DE2033668A1 - 2 Mercaptoindoldenvate, process for their production and their use as active pharmaceutical ingredients - Google Patents

Description

Dipping. A. Grünecker Dr.-Ing. H. Kinke / dey Dr.-fnj. W. Stackmair ■ 2033668

.1 Munich 22, Maximiliansir 43

3559-25

AQEHQE IfAiTOO If ^ TiP 'SB YAT ( OW n ^ T TfMf ^ H IA 5, me Bellini - HCTBiPy (Haute-de-Seine) LAB0RÄ2OIBBS ΙΕΟΗφΙΙ, $ 2 * 26, rue da Ferbe * - VMIB 20 * ββ

"2-MercaptoindolderiTate, peat obren au their Heretelluu ^ uad Their use as Arjsneinittalwlricetoffe "

The invention relates to new baeieehe 2-Heromptoindolderi- Did the sleeve

in which B ₁ a, optionally a hydroxyl group or - optionally substituted for its part, in particular with one or more halogen atoms - H & enylreat-bearing allyl radical 1 to 6 Q atoms is 1 and B ₂ and B * are identical to one another, or are different and One hydrogen tone each, one "if necessary with a" Ihenylroat substituted altylreet "it 1 fyis 6 carbon atoms or an aryl group, especially an unsubstituted

ierte or substituted Phenylreat, means »or itieaa- “En old the Stioketoffatoa to which they are bound, one 'five-, seven- or seven-ghedrigen »possibly form a« heteroatone-containing Hing, as well as their acid addition

00988A / 2112

• as · bit pharaakologiaob unanlcllolien inorganic or organic acids

The invention relates in particular to 2 ~ Marcaptolndolderlv ^l at · dtr generalgMMliien forael I, In des H ₁ »la Methyl- or Benaylreet 1st and B ₂ and H ₅ each represent a tfoaseratofftttoa, a Ko-UiJl- or Ithylreat * od @ r sueeAKftn Bit d «i Stiüketoffaton,« n el · gtlden einA ₉ an »against« b «umrafalls ait eiiMo alkyl,

·· or Axjlzmt milmtttaivetssi fffiif «· or seehagliedrlgo ling» de »jpgebenenflallg form a« wide · © Heteroatom, s, B. a 3 * uorrtoff odex 3 * iok «toffato ·» eninttlt.

The JBrfladung tteteifft “witerhtn ein fesfioliren” ur Heratellmig

duraa gelcemiMiobiiet iet »dami ■ ·» a «?» yMÄdun «de? fonml

(II)

reduslert, in the M ₁ dl · ^ Itiofl · meaning as in the Worvml I nut »I wei Va * ser» toffal »m? od «r a Saneretoffatom mnd B ^ means a tril group" or a "-substituted" Carbaaylertipde "forael

H.

iet, in the I _{2 and} I ₉ the same meaning never in de »forael I. to own

Sun reduce the TerblndiiBfen, de »forael Π ** xmmA * t nan ale neduktloaeoittea Hetallbydrid ·, imibeeanaer«

BATH ORIGINAL

drid.

Compounds of general formula II, in which the group -OX-H ^ denotes the heat -CH ₂ -CSR, can also reduce their catalytic hydrogenation to the corresponding 2-fiereaptoiiidolderiYatan of general formula I.

The reduction is carried out in a solvent which does not react with all the metal hydride used and which does not react with the solvent, for _example diethyl ether, tetrahydrofuran or dioxane, which works at a temperature between −10 ° C. and the boiling point.

The compounds of the general formula II are new terbines. fertilize their production on the well-known Auegangeetoffen in the below, the production of 2 * -heroaptoiadolderiYaten of the Porael 1 explanatory AueftOtrungsbelBpiele is described «

example 1 Manufacture τοη 3 «(2 '»

a) Here division of (2-methylthiolndol-3-yl) -acetojiitrile.

The compound is similar to indolin-thle-2-one in several Steps made

As a product of the first stage selects one τοη by Uoseteen! Jethyljodid with indoline-thio-2-one in the presence yon Triäthylaain 2-methylthioindole in a yield 85 ron i "· 2-Methylthloindol boils under a pressure τοη 0.5 Torr at 122 to 124 ⁰ C and beait is a melting point τοη 50 ⁰ C

009884/2112 ORIGINAL BATHROOM

-4- 2033888

In the second stage, 2-Methylthioindöl is converted by liannich-lteaktiön au S-Dimethylaminoäthyl ^ -raethylthioindole, woeu o to a mixture kept at 5 ° C., of 2 μg of a 40% aqueous dimethylamine solution and 3 ml of acetic acid 2.0 g of a 3Qproaentigeu aqueous foroaldehyde solution acetate 3.26 g of 2-liter ethylthioindole are then added to this mixture The result is 1 hour at ambient temperature, then if the slrupous solution thus obtained is diluted old ^ feeaer and washes them while stirring with ether. By verseteen the watery

Phase with HaOH in excess, one drops the Mannich-

she Base out and extracted with ether * after evaporation of the 3.8 g (yield 86 # of theory) of the base melting ^{at 115 ° C. are obtained of ether.} The base is then purified by recrystallization in Benaol, wodurou nan preserving the pure base with an Schmelepunkt of 118 ⁰ C.

Then one sets from the 3-Dimethylaminoäthyl-2HQethylthio ~ indole (2-4iethylthioindol-> 3 ~ yl) acetonitrile in the following way

A solution of 4.4 g (0.02 mol) of 3-Difflethylaminoftthyl-2 «iaeth7lthloindol in 50 ml of methanol is treated with a solution of 2.6 g (0.04 mol) of potassium cyanide in 5 ml of water, whereupon the solution ^{Cools to 0} ° C. and 7.1 g (0.05 Hol) methyl iodide are slowly added. This mixture is stirred for 15 hours at ambient temperature, followed by evaporating the liusungsmlttel 4Q at ⁰ C and receives the pike stand with water and Xther. The ethereal phase is washed successively with 5 percent strength aqueous hydrochloric acid solution, aqueous sodium bicarbonate solution and salt water, whereupon it is dried and reduced under reduced pressure

009884/2112, ,,, "

BATH ORIGINAL

Pressure evaporates. In this case, 3.5 g (yield 87 S * dos theory) of the desired nitrile as a crystalline Riioketand, the hot 94 ⁰ C sohmilat · stream of recrystallization in benzene is obtained pure, at 104 ° 0 acnmelsende Bitrll "

b) Preparation of 3- (2 ^l -aminoethyl) -2-diethylthioindole

At room temperature, a solution of 1.55 g (0.040 mol) of idthiumaluminium hydride in 90 μl of anhydrous ethyl ether is converted into a solution of 1.5 g (0.0075 mol) of C2-methylthioylol ml ither set "before the OwI is not heated under constant stirring for 5 hours under BUdkflusö when the demisoh nieranf ^{has cooled to 0 0} O, the Übarachüesigö hydride is then reetet durob hydrolje", t after and after water " admits. Hieraaf vird the ätherieoh * separated, extracted from the nan the product ait 5proa * ntiger wae & engined SalBßäurelöBimg "Duron offsetting the wäearigen eal" - acidic solution ait Haoh in Überaohuaa falls "to an oil-m» ₉ ü * is m with Ither extracted. Hach the Terdaarpfen of ithexe ernSlt one 1.45 g (yield 94 i "th Bieorie) of the desired amines in Tora a non kciatallieierbexen œLa.

o) Production of 3 ~ (2 ^l -AsiEioäthyl) -2'-aathylthioindole.

The base obtained naoa b) is transferred to the Ficrat, ind ««

If they are treated in methanol with an awful amount of plurine acid, then they crystallize! the Picrats in. Ithaaol he "WIth oan yellow crystals at 100 ⁰ C under Zereetsung • oheelasen · ■ Me Zusaaaenee Teung these crystals entepri <dit formula one Houopiorats with Sumoenformel ^

009884/2112

- * "- 2033868

Example 2

Production of

hydroohlorld. . ·

a) Preparation of H, H-Mmethyl- (2H »ettiylthloijidol-3-y3) -el7 <Mqrlaaid.

Mn * Xtfaung you 12 _s 2 g (ö _f 075 MgI) 2-Äatfc ^ ltbloiadol, deeeen production in example la) fc «so & rl @ bea ia * ₉ in 400 aal, waeeer« · »free ethyl ether wiixl« of -2G ⁰ C a% © 1ctiblt and la mustard β of 30 minutes under Hffiirtwa «Jt 13» 5 ssl (0 »l§5 MnI) oxalyleiiloride

ο 30 al Ither veraatst, whereby oen aid SftKp »3? atia»! mi »35 0 holds · Kan receives dab ·! -ein © - WUmig, die bim »because atitsraant» aii ither väeoht and i ». 200 ml m »m9 & £ mimm _§ am £ -SO ⁰ CJ a% etfitii-toii filyt» Sieae Suepaaeinii w ^ etfst all 40 el one? 35pTO «« atigen H3nng iroa.
{«Atejoeech ^ iii 0.25 HoI) ₉ wefeei lie feipeistiB? will. Sioeos Öflffiiüöli vlxA Hei ibjgoinniffeteBpeKmtux '30 Häeatea stirred »before the ee lilt ISissei ¹ veraeis *» as edlae · fcietallisa «tiün sa eralelasu fii @ mitf teamt san die ä FILE esteltea® Garbage? It washes off utid iaeeeg she washes? «Ad itn <§3?« Read leu ren in einea 6eai »®H ame Isiäneäu ^ ftttjlestdr (80 and Methajiol (20 mim © & te: / l ©} esäilt nm 15» 5 g, '68 jt) dee' pure Olyosqrlaiids »Ias trni 12B ° ß

1 ») Htor» division - ^ m 3 ~ (2 '~ Ma «1 & yXfÄü ^^

ι ■ · ■ -

lUae Meune rcm 8 »75 φ (P _$ 23 HoX) Idtiii-useHBsiisi'iMiij ^^ d in

300 «1 weeeertr ^ ie» fötembydrojfüra »turns 50 at the same time

under ettodigee Stfterea "with a Suapeneicm ion Q ₉ S β (Q, Q3i Hol)

in 80! ti

ORIGINAL

Tetrahydrofuran is added and the Gemieoh is heated under reflux for 24 hours. The genome is then cooled to ^{0 0} O and excess Litliliuaaluainiumhydriö. Destroyed, including first tetrahydrofuran with a water content of 10% and then an aqueous 40% sodium hydroxide solution susetxt. Then the hydroxide precipitate is filtered off and the filtrate is evaporated under reduced bridge. The Abdaapfrüokstand is in 5 percent aqueous hydrochloric acid and in Ohlorofoat to enjoy

The desired area is precipitated by mixing the aqueous solution with SaOH in excess and extracted with AaUorofora * after Bindaapfan der Ohloroforlttsung receives about 6.3 g (yield: 79 ^l / ° of theory) of the Aaine, which ends at 115 ° C, according to Recrystallization in a Ctonisoh au «Bemsol and cyclohexane (YolumenTerhÜltnis 1 t X) gives aan 4.5% (yield 57 ^) of the pure amine, which should be at 118 ° C.

q) Production of 3- (2 ^l -SinethyXaminoäthyl) -2-4iethjlfhloindol-> hydrochloride.

Of the compound prepared according to b) Base receives aan the hydrochloride in a Auebeute of 97 S * invited to a Löeung the base in an acetone-A * ther-öetaisoh sit added a äquiaolaren dissolved in Ither llenge HCl · Kach the ITnkristalliBieren In Ißopropanol obtained the pure oxide chloride at 204 ° C in a yield of 61 °.

Examples 5-5

The compounds listed in Table I below turn prepared analogously to the procedure of example 2

00988 A / 21 12 BAD ORIGINAL

Iabelle I

Example ■ pitl

Reward the Thatch

H J

Manufactured according to example 2a)

Base tfergeatellt wet Example 2b) Hydrochloric produced according to Example 2o)

-N,

M.p.

• I

to the ümlrristal lisierea

Yield 4 state

Smp $

Solvent for recrystallization

Yield,

-H:

, C ₂ H ₅ C ₂ H ₅

105

Ethanol + Methanol

Βαββ

88

Cyolohexane

HCl-Sal "

182

IsopTOpanol

51

- ■ α

205-206

liquid acid

rethyl

ester

base

130

Ethyl acetate

HCl

105-110

Acetone + isopropanol

94-

-G

.199.5

Propane pl

Bob·

Oil

salt

205

Decomposition)

Isopropanol

10

CD CaJ

Example 6

Preparation of 3 ~ (2 ¹ - ^ orpfaoliJioäthyl) »2> met] a.Ylthioindolpiorat a) Preparation of the morpholine (2-Methyltiiioindol-3-yl) -esslgsaura.

The (2-methylthiolndol-3-yl) ^ seige acid is first prepared by using a mixture of 19 g (0.094 mol) of (2-methylthioindol-3-yl) -aoetonitrile and 300 al of a 2n aqueous soda solution (0.06 mol) heated for 5 hours under the flow of water. Babel a homogeneous solution is obtained, which cools down and filtered The acid is separated off in the form of colorless crystals, washed with water and dried under a pressure change in temperature. Here, 14.7 g (exploiting 62% of theory) of pure nan receives Säuire that achstilirt at 144 ⁰ C ·

The ilopholide of acetic acid is then prepared according to the acylation method with mixed anhydrides. To this end, 5.5 s (0.025 hol) (2-methyl-uiolndol * 3 * - yl! "Acetic acid in 50 ml of chloroform old 3» 5 ml are added Triethylamine (0.025 mol), which gives the! Ssriäthylaanoniumaala.Beer, the Gemisoh is cooled to ⁰ ° C. and, while stirring, 2 ml (0.025 mol) of ethyl chloroformate are gradually added and the reaction mixture is stirred for a further 30 ^{minutes at 0 °} Then a solution of 2.6 g (0.03 Hol) of horpholine in 20% chloroform is slowly added to the mixture, the temperature being kept at 0 ° and it is then stirred for another 2 hours » where it is allowed to warm up ^{to 20 ° C.}

009884/2112

Then glesst a nan the mixture into 200 ml of water, decanted, the Ghloroforaeohioht and the aqueous phase extracted once with chloroform · 01a Chlorof ormextraicte are then washed with ffatrluablearbonatlusung, * evaporated over Ha ₂ SO dried under reduced bridge. By Uakrlstallisleren of the residue thus obtained in a mixture of petroleum ether and Cyolohexen 4.4 g (62 exploits £ represents theory) of the desired ₉ ANIDs the aohmilst at 108 to 110 ⁰ C.

b) Production τοη ^ (a'-Morpholinoäthyl ^ -methylthiolndol.

Fresh solution of 1.6 g (0.04 Hol) Uttouaaluainiumhjdrid In IpO al tetrahydrofuran nti «^ gM <rt> * with a solution τοη 2.9 g (0.01 Hol) of the horpholida of C2-nethyrthioiiwlol-3- yl) ~ acetic acid irersetst in 30 ml of tetrahydrofuran, and nan the mixture Rffhr "yn 12 hours BEickflues cooking · Haohdea then cooled to the Geniach to ⁰ ° C." hydrolyzed to one suglbt the. excess Bydria, Indea gradually ttaaoh Üeusaer . The metal hydroxides which precipitate are separated off and old tetrahydrofuran is washed out. The base is dried, and then the solvent is evaporated. One g Babel receives 1.9 (69 exploits f> of theory) of the desired Aains In forn a non .kristallisierenden oils ·

o) Production τοη 7- (2 ^t - ^ orsbollnoäthyl) -2 '«« ethylthlolndol ·.

the amine obtained is su ciently rewarding, the honopicrat is made here «By being on the verge of the theoretically required slope Piorine acid la methanol Toreetst. Make the roundabout in Plorate possesses a Gemitch of acetone and methanol

0098JA / 2112

Son point of 214 ⁰ C.

Example 7

Manufacture τοπ 3 ~ Z5 ^t - (lI '- * Bejigyl »» - pii> eraJBiao) ~ lith3rX7 »2- <ietbyI" thioindole

a) Preparation of the H-Beneylplperaslde der (S-Kethylthioindol-J-yl) -ßly oaqfteäure.

The chloride of (2-methylthioindol-3-yl) -blyoocylic acid is prepared in the mixture given in Example 2a) with 20 g (0.12 hol) 2-kethyloindole and 32 g (0.25 hol) oxalylochloride. You get 25 g of the acid halorida, which an raeoh gives in 200% of anhydrous ether. Piping suspension is cekühlt at -2O ° C a ^ and then alloählich »it with stirring a 21 ton & IiBeung (0.12 koi) H-fiensylplperasin in 50 al anhydrous * Ither rersetst and ansohlieBsend a solution τοη 15 β (0.15 Hol) rriäthylanin in 50 Bl anhydrous ether Yersetst, whereby keeps the temperature at -10 ° 0. The mixture is then stirred at room temperature for 30 minutes, whereupon the filling formed is separated "the van then washes one after the other" with 2 solar potassium carbonate solution and water and dries aneol-flowing. Ba * with receives 35 g (yield ι 74 5 · of the Bieorie, absorbed on 2-methylthiolndole) of a product sent ^{at 24-0 0 "}

By recrystallizing in 50 al lleiäiozjäthanol receives "to 28 g (yield: 60 £) of the pure Anifis that sohmilrt at 258 ⁰ O.

b) Production τοη 5-Z2 ^t - (H ^f -Ben ^ yl-K-piperaBlno) - & tliyl7-2-nethylthioindole

Sine solution of 4 g (0.1 Hol) T.n-JHiimtfiim-iw ^ nriiiyii ^ i! in 100 al

dry tetrahydrofuran is gradually with a suspen,

009884/21 1.2

2Ü33668

eion of 3.93 g (0.01 Hol) of the j-benzyl perazide of (2-kethylthioindol-3-yl) -glyoxylic acid added in 30 al tetrahydrofuran

and stirring. This mixture is heated under reflux. When s only place one Excess hydride, is loaded in 0 ⁰ G slowly 20 ml, Boeigsttureäthylester and then a solution of 2 g of sodium carbonate in 10 ml of water bub et »t. The precipitated metal hydroxides are then separated off, washed with tetrahydrofuran, the ethereal filtrates dried and never evaporated under reduced pressure. «Elan receives 2.9 g (yield: GO y») of the desired amine in the form of a yellow, non-crystallizable oil .

o) Production of 3- / 2 "- (li ^l -Ben2grl-H-piperaal" o) -öthyl7-2-mothylthioindoldihydrochlorli

Bas anine is converted into the dihydrochloride by adding the theoretically required amount of Hd in ether to an ethereal solution of the amine. By recrystallizing the resulting dihydrochloride in an acetone-ethanol mixture. receives nan 2 g (yield: 45 $>) of the pure dihydrochloride, which melts at 180 C with decomposition.

Examples 8-11

The compounds listed in Table II below are followed by the procedure described in Examples 6 and 7 manufactured.

0 G 3 8 3 /. / 2112

Table II

the

Hes-ce

CX-CO-II

NS

Manufactured according to example 6a) or 7a) S-CIi,

t H

(Base prepared according to example (hydrochloride prepared according to example 7c)

-Ii

Snip.,

⁰ O

• nel zum krietalli

Yield, lOrm

M.p., ⁰ ° C

Solvent to recrystallize

Yield,

hCG- j- ii ^ Ii- ^ CHj

120

itiiancl

base

oil

2 nca

235-240 (decomposition)

ί! ethanol

rs

150

Ethyl acetate base

196

chloroform

-CO-

X55

Acetic acid" äthyloöter

100

Diethyl ether

2U3 3668

-H-

The 2-ileroaptoindole derivatives of the invention develop sedatives and vasodilatory properties represented by the following Testa have been proven.

I - effect on the central nervous system

1 · - Refers to the spontaneous urge to move in the! Taue and at the dog

This effect is demonstrated by direct observation of the awake test animal The product to be examined is removed for 60 minutes was administered orally beforehand or lateaperitoneally 20 minutes beforehand.

For example changed; an intraperitoneal injection of 3- (2 "-mi.iethylaaino) -ätliyl-2-aef: hjlthioiaaoJ (Code Ur. IB 601) or 3" (2 ^t "Mäthylaaino) -äthyl" -2- "ethylthloindole (Cod © Hr LB 602) 2α *? Inor Doeis of 5 mg / kg the spontaneous movement in the mouse is not. If the same products are injected at a dose of 25 Bg / kg, a clear sedation is seen and at doses in the order of 50 ag / kg show violent, prize-like conditions of excitation in the test animal, as a result of which in one of two cases the 5od occurs.

In the case of the

2-H3thylbhioindols (code 2Tr * BSA OG) is feoi of the oubkutaneii administration of a dosin of. 10 lag / kg ^ ⁰⁸ occurrences of a strong ptoois and a uchwaohen muscle bonus, up to a dose of 18 ing / kg. a 3 hour arihalfeende inteziu bra Paro-. Bie (full paralyzes) and at a Doeio of 30 mg / kg dna on bvübon of halving Biitiurimgen "baw,"

Ö ü 9 B j A / 2 1 1 2

- ₁₅ .- 2U33668

ability, namely to determine the paws in the sucked position.

The same connection calls home dog in a So «l · von 10 mp / kg intravenous failure of the elbow leak ·. (decubitue), a significant increase in the Kuskeltouiui during Hours, three days of severe ataxia as well as tremors and severe

Cramps

2. - Effect on behavior in a free situation

The effect is being studied old with the help of experiments, which shed light on the pavohonotorisohe initiative of the in a new one Give the mouse to the situation

a)! Escape attempt.

Approximately 25 g heavy normal hides are in groups of four in one parallelepidepic box made of plywood brought without a lid, in which one also consists of £ ^> errhola but inclined plane covered with a fine sitter protrudes One starts the number of exits during 5 meows and then calculates the pro sent eats in view of the ^ «« ^ * π of the exits in comparison animals.

For this experiment, the compounds LB 601 and LB 602 were administered intraperitoneally at a dose of 5 μg / kg, while physiological serum (0.5 μl / 25 g body weight) was administered to the comparison animals under the same conditions. The compound LD 602 does not lead to results which differ noticeably from those obtained with the "compared animals. Instead, the compound LB 601 multiplies the minimum

00988i / 2 112

since lile sum first exit by 2.5 times and reduced the number of appearances in 5 minutes na 58 #.

b) - perforated board test>

ί
About 25 β-boned mice, which come from a breed, "ground."

«Islands are set on οία plywood board with the dimensions 40 χ 40 χ 1 * 8 OM, the with, t 16 la evenly spaced bores old a» Surchaeseer of 3 ca is provided and on the four IKsaen «Ines upturned Scheaele lies _t so that the holes appear bottomless to the Mfcueen *

You then work old, very bright, create Sfixm and at etant temperature.

The treated mice become one after Putty of the board ”is set, and one bee; iaat for 5 minutes

the number of times per minute examined ¹

the other in the

Drilling. The on

This number obtained is compared with that which was found in the Yerglelchaa & ueen brought into the same tereuch situation. For example, the compounds XB 601 and IB 602 reduced the heugi m of the animals tm 60%.

3 · - Virkxing on the agility of the house. ' This effect is determined by rasa comparing the time during which treated mice set on an old constant-speed wave watch, compared to the time during which the animals to be compared

For example, the SOe is ₀ for

009 8 84/2112

.e connection BSA 86

ORIGINAL MSPECTEp ^J

subcutaneous administration in SOria elnor Loaxing of IO mg / ml in lOproaentigeffiDiraefchylforEiamid 44- + 11 mg / lcg.

3X, Jfirlainff on darbiturate sleep

Hit an intraperitoneal dose of 5 mg / kg of the The compound to be investigated is a in hypnotic hexobarbital dose (40 mg / kg) intraperitoneally administered · Then determine the number and number of sleeps in each group of reference mice and treated houses Sleep duration.

These experiments were carried out with the compounds IB 601 and XiB 602, with DiazepaB, which serves as a reference substance and in one doeie of 1 mg / kg administered intraperitoneally »carried out. the Latency was 4 minutes for all three connections. At the- ' The following sleep percentages were found in experiments: 100 for siazepam,.

65 for the connection IB 601 and

50 for the connection I »B 602,

III. Effect on ifopnetajnin hypertoxicity An intraperitoneally administered dexaiaphetaiiiindosia of 25 mg / kg leads to a hortality of 100% in a group of cows in the course of 2 to 4 hours if the mice are kept in a group, but in no case of death if the mouse are kept isolated from each other. Attempts are made to suppress this hypertoxicity of dexanphetaine in K8ases kept in groups by "pretreating the mice with the product to be investigated" as a reference subatanü, a lieuroleptic, namely ghlorbromasin, ^^ is used

00 9884/2112

oral administration at a dose of 30 ng / kg to the mice 100% protection against amphetamine hypertoxia at . home held in groups.

You compound IiB 601 results in a Schute of $ 20 :. bia sun expiration of 4 hours and the connection XB 602 a protection of 10 0.

IV. Effect on experimentally set epileptic convulsions The experimental convulsions θ bsw · convulsive convulsions are generated as follows.

One injects the house intraperitoneally 65 ng / kg pentaethylem "- tetrasol (1 percent aqueous solution).

The vermin each show a look! of symptoms that are initially characterized by restlessness "followed by jolting jerks" followed by a tonic phase, which is usually fatal after a second erisis. In practice, the dose of the substance to be submerged is considered to be effective "the seizure and the ZuckttUßSphase m £ once inhibited ·

Even with a dose of 2 mg / kg administered iatraperitoneally, the compounds IiB 601 and £ B 602 have no protective effect whatsoever.

V. pain relievers

This effect is tested according to the Iliegamndseheii? © r-wofe * A syndrome is created by m®. der Haue -äätrafe ^ it © ii®si 'Bi ^ s ^' l ^ bensooliinon In ^ I alert, and- mmv in a &> ag © whom Ö _s 5 al a 0 _t 02 proeentlgeii tfäBrig® »Waimgls 3 pr® z @ atig «

009 8 84/2112

Between the fifth and the swansiest minute after the injection de? A group of Scheer * - krleen is observed, which calls forth so much closer to the boyfriend, which is related to the Αηϋ * Τι Τ ine observed in Vere * tche "Ku" en.

At a dose of 25 ag / kg / X? for connection 601 60 £ and for connection HB 602 25%

TI. Effect on the, tvenctative gerrenayete « Me effects of the investigated products on the rest activity» the blood pressure and the atonings are geaeaeen at bit ethylearbanat (1 _t 25 β / kg / IP) aUnliohen Hatten.

The very slow intravenous injection of the compound LB 601 or LB 602 in a dose of 1 mg / kg into the penile vein leads to a temporary drop in pressure of 30 ma

The reaction to aoetylcholine and hietanin is unchanged after Yex administration of the compounds XB 601 and HB 602.

The overpressure caused by lloradrenaline, on the other hand, is lowered by the compounds ÜB 601 and LB 602 in a dose of 1 w & / fcg. suppressed. The overpressure normally caused by shower adrenaline is suppressed by the compound LB 602 and by the compound LB 601 in a dose of 2 ag / kg inverted in most lulls. Bite treated with chloral

009884721.1-2

Dog reduces the Yarbiatusg · £ Β 601 in a dose v® & Z that by means of noraarenaline. fa®Twarg@Tutm.® taiokOThShitiig na & suppresses the adrenaline 'fcervwgenifea ©

The response to the blood pressure caused by Xenthonliia in a dose of 1 mg / kg®:!? dasigliQpl @ xl © tefaHanea- Batten. the Xnjelctioa toiü Serotonin ia ® ± ά @ τ Sosis changes eidb. after the? & mte @ icimäig the IiB 601 in the applied® »JJosesi

All of the above mentioned 1os @ b mirdsti imtr & ¥ en, 5s

Scthliesslioh calls die- ¥ © rM & diiiig BSI reloiroms in a boeie of 10 persistent pronounced of the retina (Imposition A & la very strong Speicaelfluee

.YII. Eolc alajieetheaierendejfirtoag

The surface is mixed with IcalanesthetilaiEiwirMixig, with Hilf® d © β Klaeeieohen tests on rabbit ice cream vessels "attrsucht" (feet B £ g & ier)

For example, with a 4-percent solution of the compound LD 6 (XL with an a pjj value of 7, a complete mesthesio of the coronary vessel of the rabbit is obtained, which lasts about 90 minutes and is reversible.

To be precise , the 2- »mercaptoindole derivative @ of the invention act on the central nervous system, but offer neither against experimentally frozen craps nor against group hypertoxicity

009 884/21 1 2

by Dexaniphetaain Sohutz «

They also have a weak, anti-allergic, local anesthetic and also an adrenolytic effect.

The edrenolytische effect is particularly clear and stable at the L3 connections 6CX and LB 602, separating them uröthsnieierten rats in a dose of 1 mg / kg intravenously administered and if one chlorallsierten dogs la mg administered a dose of 2 / intravenously "

VIII, 'camouflaged. goxigltat ...,. · ■

The acute toxicity of the compounds of the invention was determined by intraperitoneal administration in the case of the? Haoia beatiamt »whereby the LD _{50 was} calculated according to the method of Benrene and Kftrber«

The H> cQ was sat until 24 hours had elapsed. It is for the compound IiB 601, for example, 47

As can be seen from the results listed above, "the therapeutic range of effects" ie the difference between the pharmacologically effective and the lethal ΰοεβη in the new compounds of the invention is sufficiently large να to allow therapeutic use of the mercaptoindole derivatives according to the invention · '

Q 0 9 8 8 A / 2 1 12

The mouths are known to be sedative * wed all maodilfttorioqne blood-reducing agents are used

You own eioh bot parenterelen ₉ «adarek.ti & l®B odez? oral TeratoelOAtmg bein heneonen ttmd bei Slesen nnä βκκ? Inebesondeve in Koabiaatio »« lt for theee Te7abzeiohuagi Bsolplenten · Sb can ale oeiepieleveiaa Sn vom τα » οιαηββη kit of a dosage * m 1 mg plastic or τοη Capsules are used in which the Soeiexane Aee etoff »sweokstBesi« is 3 ag.

009884/2112

Claims (15)

in which R _{1 is} an alfcylrost bearing 1 to 6 carbon atoms, optionally a K ^ arosy group, or an alfcylrost bearing 1 to 6 carbon atoms which is optionally substituted for its part, in particular with one or more halogen atoms, and R ₂ and E are identical to one another or are different and each signify a carbonate, an "optionally substituted with a phenyl group", a phenyl group with 1 to 6 O atoms or an aryl group, in particular an unsubstituted or substituted phenyl group, or else su ~ samaen old the carbon atom to which it is bound are, "in a five," six "or seven-membered ring, optionally containing a second heteroatom, as well as their acid additions * salts bit pharaakologically harmless in organic or organic acids 2. 3- (2 ^l -aminoethyl) -2-diethylthioiadol and -piorat. 5 · 3 ^ 2 «-Dim9thyleiainoäthyl) - 2-iaethylthioinäol and -hydrochloride · 4. 3- (2 »-I) iStbylaainoethyl) <- 2-methylthioindole and hydrochloride. 0 0 9884 / '2 112 5. S-Cg'-pyrrolidinylethyl ^ -methylthioindole and hydrochloride. 6. 3- (2'-Pyrrolidinylethyl) -2-benaylthioindole and -hydroohlorld. 7 * 3- (2'-Iiorpholinottthyl) -2-methylthioindole and -piarate 8. 3- / 2 ^f - (H ^l -BeMyl-li-pipera2ino) -utyl7-2-ethylthioindole and dihydrochloride. 9. 3- / S ⁽ - (IT ^> -nothyl.-I (-pipera8ino) -ethyl7-2-ethylthlolndol and -dihydrochloride 1O- 3- / 2 »- (Ii • -o-Hethoxyphenyl-H-piporaeinoJ-äthy ^ -a-ethyl- 11. Process but production of 2-HercaptoindolderlTaten the general Forael 1 according to at least one of claims 1 to • 10, characterized in that nan a compound of the formula reduEiort, in which B _{1 has} the same meaning as in Foreel I, X denotes two hydrogen atoms or one oxygen atom and R ^ a nitrile group or a Η-substituted carbamyl group of the formula - co-äC (in) is, in the Rg ^and ^ 3 ^the same meaning as in the Pornel I. 00Soo4 / 2112 own. 12. The method according to claim U, characterized in that daas nan sum heducing metal hydrides used or catalytically with Hydrogen reduced " 13. The method according to claim 12, characterized in that the reaction is carried out in a solvent at a temperature between -1O ⁰ C and the boiling point of the solvent. 14. The method according to claim 13, characterized in that ■ DlUthylather, Tetrahydrofuran or Dloxan as a solvent used" 15. Use of 2-fIercaptoindolderivaten of the formula I and / or inorganic non-thinking loan whose Säureaddltlonssalzen with pharmakologiach or organic acids according to any one of claims 1 to 10 as Arzneiaittelwirkstoff (e) _t particularly as sedatives and vasodilatorlsche antihypertensive agent, preferably in the form of one or more these 2-Kerpaptoindolivate as well as a croipient containing, orally, rectally or parenterally administered subordinate preparations. . 009884/2112