CA1065874A - 3-substituted indoles and precursors therefor - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Substituted thioindoles and their sulfoxide and sulfone derivatives, useful as cardiac rate lowering agents and for other pharmacological properties, and precursors therefor. These compounds may be represented by the formulae:

(I) and (I1) wherein:
X and X1 are each members selected from the group consisting of hydrogen, loweralkyl, loweralkoxy, halo, loweralkylamino and acylamino; provided that X and X1 are not both acylamino;
R1 is a member selected from the group consisting of hydrogen, loweralkyl, cycloalkyl, phenyl, phenylalkyl, lower alkoxyalkyl, alkenyl, alkynyl and cycloalkyl, R2 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, biphenyl, naphthyl, and phenyl-alkyl, Z is a member selected from the group consisting of from sulfinyl, and sulfonyl;
n is the integer 1, 2 or 3;
R3 is a member selected from the group consisting of hydrogen and loweralkyl;
R4 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, phenalkyl, cycloalkyl, hydroxyalkyl, and alkenyl:
A and B taken individually are each loweralkyl:
A and B taken together is a member selected from the group consisting of -CH2CH(R5)CH2-, -CH2,CH2CH(R5)-, -N(R6)CH(R5)(CH2)m-, -(CH2)4-, and -(CH2)5-, said R5 being a member selected from the group consisting of hydrogen, loweralkyl, and phenyl, said R6 being a member selected from the group consisiting of hydrogen and loweralkyl, and said m being 1 or 2, provided that when m is 2, R5 is H.

Description

~5~74 : :

DESCRIPTION OF THE INVENTION. ~
.. .-: ~ .
This invention relates to novel substituted thio-, sulfinyl-,.and sulfonylindo~es, and more particularly to compounas having the ~ollowing ~ormulas: .
r~'" ' "
Z-(CH2) -C~-W ~ : (~) and ~:~

x~æ- ~CH2)n-~H-N ~ (Il wherein;. . R4 X and Xl are each members selected from the group consisting of hydrogen, loweralkyl, loweralkoxy, halo, loweralkylamino and acylamlno; provided that X and Xl are not bo~h acylamino;
Rl is a member selected from thP group consisting of . .
~. hydrogen, loweralkyl, cycloalkyl, phenyl, : phenylalk~l, lower alkoxyalkyl, alkenyl, alkynyl, .~: and cycloalkyl alkyl, S

R2 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, biphenyl, naphthyl, :
-- -- - :
and phenylalkyl; -Z is a member selected from the group consisting of thio, sulfinyl, and sulfonyl;
n is the integer 1, 2, or 3;
' :;~

`
- . - : ~ , . . . -7~

.
R3 is a member selected from the group consisting of hydrogen and loweralkyl, R4 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, . .
~enylalkyl, cycloalkyl, _ _ _ _ _ , . . .. .. . . . . . ...
hydr.oxyalkyl, and alkenyl;.
A and B tak2n individually are each loweralkyl~
A and B taken together i~ a member selected from the group consisting of -CH2CH~R5)CH2-, CH2CH2CH(R5), -N(R6)CH~R5)(CH2)~, -(CH2)~-, and -(CH2)5, said R5 being a member selected from the group co~sisting of hydrogen, . ~__ ... .. . . .
loweralkyl and pheny1, said R6 . .
being a member selected from the group consisting of hydrogen and loweralkyl, and said m being l or 2; provided that when m is 2, R5 is H; and therepeutically active acid addi~ion salts ~hereof and precursors therefor.

As used herei~, "low ralkyl~ and "loweralkoxy" mean a straight or branched chai~, saturated, aliphatic hydrocaxbon containing from one to about eight carbon atoms such as, for example, methy~, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, and the like loweralkyls, and respectively, methoxy, ethoxy, propoxy, isopropoxy, pentoxy, hexoxy and the li~e loweralkoxys.. As used herein, the term "halo" is.
generic to fluorine, chlorine, bromine, and iodine.

.' ' ' , ' . ~

~ ,.

: - ., , , ,. ' .
- , ~6~37~
The term "substituted phenyl" is used herein to include phenyl substituted with from one to three members each - selected from the group consisting of loweralkyl, loweralkoxy, and halo. The term "cycloalkyl" means cyclic aliphatic hydrocarbon radicals such a~ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the lika.

ALkenyl groups and alkynyl groups comprise straight and branched chain, unsa~urated, aliphatic hydrocarbons containing rom two to about eight carbon atoms such as, for example, - 10 vinyl~ allyl~ l-butenyl, 2-butenyl~ 2-methylallyl, 3-methyl-2-butenyl, ~nd the like alkenyls and, respectively, proparyyl,

2-butynyl, 3-butynyl, and the like alkynyls.

Heterocyclic aryl groups comprise five- to ten-membered heteroaromatics wherein the hetero atoms are one or more~
thia, aza or oxa atoms. Included are monocyclic heteroaryls comprising five- to six-members having at least one sulfur, nitrogen or oxygen atom as the heteroatom, and bicyclic - heteroaryls having up to ten members and having, as one of the cyclic moieties, a five- to six-membered heteroaromatic ring with at least one sulfur, nitrogen or oxygen atom as the heteroatom. Specific examples o~ such groups are pyridyl, - quinolyl, imidazolyl, pyrazinyl, pyrrolyl, thienyl, furanyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl~ oxazolyl and pyrimidinyl. The azaheterocyclic aryls may be, if so desired, - further substituted at the ring carbon and nitrogen atoms.

~)6587~ ~

For example, the hereterocyclic moiety may be substituted with a lower alkyl, e.g., 6-methyl-2-pyridyl, 4-ethyl-2-pyrimidyl, and the like; or, for example, a 2-pyrrolyl moiety may be alkylated to the corresponding N-alkyl-2-pyrrolyl. Further, the carbon heterocyclic aryl linkage may be at any one of the several carbon atoms of the heterocycle as, for example, at the 2,3, or 4-positions of the pyridyl moiety.

As used herein the. term "acyl" includes loweralkyl carboxy radicals such as acetyl, propionyl, butynyl, and the like, and phenyl and substituted phenyl carboxy radicals such as benæoyl, methylbenæoyl, and the like.

The preferred compounds of the invention are those of formula (Ij wherein Rl is othe~ than hydrogen, the more preferred being those wherein Rl is loweralkyl or alkenyl. Still more preferred are such compounds wherein X and Xl are hydrogen, R2 is hydrogen or loweralkyl, R3 is ~ydrogen, Z is thio, n is 1, R2 is loweralkyl, and A--B is -(CE2)3-.

~The compounds of formula ~I~ wherein A--B is NNCH(R5)(CH2)m .~may exist in two tautomeric forms, illustr.ated by the following-(C112 ) n- l H 2~21 m 1 (Ia) X ~. ~ ~ R5 X~- (CH ) -C -~

Rl (Ib) s ~65~

- --The compounds of formula ( I ) .and ( Il ) wherein R4 is hydrogen also may each exist in one of two tautomeric forms, illustrated by the f ollowing:

X'~ Z- (CH~ ) n~ I ~I_N=< B~

Xl ~R2 (Ic) "- , , ' .

.

~1 Z-(CH2 n~ICH_t~
' ' 1 , tId) ' .
_ _ _ _ _ _ _ . _ X ~Z (CE2)n-CH-r~

~ Ila ) X~l Z-(CH2)n-C~-r7~>
Rl (I b) .

. . .

~L~65~37~

In the above formula X, Xl, Rl, R2, Zl R3, R4, A, B, and n are as previously defined unless otherewise specified.
These tautomeric forms are included within the scope of the present invention.
.

The compounds of formula ~I) wherein z i5 thio are preferably prepared by reacting the appropriate fluoroborate salt o formùla (II) with the appropriate

3-(aminoalkylthio)indole of ~ormula (III), in which X, Rl, R~, R3, R4, A, B, and n are as previously de~ined. A slight malar excess of the fluoroborate salt is preferred. Suitable organic solvents for conduc~ing the reaction include lower aliphatic alcohols, such as, for example, methanol, ethanol, 2-propanol, te~t-butanol and the like; ethers, such as, for example diethylether, . tetrahydrofuran, dioxane and the like; lower halogenated hydrocarbons such as chloroform, methylene chloride, l,2-dichloroethane and the like; and aromatic hydrocarbons.
such as benzene, toluene, xyle~e and the likeO The temperature is not critical. While ambient temperatures 20 are preferred, elevated temperatures may be employed to increase the rate of reaction. The resulting fluoroborate .~ salt is converted to the corresponding base form by con-. ventional means; for example, by treatment with a suitable . . base such as an alkali metal or alkaline earth hydroxide, carbonate, and the like. The reaction may be illustrated by the following:

: - , ' ' ' . '- .- ~ . ' -: :

~651~7~

S- ( CH2 )n-CH-NH2 3C2H5 ~ BF4 + ~ ~ HBF4 R4 ~ (II) I (III) ~NaOH
. ................. (I) The compounds Or rormula (I) whereln Z 1~ thio may also be prepared by two other r~actions. First, by reacting an appropria~e compound of ~ormula (III) with a sllght molar excess o~ an approprlate compound Or ~ormul~
(IY), in which X, xl, Rl, R2J R31 R4~ ~5~ A~ B~
a~ previously de~lned and W i8 a bromo or chIoroJ to yield compound (I) as ~t~ acid ~al~. Thl~ reactlon i~ c~nduc~ed ln a sultab}e lnert organio ~olvent ~uch a8 an aromatic hydroearbon, for exampl~, benzene, toluene, xylene, etc.;
. 10 an ether, ~or example, diethyl ether, tetrahydrofura~ (THF), -: dioxane, etc., a halogenated loweralkane, for example, : chloro~orm~ dichlorsmethane, dichlsroethane, etc.; and the ll~e. While temperatur~ 1~ not ~rltical, rerlux tempera-ture 18 pre~erred. Seco~d, by reactlng an approprlate ~odium 3-indolylthiolate o~ ~ormula (Y3 in aqueou~ baRe wlth a stolchiometr1c amount o~ an appropriate compound o~
~ormula (VI) ln whlch X, Xl, Rl, R2, R3, R4, A, s, and n - are a~ previou~ly deflned, ln a ~uitable lnert oreanlc 801ve~t a~ pre~iou~ly d~cribed. The temperature i~ not crltisal. Whil~ amblent tempera~ures are preferred, elevated temper~tures may be employed to lncrea3e the rate o~ reactlon.

'' ``` ;~(~65~7~

~ .~ These two reactions may be illustrated by the following:

`., ,. X ~ ~ ~ S_(CH2)n~IH-NH2 X ~ ~ R3 ~ W2 P ~ RW

1.. ,i ~ , .
.
~ . . ' ,j xl ~ R ; + Cl-(C~2~n-C -N ~ ,/ --i(I) l R4 (VI) ;~ . .
Z~ . . , ~ .
The acld addition salt of ~he desired product may be con .
verted to the free base ~I) as previously des~ribed.
The compounds of formula (I) where Z is thio, and A--B
. is -N(R6)CH(R5)(CH2)m may also be prepared by reacting an - appropriate thioindole of formula (III) with an appropriate alkyl-thioimidazoline salt or alkyl-thiotetrahydropyrimidine salt of ; ormula tVII), in which X, X , Rl, R2,R4, R5, R6, and n are as . . pre~lously de~er1bed3 W 1~ a uitable anlon5 e.g., ~rom ~` 10 a mineral acid, 3uch a~ halo, and R7 18 loweralkyl. Stoichio-.~ metric amount~ are. pr~erably employed., Thi~ reac~ion is ~E . condu¢ted in an appropriate loweralkanol such a, ~or - ~xample, ethanol, i~opropanol, 2-methyl-4~propanolJ and 1~ the llke.
p .~i ~ . ' 9 ',, ~- .- , , - . . - .

. ~065~37~

While temperature is not critical, reflux temperature is preferred. This reaction may be illustrated by the fol-lowing: ~

X ~ S-(CH2)n-1H-NH2 ~5 N ~ 2 ~ (C~\ m /\-S~R7 W Q ~ HW

R~ I) R4 (VII) The acld ~ddltlon ~alt o~ the desired product may be converted to the free base (I) as previously described~

The compounds of formula (I ) where Z is thio and R3 is H may be prepared by reacting an appropriate indoline-2-thione of formula (XX) with an appropriate halvnitrile of formula (XXI3 in a suitable inert organic solvent as previously defined. An excess of the halonitrile is preferred, although equivalent amounts may be used. Ambient temperatures are also pxeferred, although temperature is not critical. The resulting nitrile of formula (XXII) is the~ isolated and purified by conventior.al methods. This l-unsubstituted nitrile may be l-substituted in a method completely analogous to that in which the compounds of formula (XVI) are l-substituted to yield the corresponding substituted nitrile of formula (XXIII).

~6~'7fl~
.

The nitrile of formula (XxIII) is then reduced with a suitable reducing agent such as borane, lithium aluminum hydride/aluminum chloride, or the like. The reaction is conducted in a suitable inert organic solvent other than a halogenated loweralkane, as previously defined, employing a large molar excess of reducing agent. The temperature is not oritical. While ambient temperatures are preferred, elevated temperatures may be employed to increase the rate of reaction.
After destruction of the excess reducing agent with mineral acid (borane~ or base :~lithium aluminum hydride/aluminum chloride), the product amine of formula (XXIV) is obtained as the acid salt or free base, respectively.

Thi~ amine may then be reacted with a suitable compound of formula (II) in a fashion identical to the preferred method described above for the preparation of compounds of formula- ~I~ to yield the desired compound of formula (Il).
. . ' . , The indoline-2-thiones are mostly known or may be prepared by the methods of E.H. Wiseman, et al~, J. Med.
- Chem., 16, 131 (1973) and T. Hino, et al., Chem. and Pharm.
Bull. (Tokyo), 17, 550 (1969). Throughout the above discussion, X, Xl, Rl, R4 and n are as previously defined and W is bromo or chloro. The above reactions may be illustrated by the following:

W- (CH2) n~CN ' ~

S ~ - (CH2) n-CN
H H
(XX) (XXI) ~XXII) ' 11 .

- .. . : .. : .. .
- , . . ,-. : . :

~065137~

R W - ~ ~
~S- (CH2 ) n-CN
Rl (XXIII) reduction `
I
(CH2 ) n-CH2NH2 11 (XXIV) + ~ ).HBF4 ~ (Il) . The compounds of formula (Il) where Z is thio and R3is not limited to hydrogen may be prepared in a~ identical . fashion as above from compounds of formula (XX~Va), which compounds are generally known or may be prepare~ by the S methods described in, for example, U.S. Patent No. 3,655,016.
This reaction may be illustrated by the following:

.
' X

X~~ H2)n-CH-NH2 +(-1)~ (Il).H~F
R R~
(XIVa) NaOH~, (Il) ,~ 12 !``
74`
!
The compounds of formulas (I) and (Il) where Z is sulfinyl may be prepared by reacting an appropriate compound of formula (I) where Z is thio with sodium metaperiodate in a suitable ` ! organic solvent as previously described. A slight molar excess of sodium metaperiodate is preferably employed. While temperature i5 not critical, ambient ~emperatures are preferred.
Elevated temperatures may be employed to increase the rate of reaction. This reaction may be illustrated by the following:

xl ~ -(CH2)n;C -N- ~ I + N~I04 --~ (cH2)n-cH-N=<~ j _ _ . . .. _ X ~ ~A ~H U ~ tN~I04 (Il) xl ~\ S- (CE~2 ) n-fl~-N~
; Rl R3 1 .

:~ - R4 (Il) -. , : :. . . -~L~65l~37~

where X, X , Rl, R2, R3, R4, A, s, and n are as previously defined.

The compounds of formula (I) and (Il) wherein Z is So2 may be prepared by oxidation of compounds of formula (I) and tIl?, respectively, wherein Z is S or SO. The oxidizing agent, which should be present in excess, is preferably hydrogen peroxide or a peracid. The reaction may be conducted in a suitable organlc solvent as previously defined or an organic acid, such as acetic acid, propionic acid, or the like, and preferably at ambient temperatures.

The subject compounds (I) and (Il) may be isolated as the ree bases by synthetic processes normally employed.
These ~ompounds in base form are convertible to therapeutically active non-toxic acid addition salts by treatment with an appropriate acid such as, for example, an inorganic acid such as ;hydrohalic acid, e.g., hydrochloric, hydrobromic or hydroiodic acid; sulfuric or nitric acid; a phosphoric acid; an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, e~hanesulfonic, hydroxy-ethanesul~onic, benzenesulfonic, ~-toluenesùlfonic, cyclohexane-sulfamic, salicylic, ~-aminosalicylic, 2-phenoxybenzoic, or 2 acetoxybenzoic acid. Conversely, the salt form can be converted in the usual manner into the free base.

The subject compounds (I) and (Il) in free base or acid addition salt form have been found to possess useful cardiac rate lowering activity in mammals by the following re1exogenic tachycardic test. A bilateral vagotomy is performed on _.A

106S~37~L `
, the anesthetized dog [anesthesia consists of i.v. administration of thiopental sodium (20 mg/kg) maintained by subsequent i.v.
injections of a-chloralose (60 mg/kg)]. Two doses of amino-phylline (5'mg/kg i.v.) are administered at 15 minute intervals.
The hypotensive effect of aminophylline activa~es,the baro-receptors of the carotid sinus which, in turn, stimulates the ' sympathetic,nervous system causing a reflex rise in the heart rate. Fifteen minutes after the second dose of ~minophylline, the compound to be tested is administered i.v. and the effect 1~ ; on the heart rate is noted over a 30-minute period. Compounds ~' ; showing heart-rate lowering activity of at least 18 sinus beats per minute for at least 5 minutes are considered to be active. Such compounds are useful in the treatment of angina pectoris, since heart rate is considered to be a major determinant of myocardial oxygen consumption.
: .
, The compounds,of the invention are active in the above test at dosages ranging from about 0.25 to about -' ' 18.5 mg/kg body weight.

The subJ'ect compounds (I)and (I1)'in free base or acid ad-- 2Q dition salt f~rm have also been found to possess useful activity as inhibitors of human platelet aggregation The compounds are: tested using collagen-induced aggregation -at'a final concentration of 100 ~ M in platelet-rich plasma by the turbidimetric method of Born [G.V.~. Born, Nature, ' 25~ 194, 927 (1962)]. The results are expressed as average per cent inhibition of aggregation. While the compounds , of the inventions are all active in the above test, the-preferred compounds for thi~ utlllty Rre those Or formula (I) wherein Y,is methylene and'Z 1~ thlo.
. .

1~6~

.` 1 The subject compounds of formulas (I) and (I ) have also been found to possess useful anti-secretory activity ~y the following acute gastric fistula rat test. The anti-secretory activity o the compound to be tested is studied in female Sprague-Dawley rats after intraduodenal ~i.d.) injection of the compound at doses generally xanging from 2.5-40 mg/kg body weight. The rats are fasted 24 hours before testing and are given water ad libidum while being kept in individual cages. On tha day of testing, the rats are weighed and are selected so that the rats in each test have weights within a range of ~20 g.

Surgery is carried out under light ether anesthesia.
As soon as the rat is anesthetized, its teeth are removed, using a small pinch pliers. A mid-line incision is made on the abdomen about 1-1/2 cm in length and the stomach and duodenum are exposedu If at this point the stomach is filled with food or fecal material, the rat is discarded. Using 4-0 suture, a purse string stitch is placed on the fundic portion of the stom~ch taking care not to pierce any blood vessels in the area. A small nick is made into the stomach in the center of the purse string, and a cannula, consisting of a small vinyl tube with a flange on one end, is put into the stomach and the purse string stitch is closed tightly around the flange.
Immediately following ~his, the test compound is administered 25- i.d. in a volume of 0.5 ml per 100 gm rat. Three rats are generally used for each drug dose tested. Control rats receive the test vehicle, usually 0.5~ aqueous methyl cellulose.

~ iS~7~ ~

After administration of the test compound, the abdominal wall and skin are closed simultaneously with 3 to 4 18 mm wound clips and a collecting tube is placed on the cannula.
Each rat is then placed in a box in which a longitudinal slit has been made to allow the cannula to hang freely and to allow the rat to move about unencumbered. After - the rat is allowed to stabilize for 30 minutes, the collection tube on the cannula is discarded and replaced with a clean tu~e to receive the gastric juice. Collections are made at one hour. At the end of the study, the cannula is removed and the rat is sacrificed.
, .
The sample of gastric contents collected is drained into a centrifuge tube and centrifuged to pack down the sediment. Volumes are read and a 1 ml aliquot of the supernatant is put into a beaker containing 10 ml distilled H~O and is titrated to pH7 using 0.01N NaOH. Results are determined for Volume, Titratable Acid, and Total Acid Output where Volume = total ml. of gastric juice minus sediment; Titratable Acid (milliequivalents/l)= amount of 0.01N NaOH needed to tit~ate the acid to pH77 and Total Acid Output= Titratable Acid X Volume. Results are reported in ~ Inhibition vs.
Controls, with 50% inhibition being the criterion for an "active" compound.

- :
-............................... . : . : ~ , 8~

Further, certain of the subject compounds (I) in free base or acid addition salt form have been found to possess additional pharmacological activity as described below.
Particularly, the compounds (I~ wherein Z is thio, Rl contains a cyclic psrtion (cycIoalkyl, phenyl, substituted phenyl, or heterocylic), and A--B is lowexalkyl, CH2CH-tR5)CH2 or CH2CH(R5)CH2C~2 are active as anti-arrhythmia agents and as inhibitors for both epinepherine- and caff~ine-stimulated lypolysis, as shown by the following three tests.

Atrial Anti-arrhythmic Test_ The right atrium of 3 an anesthetized dog ~anesthesia same as in the reflexogenic sinus tachycar~ia test~ is exposed by right thoracotomy and retraction of the pericardium. Atrial fibrillation, as - determined by standard ECG limb lead ~II), is induced by placing two drops of a 10% solution of acetylocholine on the atrium and then stroking the atrium with a blunt spatula.
:

!l .

~" ' '' , .

..... _, =
. , . .

` ~65~7~
~ : :
The period of fibrillation is recorded. Two control periods of fibrillation are produced at 15-minute intervals. The compound to be tested is administered i.v. ten seconds after the next induction. A compound is classified as active if it decreases the period of fibrillation by at least 50%. The certain compounds of formula (I), described above are active at doses from about 1.0 to about 18.5 mg/kg body weight.

Epinephrine Stimulated Lipolysis: Paired rat .
epidid~mal fat pads are incubated in Krebs-Ringer bicarbonate buffer in the presence of 5 ~g/ml of epine- i phrine bitartrate for one hour. Of the paired fat pads, - `
one isused as a control and the compound to be tested is added to the other prior to incubation, such that the final concentration of the test compound is 1.0 mM. The degree of lipolysis is determined by measuring glycerol production by a modification of the double enzyme method of Wieland ~Wieland, Biochem z., 329, 313 (1957)]. Compounds which inhibit glycerol release at greater than 30% at 1.0 mM or are significant at a 95% confidence ~` limit are considered "active".~
' ' :' Caffein Stimulated Lipolysis: Procedure same as above except that caffeine in place of epinephrine is present in the incubation mixture at a concentration of l.OmM.

`' ' '` ' ! .

1(~65~

.
The compounds of formula [III) may be prepared directly by combining an appropriate indole of formula (XVIII) with an appropriate aminoalkylthiol of formula ~XIX), in which X, Xl, Rl, R2, R3, and n are as previously d~fined, and adding an aqueous solution o~ iodine or a paroxide (~.g. hydrogen peroxide or sodium peroxide) as an oxidizing agent.
_ _ . ...... _ Stoichiometric amounts o~ all three materials are pre-ferxed. The reaction is conducted in a suitable lower alkanol as previously defined. The temperature is not critical and elevated temperatures may be employed to increase the rate o~ the reaction~ but ambient tempera-ture is preferred. The reaction is conducted in the absence of ~ir, as for example under a nitrogen atmosphere.
After the reaction is complete, the alkanol is evaporated in vacuo, and the product is purified by techniques well known in the art. This reaction may be illustrated by the following: -' ' X~ '' ~ ~ ~S-(CH2)n-~ -NH2 ~ (III) .
. ... . .
(XVIII) (XIX) . . .
The compounds of formula (III) may also be prepared by one of three other reactions. First, when n=l, by reacting 20 an appropriate 3-indolyl~hiol of formula (VIII) ~ith an ap-propriate aziridine of ~ormula (IX), in which X, Rl, R2, ...... _,.. = , ...... ..

1~6S874 and R3 are as pre~iou~l~ de~ edO The reactlon 18 con-ducted ln a ~uitable loweralkanol as previou~ly de~lned.
Stoichlometric a~ounts are pre~er~bly employed. Coollng i8 preferred durlng mlxlng of the two reactants, a~ter which the reaction ~5 pre~erably allowed to proceed a~
amblent temperature. However, temperature i8 not crltical, and eleva~ed temperatures may be employed to increase the rate Or reaction.
Second, when n iB 1 or 2, by reactlng an appropri~e sodium 3-indolyl~hlolate o~ rormula ~V) ln aqueous base with an appropriata chloroalkylamlne hydrochloride o~ `
~ormula (X), ln whlch X, Rl, R2, and R3 are a~ previously de~lned. It i8 preferable that the hydrochloride s~lt be neutralized by addltlon o~ a one molar exce~ o~ basP or, more prererably, o~ the 3-lndolylthlolate it~elr. ~owever, stoichiometrlc amount~ may be employed. Ambient temperature - 1~ al~o pre~erred, but again temper~ture 18 not critlcal and elevated temperature~ may be employed to lncre~e the rate of reactlon.
ThlrdJ when n 1~ 1 or 2.and R3 i~ H. by reducinæ
. an approp~late indol-3 ylthloalkylnltrile of formula (XI), - ~ which x, xl, ~ Rl, and R2 are as previously def~ned.
The reducing-agent is boran~, lithium aluminum hydride/
aluminum chlorlde, or the like. The reactlon 1~ conducted in a ~ultable inert organlc ~olvent as pre~iou~l~ deflned, employlng a large ex¢e ~ of redu~lng agent~ The temperature i8 not critical. Whlle ~mblent temperatures are preferred, ele~ated temperatures may be employed to lncrea~e the rate ~ o~ the reaction. A~er destructlon o~ the exceQs reducing agent 3o with mlneral acid, (borane) or b~e (lithlum ~luminum hydride/
~luminum chlorlde~., the product 1~ obtalned a~ the acld salt or free base respectlvely. The8~3 'chree reactlons may be illustrated .

.. :. . .

~ lOt;S~'7 !

I by the following:

N R2 R3 (III) (n=1) Xl I
~ ( ) (IX) .

S ~ Na~ .
Xl ~ R2 + Cl~(CH2)n~CH~NH2 HCl ---------~ (III) , Rl (V) : : -. S_(cH2)n-cN
X1~ r e ~UC ~ IG n~ ( III ) ( R3=H ) , 1 .. ' , '' . . ~XI) .' ' ' ' " '. '` ' '' ' , ` .
` ' ' '" '.

The subject compounds (III) may be isolated as the free base by synthetic processess well known in the chemical art The free bases, in turn, may be converted into therapeutically activel non-toxic~ acid addition sal~s as disclosed above for the compounds of ~ormulas;(I) and (I ).

., ', ..

. - _ . = .
_ ~)6S~3'74 The subject compounds (III) are useful as precursors for the pharmacologically useful compounds of formula (I).
Moreover, the compounds of formula (III) themselves possess useful pharmacological properties. They are active as human platelet aggregation inhibitors as shown by ~he test described above for compounds ~I). Further, cex~ain compounds (III) are active in the reflexogenic sinus tachycardia test descxibed above, particularly ~hen Rl is loweralkoxyloweralkyl, phenylalkyl, alkenyl, methyl or isopropyl; and certain Compounds lO` (III) are active in the atrial anti-arrhythmia test described above, particularly when R3 is methyl, when R2 is phenyl, or ` when Rl is methyl or isopropyl, all other substituents being hydrogen and n being ona.
It is believed that certain compounds of formula tIII) are novel, particularly those wherein at least one of Rl, R2, R3, X and Xl is other than hydrogen or wherein n is two or three.
These novel compounds of formula (III) and the therapeutically active acid addition salts thereof are to be considered within the scope of the present invention.
' ~ ' ' , . ' .

The compounds of ~ormula (II) may be prepared by reacting an appropriate compound of formula (XII), in which A, B, and R4 are as previously defined,-with triethyloxonium fluoroborate (XIII), according to the procedure described in Berichte, 89, 2063 (1956). The reaction is conducted in a suit~ble organic solvent as previously defined, preferably at ambient temperature. This reaction may be illustrated by the following:

... . . ~ . . . .

" ` ~065il~4 .

__ ,,. ,~
( ~ + (C2H5)3 B~4 ~~~~-~ (II) 1 (XII) (XI~I) .

, The compounds of ~ormula (IV) may be prepared reacting the appropriate compound of ~ormula (XII), in which A, B, and~R4 are as-~pxe~iously defined, with phosphorous oxychlo~ide in benzene according to the procedure described by Brederick, et al., Berichte, 94, 2278 (1961). Thls reaction may be illustrated by the following:
_ _ + P0013 ~ OPOC12 ¦ (XII) . R4Cl ~ (IV) .

The compounds of formula (V) may be prepared by . reacting an approprlate compound of formula (VIII), where-in X, XL; Rl and ~ are as previously defined,with an .-aqueous olutlon o~ NaOH. Both this reaction and the - preparation o~ compound ~III) have been de~cribed by R.L.N. Harrls, ~ 4465 (1969~-Precursor~ ror compound ~VIII) can be made by the pro~edure of C. E. Blades and A. L. Wlld3, Journal . ~ , 21, 1013 (1956).

` 23 _.
. ., ; ;:;

1~65B7'~1 .
The compounds of formula (V) m~y also be prepared by reaction of appropriate indole of formula (XVIII~ with thiourea in the presence of an oxidizing agent. Stoich-iometric amounts of the indole, thiourea, and oxidizing agent are preferred. The oxidizing agent may be, for example, iodine/potassium iodide, hydrogen peroxide, potassium periodate, sodium hypochlorite, or the like. The reaction ~mperature may be amhient or elevated, up to reflux. The solvent may be water, a loweralkanol, an ether (e.g. diethylether, tetrahydrofuran, etc.), a glycol, or the like. When reaction is complete, treatment of the resulting product with concentrated strong base (e.g., aqueous sodium hydroxide), preferably with heating, yields the compound (V).
The compounds of formula (VI) may be prepared by reacting the appropriate compound of formula (XIV~ in which R3, R4, A and Bj are as previously defined~ wi~h thionyl chloride.
The reaction is conducted in an appropriate inert organic solvent as previously defined and in the absence of oxygen.
A large excess of thionyl chloride is preferably employed.
While the materials are preferably cooled to about O during mixing, ele~ated temperatures may be employed during the reaction. The mixture is preferably stirred at ambient conditions and finally refluxed. This reaction may be - illustrated by the following:
.

HO (CH2)n fH ~ ~ + socl2 ~ (VI ) R3 "
R4 (XIV) .
. ~
-- - : - .

~658~
The compounds of formula (XI) may be prepared by reacting the appropriate N-~msubstituted compound of formula (XVI) in a suitable inert organic solvent as previously de-fined with an appropriate halide RlW mixed with aqueous base, in which X, Xl, Rl, and R2 are as previoulsy defined and W
is halo, preferably iodide, in the presence of benzyltriethyl-ammonium chloride. A one molar excess of the alkyl halide is pre~erably employed, but stoichiometric amounts may be used. The reaction is preferably conducted at ambient temperatures and may be illustrated by the following:

X ~ , ~ J
(XVI) (XI) - The l-substituted products of formulas (I) and (I1) may also be prepared by reacting the l-unsubstituted (Rl=H) compounds of formulas (I) and ~Il), respectively, with a strong base and then with the appropriate halide, RlW, all in a suitable inert organic solvent as previoulsy defined.
Suitable strong bases are, for example, sodium hydride, lithium hydride, sodamide, and the like, with which the unsubstituted compound (I) or (Il) is preferably mixed slowly. In the halide, W is preferably iodide or bromide, although chloride may also be used. The desired product is isolated and pur-ified by standard techniques. -' ' ~

. - . ~ ... .. ,:

3~0~;5~7~
This reaction may be illustrated by the following:
X S-5CH2)n-CH N

Xl U 1 R2 3 ~ ~ R,W

Xl~S - (CH2~n-CH-N'~
Rl The compounds of formul~ (XIV) may~be prepared~by reacting the appropriate compound of formula (II) with the appropriate aminoalkanol of formula (XV)J in which A, B, and n, and m are as prevlously defined. The reaction is conducted in a suitable organic solvent as - previously defined. Stoichiometric amounts are preferably employed. The temperature is not critical and elevated temperatures may be employed, but ambient temperature iB preferred. The reaction may be illustrated by the following:

I I ~ oC2H5 ¦ ~F4 + Ho-(CH~)n~CH~NH2 -~ IV) (II) (XV) . .

The compounds o~ formula (XVI) may b~ pEepared b~-reacting ` the appropriate compound of formula (V) in a suitable lnert organic solvent as previously defined with the appropriate haloalkylnitrile of formula (XVII) mixed with aqueous b~se, in which ~, Xl,` R2, and n are as previously de~ined. Stoichio metric amounts are preferably employed. Ambient temperatures are preferred, although temperature is not critical. Elevated~
temperatures may be employed t~ increase the rate of the reaction.
The reaction may be illustrated by the following:

- ~ S ~ Na ~ X ~ (C 2)n CN

X ~ ~ W (C~2)n CN ~

(V) (XVII) tXVI) The compounds of formulas (VII)~ (VIII), (IX), (X), (XII), (XV), (XVII), (XVIII),and (XIX) are mostly known and can be prepared by methods well known in th~ chemical art.

.
The following examples are intended to illustrate, but not to limit, the scope of the present invention.

_ . . .

)651~79~

EXAMPLE I
~ s To 240 parts of methanol is added 23.4 parts o~ indole, 15.2 parts o~ thiourea, and a suf-ficient amou~t of a 1 N aqueous solution of potassium iodide and iodine so that an equivalent o~ each i~ present for each equi~alent o~ indole. The whole i9 stirred for sixteen hours, after which tlme the solvent is evaporated in vacuo to yield S[3~1ndol~1]isothiuronlum iodide as ..
colorle~s crystals; m.p. 214-216. Tr~atment of this product with an excess of a concentrated aqueous so}u-tion o~ sodium hydroxide under a nitrogen atmosphçre at 80 for ten minutes, followed by cooling to room temperature yields a basic solution of 3-indolylthiol.
Neutralization thereof with dilute hydroch~oric acid yields as^pu~e product, 3-indolylthiol, m.-p. 100-101.

-. EXAMPLE II

I5Following the procedure of Example I but substituting - an equivalent amount of the appropriately substituted indole for the indole used therein, the following.substituted 3-- indolylthiols are prepared.

:
~5 H -.

.

. 28 .

. .
.

~06S15 74 X Xl R2 5-Cl H

C~3 H H ~ Cl H H ~ OC2~I
H3C___r_<,,Cl H H ~ Cl : .
H H -C~2 ~ Cl 5-Br - H H ~-If desired, the substituted or unsubstituted 3-indoiythiol may be left in solution as sodium 3-indolylthiolate .~ , .
by omitting the final cooling and neutralization, and this :
solution as is in subsequent preparations.
EXAMPLE III ~
~.
3-Indolylthioacetonitrile: To the basic solution of 3-indolylthiolate produced in Example I is added 12.1 parts of chloroacetonitrile with about 70 parts of diethyl -; ether. The- whole is stirred under nitrogen for about six-teen hours, after which the ether layer is separated. The aqueous layer is extracted with about 400 parts of dichloro-methane and then about 140 parts of diethyl ether. The com-bined organic fractions are washed with dilute sodium hydroxide and dried over magnesium sulfate, after which the solvent is evaporated in vacuo to leave a brown crystalline solid.

~ 29 3`7~

Recrystallization of this solid from methanol/isopropanol -yields 3-indolylthioacetonitrile; m.p. 52-54.5. ::

29a ;

lO~iS87~
EXA~.PLE IV
. . , _ Following the procedure of Example III, but substituting equivalent solutions of the substituted sodium 3-indolylthiolates o~ Example II ~or the un-substituted sodium 3 indolyl.thiolata solution used therein, the following substituted 3-indolylthioalkyl-nitriles are prepared:
... ... . _ .. . . .

xl ~CH2-CN

H

.
X Xl R2 m-p- .

5- CH30- H H 106-liO
H ~ -CH3 137-138 5- Cl H H 106-107.5 5- C2H5 H ; . H 61-63 H. H ~ Cl .~
. -H H ~ C2H5 - H3co~ Cl . . , ~.
Cl . - H CH2C6H5 H H -CH2 ~ Cl S-Br H H

~06587~

I~ desired, the substituted or unsubstituted 3-indolylthio-' acetonitrile may be kept in solution and used unisolat'ed , in subsequent preparations.

. ' . ~P~ V
, ~-Methylindol-3~ylthioacetonitrile: The 3-indolylthiv-acetonitrile ~rom Example III is dissolved in 100 parts of ether and an equal volume o~ 50% aqueous sodium hydroxide solution is added. To this combination is first added 2 parts of benzyltriethylammonium chloride and then 56.8 ~ parts of methyl iodide with cooling. The container is : ¦ 10 stoppered and the whole is stirred for about 16 hours.
The resulting solution is extracted with 500 parts of diethyl ether and 650 parts of dichloromethane. Each extract is washed twice with dilute aqueous sodium hydroxide solution and once with,brine and dried over potassiu~
' 15 carbonate. The extracts are then combined and the solvents are evaporated in vacuo to give the crude product, which is recrystallized from methanol/isopropanol to yield pure l-methylindol-3-ylthioacetonitrile, mp., ' 92.5-93.5C.- , .
.
' ' ' - 31 ~! ' .
;~ ' .-.
.
'' ' ' ' ' ' - ' . ' '`''' '' ----,. -1~i587~

EXAMP~E VI
.

~, Following the procedure of Example V, but su~stituting ¦ an equivalent amount of the appropriately subs.tituted 3-indolylthioacetonitrile.for the unsubstituted 3.-indolylthio-acetonitrile used therein and substltuting the appropriate alkyl iodide for the methyl iodide used therein, the fol-. lowing substituted l-alkylindol-3-ylthioacetonitriles are . prepared:

x~
. . Rl . . .
. . , . . .' ' . , ' ,' , X Xl Rl R2 m.p.
. . H ~ C2H5 H 37-5-39C
. H H i-C3H7 H !oill ..
. H H , -C~3 -CH3 133-138C
. .- . H H ~ H oil . . H H C~2C6 5 oil . H H -CH2CH~OCH3 H oil . . H H -CH ~ H oil .
. ~

6~B~

H H -n-C8H17 H oil H H -CH2-~ H oil ..

H H CH2C~CH2 H 45-47 C

E~ H ~C 1 H

H H ~OCH3 H
:, ....... .
H H -CH2~C1 H

H H -CH2-CaCH H oil ' H H -CH2C (CH3 ) =CH2 H . oil S-Cl H -CH3 }~
H H -n-C3H7 .

. .
., '.... ..
i - -::~06~8'7~L
; .

MP ~ VII
' , .

.
- ; 3- ~ (2-Am~noethyl)thl ~ -l-methyllndole ~umarate: , :
To a 801utlon 0~ 45 part~ 0~ 1-methyllndol-3-ylthio~ce-tonitrile in abo~t 80 parts Or tetrahydroruran ~THE'~ is ~lowly added with cooling 415 p~rt~ Or lM borane dl~sol~ed.
in.THF. Tho re~ult~ng ~olution i~ stirred ror about 16~ . .
hours protected from mol~ture, a ~urther 112.5 p~rt~ o~ -bor~ne ~re added, and the who~ i8 stirred ~or a ~urther ~lxteen hour~. Thl~ ~tirred solution 1~ ~lowly treated ~-~ith dilute hydrochlor~c acid ~ntil hydrogen evslutlon ~ea~e3tabout ~lx hour3) and i~ then made baslo w~th lN
~od~um hydroxlde. Thls basic ~olutlon i~ extrac~ed three .
.
times wlth.150 p~rts o~ diethyl ~ther; ~he csmbined ~xtracts are washed three tlmes wlth dllute ~odlum hydroxlde olu- ;
tion a~d once wlth brlne and are drle~ o~er pota~sium carbonate. The e~hereal 801ution 19 e~aporated to about - half lt~ volu~e and hydrogen chloride ga~ i~ bubbled :~ .
thr~ugh it, causlng crysta~lization oP the hydrochlorld~.
It i~ recrystalllzed from methanol/ethyl acetate to give .
pure 3- r (2 amlnoethyl)thl ~-1-methyllnd~le hydrochlorlde;
.m.p. 159-160.5.

,- . , . ' ' ' , :
.

, 34 ~

, ,~ ' ' .
_ .

58~7~

The ~umarate salt is ~repared by concentrating the above ethereal solution before addition of hydrogen chloride gas, and the resulting yellow oil is dissolved in methanol.
To t~is solution is added 9 parts of fumaric ~cid dissolved in methanol and the solvent is slowly evaporated with the gradual addition of lsopropanol. The product which is formed is recry tallized from methanol/lsopropanol to yield pure 3- r (2 aminoethyl)thio3-1 methylindole fumarate;
m.p. 169 (dec.).

Calculated for CllH14N2S.C4H404: C, 55,88; H, 5.63; N, 8-69-Found: C, 56.o4, H, 5.60; N, 8.57.

EXAMPLE VIII

Following the procedure of Example VII, but substituting the appropriately substituted 3-indolylthioacetonitrile for the l-methylindol-3-ylth1oacetonitrile used therein~ the following substituted 3- E (2-aminoethyl)thio]-indoles are prepared:

X~SCH2CH2NH2 S

Rl , , .
.

... . _ .,.. ,., - , . . .
- . ~ - . . - .
.. . . . . .

106587~
x x 1 ~ s m. p .

H H H H HCl 212-215 5-CH30- H H H HCl 192-196 H Hi-C3H7 H C4H404 176-177.5 H H -CH3 -CH3 HCl 161-165 H H H 6 5 125-126.5 5-Cl H H H HCl 245-247.5 (dec) 2 5 H H H HCl 197-198 H H H ~ Cl E~ H H ~ 2 5 CH30 Cl H H H ~ -~

Cl 5-Cl H CH3 H
.
~, , " ~6587 X ,~ Rl R2 . S m H H H -CH ~ Cl .
H H ~ H C4H~0~ 160-161 H H -CH2~ H 1/2 C4H404 168-170 H H -n C8~17 H C4H4 4 152-153 H -CH ~ H C4H404 166-167 .

H H~ Cl H
CH
. H H~ CH3 H

: . HH -C~ ~ Cl H.

H H-CH2-C-CH C6 13 3 136.5-141 5-Br H H H

H H -n-C H H 1/2C4H404 159.5-160.5 H -CH2C(CH3)=CH2 H C4H404 151.5-153 s~

EXAMPLE IX -3-(2-A.minopropylthio)indole: To 4.9 par-ts of the 3-indolylthiol prepared in Example I dissolve~ ln about 24 parts of absolute methanol is added 1.71 parts of propyleneimine. The whole is stirred 910wly under nitro-gen for about 40 mimltes, after which ~he methanol is evaporated in vacuo ~nd the residue is dissolved in di-ethyl ether. The ether solution is extracted ~hree times with 50 parts o~ lN hydrochloric acid. The com-bined extracts are washed with about 180 parts of diethyl ether and are then made basic with 2N sodium hydroxide solution. This basic aqueous solution is then extracted three times with 60 parts o~ diethyl ether; the combined ethereal extracts are washed twice with 50 parts of lN
sodium hydroxide solution and once with brine and are dried over potassium carbonate. The ether is evaporated in vacuo to give the crystalli~e pxoduct, which product is then dissolved in ethyl acetate and activated char-coal is added. After the charcoal is filtered off~ scratch-I - ing of the. filtrate yields crude product, which upon re-.¦ 20 crystallizat.ion from benzene yields as pure product, 3-(2-aminopropylthio)-indole; m.p. 110.5 - 112.5C.

."' . ' . ' ,.

1~5~74 ::

EXAMPLE X
Following the procedure of Example IX, but sub- - -stituting an equivalent amount of aziridine for the propyleneimine used therein, the following product is obtained:

3-[(2-aminoe~hyl)thio]indole; m.p. 87-89C.

EXAMPLE XI

3-C(3-Aminopropyl)thio]indole: To a basic aqueous solùtion of 3-indolylthiol produced from 63.8 parts of -3-indolylthiuronium iodide as in Example I is added -an aqueous solution of 13.0 parts of 3-chloropropyl-amine hydrochloride dropwise with stirring. The whole is then stirred for about three hours under nitrogen, after ' which the solution is extracted with about 280 parts of diethyl ether. This ether extract is washed three times with about 150 parts of lN sodium hydroxide solution and once with brine, and is dried over potassium carbonate. ~, The ether is evaporated to give an oil which crystallized on standiny to yield crystalline product. This product is recrystallized from ethyl acetate and is then re-crystallized from benzene to which a small amount of activated charcoal has been added to yield pure crystalline 3-[(3-aminopropyl)thio]-indole; m.p. 72.5-73.5.
Calculated for CllH14N2S: C, 64.03; H, 6.84.
Found: C, 64.02; H, 6.84.

"'. ~ " ' ' .
'" ' .' :,~,'-~
39 ~-' :; . : ~ , . , - , EXAMPLE XII
3-[2~ Methyl-2-imadazolinylamino)ethylthio]indole fumarate: A solution of 25.8 parts of 1-methyl-2-methyl-thio-2-imidazoline hydrochloride and 19.2 parts of 3-[(2-aminoethyl)thio]indole prepared by the procedure of Example IX in 160 parts of 2-propanol is refluxed for 18 hours while protected from light. The yellow oil remainin~ after the evaporation of the isopropanol in vacuo is treated wlth 90 parts of 2N sodium hydroxide solution, and the whole is extracted with 'lO0 parts of dichloromethane. The extract is washed twice with dilute sodium hydroxide solution and once with brine, and is dried over potassium carbonate.
Evaporation of the dichloromethane in vacuo yields the crude crystalline 3-[2-(1-methyl-2-imadazolinylamino)-ethylthio]indole, which is then converted to the fumarate salt by dissolving it in hot methanol and adding 10.8 parts of fumaric acid dissolved in methanol. The fumarate salt is crystallized from solution by addition of isopropanol and cooling and is twice recrystallized from methanol/
isopropanol to yield 3-[2-(1-methyl-2-imadazolinylamino)~
ethylthio]indole fumarate; m.p. 198.5 (dec.).
Calculated for C14H18N4S C4H404 H, 5.68; N, 14.35 Found: C, 55.33; H, 5.75; N, 14.25 6S~74 EX~PLE XIII

Following the procedure of Example XII, but sub- .
; stituting equivalent amounts of the appropriate alkyl- :
thioimidazoline and the appropriate 3-[aminoalkylthio]-indole for the l-methyl-2-methylthio-2-imidazoline : hydrochloride and 3-[(2-aminoethyl)thio]indole used therein yields the following respective products:
:

N
X ~-(CH2)n-C -N=~

X Xl ~ ~ n R3 R4 R5 6 ' `, ', . ..
5-CH o H H H 1 H CH3 H H

5-Cl H CH3 H 1 CH3 CH3 H C2H

': .-'~

`' S~374 E ~qPLE XIV
O-Ethyl-N-methylpyrrolidonium fluoroborate: To a solution of 7.76 parts of epichlorohydrin in 14 parts of anhydrous diethyl ether is slowly added a solution of 15.9 parts of boron trifluoride etherate in 14 parts of anhydrous diethyl ether and the whole is stirred pro-tected ~rom moisture or 3-1/2 hours. The ether is de canted from the resulting solid triethyloxonium tetrafluoro-borate, 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 dichloromethane is added. The whole is stirred for six hours protected from moisture to yield O-ethyl-N-methyl-pyrrolidonium fluoroborate. While this reagent may be isolated by evaporation of the solvent, it is conveniently used in solution without prior isolation.
EXAMPLE XV
Following the procedure of Example ~IV, but sub-stituting an equivalent amount of -the appropriate pyrrolidone or piperidone for the N-methyl-2-pyrrolidone used therein yields the following respective products:

~OC2~5 ~5~374 , R4 ~ m H H 1.

-CH3 ~CH3 ~1 3 ~ C 1 C2H5 ~ 1 , , ' ~
_ _ ; ~Cl H

cH~l . H

H

-CH2C~CH2 H

.

-. , -~0~ii51~174 EXAMPLE XVI
3-[2~ Methyl-2-pyrrolidinylideneamino)ethylthioJ-indole: A suspension of 16.0 parts of 3-[(2-aminoethyl)thioJ-indole hydrochloride prepared according to Example VII in aqueous base is extracted with 230 parts of benzene. The extract is then washed with lN sodium hydroxide solution and once with brine, and is dried over potassium carbonate. The benzene is then evaporated ln vacuo, and the resulting red oil is dissolved in 60 parts of dry dichloromethane. The resulting solution is added to the solution produced in Example XIV and the whole is stirred for about l8 hours protected from moisture.

~L06~74 .

The resulting brown solution is extracted twice with 60 parts of 20% sodium hydroxide and is dried cver potassium carbonate; the dichloromethane is then evaporated in vacuo to yield the crude ~ree base. This crude free base is recrystallized from isopropanol to yield pure 3-~2~ methyl-2-pyrrolidinylideneamino)ethylthio]indole;
m.p. 143.5-145.5C.

Calculated ~or C15HlgN3S: C, 65,89; H, 7.00;
N, 15.37-Found: C, 65.83; H, 6.92; N, 15.37.
.
- EXAMPLE XVII

- Following the procedure o~ Example XvIJ but sub-stituting an equivalent amount of an appropriate 3-(amino-- alkylthio)indole hydrohalide for the 3~[(2-aminoethyl)thio]-: indole hydrochloride used thereinJ and using an equivalent amount of the appropriate fluoroborate made as in Example - XIV or XV, the-following respective products are obtained:

3-~3-(1-methyl-2-pyrrolidinylideneamino)propylthio]indole hydrochloride; m.p. 216.5-218.5C.;
.

3-~2~ methyl-2-pyrrolidinylideneamino)propylthio~indole;
m.p. i78.5-180C;
~, .
3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-methylindole hemi 2-but~nedioate (E); m.p. 186-189C.;

._~
- . .: ~ , 06~i~37~

5-methoxy-3-~2-(1-methyl~2-pyrrolidinylideneamino)-ethylthio]indole; m.p. 154-157C. (when ground);

l-ethyl-3-~2~ methyl-2-pyrrolidinylideneamino)-ethylthio]indole cyclohexanesulfamate; m.p. 113.5~115.5C.;

3-~2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-methylindole; m.pL 167-168.5C. (when ground);

1,2-dimethyl-3- r2- ( 1-meth~1-2-pyrrolidinylidenqamino)-ethylthio]indole 2-butenedioate (E); m~p. 149-150C;
, 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-phenylindvle; m.p. 181-183.5C.;
.
.
5-chloro-3-~2-(1-methyl-2-pyrrolidinylideneamino)-ethylthio]indole, m.p. 164.5-165.5C.;

3-~2-(1-methyl-4-phenyl-2-pyrrolidinylideneamino) ~ ethylthio]indole; m.p. 162-163C.;
.: . . . .
- 15 3-~2-(1-methyl-2-piperidinylideneamino)ethylthio]
indole saccharinate; m.p. 124 124.5C.;

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

3-[4-(1-methyl-2-pyrrolidinylideneamino)butylthio]indole 2-butenedioate (E); m.p. 172.5-173~5C;

.
' _ . . .

~O~ 74 ~ methylethyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)-ethylthio]indole; m.p. 82-84C;
5-ethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole; m.p. 131.5-13?.5C;
2-(3-methyl-5-chloxophenyl)-3-[2-(1-methyl-2-pyrrolidinyli-deneamino)ethylthio~indole;
2-t4-ethoxyphenyl)-3-~2~ methyl-2-pyrrolidinylideneamino~-¦ ethylthiolindole;
3-~2-tl-ethyl-2~pyrrolidinylideneamino)ethylthio]-2-(2-methoxy-3,5-dichlorophenyl~indole;
3-[2-(1-methyl-4-~-tolyl-2-pyrrolidinylideneamino)ethylthio]-indole;
3-[2-(1-methyl-4-~3,4-dichlorophenyl)-2-pyrrolidinylideneamino)-ethylthiolindole;
3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-benzytindole cyclohexylsulfamate monohydrate; m.p. 133-134C;
3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio3-1-(2-me~hoxyethyl)indole cyclohexylsulfamate; m.p. 107.5-109C;
l-cyclopen yl-3-[2~ mathyl)~2-pyrrolidinylideneamino)-ethylthio~indole benzoate; m.p. 108.5-110C;
1-(2-furanylmethyl)-3-[2-(1-methyl 2-pyrrolidinylidene-amino)ethylthio]indole 2-butenedioate (P,); m.pO 167-168.5C;
l-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. 105-107.5C;

' ;~

B
~ ~, . . ...

S~il74 3-[2-(1-methyl-~-pyrrolidinylideneamino)ethylthio]-1-(_-octyl)indole fumarate; m.p. 98-100C, . ' :
¦ 3-l2-(1-methYl-2-pyrrolidinylideneamino)ethylthio]-1-¦ phenylindole cyclohexan~sulfamate ¦ 5 1-(4-chlorophenyl)-3~[2~ m~thyl 2-pyrrolidinylidene-. amino)ethylthio]indola benzoate;
:

1-(4-chlorobenzyl)-3-[2-(1-methyl~2~pyrrolidinylideneamino)-. . - ethylthio~indDle benzoate;
.''' ,'.
. 1-(3,4-dimethoxyphenyl)-3-[2-1-methyl-2-pyrrolidinyldene-. 10 amino)ethylthio]indole benzoate;

3-~2-(1-methyl-2-pyrrolidinylideneamino)ethylthio .
-: (2-propynyl)indole cycIohexy1sulfamate;m.p. L14.5-115.5C;

5,6-dimethoxy-3-~2~ methyl-2-pyrroli~inylideneamino)-. I ethylthio~indole;
: .. ' ' : , ' . I .
2-benzyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole;
, 11 - .
. . 2-(4-chlorobenzyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino) - ethylthio~indole;

3- ~-[l-(dimethylamino)ethylideneimino]ethylthi~ indole _ 20 cyclohexanesulfamate; m.p. 174-176.5~C:
j 5-bromo-3-[2-(l~methyl-2-pyrrolidinylideneamino)ethylthio]-. indole;

~1~)6587~

3-[2-(1-phenyl-~-pyrrolidinylideneamino)ethylthio]indole;
3-[2-(1-(4-chlorophenyl)-2-pyrrolidinylideneamino)ethylthio]-indole;
3-[2-(1-benzyl-2-pyrrolidinylideneamino)ethylthiolindole;
- 5 3-[2-(1-(4-chlorobenzyl)-2-pyrrolidinyldeneamino)ethyl~hio]-- indole;
3-[2-(1-cyclopentyl-2-pyrrolidinylideneamino)ethylthio]indole;
3-~2-~1-t2-hydroxyethyl)-2-pyrrolidinylideneamino~ethylthio}-indole;
3- ~-[1 (2-propenyl)-2-pyrrolidinylideneamino]ethylthi~ indole;
3- ~ [1-(2-propynyl~-2 pyrrolidinylideneamino]-ethylthio indole;
1-(2-methyl-2-propenyl)-3-[2-(1-methyl-2-pyrrolidinylidene-amino)ethylthio]indole; m.p. 126.5-128C.
7-methyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthioJ-15 - indole;
- 3-[2-~-methyl-2-pyrrolidinylid~neamino)ethylthio]-1-propylindole.2-naphthalene sulfonate; m.p. 98.5-1~0.5C;
.. ..
3-~ -~1-(2-propenyl)-2-pyrrolidinylideneam.ino]ethylt~
. indole 2-butenedioate (E); m.p. 115-117C.

EXAMPLE XVIII
; 3-[2-(1-Methyl-2-pyrrolidinylLdeneamino)ethylthio]indole:
To a solution of 23.8 parts of N-methyl-2-pyrrolidinone in 450 parts of dry benzene is added dropwise to a solution of 36.7 parts of phosphorus oxychloride in 70 parts of dry benzene. The colorless solution is refluxed under nitrogen . ' .: , '~ ` ' ', , ' ' ' :
.

` ~6s~

for 2 hours. The now yellow solution is cool~d to room temperature and a solution of 38.4 parts of 3~(2-amino-ethyl)thio]indole in 90 parts of dry benzene is added drop-wise in 20 minutes. The mixture is then refluxed for 4-1/Z
hours under nitrogen and is allowed to stand for about 18 hours at room temperature.

The resul~ing mixture is made al~aline by the addition of 300 parts of water and 120 parts of 50% sodium hydroxide solution and the whole is warmed on a steam bath to complete ~he decompositlon of the oily complex. The benzene layer is separated, and the aqueous layer is extracted twice with ether. The extracts are combined, dried over potassium carbonate, and the ether is evaporated in vacuo to give an oily solid. The ~àterial is recrystallized twice from isopropanol-pentane to give 3-~2-(1-methyl-2 pyrrolidinyli-deneamino)ethylthio]indole; m.p. 143-144C.
, EXAMPLE XIX
. . _ 3-~[2~ Methyl-2-~yrrolidinylidene.mino)et'nylthioJ indole:
To the product of ExampIe XIV is added a solution of 4.27 parts of 2-a~ino-ethanol in 260 parts of dichlormethane,and the whole is stirred at ambient temperature for sixteen hours. The solvent is then evaporated to yield the crude product as the fluoroborate salt. The fluoroborate salt is con- -verted into the free base, which in turn is con~erted into the perchlorate salt to yield 2-(pyrrolidi.nylideneamino)-ethanol perchlorate; m p. 67-69C.

5~

:

~;S~3'74 A solu~i~n of 3.5 parts o'f the above free base in 130 parts of dry chloroform at 0C. is treated dropwise over a period of 15 minutes under nitrogen with 8.4 parts ' of thionyl chloride. The who~e is khen allowed to warm to ambient temperature and is stirred for about sixteen hours. Finally, the whole is refluxed for a half-ho-lr under nitrogen, after which the chloroform and excess thionyl chlor~de are removed in vacuo to ~ield the crude product. This residue is dissolved in dichloromethane ~0 and the resulting solution is treated with 6N sodium hydroxide solution ~ith vigorous stirring. The dichloro-methane layer is separated, dried over potassium carbonate, and filtered.' Evaporation of the dichloromethane in vacuo ! yields the product~ 2-(chloroethylimino)pyrrolidine.
. . - . ~' ~5 A basic solution of 3-indolylthiol'is produced from 7.65--parts of 3-indolylthiuronium iodide as in Example I
' a~d washed twice with 175 parts of diethyl ether. ~his aqueous solution lS then treated with an ethereal solution of all of the above-prepared 2-(chloroethylimino)pyrrolidine under nitrogen, and the whole is stirred at ambient tempera-'~ ture for about 16 hours. Dichloromethane i5 added to re- place any ether which evaporated, the organic layer is separated and the aqueous layer is extracted with di-' chloromethane. The combined organic solutions are dried 25- over potassium carbonate, filtered, and'the filtrate evapora.ted ' under reduced pressure to yield the product as an amber oil ' which slowly solidified on scratchin~. This solid is re-crystallized from isopropanol/petroleum ether to yield as ' 51 . ~- . - . ... . -, , : .

~65~3~4 t r pure product J 3-[2~ methyl-2-pyrrolidinylldeneamino) ethylthio]indole. The infrared spectrum of the pure product is identical to an authentic ~ample prepared by an-alternate route.

EXAMPLE XX
,, ~ , .. . . ........ . .. . .. . . . , ~
'3~ Meth~yl-2-pyrrolidinylldeneamlno~ethy~ulfinYl~
indole hemifumarate hydrate: To a solution of 8.7 parts of 3-~2-(l~methyl-2-pyrrolidinylideneamino)ethylthio]indole in 70 parts of methanol is added .8.2 par~s of sodium meta-periodate and 3.5 parts of water with stirring. After the solution has been stixring at ambient temperature for aboutsix hours, the white sodium iodate ~;hich has formed is filtered off and washed with methanol. The washirlg is combined with the filtrate, and.the whole is acidified by addition of ~umaric acid solution. in methanol. Evaporation of the methanol and simultaneous addition of is.opropanol yields the . crude product. Recrystallization.from methanol/acetone yields as pure product, 3-[2-(1-methyl-2-pyrrolidinylidene-amino)ethylsulfoxy]indole hemifumarate hydrate; m.p. 154.5 -57.5.C.
EXAMPLE XXI

3-~2-Amin ethyl)thioindole hydrochloride: To a solution of 1.17 parts of indole and 1.13 parts of 2-aminoethylthiol in 12 parts of metharlol is added 11 parts of a lM aq~leous iodine .
. : 52 587~ `
solution slowly under a ni~rogcn atomosphere and the whole is st-irred ~or one hour. After the methanol has been evaporated in vacuo, t~le residue is aci~ified with .
2 pa~ts of concentrated hydrochloric acid and the resulting aqu ous so.lution is extracted wi~h diethyl e~her. The sus-pension of aqueous solution and solids is then made basic ~ith sodi~m hydroxide solution and is further extraGted twice with diethyl ether, these combined two extracts then being washed once with brine and dried over potassium carbonate. The ~he~ is then evaporated in vacuo to yiel-l the free base, 3-(2-aminoethyl)thioindole~ as an orange oil. Bubbling hydrogen chloride gas through an ether/
methanol solution o~ this oil yields the hydrochloride salt, 3-(2-aminoethyl)thioindQle hydrochloride; m.p.
212-215C.

, .

, ' .

- -~ 587~

,~xAI~rLe xx~i 3-[2-(1-Methyl-2-hexahydroaza~y~ideneamino)ethylthiolindole 2-butenedioate (E): A solution of 6.1g. (48 mM) of N-methylcaprolactam in 15 ml of ~ry ~H2C12 is added to a solution of triethyloxonium fluoroborate, prepared from 9.1g. (64 mM) of boron trifluoride etherate and 4.45g. (48 mM) of epichlorohydrin, and the whole is stirred under dry conditions for 2 1/2 hours. Then 7.7g (40 mM) of 3-(2-aminoethylthio)indole in 20 ml of dry CH2C12 is added and the solution is stirred under dry conditions at room temperature for 72 hours. An equal volume of CH2C12 is then added and this solution is washed once with 70 ml of lN NaOH, once with water, and once with brine, and dried over potassium carbonate. The solution is filtered and the filtrate evaporated in vacuo to give 8.6g of orange oily product, which solidified.
Purification of the product as the fumarate salt gives 3-[2-(1-Methyl-2-hexahydroazapinylideneamino)ethylthio]indole 2-butenedioate (E) as white crystals; m.p. 1280130C.
, ' EXAMPLE XXIII

3-[2-(1-Methyl-1,4,5,6-tetrah~dropy_imidin-2-yl_deneamino)-ethylthio]indole 2-butenedioate (E): To a solution of 18.9g (75.3 mM) of 1-[2-(indol-2-ylthio)ethyl]thiourea in 80 ~ ml of acetone is added 10.8g of iodomethane, and the reaction - mixture is stirred at room temperature protected from moisture for 3 1/2 hours. The acetone is evaporated in vacuo to give an orange oil. -To a solution of 13.5g (35 mM) of this ' . . - -. ~ , .

oil in 100 ml of dry DMSO is added 3.08g (35 ~M) of N-methyl- 1-3-propanediamine with stirring and heating. The temperature reached 125C after 1 hour and 40 minutes and is held there for another hour. The solvent is evaporated - in vacuo to give an oily product. This product is dissolved in 50 ml of CH2C12 and t~eated with 25 ml of water containing 2 ml of concentrated NH4OH with cooling. The solution is washed once with brine and dried over sodium carbonate. The dried solution is evaporated in vacuo to give 6.0g. of free base as a brown oil.

The fumarate salt is prepared in methanol/isopropanol to yiald the product as white-tan crystals; m.p. 212-213C.

, EXAMPLE XXIV
.
2-[2~ Methyl-2-pyrrolidinylideneamino)ethylthio]indole saccharinate: To a solution of 25g (188 mM) of oxindole in - 15 500 ml of dry benzene is added 25g of sand. Then 8~85g (40 mM) of phosphorous pentasulfide is added to the stirred mixture, and the whole is first brought to reflux and held there for 80 min,utes and then allow~d to cool. The cool reaction mixture is filtered and the solids washed with 300 20 ' ml of benzene. The combined filtrate and washings are evaporated in vacuo to give 19.0g (68%) of yellow solid, which is recrystallized ,~ from methanol to give 11.6g (41%) of yellow crystalline indoline-2-t~ione.

. ~

1~6SB74 To a stirred solution of 26.4g. (.35 mole) of chloroacetonitrile in 200 ml of pyridine is added 11.0g (74 mM) of the indoline-2-thione. After 1 hour the pyridine hydrochloride is filtered - off, and the filtrate is evaporated in vacuo to give an orange oily product. Any remaining pyridine is removed as an azeotrope with water. The oil is extracted into an ether~water mixture, which is washed twice with brine and dried o~er magnesium sul~ate. The dried solution is evaporated ln vacuo to give 13.5g of tan solid which is recr,ystallized from ethylacetate/cyclohexane to give 10.0g of white crystalline ' ' indol-2-ylthioac~tonitrile; m.p~'91.5-92.5C.
.
- , To a solution of 6.9g (52 mM) of AlC13 and 1.9Bg (52 ~1) of lithium aluminum hydride in 257 ml of anhydrous ether is added 9.8g (52 mM) of this nitrile in 50 ml of anhydrous-ether, and the whole is stirred for 2 hours'at room temperature.
A total of 10g of 50% NaOH and 2 ml of water is added to this reaction mixture over a period of 3 hours and the resulting solution is stirred for 16 hours. The ether is saparated from the soIids and dried over potassium carbonate.
The dried solution is evaporated in vacuo to give 5.4g of ¦ ;
product. Further extraction of the reaction solids with ether again after addition of 2.5 ml of water and 10g of 50%, NaOH yields an organic layer which is then combined with the 5.4g of product and dried over potassium carbonate. The , dried solution is filtered and the filtrate evaporated in vacuo to give 9.0g of 2-(2-aminoethylthio)indole. This - ~, amine is converted to the hydrochloride salt with ethereal HCl and is recrystallized once from methanol/isopropanol to give 6.4g of crystalline solid.

,.

_ _ , -, . ; ... , .; -:
. . ~ . .

A solution o~ 3.0g (lS mM) of 2-(2-aminoethylthio)indole in 30 ml of dry CH2C12 is added to a solution of fluoroborate salt prepared from 3.42g (24 mM) of boron trifluoride etherate, 1.69g (18 mM) of epichlorohydrin, and 1.80g (18 mM) of N-methyl-2-pyrrolidinone, in 15 ml of dry CH2C12. The solution is stirred at room temperature under dry conditions for 4 hours, after which it is washed once with lN NaOH and twice with brine, and dried over potassium carbonate. The dried solution is evaporated in vacuo to give 3.lg of crude product.
Purification as the saccharine salt gives 2-~2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole saccharina~e as cream colored crystals; m.p. 175-177C.

Calc. analysis for C15HlgN3S . C7H503NS (273.29/456.57): C, C, 57.87; h, 5.30; N, 12.27. Anal. found: C, 57.84; H, 5.39; N, 12.31 ~ ' .
-- EXA~LE XXV

3-~2~ M th~ phenyl-2-pyrrolidinylideneamino)ethylthio]indole cyclohexanesulfamat~: A soIution of 6.3g (36 ~M) of N-methyl-S-phenyl-2-pyrrolidone in 10 ml of dry CH2C12 is added to triethyloxonium fluoroborate in 20 ml of dry CH2C12.
This solution is stirred for 3 hours at room temperature under dry conditions. Then 5.75g (30 mM) of 3-(2-aminoethylthio) indole in 20 ml of dry CH2C12 is added, and the resulting solution is stirred under dry conditions for 3 days. Then 50 ml o~ CH2C12 is added, and the solution is washed once with 50 ml of lN NaOH, once with water, and once with brine, ... . . .
. - . - .. ~ - - , -: .

10~5~7~

and dried over potassium carbonate. The dried solution is evaporated in vacuo to yield the free base as a viscous oily - product. Purification as the cyclohexanesulfamate salt gives 3-[2-(1-Methyl-5-phenyl-2-pyrrolidinylideneamino)ethylthio]-indole cyclohexanesulamate as white crystals; m.p. 190.5 191.5C.
Anal. calc- for C21H23N3S . C6 13 3 6.86; N, 10.60.
Anal. found: C, 61.40; H, 6.89; N, 10.56 EXAMPLE XXVI

Following the procedure of Example II, but substituting an equivalent amount of chlorobutyronitrile for the chloroacetonitrile used therein, there is prepared 3-indolylthiobutyronitrile.
~ ' .
Then, following the procedure of Example VII, but substituting an equivalent amount of the 3-indolylthiobutyronitrile prepared above for the 1-methylindole-3-y}thioacetonitrile used therein, there is prepared 3-~(4-aminobutyl)thio]indole 2-butenedioate (E); m.p. 116.5-167.5C.

The above examples have been provided only by way of ; 20 illustration and not to limit the scope of the present invention, which scope is defined by the appended claims.

Claims (66)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PRO-PERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS

1. A process for preparing a compound having the formula (I) or (I') or the therepeutically active acid addition salts thereof, wherein X and X1 are each members selected from the group con-sisting of hydrogen, loweralkyl, lower alkoxy, halo, loweralkylamino or acylamino; provided that X and X
are not both acylamino;
R1 is hydrogen, loweralkyl, cycloalkyl, phenyl, phenyl-alkyl, lower alkoxyalkyl, alkenyl, alkynyl or cycloalkyl alkyl, R2 is hydrogen, loweralkyl, phenyl, biphenyl, naphthyl or phenylalkyl Z is thio, sulfinyl, or sulfonyl;
n is the integer 1, 2, or 3;
R3 is hydrogen or loweralkyl;
R4 is hydrogen, loweralkyl, phenyl, phenylalkyl, cyclo-alkyl, hydroxyalkyl, or alkenyl;

(Claim 1 continued) A and B taken individually are each loweralkyl;
A and s taken together is -CH2CH(5)CH2-,-CH2CH2CH(R5)-, -N(R6)CH(R5)(CH2)m-, -(CH2)4-, or -(CH2)5-, said R5 being hydrogen, loweralkyl, phenyl, said R6 being hydrogen or loweralkyl, and said m being 1 or 2; pro-vided that when m is 2, R5 is H, characterized by (a) reacting a compound of the formula (II) with a compound of the formula (III) in a suitable organic solvent in order to prepare the fluoro-borate salt of a compound of formual (I) and wherein Z is thio, and thereafter converting said fluoroborate salt to base form by treatment with a suitable base, or b) reacting a compound of the formula (III) above with a slight molar excess of a compound of the formula:

(IV) wherein W is bromo or chloro in a suitable organic solvent in order to prepare a compound of formula (I) or its acid salt, and wherein Z is thio; or c) reacting a compound of the formula (Claim 1 continued) (V) in aqueous base with a compound of the formula (VI) in a suitable organic solvent in arder to prepare a compound of the formula (I) wherein Z is thio, or d) reacting a compound of the formula (III) above, with a compound of the formula (VII) wherein W' is halo, in an appropriate lower alkanol, in order to prepare the acid salt of a compound of the formula (I), and wherein Z is thio and A - - - B is -N(R6)CH(R5)(CH2)m-and, if desired, converting said acid addition salt to the free base by treatment with a suitable base, or e) reacting a compound of the formula (XXIV) with a compound of the formula (II) above in a sutiable organic solvent in order to prepare the fluoroborate salt of a com-pound of the formula (I') and wherein Z is thio and R3, X and X' are all hydrogen, and thereafter, converting said fluoro-borate salt to base form by treatment with a suitable base, or f) reacting a compound of the formula (XIVa) with a compound of the formula (II) in a suitable organic solvent, in order to prepare the fluoroborate salt of a com-pound of the formula (I') wherein Z is thio, and thereafter converting said fluoroborate salt to base form by treatment with a suitable base, or g) oxidizing a compound of the formula (I) or (I'), wherein Z is thio, with sodium meta-periodate in a suitable organic solvent in order to prepare the corresponding compound wherein Z is sulfinyl or h) oxidizing a compound of the formula (I) or (I') wherein Z
is S or SO with an oxidizing agent, hydrogen peroxide or a peracid, in a suitable organic solvent, in order to prepare the corresponding compound wherein Z is -SO2 and, if desired, converting the products of steps a) to h) to therapeutically active non-toxic acid addition salts thereof.

2. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-amino-ethyl)thio]indole, and if desired, preparing the therapeutically active acid addition salt of the product thereof.

3. A process for preparing 3-[3-(1-methyl-2-pyrrolidinylideneamino)propylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(3-amino-propyl)thio]indole and, if desired, preparing the therapeu-tically active acid addition salt of the product thereof.

4. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)propylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminopropyl)thio]-1-methyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

5. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-methyl-indole or the therapeutically active acid addition salts thereof, character-ized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-methyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

6. A process for preparing 5-methoxy-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole or the therapeutically active acid addition salts thereof, charac-terized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-5-methoxy indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

7. A process for preparing 1-ethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole or the therapeutical-ly active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-ethyl indole, and, if desired, pre-paring the therapeutically active acid addition salt of the product thereof.

8. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-methylindole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methyl-pyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio] with-2-methyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

9. A process for preparing 1,2-dimethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino]ethylthio]indole or the therapeutically active acid addition salts thereof character-ized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1,2-dimethyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

10. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-phenylindole or the therapeutically active acid addition salts thereof, character-ized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-2-phenyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

11. A process for preparing 3-[2-(1-methyl-2-imidazolinylamino)ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting 1-methyl-2-methyl-thio-2-imidazoline hydrochloride with 3-[(2-aminoethyl)thio]indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

12. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylsulfonyl]indole or the therapeu-tically active acid addition salts thereof, characterized by oxidizing the corresponding thio-compound with sodium meta-periodate and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

13. A process for preparing 3-[2-(1 methyl-2-pyrrolidinylideneamino)ethylthio]-1-benzylindole or the therapeutically active acid addition salts thereof, charac-terized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-benzyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

14. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-(2-methoxyethyl)indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-(2-methoxy ethyl) indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

15. A process for preparing 1-cyclopentyl-3-[2-methyl-2-pyrrolidinylideneamino)ethylthio]indole or the thera-peutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methyl-pyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-cyclopentyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

16. A process for preparing 1-(2-furanylmethyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole or the therapeutically acitve acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-(2-furanylmethyl)indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

17. A process for preparing 1-(cyclopropylmethyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoro-borate with 3-[(2-aminoethyl)thio]-1-(cyclopropylmethyl)indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

18. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-(2-propenyl)indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-amino-ethyl)thio]-1-(2-propenyl)indole and, if.desired, pre-paring the therapeutically active acid addition salt of the product thereof.

19. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-(n-octyl)indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(-amino-ethyl)thiol-1-(n-octyl)indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

20. A process for preparing -5-ethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole or the therapeutically active aci2 acuition salts thereof, characterized by reaoting O-ethyl-N-methyl-pyrrolidonium fiuoroborate with 3-[(2-aminoethyl)thio]-5-ethyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

21. A process for preparing 3-[2-(1-methyl-4-phenyl-2-pyrrolidinyiideneamino)ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methyl-4-phenyl pyrrolidonium fluoroborate with 3- r (2-aminoethyl)thio]
indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

22. A process for preparing 5-chloro-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrroli-donium fluoroborate with 3-[(2-aminoethyl)thio]-5-chloro indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

23. A process for preparing 1-(1-methylethyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)-ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl) thio]-1-(1-methylethyl)indole and , if desired, preparing the therapeutically active acid addition salt of the product thereof.

24. A process for preparing 3-[2-(2-pyrrolidinylideneamino)ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl pyrrolidonium fluoro-borate with 3-[(2-aminoethyl)thio]indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

25. A process for preparing 3-[2-(1-methyl-2-piperidinylideneamino)ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methyl piperidonium fluo-roborate with 3-[(2-aminoethyl)thio]indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

26. A process for preparing 3-[4-(1-methyl-2-pyrrolidinyldeneamino)butylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(4-aminobutyl)thio] indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

27. A process for preparing 1-(2-methyl-2-propenyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-(2-methyl-2-propenyl)indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

28. A process for preparing 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-propylindole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-methylpyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]-1-propyl indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

29. A process for preparing 3-{2-[1-(2-propenyl)-2-pyrrolidinylideneamino]ethylthio}indole or the therapeutically active acid addition salts thereof, characterized by reacting O-ethyl-N-(2-propenyl) pyrrolidonium fluoroborate with 3-[(2-aminoethyl)thio]indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

30. A process for preparing 3-[2-(1-methyl-2-hexahydxoazapinylideneamino)ethylthio]-indole or the therapeutically active acid addition salts thereof, characterized by reacting N-methylcaproiactam with triethyloxonium fluoroborate and then with 3-(2-aminoethyl-thio)indole, and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

31. A process for preparing 3-[2(1-methyl-1,4,5,6,-tetrahydropyrimidin-2-ylideneamino)-ethylthio]indole or the therapeutically active acid addition salts thereof, characterized by reacting 1-[2-(indol-2-ylthio) ethyl]thiourea with iodomethane and then adding N-methyl-1-3 propane diamine and, if desired, preparing the thera-peutically active acid addition salt of the product thereof.

32. A process for preparing 2-[2-(1-methyl-2-pyrrolidinylideneamino)ethylhio]indole or the therapeutically active acid addition salts thereof, characterized by reacting 2-(2-aminoethylthio)indole to a fluoroborate salt prepared from boron trifluoride etherate, epichlorohydrin and N-methyl-2-pyrrolidinone and, if desired preparing the therapeutically active acid addition salt of the product thereof.

33. A process for preparing 3-[2-(1-methy-5-phenyl-2-pyrrolidinylideneamino) ethylthio]indole or the therapeutically active acid addition salts thereof, charac-terized by reacting N-methyl-5-phenyl-2-pyrrolidone with triethyloxonium fluoroborate and then with 3-(2-aminoethyl-thio)-indole and, if desired, preparing the therapeutically active acid addition salt of the product thereof.

34. A member selected from the group consisting of a compound having a formula selected from the group consisting of:

(I) and (I') and the therapeutically active acid addition salts thereof, wherein:
X and X1 are each members selected from the group con-sisting of hydrogen, loweralkyl, loweralkoxy, halo, loweralkylamino and acylamino; provided that X and X1 are not both acylamino; R1 is a member selected from the group consisting of hydrogen, loweralkyl, cycloalkyl, phenyl, phenylalkyl, lower alkoxyalkyl, alkenyl, alkynyl and cycloalkyl alkyl;

R2 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, biphenyl, naphthyl and phenylalkyl Z is a member selected from the group consisting of thio, sulfinyl, and sulfonyl;
n is the integer 1, 2, or 3;
R3 is a member selected from the group consisting of hydrogen and loweralkyl;
R4 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, phenylalkyl, cycloalkyl hydroxyalkyl and alkenyl;
A and B taken individually are each loweralkyl;
A and B taken together is a member selected from the group consisting of -CH2CH(R5)CH2-, -CH2CH2CH(R5)-, -N(R6)CH(R5)(CH2)m-, -(CH2)4- , and -(CH2)5-, said R5 being a member selected from the group consisting of hydrogen, loweralkyl and phenyl said R6 being a member selected from the group consisting of hydrogen and loweralkyl, and said m being 1 or 2; provided that when m is 2, R5 is H, whenever prepared according to the process claimed in claim 1 or by the obvious chemical equivalent thereof.

35. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 2, or by the obvious chemical equivalent thereof.

36. A member selected from the group consisting of 3-[3-(1-methyl-2-pyrrolidinylideneamino)propylthio]indole and the therapeutically active acid addition salts thereof whenever prepared according to the process claimed in claim 3 or by the obvious chemical equivalent thereof.

37. A menmer selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)propylthlo]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 4 or by the obvious chemical equivalent thereof.

38. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-methyl-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 5 or by the obvious chemical equivalent thereof.

39. A member selected from the group consisting of 5-methoxy-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 6 or by the obvious chemical equivalent thereof.

40. A member selected from the group consisting of 1-ethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 7 or by the obvious chemical equivalent thereof.

41. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-methylindole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 8 or by the obvious chemical equivalent thereof.

42. A member selected from the group consisting of 1,2 dimethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 9 or by the obvious chemical equivalent thereof.

43. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-2-phenylindole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 10 or by the obvious chemical equivalent thereof.

44. A member selected from the group consisting of 3-[2-(1-methyl-2-imidazolinylamino)ethylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 11 or by the obvious chemical equivalent thereof.

45. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylsulfinyl]-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 12 or by the obvious chemical equivalent thereof.

46. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-benzylindole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 13 or by the obvious chemical equivalent thereof.

47. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-(2-methoxyethyl)indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 14 or by the obvious chemical equivalent thereof.

48. A member selected from the group consisting of 1-cyclopentyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)-ethylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 15 or by the obvious chemical equivalent thereof,

49. A member selected from the group consisting of 1-(2-furanylmethyl)-3-[2-(1-methyl-2-pyrrolidinylidene-amino)ethylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 16 or by the obvious chemical equivalent thereof.

50. A member selected from the group consisting of 1-(cyclopropylmethyl)-3-[2,(1-methyl-2-pyrrolidinylideneamino)-ethylthio]indole and the therapeutically active acid addition salts thereof:
whenever prepared according to the process claimed in claim 17 or by the obvious chemical equivalent thereof .

51. A member selected from the group consisting of 3-[2-(1-methyl 2-pyrrolidinylideneamino)ethylthio]-1-(2-propenyl)indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 18 or by the obvious chemical equivalent thereof .

52. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-(n-octyl)indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 19 or by the obvious chemical equivalent thereof.

53. A member selected from the group consisting of 5-ethyl-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process clalmed in claim 20 or by the obvious chemical equivalent thereof .

54. A member seleeted from the group consisting of 3-[2-(1-methyl-4-phenyl-2-pyrxolidinylideneamino)ethylthio]indole and the therapeutically active acid addition salts thereof.

whenever prepared according to the process claimed in claim 21 or by the obvious chemical equivalent thereof.

55. A member selected from the group consisting of 5-chloro-3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 22 or by the obvious chemical equivalent thereof .

56. A member selected from the group consisting of 1-(1-methylethyl)-3-[2-(1-methyl-2-pyrrolidinylideneamino)-ethylthio)indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 23 or by the obvious chemical equivalent thereof.

57. A member selected from the group consisting of 3-[2-(2-pyrrolidinylideneamino)ethylthio]indole and the therapeutically active acid addition salts thereof.
whenever prepared according to the process claimed in claim 2 or by the obvious chemical equivalent therof.

58. A member selected from the group consisting of 3-[2-(1-methyl-2-piperidinylideneamino)ethylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 25 or by the obvious chemical equivalent thereof .

59. A member selected from the group consisting of 3-[4-(1-methyl-2-pyrrolidinyldeneamino)butylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 26 or by the obvious chemical equivalent thereof.

60. A member selected from the group consisting of 1-(2-methyl-2-propenyl)-3-[2-(1-methyl-2-pyrrolidinylidinylideneamino)-ethylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 27 or by the obvious chemical equivalent thereof .

61. A member selected from the group consisting of 3-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]-1-propylindole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 28 or by the obvious chemical equivalent thereof.

62. A member selected from the group consisting of 3-{2-[1-(2-propenyl)-2-pyrrolidinylideneamino]ethylthio}indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 29 or by the obvious chemical equivalent thereof.

63. A member selected from the group consisting of 3-[2-(1-methy1-2-hexahydroazapinylideneamino)ethylthio]-indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 30 or by the obvious chemical equivalent thereof.

64. A member selected from the group consisting of 3-[2-(1-methyl-1,4,5,6,-tetrahydropyrimidin-2-ylideneamino)-ethylthio]indole and the therapeutically active acid addition salts thereof, whenever prepared according to the process claimed in claim 31 or by the obvious chemical equivalent thereof .

65. A member selected from the group consisting of 2-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole and the therapeutically active acid addition salts thereof.
whenever prepared according to the process claimed in claim 32 or by the obvious chemical equivalent thereof.

66. A member selected from the group consisting of 3-[2-(1-methyl-5-phenyl-2-pyrrolidinylideneamino)ethylthio]indole and the therapeutically active acid addition salts thereof.
whenever prepared according to the process claimed in claim 33 or by the obvious chemical equivalent thereof.