IL27776A

IL27776A - 1,2,3,4,5,6-hexahydroazepino(4,5-b)-indoles and process for their preparation

Info

Publication number: IL27776A
Application number: IL2777667A
Authority: IL
Original assignee: Upjohn Co
Priority date: 1966-05-10
Filing date: 1967-04-11
Publication date: 1971-11-29
Also published as: FR6699M; ES340258A1; GB1180615A; GR35044B; GB1180616A; CH506543A; NL6706513A; IL36801A; DE1695943A1; BE698268A

Description

1.2.3 .5.6... HEXAHYDROAZEPINO - 7*.5»¾>7 INDOLES AND PROCESS FOR THEIR PREPARATION V D»¾IT3»K Zf»5-¾7" - j'-j»TsiTi»nxoi?n - 1,2,3,4,5,6 o d wherein R and R1 are selected from the group cons ist ing of hydrogen, alkoxy and alkyl containing from 1 to 3 carbon atoms, inclusive, and halogen; wherein Ri is selected from the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, incl us i ve», and bcnayl ; and wherein R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, alkanoyl groups containing 1 to 3 carbon atoms, inclusive, benzyl and benzoyl, and organic and inorganic acid addition salts of those compounds wherein ^N- 2 is an amino moiety.

The alkyl group as used in the above formulae containing from 1 to 3 carbon atoms, inclusive, comprises the members methyl, ethyl, propyl, a d isopropyl ; the alkoxy group comprises methoxy, etboxy, propoxy, and isopropoxy; the alkanoyl group comprises formyl, acetyl and propionyl . The halogen atoms herein intended as subst i tutents of the phenyl group are fluorine, chlorine and bromine.

The present invention also embraces the organic and inorganic acid add r t ion sa) ts of the novel amino compounds of formula I ( i . e ., compounds wherein R2 is hydrogen, methyl, ethyl, propyl, or benzyl) such as the hydrochlorides, hydro-bromides, hydroiod ides, perchl orates, f 1 uos-Π ica es, thio-cyanates, sulfates, cyclohexanesul famates, acetates, propionates, laurates, palmitates, maleates, tartrates, lactates, citrates, oxalates, tr i f 1 uoroacetates, tr ichloroacetates and the l ike.

The process of the present invention consists in: heating a pheny 1 hydraz i ne of formula I with 1-benzoy 1 hexahydro-4H-azepin- -one to obtain the corresponding pheny 1 hydrazone of 1-benzoy 1 hexahydro-4H-azep in- -one ( I I); heating I I with formic acid to obtain the corresponding 3-benzoyl -1,2,3,4,5,6-hexahydroazepi np[ ,5-b] indole (il l ); reducing I I I with a metal ( I V') ; hydrogenol yz ing IV in the presence of a palladium catalyst to give the corresponding 1,2,3* * 5,6-hexahydroazep ino[ , 5-b] indole (V); acylating the compound V with an acid anhydride, or if a 3"formyl product is desired, with a mixture of formic acid and acetic anhydride, to obtain the corresponding 3-acyl-1, 2,3*4, ,6-hexahydroazepino[4,5-b] indole (V I ); reducing compound VI wi th 1 ithium a 1 urn i nun* hydr ide to obta in the corresponding 3-alkyl (or benzyl )->l,2,3*4*5*6-hexahydroazepino[4,5-b] indole ( I I) .

Al ternat ivel y compound V can be alkylated with an. alkyl hal ide in which the alkyl is methyl, ethyl, propyl or i sop ropy 1 and the Halogen is bromine or iodine or benzylated with benzyl chloride or bromide, in the presence of sodium hydride to give the corresponding 6-al kyl (or benzyl )-l, 2,3*4, 5*6-hexahydro-azepino|j4,5-b] indol e (VI I I) often isolated as the hydrochloride, hydrObromide or hydroiodide; acylating VI M (as described above for compound V) to give the corresponding 3-acyl -6-al kyl (or benzyl )-l, 2, 3*4,5, 6-hexahydroazepino[4, 5-b] indole ( IX); and reducing compound IX (as described for compound VI ) to obtain the corresponding 3-alkyl (or benzyl )-6-al kyl (or benzyl)-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole (X) .

As an alternative to obtain a compound of formula I J I in good yield, a compound of formula I II is al kyl a ted with an alkyl hal ide in the presence of sodium hyd ide to -give a compound of formula IX wherein R 111 is phenyl ; treating this compound with l ithium aluminum hydride to give a 3-benzyl -6-al kyl -l,2,3*4,5,6^hexahydroazepino[4,5-b] indole ,( compound X, in which ' 1 is alkyl and-J¾M I 1 is benzyl ) ; and hydrogenol yz ing this compound in the presence of a palladium catalyst to obtain the correspond ing 6-al kyl -l,2,3*^*5,6-hexahydroazepino[4,5 ] indol e The novel compounds of formulae I I, I I I, VI and IX are essentially intermediates for the production of the active compounds of formula XI having an amino moiety at the 5-position. The novel amino compounds of formula XI are active tranquill izers and sedatives and act as ant i -depressants and as anorexigenic agents. At dosages of 1 to 3 mg./kg, of 1,2, 3j4,5i6-hexahydroazepino[4,5-b] indole cats lost interest in mice which had been placed in their cages. The cats also showed a reduced tendency to hiss or to strike out when approached by other cats. The ant i -aggress i ve behavior of rats and mice under the influence of 9-methoxy-i,2,3,4.,5,6-hexahydroazepino [4,5-b] indole, 6-methyl -l,2,3.»4,5,6-hexahydroazepino[4,5-b] indole and also the unsubst i tuted l,2,3j4,5,6-hexahydroazepino [ 4, -b] i ndol e, administered as hydrochlorides, was also shown. Ant i -aggress ive behavior was also noted in mice treated with 7-> 8- and 10-methoxy-l,2,3j 4,5,6^hexahydroazepino{4,5-b] indole hydrochlorides, with 9-f 1 uoro-1,2,3* 4,5, 6-hexahydroazepino[4,5-b] indole, with -methyl -l,2,3,4,5,6-hexahydroazepino[4,5-b] indole hydroch 1 or ide, and w i th 9-methy 1 -1,2,5*4, 5,6-hexahydroazep ino [4,5-b] -indole. If desired, the formula XI amino compounds can be administered as pharmacologically acceptable acid addition salts, e.g., hydrochlorides, cycl ohexanesul famates, maleates, tartrates, citrates and the l ike. Due to their tranquillizing abil ity, these compounds have importance for administration in animals which are transported by ship, train, truck and so on. Administration in cattle, horses, dogs, cats, or the l ike, or zoo animals on long voyages^ in a quantity between 3 to 4 mg./kg. of body weight produces t ranqu i 11 izat ion and thereby reduces losses of valuable animals due to overexc i tement and fightsamong the caged animals. These amino compounds are also _ o excited states in man. The novel amino compounds of formula XI can be administered to mammals, birds and man by both oral and parenteral routes in. order to produce their pharmacological effects. For oral adm in istrat ion, unit dosage forms such as tablets, capsules, powders, granules, syrups, el ixirs and the l ike containing the.- appropr iate amount for treatment are used. For tablets, common pharmaceutical carriers such as starch, lactose, kaol in, dicalcium phosphate and the l ike are employed. Powders may also be used in gelatin capsules with or without carriers such as methyl eel lulose, magnesium stearate, calcium stearate, talc and the l ike. For fluid preparation, these compounds may be dissolved or suspended in aqueous alcohol ic vehicles with or without buffering agents and with flavoring mixtures.

Acid addition salts of the formula XI amino compounds, which salts are not per se useful in therapy, have a variety of appl ications. Thus, for example, the f 1 uos i 1 icates of these compounds form useful moth-proof in§ agents as described in U. S. Patents 1,915,334 and 2,075,359- The thiocyanic acid addition salts of the same compounds, when condensed with formaldehyde, form resinous polymers which according to U. S. Patents 2,425,320 and 2,6o6,155 are useful as pickl ing inhibitors. The trichloroacetic acid addition salts of the amino compounds of formula XI are Useful as herbicides, for example, against Johnson grass, yellow foxtail, green foxtail, Bermuda grass and quackgrass.

The starting compounds ( l) for this invention are known pheny l hydraz ines . The 1-benzoyl hexahydro-4H-azep ιη-4-one is prepared as shown in the Preparation.

In carrying out the process of the present invention, the selected phenylhydraz ine of formula I is refluxed with 1-benzoyl-hexahydro'-4H-azep in-4-one in a solvent such as ethanol, benzene, toluene or the l ike. In the referred embodiment of this invention, an acid catalyst such as acetic acid in a quantity of about 0.25 to 1.5%, calculated on the amount of solvent, is added to obtain higher yields. The total time of the reaction may vary between half an hour and four hours at the reflux temperature of the solvent; At the termination of the reaction, the product is isolated by conventional means such as by crystall ization, filtration, extraction and the l ike.

The thus-obtained 1-benzoyl hexahydro-4H-azep in-4-one phenyl hydrazone ( I I) is thereupon heated with formic acid of a concentration of 88 to 99$ for a per iod usually between 10 minutes and 2 hours in order to provide crude 3-benzoyI-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole (111) which is isolated and purified by conventional procedures, such as pouring the reaction mixture into ice water, collecting the resulting product by filtration and recrystall i ing, chromato-graphing, or extracting the product to obtain the pure 3-benzoyl -l,2,3,4,5,6-hexahydroazepJno[4,5-b] indol e ( I I I ) .

The thus-obtained ^"benzoyl -1,2, 3,4,5, 6-hexahydroazepino [ ,5-b] indol e is reduced with a metal hydride, preferably l ithium aluminum hydride, in tet rahydrof uran solution. The reaction is, at first, generally carried out under nitrogen during a period of about one-half hour to eight hours at about room temperature, that is, between 20-30° C. Higher or lower temperatures in the initial phase can be used. Thereafter, the temperature is increased to the reflux temperature of the mixture, and the mixture is heated for a period between 6 to 24 hours. The products are obtained by decomposing the reaction mixture, after cool ing, with water and a base such as sodium hydroxide or potassium hydroxide and filtering the solution. Concentration of the filtrate gives the desired 3~benzyl- Removal of the benzyl group of the 3-benzy 1 -1 ,2,3, 4, 5, 6-hexahydroazep i no[ , 5-b] indol e is achieved by hydrogenol ys i s in the presence of a noble metal catalyst, e.g., a palladium or platinum catalyst (5 to 10$ platinum or palladium on a carbon carrier). The hydrogenol ys is may be carried out at a pressure between 10 to 75 pounds of hydrogen and is generally completed within between 1 to 8 hours at room temperature. At the termination of the reaction, the catalyst is removed by filtration, the filtrate is concentrated and the crude product purified in conventional manner, such as by recrystal 1 izat ion, formation of a salt and treating the salt with a base, or the l ike.

The thus-obtained l,2,3,4,5,6-hexahydroazepino[4,5-b] indole (V) is acylated with an acid anhydride such as benzoic anhydride, acetic anhydride, propionic anhydride arid in the case of a desired 3- formyl -1,2, 3,4,5, 6-hexahydroazepino[4,5-b] indole, by acylation with formic acetic anhydride (formed in situ from 98$ formic acid and acetic anhydride) at room temperature. Instead of acid anhydrides, acyl chlorides or bromides can be used, e.g., acetyl chloride, propionyl chloride, benzoyl chloride or bromides thereof. The acylation can be carried out at temperatures between 0 and 35° C. during a period of between 6 to 48 hours.

After termination of the reaction, the mixture is poured into water, the sol ids are collected by filtration and purified i generally by recrystal 1 izat ion or chromatography to give the desired 3-acy 1 -1, , 3, , 5, 6-hexahydroazep i no[ , 5~b] i ndol e (VI).

The thus-obta ined 3-acyl - 1,2, 3, 4, , 6-hexahydroazep i no [ 4, 5-b] i ndol e (VI) is reduced with a metal hydride such as l ithium aluminum hydride, in an organic solvent such as diethyl ether, diisopropyl ether, tet ahydrof uran or the l ike, usually at starting temperatures between about 0° C. and room temperature 2158 the reflux temperature of the mixture for a period of 6 to 48 hours. In the preferred embodiment of this invention, the reaction is carried out in a nitrogen atmosphere. The reaction mixture thereafter is decomposed with water, an aqueous base solution such as sodium or potassium hydroxide and water, and the solution is f iltered, the filtrate concentrated and the thus-obtained 3-alkyl (or benzyl )-l, 2, 3i4,5i6-hexahydroazepino [4,5-b] indol e (VI I) is purified by conventional means usual ly by recrystal 1 izat ion from organic solvents such as ethyl acetate, methanol, ethanol, and the l ike.

The thus-Obta ined 3-al ky 1 (or benzyl )-l, ,3*4, 5,6-hexa-hydroazep ino[4,5-b] indol e (VI I) can be alkylated in the 6-position, in conventional manner, with an alkyl bromide or alkyl iodide such as methyl, ethyl, propyl, isopropyl bromide or iodide or with a benzyl hal ide. In the preferred embodiment of this invention, the J-al kyl (or benzyl ) -1,2, 3>4,5, 6-hexahydro-azepino[4,5-b] indole is dissolved in a d ial kyl formam ide or d i al ky 1 acetam ide, usually in dimethyl formamide, in a nitrogen atmosphere, and thereto is added a suspension of sodium or potassium hydride in mineral oil . To this mixture is- added the alkyl (or benzyl) brom ide or iodide, usual ly at a low temperature such as about 0° C. The mixture is allowed to react for a period between 10 minutes and 1 hour and thereafter at room temperature for a period of 6 to 48 hours. The product of formula X is obtained by pouring the mixture into water and extracting the water with a water- immiscible organic solvent, such as ether, Skel lysolve B hexanes, benzene, methylene chloride or the l ike, and evaporating the solvent. The product may be further purified by recrystal 1 izat ion, extraction of impurities, chromatography, or by preparing water-soluble salts such as h drochlorides, h drobromides, sulfates or or anic salts l ike 2158. \ the acetates, chl oroacetates, benzoates or the l ike.

As is obvious to those skil led in the art, many of the different steps shown above in the sequence of formulae are intercharigeabl e and do not need to be performed in the same order as shown in this sequence. Thus, a 1,2,3, ^S^-hexa-hydroazep i no[ 4 5^b] i ndol e (V) can be 6-alkylated first to VI I I, then J-acylated ( IX ), fol 1 owed by l ithium al uminum hydride reduction to give a 3,6-dial kyl -1, 2,3,4, 5, 6- hexahydro-azep i no[ , -b] i ndol e X.

The fol lowing examples are il lustrative of the process and products of the present invention, but are not to be construed as l imiting.

Preparat ion l-Benzoyl hexahydro-4H-azep in-4-one A. l-Benzoyl hexamethy 1 ene im i ne [1-benzoyl hexahydro-4H- azep i ne] Benzoyl chloride (60 ml .) in 200 ml. of Skel lysolve B hexanes was added to a stirred, cooled ( ice-bath) solution of 200 ml . of hexamethy 1 ene im ine in 800 ml . of Skel lysolve B hexanes. The mixture was then washed several times with IN hydrochloric acid and with water, and f il tered through anhydrous sodium sulfate. Evaporation of the Skel lysolve B hexanes and distil lation of the oily residue gave 40.5 g. of 1-benzoyl hexamethy 1 ene im ine, b.p. 150-l60° C./l torr.

Anal ys i s : Calcd. for C13H17NO: N, 6.89.

Found: N, 6.54.

B. Fermentation of 1-benzoyl hexamethy 1 ene im i ne A medium. was prepared of 200 g. of cornsteep l iquor (60# sol ids), 100 g. of commercial dextrose, and 10 1. of tap water. 2158 was added as a foam preventive. This medium was sterilized and inoculated with a 72-hour vegetative growth of Sporotrichum sul f urescens, ATCC 7159, and after incubation for 24 hours at a temperature of about 28° C. using a rate of aeration of 0.5 1 » per minute and agitation of 300 r.p.m., the substrate, 2 g. of 1-benzoy 1 hexamethyl ene im ine in solution in a minimum amount of acetone (about 20 ml .) was then added to the fermentation.

After an additional 72*hour period of incubation at the same temperature and aerat ion, the beer and mycel ium were separated by filtration. The mycel ium was washed with water and the wash water was added to the beer filtrate. The thus-obtained beer filtrate was extracted four times with a volume of methylene chloride equal to one-fourth the volume of the filtrate. The combined extracts were washed with one-fourth volume of distilled water and the solvent was removed by distillation to give a res idue , The residue thus obtained was chromatographed on Florisil and eluted with Skel lysolve B hexanes containing increasing portions of acetone. The 25$ acetone-75$ Skel lysolve B hexanes eluate gave about 250 mg. of 1-benzoy 1 hexahydro-4H-azep in-4-one and the acetone eluate gave 1-benzoy 1 -4-hydroxyhexahydro-4H-azepine determined by thin layer chromatography.

C. Oxidation of 1-benzoy 1 -4-hydroxyhexahydro-4H-azep ine The 1-benzoyl -4-hydroxyhexahydro-4H-azep i ne thus obtained was dissolved in acetone and oxidized at room temperature by the addition of a visible excess of Jones' reagent (2.67 chromic acid reagent prepared from 26.7. g. of chromium trioxide and 23 ml . of sul fu i c acid, diluted to 100 ml . with water).

The excess oxidant was destroyed by the addition of isopropyl alcohol and the mixture was evaporated to dryness. Water 215 of methylene chloride. The extract was evaporated to dryness and the residual 1-benzoy 1 hexahydro-4H-azep i n-4-one thus obtained was combined with the same product obtained directly from the bio-conversion. The combined product was chromatographed on a column of Florisil (anhydrous magnesium sil icate). The column was eluted with Skel lysolve B hexanes containing increasing proportions of acetone and those fractions containing the desired products as determined by thin layer chromatography, were combined and evaporated to give about .770 mg. of 1-benzoy 1 hexahydro-4H-azepin-4-one as an oil, b'.p. 170-174° C./0..3 torr., that crystal l ized slowly.

Anal ys is : Calcd. for Ci3His 02 : C, 71.86; H, 6.96; N, 6.45.

Found: C, 71.51; H, 7-25; N, 6.46.

Example 1 Pheny 1 hydrazone of 1-benzoyl hexahydro-4H-azepin- 4-one A mixture of 20 g. (0.092 mole) of 1-benzoy 1 hexahydro-4H-azepin-4-one, 10.5 g. of pheny 1 hydraz ine (O.097 mole), 200 ml . of absolute ethanol and 1.5 ml . of acetic aci d was refluxed for a period of 1 hour and then cooled in an ice bath. Crystals formed which were collected by filtration, washed with ethanol and dried to yield 20.8 g. (74$) of the pheny 1 hydrazone of 1-benzoy 1 hexahydro-4H-azep in-4-one of melting point 185-190° C.

Example 2 p-Methoxypheny 1 hydrazone of 1-benzoy 1 hexahydro- A solution of 120.1 g. (Ο.869 mole) of p-methoxypheny 1 -hydrazine, 172.0 g. (0.792 mole) of 1-benzoy 1 hexahydro-4H-azepin-4-one and 12.9 ml . of glacial acetic acid in 1725 ml . of absolute ethanol refluxed in a period of 1 hour. The reaction mixture was then cooled and concentrated under reduced pressure. The product which had crystal 1 ized from the solution was col lected by filtration, Was heid with ethanol and dried tcJ give 108.9 g. of l-benzoy 1 -hexahyd o^4n\-aze Ιη-4ώοη€! p-methoxyphenyl hydrazone of melting pbiHt 155<5~l66.50 C. A second crop was obtained by concentrating the mother 1 iquors , providing an additional amount of 52.9 g; s0 that the total yield was 53$-.

Example 3 m-Methoxypheny 1 hydra2one of l-benzoy 1 hexahydro-4H- azep in-4-one To a 3 aqueous sodium hydroxide solution (300 ml. J; an et er ( 300 ml .) Was added 62. g. (0 3 0 mole) of m -met boxy -'phenyl hydraz ine hydrochlor ide. Thi s m ixture. was st i rred unt i l t e material went into solution, the ether layer was separated and the aqueous layer extracted with additional ether. The ether layer and extrac s Were washed with brine, dried oyer anhydrous pota'ss urn carbonate and concentrated under reduced pressure at about 25° C. to give a res idue. To a solution of the res was added a sol ut ion of .1-benzoyl (6:5 g. ; 0.3 mole) in 300 ml . of ethanol and 5 rtil . of acetic acid. The resulting solution was refluxed under nitrogen for 1 hour and then concentrated under reduced pressure. The product which crystal lized from the part ial 1 y concentrated reaction mixture was col lected by f iltration, washed with ethanol and dried to give 45.2 g. (44.7$) of m-methoxypheny 1 hydrazone of l-benzoy 1 hexahydro-4H-azepin-4-one of melting point 153-159° C.

Example 4 o-Methoxypheny 1 hydrazone of l-benzoy lhexahyd ro-4H- azepin-4-one To a stirred mixture of 3 aqueous sodium hydroxide (300 o-methoxypheny 1 hydraz ine hydrochloride. After solution was achieved, the aqueous layer was saturated with sodium chloride, separated from the ether layer and extracted with ether. The combined ether layer and extracts were washed with brine, dried over potassium carbonate and concentrated under reduced pressure at 25° C. to give a residue. The residue was dissolved in 500 ml of ethanol and was thus added to a solution of 65 g. (0.300 mole) of 1-benzoyl hexahydro-4H-azep i n-4-one in 300 ml . of ethanol and 5 ml . of acetic acid. The mixture was refluxed for 1 hour and concentrated under reduced pressure. The resulting residue was crystall ized from ethanol to give a total of 34.3 g. of o-methoxy pheny 1 hyd razone of 1-benzoyl hexahydro-4H-azep i n-4-one of melting point 145-154° C.

Example 5 p-Fl uoropheny 1 hydrazone of 1-benzoy 1 hexahydro-4H- azepin-4-one To a stirred solution of 300 ml. of 3 sodium hydroxide and 300 ml . of ether was added 8.3 g. (0.360 mole) of p-fluoro-phenyl hydraz ine hydrochloride. When solution was obtained, the aqueous layer was saturated with sodium chloride, separated from the ether layer and extracted with ether. The ether layer and extracts were combined, washed with brine, dried over anhydrous potassium carbonate and concentrated in vacuo (at about 25° C.) to give a residue. The residue was dissolved in 500 ml . of ethanol and was. thus added to a solution of 65 g. (0.3 mole) of 1-benzoyl hexahydro-4H.-azep i n-4-one in 300 ml . of ethanol and 5 ml . of acetic acid. The resulting solution was refluxed for 1 hour in a nitrogen atmosphere and concentrated under reduced pressure. The product which crystall ized from the concentrated mixture was collected by filtration, washed with ethanol and dried to yield 32.7 g. (33.3$) of p-fl uorophenyl hydrazone of 1- Example 6 o-Tol y 1 hydrazone of 1-benzoy 1 hexahydro-4H-azep i n- 4-one To 400 mV. of JN aqueous sodium hydroxide sol ut ion and 400 ml . of et er was added 79-3 g. (0.5 mole) of o-tolyl hydrazine hydrochloride. After splut ion was obtained, the aqueous layer was saturated wifh sodium chloride, separated from the ether layer and extracted with ether. The combined ether layer and extracts were washed with brine, dried over anhydrous potassium carbonate and concentrated under reduced pressure at 25° C. to give a residue. This residue, dissolved in 700 ml . of ethanol^ was mixed with a solution of 108.6 g. (0.5 mole) of 1-benzoyl-hexahydro-4H-azep i n-4-one in 400 ml . of ethanol and 6.95 ml . of acetic acid. The resulting solution was refluxed for a period of 1 hour in a nitrogen atmosphere and then concentrated under reduced pressure. The residue which was obtained was crystal l ized from ethanol to give 29.7 g. of o-tol yl hydrazone of 1-benzoyl-hexahydro-4H-azep in-4-one of melting point Ij55-l4l° C. Another crop was obtained of 4.85 g thus providing a total yield of 21.5$.

Example p-Tol y 1 hydrazone of 1-benzoy 1 hexahydro-4H-azep intone In the manner given in Example 6, a freshly prepared (from 58,5 g. of p- tol y 1 hydraz i ne hydrochloride) ethanol solution of p^toly 1 hydraz irie was reacted in the presence of acetic acid and in ethanol solution with 1-benzoy 1 hexahydro-4H-azep in-4-one (160. g.) to give in two crops 26.9 g. of p- tol y 1 hydrazone of 1-benzoy 1 hexahydro-4H-azep in-4-one of melting point 145-155° C.

Ex am pi e 8 p-Ethyl phenyl hydrazone of 1-benzoy 1 hexahydro-4H- azepin-4-one 2158 . - absolute ethanol in the presence of acetic acid to give p-ethyl -pheny 1 hydrazone of 1-benzoy 1 hexahyd ro-4H-azep ίη-4-one.

Example 9 p-Propoxypheny 1 hydrazone of 1-benzoy thexahydro-4H- azepin-4-one In the manner given in Example 1, p-propoxypheny 1 hydraz i ne was heated with 1-benzoy 1 hexahydro-4H-azep in-4-one in absolute ethanol in the presence of acetic acid to give p-propoxypheny 1 -hydrazone of 1-benzoyl hexahydro-4H-azep i n-4-one . , Exampl e 10 o-Chl oropheny 1 hydrazone of 1-benzoy 1 hexahydro~4H- azepin-4-one In the manner given in Example I o-chl oropheny 1 hydrazine was reacted with 1-benzo 1 hexahydro-4H-azep in-4-one in absolute ethanol in the presence of acetic acid to give o-chl oropheny 1 -hydrazone of 1-benzoyl hexahydro-4H-azepin-4-one.

In t;he manner given in Example 1, other substituted phenyl-hydrazones of 1-benzoyl hexahydro-4H-azepin-4-one can be prepared by heating a selected substituted pheny 1 hydraz i ne with 1-benzoyl hexahydro-4H-azep in-4-one, dissolved in ethanol, in the presence of acetic acid. Representative compounds thus obtained include: m-ethy 1 pheny 1 hydrazone ; o-ethy 1 pheny 1 hydrazone ; p-propy 1 pheny 1 -hydrazone; o-propyl pheny 1 hydrazone; m-propyl pheny 1 hydrazone ; : p- i sop ropy 1 phenyl hydrazone; o- i sop ropy 1 phenyl hydrazone; p-chloro phenyl hydrazone; o-bromopheny 1 hydrazone; m-f 1 uoropheny 1 hydrazone o- e thoxy pheny 1 hydrazone ; m-ethoxy phenyl hydrazone; p-i sopropoxyphc hydrazone ; o-propoxy pheny 1 hydrazone ; >, 4-d i chl oropheny 1 hydrazone 2, i fl uoropheny 1 hydrazone ; 2, J>-d i bromopheny 1 hydrazone ; 3,4-d imethyl phenyl hydrazone; 2, 3-d imethyl pheny 1 hydrazone; 2,3~di-ethoxyphenyl hydrazone; 2-ethoxy-3~ 1 uorophenyl hydrazone; 2-bromo 4- propox pheny 1 hydrazone ; 2 -methyl - 4- ch 1 oropheny 1 hydrazone; and the l ike of 1-benzoyl hexahydro-4H-azepin-4-one. 2158 Example 11 3-Benzoyl -1,2,3* 4, 5, 6-hexahydroazep lno[ 4, 5-b] indole A mixture of 5 g. (16.3 mmoles) of the phenyl hydrazone of 1-benzoyl hexahydro-4H-azepin-4-one and 35 ml. of 97% formic acid was heated on the steam bath in a nitrogen atmosphere for 20 minutes. It was then poured into ice-water giving a dark brown sol id wh i ch was col 1 ected by f i 1 trat ion, washed with water and dried in vacuo to yield 4.5 g. of a crude product. This material was chromatographed over 300 g. of silica gel with mixtures of 15- 0$ acetone, balance cyclohexane. The product thus obtained was evaporated and crystallized from methanol -water to give 1.9 g. (40$) of 3-benzoyl -1,2, 3,4,5, 6-hexahydroazep i no[ 4, 5-b] indole of melting point 169-1700 C.

Anal ys i s : Calcd. for Ci9H18 20: C, 78.59; H, 6.25; N, 9.65.

Found: C, 78.26; H, 6.22; N, 9-43.

Example 12 3-Benzoyl -9-methoxy-l,2,3,4,5,6-hexahydroazepino [4, 5-b] indole To 100 ml. of about 3N hydrogen chloride solution in absolute ethanol was added 3-37 g. (O.OIO mole) of p-methoxy- · pheny 1 hydrazone of 1-benzoy I hexahydro-4H-azep in-4-one. This mixture was heated on the steam bath for a period of 7 minutes, then poured into ice water. The solid was collected by filtration, washed with water and dissolved in methylene chloride.

The methylene chloride solution was dried over anhydrous magnesium sulfate, concentrated to about 10 ml. and poured over a column containing .250 g. of neutral alumina. The column was eluted with Q0 ethyl acetate-20# Ske11 ysolve B hexanes and the resulting product crystallized from ethyl acetate to yield 0.3 g. (9-37$) of 3-benzoyl -9-methoxy-l,2, 3.4,5, 6-hexa sExampl e 13 3" Benzoyl -8-methoxy-l, 2,3* 4,5, 6-hexahydroazep i no- [4, 5-b] indol e and ^-benzoyl -10-methoxy-l, 2,3, 4,5,6- hexahydroazep ino[ , -b] indole A mixture of 43.9 g. (0.130 mole) of the m-methoxypheny 1 - hydrazone of 1-benzoy 1 hexahydro-4H-azepin-4-one and 195 ml . of 88$ formic acid was heated on the steam bath in a nitrogen atmosphere for a period of 30 minutes. It was then cooled and poured into ice water. The resulting mixture was extracted with chloroform, the chloroform extracts were washed with water, dried over anhydrous magnes i urn sulfate and concentrated in vacuo. The result ing residue was ch romatographed over 2.2 kg. of sil ica gel with a mixture of 6oi ethyl acetate-4o$ cyclohexane. Twenty-five I.5 1. fractions were col lected. The first band, obta i ned from fract ions 8-11, was crystal l ized from methylene chloride-ethyl acetate to yield 2.66 g. of 3-benzoyl -10-methoxy-l, 2,3, 4,5,6-hexahydroazep i no[ 4, 5-b] indol e of melting point 263.5-267° C.

A second crop of this material was obtained weighing 0.185 g. (total yield 6.82$). The product when recrys tal 1 ized from methylene chl or ide-methanol gave pure 3-benzoy 1 -10-methoxy-l,2,3j4,5,6-hexahydroazepino[4,5-bJ indole of melting point 264.5-266.5° C Anal ys i s : Calcd. for C20H20N2O2 : C, 74.97; H, 6.29; N, 8.74.

Found: C, 74.49; H, 6.63; N, 9.01.

The second isomer, obtained from fractions 14-17, was crystall ized from methylene chloride-ethyl acetate to give .86 g. of 3-benzoy 1 -8-methoxy-l, 2, J4, 5j6-hexahydroazep ino [4, 5-b] indole of melting point 201.5-203Q C. A second fraction of 3.98 g. of the same material was also obtained. Recrystal 1 iza 3- benzoyl -8-methoxy-l, 2, Z>, , 5, 6-hexahydroazep ino[4, 5"b] i ni do 1 <=? of melting point 202-202.5° C.

Anal ys i s : Calcd. for C2oH2ON202: C, 74.97; H, 6.29; N, 8.74.

Found: C, 74.77; H, 6.50; N, 8.62.

Example 14 J>- Benzo l -7-methoxy-l , 2, J>, 4, , 6- hexahydroazep i no [4,5-b] indole A mixture of 29.9 g. (Ο.Ο888 mole) of the o-methoxypheny 1 -hydrazone of 1-benzoy 1 hexahydrd-4H-azep iri-4-one and 88#formic acid (120 ml .) was heated on the steam bath in a nitrogen atmosphere for a period of JO minutes and poured thereupon into 2.5 1. of ice water. This mixture was extracted with chloroform, the chloroform extracts were washed with water, dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a residue. This residue was ch romatog raphed over sil ica gel (1.5 kg.) and eluted with 60$ ethyl acetate-40# cyclohexane. The product thus obtained was crystal l ized from methylene chloride-ethyl acetate to give 1.15 g. of 3-benzoyl -7-methoxy-lJ2i3,4,5i6-hexahydroazepino[4,5-b] indole of melting point 203-204.5° C. A second crop of 0.754 g. was obtained of the same material providing a total yield of 6.69$. Ana 1 ys i s : Calcd. for C2oH2ON202: C, 74.97; H, 6.29; N, 8.74.

Found: C, 75.00; H, 6.45; N, 8.92.

Example 15 3-Benzoyl -9-f 1 uoro-l^J^^^-hexahydroazepino [4,5-b] indole A mixture of 3÷25 g. (O.Ol mole) of the p- f 1 uoropheny ί -hydrazone of 1-benzoy 1 hexahydro-4H-azep ίη-4-one in 88$ formic minutes and the reaction mixture was then poured into ice water. The resulting dark, semi-sol id mixture was extracted with chloroform. The chloroform extracts were washed with water and dried over anhydrous magnesium sulfate, treated with 10 g. of sil ica gel and concentrated under reduced pressure.

The resulting granular sol id was careful 1 y poured onto a column of 200 g. of sil ica gel and chromatog raphed with 6o# ethyl acetate-40# cyclohexane. The eluates were combined, concentrated and the resulting product crystal'! ized from ethyl acetate-Skellysolve B hexanes to give 1.072 g. (34v8#) of 3-benzoy 1 -9-fl uoro-1, 2,3*4, j6-hexahydroazep ino[4,5-b] i ndol e of melting point 131-133° C. This material was recrystal 1 ized from ethyl acetate-Skel 1 ysol e B hexanes to give 3-benzoy 1 -9- f 1 uoro-l,2,3j4,5,6-hexahydroazepino[4,5-b] indol e of melting point 165-1670 C.

Ana 1 ys i s : Calcd. for Ci9Hi N20F: C, 74.00; H, 5-56; N, 9.09; F, 6.16.

Found: C, 73-57; H, 6.02; N, 8.89; F, 5.93-Example l6 3_Benzoyl -7-methy 1 [4, 5-b] indole A mixture of 31.3 g. (0.0975 mole) of the o- tol y 1 hydrazone of 1-benzoy 1 hexahydro-4H-azep in-4-one was refluxed in 290 ml . of 88$ formic acid in a nitrogen atmosphere for a period of 0 minutes. The reaction mixture was poured into ice water, extracted several times with methylene chloride, the methylene chloride extracts were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue. This residue was chromatog raphed over 1.5 kg. of sil ica gel using 6o# ethyl acetate-40^ cyclohexane. The give a sol id which was recrystal l ized from ethyl acetate-Skellysolve B hexanes to give 10.0 g. of 3-benzoyl -7-methy 1 -1, 2,5, ,5, 6-hexahydroazepino[4,5-b] indole of melting point I87-I88. ° C. A second fraction of 1.26 g. of the same material was obtained raising the yield to 37·9#· Recrys ta 11 i za-tion of this material from ethyl acetate gave pure 3-benzoyl-7-methyl -1,2, 3,4,5, 6-hexahydroazepino[4, 5-b] indol e of melting point I89-I900 C.

Ana lysis: Calcd. for C2oH2ON20: C, 78.92; H, 6.62; N, 9.20.

Found: C, 78.70; H, 6.79; N, 8.99.

Example 17 3- Benzoyl -9-methyl -1,2,3, 4,5,6- hexahydroazep i no [4, 5-b] indole A stirred mixture of 26.9 g. (0.0837 mole) of the p-tolyl-hydrazone of 1-benzoyl hexahydro-4H-azep in-4-one was refluxed with 12 ml . of 88$ formic acid in a nitrogen atmosphere for a period of 30 minutes. The reaction mixture was poured into ice water, then extracted several times with chloroform. The chloro-form extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The resulting residue was chromatographed on a column containing 1 kg. of sil ica gel, using a mixture of 60$ ethyl acetate-40# cyclohexane. The eluates were combined and concentrated to give 10.33 g. of product (40.6# yield) which was recrys ta 11 i zed from methylene chl or ide-methanol to give pure 3"benzoyl -9-methyl -1,2,3,4,5, 6-hexahydroazep i no[ 4, 5-b] indole of melting point 210-211° C Ana lysis: Calcd. for C20H20N2O: 2158 ^ Example 18 3" Benzoyl -7-chloro-l,2,3,4,5,6-hexahydroazep ino- [4, 5-b] indole In the manner given in Example 11, the o-chl oropheny 1 -hydrazone of 1-benzoy 1 hexahydro-4H-azep i n-4-one was heated in formic acid to give 3-benzoyl -7-chloro-l,2, 3*4,5, 6-hexahydro-azep i no[ 4, 5-b] indole.

Example 19 3- Benzoyl -9-ethyl -l,2,3*4,5*6-hexahydroazepino- [4, 5-b] indole In the manner given in Example 11, the p-ethy 1 pheny 1 -hydrazone of 1-benzoy 1 hexahydro-4H-azep i n-4-one was heated in formic acid to give 3-benzoyl -9-ethyl -1, 2,3*4, 5*6-hexahydro-azepino[4,5-b] indole.

Example 20 J- Benzoyl -9-propoxy-1,2,3,4, ,6-hexahydroazep ino- [4, -b] indole In the manner given in Example 11, the p-propoxypheny 1 -hydrazone of 1-benzoy 1 hexahydro-4H-azep ίη-4-one was heated in formic acid to give 3-benzoy 1 -9-propoxy-l, 2,3*4, 5*6-hexahydro-azepino[4, -b] indole.

In the same manner given in Example 11, other 3-benzoyl-substituted 1, 2, 3*4, 5*6-hexahydroazep ino[4, 5-b] indoles are obtained by heating a substituted pheny 1 hydrazone of 1-benzoyl-hexahydro-4H-azep in-4-one with formic acid. Representative compounds, thus obtained, include: 3-benzoy 1 -8-ethyl -1, 2, 3*4, 5,6-hexahydroazep ino[.4, 5-b] indol e; 3-benzoy 1 -10-ethy] -1,2,3*4,5*6-hexahydroazep ino[ 4, -b] i ndol e ; 3-benzoy 1 -7-ethy 1 -1,2, 3* 4, 5*6-hexahydroazep i no[ 4, 5-b] indole; 3-benzoyl -9-propyl -1,2,3*4,5*6-hexahydroazep ino[ 4,5-b] indole; 3-benzoyl -7-propyl -1,2,3*4,5*6-hexahydroazep i no[ 4, -b] indol e ; 3-benzoy ? -8- p ropy 1 -1,2,3* 4, 5* 6-hexahydroazep i no[ , 5-b] i ndol e; 3-benzoy 1 -10- ropyl -1,2,3*4,5*6-hexahydroazep i no[ 4, 5-b] i ndol e ; 3-benzoyl -9- i sopropy 1-1,2,3*4,5,6-' 2158 hexahydroazep i no[ 4, 5-b ndol e ; 3-benzoy -9-ch1oro-l,2,3,4,5,6-hexahydroazep i no[ 4, 5-b ndol e; 3-benzoy -7-bromo-l,2,3,4,5,6-hexahydroazep i no[ 4, 5-b ndol e; 3-benzoy -8-fluoro-l,2,3,4,5,6-hexahydroazep ino[ 4, 5-b ndol e; 3-benzoy -10-f luoro-1,2,3,4,5,6-hexahydroazep ino[ 4, -b ndol e ; 3-benzoy -7÷ethoxy-l,2,3,4,5,6-hexahydroazep jno[ 4, 5-b ndol e; 3-benzoy -8-ethoxy-l,2,3,4,5,6-hexahydroazep i no[ 4, 5-b ndol e ; 3-benzoy -9- isopropoxy-1,2,3,4,5,6-hexahydroazep i no[ 4, 5-b ndol e; 3-benzoy -8,9-dichloro-l,2,3,4,5,6-hexahydroazep i no[ 4, 5-b ndol e ; 3-benzoy -9,10-dichloro-l,2,3,4,5,6-hexahydroazep ino[4,5~b ndol e ; 3"benzoy -7,8-di luoro-1,2,3,4,5,6-hexahyd roazep i no[ 4, 5-b ndol e ; 3-benzoy -7,8-d ibromo-1,2,3,4,5,6-hexahydroazep ino[4,5-b ndole; 3-benzoy -8,9-dimethyl -1,2,3,4,5,6-hexahydroazep ino[ 4, 5-b ndol e; 3-benzoy -9,10-dimethyl -1,2,3,4,5,6-hexahydroazep i no[ 4, 5-b ndol e; 3-benzoy -7,8-dimethyl -1,2,3,4,5,6-hexahydroazep ino[4,5-b ndol e ; 3-benzoy -7,8-diethoxy-l,2,3,4,5,6-hexahydroazep ino[ 4, 5-b Indole; 3-benzoy -7-ethoxy-8-f 1 uoro-1, 2, 3, 4, 5, 6- hexahydroazep ino[ , 5-b] indo e; 3-benzoy 1 -7-bromo-9- propoxy- 1,2, 3, 4, 5, 6- hexahyd roazep ino[4, 5-b] indole; 3-benzoy 1 -7-methyl -9-chl oro- 1,2, 3, 4, 5, - hexahyd roazep i no[4,5-b] indol e; and the 1 ike.

Example 21 3-Benzyl -1,2, 3,4,5, 6-hexahydroazepino[4, 5-b] indole: To a stirred mixture of 6 g. of l ithium aluminum hydride in 400 ml . of dry tetrahydrof uran was added a solution of 6 g. (20.6 mmoles) of 3-benzoyl -1,2,3, 4,5,6-hex.ahydroazepino[4,5-b] indole in 150 ml . of tetrahydrof uran . The addition was carried out in a nitrogen atmosphere during one hour. The resulting mixture was stirred at room temperature (about 25° C. ) for about 4 hours and then refluxed for 18 hours. The mixture was then cooled in an ice bath and treated first with 6 ml . of water, then with 6 ml . of 15$ sodium hydroxide solution and. then with 2158 fi ltered. The fil trate was concentrated under reduced pressure to give a residue and the residue was crystal l ized from ethyl acetate-Skel lysolve B hexanes to give 3.37 g. (59$) of 3-be,nzyl -l,2,3>4,5.,6-hexahydroazep ino[4,5-b] indole of mel ting point 116-117° C.

Anal ys i s : Calcd. for C19H20N2 : C, 82.57; H, 7.30; N, 10.14.

Found: C, 82.3 ; H, 7.52; N, 10.04.

Example 22 3"Benzyl -9-methoxy-l, 2,3,4, 5i6-hexahydroazepino- [4,5-b] indole To an ice-cold suspension of 1 g. of l ithium aluminum hydride in 100 ml. of tetrahydrof uran was added 1 g. (O.OO312 mol e) of 3-benzoyl -9--methoxy-l, 2,3*4, 5, 6-hexahydroazep ino[4,5-b] indole and the mixture was refluxed in a nitrogen atmosphere for a period of 18 hours. Thereafter, the mixture was cooled in an ice bath and treated successively with 1 ml . of water, 1 ml . of 15$ aqueous sodium hydroxide solution and 3 ml . of water. The resulting mixture was filtered and the f iltrate concentrated in vacuo to give a sol id which was recrystal 1 ized from ethyl acetate to give 0.773 g. (8l#) of product wh ich again was recrystal 1 ized from ethyl acetate-Skel 1 ysol ve B hexanes to give pure 3"benzyl -9-methoxy-l,2,3, 4,5>6-hexahydro-azepino[4,5-b] indol e of melting point 127.5-129.5° C.

Ana lysis: Calcd. for C2oHg2N20: C, 78.40; H, 7.24; |>f, 9.14.

Found: C, 78.54; H, 7-35; N, 9.42.

Example 23 3" Benzyl -8-methoxy-l,2,3, 4,5,6-hexa'hydroazep ino- [4,5-b] indole 2158 ^ 8.93 g. (0.0279 mole) of 3-benzoyl -8-methoxy-l,2,3,4,5,6-hexa-hydroazepino[4,5-b] indol e. The mixture was refluxed in a nitrogen atmosphere, for a period of 1β hours, cooled in an ice bath and treated successively with 9 ml , of water, 9 ml. of 15$ aqueous sodium hydroxide and 27 ml . of water. The mixture was then f i 1 tered, the f iltrate evaporated, the- res idue crystall ized from ethyl acetate to give 6..62 g. (77.4$) of product which upon reerystal 1 izat ion from ethyl acetate gave 3- benzyl -8-methoxy-l,2, >, 4,5, 6-hexahydroazep i rio[4, 5-b.T indol e of melting point 146.5-147° C.

Analys is : Calcd. for C20H22N2O: C, 78.40; H, 7.24; N, 9.14.

Found: G, 78.25; H, 7.44; N, 9,33.

Example 24 3- Benzyl -10-methoxy-l, 2, 3, 4,5, 6-hexahydroazep ino- [4,5-b] indole To an ice-col d, s.t i r red' suspension of l ithium aluminum hydride (3 g.) in 300 ml. of tet rahydrof uran was added 2.35 g. (7.26 mmoles) of 3-benzoyl -10-methoxy-l, 2,3,4, 5,6-hexahydro-azepino[4,5-b] indole.. This mixture was refluxed for l8 hours in a nitrogen atmosphere, then cooled in an ice bath and treated successively with 3 nil . of water, 3 ml . of 15$ aqueous sodium hydroxide and 9 ml . of water. The mixture was thereupon filtered, the collected sol ids washed with tetrahydrof uran and the washings and filtrate combined and concentrated to give a sol id crude product. This product was crystall ized from ethyl acetate-Skel 1 ysol ve B hexanes to give 1.85 g. (83.3$) of 3-benzy 1 -10-methoxy-l, 2,3, 4,5,,6-hexahydroazep i no-[ 4,5.-b] indol e, which after reerystal 1 izat ion from the same solvent mixture had ,a melting point of 163.5-164.5° C.

Anal ys is : Calcd. for C20H22 2O: C, 78.40; H, 7.24; N, 9.14.

Found: C, 78.80; H, 7-42; N, 9-03.

Example 25 3- Benzyl -7-methoxy-l,2, 3, 4,5,6-hexahydroazep ino- [4, 5-b] indole hydrochloride To a stirred, ice-cold suspension of 2 g. of l ithium aluminum hydride in 200 ml . of tetrahydrof uran was added I.85 g. (5.77 mmoles) of 2-benzoyl -7-methoxy-l, 2,3, , 5,6-hexahydroazepino[4,5-b] indole. The resulting mixture was refluxed for l8 hours in a nitrogen atmosphere and then decomposed by the successive addition of 2 ml. of water, 15$ aqueous sodium hydroxide (2 ml.) and 6 ml. of water. The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. A solution of this residue in ethyl acetate was acidified with methanol ic hydrogen chloride, and the resulting crystall ine hydrochloride was collected by filtration and dried to yield 1 „8l g. (91.5$) of 3-benzy 1 -7-methoxy-l,2, 3, 4,5,6-hexahydroazep ί no[ 4, 5-b] indole hydrochloride of melting point 251-252.5° C. The recrystai 1 ized material from methanol -ethy 1 acetate melted at 247-248° C. (dec).

Anal s i s : Calcd. for C20H23CIN2O: C, 70.06; H, 6.76; N, 8.17; CI, IO.34.

Found: C, 70.15; H, 6.94; N, 8.12; CI, 10.32.

Example 26 3"Benzyl -9-f 1 uoro-l,2,3,4,5,6-hexahydroazepino [4, 5-b] indole To a stirred, ice-cold suspension of 8 g. of l ithium aluminum hydride in 800 ml . of dry tetrahydrofuran was added - - - - - - 2158 hydroazepino[4,5-b] indole, The resulting mixture was refluxed for 10 hours under nitrogen, cooled in an ice bath and treated successively with 8 ml. of water, 8 ml . of 15$ aqueous sodium hydroxide and 24 ml. of water. The mixture was filtered, the sol ids washed with tetrahydrof uran and the f i 1 trate comb ined with the washings was concentrated in vacuo to give a residue. The residue was crystallized from ethyl acetate to yield 5.53 g. (83.6$) of product which after add i tional recrysta 11 izat ion from ethyl acetate gave 3-benzyl-9-f luoro-1, 2,3,4, 5,6-hexahydroazepino-[4, -b] indole of melting point 143-144° C.

Ana lysis: Calcd. for Ci9Hi?N2F : C, 77-52; H, 6.51; N, 9.52; F, 6.45.

Found: C, 77.81; H, 6.52; N, 9.25; F, 6.25.

Example 27 3-Benzyl -7-methyl -1,2,3* 4,5,6-hexahydroazep ino- [4, 5-b] indole hydrochloride A solution of 11.6 g. (0.0376 mole) of 3-benzoy 1 -7-methy 1 -1,2,3,4, 5, 6-hexahydroazep ino[4, 5-b] indole in 00 ml . of tetra-hydrofuran was added under nitrogen to an ice-cold, stirred suspension of 11 g. of l ithium aluminum hydride in 700 ml . of tetrahydrofuran . The resulting mixture was refluxed for 18 hours, cooled in an ice bath and treated successively with 11 ml. of water, 11 ml. of 15$ sodium hydroxide and 33 ml . of Water This mixture was filtered and the filtrate concentrated under reduced pressure. A solution of the residual oil in ethyl acetate was acidi f ied wi th methanol ic hydrogen chloride to yield 5.15 g. ('4-1.9*) of 3-benzyl -7-methyl -1,2, 3,4, 5, 6-hexahydroazep ino[4, -b] indole hydrochloride which after recrystal 1 i zat ion from methanol -ethyl acetate melted at 210.5-212° C, 2158 Anal ys i s : Calcd. for C20H23 2CI : C, 73. 9; H, 7.09; N, 8.57; CI, 10.85.

Found: C, 73-09; H, 7-27; N, 8.18; Ci, 10.60.

Example 28 3-Benzyl -9-methy 1 -1,2,3,4,5,6-hexahydroazep ino- [4, 5-b] indole A solution of 9.56 g. (O.O3IO mole) of 3-benzoy 1 -9-methy 1 -l,2,3,4,5,6-hexahydroazepino[4,5-b] indole in 00 ml . of tetra-hydrofuran was added under a nitrogen atmosphere to a stirred, ice-cold suspension of 10 g. of l ithium aluminum hydride in 700 ml . of tetrahydrof uran . The resulting mixture was refluxed for l6 hours, cooled in an ice bath and treated successively with water (10 ml .), 10 ml . of 15$ aqueous sodium hydroxide and 30 ml . of water. This mixture was al lowed to stir for 1 hour, was then filtered and the fi ltrate concentrated in vacuo to give an oil which was crystal l ized from ethyl acetate to give three crops of product: 7.27 g. melting at l40. -142° C, O.702 g. melt ing at I29-I360 C. and 0.395 g. melting at 123. -134° C. of 3-benzyl -9-methyl -1,2,3,4,5,6-hexahydroazepino-[ 4, 5-b] i ndol e (93$ yield) . Recrystal 1 iz ing this material from ethyl acetate-Skel 1 ysol ve B hexanes gave a pure product mel ting at 142.5-143.5° C.

Ana lysis: Calcd. for C20H22 2: C, 82.72; H, 7.64; N, 9.65.

Found: C, 82.38; H, 7.91; N, 9-96.

Exampl e 29 3- Benzyl -7-chl oro-1,2, 3', 4, 5,6-hexahydroazep i no- [4, 5-b] indole.

In the manner given in Example 21, 3-benzoy 1 -7-ch 1 oro-l,2,3,4,5,6-hexahydroazepino[4;5-b] indole was reduced with 2158 k_ hexahydroazep i no[ 4, 5-b] indol e.

Example 30 3- Benzyl -9- ethyl -1, 2, 3, 4, 5, 6^ hexahydroazep i no [4, 5-b] indole In the manner given in Example 21, 3-benzoy 1 -9-ethyl -1,2,3,4,5,6-hexahydroazep ino[4,5-b] indol e was reduced with l ithium aluminum hydride to give 3-benzyl -9-ethyl -1,2,3,4,5,6-hexahyd roazep i no[ 4, 5-b] i ndo 1 e .

Example 31 3~ Benzyl - 9- propoxy- 1,2, 3,4, :·· hexahyd roazep in.o- [4^5-b] indole In the manner given in Example 21, 3-benzo 1 -9-prOpoxy-1,2,3* 4,5, -hexahydroazep ino[4,5-b] indol e was reduced with l ithium aluminum hydride to give 3-benzyl ^9-propoxy-l,2, , ,5,6-hexahydroazep ino[4,5-b] indole.

In the manner given in Example 21, other 3-benzyl -subst i tuted 1,2,3,4,5,6-hexahydroazep ino[4, 5-b] indoles are obtained by reducing 3-benzoy 1 -subst i tuted 1,2,3, 4, 5, - hexahyd roazep i no[ 4,.5-b] indoles with a metal hydr'rde such as 1 i th ium al um i;num hydr ide. Representative compounds thus obtained include: 3-benzyl -8-ethyl -l,2,3,4,5,6-hexahydroazepino[4,5-b] indol e; 3-benzyl -10-ethyl-l,2,3,4,5,6-hexahydroazep ino[4,5-b] indole; 3-benzyl -7-ethy 1 ^l, 2,3,4, 5, 6- hexahyd roazep i no[ 4,5-b] indol e ; 3-benzyl -9-p ropy 1 -1,2,3,4,5,6-hexahydroazep ino[ 4,5-b]Jndol e; 3-benzyl -7-propyl -1, 2, 3, 4, , -hexahyd oazep ino[ 4, 5-b] indole; 3-benzyl -8-propyl -1,2,3,4,5,6-hexahydroazep ino[4, 5-b] indole; 3-benzyl -10-propyl -1, 2,3,4*5, 6-hexahydroazepino[4, 5-b] indol e; 3-benzyl -9-i sop ropy 1 -1,2,3,4,5,6-hexahydroazep ino[ 4,5-b] indol e; 3-benzyl - - isopropyl -1,2,3, 4,5,6-hexahydroazep ino[4,5rb] indole; 3-benzyl - 9- chloro-l,2,3,4,5,6-hexahydroazepino[4,5-b] indol e;.3-benzyl - - bromo-l, 2,3,4,5,6-hexahydroazepino[4,5-b] indol e; 3-benzyl - - f 1 uoro-1, 2, 3, 4, 5, -hexahyd roazep ino[4,5"b] indol e; 3-benzyl - 2158 .. 7- ethoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole; 3-benzyl - 8- ethoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole; 3-benzyl -10-ethoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole; 3-benzyl - 9- i sopropoxy-1,2,3, 4, 5, 6-hexahydroazep ino[4,5-b] indol e; 3-benzyl -8,9-rd ichlpro-1,2,3, indole; 3-benzyl - 9,10-dichloro-l,2,3,4,5,6-hexahydroazepino[4,5-b] indol e; 3-benzyl -7,8-dif luoro-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole; 3-benzyl - 7.8- d ibromo-1,2,3, 4, 5, 6-hexahydroazep ino[ 4, 5-b] indol e; 3-benzyl - 8.9- dimethyl -1 , 2, 3, 4, , 6-hexahydroazep ino[ 4, -b] indol e; 3-benzyl -9, 10-d i methyl -.1,2, 3,4, , 6-hexahydroazep ino[ 4, -b] indol e; 3-benzyl - 7, 8-dimethyl -1,2, 3,4,5, 6-hexahydroazepino[4, 5-b] indole; 3-benzyl -7,8-diethoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole; 3-benzyl -7-ethoxy-8-f 1 uoro-l,2,3,4,5,6-hexahydroazepino[4,5-b] indol e 3" benzy 1 -7^bromo-9-propoxy-l,2, 3, 4, 5, 6-hexahydroazep ino[ 4, 5-b] indole; 3-benzyl -7 -methyl -9" chloro-1, 2, 3, 4, 5, 6-hexahydroazep ino-[4, 5-b] indol e; and the l ike.

Exampl e 32 l,2,3,4,5,6-Hexahydroazepino[4,5-b] indole and cyclo- hexanesul famate thereof A solution of 3-benzyl -1,2, ,4,5, 6-hexahydroazep i no[ 4, 5-b] indole (1 g.; 3.6l mmoles) in 150 ml , of ethanol was treated with 100 mg , of 10$ pal ladium-on-carbon catalyst and hydrogeno-lyzed in a Parr apparatus at an initial pressure of 50 pounds p.s. i. of hydrogen. After 1.5 hours the reaction was completed and the catalyst removed by filtration. The filtrate was con-centrated in vacuo to give a residue which was dissolved in 100 ml . of benzene and the solution was concentrated to give sol id crude l,2,3,4,5,6-hexahydroazepino[4,5-b] indole. This material was dissolved in 10 ml . of ethyl acetate and treated' wi th a solution of cycl ohexanesul f am i c acid (0.5 g. ) in 3 ml . of ethanol . The crystal l ine salt which resulted was recrystal 1 ized 2158 (13.2$) of 1, 2, 3, ,5, 6-hexahydroazepino[4,5-b] indole cyclo-hexanesul famate of melting point l64-l65° C.

Anal ys is : Calcd. for Ci8H27Na03S: C, 59.15; H, 7.45; N, 11.50; S, 8.77.

Found: C, 59.16; H, 7.47; N, 11.18; S, 8.62.

Example 33 l,2,3,4,5,6-Hexahydroazepino[4,5-b] indole hydro- chlor ide A solution of 7.58 g. (0.0407 mole) of 1,2,3, 4,5, 6-hexa-hydroazepino[4,5-b] indole, obtained as in Example 32, in methanol ethyl acetate was acidified with methanol ic hydrogen chloride. Crystal l ization of the resulting hydrochloride gave 6.74 g. (74.4$) of 1,2,3,4,5,6-hexahydroazep ino[4,5-b] indole hydrochloride of melting point 250.5-251.5° C. After recrystal 1 izat ion from methanol -ethyl acetate, the material had a melting point of 247.5-248.5° C.

Anal ys is : Calcd. for Ci2Hi5N2Cl : C, 64.71; H, 6.79; N, 12.58; CI, 15-92.

Found: C, 64.93; H, 7-08; N, 12.70; CI, 16.10.

Example 34 9-Methoxy-l,2,3,4,5,6-hexahydroazep ino[4,5-b] indole and hydrochloride thereof A solution of 3-benzy 1 -9-methoxy-l,2,3,4,5,6-hexahydro-azepino[4,5-b] indole (5.21 g.; 0.017 mole) in a mixture, of 47' ml. of acetic acid and 100 ml . of 95$ ethanol was treated with $ palladium-on-carbon catalyst (1 g.) and the mixture hydrogenol yzed at an initial pressure of 40 p.s.i. in a Parr apparatus during 2 hours. The react ion -mixture was then filtered through Cel ite ( d iatomaceous earth) and the filtrate concentrated under reduced pressure to give a residue. The 2158 a 1 ka 1 ine with sodium hydroxide solution. The crystal 1 ine sol id which was thus obtained was collected by filtration, washed with water and dried in vacuo to yield 3.53 g, of 9-methpxy-l, 2,3, , , 6 hexahydroazepino[4,5-b] indole of melting point 17 -176° C.

A solution of this material in methanol was acidified with methanol ic hydrogen chloride and the resulting salt was crystall ized from methanol to yield 3.96 g. (92.3$) of 9-methoxy-l,2,3,4,5,6-hexahydroazepino[ ,5-b] indole hydrochloride of melting point 234-236° C, which after recrystal 1 izat ion. from methanol was 235-235.5° C.

Anal ys i s ; Calcd. for CI SHITCI NSO : C, 61.77; H, 6.78; CI, 14.03; N, II.09.

Found: C, 6I.3O; H, 6.85; CI, 14.11; N, 10.99.

Example 35 8-Methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole and hydrochloride thereof A mixture of 6.34 g. (0.0207 mole) of 3-benzy 1 -8-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole, 95$ ethanol (200 ml .) and 1 g. of 10$ pal 1 ad i um-on-carbon . cata 1 yst was hydrogenol yzed at an in it ia 1. pressure of 39.5 p.s. i. for 8 hours. The resulting mixture was filtered through Cel ite (d iatomaceous earth) and the filtrate was concentrated in vacuo to give a residue.

This residue was crystall ized from. methanol -ethyl acetate to give 3·24 g. (72.4$) of 8-methoxy-l,2,3,4,5,6-hexahydroazepino-[4, 5-b] indole of melting point 158-l6o.5° C? A solution of the base in methanol was acidified with methanol ic hydrogen chloride and the salt was recrystal 1 ized from water to give 8-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole hydrochloride of melting point 276-276.5° C. (dec.). 2158 Anal ys i s ; Calcd. for C13H17CIN2O: C, 61.77; H, 6.78; N, 11.09; CI, 14.03.

Found: C, 62.03; H, 6.87; N, 11.17; CI, 14.12.

Example 36 10-Methoxy-l,2,3* 4,5,6-hexahydroazep ino[ 4,5-b] indole and hydrochloride thereof A mixture of 3-benzyl -10-methoxy-l, 2,3*4, 5,6-hexahydro- azepino[4,5-b] indole (1.66 g. ; 5.42 mmoles), 200 ml. of 95# ethanol and 0.5 g. of 10$ pal 1 ad i um-on- carbon catalyst was hydrogenol yzed at an initial pressure of 41 p.s. i. over a period of 7 hours. The catalyst was removed by filtration through Cel ite (d iatomaceous earth) and the filtrate was concentrated under reduced pressure to give 10-methoxy-l, 2, 3*4, 5, 6 hexahydroazep t no[ 4, 5-b] i ndol e as an oil.

This oil was dissolved in methanol and acidified with methanol ic hydrogen chloride. The resulting salt was crystall ized from methanol -ethy 1 acetate to give 1,04 g. (75*6$) of 10-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole hydrochloride wh ich after additional recrystal ) izat ion from methanol ethyl acetate had a melting point of 2360 C.

Anal ys is ; Calcd. for Ci3Hi7ClN20: C, 61.77; H, 6.78; N, 11.09; CI, 14.03.

Found: C, 61.95; H, 6.49; N, 10.98; CI, 14.06.

Example 37 7-Methoxy-l,2,3,4,5*6-hexahydroazepino[4,5-b] indole hydrochloride A mixture of 1.6l g. (4.70 mmoles) of 3"benzy 1 -7-methoxy-1*2,3*4,5, 6-hexahydroazepino[4,5-b] indole hydrochloride, 100 ml of 95$ ethanol and 200 mg. of 10 pa .ladium-on-carbon catalyst was hydrogenol yzed for a period of 2.75 hours at an initial 2158' the filtrate was concentrated under reduced pressure to give a residue which was crystall ized from methanol to give Ο.782 g. of material , of melting point 275-277° C. and G,2¾ g. of material of melting point 278-279° C. (85. # yield). This material was recrystal 1 ized from methanol to give 7"methoxy-1,2,3,4,5,6-hexahydroazep ino[4,5-b}_indol e hydrochlor ide -of melting point 275-275.5° C.

Anal ys i s : Calcd. for Cj3Hi7C1N20: C, 61.77; H, 6.78; N, 11.09; ..CI, 14.0?.

Found: C, 61.83; H, 6.71; N, 10. '92; CI, 13-85, 13.77. Example 38 9-Fl uoro-l,2,3.»4,5,6-hexahydroazep ino[4,5-b] indol e A mixture of 5-58 g. (O.OI90 mole) of 3-benzy 1 -9-f 1 uoro-l,2,3, ,5,6-hexahydroazepino[4,5-b] indole, 250 ml, of 95% ethanol and 10$ pal 1 ad i um-on-carbon catalyst was hydrogenol yzed in a Parr apparatus for 170 minutes at an initial pressure of 29 p.s.i. The reaction mixture was then filtered through Cel ite (diatomaceous earth) and the filtrate concentrated in vacuo to give a crystall ine res idue which was recrystal 1 ized from ethyl acetate to give 3-36 g. (86,7$) of 9-fluoro-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole, which after additional recrystal 1 izat ion from ethyl acetate, had a melting point of 179-180° C.

Ana lysis: Calcd. for C12H13 2F: C, 70.56; H, 6.41; N, 13.72; F, 9.30.

Found.: C, 70.70; H, 6.09; N, 3.60; F, 9.Ο9.

Exam le 39 7-Methyl -1,2, 3,4,5, 6-hexahydroazepino[4,5-b] indole hydrochloride A mixture of 4.84 g. (0.0148 mole) of 3-benzyl -7-methy 1 - 2158. of 95$ ethanol arid 1 g. of 10$ pa 11 ad i um-on- carbon catalyst was hydrogenol yzed for a period of 2.5 hours at art initial pressure of 4l pvs. L The catalyst was rem ed* by f i l trcit ion through Cel i e (d iatomaceous- earth) and the- f i l t^are Was- concentrated under reduced pressure to y ield a crystal 1 ine res idue. T h i s crystal l ine res idue Was recrys al l ized ffom methanol- to give a total of 2.64 g. (7 .0$) of 7-methyi -1,2,3, ,5,6-hexahydro-azep ino[ ,5-b] indoTe hyd rochl or i de- wh ich" after an add i t iona l ecrystal IHzat ion f rem methanol1 melted- at 2 1° C. (dec ) .

Anal ys i s : Calcd. for CiaHi NaCV : C, 65.95; tf, 7.24; H, 11 ,84; CI ', 14.98.

Found: 0, 65.'93; H, 7.-26; jg, 11.53; CI , 14.90.

Examp l e..40 ^-Methyl -l ^^^^^-hexahydroaize^i o^^- ] r doT© A solution of 7.89 g · (0.0272 mole) of 3-behzy 1 -9-methy I -< 1 , , 3, :4 5i 6- hexahydroaze i o[ b] i ndo 1 e in 2Ό0 ml . of 95$ ethanol and 10 mi's of glacial acet ic aci d was treated with 1 g. of 10$ pal 1 ad i urn- on -carbon catalyst and hydrogenol yzed at an in it ial pressure of 30 p . s » ϊ . during a period of 1.5 hours.

The reaction m ixture was then f i 1 tered through Cel i te (diatom ma ceo us earth) and the f i 1 trate was concen rated in vacuo to gi e a residue. A sol tit ion of this residue in water was decolorized ith active charcoal (Oa co G6o) . The solution was cooled in an ice bath and made al kal ine w i t sod i urn hydroxide. The resul t ing crystal Πήβ product was col lected by f i 1 trat ion/ was hed' w i th wa te r a n d dr e d i n vac u o to g ve 5.18 g . (95-2$) of 9-methy 1 - , 2 3 , 4 > 5 , 6 - h ex a h y d r oa z e p i n o [ 4 , 5 - b ] indol e wh ^ch ;af ter recrystal 1 ization from methylene ch 16ΓΊ d'e-me thano 1 had a me'iting poi nt of 243.5-245° C ( ec . }.. 2158 Analysis : Calcd. for Ci3Hie 2: C, 77.96; H, 8.05; N; 13,99.

Found: C, 7,76; H, I.^S; N, 1393» Example 41. 7-Chloro-i 2,3j,4i56-hexahydroazepino[4J5-b] indol e In the manner given in Example 32, 3-b<6nzy 1 -7-chl oro-l,2,3,4,5,6-hexahydroazepinO[4>5-b] indole was hydrogenol yzed in the presence of a pal ladium-on-charcoal catalyst to give 7" chloro-l,2,3*4,5 6-hexahydroazepinoi4,5-b] indole.

Examp 1 e 42 9- Ethyl -1,2,3*4, ,6- hexahydroazepi no[ 4, 5-b] indole In the manner given in Example 32, 3-benzy 1 -9-ethyl * l,2,3i4,5,6-hexahydroazepino[4r/5-'b] indole was hydrogenol yzed , ip the presence of a pal ladium-on-charcoal catalyst to give 9-ethyl -l,2,3>4,5,6-hexahydroazepin0[4,5-b] indol e, Example 43 9~P ropoxy-l}2, 3, ,5, 6-hexahydroazep ino[ 4, 5-b] i ndole In the manner given in Example 32, 3-behzy 1 -9-propbxy*-1*2,3,4,5, - hexahyd roazep i no[ 4, 5-b] i ndo 1 e wa s hyd rogeno 1 yzed in the presence of a pal ladium-on-charcoal catalyst to give 9-propoxy-1, 2, 3, 4, 5, 6-hexahydroazep ino[ 4, 5-b] iridol e.

In the manner given in Example 32, other substituted 1,2,3*4,5* -hexahydroazep ino[4,5-b] indoles are prepared from 3-benzy 1 -subst ituted 1,2, 3,4,5, 6-hexahydroazep ino[4, 5-b] i ndol es by hydrogenol ys is in the presence Of a noble metal catalyst, preferably palladium on a carrier. Representative compounds thus prepared include: 8-ethy 1 -T, 2, 3* 4, 5, 6- hexahyd roazep i no-[4, 5-b] indole; 10-ethyl -1,2, 3* 4, 5, 6-hexahydroazep ino[ 4, 5-b] indole; 7- ethyl -1,2, 3, 4, 5, 6- hexahyd roazep ino[ 4, 5-b] indole; 9-propyl -1,2,3,4, 5,6-hexahydroazepino[4,5-b] indol e;: 7- p ropy 1 -1*2, 3* 4* 5*6- hexahyd roazep ino[ 4, 5-b] indole; 8- ropy 1 -1 , 2,3, '4, 5,6· hexahydroazepi no[4,5-b] indole,} lb-prppyl -1,2,3,4,5.6-hexahydrd- 2158 ; , 5-b] Indol e; 7- I sopropy 1 *i , 2 , 3* If* 5* 6- hexahyd roazep ί no-[4, 5-b] indole; 9-ΟΙΊ1ΟΓΟ*1,2,;5* 4,5*6-hexahydroazepino[4,5-b] indole; 7-bromo-l,2,3*4,5,6-hexahydroazepino[4,5-b] indol e; 8'f 1 uoro-l,2,3,4,5*6-hexahydroazepino[4,5-b] indol e ; 10-f 1 uoro-l,2,3,4,5,6-hexahydroazepino[4 5-b] indole; 7-ethoxy-l,2,3,4,5*6-hexahyd roazep ino[ 4, 5-b] indole; 8-e thoxy -1,2, 3* 4,5*6- hexahyd roazep ino[ 4, 5-b] indol e ; 10-ethoxy-l,2,3*4,5*6-hexahydroazep ino-[ 4, 5-b] i ndol e ; 9- i sopropoxy-1, 2, 3, 4, 5, 6·^ hexahyd roazep i no[ 4, 5-b] indole; 8,9-dichloro-l,2,3*4,5*6-hexahyd oazepino[4,5-b] indole; 9,10-dichloro-l,2,3*4,5,6-hexahydroazepino[4,5-b] indole; 7,8-dif l.uoro-l,2,3,4,5,6-hexahydroazepino[4,5-b] indol e; 7*8-d ibromo-1, 2, 3*4, 5*6-hexahydroazepino[4, 5-b] indole; 8,9-d imethy 1 -l*2,3,4,5*6-†vexahydroazep ino[4,5~b] indole; 9* 10-d imethy 1 -l,2,3,4,5*6-hexahydroazepino[4,5-b] indole; 7*8-d imethyl -l,2,3,4,5i6-hexahyd,roezepino[4,5-b] indole; 7*8-d iethoxy-l*2,3,4,5*6-hexahydroazepino[4,5-b] indol e; 7-ethoxy-8-f 1 uoro-1*2,3,4,5* 6-hexahydroazepino[4,5-b] indole; 7-bromo-9-propoxy-l*2,3,4,5*6-hexahydroazepino[4,5-b] indol e; 7-methyl -9-chloro- ■ 1*2, 3*4, *6-hexahydroazepino[4, 5-b] indol e; and the l ike.

Exampl e 44 3-Formyl -1,2,3*4, 5* 6-hexahydroazep i no[4, -b] indol e A mixture of 9.45 ml . of acetic anhydride arid 3.98 ml. of 98$ formic acid was stirred and allowed to stand at 25° C : for 1 hour. The mixture was then cooled in an ice bath and treated with 5.58 g. (0.03 mole) of l,2,3*4,5*6-hexahydroazepino-[4, 5-b] indole. As th i s indol e went into solution, a second precipitate formed. Then 25 ml . of ether was added to the resulting mixture which was allowed to stand in a nitrogen atmosphere for 18 hours and poured thereupon: into water. The thus-obta ined sol id was col 1 ected by f i 11 rat ion, washed w i th water and dried in vacuo to give 6.27 g. of a crude product 2158 from methanol -ethyl acetate yielded three crops: 4.24 g. having a melting point of 221*222".5° C. ; 1.19 9· melting at 220.5-221.5° C. and 0.282 g. of melting point 219-5- 221° C. of - formy 1 -1,2, 3, , 5, 6-hexahyd roazep÷i.no[ 4-, 5-b] indole (a total yield of; 89$) · Recrys'tal 1 izat ion of this material from methylene ch lorjde-methanol provided 3-formyl- 1,2,3,4, 5,6-hexahydroazep ino[4-,5-b] indol e of melting point 221-222.5° C.

Anal ys i s ; Calcd, for .ς!ΐ!3Η, Ν20: C, 72.87; H, 6.59; N, 13.08.

Found: C, 72.90; H, 6.74; N, 12.84.

Exampl e 45 3- Acetyl -8-methoxy-l,2,3,4,5,6-hexahydr0azepino- [4,5-b] indole A solution of 2 g. of 8-methoxy:l,2,3,4,5,6-hexahydro- azepino[4, 5-b] indole in 25 ml . of pyridine and 10 ml . of acetic anhydride was allowed to stand at room temperature for 20 hours in a nitrogen atmosphere. The react ion mixture was poured into water, the sol ids collected on a filter and recrysta 11 ized from methanol -ethyl acetate to give 3-acetyl -8-methoxy-l,2,3, 4,5,6-, hexahydroazep i.no[ 4, 5-b] i-ndol e.

Example 46 3-Rrop i ony 1 -9- f^uoro-l ,, 2,3, 4 > , 6-.hexal^;droa'zep^;-n-o- [4,5-b] indole In the manner given in Example! 45, 9-fl uoro-1, 2,3i4,5¼6- hexahydroazepino[4, 5-b] indol e was; reacted with prop dride in. pyridine to give 3!"?prppionyl -9-f 1 uoro-1,2, 3j455l,'6-,hexa(iydroazep inp[4, 5-b] indole.

Examp 1 e 47 3-Acetyl -7-methy 1 -1,2>3¾ ,5,6·- hexahydroazeip^no- [ 4, 5 b] indole In the manner given in Example 45, 7-methy 1 -1,2,3,4,5,6- 2158 in pyridine to give 3-acetyl -†-metb I -l,2,3*4,5*6-hexahydro-azep ino[4,5-b] fndol e.

Examp 1 e 48 3-Propionyl -9-methyl -1, 2, 3* 4, 5* 6- hexahydroazep ino- [4, 5-b] indoje In the manner given, in Example 45, 9-methyl -1, 2, 3* 4,5,6-hexahydroazep lno[ , 5-b] indol e was reacted with propionic anhydride in pyridine to g ive.3-propionyl -9-methyl -1,2, 3*4, 5,6-hexahydroazepino[4,5-b] indole..

Example.49 3-Acety 1 -9-methoxy-l,2,3* 4, 5* 6- hexahydroazep i no- [4, -b] indole In the manner, .given m Example 45, 9-methoxy-l,2,3, 4,5*6-hexahydroazepino[4, 5-b] indole, was reacted with acetic anhydride in pyridine to g ive.3-acetyl -9-methoxy-l,2,3* 4, 5,6-hexahydro-azep ino[ , 5-b] indole.

Example 50 3-Formyl -7-ch loro-l,2,3*4,5*6-hexahydroazepino- [4, 5-b] indole In the manner given in. Example 44, 7-chloro-l,2,3,4,5*6-hexahydroazep ino[4,5-b] indole was reacted with acetic anhydride,, and formic acid to give 3-formyl -7-chloro-l,2,3,4,5*6 hexahydroazep i no[ 4,,5-b] indole.

Examp 1 e 51 3-Acety 1 -7,8-d ibromo-l,2,3*4,5*6-hexahydroazep ino- [ , rb] indole In the manner, given in Example 45* 7*8-d ibromo-l,2,3*4,5*6 hexahydroazep i no[ , -b] indole was reacted with acetic anhydride in pyridine to give 3-acety l.-7*8-d ibromo-1, 2,3*4, 5*6-hexahydro-azep ino[;4,5-b] i,ndole.

Example 52 3-Acetyl -7-methyl -9-chloro-l,2,3,4,5,6-hexahydro- azepino[ 4, 5-b]; indole In the manner given in Examp 1 e 45, 7-methy 1 -9-chloro-1*2, 3*4, 5*6-hexahydroazepino[4, 5-b] indole was reacted with 2158 chloro-l,2,3,4,5,6-hexahydroazepino{4,5-b] indole. ^ In the manner g;iven in Examples , 5 and 46, other 3-,acyl derivatives of the substituted 1,2,3,4,5 6-hexahydro- azep!ino[4,5-fo] indoles of Examples 32' through 43;, including the compounds in, the l ist fol low ing ■ Ex4mpl e 43, can be prepared by. reacting such compounds with a reagent selected from acetic anhydride, acetic anhydride and formic acid, propionic anhydride, or acetyl chloride, propionyl chloride, benzoyl chloride, or b.romides thereof.

Example 53 3-Methyl-l,2,3>4,5,6-hexahydroazepino[4,5-b] indole To a ;s tir red suspension of l g. of l ithium aluminum hydride in 100 ml . of ice-cold tetrahydrof urah was added 3-formyl- 1,2,3,4,5,6-hexahydroazep ino[4,5~b] Indole (1 g. ; 0.00467 mole) . The. mixture was ref 1 uxed for 18. hours' in a nitrogen atmosphere, then cooled in an ice bath and treated successively with 1 ml . of water, 1 ml. of 1 $ -aqueous sodium hydrox ide solution and 3 ml . of water. ;The*resu1 ting mixture was stirred for 1 hour and filtered. Concentration of the filtrate under reduced pressure gave a sol id which was recrystal 1 ized from ethyl acetate to yield 0.853 g- (91.3$) of -1, 2,3,4, 5,6-hexahydro- azep ino[ 4, 5-b] Indole of mel ting point l62-l66° C. Riecrys tal 1 iza- tion of this material from ethyl acetate gave 3-methyl -1 2,3, 4, 5>6 hexahydroazep ino:[4,5-b] Indole of mel ting point 165-166. ° C.

Ana 1 vs 1 s : Calcd. for Ci3HieN2: .. C, 77.96; H, 8.D5; N, 13.99.

Found: C, 77-69; H, 8.08; N, 13.72.

I n the same manner g iven in Exam le: 3 reduct i on of 3- acety 1 -8-methoxy-l, 2, 3* , * 6-hexahydroazep i no[ 4,5*'b]Vndo1 e with 1 i thi urn a 1 urn inum hydride- gave 3-ethyl -8-methoxy-l;i ,3,4,5,6- 2158 l,2,3,4,5,6-hexahydroazepiho[4,5-b] indole gave 3- propyl -9- 1 uoro-l,2,3,4,5,6rhexahydroazep irio[4,5-b] indole; reduct ion of 3-acetyl -7-methy.l -l,2,3i i^ indole gave 3-ethyl -7-methyl -1,2, ,4,5, 6-hexahydroazepin'Q-[4, 5-b] indol e; reduction of 3-propionyl -9-methyl -1,2,3,4,5, 6-hexahydroazepino[4,5/*b] indole gave 3-Pi*opyl -9-methy 1 -l,2,3,4,5,6-hexahydroazepino[4,5-b] indol e; reduction of 3-acetyl -9-methoxy-l,2,3,4,5,6-hexahydroazepinot4,5-b] indole gave 3-e thy 1 -9-methoxy-l,2 3,4,5,6-hexahydroazepino[4,5-b] indole; reduction of 3- ormyi -7-chloro-l, 2,3,4, ,6-hexahydr6-azepiho[4,5-b] indole gave.3-methyl -7-chloro-l, 2,3, 4,5, 6-hexa-hydroazepino[4,5-b] indole; reduction of 3-acety 1 -7,8-d ibromo-l,2,3,4,5,6-hexahydroazepiho[4,5-b] indole gave 3-ethy 1 -†,8-d ibromo-l,2,3,4,5,6-hexanydroazepino[4i -b] indole; and reduction of 3-acety Γ-7-methy 1 -9-ch 1 oro-1 , 2, 3, 4, ,6- hexahyd roazep i no- [4, 5-b] indole gave 3-ethy 1 -7;i-methyl -9-cMoro-l, 2,3,4, 5,6-hexa-hydroazep iho[4,5-b] indole. .

I n the same manner g i ven in- Example 53, other 3-acy 1 deri vat i ves of subst Ttuted 1,2,3, 4 , 5 , 6 - h ex a h ,y d r o a z e p . i n o [ 4 i 5 - b ] indoles as herein shown can be converted to the correspond ing 3-al ky 1 subst i tuted 1,2, 3, 4,,5, 6- hexahyd roazep ino[ 4, 5-b] Indoles . Example 54 6-Methy 1 - 1,2,3,4 ,5,6-hexahyd roazep i no[ 4, 5-b] indole and hydrochloride thereof To an ice-cold, stirred solution of 1,2,3, 4,5, 6-hexahydro-azep ino[4, 5-b] indole (3.73g; 0.02 mol e) in 200 ml . of dry d imethyl formamide was added in a nitrogen atmosphere, 0.960 g. of a 5$ suspension of sodium hydride in mineral oil (0.022-mole of sodium hydride). This mixture was allowed to Wanm to 25° C. and stand. for 2 hours. It was then cooled in an ice bath and treated during 30 minutes with a sol ut ion of methyl . iodide 2158 C; solution was al lowed to stand for 18 hours at 25° C. It was then concentrated under reduced pressure to about 50 ml . and poured into water. The mixture was extracted four times with ether, the. ether extracts combined, washed with brine, dried over anhydrous potassium carbonate and concentrated under reduced pressure to give 6-methy 1 -l,2,3j4,5,6-hexahydroazep ino-[ , -b] i ndol e as a residue. This residue was redissolyed in ethyl acetate and acidified wi th methanol r-c hydrogen chloride and the resulting hygroscopic sal t was crystal l ized from methanol -ethyl acetate to give 3.19 g. (75-2$) of material which was again recrystal 1 ized from methanol -ethyl acetate to give 6-methyl -1,2, 3,4, 5>6-hexahydroazepino[ ,5-b] indole hydrochloride of a melting point of 214-215° C.

Anal vs i's : Calcd. for? C13H17N2CI : C, 65.95; H, 7-24; N, 11.84; C.l, 14.98.

Found: C, 66.35; H, 6,99; N, 11.78; CI, 14.90.

Example 55 6- Ethyl -1,2,3* 4,5,6-hex.ahydroazep ino[:4,5"b] indol e hydrochloride A cold solution of 7-45 g. of l,2,3i4.,5,6-hexahydroazep Ino-[ 4, 5-b] i ndol e in 400 ml . of dry dimethyl formamide in a nitrogen atmosphere was treated, w i h 1.92 g. of a 55¾ suspension of sod i um; hydr ide in mineral oil. The mixture was stirred at room temperature for 3 hours, then cooled and treated with a solution of 3.54 ml . of ethyl iodide in 50 ml . of ether. The addition took p-.lace over a period of 15 minutes. The mixture was then al lowed to stir at room, tempera tune for about 18 hours. The mixture was thereupon concentrated under reduced pressure to give a residue which was dissolved in 250 ml . of water. The aqueous mixture was extracted three times with ether and three 2150 separately, that is, washed with brine, then water and f inaf fy dried over anhydrous potassium carbonate. Thereafter, the two extracts were combined and concentrated to give a residue which was suspended on 30 g. of sil ica gel and chromatographed over 450 g. of sil ica gel using 2$ ethyl am ine-48# methanol -5052 ethyl acetate for elution. Fractions of about 150 ml . were collected. The first band (A) consisted of fractions 6-9.

The product was found in fractions 14-21 (band B) . The B fractions were combined and concentrated under reduced pressure to give a residue which was dissolved in ethyl acetate, cooled and acid ί fied wi th methanol ic hydrogen chloride, The precipitate wh i ch res ul ted was col 1 ected by f i 11 rat ion , washed wi th ethy 1 acetate and dried in vacuo to yield 7. 7 g. of material which was recrystal 1 ized from methanol and'then three times from methanol -ethy 1 acetate to give 6-ethyl -1,2,3* 4, 5 6-hexahydro-azep ino[4,5-b] indole hydrochloride of melting point 253-254° C. (dec).

Anal ys i s : Calcd. for Ci4Hi9N2Cl : C, 67.05; H, 7.64; N, 11.17; CI, 14.14.

Found: C, 67.IO; H, 7-90; N, 11.47; CI, 14.38.

Exampl e 6^Methyl -9-methqxy-l,2,3> 4, *6-hexahydroazep ino- [ 4, 5-b] i ndol e hydrochloride and 3, 6-d imethy 1 -9- methoxy-l,2,3 4,5* 6-hexahydroazep ino[4,5-b] indol e hydrochloride.

In the manner shown in Example 55v 9-methoxy-l,2,3i4,5i6-hexahydroazep ino[ 4, 5-b] indole was treated with sodium hydride and then with methyl iodide to give a mixture of amines. This mixture was separated by chromatography over sil ica gel using as eluant a mixture of 2$ d ί ethy 1 am methanol -83$ ethyl c2i58 l,2,3*4,5*6-hexahydroazep ino[4, 5-b];indole' wh ich was converted to its hydrochloride with met hand Vic hydrogen chloride. Crystall ization of this salt from methanol gave 3*6-dimethyl -9-methoxy-i,2,3*4,5*6-hexahydroazepirioI4,5-b] indole Hydrochloride having a melting point of 270° C. (dec).

Analys is : Calcd. for Ci5H2iClN20: C, 64.16; H, 7.54; N, 9.98; CI , 12.63.

Found: C, 64.20; H, 7.73; N, 9.82; CI, 12.78.

Fractions 28 - 9 from the chromatographic column contained 6-methy 1 -9-methoxy-l,2,3,4,5,6-,hexahydr0azep ino[4, 5-b] indol e which was converted to its hydrochloride with methanol ic hydrogen chloride. Crystall ization of this salt from methanol gave 6-methyl -9-methoxy-l, 2,3*4, 5*6-hexahydroazepino[4, -b] indole hydrochloride having a melting point of 272° C. (dec). Anal vs ? s : Cal cd. for C14rli9Cl 20 : C, 63.03; H, 7.18; N, 10.50; CI, 13.29.

Found: C, 62.89; H* 7.25; N* 10.36; CI, 13.25.

Example 57 6-BenzyJ -1, 2,3* 4, 5* 6- hexahydroazep i no[ 4, -b] i ndo 1 e and hydrochloride thereof, and 3, -d i benzyl - 1, 2, 3, , 5*6- hexahydroazep inoE , 5-b] ihdol e In the manner given in Example 55* 5.59 g. of 1,2,3*4,5*6-hexahydroazepino[4,5-b] indole in 300 ml. of dimethyl formamide was reacted with 1.44 g. of a 55$ suspension of sodium hydride in mineral oil and, after standing, for 3 hours and cool ing, with 4.I8 g. of benzyl chloride in 37 ml . of dry ether. The mixture was allowed to stir for 18 hours at room temperature, the solution was then concentrated under reduced pressure to give a res idue wh ich was dissolved ^ 300 ml. of Water" arid 2158 extracts were washed with water* dr ied over potass ium carbbriate and concentrated under reduced* pressure. T.he residue was re? dissolved in ethyl acetate. A small amount of material which crystall ized was, collected by filtration.. The mother l iquors were chromatographed over 50 g. of sil ica gel using a solvent system consisting of d i ethy 1 am ine, 28$ ethyl acetate and 70$ cyclohexane. Fractions of 100 ml. were collected. Fractions 13-19 contained one compound which was found to be 3*6-d ibenzy 1 1,2,3*4, 5*6-hexahydroazepino[4,5-b] indole of melting point 85.5-86.5° C.

Anal ys is : Calcd. for C2eH2eN2: C, 85.20; H, 7.15; N:, .7.65.

Found: C, 84.80; H, 7-25; N, 7-74.

The column was then eluted with a mixture of 2$ trimethyi-amine and methanol . A; methanol ic solution of the product obtained in this manner was converted to its hydrochloride.

Crystal l ization of this salt from methanol -ethy 1 acetate gave 6-benzyl -l,2,3,4,5,6-hexahydroazepIno[4,5-b] indole hydrochlor ide having a melting point of 212-213° C.

Anal ys i s : Calcd. for Ci 9H21N2 ! : C, 72.95; H, 6.77; N 8.96; CI, 11.35.

Found: C, 72.51 ; H, 6.75; N, 9.21; CI, 11.41.

Example 58 6-Propyl -9-fl uoro-1, 2,3*4, 5*6-hexahydroazep irio- [ 4,5-b] indol e and hydrochloride thereof In the manner given in Example 55, 9" uoro-1, 2,3, 4,5,6-hexahydroazep ino[4,5-b] indole was treated in sequence. with sodium hydride and then propyl iodide to give 6-propyl-9-f 1 uoro-1, 2, 3* 4,5*6-hexahydroazepino[4,5-b] indol e which was 2158 : ■ · . hydrochloride.

Example 59 6- I sop ropy 1 -9-methyl -l,,2,3*4,5*6-hexahydroazep ino- [4, 5-b] indol e and hydrochloride thereof In the manner given in Example * 9-methyl -1,2, 2*^*5* 6-hexahydroazepino[4,5-b] indol e in d imethy 1 ormam ide was treated in sequence with sod i urn . hydr ide and then with isopropyl iodide to give 6- isopropyl -9-methyl -l,2,3*4,5*6-hexahydroazepino[4,5-b] indole which was recovered as the hydrochloride.

Example 60 3-Formyl -6-methyl -1,2,3* 4,5,6-hexahydroazepino- [4, -b] indole In the manner given in Example 44, 6-methyl -1, 2, 3* , 5,6-hexahydroazepino[4, 5-b] indole was treated with acetic anhydride and formic acid to g ive 3- formyl -6-methyl -1,2, 3*4, 5, 6-hexahydro-azepino[4, 5-b] indole which after recrystal 1 izat ion from methylene ch 1 or ide-methanol had a melting point of 125-128.5° C.

Anal ys i s : Cal cd. for Ci4HieON2 : C, 73.65; H, 7.06; N, 12.27.

Found: C, 73.57; H, 7.05; N, 12.55.

In the same manner, acylating 6-methyl -1,2,3, , ,6-hexa-hydroazep i no[4, 5-b] indole with acetic or propion ic anhydr Lde yields the corresponding 3-acetyl- or 3-prop ionyl -6-methyl -l,2,3*4,5*6-hexahydroazepino[4,5-b] indol e.

Example 6l 3*6-D imethy 1 -l,2,3*4,5*6-hexahydroazepino[4,5 b] indole hydrochloride.

To a cold suspension of 5 g. of lithium aluminum hydride in 100 ml.. of tet rahydrof uran in a nitrogen atmosphere was added a solution of 5.07 g. of 3-formyl -6-methyl -1,2, 3*4,5* -hexahydro-azepino[4, 5-b] indole. The mixture was refluxed for 18 hours* then cooled in an ice bath and decomposed. by adding in sequence 2158 of water. The fixture was rVow al lowed to; st i at room1 temperature for about 1. hour and was thereupon f iltered, the precipii-tate washed with tetrahydrofuran and the washings and filtrate comb i n ed and con cen t ra ted unde r reduced p res s u re to -g i ve an oil.. This oil was dissolved in ethyl acetate and acidified with methanol ic.hydrogen chloride to give a sol id which was recovered by f iltration to yield 3-77 g. of 3,6-d imethyl -1, 2,3, , 5,6-hexa-hydroazep ino[45-b] indole hydrochloride which after recrystall i-zation from methanol -ethyl acetate had a melting point of .251-251.5° C.

Anal vs is : Calcd. for Ci4Hi9N2Cl : C, 67.05; H, 7.64; N, 11.17; CI, 14.14.

, Found: C, 67.18; H, 7.70; W, 11.37; CI, 14.28.

Ex am pi e '62 3 - B e n zoy 1 -6 - me t h y 1 - 10 -me t hox y - 1 , 2 , 3 ,4 > 5 > 6 - hex a h y d r o - azepino[4,5-b] indole A solution of 3^ benzoyl -10-methoxy-l,2,3, ,5,6-hexahydro-azep ino[4,5-b] indole in d imethyl formamide was treated with sodium hydride and thereupon wi th methyl iodide to g i ve 3-benzoy 1 6-methyl -i0-methoxy-l,2,3j 4,5» 6-hexahydroazepino[4,5-b| indol e which after several recrystal 1 izattons from methanol -methyl en e chloride had a melting point of 187.5-188° C.

Anal vs i s : Calcd. for C2iH22N202 : C, 75.42; H, 6.63; N, 8.38.

Found: C, 75.36; H, 6.8Ο; N., 8.36.

Ex amp 1 e 63 3- Ben zy 1 -6-methyl -10-methoxy-l,2,3*,4j 5/&-heXahydro- azep ino[4,5-b] indol e and hydrochlor i.de thereof Likewise as in Example .21, 3-benzoyl -6-methyl -10-methoxy-1,2,3* 4,5i6-hexahydroazep ino[4,5-b] indole was reduced with a the solution was decomposed with sodium hydroxide and water and the product isolated in conventional manner to give after re- cr all| at ^Qn f £«qm... e hy k a cet<¾fte -Skeil y so f e B*r*eacanes a m.ixture of 3-benzyl -6-methyl -10-methoxy-l,2, 3 ,5, 6-hexahydro- azepino[4,5-b] indole and 6-methyl -10-methoxy-l, 2,3, 4,5,6-hexa- hydroazepino[4,5-b] indole. Pure 3-benzy 1 -6-methyl -10-methoxy- l,2,3,^,5,6-hexahydroazepino[4,5-b] indole was obtained by ■chromatographing this mixture on sil ica gel with 2$ diethyl- am ine-15# methanol -83$ ethy 1 acetate. The product thus obtained was converted to its hydrochloride with methanol ic hydrogen chloride and crystall ized from .methanol -ethy 1 acetate to give 3-benzy 1 -6-methyl -10-metftoxy-l,2,3i 4, 5> 6- hexahydroazep i ho- [4,5-b] indole hydrochloride of mel ting point 246-247.5° C.

Anal ys i s : Calcd. for C2iH25W20Cl : C, 70.67; H, 7.06; N .85; CI i 9,94.

Found : : C, 70.49; H, 7.45; N, 7,78; CI, '10.03 « Exam pi e 64 6-;Methyl -10-methoxy-l, 2, 3, 4,5,6- hexahydroazep ino- [4,5-b] indol e hydroc loride In the manner given in Example 32, 3-benzy 1 -6-methyl -10- ' met hoxy-1, 2, y, , 5, - hexahydroazep i no[ 4, 5-b] i ndol e hydroch 1 or i de was hydrogenol yzed with 10%" pal lad ium-on-carbon catalyst at 47 p. s . i , for a durat ion of 4 hours. The product was several titties recrystal 1 ized f rom methanol to gi e 6-metnyl -lO-methoxy4-1,2,3, 4, 5, 6- hexahydroazep ino[ 4., 5-b] indole hydroch lor ide of melting point 276.5-278° C.

Analys is ; Calcd. for : C, 63.03; H, 7-18; N; 10.50; CI, .13.29.

Found: C, 62.93; H, 7.36; N, 10.52; CI, 13.35. 2158 A. 3" Benzoyl -β-methy 1-1,2,3, 4,5,6-'hexahydroazepino[4,5-b] indole To a st i r red so 1 u t i on of : -b.en'¾<^ I¾2,3, ¾5J6-heka^ ydro-azepIno[4J5-t^] indole (177.0 g.) in 2 gallons of dry r 2 hours at room temperature and then cooled in an ice bath To the react ion mixture Was -then added dropwise over 20 minutes 41.8 ml . of methyl iodide. The resul t ing mixture was al lowed to stand at room temperature for 18 hours. The dimethy formamide was then removed with t:he aid of a rotating evaporator at 7 pressure at a temperature between 55"60° C. The residue was suspended in 3 1. of water and' extracted with methylene chloride. ; The extracts were washed with water/ dried over anhydrous potassium carbonate and concentrated under reduced pressure to g ive afi oil. This oil was dissolved in 700 ml . of ben'ze'he and the resulting' solution was concentrated to dryness to give an oily res idue, 3-benzoyl ^^methyl -l,2,3>4,5i6-hexahydroazep ino-[4, 5-b] indole. This residual oil was used without purification for the preparation of 3-benzyl -6-met;hy 1 -1,2,3>4 ^^hexahydro-azep ino[4,5-b] indole.

B. ij-Be zyl -β-methyl -l,2,3,4,5,6-hexahydroaze ino[4,5-b] indole A sol ut ion of the above- crude 3-benzoyl -6 -me t hy! -1 , 2,3, 4, 6 hexahydroazepino[4, -b] indole in 1 1. of tetrahydrof uran was added slowly under nitrogen to an ice-cold, stirred suspension of 145 g. of 1 i thium aluminum hydride in '7 1. o tetrahydrof uran . The resulting mixture was warmed slowly to the reflux temperature and refluxed for 18 hours. It was then cooled in an ice bat and treated success ively with water (l45 ml . dropwise), 145 ml . 2158 mixture was stirred for about 30· minutes and f i 1 tered.. The solid was washed wel 1 with tetrahydrofgran and the combined original filtrate and washings were concentrated Under reduced pressure. The residual oil was dissolved; in 1 1. of benzene and this solution was concentrated to dryness under reduced pressure to give 3-benzyl -6-methyl -1,2,3*4,5* 6-hexahydro-azep ino[4,5-b] indole.

C. 6-Methyl -l,2,3,4,5,6-hexahydr.oazepino[4,5-b] indol e hydrochloride The above 3,-benzy ί^-6-methy 1 -1,2, 3,4,5, 6rhexahydroazepino-[4,5-b] indol e in 1.5 1. of 95$ ethanol ,, 50 ml. of glacial- .acetic acid and 20 g. of 10$ palladium-on-carbon catalyst was hydrogen-olyzed in a Parr apparatus for 1.5 hours. The, catalyst was then removed- by vacuum filtration through Cel ite (diatomaceous earth) and the "fil rate was concentrated .under; reduced pressure., A sol ut ibn?of'5the res i due in water was washed' wteh ether, cooled in an ice bath and madenalikaT ine wi th 50$ aqueous sodium hydroxide. This mixture was extracted three times with, chloroform, the chloroform extracts were combined/ washed with water.,.-' dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a residue. The residue was, dissolved 'in methanol, the solution was cooled in an ice bath i and acid if ied wi th methanol ic hydrogen chlor ide. Crysta l¾il?at ion of this salt from methanol -ethyl acetate gave three crops of 6-methyl -1,2, 3, , 5j6-hexahydroazepino[ ,5-b] indole hydrochloride;} 68.4 g. of melting point 214-216? C. ; 3,1. g. of mel ting point ; 216° C. ; and 11.1 g. of melting point 2l4-215 5° C. The overall yield Wars 76.8$. This compound was identical with the 6-methyl -l,2,3j4,5,6-hexahydroazepino[4,5-b] indole, hydrochloride prepared in Exampl e 54. 21§8 , ·4·η the manner shown in.. Exampie 65, Part A, 3-ac,y1: substitute 1,2,3,4,5,6-hexahydroazep ino[4,5-b] indoles (for example, those of Exampl es - 2) can be alkylated by treating these compounds in dimethyl- or d i ethyl formam ide in the presence of sodium hydride with methyl, ethyl, propyl or isopropyl iodides or bromides.

Representat ive compounds thus obtained include: -prop iony 1 -6-methyl -9-f 1 uoro-1,2,3, , 5,6-hexahydroazep ino[4,5-b] indol e; propi.ony 1 -6- ethyl -9-f 1 uoro-1,2,3, 4,5,6-hexahydroazepTno[4,5-b] indol e; 3-acety 1 -6- propyl -7-methyl -1,2,3,4,5,6-hexahydroazep ino [4, 5-b] indole; 3-acetyl -6- i sopropyl -7-methyl -1,2, 3,4,5, 6-hexa-hydroazepino[ , 5-b} indole; 3-prop ionyl-6, 9-d imethyl -1,2,3, 4,5,6-hexahydroazepino[4,5-b] indole; 3-prop iony 1 -6-ethy 1 -9-methy 1 -l,2,3,4,5,6-hexahydroazepino[4 5-b] indol e; 3-acety 1 -6-ethy 1 - 9-methoxy-l,2,3i^:5y6-hexahydroazepino[4,5-b] indol e; 3-ace'tyl -6-isopropyl -9-methoxy-l,2,3>4,5,6-hexahydroazepino[4,5-b] indol e; 3-formyl -6-methy 1 -7-c loro-l,2,3,4,5,6-hexahydroazep ino[ 4,5-b] indole; 3-formy 1 -6-propy 1 - J- c loro-1,2,3 5,6- hexahydroazep ί noli 4, 5-b]indole; 3-acety 1 -6-methy 1 -7, 8-dibromo-l, 2, 3, , , - hexahydroazep i no[ , -b] i ndol e ; 3-acetyl -6, 7-d imethyl -9-chldro-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole; 3-acetyl -6-ethy 1,-7-methyl -9-chloro-l,2,3i 4,5,6-hexahydroazepino[4,5-b] indole; 3-formyl -6- isopropyl -7- chlioro-l, 2 , , , - exahydroazep ino[ 4, -b] indole; and the l ike.

In the manner given in Example 65, Part B, the thus-obta ined 3-acy 1-6-al kyl substi tuted l,2,3,'4,5,6-hexahydroazepino[4,5-b] indoles can be reduced w i th 1 i th i urn al urn inum hydr i de,, "usual 1 y in tetrahydrof uran, to g ive the correspond ing 3,6-d ial'ky 1 -subset i tuted l,2,3,4,5,6-hexahydroazep¼o[4, 5+b] indol es such as, for example: 3-propyl -6-methyl .-9-f J h droaze ino[4,5-b indole; 3-prop 1 -6^eth 1 -9-f 1 uoro-1,2, 3, 4, 5, 6- 2158 l,2,3>4,5,6-hexahydroazepino[4;5-b] indole; jj-ethyl -6- isopropyl - 7-methyl -l,2,3j4,5,6-hexahydroazepino[4,5-b] indole; 3-propyl - 6, 9-d i methyl -l,2,3r4,5,6-hexahydrbazep i no[4,5-b] i ndol e; propyl - 6- ethyl -9-methyl -l,2,3,4,5,6-hexahydroazepino[4,5-b] indol e; 3,6-d iethy 1 -9-methoxy-l,2,3* 4,5^6-hexahydroazep ino[4, 5-b] indol e ; 3-ethy 6- i sop ropy 1 -9-methoxy-l,2,3,4,5,6-hexahydroazep ino[4,5-b] indol e; 3, 6-d imethyl -7-chloro-l.,2,3, 4,5,6rhexahydroazep ino[4, -b] indol e ; 3-metbyl -6-propy 1 -7-chloro-l,2,3j ,5, 6-hexahydroazep i no-[4, 5-b] indole; 3-ethyl -6-methyl -7,8-dibromo-l,2,3.»4,5,6-hexahydro azep ino[4,5-b].(indol e; 3-ethy -6, 7- dimethyl -9-chloro-l,2,3,4,5,6-hexahydrpazep iho[4,5-b] indol e; 3* -d iethy 1 -7-methyl -9-chloro-l,2,3i4,5,6s-hexahydroazepino[4,5-b] indole; 3-methyl -6- isopropyl - 7- chloro-l,2,3>4,5,6-hexahydroazepino[4,5-b] indol e; and the l ike.

Claims

1. WHAT IS CLAIMED IS: ~l-< A l,2,3,4,5,6~hexahydrpazepin0^ ^^ indple of the/ atoms j incluilivgf and halogenj wherein R^ is alkyl containing from 1 to 3 carbon atoms, inclusive, and wherein ¾2 s selected from the group consisting of hydrpgen, methyl, ethyl, propyl, alkanoyl groups containing 1 to 3 carbon atoms, inclusive, benzyl and benzoyl, and the organic and inorganic acid addition salts of those compounds wherein -B^ is an amino moiety. -2- A compound according to Claim 1, herein R, B' and R^ are hydrpgen and R^ is methyl, so that the compound is 6-methyl-1 , 2, 3 ,4, 5 , 6-hexahydroazepino 4, 5¾67indple The hydrochloride of the compound of Claim 2. A compound according to Claim 1, wherein R,R' and R^are hydrpgen and Bg is benzoyl, so that the compound is 3-benzoyl-1,2,3,4,5, 6.-hexahydroazepino 4, 5-b7indole, r 215.8 -6- A compound according, to Claim 1 wherein R, R,' , Ri and R2 are hydrogen, so that t e comp -und 15 l,2,3>4,5,6-hexahydroazepi no [4,5-b] indole. -7- The hydrochloride of the compound of Claim 6. -8- The eye 1 ohexanesu 1 famate of the compound of Claim 6. -9- A compound according to Claim 1, wherein R, R' and i are hydrogen and R2 is formyl, so that the .compound is 3" formyl - 1,2, 3,4,5,6- hexahydroazep'i no[4,5-b] indole. -10- A compound according to Claim 1,, herein R, R1 and Ri are hydrogen and R2 is methyl, so that the compound is 3-methy 1- 1, 2, 3j , , 6- hexahydroazep i no[4, 5~b] indole. -11- A compound according to Claim, 1, wherein R and Ri are hydro-gen, R' is 9-methoxy, and R2 is benzoyl, so that the compound is 3-benzoy 1 -9-methoxy- l,2,3,4,5,6-hexahydroazepino[4,5-b] indole. -12- A compound according to Claim 1, wherein R and Ri are hydro-gen, R1 is 9-methoxy, and R2 i s benzyl , so that the compound is 3- benzyl -9- me thoxy- 1, 2,3,4,5,6- exahydroazep i no[4, 5-b] indole. -13- A Compound according to Claim 1, wherein R, Ri and R2 are hydrogen and R1 is 9-methoxy, as , hyd pch lor i de, so that the com-pound is 9"methoxyi 1,2,3,4, 5, 6- hexa;hydroazepjno[4,5-b] indole hydrochloride. -14- •V 2158 gen, R' is 8-methoxy, and R2 is benzoyl, so that the compound i s 3-benzoyl-8-methoxy-l,2,3,4,5,6-hexahydro¼zepino[4,5-b] indole. ,15- A compound according to Claim 1, wherein R and Ri are hydro-gen, R' is 8-methoxy, and R2 is benzyl, as hydrochloride, so that the compound is 3-benzyl- 8-methoxy- 1,2, 3, 4, 5, 6- hexahydroazep! no [4, 5-b] i ndole hydrochloride. -16- A compound according to Claim 1, wherein R and Ri are hydro-gen, R' is 10-methoxy, and R2 is benzoyl, so that the compound is 3-benzoyl -10-methoxy-l,2,3,4,5,6-hexahydroazepi no[4,5-b] indole. -17- A compound according to Claim 1, wherein R and Ri are hydro-gen, R.1 is 10-methoxy, and R2 is benzyl, so that the compound is 3-benzyI-10-meth0xy-l,2,3-, ,5,6-hexahydroazepino[4,5-b] indole. -18- A compound according to Claim 1, wherein R, Ri and R2 are hydrogen, and R1 is 10-methoxy, as hydrochloride, so that the compound is 10-methoxy- 1, 2,3, 4, 5, 6- hexahydroazep i no[4 , 5~b ] i ndo le hydrochloride. -19- A compound according to Claim 1, here in R and Ri are hydro-gen, R1 is 7_methoxy, and R2 is benzoyl, so that the compound is 3" benzoyl met hoxy- 1,2,3,4, 5, 6- hexahydroazep i no [4, 5-b] i ndol e . -20- A compound according to Claim 1, wherein R and Rj. are hydro-gen, R' is 7-methoxy, and R2 is benzyl', as hydrochloride, so that the compound is 3-benzyl-7-methoxy-l,2,3,4,5,6-hexahydroazepino [4, 5-b] i ndole hydrochloride. -21- compound is 7-methqxy÷l,2,3,4,5,6-hexabydroaz:epi no[4,5-b] indole hydrochloride. -22- A compound accosrding to Claim 1, wherein ;R and Ri are hydro gen, R1 is 9-fluoro, and R2 is benzoyl, so that the compound is 3- benzoy 1 -9 - f 1 uo o-l, 2, 3 , , 6- hexahydroazep i no[ , " b ] i ndo 1 e . -23- A compound according to Claim 1, wherein R and Ri are hydro gen, R1 is 9- f 1 uoro, and Ra is benzyl, so t'hat the compound is 3-benzyl-9-f 1uoro-l,2,3^i5i6-hexahydroazepi no[4,5-b] indole. -24- A compound according to Claim 1, wherein R, Ri, and R2 are hydrogen, and R' is 9-fluoro^ so that the compound is 9-fluoro-1,2,3,4,5,6- hexahydroazepi no[4, -b] indole. -25- A compound according to Claim 1, wherein R and Ri are hydro gen, R1 is 7-methyl, and R2 is benzoyl, so that the compound is 3- benzoy 1-7-me thy 1-1, 2, 3, 4, 5, 6- hexahydroazepi no[4,5-b] indole. -26- A compound according to Claim 1, wherein R and Ri are hydro gen, R1 is 7"methyl and R2 is benzyl, as hydrochloride, so that the compound i s 3-benzyl-7_methyl-l, 2,3*^5, - hexahydroazepi no [4, 5-b] indole hydrochloride. -27- A compound according to Claim 1, wherein R, Ri and R2 are hydrogen, and R1 is 7-methyl, as hydrQch lor ide, so that the com-pound is 7-methyl-l, 2, 3,4,5, 6- hexahydroazepi no[4, -b] indole hydrochloride. -28- A compound according to Claim 1, wherein R and x are hydro 3-benzoy 1-9-methy 1- 1,2,3, 4,5, 6-hexahydroazepi nof^^S-b] ' ndole. -29- A compound according to Claim 1 wherein R and Ri are hydro- gen, R1 is 9_methyl and R2 is benzyl, . so that the compound is 3-ben?y 1 -9-methy 1 - 1,2,3^ , , 6- hexahydroazepi no[4, -b] i ndole . -30- A compound according to Claim 1, wherein R, Ri and R2 are /hydrogen, and ,R' is 9-methyl, so that the compound is 9-methyl- 1,2,3, , ,6-Ιιβ 3ΐ^Γθ3ζβρίηο[4, -^ indole. v, -31- A compound according to Claim 1, wherein R, R' and R2 are hydrogen, Ri is ethyl, as hydrochloride, so that the compound is 6-ethy 1-1, 2,3j, i5j6-hexahydroazepino[4,5-b] indole hydrochlor- ide. ' -32- A compound accordi r»g . to Claim 1, wherein R and R2 are hydro- gen, R' is 9-methoxy and Ri is methyl, as. hydroch lor i de, so that the compound i s 6-methy l -9-methoxy- 1,2,3,4,5, 6-hexahydroazepi no [4, ~b indole, hydrochloride. -33- A compound according to Claim 1, wherein R and R1 are hydro- gen, and Ri and R2 are benzyl, so that the compound is 3,6-. dibenzyl-1, 2,3,4,5,6-hexahydroazepino[4,5-tb] indole. -34- A compound according to Claim 1, wherein R and are hydro- gen, Ri is methyl and R2 is formyl, ,so that the compound is 3- f ormy 1 - 6-met hy 1-1,2,3,4,5,6- hexahyd roazep i r>o[4 , - b ] i ndol e . -35- . A compound according to Claim 1, wherein R and R' are hydro- gen and Rx and R2 are methyl, so that the compound is 3,6-di- 36· A compound according to Claim 1, wherein R is hydrogen, "I R is 10-methody, R^ is methyl and R^ is benzoyl, so that the compound is 3-benzoyl-6-methyl-10-methoxy-l,2,3,Ut5»6-hexahydroazepino^/^T, 5-b7indole. 37· A compound according to Claim 1, wherein R is hydrogen, R* is 10-methoxy, ^ is methyl and R^ s benzyl, so that the compound is 3-benzfl-6-methyl-10-methoxy-l,2,3, ,5,6-hexahydroazepino^T,5-h¾iiidole. 38. A compound, according to Claim 1, wherein R and R^ are hydrogen, R* is 10-methoxy and R^ is methyl, as hydrochloride, so that the compound is 6-methyl- 10-methoxy- 1,2, 3,^» 5, 6-hexahydroazBpino.^*,5-b7indole hyd ochloride. 39· A process for the production of a compound of the formula : 2158 wherein ψ is phenyl and wherein R and R' are selected from the group consisting of hydrogen, a lkoxy and alkyl containing from 1 to 5 carbon atoms, inclusive, and halogen, which comprises: heating a phenyl hydraz i ne of formula I: R I wherein R and R' have the significance of above with 1-benzoyl hexahydro-4H-azepi n-<4-one to obtain the corresponding phenyl-hydrazone of 1-benzoyl hexahydro-4H-azepi n-4-one of formula II: I I wherein R, R' and φ have the same significance as above; and heating this compound with formic acid to obtain the correspond- ing 3"benzoyl-l,2,5i4,5,6-hexahydroazepi no[4,5Tb] indole of formula I I I above. -i — o- .39 A process according to Claim 4 , wherein the end product I I I is reduced with a metal hydride to give the corresponding 3-benzyl-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole of the formula IV: V wherein azepi n-4-one to obtain the corresponding phenylhydra-zone of 1-benzo 1 hexahydro-4H-azepi n-4-one of formula I I: I I wherein R, R1 and have the same significance as above; heating this compound with formic acid to obtain the corresponding 3" benzoyl-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole I II; treating compound I I I with a metal hydride to obtain the corresponding 3- benzyl-l,2,3i4,5,6-hexahydroazepino[4,5-b] indole IV; hydrogen-olyzing IV in the presence of a catalyst to obtain the compound v.- 2158 -42- / The process of Claim 4^' wherein the hyd rogenol ys i s catalyst is palladium suspended on carbon, A process according to Claim Itrf for the production of a compound of formula VI : wherein R and R! are selected from the group consisting of hydrogen, alkoxy and alkyl containing from 1 to 3 carbon atoms, inclusive, and halogen; and wherein R11 1 is selected from the group consisting of hydrogen, methyl, ethyl and phenyl which comprises: heating a phenylhydrazine of formula I; wherein R and R1 have the significance of above with 1-benzoyl hexahydro-4H-azep i n-4-one to obtain the corresponding phenyl-hydrazone of 1-benzoyl hexahydro-4H-azep i n-4- one of formula I I: I I wherein R, R' and <$ have the same significance as above; heating 28 benzoy 1-1,2, , , 5, 6-hexahydroazepi no[ ,5-b] indole I I I ; treating 29 compound M l with a metal hydride to obtain the correspondi g 5_ 50 benzy 1-1,2,5,4,5,6-hexahydroazepi no[4,5-b] indole I ; hydrogenoly- 51 ¾ing IV in the presence of a noble metal catalyst, to obtain the 52 corresponding 1,2,3,4,5,6-hexahydrpazepi no[4,5-b] indole (V) ; and 55 acylating the compound V with an acylating reagent selected from 34 the group consisting of benzoic anhydri de,acet ic anhydride, ace35 tic anhydride and formic acid, propionic anhydride, and acetyl, 36 propionyl and benzoyl chlorides and bromides, to obtain the com57 pound of formula VI. •f>t- -hh- 1 A process for the production of 3-aikyl- 1,2,3*4, 5, 6' hexa- 2 hydroazepi no[ ,5-b] i ndole of formula VII: drogroup es: l- : 2158 wherein R and R' have the same signi icance as above and wherein φ is phenyl; heating II with formic acid to obtain the corre- sponding 3-benzoy 1 - 1, ,3* , , 6- hexahydroazep i no[4 , -bj i ndole III ; reducing the compound I'll with a metal hydride to obtain the 3~ benzyl-l,2,3j4,5,6-hexahydroazepino[4,5-b] indole IV; hydrogen- olyzing IV in the presence of a noble metal catalyst, to obtain the corresponding l,2,3,4,5,6-hexahydroazepino[4,5-b] indole (V); and acylating the compound V with an acylating reagent selected from the group consisting of benzoic anhydride, acetic anhydride, acetic anhydride and formic acid, propionic anhydride, acetyl, propionyl and benzoyl chlorides and bromides, to obtain the corresponding 3-acyl-l, 2, 3^*5, 6- hexahydroazep i no[4,5-b] indole VI and reducing VI . with a metal hydride to obtain the compound VI I above. -45- A process f o r the production of a 6- alkyl-l,2,3,^5,6-hexahydroazepino[4,5-b] indole (VI M): wherein R and R' are selected from the group consisting of hydrogen, alkoxy and alkyl containing from 1 to 3 carbon atoms, 2158 group consisting of alkyl containing from 1 to 5 carbon atoms, inclusive, a«-d-fe«-p«-y4, which comprises: alkylating a compound of formula V: wherein R and R1 are defined as above, with a reagent selected from the group consisting of alkyl bromides and iodides in which the alkyl group has from 1 to 5 carbon atoms, inclusive, and benzyl chloride and bromide, in the presence of a base, to obtain the compound VI I I above. -0- -46- A process aeee^+ ^— te— C4-a4m-49-for the production of ' 3-acy1-6-al kyl-l:,2,5,4,5,6-hexahydroazepi no[4,5-b] indole of the formula IX ; IX wherein R and Rl are selected from the group consisting of hydrogen, alkoxy and alkyl containing from 1 to 5 carbon atoms, in' clusive, and halogen, wherein R is selected from the group consisting of alkyl containing from 1 to 5 carbon atoms, inclusive, a«d-b©psyJ and wherein R1 ' ' is selected from the group consisting of hydrogen, methyl, ethyl, and phenyl, which comprises: treating a 1, 2,5* , 5, 6- hexahyd roazep i nb 4, 5~b] i ndol e of the formula V : 2158 wherein R and R1 are defined as above, with a reagent selected from the group consisting of alkyl bromides and iodides in which the alkyl group has from 1 to 3 carbon atoms, inclusive, and benzyl chloride. and bromide in the presence of a base to obtain the correspond! ng 6-al kyl- 1,2,3* * 5, 6-hexahydroazepi no[4,5-b] indole (VI M); and acylati ng the compound VI II with an acylati ng reagent selected from the group consisting of benzoic anhydride, acetic anhydride, acetic anhydride and formic acid, propionic. anhydride, acetyl, propionyl and benzoyl chlorides, and bromides, to obtain the product of compound IX above. -66- -*7- A process ¾¾¾¾frsl-i-EK)- -to- J-aJ-ca. ik¾. for the production of a 3*6-dialkyl-1, 2, 3*4, *6-hexahydroazepino[4,5"b] indole of the formula X: wherein R and R' are selected from the group consisting of hydrogen, alkoxy and alkyl containing from 1 to carbon atoms, inclusive, and halogen; wherein R1 ' is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms, inclusive, aR -be.azy.I;- and where i n R' 111 i s selected from the group 2158 alkylating a compound of formula V: wherein R and R' are defined as above with a reagent selected from the group consisting of alkyl bromides and iodides in which the alkyl group has from 1 to carbon atoms, inclusive, and benzyl chloride and bromide in the presence of a base to obtain the corresponding 6-alkyl-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole (VI I I); acylating the compound VI I I with an acylating reagent selected from the group consisting of benzoic anhydride^ acetic anhydride, acetic anhydride and formic acid, propionic anhydride, acetyl, propionyl and benzoyl chlorides and bromides to obtain the corresponding 3-acyl-6-al kyl-1, 2, 3, ^, , 6-hexahydro azepi no[4,5-b] indole IX; and treating IX with a metal hydride to obtain the compound X above. -00- -48- A process for the production of a 6-alkyl-l, 2,3*^5,6-hexahydroazepi no[ ,5-b] indole of the formula VI M: wherein R and R' are selected from the group consisting of hydros gen, alkoxy and alkyl containing from 1 to 3 carbon atoms, i n-elusive, and halogen, wherein R1' is selected from the group consisting of alkyl containing from 1 to carbon atoms, inclu- wherein R and R* are defined as above, and signifies phenyl, with an agent selected from the group consisting of alkyl bro-mides and iodides in which the alkyl group has from 1 to 3 carbon atoms, inclusive, and benzyl chloride and bromide, in the presence of a base, to obtain the corresponding 3-benzoy 1-6-al kyl 1,2,3, ,5,6-hexahydroazepi no[ j5-b] indole; treating this com-pound with a metal hydride to obtain the corresponding 3-benzyl-6-al kyl-l,2,3,4,5,6-hexahydroazepi no[4,5-b] indole; and hydrogen-olyzing this compound in the presence of a noble metal catalyst to obtain compound VIII of above. -ffl- -49- 48 The process of Claim J^, wherein the compound of formula I I I is 3-benzoyl-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole; the alkylating reagent is methyl iodide, the metal hydride used is ... lithium aluminum hydride and the catalyst i s pal lad i urn- on- carbon and the end product is, therefore, 6-methyl - 1,2,3,4,5,6- hexa-hydroazepi no[4,5~b] indole. D 'JTD THIS 10th day of April, 196? COHtVJS ΖΕΏΕΚ & SPISBACH" : . ' .P.O.BOX 1169, TEL-AVIV Attorneys for Applicants