effect is investigated according to the classical method of Gornea anesthesia according to Regnier, with the Cornea of a rabbit exposed to ainea mjchaixischsn stimulus v / ird, which normally causes an esflex in the eyelid This reflex is temporarily canceled by local anesthesia, The duration of the failure is the local anesthetic effect of the examined substance indicates *

Succeeded

Total anesthesia is assumed to be present if the reflex does not occur in the 100th consecutive period of time. It has been found that the local anesthetic effect of procaine is only transient in a concentration of $ 2 »lidocaine in a concentration of 0.5 ^" raf ^ "- a reflex loss of 10 meows- Dautr; at a concentration of 1 # the Daaer is 1 hour. In the case of a concentration of 0.1 $, the inventiveness of the Pre ^ nanverbiiidiiig produces a total aesthesia of more than 30 minutes, and with a consentration of 0.5 $ S of more than 2 1/2 hours.

The results of the Tergleiehsversuche are in the next table specified: -

771 tlM

Procaine « 2 ^l a»

Xddocairij, $ 0.1
LidoCain, 0.2 t>
liidoeain, 1 ^r P

0.5

insignificant.

\ vir? iiin _: g insignificant-

very kurae V / iji'Liuigsda ¹ - ^1. «! ' -

■ local anesthesia, duration Ό6 Hinutan

yotalanädthe3: is _? rough 32 "oia ΦΦ Ifotalanästhealej, j3au-oi -150 Ma 162," _Minurt.ön

S "*; here mid in xolg as Hyd.i-ocJilorJ.d

The lokals2iäst.Usti3oh3 WirMing der oi \ fInf.H.ing3geffläaaeii; Polluting. v / ird also rzihaon.d dar jinäatiiesie der Haiit'in: ajbjieoi-.irei ':' - glaioiisveTEuch ■ under Terv / ending van - Lidocain uiitersueliii .: The / two Yar bindings en werdöii in iorp. von wasarisen! «a serlö & liGheii.GrsiasB auf die Schimicaliiaufc .eines d> eaap ^; lsfi; e2t ^ n frog aufrag63ii. Let dij. Preparations,; eM ©: gewafSS: ®- act, then remove them and reiat.dia Hauli Jüii ^ 5 ^ igen salic acid solution. In Vorließ sii occurs within a iuindeateaa Minttfes no J ^ tion reflex on _o A Lidocaiaiipräparat ift

from 1 $ WiM 20 aiäSn «; to £ deu Attii

ndö ^ art ^ ®

as! Miaate? *; Eiä preparation M, CEeiöieißiairaM ^ mmt ^ eim & ^ ammn $ ^ & ä & i von OyI i> des erfinefcanssfeaä & seöv Wii ^ sxtmSl ^ i ^^ dar · 'Haul! ^ tmlasseiii ,: - Bast- .. 6 '· ■■; ■ \ fOl ^ ίyίl anäsiifeesjie- from: meiitv ais 1 IMiiltd

The i

sucne / an *

90 9 84 771 12 0:

material

Lidooain S.

KoxiZQu entered ί on »

j. 0.1

Duration of application _s Hin,

2.0

Number of l'iere with Anesthetists

nings

4 out of 6 6 out of 10

Pas pregnane causes ecnit a Berührungsunempfiiidlichkeit _f the aehnmal Jiüher ALSs is caused by lidocaine O

3) Spasmolytic V / irkuii ^ ■

The spasmolytic effect of the pregnane compound according to the invention is examined in conjunction with the known musoulotropic spaamolytikiita P & paverine. The main effects were on
The 'coronary arteries nor the Engendorff's method' observed. The compounds to be examined are injected into the perfusion liquid of an isolated rabbit heart.

The cardiac contractions are grounded by means of a scribe, an
a fixed Auegleichfader iet _B registered The Koronardurchfluss is made on the drawing by means of an apparatus Gondon-visible _{whereby the frequency of evacuation of a Be ~
chers with constant volume can be determined ₀ the higher
this frequency eats _P, the greater the flow (which is directly proportional to the coronary vasodilatation). «The sensitivity of the preparation is previously determined with papaverine as a reference substance
examined.

At a dose of 50 μg of the pregnane derivative according to the invention a coronary vascular suppuration is caused, that of a dose of 200 μg papaverine, but no blood pressure

9 0 & 8 & 77Ί »BAD ORIGINAL

Subsidence occurs,

At a dose of 200 jig dee novel pregnane, increases the koronargefäBßerwelternde effect, but a Bl'utdrucksenkung takes place only at higher doses, while this jug with papaverine at the doses of 200 to occur _β

4) Central effect

a) Antireserpine effect

In this experiment, ver & en male mice weighing 23-27 g (GD »Charles River) in groups of _t Fe '■ bored 6 animals used is diluted with a pointing ascorbic ο The active ingredient, a rapid oxidation of the" ^c product to prevent »The Eesefpin is injected eubcutaneously in eggs · ^; dose of 5 mg / kg.

The compounds to be investigated are injected subcutaneously 30 minutes before the reserpine. The animals are kept at constant temperature (23 ° G + 0 _f 5) and their body temperature is measured with a thermoelectric probe which is inserted into the flexura sigmoides with an accuracy of 3 cm. irdo The degree of ptosis is measured according to the Rubin et al. (JPΕ, ϊ, 1957? pp. 120-125) scale. The measurements are taken at the time of the reserpine injection, 30 minutes before and 4 hours after. "" ■. ■ ■ ■■■ - ■■ -

The results are given in the table below,

9 Q 9.8 kX / 1120 bad original

Dose ι
mg / kg Damping, # Ptoaia Imlpramin 10 Hypothermia 25th ι
i ^s 10
30th
100 42 8th
25th
25th 12th
17th
θ

These results show that the pregnan according to the invention « derivative possesses an antireserceptive effect on an atentral analeptic Activity can be lessened, without quantitatively the To match the effect of Iraipramin.

b) Ant! hypnotic effect of the pregnane derivative according to the invention

Male mice weighing 25 to 30 g 37.5 g / kg sodium pentobarbital are injected subcutaneously Groups of 10 animals each are given amphetamine tartrate or the pregnane derivative according to the invention orally or subcutaneously administered. Only sodium pentobarbital is administered to a control group of 10 animals. The average Sleep duration of the animals is measured and based on for each group Graph paper is applied, which increases the EDcQ value can be graphed for each antidote. The results are given in the table below.

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!
ι subcutaneous 40 mg orally 10 mg 20 mg 30 mg 40 mg \ Dose / kg
substance 30 mg 17th - - 31 13th Amphetamine tartar α
ί
t 26th 18th 36 19th 15th 11th k 28

Amphetamine tartrate ED S ED

sufccutan
35
36.5

orally

35.09

17.4

ED = mean v / irksarae dose (mg / kg). In summary, the following can be stated:

The pregnane derivative according to the invention has a pharmacological local anesthetic effect on the cornea which is superior to that of the comparative substances (procaine and lidocaine).

Its spasmolytic effect on the coronary arteries (measured by the Langendorff ⁸ see method) is at least equal to that of papaverine, the blood pressure-lowering effect of the pregnane derivative according to the invention being weaker.

With regard to the central effects, the invention calls for In high doses, the pregnancy derivative produced convulsions, similar to the central stimulants. Like amphetamine, administered orally or subcutaneously, it acts as an antidote to sleeping pills such as barbiturates (sodium pentobarbital) in mice and counteracts the blood pressure-lowering effect of reserpine

It can be seen from this that the Fregnan derivative according to the invention, similar to certain anti-hypertensive thymoanaleptics, zen-

909847/1120 BADORfGiNAL

~ ii -

tralotropic activity gate, sits. This is confirmed by clinical results, m-.ö swar through its antagonistic effect on jiaruil; uraten. _f as a remedy for intellectual asthejiie. in adults, in geriatrics or in children with A.npafcöungfiSGhY.

The clinical results are summarized below.

The experiments were carried out on a group of 32 patients (20 women, 12 men) in the old; carried out from 62 to 83 years. The patients showed the usual symptoms of simple or severe senile symptoms. Astlienie, psyehodepresßive fcuatände, erechwert part by Sjaaptonie or .Folgeerscheinungen the brain arteriosclerosis _P Patients, vnirde or suchlike According to the invention, pregnane derivative orally administered in a dose of 100 to 250 mg per day for 3 to 9 weeks in 20 voa. All of them _{experienced a clear improvement o} For example, the patients showed increased liveliness, "greater interest in the environment, greater initiative and / or willingness to participate in the social life of their Uta world (reading, television, board games)"> In many cases it improved Fatigue during the day or disappeared completely, memory increased and the tendency to depression decreased.

B) Difficulties in school in children and adolescents 12 patients (7 boys and 5 girls) between the ages of 11 and 14 x / 2 years who. Difficulties- i & the school had,

909847/112 Q

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.- 12 -

For example, poor concentration or psychomotor instability, were given 80 to 200 mg des per day for 6 to 12 weeks According to the invention the pregnancy derivative administered orally.

During and after the treatment, the families and the teachers noticed an improvement, which was mainly expressed by the fact that the children were more happy to work in school and showed greater willingness to work together and take part in team games « '''■ -

0) Itching of the skin and mucous membranes

a) Tolerance tests " - ■■■; -100 patients with" hypersensitivity to the most varied of allergens who suffered from the most varied of eczema were examined for their sensitivity to the pregnane derivative according to the invention. The test subjects were each given a compress on the skin for 48 hours set, wherein the first strength with a £ lj solution of the active ingredients _t - the second strength with a 0.1 ^ solution of the drug and the third nur.mit the solvent impregnated v / ar (distilled water) "After 48 hours With a single exception, none of the test subjects showed a reaction to the active ingredient according to the invention. The person who reacted to the test substance had also shown a reaction to distilled water

b) therapeutic attempts; . . ., _

Th 44 male and female persons in attempts Old QIE of '8 to 72 years, all of itching of the skin or mucous membranes lit t of the variously en causes had once been to 55weima3 ... ENTV daily / eder with a preparation in Gölform with a

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'ORIGINAL

Wirksfcoffkonzentrafcion treated by $ 3 or in Cremeforra or in the form of an emulsion in a continuous v / äseriger phase with a workest ο i'fkonz ent rat ion of 5 ° i.

The itching disappears within 10 to 30 minutes .Application of the preparation, the effect lasts during the whole Treatment time on (2 to 20 days).

The inventive Q pregnane derivative can be in the following forms administered:

• 25 mg tablets - sugar-coated if necessary - (conventional carrier) _;
50 mg capsules.

As an injectable solution

Aqueous, pyrogen-free solution with a concentrate of active ingredients

from $ 0.5> ι '

Ampoules from 2 to 10 ml.

In the form of a gel from a compatible carrier with a Active ingredient concentration from 1 to 5 &

Cream (emulsion in a continuous aqueous or continuous oil phase)
- same active ingredient concentration »

Suppositories

100 to 200 mg per suppository from 2 to 3g

(Children and adults) ·.

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Claims (2)

- 14 -P & _m t e η ta η a pi ü a he 3ß »Mäthylamineethoxy ~ 20 ~ -k8to ~ ₍ A ' ^{J :!} = -pregnan and its salts t acids. 2. Process sur preparation of the compound according to claim l _p characterized; that one is the
20 ~ keto group of pregnenolone blocked by ketalysis? thereupon the ketal is converted into the salt by reaction with an inorganic or organic acid in the presence of a bass condensing egg and the resulting compound with fl-diethylaminoethyl chloride in the presence of a condenser. BAB ORIGINAL
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