NO145383B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE SUBSTITUTED INDOLS - Google Patents

Description

The present invention relates to the production of new therapeutically active substituted indoles or acid addition salts thereof, more particularly compounds with the formula:

where;

X and X 1 are both hydrogen, lower alkyl of 1-6 carbon atoms, lower alkoxy of 1-6 carbon atoms, halogen;

R, is hydrogen, lower alkyl of 1-8 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, benzyl, lower alkoxy-alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, cycloalkyl-alkyl of 4-6 carbon atoms and furanmethyl;

R2 is hydrogen, lower alkyl of 1-6 carbon atoms, phenyl,

n is 1, 2 or 3;

A and B together can form a group chosen from

-CH2CH(R5)CH2-, -CH2CH2CH(R5)-, -(CH^- and

-(CH2)j--, and where Rj. is hydrogen or phenyl.

The preferred compounds according to the present invention are those of formula (I) where R 1 is different from hydrogen, most preferred are those where R 1 is lower-alkyl or alkyl-

nyl. Most preferred are such compounds where X and X are hydrogen, R 2 is hydrogen or lower alkyl, n is 1,. R2 is lower alkyl and A—B is -(CH?K-.1

In the above formula, X, X , R 1 , R 2 are A, B and n

as defined previously unless otherwise stated.

Compounds of the formula (I) are preferably prepared by to react a suitable fluoroborate salt with pre-

mel (II) with a suitable 3_(aminoalkylthio)indole with for-

mel (III) where X, R-j^, R2, A, B and n are as defined previously

do. It is preferred to use a slight molar excess

of the fluoroborate salt. Suitable organic solvents in which the reaction can be carried out include lower aliphatic alcohols such as methanol, ethanol, 2-propanol, tertiary butanol and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane etc., lower halogenated hydrocarbons such as chloroform, methylene chloride, 2,2- dichloroethane and the like, and aromatic hydrocarbons such as benzene, toluene, xylene and the like. The temperature is not critical. Although it is preferred to use room temperature, elevated temperatures can be used to increase the reaction rate. The resulting fluoroborate salt is then converted to a corresponding base in the usual manner, e.g. by a treatment with a suitable base such as an alkali metal or alkaline earth metal hydroxide, carbonate, etc. This reaction can be illustrated as follows:

Compounds of formula (I) can also be prepared by means of two other reactions. First, one can react a suitable compound of formula (III) with a slight molar excess of a suitable compound of formula (IV) where X, X1, R-^, R2, A, B and n are as previously defined, and where W is bromine or chlorine, whereby a compound of formula (I) is obtained as an acid salt. This reaction can be carried out in a suitable inert organic solvent such as an aromatic hydrocarbon, e.g. benzene, toluene, xylene, etc., an ether such as diethyl ether, tetrahyrofuran (THF), dioxane etc, a halogenated lower alkane such as e.g. chloroform, dichloromethane, dichloroethane etc., etc. Although the temperature is not critical, it is preferred to carry out the reaction under reflux. Furthermore, as mentioned second reaction, a suitable sodium 3-indolylthiolate of formula (V) can be reacted in an aqueous base with a stoichiometric amount of a suitable compound of formula (VI) where X, X"*", R-^, R2j A , B and n are as defined previously.

in a suitable inert organic solvent as described above. The temperature is not critical. Room temperature is however preferred, but elevated temperatures can be used to increase the reaction rate.

These two reactions can be illustrated as follows:

The acid addition salt of the desired compound can be converted to the free base of formula (I) as previously described.

The desired compounds of formula (I)

can be isolated as the free bases by means of methods known per se. These compounds, in their base form, are easily converted into therapeutically active, non-toxic acid addition salts by treatment with a suitable acid, such as, for example an organic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or nitric acid, some type of phosphoric acid, organic acids such as 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, 2-phenoxybenzoic acid or 2-acetoxybenzoic acid. On

similarly, the salt form can be easily converted in a commonly known manner into the free base.

The present compounds of formula (I)

in the form of a free base or as an acid addition salt, has

proved to have a very good activity to lower the cardiac activity in mammals which was shown by the following reflexogenic tachyardic test. A bilateral vagotomy was performed on anesthetized dogs (anesthesia consisted of intravenous sodium thiopental (20 mg/kg body weight) and anesthesia was maintained by subsequent intravenous injections of α-chloralose (60 mg/kg body weight)). Two doses of aminophylline (5 mg/kg intravenously) were administered fifteen minutes apart. Aminophylline's hypotensive effect activates the baroreceptors in the carotid artery fistula which in turn stimulate the sympathetic nervous system which produces an increase in heart rate. 15 minutes after the second dose of the amino-phylline was administered, the compound to be tested was administered intravenously and the effect on the heart rate was then noted over a period of half an hour. Compounds that showed a reduction in heart rate of at least 18 beats per minute. minute for at least 5' minutes were considered to be active. Such compounds can be used in the treatment of angina pectoris, as heart rate is considered to be of significant importance for myocardial oxygen consumption.

Compounds according to the present invention are active in the above samples at doses which varied from 0.25 to approx. 18.5 mg/kg body weight.

It has also been shown that connections with

formula (I) in the form of free bases or as acid addition salts has valuable activity as inhibitors of platelet aggregation in humans. The compounds were tested using a collagen-induced aggregation at a final concentration of 100 µM in a platelet-rich plasma using the turbidimetric method described by Born (G.V.R. Born, Nature, 194, 927

(1962)). The results are given as mean percent inhibition of aggregation. All compounds present were active in the above sample.

It has further been found that the present compound of formula I also has valuable anti-secretory activity in the following acute gastric fistula test performed on rats. The anti-secretory activity was studied in female Sprague-Dawley rats after an intraduodenal injection of the compound in doses ranging from 2.5 - 40 mg/kg body weight. The rats were fasted for 24 hours before being tested, but were given water ad libitum

libidum while kept in individual cages. On the day the compounds were tested, the rats were weighed and selected so that the rats in each sample had weights in the range of + 20 g.

A surgical procedure was performed under weak ether anesthesia. Once the rat was anesthetized, the teeth were removed using small forceps. An incision was made along the abdomen in a length of approx. 1.5 cm, and the stomach and abdominal cavity were then exposed. If at this time the stomach was found to be filled with food or other material, the rat was killed and discarded. Using a 4-0 suture, a drain loop stitch was placed in the part of the stomach that is close to the fundus gland, taking care not to destroy any blood vessels in this area. A small incision was made in the stomach in the center of the drain loop, and a small cannula consisting of a small vinyl tube with a flange at one end was inserted into the stomach and the drain loop was fastened tightly around the flange. Immediately after this, the test compound was administered intraduodenal in a volume of 0.5 ml per 100 g rat. 3 rats were typically used for each dose level. The control rats received the liquid in which the test compound was dissolved, usually 0.5% aqueous methylcellulose.

After administration of the test compound, the abdominal skin was closed using small forceps and a collection tube was placed in the cannula. Each rat was then placed in a box with a longitudinal slot which allowed the cannula to hang freely and which allowed the rat to move without particular obstruction. After approx. ' 30 min. what was collected in the cannula was discarded, and a clean tube was inserted to collect the gastric juice. Collections were made within 1 hour. The cannula was then removed and the rats killed.

The stomach contents samples were centrifuged to collect the sediments. The volumes were read and a 1 ml sample of the clear supernatant was added to a beaker containing 10 ml of distilled H 2 O and titrated to pH 7 using 0.01 N NaOH. The results were determined for volume, titratable acid and total acid production' where volume = total mi gastric juice minus sediment; titratable acid (milliequivalents/liter) = amount of 0.01 N

NaOH which is needed to titrate the acid to pH 7, and total acid production = titratable acid x. volume. The results are indicated in % inhibition in relation to the control rat, and if 50% inhibition was obtained, the compound was considered. to be active.

It has further been shown that certain compounds of formula I in the form of free bases or in the form of acid addition salts have valuable pharmacological activities of the type described below. In particular, it was found that compounds of formula I containing a cyclic group (cycloalkyl, 'phenyl,' substituted phenyl or heterocyclic group) and A--B'' are lower alkyl', CH2CH-'(R5)CH2 or ( CH2)',(. are active as anti-arrhythmic agents and inhibitors of both epinephrine- and caffeine-stimulated lyolysis, as shown in the following three samples.

Atrial' anti-arrhythmic test: "'"' The right atrium of an anesthetized dog (same type of anesthesia as in the aforementioned reflexogenic sinus Ttachycardia test)• was exposed by a right thoracotomy and retraction of the per-cardium. Atrial fibrillation as can be determined by standard ECG was induced by placing two drops.of en-.10 . dissolving acetylcholine on said atrium and then stroking the atrium with a rounded spatula.....

The fibrillation period itself was noted. -Two control fibrillation periods were then produced with an interval of fifteen minutes. The compound to be tested was added i.v... 10 sec. after the next induction. A compound was classified as active if it lowered the fibrillation period by at least -50%, .-. Certain compounds of formula I described above are. active to - doses of from 1.0 - 18.5 mg/kg body weight. Epinephrine-Stimulated Lipolysis: Paired rat epididymal fat deposits were incubated in a Krebs-Ringer bicarbonate buffer in the presence of 5 µg/ml epinephrine bitartrate for 1 hour. Of the aforementioned provisions, one was

used as a control and the compound to be tested was added to another before incubation, so that the final concentration of the test compound was 1.0 mM. The degree of lipolysis was determined

by measuring glycerol production by a modification of the double-enzyme method described by Wieland (Wieland, Biochem Z., 329, 313 (1957)). Compounds inhibiting glycerol release by more than 30% at 1.0 mM or significant at a >95% confidence limit were considered active. Caffeine-stimulated lipolysis: The procedure was as described above, except that caffeine was used instead of epinephrine in the incubation mixture at a concentration of 1.0 mM.

Compounds of formula III may be prepared directly by combining an appropriate indole of formula XVIII with an appropriate aminoalkyl thiol of formula XIX, wherein X, X"<1>", R-^, Rg> and n are as previously defined, and adding a aqueous solution of iodine or a peroxide (eg hydrogen peroxide or sodium peroxide) as an oxidizing agent. It is preferred to use stoichiometric amounts of all three compounds. The reaction can be carried out in a suitable lower alkanol as defined earlier. Temperature is not critical, and elevated temperatures can be used to increase the reaction rate, but room temperature is preferred. The reaction is carried out in an absence of air, e.g. under a nitrogen atmosphere. After the reaction is complete, the alkanol is evaporated in a vacuum and the product is purified in a commonly known manner. This reaction can be illustrated as follows:

The compounds of formula III can also be prepared by one of three other reactions. First, when n=1 one can prepare the compound by reacting an appropriate 3-indolylthiol of formula VIII with an appropriate aziridine of formula IX where X, R 2 °S R 2 are as defined previously. The reaction is suitably carried out in a lower alkanol as defined earlier. Stoichiometric amounts are again preferred. Cooling can be used during the mixing of the two reactants, after which the reaction is preferably allowed to take place at room temperature. However, the temperature is not critical, and elevated temperatures can be used to increase the reaction rate.

Alternatively, when n=1 or 2, the compound may be prepared by reacting an appropriate sodium 3-indolylthiolate of formula V in aqueous base with an appropriate chloroalkylamine hydrochloride of formula X, where X, and R^ are as defined previously . It is preferred that the hydrochloride salt is neutralized by adding a molar excess of base or more preferably by the 3-indolylthiolate itself. One can, however, use stoichiometric amounts. Room temperature is preferred but again the temperature is not critical and elevated temperatures can be used to increase the reaction rate.

Third, when n is 1 or 2, the compound can be prepared by reducing an appropriate indol-3-yl-thioalkylnitrile of formula XI wherein X, X<1>, R-1 and R2 are as previously defined. Borane, lithium aluminum hydride/aluminium chloride or the like can be used as a reducing agent. The reaction is carried out in a suitable inert organic solvent as defined earlier, and by using a large excess of reducing agent. The temperature is not critical. Room temperature is preferred, but elevated temperatures can be used to increase the reaction rate. After the excess of reducing agent has been destroyed with mineral acid (borane) or base (lithium aluminum hydride/aluminum chloride), the product can be prepared as an acid addition salt or as a free base. These three reactions can be illustrated as follows:

The desired compounds of formula III can be isolated as free bases by methods which are themselves well known. Said free bases can then be converted into therapeutically active, non-toxic acid addition salts as indicated above for compounds of formula I.

Said compounds of formula III are usable as starting compounds for the preparation of pharmacologically usable compounds according to formula I. Furthermore, it has been shown that compounds of formula III in themselves have usable pharmacological properties. They are active as facilitators of platelet aggregation in humans as shown by assays described above for compounds of formula I. Further, certain compounds of formula III have been shown to be active in said reflexogenic sinus tachycardia assay, particularly when R-^ is lower alkoxy lower alkyl, phenylalkyl, alkenyl, methyl or isopropyl, and certain

.compounds of formula III are active in the atrial anti-arrhythmia test described when B.sub.1 is phenyl or R.sub.1 is methyl or isopropyl, while all other substituents are hydrogen and n is 1. It is assumed that certain compounds with formula III are new, especially those where at least one of the groups Rg, X and X^" is different from hydrogen, or where n is 2 or 3. These new compounds with formula III and therapeutically active acid addition salts of these compounds are thus included in the invention Compounds of formula II may be prepared by reacting an appropriate compound of formula XII where A and B are as previously defined with triethyloxonium fluoroborate (XIII) by the method described in Berichte, 89, 2063 (1956). The reaction may is suitably carried out in an organic solvent as defined earlier, preferably at room temperature. This reaction can be illustrated as follows: Compounds of formula IV can be prepared by reacting a suitable compound with formula XII where A and B are as previously defined, with phosphorus oxychloride in benzene by the method described by Brederick et al., Berichte, 94, 2278 (1961). This reaction can be illustrated as follows:

Compounds of formula V can be prepared by reacting an appropriate compound of formula VIII where X, X<1>, R-^ and R2 are as defined previously, with an aqueous solution of NaOH. Both this reaction and the preparation of compounds of formula VIII are described by R.L.N. Harris, Tetrahedron Letters, 4465 (1969). Starting compounds for the preparation of compounds of formula VIII can be prepared using the method described by CE. Blades and A.L. Wilds, Journal of Organic Chemistry, 21, 1013 (1956).

Compounds of formula V can also be prepared by reacting an appropriate indole of formula XVIII with thiourea in the presence of an oxidizing agent. It is preferred to use stoichiometric amounts of the indole compound, thiourea and the oxidizing agent. As an oxidizing agent, you can e.g. use iodine/potassium iodide, hydrogen peroxide, potassium periodate, sodium hypochlorite or similar. The reaction temperature can be room temperature or elevated to boiling under reflux. The solvent can be water, a lower alkanol, an ether (e.g. diethyl ether, tetrahydrofuran, etc), a glycol or the like. When the reaction is complete, the resulting product can be treated with a concentrated strong base (e.g. aqueous sodium hydroxide), preferably under heating, to give the compound of formula V.

Compounds of formula VI can be prepared by reacting an appropriate compound of formula XIV where A and B are as previously defined with thionyl chloride. The reaction is carried out in a suitable inert organic solvent as defined earlier, and in the absence of oxygen. A large excess of thionyl chloride is preferably used. Although it is preferred to cool the compounds to approx. 0°C during the mixture, elevated temperatures can also be used during the reaction. The reaction mixture should preferably be stirred at room temperature and finally boiled under reflux. The reaction can be illustrated as follows:

Compounds of formula XI can be prepared by

reacting a suitable N-unsubstituted compound of formula XIV in a suitable inert organic solvent as defined previously, with a suitable halide R,W mixed with aqueous base,

where X, X , R 1 and R 2 are as defined previously and W is halogen, preferably iodine, in the presence of benzyltriethylammonium chloride. A molar excess of the alkyl halide is preferably used. but stoichiometric amounts can be used. The reaction is preferably carried out at room temperature and can be illustrated as follows:

■ 1-substituted products of formula I can also be prepared by reacting 1-unsubstituted (R^=H) compounds of formula I, respectively, with a strong base and then with a

suitable halide R-j^W, all in a suitable inert organic solvent as defined earlier. Suitable strong bases are e.g. sodium hydride, lithium hydride, soda amide and the like, where the unsubstituted compound (formula I) is preferably slowly added. In the aforementioned halide, it is preferred to use an iodide or bromide, although a chloride can also be used. The desired product can be isolated and purified in a conventional manner. This reaction can be illustrated as follows:

Compounds of formula XIV may be prepared by reacting an appropriate compound of formula II with an appropriate aminoalkanol of formula XV wherein A, B and n are as previously defined. The reaction is carried out in a suitable organic solvent as defined earlier. Stoichiometric amounts are preferred. The temperature is not critical, and elevated temperatures can be used, but it is preferred to use room temperature. The reaction can be illustrated as follows:

Compounds of formula XIV can be prepared by reacting a suitable compound of formula V in a suitable inert organic solvent as defined earlier with a suitable haloalkylnitrile of formula XVII mixed with aqueous base wherein X, X<1>, R2 and n are as defined earlier. Stoichiometric amounts are preferably used. Room temperature is preferred, although the temperature is not critical. One can e.g. use elevated temperatures to increase the reaction rate. This reaction can be illustrated as follows:

The compounds of the formulas VII, VIII, IX, X, XII, XV, XVII, XVIII and XIX are mostly known and can be prepared by methods which are themselves known.

The following examples illustrate the production of intermediate products.

Example a

3- indolyl thiol: 240 parts of methanol were added to 23.4 parts of indole, 15.2 parts of thiourea and a sufficient amount of a 1 N aqueous solution of potassium iodide and iodine so that one equivalent of each compound was present for each equivalent amount of the indole compound. The mixture was stirred for 16 hours, after which the solvent was evaporated in vacuo to give S(3-indolyl)isothiuronium iodide as colorless crystals, m.p. 214 -216°C. This product was treated with an excess of concentrated aqueous sodium hydroxide solution under a nitrogen atmosphere for 10 min. at 80°C, after which the mixture was cooled to room temperature and a basic solution of 3-indolylthiol was obtained. Neutralization of the mixture with dilute hydrochloric acid gave a pure product, i.e. 3-indolylthiol, m.p. 100-101°C.

Example b

Using the same procedure as in example a, but using an equivalent amount of a suitably substituted indole instead of the indole mentioned in example 1, the following substituted 3-indolylthiols were prepared:

If desired, the substituted or unsubstituted 3-indolyl thiol can remain in solution as sodium 3-indolyl thiolate by omitting the final cooling and neutralization, and then this solution can be used in the subsequent syntheses.

Example c

3-indolylthioacetonitrile: The basic solution of 3-indolylthiolate prepared as described in example a was added to 12.1 parts of chloroacetonitrile in approx. 70 parts diethyl ether. The mixture was stirred under nitrogen for approx. 16 hours, after which the ether layer was separated. The aqueous layer was extracted with approx. 400 parts of dichloromethane and then with 140 parts of diethyl ether. The combined organic fractions were washed with dilute sodium hydroxide and dried over magnesium sulfate, after which the solvent was evaporated in vacuo to give a brown crystalline solid. Recrystallization of this substance from methanol/isopropanol gave 3-ind'olylthioacetonitrile, m.p. 52-54.5°C.

Example d

By using the method described in example c, but by using equivalent solutions of the substituted sodium 3-indolyl thiolates from example 2 instead of said substituted sodium 3-indolyl thiolate solution used in example c, the following was prepared substituted 3-indolylthioalkylnitriles:

If desired, the substituted or unsubstituted 3-indolylthioacetonitrile can be kept in solution and used unisolated in the subsequent syntheses.

Example e

1-Methylindol-3-ylthioacetonitrile: Said 3-indolylthioacetonitrile from example c was dissolved in 100 parts of ether and a corresponding volume of a 15% aqueous sodium hydroxide solution was then added. To the mixture was then added 2 parts of benzyltriethylammonium chloride and then 56.8 parts of methyl iodide while cooling. The container was closed and the whole thing stirred for approx. 16 hours. The resulting solution was extracted with 500 parts of diethyl ether and 650 parts of dichloromethane. Each extract was washed twice with a dilute aqueous sodium hydroxide solution and once with brine solution and then dried over potassium carbonate. The extracts were combined and the solvents evaporated in vacuo, whereby a crude product was obtained which was recrystallized from methanol/isopropanol, and pure 1-methylindol-3-yl-thioacetonitrile was obtained, m.p. 92.5-93.5°C.

Example f

Using the procedure of Example e but using an equivalent amount of an appropriately substituted 3-indolyl-thioacetonitrile-1 in place of said unsubstituted 3-indolylthioacetonitrile used in Example e, and using an appropriate alkyl iodide in place of The methyl iodide used in example e produced the following substituted 1-alkyl-indol-3-ylthioacetonitrile:

Example g

3- C (2- aminoethyl) thio]- 1- methylindole fumarate:

A solution of 45 parts of 1-methylindol-3-ylthioacetonitrile in 80 parts of tetrahydrofuran (THF) was slowly added to 415 parts of 1 M borane dissolved in THF while cooling. The resulting solution was stirred for approx. 16 hours and protected from moisture, after which an additional 112.5 parts of borane was added and the mixture stirred for an additional 16 hours. The solution was then slowly treated with dilute hydrochloric acid until hydrogen evolution stopped (this took about 6 hours), after which the mixture was made basic with 1 N sodium hydroxide. The basic solution was extracted three times with 150 parts of diethyl ether, and the combined extracts were washed three times with dilute sodium hydroxide solution and once with brine and then dried over potassium carbonate. The ether solution was evaporated to half its volume, after which hydrogen chloride gas was bubbled through the solution and this produced crystallization of the hydrochloride. This was recrystallized from methanol/ethyl acetate and pure 3-[(2-aminoethyl)thio]-1-methylindole hydrochloride was obtained, m.p. 159-160.5°C.

The fumarate salt was prepared by concentrating the above ether solution before adding the hydrogen chloride gas, and the resulting yellow oil was dissolved in methanol. 9 parts of fumaric acid dissolved in methanol were added to this solution, and the solvent was slowly evaporated by gradual addition of isopropanol. The product that was formed was then recrystallized from methanol/isopropanol, and pure 3-[(2-aminoethyl)-thio]-1-methylindole fumarate was obtained. Sm.p. l69°C (decomp.).

Calculated for C^H-^l^S.C^H^O^: C 55.88, H 5.63, N 8.69 Found: C 56.04, H 5.60, N 8.57.

Example h

Using the procedure set out in example g, but using a suitably substituted 3-indolylthioacetonitrile instead of the 1-methylindol-3-ylthioacetonitrile used in said example, the following substituted 3-2-aminoethyl) was prepared thio]-indoles:

Example i

3-(2-Aminopropylthio)indole: 4.9 parts of the 3-indolyl thiol prepared as described in examples a and b were dissolved in approx.

24 parts of absolute methanol and 1.71 parts of propylene imine were added. The mixture was slowly stirred under nitrogen for approx. 40 min. after which the methanol was evaporated in vacuo. The residue was then dissolved in diethyl ether. The ether solution was extracted three times with 50 parts of 1N hydrochloric acid. The combined extracts were washed with approx. 180 parts of diethyl ether and then basified with 2N sodium hydroxide solution. This basic aqueous solution was then extracted three times with 60 parts of diethyl ether and the combined ether extracts were washed twice with 50 parts of 1N sodium hydroxide solution and once with brine and then dried over potassium carbonate. The ether was evaporated in vacuo and a crystalline product was obtained which was dissolved in ethyl acetate, after which activated charcoal was added. After the charcoal had been filtered off, a scraping was carried out on the wall of the beaker where the filtrate was, and a crude product was precipitated which was recrystallized from benzene, whereby the pure product, 3-(2-aminopropylthio)-indole, sm. p. 110.5-112.5°C.

Examplej

By using the method from example i, but by using a corresponding amount of aziridine instead of said propylene imine, the following compound was produced:

3-[(2-aminoethyl)thio]indole, m.p. 87-89°C.

Example k

3-[(3-aminopropyl)thio]indole: A basic aqueous solution of 3-indolylthiol prepared from 63.8 parts. 3-indolylthiuronium iodide, prepared as described in example a, was added dropwise with stirring to an aqueous solution of .13.0 parts of 3-chloro-propylamine hydrochloride. The mixture was stirred for approx. 3 hours under nitrogen, after which the solution was extracted with approx. 280 parts diethyl ether. This ether extract was washed three times with approx. 150; parts 1N sodium hydroxide solution and once with 5 brine and was then dried over potassium carbonate. The ether was evaporated and. one oil was obtained which crystallized on standing to a crystalline linseed product. This product was recrystallized from ethyl acetate. and then from benzene," added a small amount of activated charcoal, whereby pure crystalline 3-[(3-aminopropyl)thio]-indole was obtained, m.p. 72.5-73.5°C

Calculated for C-^H-^N^: C 64.03, H 6.84. ,.. Found: " C 64.02, H 6.8.4...

The following examples shall illustrate the invention.

Example il

3-[2-(1-methyl-2-pyrrolidinylideneamino)ethyltiq]indole:

A suspension of 16.0 parts of 3-[(2-aminoethyl)thio]indole hydrochloride prepared as described in Example g, in aqueous base, was extracted with 230 parts of benzene. The extract was then washed with IN sodium hydroxide solution and once with brine, then dried over potassium carbonate. The benzene was evaporated in vacuo and the resulting red oil was dissolved in 60 parts of dry dichloromethane. The resulting solution was added to a solution prepared by slowly adding a solution of 7.76 parts of epichlorohydrin in 14 parts of anhydrous diethyl ether to a solution of 15.9 parts of boron trifluoride etherate in 14 parts of anhydrous diethyl ether and the mixture was stirred protected from moisture for about . 3.5 hours. The ether was poured off the resulting solid triethyloxonium tetrafluoroborate, which was then washed twice with anhydrous ether and then dried under a stream of nitrogen.

The dried triethyloxonium tetrafluoroborate was dissolved in 26 parts of dry dichloromethane and a solution of 8.32 parts of N-methyl-2-pyrrolidone in 26 parts of dry dichloromethane was added. The mixture was stirred for 6 hours protected from moisture and O- ethyl N-methyl-pyrrolidonium fluoroborate.

The resulting mixture was stirred for approx. 18 hours protected against moisture.

The resulting brown solution was extracted twice with 60 parts of 20% sodium hydroxide and then dried over potassium carbonate. The dichloromethane was then evaporated in vacuo and a crude product of the free base was obtained. This crude product of the free base was recrystallized from isopropanol and pure 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole was obtained, m.p. 143.5 -145.5°C.

Calculated for <C>15Hig<N>3<S:> C 65.89, H 7.00, N 15.37.

Found: C 65.83, H 6.92, N 15.37.

Example 2

Using the procedure described in Example 1, but using appropriate amounts of an appropriate 3-(aminoalkylthio)indole hydrohalide in place of said 3-[(2-aminoethyl)tiq]indole hydrochloride used in example 1, and using an equivalent amount of an appropriate fluoroborate prepared as described in example 1, the following compounds were prepared: 3-[3-(1-methyl-2-pyrrolidinylideneamino)propylthio] indole hydrochloride, m.p. . 216.5-218.5°C, 3-[2-(1-methyl-2-pyrrolidinylideneamino)propylthio] indole, m.p. 178.5-180°C, 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-methylindole-hemi-2-butenedioate (E), m.p. 186-189°C, 5"Methoxy-3-[2-(l-methyl-2-pyrrolidinylideneamino)ethylthio]indole, m.p. 154-157°C (on crushing), l-ethyl-3-[2-(l-methyl- 2-pyrrolidinylideneamino)ethylthio]indole-cyclohexanesulfamate, m.p. 113}5-H5 j5°C, 3- [2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-methylindole, m.p. 167- 168.5°C (on crushing), 1,2-dimethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole-2-butenedioate (E), m.p. 149-150°C, 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-phenylindole, m.p. l8l-l83.5°C, 5-Chloro-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylticQ indole, m.p. 164.5 -165.5°C, 3-[2-(1-methyl-4-phenyl-2-pyrrolidinylideneamino)ethylthio]indole, m.p. 162-163°C, 3-[2-(1-methyl-2-piperidinylideneamino)ethylthio]indole saccharinate, m.p. 124-124.5°C, 3- [4-(l-methyl-2-pyrrolidinylideneaminolbutylthio]indole-2-butanedioate (E), mp 172.5-173.5°C, l-(l- methylethyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole, m.p. 82-84°C,

5-ethyl-3-[2-(1-methyl-^-pyrrolidinylideneamino)ethylthio]indole, m.p. 131.5-132.5°C,

3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthiol-1-benzylindole-cyclohexylsulfamate monohydrate, m.p. 133-131J0C,

3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-(2-methoxyethyl)indole cyclohexylsulfamate, m.p. 107.5-109°C,

1-cyclopentyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole benzoate, m.p. 108.5-110°C,

1-(2-furanylmethyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)-ethylthio]indole-2-butenedioate (E), m.p. l67-l68.5°C,

1-cyclopropylmethyl-3-[ 2-(1-methyl-2-pyrrolidinylideneamino)-ethylthio]indole-2-butenedioate (E), m.p. 133-134°C,

3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-(2-propenyl)-indole-cyclohexylsulfamate, m.p. 105-107.5°C,

3-[2-(1-methyl-2-pyrrolidinylideneamino)ethyl io]-1-(n-octyl)-indole fumarate, m.p. 98-100°C,

3-[ 2-(1-methyl 1-2-pyrrolidinylideneamino)ethylthio]-1-(2-propynyl)

indole cyclohexylsulfamate, m.p. ll4.5-115.5°C,

]__ (2-methyl-2-propeny 1)-3- [2-(1-methyl 1-2-pyrrolidinylideneamino)-ethylthio]indole, m.p. 126.5-128°C,

,'-methyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole,

3-[2-(1-methyl-2-pyrrolidinyldenamino)ethylthio]-1-propylindole-2-naphthalenesulfonate, m.p. 98.5-100.5°C,

Example 3

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

A solution of 23.8 parts of N-methyl-2-pyrrolidone i

450 parts of dry benzene were added dropwise to a solution of 36.7 parts of phosphorus oxychloride in 70 parts of dry benzene. The colorless solution was refluxed under nitrogen for 2 hours. The yellow solution was cooled to room temperature, and added dropwise over approx. 20 min. a solution of 38.4 parts of 3-t(2-aminoethyl)thio]indole in 90 parts of dry benzene. The mixture was refluxed for 4.5 hours under nitrogen and then allowed to stand for approx. 18 hours at room temperature.

The resulting mixture was made alkaline by adding approx. 300 parts of water and 120 parts of 50% sodium hydroxide solution, and the mixture was heated on a steam bath to obtain

a complete decomposition of the oily complex. The benzene layer was separated and the aqueous layer extracted twice with ether. The extracts were combined, dried over potassium carbonate after which the ether was evaporated in vacuo to give an oily solid. This compound was recrystallized twice from isopropanol-pentane and 3~[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole was obtained, m.p. 143-144°C.

Example 4

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

The O-ethyl-N-methylpyrrolidonium fluoroborate prepared in Example 2 was added to a solution of 4.27 parts of 2-aminoethanol in 260 parts of dichloromethane, and the mixture was stirred at room temperature for approx. 16 hours. The solvent was evaporated and a crude product was obtained as a fluoroborate salt. This salt was converted into the free base which was then converted into a perchlorate salt, and 2-(pyrrolidinylideneamino)ethanol perchlorate was obtained, m.p. 67-69°C.

A solution of 3.5 parts of the above-mentioned free base in 130 parts of dry chloroform at 0°C was in the course of 15 min.

and under nitrogen added dropwise 8.4 parts of thionyl chloride. The mixture was then allowed to warm to room temperature and

stirred for approx. 16 hours. Finally, the mixture was refluxed for 1/2 hour under nitrogen, after which the chloroform and excess thionyl chloride were removed in vacuo, and a crude product was obtained. This was dissolved in dichloromethane and the resulting solution was treated with 6N sodium hydroxide solution with vigorous stirring. The dichloromethane layer was separated, dried over potassium carbonate and filtered. Evaporation of dichloromethane in vacuo gave the product, 2-(chloroethylimino)pyrrolidine.

A basic solution of 3-indolylthiol prepared from 7.65 parts of 3-indolylthiuronium iodide, the preparation of which is described in Example'a, was washed twice with 175 parts of diethyl ether. The aqueous solution was then treated with an ether solution of the above prepared 2-(chloroethylimino)pyrrolidine under nitrogen and the mixture was stirred at room temperature for approx. 16 hours. Dichloromethane was added to replace any ether present and the organic layer was evaporated while the aqueous layer was evaporated. aqueous layers were extracted with dichloromethane. The combined organic solutions were dried over potassium carbonate, filtered, after which the filtrate was evaporated under reduced pressure and this gave the product as an amber colored oil which slowly solidified by scraping the wall of the beaker. The solid was recrystallized from isopropanol/petroleum ether, and the pure product 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole was obtained.

The infrared spectrum of this product is identical to an authentic sample produced by an alternative synthesis route.

Example 5

3-[ 2-( 1-methy1-2-hexahydroazapiny 1idenamirioVétyTthio] iridoT- 2-butenedioate ( E ) : A solution of 6.1 g (48 mmol) of N-methyl-caprolactam in 15 ml of dry CH 2 Cl 2 was added a solution of triethyloxonium fluoroborate, prepared from 9.1 g (64 mmol) of boron trifluoride etherate and 4.45 g (48 mmol) of epichlorohydrin, and the mixture was stirred under dry conditions for 2.5 h. Then 7.7 g (40 mmol) of 3"(2-aminoethylthio)indole in 20 mL of dry CH 2 Cl 2 was added, and the solution was stirred protected from moisture at room temperature for 72 hours. An equal volume of CH 2 Cl 2 was added and the solution was washed once with 70 ml 1N NaOH, once with water, once with brine and then dried over potassium carbonate The solution was filtered, after which the filtrate was evaporated in vacuo

and 8.6 g of an orange oily product which solidified was obtained. Purification of the product as the fumarate salt gives 3-[2-(1-methyl-2-hexahydroazapylideneamino)ethylthio]indole-2-butenedioate (E) as white crystals. Sm.p. 128-130°C.

Example 6

3- [ 2-( 1- methyl1- 5- phenyl1- 2- pyrrolidinylideneamino) ethylthio] indole-cyclohexanesulfamate: A solution of 6.3 g (36 mmol) of N-methyl-5-phenyl-2-pyrrolidone in 10 ml of dry CH 2 lg was added triethyloxonium fluoroborate in 20 ml of dry CH 2 Cl 2 . The solution was stirred for 3 hours at room temperature in the absence of moisture. Then 5.75 g (30 mmol) of 3-(2-aminoethylthio)indole in 20 ml of dry CH 2 Cl 2 were added, and the resulting solution was stirred under dry conditions for 3 days. Then 50 ml CH 2 Cl 2 was added and the solution was washed once with 50 ml 1N NaOH, once with water, once with brine and then dried over potassium carbonate. The dried solution was evaporated in vacuo and the free base was obtained as a viscous oil. Purification of the cyclohexanesulfamate salt gives 3-[2-(1-methyl-5-phenyl-2-pyrrolidinylideneamino)ethylthio]-indole cyclohexanesulfamate as white crystals, m.p. 190.5-191.5°C.

Analysis, calculated for C^H^N^S . CgH^NO^S (3^9.72):

C 61.33, H 6.86, N 10.60

Found: C 61.40, H 6.89, N 10.56.

Claims (1)

Analogous method for the preparation of therapeutically active indoles with the formula: or therapeutically active acid addition salts thereof, where: X and X<1> are both hydrogen, lower alkyl of 1-6 carbon atoms, lower alkoxy of 1-6 carbon atoms, halogen; R^ is hydrogen, lower alkyl of 1-8 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, benzyl, lower alkoxy-alkyl of 1-6 carbon atoms, .alkenyl of 2-6 carbon atoms, cycloalkyl-alkyl of 4- 6 carbon atoms and furanmethyl"; R2 is hydrogen, lower alkyl of 1-6 carbon atoms, phenyl; n is 1, 2 or 3; A and B together may form a group selected from -CH2CH(R5)CH2-, -CH2CH2CH( R5)-, -(CH^- and . • -(CH2)[--, and where R,- is hydrogen or phenyl, characterized by a) reacting a compound with the formula: with a compound of the formula: In a suitable organic solvent whereby the fluoroborate salt of a compound of formula I is produced, after which said fluoroborate salt is converted into a base by treatment with a suitable base, or b) reacts a compound of the formula (III) above with a slight molar excess of a compound with the formula: where W is bromine or chlorine in a suitable organic solvent by which a compound of formula I or its salt is produced, or c) reacts a compound of the formula: in aqueous base with a compound of the formula in a suitable organic solvent, and, if desired, convert the compounds into therapeutically active non-toxic acid addition salts.