CS231158B2 - Processing method of indole derivative - Google Patents

Description

As well as the therapeutically effective addition salts of said novel compounds of formula I and acids.

According to the invention, the compounds of formula I are prepared by reacting a compound of formula II

(II), in which the general symbols have the meanings given above, with a compound of the general formula III

S- (CH) _n -CH 3 -NH ₂ (III) in which the general symbols are as defined in reference to the above, in a suitable organic rozpouitidle, it Jaouich Nizio aliphatic alcohols, for example methanol, ethanol, 2-propanol or tert. butanol, or ethers, such as diethyl ether, tetrahydrofuran or dioxene, or halogenated hydrocarbons, such as chloroform, methylene chloride or 1,2-dichloroethane, or aromatic hydrocarbons, such as benzene, toluene or xylene, to form the fluoro-bromide salt of the compound of formula I above; converting the resulting fluoroborate salt into the free base by treatment with a suitable base such as, for example, an alkali metal or alkaline earth metal hydroxide or carbonate;

optionally, the compound of formula (I) is converted into a therapeutically active non-toxic addition salt by treatment with an acid.

Compounds of formula I in which A, "" B is NHCH (II ^) _{(CH2), and} can exist in two tautomeric forms, illustrated by the following formulas Ia and Ib

H

(lb)

Compounds of formula I in which R @ 1 is hydrogen may also exist in one of the two tautomeric forms illustrated by the following formulas Ic and Id '

Z- (CH ₂ ) _n -CM-N-

V (Ic)

'1

Z- (CH ₂ ) _n -CH-N. (Id)

In the above formulas, X, X ¹ , R ₁ , R 8, Z, R 6, R 6, A, B and n are as defined above unless otherwise indicated.

Compounds of formula I wherein Z is thio are prepared preferably by reacting the corresponding fluoroborate salt of formula II with the adjacent 3- (aminoelkylthio) indole of formula III, wherein X, R, Rg, R, R, A, B and n are as defined above. A small excess of the fluoroborate salt is preferred. Suitable organic solvents for carrying out the reaction include lower aliphatic alcohols such as methanol, ethanol, 2-propanol, tert. butanol, etc .; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; lower halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane and the like; and aromatic hydrocarbons such as benzene, toluene, xylene and the like.

The temperature is not critical, although normal temperatures are recommended to increase the rate of reaction, elevated temperatures may be used. The fused fluoroborate salt is converted into the appropriate base by conventional means; for example by treating with a suitable base such as an alkali metal or alkaline earth hydroxide, carbonate and the like.

The reaction can be illustrated by the following scheme:

⁺ BF,

R, (H)

-S- (CH _{2) n} -CH ₂ -NH «3» 2 (M) (L), HBF ₄ · ^{Ζ Ν} ΟΗ (0

Compounds of formula I wherein Z is thio may be prepared by two different reactions. 1) Reaction of the corresponding compound of formula III and a slight molar excess of the corresponding compound of formula IV in which X, X ¹ , R ₁ , R ⁶ , R ₆ , R 6, R 6,

A, B and n are as defined above and W is bromo or chloro, the compound of formula I is obtained in the form of an acid salt. This reaction is carried out in a suitable inert organic solvent such as an aromatic hydrocarbon, for example benzene, toluene, xylene, etc .; in ether, such as in diethyl ether, tetrahydrofuran (THF), dioxane, etc .; in a halogenated lower alkane such as chloroform, methylene chloride, dichloroethane, etc.; and the like. Although the temperature is not critical, boiling point is preferred. 2) Reaction of the corresponding sodium salt of 3-indolylthionate of formula V in an aqueous base solution with a stoichiometric amount of the corresponding compound of formula VI wherein X, X ¹ , R ¹ , R 6, R 6, R 6,

A, B and n are as defined above, in a suitable inert organic solvent as described above. The temperature is not critical. Although normal temperatures are preferred, elevated temperatures may be used to increase the reaction rate.

These two reactions can be illustrated as follows:

A '') '' - * • * ^B β IW ® (IV) r ₄ / ^A '_; + Cl- (CH ₂₎ n ^{-CH = N} ~ \ '--I' n ^ ^{B r} 3 I

R. (VI) (I). HW (I)

The acid addition salt of the desired product can be converted into the free base as described above.

A compound of formula I wherein Z is thio and A-B is -N / Rg / CH / Rg / CH2 / m may also be prepared by reacting the corresponding thioindole of formula III with the appropriate alkylthioimidazoline salt or alkylthiotetrahydropyrimidine salt. formula VII wherein X, X ^1, R ,, R₂, R₃, R₅, R₆ and n are as hereinbefore defined, W represents a suitable anion, for example a mineral acid such as hydrohalic acid, and Ry is lower alkyl. Stoichiometric amounts are preferably used. This reaction is carried out in an appropriate lower alkanol, for example ethanol, isopropyl alcohol, 2-methyl-4-propanol and the like. Although the temperature is not critical, the boiling point is preferred.

This reaction can be illustrated as follows:

The acid addition salt of the desired product can be converted into the free base 1 as described above.

The Hitrile (XXIII) is then reduced with a suitable reducing agent, such as decomposed, lithium aluminum hydride (aluminum chloride or the like). The reaction is carried out in a suitable inert organic solvent other than the lower halogenated alkane as described above using a large molar excess of the reducing agent. Temperature is not critical. Normal temperatures are preferred if elevated temperatures can be used to increase the reaction rate. After decomposition of the excess reducing agent with a mineral acid (borane) or a base (lithium aluminum hydrides) of aluminum chloride, the amine of formula XXIV is obtained as the acid salt or the optional free base.

This amine can then be reacted with a suitable compound of formula (II) in a manner identical to the preferred method described above for preparing compounds of formula (1) to give the desired compound of formula (I).

Indolin-2-thiones are generally known or can be prepared according to E. H. Wlsemen et al., J. Med. Chem. 16, 131 (1973) and T. Hina et al., Chem. and Pharm. Bull. (Tokyo),

550 (1969). X, X ¹ , R ¹ , and n are as defined above; β E represents a bromine or chlorine atom. The above reactions can be illustrated as follows:

ΟξΧ- ^{+ W} - ^{(CH 2 '} n ^CN

H (XX)

+ R-jW

N S- (CH ₂ ) _n -CH ₂ CN (XXIII) reduction

S- (CH ₂ ) _n -CH ₂ NH ₂ ^R 1 (XXIV)

The compounds of the formula I according to the invention can be isolated in the form of the free bases by conventional synthetic methods. These base compounds are convertible into physiologically acceptable acid addition salts by treatment with an appropriate acid such as hydrohalic acids, for example hydrochloric, hydrobromic, hydroiodic; sulfuric or nitric acid; phosphoric acids, organic acids such as acetic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citroic, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexansamic acid p-aminosalicyl, 2-phenoxybenzoic or 2-acetoxybenzoic. Conversely, the salt form may be converted into the free base in a conventional manner.

Compounds I in free base or acid addition salt form have useful mammalian heart rate retarding activity following subsequent reflexogenic tachycardic assays. Anesthetized dogs are subjected to a bilateral vagotomy consisting of intravenous administration of thiopental sodium (20 mg / kg) maintained by the following intreventive administration of alpha-chloralose (60 mg / kg). After 15 minutes, two doses of aminopyllin are administered. The hypotensive effect of aminophyllin activates carotid sinus barireceptors, which in turn stimulate the nervous system causing a reflex of heart rate increase.

The compound to be tested is palliated intravenously 5 minutes after the second dose of aminophyllin, and the effect on heart rate is recorded over a 30 minute interval. Compounds showing heart rate retarding activity of at least 18 sine beats per minute are considered to be active. Such compounds are useful in the treatment of angina pectoris because heart rate is considered to be a major determinant of myocardial oxygen consumption.

The compounds of the invention are active in the above assay at doses ranging from about 0.25 to about 18.5 mg / kg body weight.

Compounds 1 in free base or acid addition salt form also have useful activity as an inhibitor of human platelet aggregation. Compounds were tested using aggregation induced by collagen at a final concentration of 100 µm in platelet-rich plasma by the Borne turbidimstric method (O. R. R. Born, Nature, 194, 927 (1962)). Results are expressed as a percentage of the average inhibition of aggregation. While the compounds of the invention are all active in the above assay, preferred compounds for use in the present invention are those compounds of formula I wherein, is an acetyl group and Z is a thio group.

The compounds of formula I have been found to have useful antisecretory activity in the following test in rats with acute gastric fistula in rats. The antisecretory ectibity of the test compound is eluted in female Spregue-Dawley rats following intraduodenal injection of the compound at doses typically ranging from 2.5 to 40 mg / kg body weight. Rats are fasted 24 hours prior to testing and ad libidum water are housed in individual cages. On the day of testing, the rats are weighed and selected so that the rats in each test weigh in the range of 20 g.

Surgery is performed using mild ether anesthesia. Once the rat is anesthetized, it is removed with small pincers. A 1 to 0.5 cm long incision is made on the abdomen and the stomach and duodenum are exposed. If at this point the stomach is filled with food or faeces, the rat is discarded.

Using a 4-0 stitch, not the stomach fundus, a cam string stitch is made, taking care not to damage the blood vessel. In the middle of the stitch, a gastric incision is made and a cannula is inserted into the stomach consisting of a small vinyl tube with a flange at one end around which the cam stitch is tightly closed. Immediately after this, 0.5 ml of intraduodenally test substance is administered per 100 g of rat. Typically, three rats are used for each dose of compound tested.

Control rats receive a placebo, typically 0.5% aqueous methylcellulose solution. After application of the test compound, the abdominal wall and skin are closed at the same time with three to four 18 mm clips and a collecting tube is placed on the cannula. Each rat is then placed in a box in which a longitudinal notch has been made allowing the cannula to hang freely and allowing the rat to move freely. The rat is allowed to stabilize for 30 minutes, the cannula collecting tube is removed and replaced with a clean gastric juice collection tube. Samples are taken within 1 hour At the end of the test, the cannula is removed and the rat is sacrificed.

The sample of gastric juice collected is drained into a centrifuge tube and centrifuged to separate the sediment. The volumes are read and 1 ml of the upper layer is placed in a beaker containing 10 ml of distilled water and titrated to pH 7 with 0.01 N sodium hydroxide. The results determine the volume, titratable acid and total acid, the total volume ml ml of gastric juice without sediments; titratable amounts of acid (milliequivalents / l) - amount of 0.01 N sodium hydroxide required to filter the acid to pH 7; and total amounts of acid - titratable acid x volume. The results are given in% inhibition versus control, with 50% inhibition being the criterion of the active compound.

It has further been found that some of the compounds of formula (I) in free base or acid addition salt form and acid have additional pharmacological activity as described below. In particular, compound I, wherein Z is thio, R 1 contains a cyclic moiety (cycloalkyl, phenyl, substituted phenyl or heterocyclic), and A-B is lower alkyl, CH ₂ CH- (S 2) (CH ₂ or CH ₂ CH ₂ ) The CHgCHg moieties are active as antiarrhythmics and as inhibitors of adrenaline and caffeine-stimulated lipolysis, as shown by the following three assays.

Sine Antarrythmic Test:

The right atrium of an aesthetized dog (snestes of the same species as the reflexogenic tachycardia test) is exposed to right-sided toractoaia and pericardium tear. Sinus fibrillation, determined by standard limb lead KO II, is induced by placing two drops of a 10% ecetylcholine solution in the sinus by pushing with a sintered spatula. The flbrillation interval is recorded. Two fibrillation control periods are formed over 15-minute intervals. The test compound is administered intra-intravenously 10 seconds after the subsequent induction. A compound is classified as active if it reduces fibrillation by at least 50%. Some of the compounds of Formula I described above are effective at dosages of from about 1.0 to about 18.5 mg / kg body weight.

Adrenaline-stimulated lipolysis:

Rat epididymal fat paired pads are incubated in Krebs-Ringer's hydrogen carbonate buffer in the presence of 5 (Ug / ml adrenaline tartrate for 1 hour. One pair of fat pads is used as a control and the test compound is added to the other before incubation The test substance was 1.0 mmol The degree of lipolysis was determined by determining the formation of glycerin by modifying the Wieland double enzyme method (Wieland, Biochem. Z., 329. 313 (1957)) A compound that inhibits glycerin release by more than 30% at 1, 0 mM or significant at 95% confidence limits are considered active.

Caffeine-stimulated lipolysis:

The same procedure as above except that caffeine at 1.0 mmol is present in the incubation mixture instead of adrenaline.

Compounds of formula (III) may be prepared directly by combining the corresponding indole of formula (XVIII) with the corresponding aminoalkylthiol of formula (XIX) wherein X, X ¹ ,

R 1, R ₂ , R ₃ and _n are as defined above and by the addition of an aqueous solution of iodine or peroxide (e.g. hydrogen peroxide or sodium peroxide) as oxidizing agent. Stoichiometric amounts of all three materials are preferred. The reaction is carried out in a suitable lower alkanol as described above. The temperature is not critical in order to increase the reaction rate. An elevated temperature may be used, but normal temperature is preferred. The reaction is carried out in the absence of air, such as under a nitrogen atmosphere. When the reaction is complete, the alkanol is evaporated in vacuo and the product is purified by a technique well known in the art.

This reaction can be illustrated by the following:

X ¹

(XVIII) XIX

Compounds of formula III may also be prepared by one of three other reactions. 1), when η = 1, by reacting the corresponding 3-indolytiol of formula VIII with the corresponding aziridine of formula IX in which X, R 1, R ₂ and R 3 are as defined above. The reaction is carried out in a suitable lower alkanol such as is shown above. Stoichiometric amounts are preferably used. While mixing the two reactants, cooling is preferred, but it is preferable to allow the reaction to proceed at normal temperature. However, the temperature is not critical and an elevated temperature may be used to increase the reaction rate.

2) When η 1 or 2, the reaction of the corresponding sodium salt of 3-indolyltolate of the formula V in an aqueous base solution and the corresponding chloralkylemine hydrochloride of the formula X in which X, R,? And R @ ₂ are as defined above, it is preferable to neutralize the hydrochloride AUL molárnlho addition of excess base or výhodnéJíl 3 indolyltiolátu aamotného. However, atechiometric amounts can be attracted. Normal temperature is preferred, but again, the temperature is not critical and elevated temperatures may be used to increase the reaction rate.

3) When η 1 or 2 and R 1 represents a hydrogen atom, reduction of the corresponding indol-3-ylthioalkylnitrile of the general formula XI in which X, X ¹ , R ¹ and R ₂ are as defined above. The reducing agent is boron, lithium aluminum hydride / aluminum chloride or the like. The reaction ae is carried out in a suitable organic reagent as mentioned above using a large excess of reducing agent. The temperature is not critical. While normal temperature is preferred, elevated temperatures may be used to increase the reaction rate. After decomposition of the excess reducing agent with a mineral acid (borane) or base (lithium aluminum hydride / aluminum chloride), the product is obtained in the form of an acid salt or free base.

These three reactions can be illustrated by the following:

+ Cl - (CH ₂ ) _n -CH-NH ₂ · HCl (V) (III) (n-1) (IX) d) (X)

reduction (III) (R ₃ -H)

The compounds of the formula III can be isolated as the free base by well-known synthetic methods. Conversely, the free base may be converted into a therapeutically active, non-toxic acid addition salt as described above for compounds of the formulas: I.

The compounds of the formula III are useful as intermediates of pharmacologically useful compounds of the formula I. In addition, the compounds of the formula III exhibit useful pharmacological properties themselves. They are active in the sense of inhibiting platelet aggregation in humans, as shown by the above tests for compounds of formula I In addition, some of the compounds of formula III are active in the sinus tachycardia test described above, especially when R, lower alkoxy is lower alkyl, phenylalkyl, alkenyl, methyl or isopropyl; and some compounds of formula (III) are active in the atrial antithermal test described above, especially when R ₁ is methyl, R g is phenyl, or when R _{1 is} methyl or isopropyl, all other substituents are hydrogen and n is one.

It is believed that certain compounds of formula (III) are novel, especially those wherein at least one of R 1, R ₂ , R p and X 'is different from a hydrogen atom and wherein n is two or three. These novel compounds of formula III and their therapeutically active acid addition salts 8 are within the scope of the invention.

Compounds of formula (II) may be prepared by reacting a corresponding compound of formula (XII) wherein A, B and R R are as defined above with triethyloxonium fluoroborate of formula (XIII). as described in Berřicht, 82, 2063 (1956). The reaction is carried out in a suitable organic solvent as described above. This session can be illustrated by the following:

+ (c ₂ h ₅ | ₃ o ⁺ bf ₄ - -► (II) (XII) (XIII)

Compounds of formula (IV) may be prepared by reacting the corresponding compound of formula (XII) wherein A, B and R R are as defined above with phosphorus oxychloride in benzene as described by Brederick et al., Berichte, 94, 2278 (1961). The reaction can be illustrated by the following:

+ NIGHTS ₃ (XII)

Compounds of formula V may be prepared by reacting the corresponding compound of formula VIII, wherein X, X ¹ , R ₁ and R ₂ are as defined above with aqueous sodium hydroxide solution. This reaction and the preparation of the compound of formula VIII are described by RLN Herris, Tetrahedron Letters, 4,465, (1969). Intermediates of the compound of formula (VIII) may be prepared by the method of CE Blades and AL Wilds: J. org. Chem. 21. 1 (3) (1956).

Compounds of formula V may also be prepared by reacting the corresponding indole of formula XVIII with thiourea in the presence of an oxidizing agent. Stoichiometric amounts of indole, thiourea and oxidizing agent are preferred. The oxidizing agent may be, for example, potassium iodide / potassium iodide, hydrogen peroxide, potassium periodate, sodium hypochlorite and the like. The reaction temperature may be normal or raised to the boiling point. The solvent may be water, a lower alkanol, an ether (e.g., diethyl ether, tetrahydrophthirane, etc.), glycol or the like. When the reaction is complete, treating the end product with a concentrated strong base (e.g., aqueous sodium hydroxide) of formula V.

231158 10

Compounds of formula (VI) may be prepared by reacting the corresponding compound of formula (XIV) wherein K i, A β B are as defined above, with tlonyl chloride. The reaction ae is carried out in an appropriate inert organic solvent as described above and in the absence of oxygen. A large excess of thionyl chloride is preferred. While the materials are preferably cooled to about 0 ° C during mixing, elevated temperatures may be used during the reaction. The mixture is preferably stirred under normal conditions and finally heated to reflux. The reaction can be illustrated as follows:

+ SOCI ₂

Compounds of formula XI may be prepared by reacting an appropriate N-substituted compound of formula XVI in a suitable inert organic solvent as described above with the corresponding halide R, W mixed with an aqueous base solution in which X, X ¹ ,

R 1 and R 1 are as defined above and W represents a halogen atom, preferably iodide, in the presence of benzyltriethylammonium chloride. Preferably, a molar excess of the alkyl halide is used, but a stoichiometric amount may be used. The reaction is carried out preferably from normal temperatures and can be illustrated as follows:

-S- (CH _{2) n} -CN

S- _(CH2) n-CN

X ¹

N ^-

AND

H + R ₂ WR

X ¹

N '

I (XVI) XI

The 1-substituted products of formula (I) may also be prepared by reacting 1-unsubstituted (R ₁ = H) compounds of formula (I), optionally with a strong base and then with the appropriate halide R, W in a suitable inert organic solvent mentioned above. Suitable strong bases are, for example, sodium hydride, lithium hydride, sodium amide and the like with which the unsubstituted compound of formula I is preferably slowly stirred. W in the halide is preferably iodide or bromide, although chloride may also be used. The desired product is isolated and purified by conventional means.

This reaction can be illustrated as follows:

, S- (CH ₂ ) _{n -} CH

I strong base

-B RlW

R ₄

1)

Compounds of formula XIV may be prepared by reacting a corresponding compound of formula II with an appropriate aminoalcohol of formula XV, wherein A, B and n are as defined above. The reaction is carried out in a suitable organic solvent as described above. Stoichiometric amounts are preferably used. The temperature is not critical and elevated temperatures may be used, but preferably normal temperatures are used. The reaction can be illustrated as follows:

(II) + HO- (CH ₂ ) _n -CH-NH ₂ (XIV) (XV)

Compounds of formula XVI may be prepared by reacting the corresponding compound of formula V in a suitable inert organic solvent as described above with the appropriate haloalkylnitrile of formula XVII mixed with an aqueous base solution wherein X, X ¹ , R 8 and n are as defined above. Stoichiometric amounts are preferably used. Normal temperatures are preferred, although the temperature is not critical. Elevated temperatures may be used to increase the reaction rate.

The reaction can be illustrated as follows: X _x S - (CH ₂ ) _{n -} CN and H _χ + W- (CH) _n -CN -> Γ ^R 2 X V ^{I 1} XX _R H ”2 (IN) (XVII) (XVI)

Compounds of formulas VII, VIII, IX, X, XII, XV, XVII, XVIII and XIX are generally known and can be prepared by known methods.

The following examples are intended to illustrate but not limit the scope of the invention. Parts are by weight unless otherwise indicated.

Example 1

To 240 parts of methanol are added 23.4 parts of indole, 15.2 parts of thiourea and a sufficient quantity of 1N aqueous potassium iodide and iodine solution so that for each equivalent of indole an equivalent of each component is present. The reaction mixture was stirred for 16 hours, after which time the solvent was evaporated under reduced pressure to give S [3-indolyl] isothiuronium iodide as colorless crystals of m.p. 214-216 ° C. Treatment of this product with an excess of concentrated aqueous sodium hydroxide solution under nitrogen atmosphere at 80 ° C for 10 minutes followed by cooling to normal temperature gave an alkaline solution of 3-indolylthiol. After neutralization with dilute hydrochloric acid, the pure substance, 3-indolylthiol, melting at 100-101 ° C is obtained.

Example 2

According to the method of Example 1 and by substituting the indole used therein for an equivalent amount of the appropriately substituted indole, the following substituted 3-indolylthiols were prepared:

X X ^{1 R} 2 H H - ° 6 ^H 6 5-CH ₃ O- H H H H -ch ₃ 5-C1 H H 5-C ₂ H ₅ H H, ^CH3 H H - (o / -ci H H —Oc ₂ h ₅ H.CO Cl H H Cl TO H -ch ₂ c ₆ h ₅ H H - ^ch 2 - ^< \ Q / ^> —Cl 5-OCH3 6-OCH ₃ H 5-Br H H _7-CH3 H H

If desired, substituted or unsubstituted 3-indolylthiols may be left in solution as the sodium salts of 3-indolylthiols by omitting the final cooling and neutralization and this solution is used directly in the following preparations.

23 ’1

Example 3

3-Indolylthioacetonitrile

To the basic 3-indolylthiolate solution prepared in Example I was added 12.1 parts of chloroacetonitrile with about 70 parts of diethyl ether. The reaction mixture was stirred under a nitrogen atmosphere for about 16 hours, after which time the ether layer was separated. The aqueous layer was extracted with about 400 parts of methylene chloride and then about 140 parts of diethyl ether. The combined organic fractions were washed with dilute aqueous sodium hydroxide solution and dried over magnesium sulfate, then the solvent was evaporated under reduced pressure to give a brown crystalline solid. Recrystallization of this solid from methanol / isopropyl alcohol gave 3-indolylthioacetonitrile; mp 52-54 ° C.

Example 4

According to the method of Example 3, but using an unsubstituted 3-indolylthiol sodium salt solution to replace the equivalent of the substituted 3-indolylthiol sodium solutions of Example 2, the following 3-indolylthioalkylnitriles were prepared:

sch ₂ -cn

Melting point (° C)

H H -c ₆ h ₅ 150 to 153 5-CH 2 O- H H 106 to 110 H H -ch ₃ 137 to 138 5-C1 H H 106 to 107.5 5-C ₂ H ₅ H H 61 to 63 CH. / ³ H H H H - (5) - ^oc 2 ^h 5 h ₃ co Cl H H H H -CH-C ₆ H ₅ H H -ch ₂ - (& - Cl

OF X ¹ «2 Melting point 5-OCH ₃ H H 5-Br H H _7-CH3 H H

If desired, substituted or unsubstituted 3-indolylthioacetonitrile can be stored in solution and used unisolated in the following preparations.

Example 5

methylindol-3-ylthioecetonitrile

The 3-indolylthioecetone trll of Example 3 was dissolved in 100 parts of ether and an equal volume of 50% aqueous sodium hydroxide solution was added. To this mixture was added first parts of benzyltriethylammonium chloride and then 56.8 parts of methyl iodide, the reaction mixture was cooled. The reaction vessel is sealed and the mixture is stirred for about 16 hours. The resulting solution was extracted with 500 parts of diethyl ether and 650 parts of methylene chloride.

Each extract was washed twice with dilute aqueous sodium hydroxide solution, once with saturated aqueous sodium chloride solution, and dried over potassium carbonate.

Then, the extracts were combined and the solvent was evaporated under reduced pressure to give a crude product which was recrystallized from methanol / isopropyl alcohol to give pure 1-methylindol-3-ylthioacetonitrile; mp 92.5-93 ° C.

Example 6

According to the method of Example 5, but substituting an equivalent amount of the appropriately substituted 3-indolylthioacetone trile from the unsubstituted 3-indolylthioecetonitrile used herein and replacing the alkyl iodide with the methyl iodide used herein, the following is prepared. substituted 1-alkylindol-3-ylthioacetonitriles:

X i

χ 'sch ₂ cn

Ν '

I «2

X X ¹ «1 «2 Melting point Η Η ^C 2 ^H 5 H 37.5-39 ° C Η Η iC ₃ Hy H oil Η Η -CH ₃ -ch ₃ Mp 133-138 ° C Η Η H oil Η Η -ch ₂ c ₆ h ₅ H oil Η Η -CHgCHgOCHi H oil Η Η -CH ₂ -? H oil Η Η -n-CgH ₁ γ H oil Η Η -ch ₂ - <> o H oil Η Η -CH ₂ CH = CH ₂ H Mp 45-47 ° C Η Η -c ₆ h ₅ H Η Η jol · “OCH, _ / ³ H Η Η _ / o \ —och ₃ H Η Η ch ₂ - (o) —ci H Η Η -CHgCSCH H oil Η Η -CH ₂ C (CH ₂ ) = CH ₂ H oil 5-OCH ₃ 6-OCH ₃ - ^C 2 ^H 5 H 5-C1 Η -CH ₃ H Η Η -N-CjHy H

Example 7

-methylindole; mp: 169 ° C

3 - [[2-Aminoethyl] thio] -1-methylindole formate:

To a solution of 45 parts of 1-methylindol-3-ylthioacetonitrile in about 80 parts of tetrahydrofuran (THF) was slowly added, while cooling, 415 parts of 1M boron dissolved in THF. 5 parts of borane and the reaction mixture was stirred for an additional 16 hours. This solution was slowly treated with dilute hydrochloric acid with stirring until the evolution of hydrogen ceased (after about 6 hours), then basified with 1N sodium hydroxide. The basic solution was extracted with 3 x 150 parts diethyl ether; The combined ether extracts were washed 3 times with dilute sodium hydroxide solution and once with saturated aqueous sodium chloride solution and dried over potassium carbonate. The ether solution was evaporated to about half volume and hydrogen chloride gas was reported to cause the hydrochloride to crystallize. This was recrystallized from methanol / ethyl acetate to give 3 - [[2-aminoethyl] thio] -1-methylindole hydrochloride; mp: 159-160.5 ° C.

The fumaric acid salt is prepared by concentrating the above ethereal solution before adding hydrogen chloride gas, and the resulting yellow oil is dissolved in methanol. To this solution was added 9 parts of fumaric acid, which was dissolved in methanol, and the solvent was slowly evaporated while the isopropanol was added gradually. The resulting product was recrystallized from methanol / isopropyl alcohol to give pure 3 - [[2-aminoethyl] thio] -i fumarate (decomposition)

For: _Cl1 H ₁₄ N ₂ SC ₄ H ₄ O ₄ :

calculated: 55.88% C; 5.63% H; Found: 56.04% C; 5.60% H;

N, 8.69. N, 8.57

Example 8

According to the method of Example 7, but by substituting the appropriately substituted 3-indolylthioecetonitrile for the 1-methyl-3-ylthioacetonitrile used herein, the following 3- [(2-eminoethyl) thio] indoles are prepared:

sch ₂ ch ₂ nh ₂ .s

X ¹ «1

X X ^{1 R} 1 ^K 2 WITH Melting point H H H H HCl Mp 212-215 ° C 5-CH ₃ O- H H H HCl Mp 192-196 ° C H H ^C 2 «5 H 1 / 2C ₄ H ₄ O ₄ Mp 181-182 ° C H H ^ 3¾ H ^C 4 ^H 4 ° 4 176-177.5 ° C H H -ch ₃ -ch ₃ HCl Mp 161-165 ° C H H H - ^C 6 ^H 5 - Mp 125-126 ° C 5-C1 H H H HCl 245-247.5 ° C (decomposition) 5-C ₂ H ₅ H H H HCl Mp 197-198 ° C

S Melting point

Η H

Η H

Η H

Η H

5-C1 H

Η H

Η H

H

H

H

H

IH.

H

H

Mp 124-127 ° C

5-OCH ₃ 6-OCH _3- H

H H <l H ° 4 ° ^C 4 ° 4 ° C 160 to 161 ° C H H -CH ₂ CH ₂ OCH ₃ H ^C 4 ^H 4 ° 4 147 až 148 [deg.] C H H -ch ₂ - <] H 1/2 C ₄ H ₄ O ₄ 168 až 170 [deg.] C H H -n H ^C 4 ^H 4 ° 4 152 až 153 [deg.] C H H -ch ₂ -Q H ^C 4 ^H 4 ° 4 166 až Mp 167 ° C H H -c ₆ h ₅ H H H - <ζθ ^> - ^{C |} H och ₃ H H —Ζθ / - ^och 3 H H H ch ₂ ——Cl H

-CH -C = CH2

C ₆ ^H 1 ₃ NO ₃ S

136.5-141 ° C

X X ¹ »1 R 2 WITH Melting point 5-Br H H H _7-CH3 H H H H H 1/2 _W4 159.5-160.5 ° C H H -CHgCHsCHg H ^C 4 ^H 4 ° 4 Mp 158-159 ° C H H -ch ₂ c ₆ h ₅ H ^C 4 ^H 4 ° 4 183-185 ° C H H -CH ₂ C (CH ₃ ) = CH ₂ H ^C 4 ^H 4 ° 4 15 ', 5-153 ° C

Example 9

3- (2-aminopropylthio) indole:

To 4.9 parts of the 3-indolylthiol prepared in Example 1 dissolved in about 24 parts of absolute methanol was added 1.71 parts of propyleneimine. The reaction mixture is stirred under nitrogen for about 40 minutes, then the methanol is evaporated off under reduced pressure and the residue is dissolved in diethyl ether. The ether extract was extracted with 3 x 50 parts of 1N hydrochloric acid. The combined extracts were washed with about 180 parts of diethyl ether and then basified by addition of 2N sodium hydroxide solution.

The alkaline solution was then extracted with 3 x 60 parts diethyl ether; the combined ether extracts are washed with 50 parts of 1N sodium hydroxide with one saturated aqueous sodium chloride solution and dried over potassium carbonate, the ether is evaporated under reduced pressure and the crystalline product obtained is dissolved in ethyl acetate and activated carbon is added. When the activated carbon is filtered off, scratching the reaction vessel containing the filtrate yields a crude product which, after crystallization from benzene, yields pure 3- (2-aminopropylthio) indole; mp 110.5-112.5 ° C.

Example 10

According to the method of Example 9, but the propyleneimine used therein was replaced with an equivalent amount of aziridine, the following product was obtained: 3- [(2-aminoethyl) thio] indole; mp: 87-89 ° C.

Example 11

3 - [[3-Aminopropyl / thio] indole:

To an alkaline aqueous solution of 3-indolylthiol prepared from 63.8 parts of 3-indolylthiuronium iodide as in Example 1 was added dropwise an aqueous solution of 13.0 parts of 3-chloropropylamine hydrochloride with stirring. The reaction mixture is then stirred for 3 hours under a nitrogen atmosphere, after which the solution is extracted with 280 parts of diethyl ether. This extract was washed 3 x about 150 parts with 1N sodium hydroxide and once with saturated sodium chloride solution and dried over potassium carbonate. The ether was evaporated and the residual oil crystallized on standing. This product was recrystallized from ethyl acetate and then recrystallized from benzene to which a small amount of activated carbon was added to give a pure crystalline 3- [(3-aminopropyl) thio] indole; mp 72.5-73.5 ° C.

For: Ο ,, Η ^ γ:

calculated: 64.03% C, 6.84% H;

found: C, 64.02; 6.84% H.

Example 12

3- [2- (1-Methyl-2-imidezolinylamino / ethylthio) indole fumarate:

A solution of 25.8 parts of 1-methyl-2-methylthio-2-imidazoline hydrochloride and 19.2 parts of 3 - [(2-aminoethyl) thio indole prepared by the method of Example 9 in 160 parts of 2-propanol is heated to reflux. for 18 hours and the mixture is protected from light. The yellow oil obtained after evaporation of isopropyl alcohol under reduced pressure was treated with 90 parts of 2N sodium hydroxide solution and the mixture was extracted with 400 parts of methylene chloride. The extract was washed twice with dilute sodium hydroxide solution and once with saturated aqueous sodium chloride solution and dried over potassium carbonate. Evaporation of the methylene chloride under reduced pressure affords crude crystalline 3- [2- (1-methyl-2-imidazolyl-amino / ethylthio) indole, which is then converted into the fumarate salt by dissolving in hot methanol and adding 10.8 parts of fumaric acid dissolved in methanol. . The fumarate salt is crystallized from solution by addition of isopropyl alcohol and recrystallized twice from methanol / isopropyl alcohol to give 3- [2- (1-methyl-2-imidazolinylamino) ethyl] indole fumarate; mp 198.5 (dec.).

For C ₁₄ H ₁₈ N ₄ SC ₄ H ₄ O ₄ calculated: 55.37% C; 5.68% H; 14,35 «N.

Found: 55.33% C; H, 5.75; 14.25% N.

Example

According to the method of Example 12, however, substituting equivalent amounts of the appropriate alkylthioimidazoline and the corresponding 3- (aminoalkylthio) indole for the 1-methyl-2-methylthio-2-imidazoline hydrochloride and 3- [[2-aminoethyl] thio] indole used therein to give the corresponding products:

S-CH 2 O · H

Η Η H

Η Η H

5-Cl H CH ₃

H 1

H 1

H 2

Ch 1 ch ₃ hh ch ₃ h ch ₃

CH ₃ C ₅ H ₅ H ch ₃ hc ₂ h ₅

Example 14

O-ethyl-N-methylpyrrolidonlum fluoroborate:

To a solution of 7.76 parts of epichlorohydrin in 14 parts of anhydrous diethyl ether is slowly added a solution of 15.9 parts of boron trifluoride etherate in 14 parts of anhydrous diethyl ether and the reaction mixture is stirred for 3.5 hours and protected from atmospheric humidity. Ster decant the solid triethyloxonium tetrefluoroborátu excluded and washed twice with anhydrous aminoester ^of e ^ Otom and dried under a stream of nitrogen.

Dried triethyloxonium tetrafluoroboret was dissolved in 26 ml dry methylene chloride and a solution of 8.32 parts H-methyl-2-pyrrolldone in 26 parts dry methylene chloride was added. The reaction mixture was stirred for 6 hours protected from atmospheric humidity to form O-ethyl-N-methylpyrrolidonium fluoroborate. This reagent can be isolated by evaporation of the solvent, but is preferably used in solution without prior isolation.

Example 15

Using the procedure of Example 14, but substituting an equivalent amount of the appropriate pyrrolldone or piperidone for the N-methyl-2-pyrrolidone used therein, the following respective products were obtained:

ch ₃

CH,

CH,

CH, c ₂ H ₅ ^C 6 ^H 5

- <>> Cl

-ch ₂ c ₆ h ₅

^C 6 ^H 5 —ch ₃ .ci

O) -CI

H

H

«4 R 5 m —CHg —— Cl H 1 H 1 -CH ₂ CH ₂ OH H 1 -ch ₂ ch = ch ₂ H 1 -GHgCSGH Η 1

Example 16

3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio [I indole:

A suspension of 16.0 parts of 3 - [(2-aminoethyl) thio] indole hydrochloride prepared according to Example 7 in an aqueous base is extracted with 230 parts of benzene. The extract was then washed with 1N sodium hydroxide solution and once with saturated sodium chloride solution and dried over potassium carbonate. The benzene was then evaporated under reduced pressure and the red oil obtained was dissolved in 60 parts dry methylene chloride. The resulting solution was added to the solution prepared in Example 15 and the reaction mixture was stirred for about 18 hours, protected from atmospheric humidity.

The resulting brown solution was extracted with 2 x 60 parts of 20% sodium hydroxide and dried over potassium carbonate; The methylene chloride was then evaporated under reduced pressure to give the crude free base. This crude free base was recrystallized from isopropyl alcohol to give pure 3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole: mp 143.5-145.5 ° C.

H, 7.00; N, 15.37.

Found:% C, 65.83;% H, 6.92;% N, 15.37

Example 17

According to the method of Example 16, but substituting an equivalent amount of the corresponding 3 - [(2-aminoethyl) thio] indole hydrogen halide for the 3 - [[2-aminoethyl] thio] indole hydrochloride used therein and using an equivalent amount of the corresponding fluoroborate prepared as in of Example 14 or 15 the corresponding products are obtained

3- [3- (1-Methyl-2-pyrrolidinylideneamino / propylthio) indole hydrochloride; melting point:

216.5-218.5 ° C.

3- [2- (1-methyl-2-pyrrolidinylideneamino) -propylthio] indole; mp 178.5-180 ° C.

3- [2- (1-Methyl-2-pyrrolidinylamino-amino) -ethylthio] -1-methylindole hemi-2-butenedioate; mp 186-189 ° C.

5-methoxy-3- [1- (1-methyl-2-pyrrolidinylideneamino) -ethylthio] indole; m.p .: 154-157 ° C (triturated).

1-ethyl-3- [2- (1-methyl-2-pyrrolidinylideneamino) -ethylthio] indole cyclohexanesulfamet; mp: 113.5-115.5 ° C.

3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] -2-ethylindole; Melting point: 167 to 170 DEG

168.5 ° C.

1,2-dimethyl-3- [2- (1-methyl-2-pyrrolidinyladenamino) -ethylthio] indole 2-butanedioate; mp: 149-150 ° C.

3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] -2-phenylindole; mp 181 ež

183.5 ° C.

5-chloro-3- [2- (1-methyl-2-pyrrolidinylidenemino) ethylthio] indole; melting point: 164.5 ež

165.5 ° C.

3- [2- (1-Methyl-4-phanyl-2-pyrrolldinylideneamino) -ethylthio] indole; mp: 162-163 ° C.

3- [2- (1-methyl-2-pyperidinylideneamino / ethyltlo) indole secherinate; melting point: 124 ež

124.5 ° C.

3- [2- (2-pyrrolidinylideneamino) ethylthio] indole saccharinate; m.p .: 141-142 ° C.

3- [4/1-methyl-2-pyrrolidinylideneamino-butylthio] indole; mp 172.5-173.5 ° C.

- (1-methylethyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole; melting point:

to 84 ° C.

5-ethyl-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole; Melting point: 131.5 to

132.5 ° C.

2- (3-methyl-5-chlorophenyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole;

2- (4-ethoxyphenyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole;

3- [2- (1-ethyl-2-pyrrolidinylideneamino) ethylthio] -2- (2-methoxy-3,5-dichlorophenyl) indole; 3- [2- (1-methyl-4-p-tolyl-2-pyrrolidinylideneamino) ethyl] indole;

3- [2- (1-methyl-4- (3,4-dichlorophenyl) -2-pyrrolldinylideneamino) ethylthio] indole;

3- [2- (1-Methyl-2-pyrrolidinylideneamino) -ethylthio] -1-benzylindole-cyclohexylsulfamate monohydrate; melting point: 133-134 ° C.

3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] -1- (2-methoxyatyl) indole cyclohexylsulfamate; mp 107.5-109 ° C.

1-Cyclopentyl-3- [2- (1-methyl) -2-pyrrolidinylideneamino / ethyltl] indole benzoate; mp 108.5-110 ° C.

1- [2-fursnyloethyl] -3- [2- (1-methyl-2-pyrrolidinylidinyl) affino] ethylthio] indole 2-butenedioate; mp: 167-168.5 ° C.

231ι58

-cyclopropyloethyl-3-L2- (1-methyl-2-pyrrolidinesdenamino / ethylthio) indole 2-butenedioate; mp: 133-134 ° C.

3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] -1- (2-propenyl) indole cyclohexylsulfaate; mp 105-107.5 ° C.

3- [2- (1-methyl-2-pyrrolidinylldenamino) ethylthio] -1- (n-octyl) indole fumarate; mp 98-100 ° C.

3- [2- (1-Methyl-2-pyrrolidinylidenemino) ethyl] -1-phenylindole cyclohexanesulfamate;

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

1- (4-chlorophenyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthi] indole benzoate;

1- (3,4-dimethoxyphenyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole benzoate;

3- [2- (1-methyl-2-pyrrolidinylideneamino) -ethylthio] -1- (2-propynyl) indole cyclohexylsulfamate; mp 114.5-115.5 ° C;

5,6-dimethoxy-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole;

2-Benzyl-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole;

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

3- {2- [1-dimethylamino / ethylidenimino] ethylthio} indole cyclohexylsulfamate; mp 174-176.5 ° C.

5-bromo-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthi] indole;

3- [2- (1-phenyl-2-pyrrolidinylideneamino / ethylthio) indole;

3- [2- (1-4-chlorophenyl) -2-pyrrolidinylideneamino] ethylthio] indole;

3- [2- (1-benzyl-2-pyrrolidinylideneamino) ethylthio] indole;

3- [2- [1- (4-chlorobenzyl) -2-pyrrolidinylideneamino] ethylthio] indole;

3- [2- / 1-cyclopentyl-2-pyrrolidinylideneamino / ethylthio] indole;

3- {2- [1- (2-hydroxyethyl) -2-pyrrolidinylidenemino] ethylthio} indole;

3- {2- [1- [2-propenyl] -2-pyrrolidinalidenemino] ethylthio} indole;

3- {2- [1- (2-propynyl) -2-pyrrolidinylidanamino] ethylthio) indole;

1- (2-methyl-2-propenyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole; mp 126.5-128 ° C.

7-methyl-3- [2- (1-methyl-2-pyrrolidinylidenemino) ethylthio] indole;

3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] -1-propylindole 2-naphthalenesulfonate; mp 98.5-100.5 ° C.

231’5β

3- (2- [1- (2-Propenyl) -2-pyrrolidinylideneamine) ethylthio} indole 2-butenedioate; m.p .: 115-117 ° C.

Example 18

3- [2- (1-Methyl-2-pyrrolldinylideneamino / ethylthio) indole

To a solution of 23.8 parts of N-methyl-2-pyrrolidinone in 450 parts of dry benzene was added dropwise a solution of 36.7 parts of phosphorus oxychloride in 70 ml of dry benzene. The colorless solution was refluxed under nitrogen for 2 hours. Now the yellow solution was cooled to normal temperature and a solution of 38.4 parts of 3 - [[2-aminoethyl] thio] indole in 90 ml dry benzene was added dropwise over 20 minutes. The reaction mixture is then heated at reflux for 4.5 hours under a nitrogen atmosphere and allowed to stand for about 18 hours at normal temperature.

The resulting reaction mixture was made basic by the addition of 300 ml of water and 120 parts of 50% sodium hydroxide solution and the reaction mixture was heated on a water bath to complete the decomposition of the oily complex. The benzene layer was separated and the aqueous layer was extracted twice with ether. The extracts were combined, dried over potassium carbonate and the ether evaporated under reduced pressure to give an oily product. This was recrystallized twice from isopropanol / pentene to give 3- [2- / 1-methyl-2-pyrrolidinylidene / ethylthio] indole; melting point:

Mp 143-144 ° C.

Example 19

3- [2- (1-Methyl-2-pyrrolidinylideneamino / ethylthio) -indole:

To the product of Example 14 was added a solution of 4.27 parts of 2-amino-ethanol in 260 parts of methylene chloride, and the reaction mixture was stirred at normal temperature for 16 hours. The solvent was then evaporated to give the crude fluoroborate salt product. The fluoroborate salt is converted into a solid base which is converted into perchlorate, 2- (pyrrolidinylideneamino) -ethanol perchlorate; mp 67-69 ° C.

To a solution of 3.5 parts of the above free base in 130 parts of dry chloroform was added dropwise over 15 minutes 8.4 parts of thionyl chloride at 0 ° C under a nitrogen atmosphere. The reaction mixture was then allowed to warm to normal temperature and stirred for about 16 hours. Finally, the reaction mixture is refluxed under nitrogen for 0.5 hours, after which time the chloroform and excess thionyl chloride are removed under reduced pressure to give the crude product.

This residue was dissolved in methylene chloride and treated with 6N sodium hydroxide solution. The methylene chloride layer was separated, dried over potassium carbonate and filtered. Evaporation of methylene chloride under reduced pressure gave 2- (chloroethylimino) pyrrolidine.

The alkaline solution was prepared from 7.65 parts of 3-indolytiuronium iodide as in Example 1 and washed twice with 175 parts of diethyl ether. This aqueous solution is then reacted with an ether solution of pre-treated 2- (chloroethylimino) pyrrolidine under a nitrogen atmosphere and the reaction mixture is stirred from normal temperature for about 16 hours. Methylene chloride was added to replace the ether that was evaporated, the organic layer was separated and the aqueous layer was extracted with methylene chloride.

The combined organic solutions were dried over potassium carbonate, filtered, and the filtrate evaporated under reduced pressure to give an amber oil which solidified slowly upon scratching. The solid was recrystallized from isopropyl alcohol / petroleum ether to give pure product, 3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole. The infrared spectrum of the pure product is identical to the authentic sample prepared by an alternative procedure.

Example 20

3- [2- (1-Methyl-2-pyrrolidinylnylideneamino) ethylsulphinyl] indole hemifumarate hydrate:

To a solution of 8.7 parts of 3- (2- (1-methyl-2-pyrrolidinylideneamino / ethylthio) indole in 70 parts of methanol was added 8.2 parts of sodium periodate and 3.5 parts of water with stirring. for about 6 hours, the white sodium iodate formed is filtered and washed with methanol, and the wash solution is combined with the filtrate and acidified by adding a solution of fumaric acid in methanol. methanol / acetone gives pure product, 3- [2- (1-methyl-4-pyrrolidinylideneamino / ethylsulfoxy) indole hemifumarate hydrate, m.p. 154-157.5 ° C.

Example 21

3- (2-Aminoethyl) thioindole hydrochloride:

To a solution of 1.17 parts of indole and 1.13 parts of 2-aminoethylthio in 12 parts of methanol was added 11 parts of an aqueous solution of 1 mol of iodine under nitrogen and the reaction mixture was stirred for 1 hour. The methanol was evaporated under reduced pressure, the residue acidified with two portions of concentrated hydrochloric acid and the resulting aqueous solution was extracted with diethyl ether. The aqueous solution and solids suspension is then basified with sodium hydroxide solution and further extracted twice with diethyl ether, the two combined extracts are washed with saturated sodium chloride solution and dried over potassium carbonate. The ether was evaporated under reduced pressure to give the free base, 3- (2-aminoethyl) thioindole as an orange oil. Hydrogen chloride gas solution of this oil in methanol / ether gives the hydrochloride salt, 3- (2-aminoethyl) -indole hydrochloride; mp 212-215 ° C.

Example 22

3- [2- (1-Methyl-2-hexahydroazepinylideneamino / ethylthio) indole 2-butanedioate:

A solution of 6.1 g / 48 maol of N-methylceprolactam in 15 ml of dry methylene chloride is added to a solution of triethyloxonium fluoroborate prepared from 9.1 g (64 mM) boron trifluoride etherate β 4.45 g (48 mmol) of epichlorohydrin and the reaction mixture is stirred in a nitrogen atmosphere, protected from moisture for 2.5 hours. Then 7.7 g (40 mmol) of 3- (2-aminoethylthio) indole in 20 ml of dry methylene chloride are added and the solution is stirred under anhydrous conditions at normal temperature for 72 hours. An equal volume of methylene chloride β is then added. The solution is washed once with 70 ml / 1 N sodium hydroxide, water and saturated aqueous sodium chloride solution and dried over potassium carbonate. The solution was filtered and the filtrate was evaporated under reduced pressure to give 8.6 g of an orange oil which solidified. Cross-linking of this product with the fumaric acid salt affords 3- [2- (1-methyl-2-hexahydro-zepinylideneamino) ethylthio] indole 2-butenedioate as colorless crystals; mp: 128-130 ° C.

Example 23

3- [2- (1'-Methyl-1,4,5,6-tetrahydropyrimidin-2-ylideneamino) ethylthio] indole 2-butenedioate:

To a solution of 1- (2-indol-2-ylthio) ethyl] thiourea (18.9 g, 75 mmol) in acetone (80 mL) was added methyl iodide (10.8 g) and the reaction mixture protected from atmospheric humidity was stirred at room temperature for 3. 5 hours. The acetone was evaporated under reduced pressure to give an orange oil. To a solution of 13.5 g (35 mmol) of this oil in 100 mL of anhydrous dimethylsulfoxide was added 3.08 g (35 mmol) of N-methyl-1,3-propanediamine with stirring and heating. After 1 hour and 40 minutes, the temperature reached 125 ° C and maintained for an additional hour.

The solution was evaporated under reduced pressure to give an oily product. This was dissolved in 50 ml of methylene chloride and treated with cooling with 25 ml of water containing 2 ml of concentrated ammonia water. The solution was washed with a saturated aqueous solution of sodium chloride and dried over potassium carbonate. The dried solution was evaporated under reduced pressure to give 6.0 g of the free base as a brown oil.

The fumaric acid salt is prepared in the form of colorless crystals in methanol / isopropyl alcohol; mp 212-213 ° C.

Example 24

2- (1-methyl-2-pyrrolidinylideneamino / ethylthio) indole saccharinate:

To a solution of oxindole (25 g, 188 mmol) in dry benzene (500 mL) was added sand (25 g).

Then, 8.85 g (40 mmol) of phosphorus pentasulphide is added to the stirred mixture, which is first brought to reflux, kept at this temperature for 80 minutes and then allowed to cool. The cooled reaction mixture was filtered and the solid on the filter was washed with 300 mL of benzene. The combined filtrates and washings were evaporated under reduced pressure to give 19.0 g (68%) of a yellow solid which was recrystallized from methanol to give 11.6 g (41%) of a yellow, crystalline indolin-2-thione.

To a stirred solution of chloroacetonitrile (26.4 g, 0.35 mol) in pyridine (200 mL) was added indolin-2-thione (11.0 g, 74 mmol). After 1 hour pyridine hydrochloride was filtered off and the filtrate was evaporated under reduced pressure to give an orange oil. Remaining pyridine ae is removed by azeotropic distillation with water. The oil was extracted into dry ether / water, the extract was washed twice with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The dried solution was evaporated under reduced pressure to give 1.5 g of a solid which was recrystallized from ethyl acetate / cyclohexane to give 10.0 g of colorless crystalline indol-2-ylthioacetonitrile; mp 91.5-92.5 ° C.

To a solution of 6.9 g (52 mmol) of aluminum chloride and 1.98 g (52 mmol) of lithium aluminum hydride in 257 ml of anhydrous ether was added 9.8 (52 mmol) of this nitrile in 50 ml of anhydrous ether and the reaction mixture was stirred for for 2 hours at normal temperature. A total of 10 g of 50% sodium hydroxide and 2 ml of water are added to the reaction mixture over a period of three hours, and the solution is stirred for 16 hours, the ether is separated from the solid and dried over potassium carbonate. The dried solution was evaporated under reduced pressure to give 5.4 g of product.

Further extraction of the solid from the reaction mixture with the ester again after the addition of 2.5 ml of water and 10 g of 50% sodium hydroxide gave an organic layer which was then combined with 5.4 g of product and dried over potassium carbonate. The dried solution was filtered, and the filtrate was evaporated under reduced pressure to give 9.0 g of 2- (2-aminoethylthio) indole. This amine was converted into the hydrochloride salt with an ester solution of hydrogen chloride and recrystallized with one of the methanol / isopropyl alcohol mixtures to give 6.4 g of crystalline solid.

A solution of 3.9 g (15 mmol) of 2- (2-aminoethylthio) -indole in 30 ml of dry methylene chloride was added to the fluoroborate salt solution from 3.42 g (24 mmol) of boron trifluoride / tate, 1.69 g (18 mmol) of eplchlorobenzene. β 1.80 g (18 mmol) of N-methyl-2-pyrrolidinone in 15 ml of dry methylene chloride. The solution was stirred under anhydrous conditions at normal temperature for 4 hours, then washed once with 1N sodium hydroxide and twice with saturated aqueous sodium chloride solution, dried over potassium carbonate. The dried solution was evaporated under reduced pressure to give 3.1 g of crude product. Purification with the saccharide salt affords cream colored crystals of 2- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole: mp 175-177 ° C.

For C ₅ H ₃ N _g SC ₇ H ₅ O ₃ NS / 273.29 / 456.57} calculated: 57.87% C, 5.30% H, 12.27% N i Found: 57.84 H, 12.31;

E

Example 25 t 3- (2- (1-Methyl-5-phenyl-2-pyrrolidiethylideneamino) ethylthio) indole cyclohexene sulfamate:

A solution of 6.3 g (36 mmol) of N-methyl-5-phenyl-2-pyrrolidone in 10 mL of anhydrous methylene chloride was added to triethyloxonium fluoroborate in 20 mL of anhydrous methylene chloride. This solution was stirred from normal temperature from anhydrous conditions for three hours. 5.75 g (30 mmol) of 3- (2-ammoniethylthio) indole in 20 ml of anhydrous methylene chloride are then added and the obtained solution is stirred under anhydrous conditions for three days. 50 ml of methylene chloride are then added and the solution is washed once with 50 ml of 1N sodium hydroxide solution, once with water and once with saturated aqueous sodium chloride solution, and is then concentrated over potassium carbonate. The dried solution was evaporated under reduced pressure to give the free base as a viscous oil. Purification by cyclohexane sulfamate gave colorless crystals of 3- [2- / 1-methyl-5-phenyl-2-pyrrolidinylideneamino / ethylthio] -indole cyclohexene sulfamate; mp: 190.5-191.5 ° C.

Analysis for 3NO3S (349.72) calculated: 61.33% C, 6.86% H, 10.60% N; Found: C, 61.40; H, 6.89; N, 10.56.

Example 26

According to the method of Example 2, but replacing the chloroacetonitrile of Example 2 with chlorobutyronitrile, 3-indolylthiobutyronitrile was prepared. Then, according to the method of Example 7, but by substituting the 1-methylindol-3-ylthiocetonitrile as used herein with an equivalent amount of the above 3-indolylbutyronitrile, 3- ([(4-aminobutyl) thio] indole 2-butenedioate) was prepared; mp 116.5-167.5 ° C.

The above examples are provided by way of illustration only and are not intended to limit the scope of the invention, the scope of which is determined by the appended claims.

and

23,158

A process for the preparation of the novel indole derivatives of the general formula I

(AND),

Claims (1)

P S E D i n i nn ll of the invention Z- (CH ₂ ) _n -CH-N 4 X 'wherein each of X and X ¹ is hydrogen, C ¹ -C 8 -alkyl, C 1 -C 8 -alkoxy or halogen, 8, represents hydrogen, C1-C6-alkyl. C 1 -C 8 -alkoxyC 1 -C 8 -alkyl, C 8 -C 8 -alkenyl, C 8 -C 8 -alkynyl, C 1 -C 8 -cycloalkyl-C 1 -C 8 -alkyl or phenyl-C 1 -C 8 -alkyl, K ₂ is hydrogen, O, -C 8 -alkyl or phenyl, n is 1, 2 or 3, R 1 represents hydrogen or C 1 -C 8 -alkyl, R 6 represents hydrogen, O, -C 8 -alkyl, phenyl or C 8 -C 8 -alkenyl, Z denotes a thio group, A and B individually represent C 1 -C 8 -alkyl, or A and B taken together are - (CH ₂ ) ₂ -, - (CH ₂ ) g -, -CH ₂ CH (R g) CH ₂ -, -CH ₂ CH ₂ CH (R g) or -N (R g) CH ( R j) (CH ₂ ) _m , wherein R g is hydrogen, Ο, -Οθ-alkyl or phenyl, R g is hydrogen or C 1 -C 8 -alkyl, and ft is 1 or 2, but if R is 2 then R g is hydrogen, as well as the therapeutically active acid addition salts of said novel derivatives of formula (I), characterized by reacting a compound of formula (II) wherein the compounds are as defined above with a compound of formula (III) (XII); wherein the general symbols have the meanings given above, in a suitable organic solvent which is lower aliphatic alcohols, for example methanol, ethanol, 2-propanol or a target. butanol, or ethers, such as diethyl ether, tetrahydrofuran or dioxane, or halogenated hydrocarbons, such as chloroform, methylene chloride or 1,2-dichloroethane, or aromatic hydrocarbons, such as benzene, toluene, or xylene, to form the fluoroborate salt of a compound of formula I above; whereupon the resulting fluoroborate salt is converted into the free base by treatment with a suitable base such as an alkali metal or alkaline woman metal hydroxide or carbonate, and optionally converting the compound of formula I into a therapeutically active non-toxic editorial salt by treatment with the appropriate acid.