FI64590C - ANALOGIFICATION OF THE THERAPEUTIC ACTIVITY FOR THERAPEUTIC ACTIVITIES - Google Patents

Description

rBl ANNOUNCEMENT s A C Q ft ™ UTLÄCGN! NGSSKRIFT 6 4 * J 9 0 es) Γ: .Γ ;;.: Ϊ́ΐ;: · Γι "........ '(51) κ.Λ.> η.α.3 c 07 D 403 / 12 // C 07 I) 209/30 ENGLISH —FI N LAN D (21) PK * nttlh »k # mu * - P> Unun * Oknlng 753669 (22) Htkmilspllvt —An * ekntn {« dag 29.12.75 ' (23) The beginning of the cloud — Glklghattdag 29.12.75 (41) Tullut] ulklMk * l - BllvK olTwttllf 01.07.76

National Board of Patents and Registration / 44) Date of issue and date of issue. - a

Patents and registries '' Amskan uttagd och utUkrHtan pubttcmd 11. uo. 01 (32) (33) (31) requested * tuolk * u * —Bagird prlorltet 30.12. jh, 13-11.75 USA (US) 537612, 63179Ö (71) McNeil Laboratories, Incorporated, Camp Hill Road, Fort Washington,

Pennsylvania, USA (72) Michael Zelesko, Warminister, Pennsylvania, David McComsey, Hatboro, Pennsylvania, USA (7 ^) Oy Kolster Ab (5k) Analog method for the preparation of therapeutically active indoles -Analogiförfarande för framställning av therapeutiskt aktiv

The invention relates to an analogous process for the preparation of therapeutically active indoles of the formula (I) or their acid addition salts, X A ~ - S- (CH 2) -CH-N = * 1 (1) · s ^ b Π I 's

> 1 --------- 'H' N-B

1: i I; I

/ N - '- R 0 3 1 1 K 2 X R x in which X and X 1 are each hydrogen atoms, lower C 1 -C 6 alkyl groups, halogen atoms or lower C 1 -C 6 alkoxy groups; is 2,64590 hydrogen atoms, lower C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, phenyl, benzyl, lower C 1 -C 6 alkoxyalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkyl ib zbz 6 an alkynyl, C 1 -C 6 cycloalkylalkyl or furanmethyl group; R 2 is a hydrogen atom, a lower C 1 -C 4 alkyl or phenyl group; n is an integer of 1, 2 or 3, A and B together form -CH 2 CH (R 2) CH 2 -, -CH 2 CH 2 CH (R 1 -) -, -NHCH 2 CH 2 -, - (CH 2) 4 -, or - (CH 2) 4 -. a group having a hydrogen atom or a phenyl group.

"Lower alkyl group" and "lower alkoxy group" as used herein mean a straight-chain or branched saturated aliphatic hydrocarbon group containing from 1 to about 8 carbon atoms, such as methyl-> ethyl, propyl, isopropyl, butyl, pentyl, hexyl. , heptyl and octyl groups and methoxy, otoxy, propoxy, isopropoxy, pentoxy and hexoxy groups, respectively. As used herein, the term "halogen" means fluorine, chlorine, bromine and iodine atoms. The term "cycloalkyl group" means cyclic aliphatic hydrocarbon radicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkenyl groups and alkynyl groups include straight-chain and branched, unsaturated aliphatic hydrocarbon groups containing from 2 to about 6 carbon atoms, for example, vinyl, allyl and 1-butenyl groups, propargyl, 2-butynyl and 3-butynyl groups, respectively.

Preferred compounds within the scope of the invention are those compounds of formula (I) in which R 1 is other than a hydrogen atom, and even more preferred are those in which R 1 is a lower alkyl or alkenyl group. Even more preferred are those compounds wherein X 1 is a hydrogen atom, R 2 is a hydrogen atom or a lower alkyl group, n is 1, R 2 is a lower alkyl group and A-B is

The compounds of formula I are prepared in such a way that a) the compound of formula (II) “Ί + / 'A! (II) OC2H5 in BP® B-N | 4 I! I! ch3 i 3 64590

is reacted with a compound of formula (III) X

'S- (CH_) -CH9-NH9 r · .-------- f- 2 n 2 2 (ΠΙ) 1 i · i * »if 1' X N 'x1 | R 2 R 1 in a suitable organic solvent to form a fluoroborate salt of a compound of formula (I), and then converting said fluoroborate salt to a base form by treatment with a suitable base, or b) reacting a compound of formula (III) with a small molar excess of a compound of formula (IV): IV) W ~ OPO e. © / NB- 1 O ch3 W w wherein W is a bromine or chlorine atom, in a suitable organic solvent to form a compound of formula (I) or an acid salt thereof, or c) a compound of formula (V) X is obtained o © Na0 wa (V)

(> Γ IL

X1 1 R2 X R1 to react in a basic aqueous solution with a compound of formula (VI) A "/ \

Cl- (CH 2) n -CH-N =, H> -B '(VI) CH 3 4 64590 in a suitable organic solvent to prepare a compound of formula (I), or d) reacting a compound of formula (III) with a compound of formula (VII) with the compound

B

'N

© \ p (VII) ch2 w s-r7

OF

CH3 where W is a suitable anion such as halogen and R? is alkyl, in a suitable lower alkanol to prepare an acid salt of a compound of formula (I) wherein A-B is -NHCH 2 CH 2 -, and if desired converting said acid addition salt to the free base by treatment with a suitable base and optionally converting the products from process options a-d to therapeutically active.

In process variant a) a suitable fluoroborate salt of formula (II) is reacted with a suitable 3- (aminoalkylthio) indole of formula (III) wherein X, R 1, R 2, A, B and n are as defined above. A small molar excess of fluoroborate salt is preferred. Suitable organic solvents for carrying out the reaction include lower aliphatic alcohols such as methanol, ethanol, 2-propanol, tert-butanol and the like; 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. Temperature is not critical. Room temperature is preferred, but elevated temperatures can be used to accelerate the reaction. The resulting fluoroborate salt is converted to the corresponding base form in the usual manner; for example, by treating it with a suitable base such as an alkali metal or alkaline earth metal hydroxide, carbonate and the like. The reaction can be described as follows: 5 64590 -; +

^ -s I

ί '"Α ί 1 I! X ._________,. S- (CH2) n-CH2-NH2. Β Κ /' <Μ'2" '·· BF4- + V! t. ν ^ -. (I) · ΗΒΓ4

I χ1 I R2 (III) L NaOH

I (ID R1 (I) 3.!

Compounds of formula (I) may also be prepared by reacting a suitable compound of formula (III) with a small molar excess of a suitable compound of formula (IV) wherein X, X, R 1, R 2, A, B and n are as defined above. and W is a bromine or chlorine atom to give compound (I) as its acid salt. The reaction is carried out in a suitable inert organic solvent such as an aromatic hydrocarbon (for example, benzene, toluene, xylene, etc.); in ether (e.g. diethyl ether, tetrahydrofuran (THF), dioxane, etc.); in a halogenated lower alkane (e.g. chloroform, dichloromethane, dichloroethane, etc.); and the like. The temperature is not critical, but the boiling temperature is preferred. These compounds can also be prepared by reacting the appropriate sodium 3-indolylthiolate of formula (V) in a basic aqueous solution with a stoichiometric amount of the appropriate compound of formula (VI) wherein X, X 1, R 1, A, B and n are as defined above, in the appropriate in an inert organic solvent as described above. Temperature is not critical. Room temperature is preferred, elevated temperatures can be used to accelerate the reaction. These two reactions can be described as follows: X _ / S- <CH2> n-CH2-BH2 a '+ W opo ((I) · m χ1 ^^ T r2 (III) 2 \ © B' R1 f wö (IV) CH3 6 64590 x. S O Na Θ · ";! I '+ Cl- (CH) -CH -N =' - 7 d>

'N "XR -N 2 B

Λ <2

x p (V) I

K1 CH3 (VI)

The acid addition salt of the desired product can be converted to the free base (I) as described above.

Compounds of formula (I) wherein AB is -NHCH 2 CH 2 - may also be prepared by reacting the appropriate thioindole of formula (III) with the appropriate alkylthioimidazoline salt of formula (VII) wherein X, x, R 1, R 2 and n is as defined above, W is a suitable anion, for example a mineral acid anion such as halogen, and R? is a lower alkyl group. Stoichiometric amounts are preferably used. This reaction is performed in a suitable lower alkanol such as ethanol, isopropanol, 2-methyl-4-propanol and the like. The temperature is not critical, but the boiling temperature is preferred. This reaction can be described as follows:

B

X is S- (CH) -CH -NH

'· ------- / N. ^

i i: I; + CH s-r7 »ö (i) - HW

X ^ 2 N '

Rx (III) CH (VII)

The acid addition salt of the desired product can be converted to the free base (I) as described above.

The compounds of formula I can be isolated as free bases by conventional synthetic methods. These compounds in base form can be converted into therapeutically active non-toxic acid addition salts by treatment with a suitable acid such as an inorganic acid (for example hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid; sulfuric or nitric acid; glycol, milk, 64590 fire grape, malonic, amber, maleic, fumaric, apple, wine, lemon, benzoic, cinnamon, almond, methanesulfonic, p-to-toluenesulfonic, cyclohexanesulfame, salicylic, p-aminosalicyl, 2-phenoxybenzoic or 2-acetoxybenzoic acid). Conversely the salt form can be converted into the free base in the usual manner.

The compounds of formula I in free base or acid addition salt form have been found to have a beneficial heart rate slowing effect in mammals according to the following refluxic tachycardia test. Bilateral vagotomy is performed on an anesthetized dog (under anesthesia, thiopental sodium is administered intravenously (20 mg / kg) and anesthesia is further maintained by intravenous β-chloralose injections (60 mg / kg)). Two doses of aminophylline (5 mg / kg intravenously) are given every 15 minutes. The hypotensive effect of aminophylline causes the action of baroreceptors in the carotid sinus, which in turn causes a reflex increase in heart rate caused by the sympathetic nervous system. Fifteen minutes after the second dose of aminophylline, the test compound is administered intravenously and the effect on heart rate is monitored for 30 minutes. Compounds that cause a slow heart rate of at least 18 sinus beats per minute are considered active. Such compounds are useful in the treatment of angina pectoris because the heart rate is considered to be the major influencing factor in myocardial oxygen consumption.

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

The compounds of formula I in free base form or in acid addition salt form have also been found to have activity as inhibitors of platelet aggregation. The antiplatelet effect of the compounds has been studied using a collagen-induced platelet aggregation assay with a final concentration of test compound of 100 μM / l in platelet-rich plasma (turbidimetric method, G.V.R. Born, Nature 194 (1962) 927). Results are expressed as mean% inhibition.

8 64590

In addition, the compounds of formula I have been found to have an inhibitory effect on gastric acid secretion. The inhibitory effect on gastric acid secretion was studied in female Sprague-Dawley rats given intraduodenally (i.d.) by injection of test compounds at a dose of 2.5-40 mg / kg. The rats are fasted for 24 hours before the experiment, however, water is freely available. At the start of the experiment, the rats are weighed and individuals weighing no more than - 20 g are selected for each experiment. The rats are anesthetized, their teeth are removed, and an incision about 1 to 1/2 cm long is made in the center of the abdomen to expose the stomach and duodenum. If there is food or secretions in the stomach at this stage, no the experimental animal is no longer continued. The surgeon's thread is used to sew a pull-loop stitch to the base of the abdomen, taking care not to damage the blood vessels in the area. A small notch is made in the center of the abdominal traction loop, and a cannula formed by a small vinyl tube with a flange at one end is placed in the abdomen, and the traction loop stitch is tightly closed around the flange.

Immediately thereafter, the test compound is administered i.d. 0.5 ml volume per 100 g rat. Generally, three rats are used for each dose of drug tested. Control rats usually receive vehicle alone in 0.5% aqueous methylcellulose. After administration of the test compound duodenal wall and skin are closed simultaneously to 3-4 with 18 mm haavanipistimellä and the cannula placed in the collection tube. Each rat is then placed in a box with a longitudinal slot so that the cannula can hang freely and the rat can move without hindrance. After allowing the rat to calm for 30 minutes, the collection tube is removed from the cannula and replaced with a clean tube into which gastric fluid collects. Collections are made within an hour. At the end of the study, the cannula is removed and the rat is sacrificed.

The collected gastric sample is emptied into a centrifuge tube and centrifuged to concentrate the precipitate. The volumes are read and 1 ml of the supernatant is taken up in a beaker containing 10 ml of distilled water and titrated to pH 7 using Ο, ΟΙΝ HaOH. From the results, the volume, titratable acid and total weight are deduced, where volume = total ml of gastric fluid minus precipitate; titratable acid 9 64590 (milliequivalents / l) = Ο, ΟΙΝ the amount of NaOH needed to titrate the acid to pH 7; and total acid = titratable acid X volume. Results are expressed as% inhibition relative to controls, with 50% inhibition defining the "active" compound.

Furthermore, certain compounds of formula (I) in the free base or acid addition salt form of the present invention have been found to be further pharmacologically active as described below. In particular, compounds of formula (I) in which contains a cyclic moiety (cycloalkyl, phenyl, substituted phenyl or heterocyclic group) and AB is a lower alkyl group, C 1-4 CH (R 2) -CH 2 or C 1 -C 4 CH 2 Cl 2 ^ CH t are active antiarrhythmic agents and inhibitors of epinephrine and caffeine-induced ly polyols, as shown by the following three experiments:

Atrial antiarrhythmic test:

The right Atrium of a anesthetized dog (anesthesia the same as in the reflexogenic tachycardia test) is revealed by a right-to-tachotomy and pulling the pericardium aside. Atrial fibrillation as defined by a normal ECG member lead (II) is obtained by placing two drops of a 10% acetylcholine solution on the atrium and then brushing the atrium with a blunt spatula.

The flicker time is registered. Two vibration check periods are caused at 15 minute intervals. The test compound is administered intravenously ten seconds after the next induction, the compound is considered active if it reduces the vibration time by at least 50%. Certain compounds of formula (I) as described above are active at doses of from about 1.0 to about 18.5 mg / kg body weight.

Epinephrine-induced lipolysis:

Two rat epididymal adipose tissue samples are incubated in Krebs-Ringer's bicarbonate buffer in the presence of 5 μg / ml epinephrine bitartrate solution for one hour. The second sample is used as a control and the test compound is added to the other before incubation so that the final concentration of test compound is 1.0 mM. The degree of lipolysis is inferred by measuring glycerol production by the modified Wieland double enzyme method / Wieland, Biochem Z., 329, 313 (1957j7. Compounds that inhibit glycerol formation by more than 30% at a concentration of 1.0 mM or are significant at 95% confidence limits are considered "active".

64590 10

Caffeine-induced lipolysis:

The procedure is the same as above, except that instead of epinephrine, caffeine is present in the incubation mixture at a concentration of 1.0 mM.

The compounds of the present invention were compared to known heart rate retarding compounds, propanolol and perhexylene. A triazine infusion test was used as a control. Here, the experimental animals were first anesthetized. The left carotid artery and left jugular vein were isolated and connected to cannulas filled with saline supplemented with heparin (1000 U.S.P. units / ml). The intestines of the dogs were emptied and the animals were allowed to recover from the surgical treatment. After about 24 hours, the animals were administered U20388 at 12 mg / kg p.o. After about an hour, arterial pressure and ECG were measured. The test animals were then cannulated with test compounds at a rate of 0.8 mg / kg / min. iv The lowest effective dose, i.e., the dose that reduces the heart rate to 18-20 beats / minute (CS), and the dose that causes the maximum decrease in heart rate (csmx) and the dose that reduces the heart rate of the test animal by 50% were determined: 11a (CS 2). Animals were administered a total of 30 mg / kg of test compound. Possible side effects and mortality were considered.

The effect of the compounds on the contractile force of the heart was also studied. In this case, the animals were first anesthetized with thiopental (20 mg / kg i.v.) and alpha-chloralose (60 mg / kg i.v.). Arterial pressure was measured by inserting a cannula into the femoral artery, and a cardiac electrical curve (Limb Lead II) was recorded. The breast of the test animal was opened at the sternum and a Brodie-Walton probe was placed in the right ventricle of the heart to measure the contractile force of the heart. The following parameters were measured: arterial pressure, heart rate, cardiac contractile force, and cardiac electrical curve. Test compounds were administered to experimental animals intravenously via a femoral catheter. The compounds were administered to the animals in batches, and the test parameters were measured 1, 5, 15, and 30 minutes after a certain dose of the test compound was administered. The aim was to determine the dose that causes a reduction in cardiac contractility by 25-30% (MD2 ^ _3q%) · il 64,590

The therapeutic index was evaluated by comparing the MO-c,., - ar- 2 b "jU i) force, which is considered to be the maximum allowable value at which the contractile force of the heart can be reduced, to the CSQ value which causes a 50% slowing of the heart rate.

The results are shown in the following table.

Compound CS Experimental MDoc _n „Experimental MDoc ΟΛ„ Therapeutic- 5U 25-30% 25-30% mg / kg number mg / kg i.v. number of t- C & 50 dex relative to pro-pranolol

Propranolol 0.7 4 3.5 3 0.52 1.0

Perhexylene 22.0 2 18.5 3 0.88 1.69 1 · 2.53 7 3.5 4 1.38 2.65 2. 3.78 5 3.5 2 0.93 1.79 3. 2 .85 4 3.5 3 1.23 2.37 4. 2.72 5 1.0 2 0.37 0.71 5- 1.20 5 8.5 5 7.10 13.65 6. 2.32 3 3.5 2 3.66 7.04 7. 0.83 6 4.0 4 4.90 9.42 8. 4.53 5 9.0 4 1.99 3.82 9. 0.92 2 3 .5 1 3.80 7.31 10. 0.99 5 9.0 5 9.1 17.5 11. 3.49 4 8.5 2 2.5 4.81 12. 2.95 4 3.5 3 1.19 2.29 13. 1.54 5 8.5 3 5.5 10.58 14. 1.40 3 3.5 3 2.5 4.81 15. 7.32 2 8.5 3 1 .16 2.23 16. 2.63 3 1.0 2 0.4 0.77 17. 1.01 3 8.5 2 8.42 16.19 1. 3- [2- (1-methyl-2 -pyrrolidinylideeniamino) ethylthio / indole.

2. 3- [3- (1-Methyl-2-pyrrolidinylideneamino) propylthio] indole.

3. 3- [2- (1-Methyl-2-imidazolinylamino) ethyl] thio] indole.

4. 3- [2- (1-Methyl-2-pyrrolidinylideneamino) propylthio] indole.

i2 64 590 5. 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethyl] -7-methyl-indole.

6. 5-Methoxy-3- [N- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole.

7. 1-Ethyl-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole.

8. 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethyl] thi] -2-methylindole.

9. 1,2-Dimethyl-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole.

10. 1- (1-Methylethyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole.

11. 5-Chloro-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethyl] pyrrolidine.

12. 3- [2- (1-Methyl-2-piperidinylideneamino) ethylthio] indole.

13. 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethylthio] -1- (2-methoxyethyl) indole.

14. 1- (Cyclopropylmethyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole.

15. 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethyl] thi [1- (n-octyl) indole.

16. 1- (2-Furanylmethyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethyl] thio] indole.

17. 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethylthio] -1- (2-propenyl) indole.

Compounds of formula (III) may be prepared directly by coupling a suitable indole of formula (XVIII) with a suitable aminoalkylthiol of formula (XIX) wherein X, X 1, R 2, and n are as defined above and adding an aqueous solution of iodine as an oxidant or a peroxide (e.g., hydrogen peroxide or sodium peroxide). Stoichiometric amounts of all three substances are preferred. The reaction is performed in a suitable lower alkanol as defined above. Temperature is not critical and elevated temperatures can be used to increase the reaction rate, but ambient temperature is preferred. The reaction is carried out in an airless state such as a nitrogen atom. When the reaction is complete, the alkanol is evaporated in vacuo and the product is purified by methods well known in the art. This reaction can be described as follows: x 12 I! j1 + HS- (CH ") -CH" -NH ~ -> (li!)

Sx ': · k 2 n 2 2 X1 "| R2 R1 (XVIII) (XIX)

The compounds of formula (III) may also be prepared by any of three other methods. First, when n = 1, the appropriate 3-indolylthiol of formula (VIII) is reacted with the appropriate aziridine of formula (IX) wherein X, R 1 and R 2 are as defined above. The reaction is performed in the appropriate lower alkanol as defined above. Stoichiometric amounts are preferably used. Cooling by stirring the two reactants is preferred, after which the reaction is preferably allowed to proceed at ambient temperature. However, temperature is not critical and elevated temperatures can be used to increase the reaction rate. Second, when n is 1 or 2, the appropriate sodium 3-indolylthiolate of formula (V) is reacted in a basic aqueous solution with the appropriate chloroalkylamine hydrochloride of formula (X) wherein X 1 and R 2 are as defined above. It is preferred that the hydrochloride salt be neutralized by the addition of one mole of excess base or, more preferably, 3-indolylthiolate itself. However, stoichiometric amounts may be used. Ambient temperature is also preferred, but again temperature is not critical and elevated temperatures can be used to increase the reaction rate.

Third, when n is 1 or 2, the appropriate indol-3-ylthioalkylnitrile of formula (XI) is reduced, wherein X, X1, and R2 are as defined above. The reducing agent is borane, lithium aluminum hydride / aluminum chloride or the like. The reaction is carried out in a suitable inert organic solvent as defined above using a large excess of reducing agent. Temperature is not critical. Room temperature is preferred, but elevated temperatures are used to accelerate the reaction. When destroyed with mineral acid, bor4 64590 ί ι with mineral acid, (borane) or base (lithium aluminum hydride / aluminum chloride), the product is obtained as the acid salt or the free base, respectively. These three reactions can be described as follows:

X H

\ / __. sh N

':, | + ‘Ι (III) (n = 1) xlX /’ 7 R2 (IX)

RjL (VIII) \, _______ ^ s 0Na +

| h I

j ij | + Cl- (CH2) n-CH2-NH2-7 HCl (III)

λ / 'N "" R

x k (V) (X)

_____ / S- (CH_) -CN

I |! i | n reduction (m) x 7 1 'K2 x k (XI)

The desired compounds (III) can be isolated as free bases by synthetic methods well known in the chemical arts. The free bases, in turn, can be converted into therapeutically active non-toxic acid addition salts as described above for the compounds of formula (I).

Said compounds (III) are useful as pre-cursors for pharmacologically useful compounds of formula (I). Furthermore, the compounds of formula (III) themselves have useful pharmacological properties. They are active as inhibitors of human platelet aggregation, as shown in the experiment described above for compounds (I). Furthermore, certain compounds (III) are effective in the reflexogenic sinus tachycardia test described above, especially when R 1 is a lower alkoxy, lower alkyl, phenylalkyl, alkenyl, methyl or isopropyl group; and certain compounds (III) are effective in the atrial

15 64590 I

in the anti-arrhythmia test, especially when R2 is a phenyl group or when there is a methyl or isopropyl group, all other substituents being hydrogen atoms and n being 1.

Certain compounds of formula (III) are novel, in particular those in which at least one of the group, R 2, X and X 1 is other than a hydrogen atom, or in which n is two or three.

Compounds of formula (II) may be prepared by reacting a suitable compound of formula (XII) wherein A and B are as defined above to react with triethyloxonium fluoroborate (XIII) according to the method described in Berichte, 89, 3063 (1956). . The reaction is carried out in a suitable organic solvent as defined above, preferably at ambient temperature. This reaction can be described as follows:

/ - ^ A

'\ _> 0 + <c2h5) 3o + bf4- ......... V (II) j (χΐ1) (XIII) ch3

Compounds of formula (IV) may be prepared by reacting the appropriate compound of formula (XII) wherein A and B are as defined above with phosphorus oxychloride in benzene according to the method described in Brederick, et al. ai., Berichte, 94, 2278 (1961). This reaction can be described as follows: j [/ S + POC13 7 i —OPOC19 Y (XU) θ CH, I C1 (IV) 3 CH3

Compounds of formula (V) may be prepared by reacting a suitable compound of formula (VIII) wherein X, X 1, R 1 and R 2 are as defined above with aqueous NaOH.

Both this reaction and the preparation of compound (VIII) are described in R. 64. 90, R.L.N. Harris, Tetrahedron Letters, 4465 (1969). Precursors of compounds (VIII) can be prepared by the method of C.E. Blades and A.L. Wilds, Journal of Organic Chemistry, 21, 1013 (1956).

Compounds of formula (V) may also be prepared by the reaction of an appropriate indole of formula (XVIII) with a thiourea in the presence of an oxidant. Stoichiometric amounts of indole, thiourea and oxidant are preferred. The oxidant may be, for example, iodine / potassium iodide, hydrogen peroxide, potassium periodate, sodium hypochlorite or the like. The reaction temperature can be the same as in the environment or raised up to the boiling point. The solvent may be water, lower alkanol, ether (e.g. diethyl ether, tetrahydrofuran, etc.), glycol or the like. When the reaction is complete, the obtained compound is treated with a concentrated strong base (e.g., aqueous sodium hydroxide solution), preferably with heating, to give compound (V).

Compounds of formula (VI) may be prepared by reacting a suitable compound of formula (XIV) wherein A and B are as defined above with thionyl chloride. The reaction is carried out in a suitable inert organic solvent as defined above and in an oxygen-free state. Preferably a large excess of thionyl chloride is used. When the materials are preferably cooled to about 0 ° C during stirring, elevated temperatures can be used during the reaction. The mixture is preferably stirred under ambient conditions and finally boiled under a vertical condenser. This reaction can be described as follows: 5 i HO- (CH2) n-CH2-N = <- 'A \ + SO0i ^ (VI) I \

i N - B

}! (xiv) f CH3

Compounds of formula (XI) may be prepared by reacting the appropriate N-unsubstituted compound of formula (XVI) in an inert organic solvent as defined above; 17 64590 van with halide R..W mixed with aqueous base, 1.

wherein X, X, R 1 and R 2 are as defined above, and W is a halogen atom, preferably iodine, in the presence of benzyltriethylammonium chloride. Preferably, an excess of one mole of alkyl halide is used, but stoichiometric amounts may also be used. The reaction is preferably carried out at ambient temperatures and can be described as follows:

x w yf S- (CH) -CN> <·. -S- (CH2) -CN

fv, Γ jf 2 n ^: ["'" N \ R f,. ·' N \ X | ^ X R2 H (XVI) R1 (XI)

The 1-substituted products of formula (I) may also be prepared by reacting the 1-unsubstituted (R 1 = H) compounds of formula (I) with a strong base and then the appropriate halide R 1 W, respectively, all in a suitable inert organic solvent as above. is defined. Suitable strong bases include, for example, sodium hydride, lithium hydride, sodium amide and the like, with which the unsubstituted compound (I) is preferably mixed slowly. The halide W preferably contains iodine or bromine, although chloride may be used. The desired product is isolated and purified by standard methods. This reaction can be described as follows:

X / A

V, 'S- (CH0)' - CH0-N

rX ', - v 2 n 2 \ b

I I N · - 'strong base R, W

.. K J i 7 —y

x1 N - R_ CH

I 2

B

X Α Χ - S- (CH-) -CH_-N v /

N II, 1 V

1 ^, ίχΝ Λ R CH

XX N R2 3 R1 18 64590

Compounds of formula (XIV) may be prepared by reacting a suitable compound of formula (II) with an appropriate aminoalkanol of formula (XV) wherein A, B and n are as defined above. The reaction is performed in a suitable organic solvent as defined above. Stoichiometric amounts are preferably used. Temperature is not critical and elevated temperatures may be used, but ambient temperature is preferred. The reaction can be described as follows: x A \! ! v. - OC2H5 bf4 "+ H0 - (CH2) n-CH2-NH2 ^ (XIV) B \ N '' 'j i I i CH3 i - (II) (XV)

Compounds of formula (XVI) may be prepared by reacting a suitable compound of formula (V) in a suitable inert organic solvent as defined above with a suitable haloalkyl nitrile of formula (XVII) in a basic aqueous solution wherein X, x and n are the same. as above. Stoichiometric amounts are preferably used. Ambient temperatures are preferred, although the temperature is not critical. Elevated temperatures can be used to accelerate the reaction. The reaction can be described as follows: p

'V *

x v ^ |. B x. I .......... r, CH ^ "- CN

l | I! + W-ICH) -CN ------------ 7 j li * H * x H 2 (V) (XVII) (XVI)

The compounds of formulas (VII), (VIII), (IX), (X), (XII), (XV), (XVII), (XVIII) and (XIX) are for the most part known and can be prepared by methods well known in the chemical arts. according to mcne- \ i9 6 4 5 9 0. The following examples are intended to illustrate the scope of the present invention.

Manufacture of intermediates;

Preparation I

3-Indolylthiol To 240 parts of methanol are added 23.4 parts of indole, 15.2 parts of thiourea and a sufficient amount of 1N aqueous potassium iodide solution and iodine so that an equivalent of each is present for each indole equivalent. The mixture is stirred for 16 hours, after which the solvent is evaporated in vacuo to give S- [3'-indolyl] -7-isothiourunium iodide as colorless crystals; mp. 214-216 ° C. This product is treated with a concentrated excess of aqueous sodium hydroxide in a nitrogen atom at 80 ° C for ten minutes, after which the mixture is cooled to room temperature to give a basic solution of 3-indolylthiol. This is neutralized with dilute hydrochloric acid to give the pure product, 3-indolylthiol; mp. 100-101 °.

Preparation II

Following the procedure of Section I, but replacing the indole used therein with an equivalent amount of an appropriately substituted indole, the following substituted 3-indolylthiols were prepared: X ..

JTn “I 2

B

X X1 r2 H H _C6H5

5-CH 3 O- H H

H H -CH 3

5-Cl H H

If desired, the substituted or unsubstituted 3-indolylthiol can be left in solution as sodium 3-indolylthiolate, omitting final cooling and neutralization, and this solution is used in the following preparations.

20, 64590

Preparation III

3-indolyylitioasetonitriili

To a basic solution of the 3-indolylthiolate prepared in I is added 12.1 parts of chloroacetonitrile with about 70 parts of diethyl ether. The mixture is stirred under a nitrogen atmosphere for about 16 hours, after which the ether layer is separated. The aqueous layer is extracted with about 400 parts of dichloromethane and then about 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 leave a brown crystalline solid. Recrystallization of this solid from methanol / isopropanol affords 3-indolylthioacetonitrile; mp. 52 to 54.5 °.

Preparation IV

Following the procedure of Section III, but replacing the unsubstituted sodium 3-indolylthiolate used therein with the substituted sodium 3-indolylthiolates of Section II, the following substituted 3-indolylthioalkylnitriles are prepared: 'x -v.

> <- ^ SCH2-CN

! L l: i X1 l R2 X xi R2 s, p.

H H -C, Hc 150-153 °

O D

5-CH 3 O- H 106-110 ° H H -CH-, 137-138 ° C 3 I 5-Cl H H 106-107.5 °) 5_C 2 H 5 H H 61-63 ° i | If desired, the substituted or unsubstituted 3-indolylthio / acetonitrile can be kept in solution and used in the following preparations uninsulated.

Preparation V

l-methyl-indol-3-yylitioasetonitriili

The 3-indolylthioacetonitrile from ITI is dissolved in 100 parts of ether and an equal volume of 50% aqueous sodium hydroxide solution is added. To this combination is added first 2 parts of benzyltriethylammonium chloride and then 56.8 parts of methyl iodide under cooling. The vessel is sealed and the mixture is stirred for about 16 hours. The solution obtained is extracted with 500 parts of diethyl ether and 650 parts of dichloromethane. Each extract is washed twice with dilute sodium hydroxide solution and once with brine and dried over potassium carbonate. The extracts are then combined and the solvents evaporated in vacuo to give the crude product which is recrystallized from methanol / isopropanol to give pure 1-methylindol-3-ylthioacetonitrile; mp. 92.5 to 93.5 °.

Preparation VI

Following the procedure of Section V, but replacing the unsubstituted 3-indolylthioacetonitrile with an equivalent amount of appropriately substituted 3-indolylthioacetonitrile and replacing the methyl iodide used therein with the appropriate alkyl iodide, the following substituted 1-alkylindol-3-ylcitrile acetones are prepared:

I I

i / '·' - ·· "'-s„ X | 2 R1 x> d: r2 s. p.

H H Cl 2 H 5 ΪΓ 37.5-3 9 ° C

H H i-C ^ H ^ H oil

H H -CH 3 -CH 3 133-138 ° C

H H - ^ | H oil H H -CH2CgH5 H oil H H -d ^ CHjOCHj H oil H H -CH ^ <1 H oil H H -n-CgH ^ H oil H H -CH2_ £> H oil

H H -CH 2 CH = CH 2 H 4 5-47 ° C

H H -CgH5 h H H -CH2 = CH h oil H H -CH2C (CH3) = CH2h oil 64590

Preparation VII

3- [(2-aminoethyl) thio] -1-methylindole fumarate

To a solution of 45 parts of 1-methylindol-3-ylthioacetonitrile in about 80 parts of tetrahydrofuran (THF) is slowly added, with cooling, 415 parts of 1M borane dissolved in THF. The resulting solution is stirred for about 16 hours under protection from moisture, a further 112.5 parts of borane are added and the mixture is further stirred for 16 hours. This stirred solution is slowly treated with dilute hydrochloric acid until hydrogen evolution ceases (about 6 hours) and then basified with 1N sodium hydroxide. This basic solution is extracted three times with 150 parts of diethyl ether; the combined extracts are washed three times with dilute sodium hydroxide solution and once with brine and dried over potassium carbonate. The ether solution is evaporated to about half its volume and hydrogen chloride gas is passed through it, causing the hydrochloride to crystallize. It is recrystallized from methanol / ethyl acetate to give pure 3- (12-aminoethyl) -p / -1-methylindole hydrochloride; mp. 159 to 160.5 °. The fumarate salt is prepared by concentrating the above ether solution before the addition of hydrogen chloride and the resulting yellow oil is dissolved in methanol. To this solution is added 9 parts of fumaric acid dissolved in methanol and the solvent is slowly evaporated by gradual addition of isopropanol. The resulting product is recrystallized from methanol / isopropanol to give pure 3- [2 (aminoethyl) -tipZ-1-methylindole fumarate; mp. 169 ° (dec.).

Calculated for C11H14N2S * C4H4 ° 4: c '55'88? H, 5.63; N, 8.69.

Found; C, 56.04; H, 5.60; N, 8.57.

Preparation VIII

Following the procedure of Section VII, but substituting the appropriately substituted 3-indolylthioacetonitrile for 1-methylindol-3-ylthioacetonitrile used therein, the following substituted 3- (12-aminoethyl) tip7-indoles are prepared: \ 23 64 5 90

XX -. ^ SCH „CH .., NH„ .S

I \ / 1-; i 2 2 2 I 1! ,:

'R

X and K2 kl - 2L_ R2 - s, p.

HHH ~ H ~ HCl 212-215 ° 5_CH3 ° - HHH HCl 192-196 ° HH C2H5 H 1 / 2C4H4 ° 4 181-132 ° HK i_c3H7 H C4H4 ° 4 176-177.5 ° HH -CH3 -CH3 HCl 161-165 ° HHH "C6H5" 125-126.5 ° 5 "cl HHH HCl 245-247.5 ° (decomposes) 5" C2H5 HHH hc1 197-198 ° HH JL CH3 - 124-127 ° HHH C4H4 ° 4 160-161 ° HH -CH2CH2OCH3 H C4H4 ° 4 147-148 ° HH -CH2— <1 H 1/2 C4H404 168-17 0 ° HH '£' CA7 H C4H4 ° 4 152-153 ° HH "CHrO H C4H4 ° 4 166-167 ° HH -CH2- C = CH H C6H13NO3S 136.5-141 ° HH -n-C3H2H1 / 2C4H404 159.5-160.5 ° HH -CH2CH = CH2 H C4H4 ° 4 158-159 ° HH -CH2CgH5 H C4H4 ° 4 183-185 ° HH -CH , C (CH „KH, H CH 0 151.5-153 ° £ · Δ 4 4 4

Preparation IX

3- (2-Aminopropylthio) indole To 4.9 parts of the 3-indolylthiol prepared in I in about 24 parts of absolute methanol is added 1.71 part of propyleneimine. The mixture is stirred slowly under a nitrogen atmosphere for about 40 minutes, after which the methanol is evaporated in vacuo and the residue is dissolved in diethyl ether. The ether solution is extracted three times with 50 parts of 1N hydrochloric acid. The combined extracts are washed with about 180 parts of diethyl ether and then basified with 2N sodium hydroxide solution. This basic aqueous solution is then extracted three times 24,64590 times with 60 parts of ethyl acetate; the combined ether extracts are washed twice with 50 parts of 1N sodium hydroxide solution and. once with brine and dried over potassium carbonate. The ether is evaporated in vacuo to give a crystalline product which is then dissolved in ethyl acetate and activated carbon is added. After the carbon has been filtered off, scraping the filtrate yields the crude product, which is recrystallized from benzene to give the pure product, 3- (2-aminopropylthio) indole; mp. 110.5 to 112.5 ° C.

Preparation X

Following the procedure of IX, but replacing the propyleneimine used therein with an equivalent amount of aziridine, the following product is obtained: 3- (Cl2-aminoethyl) thio / indole; mp. 87-89 ° C.

Preparation XI

2- [T (3-aminopropyl) tip / indole

To a basic solution of 3-indolylthiol iodide prepared from 63.8 parts of 3-indolylthiouronium iodide as described in I, 13.0 parts of 3-chloropropylamine hydrochloride in aqueous solution are added dropwise with stirring. The mixture is then stirred for about three hours under a nitrogen atmosphere, after which the solution is extracted with about 280 parts of diethyl ether. The ether extract is washed three times with about 150 parts of 1N sodium hydroxide solution and once with brine and dried over potassium carbonate. The ether is evaporated to give an oil which crystallizes on standing to a crystalline product. This product is recrystallized from ethyl acetate and then recrystallized from benzene to which a small amount of activated carbon has been added to give pure crystalline 3- (3- (aminopropyl) thio) indole; 72.5 to 73.5 °.

Calculated for C 11 H 14 N 2 S: C, 64.03; H, 6.84.

Found: C, 64.02; H, 6.84.

Manufacture of finished products:

Example 1 3- [2- (1-Methyl-2-imidazolinylamino) ethylthio / indole fumarate 25.8 parts of 1-methyl-2-methylthio-2-imidazoline hydrochloride and L9.2 parts of 3 - [2] -aminoethyl) thio / indole prepared by the procedure of Hohdan IX, 160 parts of 2-propanol are boiled under a vertical condenser for 18 hours, protected from light. The isopropanol is evaporated in vacuo and the residual yellow oil is treated with 90 parts of 2N sodium hydroxide solution and the mixture is extracted with 400 parts of dichloromethane. The extract is washed twice with dilute sodium hydroxide solution and once with brine and dried over potassium carbonate. The dichloromethane is evaporated in vacuo to give crude crystalline 3- [12- (1-methyl-2-imidazolinylamino) ethyl thio] indole fumarate; mp. 198.5 ° (decomp.).

Calcd for C 14 H 18 N 4 S-C 2 Cl 2, C, 55.37; H, 5.68; N, 14.35

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

Example 2 3- [T- (1-Methyl-2-pyrrolidinylideneamino) ethyl] -7-indole a) To a solution of 7.76 parts of epichlorohydrin in 14 parts of anhydrous diethyl ether is slowly added 15.9 parts of trifluoride etherate in 14 parts of anhydrous diethyl ether and the mixture stir protected from moisture for 3-1 / 2 hours. The ether is poured off from the solid triethyloxonium tetrafluoroborane obtained, which is washed twice with anhydrous ether and then dried under a stream of nitrogen.

The dried triethyloxonium tetrafluoroborate is dissolved in 26 parts of dry dichloromethane and a solution of 8.32 parts of N-methyl-2-pyrrolidone in 26 parts of dry dichloro-i-methane is added. The mixture is stirred for 6 hours under protection from moisture to give O-ethyl-N-methylpyrrolidone fluoroborate.

b) A basic aqueous suspension prepared according to VII with 16.0 parts of 3- [~ (2-aminoethyl) thi] -7-indole hydrochloride is extracted with 230 parts of benzene. The extract is then washed with 1N sodium hydroxide solution and once with brine and dried over potassium carbonate. The benzene is then evaporated in vacuo and the residual red oil is dissolved in 60 parts of dry dichloromethane. The resulting solution is added to the solution prepared in a) and the mixture is stirred for about 18 hours under protection from moisture. The resulting brown solution is extracted twice with 60 parts of 20% sodium hydroxide and dried over potassium carbonate; then the dichloromethane is evaporated in vacuo to give the crude free base. This crude free base is recrystallized from isopropanol to give pure 3- [7- (1-methyl-2-pyrrolidinylideneamino) ethyl] n-indole; mp: 143.5 to 145.5 ° C.

26 64 5 90

Calculated for C 18 H 18 N 2 O 2: C, 65.89; H, 7.00; N, 15.37.

i j j- y 4

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

Example 3

Following the procedure of Example 2, but replacing the 3- (7-aminoethyl) thio / indole hydrochloride used therein with an equivalent amount of the appropriate 3- (aminoalkylthio) indole hydrohalide and using an equivalent amount of the appropriate fluoroborate prepared according to Example 2 (a), the following corresponding products are obtained: 1 (l-methyl-2-pyrrolidinylideneamino) propyylitiq / indole hydrochloride; mp. 216.5 to 218.5 ° C; 3- / 2- (l-methyl-2-pyrrolidinylideneamino) propylthio / indole; mp. 178.5 to 180 ° C; 3- [1- (1-Methyl-2-pyrrolidinylideneamino) ethyl] -1H-methylindole hemi-2-butenedioate (E); mp. 186-189 ° C; 5-Methoxy-3- [N- (1-methyl-2-pyrrolidinylideneamino) ethyl] -quinol; mp. 154-157 ° C (ground); 1-Ethyl 3- [1- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indolecyclohexanesulfamate; mp. 113.5 to 115.5 ° C; 3- / 2- (l-methyl-2-pyrrolidinylideneamino) ethylthio / -2-methyl-indole; mp. 167-168.5 ° C (ground); 1,2-Dimethyl-3- [7- (1-methyl-2-pyrrolidinylideneamino) ethyl] indole-2-butenedioate (E); mp 149-150 ° C; 3- [2- (1-methyl) -2-pyrrolidinylideneamino) ethylthio [-2-phenylindole; mp 181-183.5 ° C; S-chloro-Sy] [N- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole, mp 164 -5-165.5 ° C, 3- [2- (1-methyl-4-phenyl-2-pyrrolidinylideneamino) ethylthio] indole, mp 162-163 ° C, 3- [2- (1-methyl) 2-piperidinylideneamino) ethylthio / indole saccharinate, mp 124-124.5 ° C, 3- [4- (1-methyl-2-pyrrolidinylideneamino) butylthio] / indole-2-butenedioate (E), mp 172, 5 to 173.5 ° C.

1- (1-methylethyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethyl] thiridol; mp. 82-84 ° C; 5-Ethyl-3- [2- (1-methyl-2-pyrrolidinylideneamino) ethyl] thiol indole; mp. 131.5 to 132.5 ° C; 27 6 4,590 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethylthio] -1-benzylindolecyclohexyl sulfamate monohydrate; mp. 133-134 ° C} 3- [2- (1-methyl-2-pyrrolidinylideneamino) ethyl] trifluoro-1- (2-methoxyethyl) indolecyclohexyl sulfamate; mp. 107.5 to 109 ° C; l-cyclopentyl-3- / 2- (l-methyl-2-pyrrolidinylideneamino) -etyylitioy-indolibentsoaatti; mp. 108.5 to 110 ° C; 1- (2-Furanylmethyl) -3- [1- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole-2-butenedioate (E); mp. 167 to 168.5 ° C; 1-Cyclopropylmethyl-3 H - (1-methyl-2-pyrrolidinylideneamino) ethylthio] -indole-2-butenedioate (E); mp. 133-134 ° C; 3- / 2- (l-methyl-2-pyrrolidinylideneamino) etyylitiq7-L- (2-propenyl) -indolisykloheksyylisulfamaatti; mp. 105 to 107.5 ° C? 3- / 2- (l-methyl-2-pyrrolidinylideneamino) ethylthio / -L (n-octyl) indole; mp. 98-100 ° C; 3- [2 "- (1-Methyl-2-pyrrolidinylideneamino) ethylthio [1- (2-propynyl) indolecyclohexyl sulfamate; mp 114.5-115.5 ° C; 1- (2-methyl-2-propenyl) -3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] indole, mp 126.5-128 ° C; 3- [2- (1-methyl-2-pyrrolidinylideneamino) ethylthio] -1- α-p-indole-2-naphthalenesulfonate, mp 98.5-100.5 ° C Example 4 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethyl] indole To a solution of 23.8 parts of N-methyl-2-pyrrolidinone in 450 parts of dry benzene, 36.7 parts of phosphorus oxychloride are added dropwise in 70 parts of dry benzene. The colorless solution is boiled under a vertical condenser under a nitrogen atmosphere for 2 hours, then the yellow solution is cooled to room temperature and 38.4 parts are added. - / (2-aminoethyl) thid / indole in 90 parts of dry benzene for 20 minutes, the mixture is then refluxed for 4-1 / 2 hours under a nitrogen atmosphere and allowed to stand at room temperature for about 18 hours.

The resulting mixture is basified by adding 300 parts of water and 120 parts of 50% sodium hydroxide solution, and the mixture is heated on a steam bath to terminate the decomposition of the oily complex. The benzene layer is separated and the aqueous layer is extracted twice with ether. The extracts were combined, dried over potassium carbonate and the ether evaporated in vacuo to give an oily solid. Substance 1 is recrystallized twice from isopropanol-pentane to give 3- [2- (1-methyl-2-pyrrolidinylideneamino) ethyl] / indole] m.p. 143-144 ° C.

Example 5 3- [2- (1-Methyl-2-pyrrolidinylideneamino) ethylthio / indole

A solution of 4.27 parts of 2-aminoethanol in 260 parts of dichloromethane is added to the product prepared in Example 2 a) and the mixture is stirred at ambient temperature for 16 hours. The solvent is then evaporated to give the crude product as the fluoroborate salt. The fluoroborate salt is converted to the free base, which in turn is converted to the perchlorate salt to give 2- (pyrrolidinylideneamino) ethanol perchlorate; mp. 67-69 ° C.

A solution of 3.5 parts of the above free base in 130 parts of dry chloroform at 0 ° C is treated dropwise over 15 minutes under a nitrogen atmosphere with 8.4 parts of thionyl chloride. The mixture is then allowed to warm to ambient temperature and stirred for about 16 hours. Finally, the mixture is boiled pystyjääh-cooler under nitrogen atmosphere for half an hour, after which the chloroform and excess thionyl chloride was removed in vacuo to give the crude product. This residue is dissolved in dichloromethane and the resulting solution is treated with 6N sodium hydroxide solution with vigorous stirring. The dichloromethane layer is separated, dried over potassium carbonate and filtered. Evaporation of dichloromethane in vacuo gives the product, 2- (chloroethylimino) -pyrrolidine.

A basic solution of 3-indolylthiol is prepared from 7.65 parts of 3-indolylthiouronium iodide as in I and washed twice with 175 parts of diethyl ether. This aqueous solution is then treated with any ether solution of 2- (chloroethylimino) pyrrolidine prepared above under a nitrogen atmosphere and the mixture is stirred at ambient temperature for about 16 hours. Dichloromethane is added to replace any evaporated ether, the organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic solutions are dried over potassium carbonate, filtered and the filtrate is evaporated under reduced pressure to give the product as an amber oil which solidifies slowly on scraping. This solid is recrystallized from isopropanol / petroleum ether to give pure 3- [2- (1-methyl-2-pyrrolidinyl-L-64590 29 amino) ethyl] ethyl / indole. The infrared spectrum of the pure product is identical to that of an authentic sample prepared in another way.

Example 6 3- [2- (1-Methyl-2-hexahydro-azapinylideneamino) ethylthio] -indole-2-butenedioate (E)

A solution of 6.1 g (48 mM) of N-methylenecaprolactam in 15 ml of dry CH 2 Cl 2 is added to a solution of triethyloxonium fluoroborate prepared from 9.1 g (64 mM) of boron trifluoride etherate and 4.45 g of: (48 mM) epichlorohydrin, and the mixture is stirred under dry conditions for 2 1/2 hours. 7.7 g (40 mM) of 3- (2-aminoethylthio) indole in 20 ml of dry CH 2 Cl 2 are then added and the solution is stirred under dry conditions at room temperature for 72 hours. An equal amount of Cl 2 Cl 2 is then added and this solution is washed once with 70 ml of 1N NaOH, once with water and once with brine and dried over potassium carbonate. The solution is filtered and the filtrate is evaporated in vacuo to give 8.6 g of an orange oily product which solidifies. Purification of the product as the fumarate salt gives 3- [2- (1-methyl-2-hexahydro-azapinylideneamino) ethylthio] indole-2-butenedioate (E) as white crystals; mp. 128-130 ° C.

Example 7 3- [2- (1-Methyl-5-phenyl-2-pyrrolidinylideneamino) ethylthio] indole chexane sulfate 6.3 g (36 mM) of N-methyl-5-phenyl-2-pyrrolidone in 10 ml of dry C A solution containing Cl 2 is added to triethyloxonium fluoroborate in 20 ml of dry Cl 2. This solution is stirred for 3 hours at room temperature under dry conditions. 5.75 g (30 mM) of 3- (2-aminoethylthio) indole in 20 ml of dry matter are then added and the resulting solution is stirred under dry conditions for 3 days. 50 ml of CH2Cl2 are then added and the solution is washed once with 50 ml of 1N NaOH, once with water and once with brine and dried over potassium carbonate. The dried solution is evaporated in vacuo to give the free base as a viscous oily product. Purification as the cyclohexanesulfamate salt gives 3- [2 "- (1-methyl-5-phenyl-2-pyrrolidinylideneamino) ethylthio] -indolecyclohexanesulfamate as white crystals: mp 190.5-191.5 ° C.

Calculated for C 10 H 10 NO 5 -C-H., NO, S (349.72) C, 61.33; H, 6.86; N, 10.60.

21 23 3 6 13 3

Found: C, 61.4 °; H, 6.89; N, 10.56.

Claims (2)

An analogous process for the preparation of therapeutically active indoles of the formula (I) or their acid addition salts, X A ^ '\ S- (CHL ·) -CH-N *:' Λ '"N" N-P 3 1 K 2 x wherein X and X 1 are each hydrogen atoms, lower C 1 -C 10 alkyl groups, halogen atoms or lower C 1 -C 6 alkoxy groups; R 1 is a hydrogen atom, lower C 1 -C 6 alkyl, C 8 -C 8 cycloalkyl, phenyl, benzyl, lower C 1 -C 8 alkoxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl -, a C 1 -C 6 cycloalkylalkyl or furanmethyl group; R 2 is a hydrogen atom, a lower C 1 -C 6 alkyl or phenyl group; n is an integer 1, 2 or 3; A and B together form a -CH 2 CH (R 8) CH 2 -, -CH 2 CH 2 CH (R 5) -, -NHCH 2 CH 2 -, - (CH 2) 4 -, or - (CH 2) 5 - group having a hydrogen atom or a phenyl group; characterized in that a) a compound of formula (II); ~ + I> * 2h5 I BF.® ”i 'B — N;' | 4 1 '1! tH3! i -1 is reacted with a compound of formula (III) XV \, ____ r S- <CH2> n-CH2-NH2 I π Ί III X11R1 * 2 31 64590 in a suitable organic solvent to form a fluoroborate salt of a compound of formula (I), and then converting said fluoroborate salt to a base form by treatment with a suitable base, or b) reacting a compound of formula (III) with a small molar excess of a compound of formula (IV): / A ~ W-, OPO <5n® ' 2 Nj-b x (IV) I w® CH 3 wherein W is a bromine or chlorine atom, in a suitable organic solvent to form a compound of formula (I) or an acid salt thereof, or "c) subjecting a compound of formula (V) ^ SöNa® Γ Γ 1 x1 I R2 R1 to react in a basic aqueous solution with a compound of formula (VI) Cl- (CH-) -CH-N = \ I (VI) 2. L ch3 in a suitable organic solvent for the preparation of a compound of formula (I), or d) reacting a compound of formula (III) with a compound of formula (VII) 32 6 4 5 9 0 H CB2®VS-R7 W® 'N' (VII) CH 3 wherein W is a suitable anion such as halogen and is alkyl in a suitable lower alkanol to prepare an acid salt of a compound of formula (I) wherein AB is -NHCl 2 CH 2 - and if desired converting said acid addition salt to the free base by treatment with a suitable base , and, if desired, converting the products obtained from process alternatives ad to therapeutically active non-toxic acid addition salts. 33 64590 Analogs of the formulation of a therapeutically active indoler with a formula I or a syringate salt, X .A ^ N \ .. S— (CH 2) -CH-N =! T \ - - 2 n | X / 1; r H i \ tH3 x1! R 2 R 1 represents a formula X and X "*" as a hydrogen atom, a C 1 -C 6 alkyl group, a halogen atom or a C 1 -C 6 alkoxy group; R 1 is not C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, phenyl, benzyl, C 1 -C 6 alkoxyalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkynyl -, C 1 -C 6 cycloalkylalkyl or furanmethyl; R 2 is a hydrogen atom, a C 1 -C 6 alkyl- or phenyl group; n är ett heltal 1,2 eller 3; A and B are further selected from the group consisting of -CH 2 CH (R 2) CH 2 -, -CH 2 CH 2 CH (R) -, -NHCH 2 CH 2 -, - (CH 2) 2 - or - (CH 2) 2 -, or other than hydrogen or phenyl; kännetecknat därav, att a) en förening med formuleln + "a ii OC ~ Hc Θ BN - 2 5, BF CHL omsätts med en förening med formula (III) X · x. ) n-CH2-NH2! '1 ί! III /' N '"" " the basal genome is used in addition to the base, or b) in the case of the formula (III) omsätts med et litet molöverskott av en förening in the form (IV) W ~ 0P0 Λ, 2 SU 'e (IV)! we CH3 color W is a bromine or chlorine atom, which is a warm organic compound obtained from the formulation of formula (I) or a solid form of a formulation, or (c) a formulation of formula (V) X / ^ S Na C rt x1 i R2 is selected from the group consisting of compounds of formula (VI), A '"> Cl- (CH_) —CH — N = C / (VI) 2 n |' NB 'H! CH3 and heated organic solvents framställning av föreningen med formuleln I, eller d) en förening med formula (III) omsätts med en förening med formula (VII)