GB1570374A - Indoles - Google Patents

Description

(54) INDOLES (71) We, LABORATOIRES SAUBA S.A., a French Body Corporate of 260 rue de Rosny, 93104 Montreuil, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to therapeutic substances piperazino-3-indoles; a method of preparing them, and the therapeutic applications of these substances.

Some known indole derivatives have pharmacological properties, inter alia indole amines having the following general formula:

in which: R1 represents a lower alkyl, a phenyl without a substituent, a phenyl bearing a halogen atom or a nitro group, a lower amino or alkoxy, a pyridyl, benzyl, lower benzyl alkoxy, halogeno benzyl or a hydrogen atom, when R2 is a phenyl; R2 represents H, a methyl or phenyl; R3 and R4 each denote a hydrogen atom or lower alkyl or

represents the radical of a cyclic amine having 5 or 6 atoms in the ring and another hetero-atom if required, more particularly a pyrolidine, piperidine, morpholine or N-methyl piperazine radical, and R5 represents H, F, Cl or OCH3.

In these derivatives, the nitrogen atom of the amine is not directly fixed to the indole ring. The derivatives mainly have analgesic properties.

According to the invention, novel indole derivatives have been discovered and have different therapeutic properties from the aforementioned known derivatives.

According to the invention, the derivatives are piperazino-3-indoles having the following general formula:

wherein: A is a hydrogen atom, a carboxylic acid radical or an alkyl, dialkylamino alkyl, benzyl or phenyl group, which may or may not be substituted, R, is a hydrogen or chlorine atom or an alkyl group having less than five carbon atoms, methoxy or hydroxy group, and R2 is an alkyl, benzyl or phenyl group or a cyclic or heterocyclic group, which may or may not be substituted.

Preferably, the piperazino-3-indoles according to the invention are chosen either from the group of 3-piperonyl piperazino-indoles wherein R2 is a piperonyl radical:

or from the group containing 3-alkylpiperazino-indoles, 3-benzylpiperazino indoles, 3-phenylpiperazino indoles and 3-cyclohexylpiperazino-indoles. The radical A can be chosen from a number of substitution radicals such as acetyl, benzyl, phenyl, methyl, ethyl or diethylaminoethyl. The phenyl radical can be a substituted derivative, e.g. a methoxyphenyl or trifluoromethylphenyl.

Radical R, can be a methoxy radical or a chlorine atom.

The following piperazino-3-indoles are preferred according to the invention; I-acetyl 3 piperonylpiperazino indole, l-benzyl 3 piperonylpiperazino indole, I -acetyl 5 chloro 3 piperonylpiperazino indole, I-acetyl 5 methoxy 3 piperonylpiperazino indole, 5-methyl 3 piperonylpiperazino indole, Methyl 3 piperonylpiperazino indole, I-acetyl 3 benzylpiperazino indole, l-acetyl 30 methoxyphenylpiperazino indole, I-acetyl 3 m. trifluoromethylphenylpiperazino indole, 1-N diethylaminoethyl 3 m. trifluoromethylphenylpiperazino indole, 5-chloro 3 methylpiperazino indole, 5-chloro 3 cyclohexylpiperazino indole, I-phenyl 5-chloro 3 methylpiperazino indole, and l-phenyl 5 chloro 3 cyclohexylpiperazino indole.

The invention also relates to salts of pharmaceutically acceptable acids of piperazino-3-indoles according to the invention, more particularly hydrochlorides, iodomethylates and maleates, the hydrochlorides being generally preferred.

Table I hereinafter gives the structural formula and names of some derivatives according to the invention.

Table II hereinafter gives some physical and chemical properties (i.e. the preparation yield, melting point, main absorption bands in the infra-red (IR in KBr) and elementary analysis) for certain derivatives according to the invention.

The invention also relates to a method of preparing piperazino-3-indoles according to the invention.

In one version of the method, a substituted or non-substituted 3-indolinone is reacted with a piperazine derivative in an inert solvent.

Indolinones used as synthesis intermediates are prepared by known methods.

The preparation of N-acetylindolinones has been described by C. D.

NENITZESCU and D. RAILEANU, Chem. Ber. 1141, 1958 and the preparation of N-phenylindolinones has been described by P. FRIEDLANDER and K. KUNTZ, Chem. Ber. 1597, 1922.

The following are some non-limitative examples of preparing derivatives according to the invention.

EXAMPLE I.

1 acetyl 3 m. trifluoromethylphenylpiperazino indole (Compound No. V in Table I) 50.6 g (0.22 mol) of metatrifluoromethylphenylpiperazine was added to a solution of 35 g (0.2 mol) of N-acetyl-3-indolinone in 200 ml of dry toluene in a nitrogen atmosphere. The reaction mixture was refluxed in the presence of paratoluene sulphonic acid (0.500 g) for 24 hours, the water being removed as it was formed during the reaction. Next, the solvent was evaporated at reduced pressure and the crystalline residue was dissolved in 250 ml of boiling ethanol. In this manner, 54.7 g of the desired product was separated.

M.P. = 1480 (methanol). Yield = 70% IR(KBr): 2860, 1690, 1620 cam~' C2tH20N3OF3 = 387.4 Calc. C: 65.10 H: 5.20 N: 10.84 Found C: 64.95 H: 5.10 N: 10.88 Hydrochioride of the aforementioned derivative: Gaseous hydrochloric acid dissolved in ethanol was added to a suspension in 80 ml ethanol of 8 g of the derivative obtained according to Example I. The acid was added in the amount necessary to obtain complete dissolution. After agitation for 1 or 2 hours, the hydrochloride crystallized and 7.4 g of the product was separated. Yield = 87%.

EXAMPLE II.

1 acetyl 3 piperonylpiperazino indole (Compound No. III) 35 g (0.2 M) of N acetyl-3-indolinpne was dissolved in 200 ml toluene and 53 g (0.22 M) piperonylpiperazine was added. The mixture was refluxed for 24 hours in the presence of para-toluene-sulphonic acid (0.5 g) the water being separated as soon as it was formed. Treatment was as in Example I, the solvent being driven off.

The residue was dissolved in ethanol hydrochloride and the monohydrochloride was crystallized out.

Weight: 52 g. Yield: 55% MP = 250"C IR (KBr): 3100, 2400, 1685, 1610 cm-l C22H23N3o3, MCI - 413.9 Calc. C: 63.84 H: 5.86 N: 10.15 Found C: 63.95 H: 5.93 N: 10.13 EXAMPLE III.

3 piperonylpiperazino indole (compound No. XIII in Table I) 25 g soda in 50 ml water was added to a solution in 150 ml ethanol of 25 g (0.06 mol) of hydrochloride obtained as in Example II. The mixture was boiled for 90 minutes. The solution was cooled and poured on to iced water. 13.5 g of 3 piperonylpiperazino indole was separated.

Yield = 66 ó M.P. = 155 (ethyl acetate-ethanol) IR (KBr): 3300, 3400, 2810, 1620 cam~' C20H2,N302 = 335A Calc. C: 71.62 H: 6.31 N: 12.53 Found C: 71.53 H: 6.21 N: 12.39 EXAMPLE IV.

3-m. trifluoromethylphenylpiperazino indole (Compound No. XIV) Yield = 89 ó M.P. = 154" (ethanol) IR (KBr): 3400, 3260, 2840, 1610 cam~' C1gH,8N3F3 = 345.3 Calc. C: 66.07 H: 5.25 N: 12.16 Found C: 66.05 H: 5.19 N: 12.12 Dihydrochloride of compound No. XIV: IR (KBr): 3400, 2500, 2400, 1620 cm~' Analysis by anhydrotitrimetry C25H3,N4F3, 2HCI, H2O = 535.

EXAMPLE V.

I benzyl 3 piperonylpiperazino indole (Compound No. XV in Table I) A suspension of 3.35 g (0.01 mol) of the product obtained as in Example III and 1.24 g (0.011 mol) of potassium tertiobutylate in 20 ml distilled HMPT cooled to 0 C was agitated for 90 minutes in a nitrogen atmosphere. A solution of 1.26 g benzyl chloride in solution in 5 ml HMPT was added dropwise to the first solution, which was kept at OOC.

Agitate at the same temperature for 60 minutes and pour on to 100 ml iced water. The precipitate was dissolved in a few millilitres of ether and separated, giving 4 g of product.

Yield = 94% MP = 124" (ethanol) IR (KBr): 2830, 2790, 1610 cam~' C2,H27N3G2 = 425.5 Calc. C: 76.21 H: 6.40 N: 9.88 Found C: 76.20 H: 6.39 N: 10.21 EXAMPLE VI.

1 N diethylaminoethyl 3 m. trifluoromethylphenyl piperazino indole (Compound No. XVI in Table I).

The method was as in Example V, using diethylaminoethyl chloride and 1acetyl 3 piperonylpiperazino 2-3 dihydro indole.

Yield = 60% of crystalline product. MP < 50% (purification by chromatography on an alumina column).

EXAMPLE VII.

1 phenyl 5 chloro 3 methylpiperazino indole (Compound No. XIX in Table I).

The reaction was similar to that between secondary amines and N acetylindolines, i.e. l-phenyl 5-chloro 3-indolinone was reacted with methyl piperazine in accordance with the following equation:

Cg HN/ APTS N N-CH3 HN N-CH3 S IImi N mi Totuene Place the following in a 250 ml three-necked flask under nitrogen, fitted with an agitator and a condenser: 3 g of 5 chloro N phenylindolinone 2.7 g of N methyl piperazine 50 ml distilled toluene and APTS (added several times during refluxing) Cool, concentrate to dryness.

Send through a neutral alumina column (180 g), eluting with benzene and then with a mixture of benzene and methylene chloride. I g of pure product is obtained.

MP = 171"C. Yield = 23% IR: 2810 cm-' N-CH3 1600 cam~' aromatic no C = O no N = H 950 mg was converted into the hydrochloride in ethyl alcohol, using a mixture of ethyl alcohol and hydrochloric acid. 750 mg of slightly pink hydrochloride was obtained. MP < 250 C.

EXAMPLE VIII.

1 phenyl 5 chloro 3 cyclohexylpiperazino indole (Compound No. XX) 1 g of 5 chloro 3 cyclohexylpiperazino indole (Compound No. XVIII), 20 ml bromobenzene, 1.4 g iodobenzene, 3.2 g anhydrous K2CO3 and 1.75 g powdered copper were poured into a 100 ml three-necked flask under nitrogen, with agitation. The mixture was refluxed for 24 hours, separated when cold, concentrated, conveyed through a neutral alumina column (50 g) and eluted with methylene chloride. 300 mg of base was obtained.

MP = 165"C. Yield = 24% IR (KBr): 2940, 2860, 2820, 1600 cam~' Absence of NH Analysis: C24H2SCIN3 M = 393.5 Calc. C: 73.20 H: 7.12 N: 10.68 Found C: 72.84 H: 7.28 N: 10.52 The invention also relates to the medical and veterinary use of piperazino-3indoles according to the invention and their pharmaceutically acceptable salts, inter alia hydrochlorides.

The following are the results of pharmacological tests made on the derivatives according to the invention.

1) Toxicity The importance of the derivatives according to the invention is that they all have very low toxicity - i.e. the LDso is greater than 600 mg/kg per os in the mouse, i.e. is impossible to determine.

The pharmacological research was based on the following tests: Acute toxicitv in the mouse: This was evaluated from the observed death rate during *8 hours of batches of 4 animals at each dose administered.

The doses were administered in geometrical progression, doubling from 100 to 1600 mg/kg.

2) Sedative activity Actimetry in the mouse: This test was made by the method described by J. R. BOISSIER and P.

SIMON, "Action of caffeine on the spontaneous motility of the mouse" (Arch. Int.

Pharmacodyn., 1965, 158, 212-221).

Twenty minutes after the test product had been administered to batches of 12 animals per dose, the mice were placed in actimeters comprising individual photoelectric cells. The number of spokes travelled in 5 minutes was counted.

The activity of the product at each dose was expressed as a percentage increase or reduction in the exploration reaction, calculated by the following formula: Average number of spokes travelled by the treated mice x - x 10 Average number of spokes travelled by the controls The EDso was graphically evaluated, based on these results.

3) Analgesic activity SIEGMUND test with phenylbenzoquinone in the mouse: This test was made by the method described by E. SIEGMUND, R. CADMUS and G. LU, "A method for evaluating both non-narcotic and narcotic analgesics" (Proc. Soc. Exp. Biol. Med., 1957, 95, 729-731).

Thirty minutes after the test product had been administered to batches of 12 animals per dose, phenylbenzoquinone in 0.02% solution in water containing 5% ethyl alcohol was intra-peritoneally injected, the amount being 0.25 ml per 20-g mouse.

A count was made of the wriggles by each animal between 5 and 10 minutes after injection of phenylbenzoquinone.

The activity of each dose of product was expressed as a percentage protection, calculated from the following formula: Average number of wriggles by treated rats 1-- x 100 Average number of wriggles by controls The EDso was graphically evaluated from these results.

4) Anti-inflammatory activity Carrageenin oedema in the rat determined by the method described in C. A.

WINTER, E. A. RISLEY and G. W. NUSS "Carrageenin-induced oedema in hind paw of the rat as an assay for anti-inflammatory drugs (Proc. Soc. Exp. Biol. Med., 1962, 111, 544547).

One hour after the test product had been adminstered to batches of 6 animals per dose, oedema was brought about by injecting 0.05 ml of a 1% carrageenin suspension in physiological serum into the left plantar aponeurosis.

The volume of the paw was measured by plethysmography before the oedema had been produced (VO) and three hours afterwards (V3).

The activity of each dose of product was expressed as a percentage protection, calculated from the following formula: V3-V0 in the treated rats 1 - x 100 V3-V0 in the control rats The activity of the product relative to 60 mg/kg phenylbutazone was expressed as a percentage calculated from the following formula: V3-V0 for the product x 100 V3-V0 for 60 mg/kg phenylbutazone Interaction in vitro with serotinin in the uterus ofafemale rate in oestrus. This test was made by the method described in J. M. GADDUM and K. A. HAMEED, "Drugs which antagonize 5-hydroxytryptamine" (Brit. J. Pharmacol., 1954, 9, 240--248).

An attempt was made to find that concentration of the test product which, when previously added in the bath, produced a 50% reduction in the concentration caused by the antagonist.

Antipyretic activity in the rabbit.

Hyperthermia was produced in rabbits by intravenous injection of 0.6 ml of Professor Pierre Delbet's stock-vaccine broth.

The test product was orally administered two hours later to batches of two rabbits.

The rectal temperature was measured 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after administration.

The rectal temperature curve was compared with that for the controls.

The results of these pharmacological tests are given in Table III hereinafter.

The results are expressed in mglkg of live weight for the LD50, the actimetry test and the analgesic test measured by the test with phenylbenzoquinone. The results are expressed relative to phenyl butazone when measuring the anti-inflammatory activity, Harmine when measuring the anti-serotonin activity, and aspirin when measuring the anti-pyretic activity.

The aforementioned pharmacological test results show that piperazine-3indoles according to the invention have remarkable anti-inflammatory and analgesic properties.

Derivative IV, which has low toxicity, is a strong analgesic and has an antiinflammatory effect equal to phenylbutazone, is mainly indicated for treatment of painful rheumatism.

Derivative X, which has the same analgesic activity but only a slight antiinflammatory effect, is preferably used as an analgesic. It is also indicated in certain forms of migraine, owing to its anti-serotonin activity.

Derivative XI, which has very low toxicity, a considerable analgesic and anti inflammatory effect and an interesting anti-pyretic action, may be efficiently used for the same complaints as acetyl-salicylic acid.

Derivative XIII is strongly analgesic and slightly sedative; it is preferably used for treating pain interfering with sleep or accompanied by agitation.

The preferred dose of the aforementioned derivatives is as follows:

Derivative Intramuscular No. Oral Administration Rectal Administration Administration IV 100-200 mg per dose 250 mg per unit 400 mg per ampoule 300-1000 mg per 24 3 suppositories per 1-2 per day hours day X 100 mg per dose 200 mg per unit 200 mg per day 3 suppositories per 24 hours XI 200 mgper dose 300 mgper unit 600 mg per day 3 suppositories per 24 hours XIII 100 mgper dose 300 mgper unit 300 mgper ampoule 4 doses per day 2-3 doses per 24 1-2 per day hours All these derivatives, in suitable doses, can be presented in tablets, capsules, and suppositories. The most soluble derivatives (e.g. IV and XIII) can be presented in injectable ampoules.

The following are some examples of pharmaceutical forms of drugs according to the invention: 1) Tablets: Derivative No. IV X XI Polyvinylpyrrolidine 100 mg 100 mg 200 mg Corn starch Q.S. for Q.S. for Q.S. for Talc 1 tablet 1 tablet 1 tablet Stearate 150mg 150mg 150mg 2) Capsules: Derivative No. IV X XI Polyvinylpyrrolidone 100 mg 100 mg 200 mg Corn starch Q.S. for Q.S. for Q.S. for Aerosil 1 capsule 1 capsule I capsule (Registered Trade Mark) 3) Suppositories: Derivative No. IV X XI Water Q.S. for dissolving 250 mg 200 mg 300 mg Semi-synthetic glycerides Q.S. for 1 suppository of approx. 2 g ,, ,, 4) Injectable Solution: Derivative No. IV XIII Distilled apyrogenic water 400 mg 300 mg Q.S. for a 5-mg ampoule TABLE I

e, o z; CO-CH3 H (NiZN phenylpiperazino indole OCH3 Co ' = ~ l - ~ CH3 - n- t- E $ CZ) g LZ~8~I 2 /ny z W N N- CH -acetyl 3-benzyl 2 piperazino indole N e ; I N X :: = l e a I .~ 4 E tzD CZ 9 CZ 3 Cz 3 2 m = < C) > , n e Ct 00 ~ > O TABLE I (Continued)

o No. A i Piperazine Substituted by R2 Structural Formula Name ga FI '," a a "a VI CO-CH3 H N N 1-acetyl 3-phenyl acetyl mi, piperazino indole tL j piperazino indole N VIII ,, " N N 1-acetyl 3-pyrimidine mi'N piperazino I IX ,, " N N j=\Z 3m.chlorophenyl mi piperazino indole Ct /m m\ 0 t; N-CH2 l-acetyl 5-chloro x CI mi, 0 0 Zf | Z XZ t W X o Cf COCH3 TABLE I (Continued)

O c No. A R1 Piperazine Substituted by R2 Structural Formula Name XI NN C CH3O N N-CH2 -3 3 - 0 0 O' 5-methoxy acetyl mi, i9 0N11 ic 01OlO PX E. n e Z E XIII H H " 3-piperonyl 4: indole XIV ,, Th 3m. trifluoromethylphenyl l'mi, piperazino indole CF3 LL N N- CH0 i!on ,, piperonyl piperazine ('w X i-benzyl 3-piperonyl CH2 piperazino indole (Do N , N-diethyl- IE, t a mi, I 3m.trifluoromethylphenyl 3 h, .a piperazino indole CF3 Et Et TABLE I (Continued)

Compound No A R1 Piperazine Substituted by o Structural 5 > Name o d o U 5 Cl E'P 5-chloro c O U Ill N < , .~ H methylpip erazine XVIII 9 I 9 o 0N1 piperazino indole E c, = zz > Wzz z = = ci N-CH3 XIX a ) > o ~ > .

N Eu h (Do O N CI XX ,, ,' 01N 1-phenyl 5-chloro N 3-cyclohexyl (Do piperazino indole DSH U n > I X E Z x x x x TABLE II

Derivative No. Yield M.P. ( C) IR (KBr) Analysis I 66 % *155 **2850, 2460, 1705, 1610 cm-1 **C21H23N3O2, HCl = 385.9 **220 C Calc. 65.36 Found 65.29 H 6.27 6.34 N 10.89 11.14 II 65 % **188 **2850, 2360, 1700, 1615 cm-1 **C20H20ON3F, HCL = 373.8 C Calc. 64.25 Found 64.94 H 5.65 5.50 N 11.24 11.39 III 55% **254 **3100, 2400, 1685, 1610 cm-1 **C22H23N3O3, HCl=413.9 C Calc. 63.84 Found 63.95 H 5.86 5.93 N 10.15 10.13 IV 46% *114 *2800, 2770, 1680, 1595 cm -1 **C21H23N3O = 33.4 C Calc. 75.64 Found 75.02 H 6.95 6.65 N 12.60 12.86 V 70% *148 *2860, 1690, 1620 cm-1 *C21H20N3OF = 387.4 C Calc. 65.10 Found 64.95 H 5.20 5.10 N 10.84 10.88 VI 51% *146 *2820, 1685, 1600 cm-1 *C20H21N3O = 319.4 C Calc. 75.21 Found 74.98 H 6.63 6.59 N 13.16 13.45 TABLE II (Continued)

Derivative No. Yield M.P. ( C) IR (KBr) Analysis VII 55% *174 *2840, 1680, 1600 cm-1 *C19H20N4O = 320.4 C Calc. 71.22 Found 71.33 H 6.29 5.89 N 17.49 17.56 VIII 58% *169 *2820, 1715, 1590 cm-1 *C18H19N5O = 321.4 C Calc. 67.26 Found 66.95 H 5.96 5.97 N 21.79 21.49 IX 58% *158 *3210, 2840, 1680, 1600 cm -1 *C20H20N3OCl = 353.8 C Calc. 67.89 Found 66.90 H 5.70 5.79 N 11.87 11.77 X 40% **252 **1700 cm-1 **C22H23N3O3Cl2 = 438 C Calc. 59.00 Found 57.75 H 5.13 4.99 N 9.38 9.91 XI 45% **232 **1690 cm-1 **C23H27N3O4Cl2 (dichlorhydrate) = 480 C Calc. 57.5 Found 59.84 H 5.63 6.18 N 8.75 9.49 XVII 55% *134 **3250 cm-1 **C13H16N3Cl, HCl = 286 250** C Calc. 54.55 Found 54.28 H 5.44 5.77 N 14.68 15.12 TABLE II (Continued)

Derivative No. Yield M.P. ( C) IR (KBr) Analysis XVIII 47% *132 *3150 cm ***C18H24N3Cl, C4H4O4 = 433.5 ***190 C Calc. 60.50 Found 60.80 H 6.46 6.58 N 9.68 9.61 XIX**** 25% *71 *2810, 1600 cm *C19H20N3Cl = 325.5 C Calc. 70.05 Found 70.45 H 6.11 6.24 N 12.90 13.12 * Base ** Hydrochloride *** Monomaleate **** Prepared by method similar to Example IX TABLE III

LD50 Derivative Carrageenin Anti-serotonin Antipyretic activity No. P.O. I.V. Actimetry Siegmund Test oedema (Harmine = 1) AAS = 1 (aspirin) I 1400 - Stimulant 100 55 1/10 Inactive 120 100 II 1600 - Inactive 400 45 1/5 Inactive 400 100 III 1400 - Sedative 30 15 1 0.5 30 IV 1000 100 Sedative+ 18 100 2 Inactive 20 min + 1 h 100 80 Stimulant+ 2 h 100 V 1600 - Inactive 400 55 1/10 Inactive 400 100 VI 1600 - Inactive 70 35 1/10 Inactive 200 + 2 h 100 VII 800 - Inactive 40 40 Inactive 200 100 VIII 1600 - Inactive 140 20 Inactive 100 100 IX 1600 - Inactive 120 15 2 Inactive 400 100 TABLE III (Continued)

LD50 Derivative Carrageenin Anti-serotonin Antipyretic activity No. P.O. I.V. Actimetry Siegmund Test oedema (Harmine = 1) AAS = 1 (aspirin) X 1000 - Sedative 18 30 2 Inactive 120 + 1 h 100 XI 1600 Sedative 45 75 1 2 80 XIII 800 75 Sedative 9 30 1 Inactive 10 + 1 h 100 XIV 1600 - Inactive 250 30 2 2 400 XV 1200 - Inactive 70 0 4 Inactive 160 100 XVI 1000 75 Sedative 150 55 2 Inactive 400 100

Claims (11)

1. WHAT WE CLAIM IS:1. Piperazino-3-indoles having the following general formula:

   wherein: A is a hydrogen atom, a carboxylic acid radical or an alkyl, dialkylaminoalkyl. benzyl or phenyl group, which may or may not be substituted, R1 is a hydrogen or chlorine atom or an alkyl group having less than five carbon atoms, methoxy or hydroxy group, and R2 is an alkyl, benzyl or phenyl group or a cyclic or heterocyclic group which may or may not be substituted.
2. 2. Piperazino-3-indoles according to Claim 1, chosen from the 3piperonylpiperazino indoles group.
3. 3. Piperazino-3-indoles according to Claim 1, chosen from the group containing 3-alkylpiperazino indoles, 3-benzylpiperazino indoles, 3-phenylpiperazino indoles and 3-cyclohexylpiperazino indoles.
4. 4. Piperazino-3-indoles according to Claim 2, chosen from the group containing: I-acetyl 3-piperonylpiperazino indole, I-benzyl 3-piperonylpiperazino indole, 1-acetyl 5-chloro 3-piperonylpiperazino indole, I-acetyl 5-methoxy 3-piperonylpiperazino indole, 5-methyl 3-piperonylpiperazino indole, and methyl 3-piperonylpiperazino indole.
5. 5. Piperazino-3-indoles according to Claim 3, chosen from the group containing: I-acetyl 3-benzylpiperazino indole, l-acetyl 3-0 methoxyphenylpiperazino indole, I-acetyl 3 m. trifluoromethylphenylpiperazino indole, l-N diethylaminoethyl 3 m. trifluoromethylphenylpiperazino indole, 5-chloro 3-methylpiperazino indole, 5chloro 3-cyclohexylpiperazino indole, I-phenyl 5-chloro 3-methylpiperazino indole, and l-phenyl 5-chloro 3-cyclohexylpiperazino indole.
6. 6. A method of preparing piperazino-3-indoles according to any of Claims 1 to 5, comprising the step of reacting a 3-indolinone with a substituted piperazine in an inert solvent.
7. 7. An anti-inflammatory, analgesic and antipyretic drug, having as the active substance a piperazino-3-indole according to any of Claims 1 to 5, or a salt thereof from a pharmaceutically acceptable acid.
8. 8. A drug according to Claim 7 wherein the active substance is l-acetyl 5chloro 3-piperonylpiperazino indole hydrochloride.
9. 9. A drug according to Claim 7 wherein the active substance is l-acetyl 3benzyl piperazino indole base.
10. 10. A drug according to Claim 7 wherein the active substance is l-acetyl 5methoxy-3-piperonylpiperazino indole dihydrochloride.
11. 11. A drug according to Claim 7 wherein the active substance is 3piperonylpiperazino indole hydrochloride.