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United States Patent Office Patented Feb 3,562,278 United States Patent Office Patented Feb. 9, 1971 2 3,562,278 enumerated above, the substituents can be the same or 1-2-(2-SUBSTITUTED-3-INDOLYL)ETHYL-4-SUB different and can occupy any available carbon atom of the STITUTED.PPERAZINES phenyl ring. Sydney Archer, Bethlehem, N.Y., assignior to Sterling The compounds of Formula I where R2 is carbo-lower Drug inc., New York, N.Y., a corporation of Dela 5 alkoxy are prepared by reacting a 2-carbo-lower-alkoxy Ware 3-(2-haloethyl)indole of Formula II with an appropriate No Drawing. Continuation-in-part of application Ser. No. 1-substituted-piperazine of Formula III according to the 733,250, May 31, 1968, which is a continuation-in-part reaction: of application Ser. No. 634,899, May 1, 1967. This application Sept. 16, 1969, Ser. No. 858,499 R Claims priority, applicity Canada, Apr. 16, 1968, 10 XY-n-CHCH-x 17,589 - H-N N-R1 - I int. C. C07d 51/70 y-COO Alk N-/ U.S. C. 260-268 17 Claims N R H 5) ABSTRACT OF THE DISCLOSURE I III where R1, R3, and R4 have the meanings given above, Alk Novel 1-2-(2-substituted - 3 - indolyl)ethyl-4-substi represents lower-alkyl, and X represents halogen. The re tuted-piperazines having psychomotor depressant activity. action can be carried out either in the absence of a sol 20 vent or in an organic solvent inert under the conditions of the reaction, for example methanol, ethanol, isopropanol, This application is a continuation-in-part of my prior and the like, and in the presence of an acid-acceptor, the co-pending application S.N. 733,250, filed May 31, 1968, purpose of which is to take up the hydrogen halide split which is turn is a continuation-in-part of my prior appli out during the course of the reaction. Suitable acid-ac cation S.N. 634,899, filed May 1, 1967, both now aban 25 ceptors are alkali metal hydroxides, carbonates, or bicar doned. bonates. An excess of the 1-substituted-piperazine can also The present invention relates to 1-2-(2-substituted-3- be used as the acid-acceptor. indolyl)ethyl)-4-substituted-piperazines having the for The compounds of Formula II, required as intermedi mula ates in the above reaction, are prepared by reaction of an 30 appropriate phenylhydrazine with ox-keto-6-valerolactone, CHCH-N under Fischer indole synthesis conditions, and conversion Y of the resulting 2-carboxy-3-(2-hydroxyethyl indole of R2 Formula IV to the compounds of Formula II as described N R hereinbelow. The reactions are represented by the H 35 equations: I where R is lower-alkyl, hydroxy-lower-alkyl, phenyl, -CH2CH2OH. phenyl-unbranched-lower-alkyl, cinnamyl, pyridyl, or 2 -- Hs pyrimidyll; R2 is carbo-lower-alkoxy, carboxy, sulfo -NEINEI, O=l 9 o (SOH), hydroxymethyl, lower-alkanoyloxymethyl, car 40 N bamyl, N-lower-alkylcarbamyl, N,N-di-lower-alkylcar O H bamyl, formyl, or isonitrosomethylene (CH=NOH), and IV alkali metal salts of compounds where R2 is carboxy or u1 sulfo; R is hydrogen, halogen, straight or unhindered 1. lower-alkyl, lower-alkoxy, lower-alkylmercapto, trifluoro I methyl, or hydroxy; and R4 is hydrogen, halogen, straight The c-keto-8-valerolactone is in turn prepared by de or unhindered lower-alkyl or lower-alkoxy, or R3 and R4 carboxylation of an ox-carbo-lower-alkoxalyl-y-butyrolac together represent methylenedioxy or ethylenedioxy at tone by heating the latter in the presence of Sulfuric acid. tached to adjacent carbon atoms, and wherein the benzene The product isolated from the Fischer indole synthesis ring of R1 as phenyl, phenyl-lower-alkyl, or phenyl-lower described above generally consists of a mixture of the de alkenyl is unsubstituted or substituted by methylenedioxy sired 2-carboxy-3-(2-hydroxyethyl)indole and the lactone or ethylenedioxy or by one or two of the same or differ resulting from esterification between the 2-carboxy and ent members of the group consisting of halogen, lower the 3-(2-hydroxyethyl)groups. It is therefore advanta alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkylsul 5 5 geous to reflux the crude product obtained in a lower-alka finyl, lower-alkylsulfonyl, trifluoromethyl, or hydroxy. nol in the presence of excess anhydrous hydrogen halide, As used herein, the terms lower-alkyl, lower-alkoxy, and which results in the transformation of both Fischer in lower-alkanoyl mean such groups which can be either dole products to the desired 2-carbo-lower-alkoxy-3-(2- straight or branched, and which contain from one to seven haloethyl)indole of Formula II. carbon atoms, and thus the lower-alkyl moiety of such The compounds of Formula I where R is carboxy are lower-alkyl or lower-alkoxy groups represents, for ex 60 prepared by alkaline hydrolysis of the corresponding com ample, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-hexyl, pounds where R2 is carbo-lower-alkoxy. The reaction and the like, and lower-alkanoyl represents, for example, is preferably carried out either in an aqueous or an aque formyl, acetyl, propionyl, c-methylhexanoyl, and the like. ous-alcoholic medium at the reflux temperature thereof As used herein, the term lower-alkenyl means lower and in the presence of an alkali metal hydroxide. If de alkenyl which can be either straight or branched, and sired, the compounds can be isolated from the alkaline which can contain from three to seven carbon atoms, and reaction medium to produce the alkali metal salts of the thus represents 1,3-(1-propenyl), 1,3-(1-butenyl), 1,4-(2- compounds where R2 is carboxy. butenyl), and the like. The compounds of Formula I where R2 is carbamyl, In the above general Formula I, when Ri as phenyl, 70 N-lower-alkylcarbamyl, or N,N-di-lower - alkylcarbamyl, phenyl-lower-alkyl, or phenyl-lower-alkenyl is substituted are prepared by reacting the corresponding compounds in the benzene ring by one or two of the substituents where R is carboxy with a thionyl halide, either in the 3,562,278 3 4 absence of a solvent or in an inert organic solvent such as pharmacologically acceptable salts within the scope of benzene, toluene, or xylene, and reacting the resulting the invention are those derived from mineral acids such 2-haloformyl compound with, respectively, anhydrous am as hydrobromic acid, hydriodic acid, nitric acid, phos monia, a lower-alkylamine (e.g. methylamine (CH3NH2), phoric acid, sulfamic acid, and sulfuric acid; and organic ethylamine (C2H5NH2) or 2-pentylamine acids such as acetic acid, citric acid, tartaric acid, lactic 5 acid, methanesulfonic acid, ethanesulfonic acid, quinic (CHCHCHCHCCH)NH) acid, and the like, giving the hydrobromide, hydriodide, or a di-lower-alkylamine {e.g. dimethylamine nitrate, phosphate, sulfamate, sulfate, acetate, citrate, tar trate, lactate, methanesulfonate, ethanesulfonate and qui (CH)NH nate, respectively. or methylpentylamine (CH3NHCH)}. O Although pharmacologically acceptable salts are pre The compounds of Formula I where R2 is hydroxy ferred, those having toxic anions are also useful. All acid methyl are prepared by reducing the corresponding com addition salts are useful intermediates as sources of the pounds where R2 is carboxy or carbo-lower-alkoxy with free base form even if the particular salt per se is not de an alkali metal aluminum hydride. The reaction is prefer sired as the final product, as for example when the salt is ably carried out in an organic solvent inert under the formed only for purposes of purification or identification, conditions of the reaction, for example diethyl ether, tetra or when it is used as an intermediate in preparing a hydrofuran, dibutyl ether, and the like, at temperatures pharmacologically acceptable salt by ion-exchange pro in the range from 0-100 C. cedures. The compounds of Formula I where R is hydroxy 20 Pharmacological evaluation of the compounds of methyl can also be prepared by alkali metal aluminum Formula I according to standard pharmacological test hydride reduction, as described above, of a 1-(2-R-3- procedures has demonstrated that they possess psychomo indolyl)acetyl - 4 - substituted-piperazine having the tor depressant activity thus indicating their usefulness as formula: tranquilizers. R3 Psychomotor depressant activity was determined in CHCO-N N-R standard activity cages using the method of Dews, Brit. N-/ J. Pharmacol. 8, 46 (1953) in which mice, medicated with R2 the test compound, are placed in wire mesh cages equip N ped with a photoelectric cell so adjusted that a mouse Rs. 30 breaking the beam activates a magnetic digital counter. H Thus the number of times the light beam is broken over where R3, R4, and Y have the meanings given above, a period of time is an indication of the motor activity of and R2 is carbo-lower-alkoxy, carboxy, or hydroxy the animals, and a reduction in the number of counts in methyl. the medicated mice over control groups run simultane The compounds of Formula I where R is lower-al ously, is taken as evidence of psychomotor depressant ac kanoyl-oxymethyl are prepared by reacting the corre tivity. The dose at which such reduction in motor activ sponding compounds where R2 is hydroxymethyl with a ity was observed was recorded as the active-dose. Alter lower-alkanoyl halide in an organic solvent inert under natively, the ED50, the Effective Dose in 50% of the the conditions of the reaction, for example benzene, tolu animals, was determined from a dose-response curve. ene, xylene, and the like, and in the presence of an acid 40 Instead of determining the motor activity of the test acceptor, for example pyridine, dimethylaniline, triethyl animals using a digital counter activated by a photoelectric amine, and the like, which is used to take up the hydrogen cell, there can also be used a counting apparatus such halide split out during the course of the reaction.
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