DE2559211A1 - SUBSTITUTED INDOLES - Google Patents

Description

DiPL-CHEM. DR. VOLKER VOSSIUS PATENT ADVERTISER

7559211

MON'iHENee, ¹ ^ " ^V ,:"

PO dOX 6S 07 37 <Yy yyy · "" ⁷ 'D / S

SiHB = ^ TSTRASSE4

PKON =: {0 35) 47 40 75 CABLE ADDRESS: BSNZOLPATENT MÖNCHEN TELEX 5-23453 VOPAT D.

u.z .: L 545 (Yo / lcä) Case: KK 292

l-IcKSIL LABORATORIES, IiTC.

Canrp Hill Road. Fort 'Aashington. Pa., V.St.A.

"Substituted Indoles"

Priority;

13. Iloveniber 1975, Y.St-A., No. 63I 793

The ^ r.
formula

ng relates to substituted Ϊηαο1 ~ · di-r all "-3nc-.iri-; n

Z- (CH,)

-CH-N = T _ /

(D

and.

1- T nrv-1 T 'τ-,

lower in the X and X 'ivasssrstoff- or halogen atoms, alkyl, alkoxy or alkylamino or Acylamlrioreste bsdeutan not provide jadoch Ii tuid X simultaneously Acyia ^ inorests clar ·, R ^ a Viasserstoff atom, a lower x \ lkyl- or alkoxyalkyl, an alkenyl or alkynyl radical, a cycloalkyl odor Cycloalkylallcylre-jt, an optionally GUb: 3Titu-

80982 8/0988 BAD ORIGINAL

- P -

ated phenyl or phenylalkyl group or a heterocyclic arylalkyl group, R _{2 is} a hydrogen atom, a lower alkyl group, an optionally substituted phenyl or phenylalkyl group, a biphenyl or ITaphthyl group or a heterocyclic aryl group and Z is a thio, sulfinyl or sulfonyl group ¥ ert has 1, 2 or 3, IW a hydrogen atom or a lower alkyl radical and. R _{7 represents} a hydrogen atom, a lower alkyl radical, a hydroxyalkyl or alkenyl radical, a cycloalkyl radical or an optionally substituted phenyl or phenylalkyl group, A and B individually represent lower alkyl radicals or A and B together represent a group of the formula
-GH ₂ GH (R ₅ ) CH ₂ -, -CH ₂ GH ₂ GH (R ₅ ) -, -N (R ₆ ) CTCR ₅ ) (CH ^ -,

- (CH ₀ ) .- or - (CH ₂ ) _Γ - * ₇

form, where Rp; a barrel of substance atom, a lower alkyl radical or an optionally substituted phenyl group and an hydrogen atom or a lower alkyl radical,

m has 1 or 2 and if m has 2, the rest represents a hydrogen atom, and their salts with acids.

The term "lower alkyl and alkoxy" means unbranched or branched saturated radicals with 1 to about 8 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, Butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, Propoxy, isopropoxy, pentoxy and hexoxy groups. As halogen atoms Koramen fluorine, chlorine, bromine and iodine atoms are possible. the Phenyl group can be substituted by 1 to 3 lower alkyl and / or alkoxy radicals and / or halogen atoms. examples for

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Cycloalkyl radicals are the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group. The alkenyl and alkynyl radicals can be straight or branched radicals with 2 to about 8 carbon atoms, such as the vinyl, allyl, 1-butenyl, 2-3utenyl-, 2-methylallyl-, 3-methyl-2-butenyl-, propargyl-, 2-butynyl and 3-butynyl groups.

The heterocyclic aryl radicals are 5- "to 10-membered radicals siit at least one sulfur and / or nitrogen and / or Oxygen atom as a hetero atom. Specific examples are inonocyclic ones 5- or 6-membered heteroaromatic radicals with at least one sulfur, nitrogen or oxygen atom as a heteroatom and Mcyclic heteroaromatic radicals with up to to 10 ring members, which as one of the cyclic radicals a 5- or 6-membered heteroaromatic ring with at least contain a sulfur, nitrogen or oxygen atom as a hetero atom. Specific examples of these residues are the Pyridyl, quinolyl, imidazolyl, pyrazinyl, pyrrolyl, thienyl, furanyl,! Thiazolyl, thiadiazolyl, pyrazolyl, Triazolyl, oxazolyl and pyrimidinyl groups. The heterocycle

See aromatic radicals with a nitrogen heteroatom can optionally be substituted on the carbon atoms and nitrogen atoms of the ring. Examples of heterocyclic radicals substituted by lower alkyl radicals are the 5-ethyl-2-pyridyl and 4-ethyl-2-pyrimidyl groups. A 2-pyrrolyl radical can, for example, also be alkylated on the nitrogen atom and form an IT-alkyl-2-pyrrolyl radical. The bond of the carbon atom to the heterocyclic aryl radical can be at

609828/0988 *

any of the various carbon atoms of the heterocyclic Residues take place, for example in the 2-, 3- or 4-position of the pyridyl radical.

The term "acyl radical" means lower aliphatic radicals Carboxylic acids, such as the acetyl, propionyl and butyryl radicals. Also possible as acyl radical are radicals which may differ from Derive substituted benzoic acids, such as the benzoyl and p-Hethylbenzoylrest.

Preference is given to compounds of the general formula I in which R ^ has a different meaning than a hydrogen atom. In particular compounds of general formula I are preferred, in which R ^ represents a lower alkyl or an alkenyl radical. Compounds of the general are particularly preferred

-j

Formula I in which X and X are hydrogen atoms, R2 is a hydrogen atom or a lower alkyl radical, R is a hydrogen atom and Z is a thio group, η is 1, R _{2 is} a lower alkyl radical and the grouping A — B is the trimethylene group .

The compounds of the general formula I in which the grouping A-B represents the group NHGH (Rp-) (CH ₀ ) can occur in three tautomeric forms, which have the following general formulas Ia and Ib:

609828/0988

· »--V _tmm

JL- (CH ₉ ) r CH-N

MR

J- <

R.

-u /

ί N <&

ι V J

(Ia)

(Ib)

The compounds of the general formula I and I ^f , in which R <

a VJassarstoffatora means can also voräoniraen in zv / ei various tautomeric forms, the following general formula Ic and Id and I ^l a and I'b have.

Ϊ ^Β '

/ (Ic)

(Id)

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(I'a)

. (I'b)

The compounds of general formula I, in which Z denotes a To group, are preferably prepared by reacting the corresponding fluoborate of a compound of general formula II with the corresponding 3- (aminoalkylnercapto) indole of general formula III. The reaction proceeds according to the following reaction scheme:

(II) '-

S- (CH ₂ J _n -CH-NH ₂

-? (I) -HBF ^

ynaon j

X ₁ R ^, H ^ ₅ , R ^, R ^ y A, B and η have the meaning given above. That. Pluoborate is used in a slight excess. The reaction is preferably carried out in an organic solvent

60982 8/0988

1 ι

• tel carried out, for example a lower aliphatic Alcohol, such as methanol, ethanol, isopropyl alcohol or tert.-butanol, an ether such as diethyl ether, tetrahydrofuran or dioxane, a lower halogenated hydrocarbon such as chloroform, Methylene chloride or 1,2-dichloroethane, or an aromatic one Hydrocarbons such as benzene, toluene or xylene. The reaction can be carried out in a relatively wide temperature range v / earth. The reaction already proceeds to room temperature, but elevated temperatures can also be used to accelerate the reaction applied v / earth. The resulting fluoborate of the compounds of general formula I is in the usual manner in the converted free base, for example by reacting with a stronger base, such as an alkali or alkaline earth metal hydro: cid or carbonate.

The compounds of general formula I in which Z is a thio group means can also be prepared by two other methods. In the first method, the appropriate connection is made of the general formula III with a slight excess of the corresponding compound of the general formula IV to the compound of the general formula I reacted in the form of its salt with an acid. This reaction takes place according to the following reaction scheme:

(I). · HW

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X, X, R ^, R ₀ , R-, R ^, Rc, A, B and η have the introductory meaning. ¥ means a chlorine or bromine atom. The reaction is carried out in an inert organic solvent, for example an aromatic hydrocarbon such as benzene, toluene or xylene, an ether such as dietary ether, tetrahydrofuran or dioxane, or a halogenated lower alkane such as chloroform, dichloromethane or dichloroethane. The implementation can

moderate

can be carried out in a relatively wide temperature range. Preferably the reaction is carried out at reflux temperature of the reaction mixture carried out.

The other method of making the compounds of general Formula I consists in the implementation of the sodium salt 3-indolyl mercaptans of the general formula V in aqueous alkaline · schem medium with a stoichiometric amount of the corresponding Compound of the general formula VI, This reaction takes place according to the following reaction scheme:

■ ... + Cl- (CH ₂ J _n -CH-

(V) R ₃

H ₄ (VI)

X, X, R ^, R, p, R ^, P ^, A, B and η have the above meanings. The reaction is carried out in an inert organic solvent of the aforementioned type. The reaction temperature can be in a relatively wide range. The reaction at room temperature is preferred, but

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- Q -,

elevated temperatures are used to accelerate the implementation will.

The salts of the compounds of general formula I can be based on the above-described vieise converted into the free bases will.

The compounds of the general formula I in which Z is a thio group and the group A-B is the group -N (Rg) CH (R ^) (CH ₂ ) - can also be prepared by reacting a mercaptoindole of the general formula III with an alkylthioimidazoline salt or alkylthiotetrahydropyrimidine salt of the general formula VII. This implementation takes place according to the following implementation s chema:

S- (CH ₂ ) _n -CH-NH ₂

^R 3

R ₂ * ■

(III)

(I) ··. HW

(VII)

X, X, R ₁ , R ₂ , R ^, R ^, Rg and η have the above meanings. "W is an anion derived, for example, from a mineral acid, such as a halidxone, and Ry means a lower alkyl radical. The compounds are converted in stoichiometric amounts at preferential rates. The reaction is preferably carried out in a lower aliphatic alcohol such as ethanol, isopropanol or 2 -Methylpropanol, also carried out

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Implementation can take place in a relatively "broad temperature range." be performed. The reaction is preferably carried out at the reflux temperature for the reaction mixture.

The salts of the compounds of general formula I can be based on converted into the free bases in the manner described above.

The compounds of the general formula I 'in which Z is a thio group and R- * represents a hydrogen atom, can by reaction of the corresponding indoline-2-thione of the general formula XX with the corresponding halonitrile of the general formula Formula XXl in an inert solvent of the aforementioned type The halonitrile is preferably used in excess. Implementation can be done in a proportionate way wide temperature range. The reaction at room temperature is preferred. The resulting nitrile of the general formula XXII is isolated and according to conventional methods cleaned. These nitriles unsubstituted in the 1-position can be added to the 1-position by customary methods corresponding nitriles of the general formula XXIII are substituted.

The nitriles of the general formula XXIII are thereupon with a reducing agent such as diborane or a mixture of lithium aluminum hydride and aluminum chloride. These Reaction is carried out in an inert organic solvent using a large excess of reducing agent

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- 11 -

carried out. The reduction can be proportionate wide temperature range. The work room temperature is preferred, but elevated temperatures can also be used to increase the rate of reaction to accelerate. After the reduction is complete, excess reducing agent is decomposed, in the case of diborane with a mineral acid, and when using lithium aluminum hydride / Aluminum chloride has a base. The resulting amines of the general formula XXIV are either as salts or free bases obtain.

The amines of the general formula XXIV can be reacted with a compound of the general formula II in the manner described above to give the compounds of the general formula I ^1.

The indoline-2-thiones are either known or can be according to the in J. Med. Chem. 16: 131 (1973) and Chem. and Pharm. ' Bull. (Tokyo), 17, 550 (1969). The reactions described above v / earth explained by the following reaction scheme:

609828/0988

(XX)

+ Eleven

- 12 -

W- (CH ₂ J _n -CN

(XXI)

reduction

(ID

(I) .HBF

- (CH ₉ ) -CN

S- (CH ₀ ) -CN

(XXIII)

(XXIV)

NaOHv ^ ₁ ij

The compounds of the general formula I », in which Z is a thio group and R is not restricted to a hydrogen atom,
can be prepared in the same way as described above from compounds of the general formula XXIVa. The compounds of the general formula XXIVa are either known
or can be prepared by the process described in U.S. Patent 3,655,016. The implementation is through the following
Reaction scheme explained:

609828/0988

ζ η ι 2

^R 3
(XIVa)

(I ¹ )

The compounds of the general formula I and I ¹ in which Z is a sulfinyl group can be prepared by oxidation of the corresponding compounds of the general formula I in which Z is a thio group with sodium tetaperiodate in an organic solvent of the type described above. The sodium metaperiodate is preferably used in a slight excess. The reaction temperature can be in a relatively wide range, but the oxidation is preferably carried out at room temperature. Elevated temperatures can be used to accelerate the reaction. This reaction is illustrated by the following reaction scheme;

T ^ ι I Il

R ₃

- (CH ₂ J _n -CH-N

• 4 ■

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CH-N =.

^R3 L.

1 ο

+ Na-JU ^

- (CH ₉ ) -CH-iI = £

X, Xj R ₁ , R ₂ , 3-2,
bene meaning.

^ j A, B and η have the above-indicated compounds of the general formula I and I ^f , in which Z is a sulfonyl group, can be prepared by oxidation of the corresponding compounds of the general formula I and I ¹ , in which Z is a T? hio ~ or sulfinyl group means, hydrogen peroxide or a peracid is preferably used in excess as the oxidizing agent. The reaction can be carried out in an organic solvent of the above. Type or a carboxylic acid, v / ie acetic acid or propionic acid, and preferably "at building temperature.

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The compounds of general formula I and I 'fall in all-, common in the form of the free bases. The free bases can be converted into the corresponding with an inorganic or organic acid Salts are transferred. Examples of acids that can be used are hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydriodic acid, sulfuric acid, nitric acid, Phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, Fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, Cinnamic acid, mandelic acid, methanesulfonic acid ,. Ethanesulfonic acid, Hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid, Phenoxybenzoic acid and 2-acetoxybenzoic acid. The salts can be converted back into the free bases in the usual way.

The compounds of the general formula I and I 'and their salts are medicinal substances which reduce the heart rate. this has result in the following experiment:

Bilateral vagotonia develops in an anesthetized dog carried out. Two doses of aminophylline (5 mg / kg IV) are injected every 15 minutes. The antihypertensive Effect of aminophyllin activates the pressure receptors of the carotid sinus, which in turn controls the sympathetic nervous system stimulates and reflexively increases the heart rate. 15 minutes after the second dose of aminophylline becomes the one to be examined Compound injected intravenously and its influence on heart rate over a period of 30 minutes measured.

609828/0988

Compounds with a heart rate lowering effect of at least 18 sine beats / minute for a period of at least 5 minutes are considered active. These compounds can be used to treat angina because the heart rate determines the heart's consumption of acid.

The compounds of the invention exhibit in that described above Test at doses of about 0.25 to 18.5 mg / kg body weight. Activity.

The compounds of the general formula I and I · and their salts are also inhibitors of platelet aggregation. The connections using collagen-induced aggregation at a final concentration of 100 jjMoI in thrombocyte-rich plasma by measuring turbidity according to the method of G.V.R. Born, Nature, 194: 927 (1962). The results are expressed as the average of the percentages. Expressed inhibition of aggregation. All compounds of the invention while active in the experiment described above, the preferred compounds for this indication are those of the general formula I, in which Y is a methylene group ■ and Z is a thio group.

The compounds of the general formula I xmd I ^{1 also} inhibit gastric juice secretion. This has shown the following experiment: Female rats of the Sprague-Dawley strain were given the compound to be investigated intraduodenally (i, d.) In a dose of 2.5

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injected up to 40 mg / kg body weight. Before the experiment, the rats, which are kept individually in cages, have to starve for 24 hours. However, it is ^T // ater offered to them. On the day of the experiment, the rats are fed and those animals are selected whose weight is within a range of + 20 g. The operation is carried out under weak ether anesthesia. Once the rat is anesthetized, its teeth are extracted with forceps. The median section is also cut about 1 1/2 cm long and the hagen and duodenum are exposed. If the stomach and duodenum are covered with food or food residues

The experiment is not used / which is filled, the rat is used for the / With suture material 4-0 a tobacco buttal suture is carried out on the gastric fundus. Care is taken to ensure that no blood vessels are pierced in this area. A small incision is made in the stomach in the center of the purse-string suture, and a cannula, which is a small tube with a flange at one end, is inserted into the stomach. The purse-string seam is tightly closed around the flange. Immediately thereafter, the compound to be examined is injected intraduodenally in an amount of 0.5 ml / 100 g rat. Three rats are generally used for each dose. Control rats receive only the vehicle, usually 0.5 percent aqueous methyl cellulose solution. After the compound to be tested has been administered, the abdominal wall and the skin are closed simultaneously with 3 to 4 wound staples, each 18 mm wide, and a collecting tube is inserted into the cannula. Each rat is then placed in a box which is provided with a longitudinal slot so that the cannula can hang freely and the rat is unconstrained

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can move. After a stabilization time of 30 minutes, the collecting tube is removed from the cannula and replaced with a clean one Tube replaced and gastric juice collected. The gastric juice is removed after 1 hour. At the end of the experiment, the cannula opens removed and the rat killed.

The collected hag juice is placed in a centrifuge tube and centrifuged. The volume is read and a 1 ml aliquot of the supernatant is placed in a beaker containing the Contains 100 nl of distilled water. The solution is with 0.01 η Sodium hydroxide solution titrated to pH 7. The volume, the titratable acidity and the total acidity are determined. The volume is the total amount of gastric juice without sediment. The titratable acidity (kill equivalents / liter) is that amount of 0.01 η Caustic soda, which is required to titrate the acid up to pH 7 is. The total acidity is the titratable acidity multiplied by the volume. The results are expressed as a percentage Inhibition indicated in relation to the control animals. A 50 percent inhibition is the criterion for an active connection.

Certain compounds of the general formula I and their salts have further pharmacological effects of the type described below. In particular, compounds of the general formula I in which Z represents a thio group, R 1 has a cyclic radical, such as a cycloalkyl, phenyl, substituted one Phenyl or heterocyclic group, and A — B is a lower alkyl radical, the group -CH ₂ CH (R ₅ ) CH ₂ - or -CH ₂ CH (R ₅ ) CH ₂ CH ₂ - is

6 0 9 8 2 8/0988

suggests antiarrhythmic effect. They also inhibit them Epinephrine and caffeine stimulated lipolysis. These have the following Attempts result.

Atrial arrhythmia s t

The right atrium of the heart of an anesthetized dog is exposed by thoracotomy and retraction of the pericardium. Atrial fibrillation, determined by standard EKG recording (IJ), is induced by applying 2 drops of a 10 percent acetylcholine solution to the atrium. The atrium is then painted with a spatula. The flicker time is determined. Two control periods of flicker are generated every 15 minutes. The compound to be tested is administered intravenously 10 seconds after the next induction of fibrillation. A connection is considered active if it reduces the flicker time by at least 50%. Certain compounds of general formula I are active in doses of about 1.0 to 18.5 mg / kg of body weight.

Lipolysis stimulated by epinephrine

Two epididymal fat pads from Hatten are placed in Krebs-Ringer bicarbonate puff he in the presence of 5 jig / ml epinephrine bitartrate Incubated for 1 hour. One of the fat pads is used as a control used, and the compound to be investigated is added to the other fat pole star prior to incubation in such an amount that ' the final concentration of the compound to be examined 1.0 mmol amounts to. The extent of lipolysis is determined by determining the formation of glycerol after a modification of the double enzyme

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method von Wieland, Biochemische Zeitschrift, Vol. 329 (1957), p. 313, determined. Compounds which inhibit glycerol production by more than 30 % at a concentration of 1.0 µmole or are significant at a 95% confidence limit are considered active.

Caffeine-stimulated lipolysis

The procedure is the same as for epinephrine-stimulated lipolysis, but instead of epinephrine, caffeine is used at a concentration of 1.0 µmole was used.

, The compounds of general formula III can be used directly by reacting an indole of the general formula XVIII with an aminoalkyl mercaptan of the general formula XIX with addition an aqueous solution of iodine or a peroxide such as hydrogen peroxide or sodium peroxide as an oxidizing agent getting produced. The three reactants are preferably used in stoichiometric amounts. The implementation will preferably carried out in a lower aliphatic alcohol. The reaction temperature can be proportionate wide range. Elevated temperatures can be used to increase the rate of reaction. Preferred way however, the reaction is carried out at room temperature. The reaction is in the absence of air, for example carried out under nitrogen as protective gas.

After the reaction has ended, the alcohol is distilled off under reduced pressure and the product

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cleaned in the usual way. The implementation is through the following Reaction scheme explained:

I ₂
> (IH)

(XVIII)

The compounds of general formula III can also according to three other methods are established. According to the first method, the compounds of the general formula III, in the η has the value 1, from the corresponding 3-indolylthiol of the general formula VIII and the corresponding aziridine of the general formula IX. The reaction is carried out in a lower aliphatic alcohol. Preferably the reactants are used in stoichiometric amounts. While mixing the two reaction partners becomes cooled, then the reaction is brought to completion at room temperature. However, the reaction temperature is not critical, and the reaction can also be carried out at elevated temperatures.

In the second method, the compounds of general formula III, in which η has the value 1 or 2, are grounded from the corresponding sodium salt of 3-indolylraercaptan of general formula V in four alkaline solution with the corresponding chloroalkylamine hydrochloride of the general Formula X made. Before-

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The hydrochloride is assigned by adding a molar Excess of the base or, preferably, the salt of 3-indolyl mercaptan neutralized. However, stoichiometric amounts of the reactants can also be used. The implementation is preferably carried out at room temperature, they however, it can also be carried out at elevated temperatures.

In the third method, the connections are general Formula III, in which η has the value 1 or 2 and FU is a hydrogen atom means by reducing the corresponding indole-3— ylthioalkylnitrils of the general formula XI produced. The reduction is carried out in the manner described above with diborane or a mixture of lithium aluminum hydride and aluminum chloride. The reaction mixture is changed to that described above Way worked up. These three reactions proceed according to the following reaction scheme:

^R 3
(IX)

■ + Cl- (CH ₂ J _n -GH-NH * HCl

(X)

->. (III) (n-1)

reduction

-> (in)

X, X, R ^, E ₂ and R-. have the meaning given above, *

_ 809828 / 0-988

The compounds of the general formula III can be isolated in the form of the free bases. The free bases can with Acids of the type described above are converted into the corresponding salts.

The compounds of the general formula III are valuable intermediates for the preparation of the compounds of the general formula I. In addition, these compounds themselves have pharmacological properties. They inhibit the aggregation of platelets. This was demonstrated by the experiment described above. Furthermore, certain compounds of the general formula III are effective agents for reducing the heart rate, especially if the radical R ^ is a lower alkoxy-lower-alkyl, alkenyl or phenylalkyl radical, the methyl or isopropyl group. Certain compounds of the general formula III shorten the atrial fibrillation and can therefore be used as antiarrhythmic agents, especially when R 1 is a methyl group and R _{2 is} a phenyl group. or R ₁ denotes a methyl or isopropyl group and all other substituents represent hydrogen atoms and η has the value 1 /

Certain compounds of the general formula III are new, in particular those in which at least one of the radicals Rvj, - R ₂ , Rz, X and X has a meaning other than a hydrogen atom and η has the value 2 or 3. These compounds and their salts are also claimed.

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The compounds of the general formula II can be prepared by reacting a compound of the general formula XII, in which A, B and Rl have the above meanings, with triethyloxonium fluoroborate (XIII) according to the method described in Chemical Reports, Vol. 89 (1956), p. 2063 Process are produced. The reaction is carried out in an organic solvent and preferably at room temperature. This implementation proceeds according to the following scheme:

(XIII)

The compounds of the general formula IV can be prepared by reacting a compound of the general formula XII in which A, B and R ^ have the above meaning., with phosphorus oxychloride in benzene according to the chemical reports, Vol. 94 (1961), P. 2278 prepared v / earth method. This implementation proceeds according to the following reaction scheme:

+ POCIo

(XII)

OPOCl Cl

(IV)

The compounds of the general formula V can be prepared by reacting the compounds of the general formula VIII, in which X,

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X, R ^ and R2 have the above meaning, with sodium hydroxide solution produced v / earth. This reaction and the preparation of the compounds of general formula VIII is in tetrahedron Letters, 4465 (1969). Precursors for the compounds of the general formula VIII can according to the in J. Org. Chem., 3d. 21 (1956), p. 1013 v / earth.

The compounds of the general formula V can also be reacted of an indole of the general formula XVIII prepared with thiourea in the presence of an oxidizing agent will. The reactants are preferably in stoichiometric Amounts used. Examples of oxidizing agents that can be used are iodine-potassium iodide, hydrogen peroxide, potassium periodate and sodium hypochlorite. The oxidation can take place at room temperature or elevated temperatures up to the reflux temperature be performed. Examples of solvents that can be used are water, lower aliphatic alcohols, ethers, such as diethyl ether or tetrahydrofuran, and glycols. After the reaction has ended, the reaction product is concentrated with a Solution of a strong base, such as sodium hydroxide, preferably treated with heating. It will be the connections of the general Formula V received.

The compounds of the general formula VI can by reaction of the compounds of the general formula XIV, in which R ^, R ^, A and B have the preceding meaning with thionyl chloride produced v / earth. The implementation is in an inert

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organic solvents and carried out in the absence of oxygen. Preferably, thionyl chloride is used in large. Used excess. The reactants are preferably ^{mixed with one another at about 0 °} C., and the reaction is carried out at elevated temperatures. The mixture is preferably stirred at room temperature and finally refluxed. This reaction is illustrated by the following reaction scheme:

F.0- (CH ₂ ) _n -CH-H ' ^R 3

SOCl ₂

(XIV)

The compounds of the general formula XI can by reacting a compound of the general formula XVi in an organic Solvent with a halide R ^ W in aqueous alkaline Solution and in the presence of Benzyltriethylammoniurachlorid getting produced. The alkyl halide is preferably used in a molar excess. However, it can also be stoichiometric Quantities are used. Implementation is preferred carried out at room temperature, and it runs after following Eeaktionssciiemai

.S- (CHg) _n -CM

(XI)

X, X, R ₁ and Rg have the above meanings? ¥ is ^ t a

809828 / 0t8S

Halogen atom, preferably an iodine atom.

The compounds of the general formula I and I ^f substituted in the 1-position can also be prepared by reacting the compounds of the general formula I and I * unsubstituted in the 1-position with a strong base and then with the corresponding halide R ^ i in an inert one organic solvents are produced. Examples of strong bases that can be used are sodium hydride, lithium hydride and sodium amide. The unsubstituted compound is preferably mixed slowly with the base. The iodide or bromide is preferably used as the halide, but the chloride can also be used. The product is isolated and purified in the usual way. This reaction is illustrated by the following reaction scheme.

strong base \

S - (CH ₂ ) ^ CH-tK ^ y

The compounds of the general formula XIV can by reaction of the compounds of the general formula II with an aminoalkanol of the general formula XV in an organic

609828/0988

Solvent prepared using stoichiometric amounts of the reactants v / ground. The reaction temperature can be in a relatively wide range. Preferential rates the reaction is carried out at room temperature. Elevated temperatures can also be used. The implementation proceeds according to the following reaction scheme:

^7-0C 2 ^H 5

+ H0- (CH ₂ ) _n -CH-NH ₂ V (XIV)

^R 3

(II) (XV)

A, B and η have the above meanings.

The compounds of the general formula XVI can by reaction of the compounds of the general formula V in an inert organic solvent with a haloalkyl nitrile of the general formula XVII are prepared in an aqueous alkaline solution. The reactants are preferably in stoichiometric amounts are used. The reaction temperature can be within a relatively wide range. Preferably The reaction is carried out at room temperature. To increase the reaction rate, however, increased Temperatures are applied. The reaction proceeds according to the following reaction scheme:

60 9 8 28/0988

X, X

S ^G Na

(XVII) and η have the above meanings.

The compounds of the general formulas VII "to X, XII, XV and XVII Ms XIX are largely known and are produced in a manner known per se.

The examples illustrate the invention.

Example 1 3-indolylthi oil

240 parts of methanol are mixed with 23.4 parts of indole, 15.2 parts of thiourea and 1 η potassium iodide solution and iodine in such an amount that each reactant is present in one equivalent per equivalent of indole. The mixture is stirred for 16 hours. The solvent is then distilled off under reduced pressure. S- / 3-indolyl / -isothiuronium iodide remains in colorless crystals with a melting point of 214 to 216 ° C. ^{The compound is heated to 80 °} C. with excess concentrated sodium hydroxide solution and under nitrogen as a protective gas for 10 minutes and then cooled to room temperature. The corresponding solution of the sodium salt of 3-indolylthiol is obtained. The solution is neutralized with dilute hydrochloric acid. The pure 3-indolylthiol precipitates and is filtered off

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and is dried. F. 100 to 101 ⁰ C.

example

As in Example 1, but using equivalent amounts of the correspondingly substituted indoles are as follows 3-indolylthiols produced:

χ D. --SH. ( • ~ ^c 6 ^K i ) H H H 5- CH ₃ O- xi -CH H H H 5-Cl H H 5-C ₂ H ₅ H H H

.H

5 - OCH-

S-Br.
7-CH.,

H
H

H ·

6-OCH.

E, H

HoCO

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If appropriate, the resulting solution of the sodium salt of 3-indolylthiols can be used as such in the next stage will.

.Example 3 3-Indolvlthioacetonitrile

The solution of the sodium salt of 3-indolylthiol prepared according to Example 1 is mixed with 12.1 parts of chloroacetonitrile and 70 parts of diethyl ether. The mixture is stirred for 16 hours under nitrogen as an inert gas. The ether solution is then separated off. The aqueous solution is extracted with 400 parts of dichloromethane and then with 140 parts of diethyl ether. The organic solutions are combined, washed with dilute sodium hydroxide solution, dried over magnesium sulfate and evaporated under reduced pressure. A brown crystalline solid remains. After recrystallization from a mixture of methanol and isopropanol, the title compound is obtained, mp 52 Ms 54.5 ⁰ C.

Example4

According to Example 3 »but using equivalent amounts of the sodium salts of 3-indolylthiols obtained in Example 2, the following 3-indolylthioalkylnitriles are produced:

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SCH ₂ -CN

H
S-. CH ₃ O-

H
5- Cl

3 ^mm \ j -. η

Oc

H.
H

5-OCH ₃
5-Br
7-CH-,

H H H H H

H H

6-OCH,

E-.

NR _o
H 2 F., ⁰ C. 150-153 ^C 6 ^H 5 ■ ιοβ-1-io H • 137-138 CH ₃ 106-107.5 H. 61-63 H '

-CH ₂ C ₆ H ₅

-CH, H H H

Cl

If appropriate, the 3-indolylthioacetonitriles obtained can can be used as a solution in the next stage.

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Example 5
i-ethylindole-j-vlthioacetonitrile

The 3-indolylthioacetonitrile obtained in Example 3 is in Dissolve 100 parts of diethyl ether and add the same volume of 50 percent sodium hydroxide solution. Then the Geraisch is with 2 parts of benzyltriethylammonium chloride and then mixed with 56.3 parts of methyl iodide with cooling. The mixture will closed and stirred for about 16 hours. The resulting solution is then treated with 5C0 parts of diethyl ether and 650 parts of dichloroethane extracted. The extracts v / ground twice with dilute Sodium hydroxide solution and washed once with saline solution and dried over potassium carbonate. Then the extracts are combined, and the solvent is distilled off under reduced pressure. The title compound remains as a crude product, which is recrystallized from a mixture of methanol and isopropanol. M.p. 92.5 to 93.5 ° C

Example 6

According to example 5, but using the appropriate, in the 1-position unsubstituted ^ -indolylthioacetonitrile are the 3-indolylthioacetonitriles substituted in the 1-position obtain.

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SCH CN

H
H
H
H

'

K
H
H
H

C ₂ H ₅

ⁱ ~ ^c 3 ^H 7

-CH.

-C

-CH ₂ C ₆ H ₅
-CH ₂ CH ₂ OCH ₃

H H

HH.-CH ₂

H H

H H

H H

H H

H H -CH,

-CH ₂ CH = CH ₂
" ^C 6 ^H 5

H H -CH:

• Η H H H

Cl H F., ⁰ C 37.5-39 oil 133-138

Oil oil oil "oil

Oil oil

45-47

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H H -CH ₂ -C = CH H H H -CH ₂ C (CH ₃ J = CH ₂ H' 5-OCH ₃ 6-OCH ₃ - ^C 2 ^H 5 H 5-Cl H ' -CH ₃ H . H H -11-C ₃ H ₇ H

Oil oil

Example 7

3- / C 2-Aminoäthvl) -thio / -1-methylindole fumarate A solution of 45 parts of i-ethylindol-3-ylthioacetonitrile in 80 parts of tetrahydrofuran is slowly mixed with 415 parts of a 1 molar solution of diborane in tetrahydrofuran with cooling. The resulting mixture is stirred for 16 hours with exclusion of moisture. An additional 112.5 parts of diborane are then added and the mixture is stirred for an additional 16 hours. Dilute hydrochloric acid is slowly added to the solution obtained, while stirring, until the evolution of hydrogen ceases. This takes about 6 hours. The solution is then made alkaline with 1 η sodium hydroxide solution. The alkaline solution is extracted three times with 150 parts of diethyl ether each time. The combined ether extracts are washed three times with dilute sodium hydroxide solution and once with sodium chloride solution, dried over potassium carbonate and then concentrated to half their volume. Hydrogen chloride gas is passed into the resulting solution. The hydrochloride precipitates out in the process. After recrystallization from a mixture of methanol and Athylace-

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Indeed, the title compound is obtained as the hydrochloride, melting at 159 Ms 160.5 ⁰ C.

To prepare the Pumarats, the concentrated ether solution is concentrated further and the yellow oil obtained is taken up in methanol and with a solution of 9 parts of fumaric acid in
Methanol added. The solvent is then slowly distilled off and isopropanol is added at the same time. The fumarate formed is recrystallized from a mixture of methanol and isopropanol. F. 169 ⁰ G (dec.).

Example 8

According to Example 7, but using the corresponding 3-indolylthio.acetonitrile ^ the following 3 - / (2 .-- Aminoethyl) - ± hiq / ~ indole made *

acid

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5- CH O- H H ' H H H H - H H ■ H '5- Cl H

H
H-

H
H

5- Cl H

H ■ ^H H

-OH ₃ j / ^0H 3

H H

H H

H H

^{; Η} 3

ChV

-CH

ο sura

τ?

HCl 212-215

HCl, 192-196

181-182

HCl. . 161-165

■ 125-126.5 HCl 2 * 15-247.5

(Ζ)

HCl 197-198

124-127

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H
H

H-

- 38 - -egg· satire 255921 1 Rl R2 p7; ° c H -CH ₂ ^C 6 ^H 5 I.

5-OCH ₃ cn -OCH ₃ Ή H C ₄ H ₄ O ₄ 160-161 H H ~ { H ■ ^C 4 ^H 4 ° 4 147-148 ' -H H H • I / ² C ₄ H ₄ O ₄ 168-170 '■ H H H C ₄ H ₄ O ₄ 152-153 H H -CH ₂ CH ₂ OCH ₃ H ^C 4 ^H 4 ° 4 166-167 H H -CH ₂ - ( H -HC ₈ H ₁₇ -CH- /

-C ₆ H ₅

H . H H H

-CH

Cl

• η a. -CH ₂ -CsCH H 5-Br H H H 7-CH ₃ H H H H H -HC ₃ H ₇ H H H -CH ₂ CH = CH ₂ H H H -CH ₂ C ₆ H ₅ H H H -CH ₂ C (CH ₃ ) ^S CH-

^C 4 ^H 4 ° 4 C ₄ H ₄ O ₄

^C 4 ^H 4 ° 4

136! 5-

159, 5-160 j 5 -I 158-159 ° 183-185 * 151 _f 5-153

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Example 9
5- (2-aminopropylthio) indole

A solution of 4.9 parts of the 3-indolylthiol prepared according to Example 1 in 24 parts of anhydrous methanol is mixed with 1.71 parts of propyleneimine. The mixture is stirred for 40 minutes under nitrogen as a protective gas. The methanol is then distilled off under reduced pressure, the residue is dissolved in diethyl ether and the ether solution is extracted three times with 50 parts of 1 η hydrochloric acid each time. The combined hydrochloric acid extracts are washed with 180 parts of diethyl ether and then made alkaline with 2 η sodium hydroxide solution. The aqueous alkaline solution is then extracted three times with 60 parts of diethyl ether each time. The combined ether extracts are washed twice with 50 parts each of 1 η sodium hydroxide solution and once with sodium chloride solution and dried over potassium carbonate. The ether solution is evaporated under reduced pressure. The crystalline residue is dissolved in ethyl acetate and activated charcoal is added to decolorize. The activated carbon is then filtered off. The crude product crystallizes out of the filtrate. After recrystallization from benzene, the pure title compound with a melting point of 110.5 to 112.5 ° C. is obtained.

Example 10

According to Example 9, but using an appropriate amount of aziridine, 3- / 12-aminoethyl) thio / indole is obtained from 87 to 89 ° C.

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Example 11 3- / 13-Arainopropyl) -thio_7-indole

One according to Example 1 from 63.8 parts of 3-indolylthiuronium iodide produced aqueous alkaline solution of 3-indolylthiol is with stirring dropwise with an aqueous solution of 13.0 parts 3-chloropropylamine hydrochloride added * The mixture is For 3 hours the mixture was stirred under nitrogen as a protective gas and then extracted with 280 parts of diethyl ether. The ither extract is three times with 150 parts of 1 η sodium hydroxide solution and once washed with brine, dried over potassium carbonate and evaporated. The oily residue crystallizes on standing. The product is recrystallized from ethyl acetate and then from benzene with the addition of a small amount of activated charcoal. It the pure title compound with a melting point of 72.5 ° to 73.5 ° C. is obtained.

Example 12

5- / 2- (1-methyl-2-imidazolinylamino) ~ ethylthio / indole fumarate A solution of 25.8 parts of i-methyl ^ -methylthio ^ -imidazoline hydrochloride and 19.2 parts of 3 - / (2 Aminoethyl) thio7-indole in 160 parts of isopropanol is refluxed for 18 hours with exclusion of light. Thereafter, the reaction mixture is evaporated under reduced pressure. The remaining yellow oil is mixed with 90 parts of 2 η sodium hydroxide solution and the resulting mixture is extracted with 400 parts of dichloromethane. The dichloromethane extract is washed twice with dilute sodium hydroxide solution and once with sodium chloride solution, dried over potassium carbonate and reduced under reduced pressure. Evaporated pressure. The crude crystalline 3 -jjk- (1-methyl-2-

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imidazolinylaraino) -ethyl thio_7-indole, which is converted into the Fuinarat by dissolving in hot methanol and adding a solution of 10.8 parts of fumaric acid in methanol. By addition of isopropanol and cooling, the Pumarat crystallizes out of the solution. After zv / eimaliger recrystallization from a mixture of methanol and isopropanol, the title compound, melting at 198.5 ⁰ C (dec.) Is obtained.

Example 13

According to Example 12, but using equivalent Kengen the corresponding alkylthioimidazolines and the corresponding 3- (Aminoalkylthio) indoles, the compounds of the following get general formula:

HhH

-CR-li

5-CH ₃ OHHH IH

St.

HHH- H 2 H

5-Cl • H CH ₃ ■. H 1 CEL

n. ' .. · R ₃ R ₄ R

CH ₃ H CH ₃ H-CH,

CH-

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Examplei4 O-ethyl-M-niethYlPvrrolid.onium-fluoborat

Its solution of 7.76 parts of epichlorohydrin. 14 parts of anhydrous diethyl ether are slowly mixed with a solution of 15.9 parts of sortrifluoride etherate in 14 parts of anhydrous diethyl ether. The mixture is then stirred for 31/2 hours with exclusion of moisture. Then the ether is decanted from the solid triethyloxonium tetrafluoborate. The product is washed twice with anhydrous diethyl ether and
then dried in a stream of nitrogen.

The dried product is dissolved in 25 parts of anhydrous dichloromethyl and a solution of 8.32 parts of N-methyl-2-.
pyrrolidone added in 26 parts of anhydrous dichloromethane. The mixture is then stored for 6 hours with the exclusion of moisture
touched. The title compound is obtained. The connection
can be isolated by evaporating the solvent, them
however, it is preferably in solution without prior isolation
used.

Example 15

According to Example 14, but using equivalent amounts
of the corresponding pyrrolidone or piperidone, the following fluoborates are obtained:

R5

BFi

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R.

H.

CH,

CH,

CH,

C ₂ H ₅

~ ^C 6 ^H 5

-CH

-CH ₂ CH ₂ OH

-CH ₂ CB = CH ₂

-CH ₂ C = CH

^C 6 ^H 5

1.

H H

H H

- H

1 1

1 1

1 1 1

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Example 16

5- / 2- (1-Methyl-2-pyrrolidinvlidenamino) -äthylthioZ-indole
A suspension of 16.0 parts of 3 - / (2-aminoethyl) -thio7-indole hydrochloride prepared according to Example 7 in sodium hydroxide solution is extracted with 20 parts of benzene. The benzene extract comes with
1 η sodium hydroxide solution and sodium chloride solution and dried over potassium carbonate. Then the benzene is reduced under. Brück is distilled off and the remaining red oil is dissolved in 60 parts of anhydrous dichloromethane. The solution obtained
is added to the solution of the fluoborate prepared according to Example 14, and the mixture is stirred for 18 hours with exclusion of moisture. The brown solution obtained is then extracted twice with 60 parts of 20 percent sodium hydroxide solution and dried over potassium carbonate. The dichloromethane is then distilled off under reduced pressure. It is left behind
crude free base of the title compound, which is recrystallized from isopropanol. The pure Tite! Compound melts at
143.5 to 145.5 ° C

Example 1?

Geisäe _S Example 16 but using equivalent amounts of the appropriate 3- (liainoalkyitnio) indole-hyd.rohalogenide taid according to Example 14 or 15 corresponding fluoborate prepared following compounds are prepared t 3- / 3- methyl-2-pyrrolidinylideneamino C1 ) -propylthioj-indole hydrochloride, mp 216.5 to 218.5 ° €;

3- / 2- (1 -Hethyl-2-pyrrolidinylideneamino) -propylthio7-indole _i
F. 176.5 to ieO ° Ci

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3- / 2 "- (1 -Methyl-2-pyrrolidinylideneamino) -ethylthio / -1-methylindole half salt of 2-3utenedicarboxylic acid, mp 186-119 ° C; 5-methoxy-3- / 2- (1-niethyl -2-pyrrolidinylidenaaino) -äthylthio / -indole, m.p. 154 to 157 ⁰ C (ground in a mortar); 1-ethyl-3- / 2- (1-methyl-2-pyrrolidinylid9namino) -äthylthio7-indole-cyclohexanesulfamate, F 113.5 to 115.5 ° C; 3- / 2- (1-methyl-2-pyrrolidinylidenainino) -äthylthiq / ^ - iasthylindol, mp 167 to 168.5 ° C (ground in a mortar); 1.2 -Dinathyl-3- / 2- (1-methyl-2-pyrrolidinylideneamino) ~ ethylthio / indole-2-butenedicarboxylate, mp 149 to 150 ⁰ C; 3- / 2- (1 ~ methyl-2-pyrrolidinylidenaraino) - ethylthio_7-2-phenylindole, mp 181 to 183.5 ° C;

5-chloro-3- / 2- (1-methyl-2-pyrrolidinylidenanino) -äthylthio7-indole, 7 164.5 to 165> 5 ° C;

3- / 2- (1-Kethyl-4-phenyl-2-pyrrolidinylideneamino) ethylthio / indole, 162-163 ° C;

3- / 2- (1-Methyl-2-piperidinylidenamino) -äthylthioZ-indole saccharinate, M.p. 124 to 124.5 ° C;

3- / 2- (2-pyrrolidinylideneaminoJ-ethylthioZ-indole-saccharinate, P-141 to 142 ° C;

3- / 4- (1-Methyl-2-pyrrolidinylideneamino) butylthio / indole-2-butenedicarboxylate, mp 172.5-173.5 ° C; 1- (1-methylethyl) -3- / 2- (1-methyl-2-pyrrolidinylideneamino) -äthylthio7-indole, m.p. 82 to 84 ⁰ C;

5 ~ ethyl-3 ~ / 2- (1-methyl-2-pyrrolidinylideneamino) -äthylthiq / -indole, Mp 131.5-132.5 ° C;

2- (3-Kethyl-5-chlorophenyl) -3- / 2- (1-methyl-2-pyrrolidinylideneamino) -ethylthio7-indole;

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2- ("4-Ethoxyphenyl) -3- / 2- (1 -methyl-2-pyrrolidinylideneaaino) ethylthio7-indole;

3- / 2- (1-ethyl-2-pyrrolidinylidenaniino) ~ ethylthio_7-2- (2-ethoxy- 3, 5-dichlorophyll) indole;

3- / 2- (1-methyl-4-p-tolyl-2-pyrrolidinylideneamino) -ethyithio7-indole;

3- / 2- (1-methyl-4- (3,4-dichlorophenyl) -2-pyrrolidinylidenearaino) ethylthiq / indole;

3- / 2- (1 -Methyl-2-pyrrolidinylideneamino) -äthylthio7-1 - "benzylir.dül-cyclohexylsulfamate monohydrate, mp 133 Ms 134 ° C; 3- / 2- (1 -Methyl-2-pyrrolidinylidenamino) -äthylthiq / _i _ (2-methoxyethyl) -indole-cyclohexylsulfamate, mp 107.5 to 109 ° C; 1-cyclopentyl-3- / 2- (1-methyl) -2-pyrrolidinylideneamino) ethylthio7-indole-benzoate F. 108.5 to 110 ⁰ C; 1 - (2-furanylmethyl) - 3- / 2- (1 -methyl-2-pyrr olidinylidenamino) -r äthylthio7-indol-2-butendicarboxylat, F. 167 to 16S, 5 ° C; 1-Cyclopropylmethyl-3- / 2- (1-methyl-2-pyrrolidinylideneamino) -ethylthic ^ -indole-Z-tutendlcarboxylate, mp 133 to 134 ° C; 3- / 2- (1 -Msthyl- 2-pyrrolidinylidenainin.o) -äthylthio / -1 - (2-prope-.

nyl) indol-cyclohexylsulfamate, F. 105 to 107.5 ⁰ C; 3- / 2- (1-methyl-2-pyrrolidinylideneamino) -äthylthio7-1- (n-octyl) indole fumarate, m.p. 98 to 100 ⁰ C;

3- / 2- (1-methyl-2-pyrrolidinylideneamino) -ethylthio / -1-phenylindole-cyclohexylsulfamate;

1 - (4-chlorophenyl) -3- / 2- (1-methyl-2-pyrrolidinylideneamino) ethylthio / indole benzoate;

1- (4-chlorobenzyl) -3- / 2- (1-methyl-2-pyrrolidinylideneamino) ethylthio / indole benzoate;

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•, - 47 -

1- (J, 4-dimethoxyphenyl) -3- / 2-6-methyl-2-pyrrolidinylideneamino) -ethyl thio7-indole-T-benzoate:

3- / 2- (1-Methyl-2-pyrrolidinylideneamino) -ethyl thio_7-1- (2-propynyl) -indole-cyclohexylsulfaate, mp 114.5 Ms 115.5 ° C; 5, 6-dimethoxy-3- / 2- (1-ynethyl-2-pyrrolidinylideneamino) -ethyl- 'thiq7-indole; 2-banzyl-3- / 2- (1-niethyl-2-pyrrolidir.ylidenamino) ethylthio / indole; Z- (4-chlorobenzyl) -3- / 2- (1-methyl-2-pyrrolidinylideneamino) ethylthio / indole; 3- f2 / i- (dimethylamino) -athylidenarainqZ-athylthioJ-indol-cyclohexylsulfamate, F. 174 Ms 176.5 ⁰ C; 5-bromo-3- / 2- (1-methyl-2-pyrrolidinyl i denamino) ethylthio7-indole; 3- / 2- (1-phenyl-2-pyrrolidinylideneamino) -ethylthioZ-indole; 3- / 2- (1- (4-chlorophenyl) -2-pyrrolidinylideneamino) ethylthioj ⁷ indole; 3- / 2- (1-Benzyl-2-pyrrolidinylidenearaino) -ethylthioJZ-indole; 3- / 2- (1- (4-chlorobenzyl) -2-pyrrolidinyldenamino) ethylthio / indole; 3- / 2- (1-cyclopentyl-2-pyrrolidinylideneamino) -ethyl thio7-indole; 3- Iz- / λ - (2-hydroxyethyl) ^ -pyrrolidinylideneamineqZ-ethylthioJ-indole; 3- [2- / Ϊ- (2-propenyl) -S-pyrrolidinylideneaminoZ-ethylthioJ-indole; 3-ί2- / ϊ- (2-propynyl) -Z-pyrrolidinylideneaminoT-ethylthio} indole; 1- (2-Methyl-2-propenyl) -3- / 2- (i-methyl-2-pyrrolidinylideneamino) -ethylthio7-indole, mp 126.5 Ms 128 ° C; 7-ethyl-3- / 2- (1-methyl-2-pyrrolidinylideneamino) ethylthio7-indOl;

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3- / 2- (1 -Methyl-2-pyrrolidinylidenaraino) -äthylthiq / -1-propylindole-2-naphthaliisulfonat, 98.5 msec 100.5 ° C;

- (2-Propenyl) -2-pyrrolidinylidenaraino7-äthylthiq} -ir.dol-2-butenedicarboxylate, 115 Ms 117 ° C.

Example 18

3-.Z2- (1-riethYl-2-iovrrolidinvlidenaraino) -äthylthiQ7-indole A solution of 23.8 parts of N-methyl-2-pyrrolidinoii in 450 parts of anhydrous benzene is added dropwise to a solution of 3- 5.7 parts of phosphorus oxychloride in 70 parts of anhydrous benzene were added. The colorless solution obtained is refluxed under nitrogen as a protective gas for 2 hours. The yellow solution obtained is cooled to room temperature and treated dropwise with a solution of 38.4 parts of 3 - / (2-amino "ethyl) -tihIo / - over the course of 20 minutes. indole in 90 parts of anhydrous benzene is added, the mixture is refluxed under nitrogen as a protective gas for 4 1/2 hours and then left to stand for 18 hours at room temperature The bath is warmed up when the oily complex is completely decomposed * The benzene layer is separated off and the aqueous solution is extracted twice with diethyl ether. The ether extracts are combined, dried over potassium carbonate and evaporated under reduced pressure. An oily solid inherits, which is recrystallized twice from a mixture of isopropanol and pentane. The title compound is obtained from F, 143 Ms 144 ° C.

Example 19

3 - ^ - ( 1 -Kethvl-2-Oyrrolidinylidenaaino) -äthylthio ./- indole The product obtained according to Example 14 is mixed with a solution of 4.27 parts of 2-aminoethanol in 260 parts of dichloro / nethane and stirred for 16 hours at room temperature . The solvent is then distilled off. The crude product remains as pluoborate. The fluorate is stirred into the free base, which in turn is converted into the 2 »(pyrroliainylidena;: aino) ethanol perchlorate with a melting point of 67 to 69 ° C will.

8.4 parts of thionyl chloride are added dropwise to a solution of 3.5 parts of the free base in 130 parts of anhydrous chloroform at ⁰ ° C. in the course of 15 minutes under nitrogen as protective gas. The mixture is then warmed to room temperature and stirred for 16 hours. Finally, the mixture is refluxed for 30 minutes under nitrogen as a protective gas. The chloroform and excess thionyl chloride are then distilled off under reduced pressure. The crude product remains, which is dissolved in dichloromethane. The solution is vigorously stirred with 6 η sodium hydroxide solution. The dichloromethane layer is then separated off, dried over potassium carbonate and filtered. The filtrate is evaporated under reduced pressure. The 2- (chloroethylimino) pyrrolidine remains.

An alkaline solution of 7.65 parts according to Example 1 3-Indolylthiol made from 3-indolylthiuronium iodide is used twice washed with 175 parts of diethyl ether. Then the aqueous Solution under nitrogen as a protective gas with a solution of the

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2- (chloro- ■■ äthyliraino) -pyrrolidino prepared in the manner described above in diethyl ether and stirred for 16 hours at room temperature. To replace the evaporated diethyl ether, dichloromethane is added. The organic solution is separated off and the aqueous solution is extracted with dichloromethane The combined organic solutions are dried over potassium carbonate, filtered, and the filtrate is evaporated under reduced pressure. The product remains as an amber-colored oil, which slowly crystallizes on scratching. The product is recrystallized from a mixture of isopropanol and petroleum ether pure 3- / 2- (1-methyl-2-pyrrolidinylidenarüino) -äthylthio7-indole obtained.

The IR absorption spectrum of the pure product is with a authentic sample idsntisch looking for an alternative / experienced was produced.

Example 20

5- / 2- (1-methyl-a-ovrrolidinvlidenamino) -ethylsulf invl7-indole hemifumarate hydrate

A solution of 8.7 parts of the compound of Example 19 in 70 parts of methanol is mixed with 8.2 parts of sodium metaperiodate and 3.5 parts of water are added with stirring. The mixture is then stirred for β hours at room temperature. That crystallized out Sodium iodate is filtered off and washed out with methanol. The './aschlösung is combined with the filtrate and the mixture acidified with a solution of fumaric acid in methanol. Then the methanol is distilled off and at the same time isopropanol admitted. The title compound crystallizes as a crude product

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the end. After recrystallization from a mixture of methanol and acetone, the pure title compound melts at 154.5 to 157.5 ° C.

Example 21

3- (2-Alinoethyl) thioindole hydrochloride A solution of 1.17 parts of indole and 1.13 parts of 2-aminoethyl mercaptan in 12 parts of methanol is slowly mixed with 11 parts of a 1 molar aqueous iodine solution under nitrogen as protective gas and stirred for 1 hour . The methanol is then distilled off under reduced pressure, the residue is acidified with 2 parts of concentrated hydrochloric acid and the aqueous solution obtained is extracted with diethyl ether. The suspension of the aqueous solution and the solids is then made alkaline with sodium hydroxide solution and extracted twice with diethyl ether. The combined ether extracts are washed once with sodium chloride solution and dried over potassium carbonate. The ether is then distilled off under reduced pressure. The free base remains, i.e. the 3- (2-aminoethyl) thioindole as an orange oil. The oil is dissolved in a mixture of diethyl ether and methanol, and hydrogen chloride gas is bubbled into the solution. The crystalline hydrochloride of the title compound is obtained. F. 212 to 215 ⁰ C.

Example 22

3 - / 2- (1-Methvl-2-hexahydroaza-öinvlidenamino) -ethylthio ^ -indole-2-butenedicarboxylate

A solution of 6.1 g (48 mmol) of N-methylcaprolactam in 15 ml anhydrous methylene chloride becomes one of 9.1 g (64 mmol)

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Boron trifluoride etherate and 4.45 g (48 mmol) of epichlorohydrin prepared solution of triethyloxonium fluoborate are added, and the mixture is stirred for 2 1/2 hours with exclusion of moisture. A solution of 7.7 g (40 mmol) of 3- (2-aminoethylthio) indole in 20 ml of anhydrous methylene chloride is then added, and the mixture is stirred for 72 hours at room temperature with the exclusion of moisture. After adding the same volume of methylene chloride, the solution is washed with 70 ml of 1 η sodium hydroxide solution, with water and sodium chloride solution and dried over potassium carbonate. The solution is then filtered and the filtrate is evaporated under reduced pressure. 8.6 g remain of an orange-colored oil, which solidifies. The oil is converted into the title compound with fumaric acid. The white crystals obtained melt at 128 to 130 ^° C.

Example 23

thio7 ~ indole-2-butenedicarboxylate

A solution of 18.9 g (75.3 mmol) of 1- / 2- (indol-2-ylthio) ethyl7-thiourea 10.8 g of methyl iodide are added in 80 ml of acetone and the mixture is kept at room temperature for 3 1/2 hours with exclusion of moisture touched. The acetone is then distilled off under reduced pressure. An orange-colored oil remains. 13.5 g (35 mmol) of this oil are dissolved in 100 ml of anhydrous diethyl sulfoxide dissolved and mixed with 3.08 g (35 mmol) of N-methyl-1,3-diaminopropane while stirring and heated. After 1 hour and 40 minutes the temperature reaches 125 ° C, and the mixture is heated for one more hour at this temperature

609828/0988

the solvent is distilled off under reduced pressure. The oily residue is taken up in 50 ml of methylene chloride and, while cooling, a solution of 2 ml of concentrated ammonia solution in 25 ml of water is added. The solution is washed with brine, dried over sodium carbonate and evaporated under reduced pressure. 6.0 g of the free base are obtained as a brown oil which is converted into the fumarate. After recrystallization from a mixture of methanol and isopropanol, yellowish-white crystals of the title compound with a melting point of 212 ° to 213 ° C. are obtained.

Example 24

2- / 2- (1 -Hethyl-2-'DvrrolidinYlidenaraiiio) -äthylthio.7-indole ~ saccharinate

A solution of 25 g (138 mmol) of oxindole in 500 ml of anhydrous benzene is mixed with 25 g of sea sand. 8.85 g (40 mmol) of phosphorus pentasulfide are added to the mixture, while stirring, and the mixture is refluxed for 80 minutes. The mixture is then cooled and filtered, and the filter residue is washed with 300 ml of benzene. The filtrate and the washing solution are evaporated under reduced pressure. 19.0 g (68 % of theory ) of a yellow solid remain, which is recrystallized from methanol. Yield 11.6 g (41% of theory) of yellow crystalline indoline-2-thione.

A solution of 26.4 g (0.35 mol) of Ciiloracetonitril in 200 ml ' Pyridine is mixed with 11.0 g (74 mmol) of indoline-2-thione while stirring offset. After 1 hour, the pyridine hydrochloride is filtered off

609828/0988

trated and the filtrate evaporated under reduced pressure. An orange oily product remains. Remaining pyridine is distilled off as an azeotropic mixture with water. The oil is extracted using a mixture of diethyl ether and water. The ether extract is washed twice with sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. 13.5 g of a yellowish solid remain, which is crystallized from a mixture of ethyl acetate and cyclohexane. Yield 10.0 g of white crystalline indol ~ 2-ylthioacetonitril from F. 91.5 to 92.5 ⁰ G.

A solution of 6.9 g (52 mmol) of aluminum trichloride and 1.98 g (52 ml of anhydrous) lithium aluminum hydride in 257 ml of anhydrous diethyl ether is mixed with a solution of 9-8 g (52 mmol) of acetonitrile in 50 ml of anhydrous diethyl ether added and stirred for 2 hours at room temperature. Thereafter, the reaction mixture is mixed within 3 hours with a total of 10 g of 50 percent sodium hydroxide solution and 2 ml of Viasser and the resulting solution is stirred for 16 hours. The ethereal solution is then separated from the solids, dried over potassium carbonate and evaporated under reduced pressure. 5.4 g of the product remain. After adding 2.5 ml of water and 10 g of 50 percent sodium hydroxide solution, the solids are extracted again with diethyl ether. The ether extract is combined with the 5.4 g of the product and dried over potassium carbonate. The dried solution is filtered and the filtrate is evaporated under reduced pressure. Yield 9.0 g of 2- (2-aminoethylthio) indole. The amine is with a solution of hydrogen chloride in diethyl ether in the

transferred and from a mixture of methanol and isopropanol recrystallized. Yield 6.4 g of crystalline hydrochloride.

A solution of 3.0 g (15 ml-Iol) 2- (2-Aminoäthylthio) -indöl in 30 ml of anhydrous methylene chloride is converted into one of 3.42 g (24 mmol) of boron trifluoride etherate and 1.69 g (18 mmol) of epichlorohydrin and 1.80 g (18 ml-lol) N-Kethyl-2-pyrrolidinone prepared solution given the fluoborate in 15 al anhydrous methylene chloride. The solution is stirred for 4 hours at room temperature with exclusion of moisture, then once with 1 η 'sodium hydroxide solution and washed twice with brine and dried over potassium carbonate. The dried solution is reduced under reduced Evaporated pressure. 3.1 g of crude product remain, which is converted into the saccharinate. The cream colored crystals melt at 175 to 177 ° C.

Example 25

3- / 2- (1 "Methvl ~ 5-phenvl - 2-pvrrolidinvlidenamino) -ethylthioZ- ' indole-cyclohexylsulfamate

A solution of 6.3 g (36 mmol) of N-methyl-5-phenyl-2-pyrrolidinone in 10 ml of v / anhydrous methylene chloride becomes a solution of Triethyloxonium fluorate in 20 ml of anhydrous methylene chloride. The resulting solution is 3 hours at room temperature stirred with exclusion of moisture. Then a solution of "5.75 g (30 mmol) of 3- (2-Aminoäthylthio) indole in 20 ml of anhydrous Mathylene chloride is added and the resulting solution is. Stirred -3 days with exclusion of moisture. Be on it 50 ml of methylene chloride are added, and the solution is diluted with 50 ml

609828/0988

1 η sodium hydroxide solution, washed with ', barrels and sodium chloride solution and dried over potassium carbonate. The dried solution is evaporated under reduced pressure. The free base remains as a viscous oil, which is converted into the cyclohexyl sulfamate. The white crystals of the title compound melting at 190.5 to 191.5 ⁰ C

Example 26

The 3-indolylthiobutyronitrile is prepared according to Example 2, but using an equivalent Hange of chlorobutyronitrile. Then, Example 7, the 3-Indolylthiobutyronitril in accordance with the 3 ~ Zl ^ - ^ i ⁿ transferred okutyl) -thioy carboxylate, melting at 166.5 to 167.5 ⁰ C.

609828/0988

Claims (1)

(CH ₂ ) -CH-I
* 3 R ₄ wherein X and X 'or halogen atoms, lower alkyl, alkoxy or alkylamino or acylamino groups hydrogen- importance \ 1 ' ten, but X and X do not represent acylamino radicals at the same time R ^ represents a hydrogen atom, a lower alkyl or alkoxyalkyl radical, an alkenyl or alkynyl radical, a cycloalkyl or cycloalkylalkyl radical, an optionally substituted phenyl or phenylalkyl group or a heterocyclic arylalkyl radical, R ₂ a hydrogen atom, a lower one
Alkyl radical, an optionally substituted phenyl or phenylalkyl group, a biphenyl or kaphthyl group or a heterocyclic aryl radical and Z a thio, sulfinyl or
Sulphonyl group means, η has the value 1, 2 or 3, R, a
Hydrogen atom or a lower alkyl radical and R ^ a V / water atom, a lower alkyl radical, a hydroxyalkyl or alkenyl radical, a cycloalkyl radical or optionally 609828/0988 represents substituted phenyl or phenylalkyl groups, A and · B individually represent lower alkyl radicals or A and B together represent a group of the formula
-CH ₂ CH (R ₅ ) CK ₂ -, -CH ₂ CH ₂ CH (R ₅ ) -, -N (R ₆ ) CH (R ₅ ) (CH ₂ ) _m -, - (CH ₂ ) ₄ - or ~ (CHg) ₅ -ι form, where R _{5 is} a hydrogen atom, a lower alkyl radical or an optionally substituted phenyl group and R ^ - means a hydrogen atom or a lower alkyl radical, ο m has the value 1 or 2 and v / if m has the value 2, the radical R _{5 represents} a hydrogen atom, and their salts with acids. 2. 3- / 2- (1-methyl-2-pyrrolidinylideneamino) -ethylthio_7-indole and its salts with acids. 3 · 3- / 3- 0 ~ Kathyi-2-pyrrolidinylid3namino) -propylthiq7-indole and its salts with acids. 4. 3- / 2- (1-Methyl-2-pyrrolidinylideneamino) -propylthio_7-indole and its salts with acids. 5. 3- / 2- (1-methyl-2-pyrrolidinylideneamino) -ethylthio7-1-methylindole and its salts with acids. 6. 5-methoxy-3- / 2- (1-aiethyl-2-pyrrolidinylideneamino) ethylthio / indole and its salts with acids. 7. 1-ethyl-3- / 2- (1-methyl-2-pyrrolidinylideneamino) -ethylthi oxindole and its salts with acids. 609828/0988 8. 3- / 2- (1-Methyl-2-pyrrolidinylideneamino) -ethylthiq / -2-methylindole and its salts with acids. 9. 1,2-Diir ₁ ethyl-3- / 2- (1-netliyl-2-pyrrolidinylideneamino) - ethylthio / -indoi and its salts with acids. 10. 5- / 2- (1 -Me thyi-2-pyrrolidinylideneamino) -ethylthio7-2-phenylindole and its salts with acids. 11. 3- / 2- (1-methyl-2-imidazolinylamino) -ethylthiq / -indole and its salts with acids. 12. 3- / 2- (1-methyl-2-pyrroli'din2 / lidenarnino) -ethylsulfynyl / -indole and its salts with acids. 13-3 / 2- (1-methyl-2-pyrrolidinylideneamino) ethyl thio_7-1-benzylindole and its salts with acids. 14. 3- / 2- (1-Methyl-2-pyrrolidinylideneamino) ethylthio / -1 - (2-methoxyethyl) indole and its salts with acids. 15. 1-Cyclopentyl-3- / 2- (1-methyl-2-pyrrolidinylideneamino) -äthyltliio7-indole and its salts with acids. 16. 1- (2-? Uranylmethyl) -3- / 2- (1-methyl-2-pyrrolidinylidenearino) -ethylthiq7-indole and its salts with acids. 609828/0988 . - 60 - .17. 1- (Cyclopropylmethyl) -3- / 2- (1-methyl-2-pyrrolidinylidene ^ · amino) -äthylthio7-indole and its salts with acids. 18. 3- / 2- (1-Methyl-2-pyrrolidinylideneamino) ethylthio7-1- (2-propenyl) indole and its salts with acids. " 19. 3- / 2- (1-Methyl-2-pyrrolidinylideneamino) ethylthlo7-1- (n-octyl) indole. and its salts with acids. 20. 3- [ 2- / Ϊ - (Dimethylamino) -äthylidenamino.7} -indole and its salts with acids. 21. 5-Ethyl-3- / 2- (1-methyl-2-pyrrolidinylideneamino) -ethylthio7-indole and its salts with acids. 22. 3- / 2- (1-Methyl-4-phenyl-2-pyrrolidinylideneamino) -ethylthio7-indole and its salts with acids. 23-5-chloro-3- / 2- (1-methyl-2-pyrrolidinylideneamino) ethylthio / indole and its salts with acids. 24. 1 - (1 -Methylethyl) -3- / 2- (1 -methyl-2-pyrrolidinylideneamino ) -äthylthio.7-indole and its salts with acids. 25. 3- / 2- (2-Pyrrolidinylidenamino) -äthylthio7-indole and its Salts with acids. 609828/0988 26. 3- / 2- (1-Methyl-2-piperidinylideneamino) -ethyl thiq7-indole and its salts with acids. 27 · '3- / 4- (1-methyl-2-pyrrolidinylideneaino) -butylthio7-indole and its salts with acids. 28. 1- (2-Methyl-2-propenyl) -3- / 2- (1-m3thyl-2-pyrrolidinylideneamino) -ethylthiq7-indole and its salts with acids. 29. 3- / 2- (1-Methyl-2-pyrrolidinylidenearaino) -ethylthiq / -1-propylindole and its salts with acids. 30. 3- {2- / Ϊ- (2-propenyl) -2-pyrrolidinylideneamine / ethylthio} indole and its salts with acids. 31. 3- / 2- (1-Methyl-2-hexahydroazapinylideneamino) ethylthio / indole and its salts with acids. 32. 3- / 2- (1-methyl-1,4,5,6-tetrahydropyriraidin-2-ylidenainino) -ethylthio7-indole and its salts with acids. 33. 2- / 2- (1-Methyl-2-pyrrolidinylideneamino) -ethylthio7-indole and its salts with acids. 34. 3- / 2- (1-Methyl-5-phenyl-2-pyrrolidinylideneamino) ethylthio / indole and its salts with acids. 609828/0988 35.3- (Aminoalkylmercapto) -indoles of the general formula III (III) in which X and X are hydrogen or halogen atoms, lower alkyl, alkoxy or alkylamino radicals or acylamino radicals, but X and X are not acylaraino radicals at the same time, FL is a hydrogen atom, a lower alkyl or alkoxyalkyl radical, an alkenyl or alkynyl radical, a cycloalkyl ■ - or cycloalkylalkyl, optionally substituted phenyl or phenylalkyl group or a heterocyclic. Arylalkyl radical, R _{2 is} a hydrogen atom, a lower alkyl radical, an optionally substituted phenyl or phenylalkyl group, a biphenyl or naphthyl group or a heterocyclic aryl radical and R- is a hydrogen atom or a lower alkyl radical, η is 1, 2 or 3 and at least one of the radicals R ₁ , R ₂ , R3 »X and X has a different Be has the meaning as a hydrogen atom when η has the value 1 , and its salts with acids. 36. Medicaments, characterized by a content of a compound according to claim 1 or 35 and customary carriers and / or diluents and / or auxiliaries. - '- 609828/0988 .37. Process for the preparation of substituted indoles of the general formula K = C J ^R 4 *. and in which X and X represent hydrogen or halogen atoms, lower alkyl, alkoxy or alkylamino radicals or acylamino radicals, However, X and X do not represent acylamino _{radicals at the same time, R 1 represents} a hydrogen atom, a lower alkyl or alkoxyalkyl radical, an alkenyl or alkynyl radical, a Cycloalkyl or cycloalkylalkyl _{radical, an optionally substituted phenyl or phenylalkyl group or a heterocyclic arylalkyl radical, R 2} a hydrogen atom, a lower alkyl radical, an optionally substituted phenyl or phenylalkyl group, a biphenyl or naphthyl group or a heterocyclic aryl radical and Z a thio, SuIfinyl or sulfonyl group, η has the value 1, 2 or 3, R _{3 is} a hydrogen atom or a lower alkyl radical and Ra is a hydrogen atom, a lower alkyl radical, a hydroxyalkyl or alkenyl radical, a cycloalkyl radical or an optionally substituted phenyl or Represents phenylalkyl group, A and 609828/0988 , B individually lower alkyl radicals or A and B together a group of the formula -CH ₂ CH (R ₅ ) CH ₂ -, -CH ₂ CH ₂ CH (R ₅ ) -, -N (R ₆ ) CH (R ₅ ) (GH ₂ ) _m -, - (CH ₂ ) ₄ - or. - (CH ₂ J ₅ -, form, v; whether R _{5 is} a hydrogen atom, a lower alkyl radical or an optionally substituted phenyl group and Rg is a hydrogen atom or a lower alkyl radical, m has the value 1 or 2 and v / if m has the value 2, the radical R ₅ is Represents hydrogen atom, and their salts with acids, characterized in that either (a) for the preparation of compounds of the general formula I in which Z denotes a thio group, a compound of the general formula II (H) with a compound of the general formula III S- (CHg) _n -CH-NH ₂ (III) reacted in an organic solvent and converted the fluoborate obtained with a base into the free base 609828/0988 or (b) for the preparation of compounds of the general formula I in which Z is a thio group, the compound of the general formula III with a slight molar excess
a compound of the general formula IV QPO (IV) in which W represents a chlorine or bromine atom, in an organic one Reacts solvent or (c) for the preparation of compounds of the general formula I in which Z is a thio group, a compound of the general formula Formula V (V) in aqueous alkaline solution with a compound of the general formula VI (VI) Cl- (CH ₂ J _n -CH-H ^ 60 9 8 28/0988 6t reacts in an organic solvent or * "* '' (d) for the preparation of compounds of the general formula I, 'in which Z is a thio group and A — B is a group of the general formula -N (R ₆ ) CH (R ₅ ) (CH ₂ ) _m -, the compound of the general Formula III with a compound of the general formula VII H (VII) ₂ ) Jj ⁵ Vs-R ₇ .W '⁰; in which ¥ 'is a halide ion, reacts in a lower aliphatic alcohol and optionally the salt obtained converted into the free base by treatment with a base or (e) for the preparation of compounds of the general formula I / in which Z is a thio group and R- *, X and X ^{1 represent} hydrogen atoms, a compound of the general. Formula XXIV - ^iCH 2 ⁾ if ^CH 2 ^HH 2. {XXIV) with the compound of the general "Formula II" in an organic Reacts solvent and the resulting fluoborate of the general formula I * with a base in the free base convicted or 603328/0383 (f) for the preparation of compounds of the general formula I ¹ in which Z represents a thio group, a compound of the general formula XIVa . (XIVa) _n
R ₃ . with the compound of general formula II in an organic Reacts solvent and the resulting fluoborate of the compound of general formula I 'with a base in the free base converted or (g) for the preparation of the compounds of general formula I,. in which Z is a sulfinyl group, the compound of general formula I or I ', in which Z represents a thio group, oxidized with sodium metaper ^ odate in an organic solvent or (H) for the preparation of compounds of the general formula I and I ¹ , in which Z is a sulfonyl group, the compound of the general formula I or I ', in which Z is a thio or sulfinyl group, with hydrogen peroxide or a peracid in an organic The solvent is oxidized and, if appropriate, the compound obtained according to (a) to (h) is converted into a salt with an inorganic or organic acid. 609828/0988 38. Process for the preparation of 3- (aminoalkyl mercapto) indoles of the general formula III (in) 1
in which X and X are hydrogen or halogen atoms, lower alkyl, alkoxy or alkylamino radicals or acylamino radicals, but X and X are not acylamino _{radicals at the same time, R 1 is} a hydrogen atom, a lower alkyl or alkoxyalkyl radical, an alkenyl or Alkynyl radical, a cycloalkyl or cycloalkylalkyl radical, an optionally substituted phenyl or phenylalkyl group or a heterocyclic arylalkyl _{radical, R 2} a hydrogen atom, a lower alkyl radical, an optionally substituted phenyl or phenylalkyl group, a biphenyl or naphthyl group or a heterocyclic aryl radical and R ^ denotes a hydrogen atom or a lower alkyl radical, η has the value 1, 2 or J5 and at least one of the radicals R ^, Rp »R ^ ι X and X has a meaning other than a hydrogen atom when η has the value 1, and their Salts with acids, characterized in that (a) a compound of the general formula XVIII (XVIII) 609828/0988 with a compound of the general formula XsX * ^ ^ ⁴ ^ '' ^R 3 with the addition of an aqueous solution of iodine or a peroxide as an oxidizing agent in a lower aliphatic Reacts alcohol as a solvent and with the exclusion of air or. " (b) for the preparation of compounds of the general formula III in which η is 1, a compound of the general formula Formula VIII (VIII) with a compound of the general formula IX «3 in a lower aliphatic alcohol as a solvent or (c) for the preparation of compounds of the general formula III in which η is 1 or 2, a compound of the general formula Formula V 609828/0988 (ν) in an aqueous alkaline medium with a compound of the general formula X "« ■ 1 R. HCl (X) implements or (d) for the preparation of compounds of the general formula III in which R _{3 is} a hydrogen atom, a compound of the general formula XI ■ - S- (CHg) _n -CN with a reducing agent in an inert organic solvent reduced and optionally the compound obtained according to (a) to (d) by reaction with an inorganic one or organic acid converted into a salt. 609828/0988