CH506543A - Process for the preparation of new 1,2,3,4,5,6-hexahydroazepino (4,5-b) indoles - Google Patents

Description

  

  
 



     Process for the preparation of new 1,2,3,4,5,6-IIexahydroazepino (4,5-b) indoles
The present invention relates to a process for the preparation of new 1,2,3,4,5,6-Hexahiy droazepino (4,5-b) indoles and their acid addition salts.



   The new compounds have the following formula:
EMI1.1
 wherein R and R 'are hydrogen, an alkoxy or alkyl group with 1-3 C atoms or halogen.



   The process according to the invention is characterized in that a phenylhydrazine of the formula
EMI1.2
 while heating with 1-benzoyihexahydro-4H-azepin-4-one to the corresponding phenylhydrazone of the l-benzoylhexahydro-4H-azepin-4-one of the formula
EMI1.3
 wherein a phenyl group is reacted and then, by heating the compound thus obtained with formic acid, the 3-benzoyl-1,2,3,4,5,6hexahydroaepin (4,5-b) indole of the formula
EMI1.4
 wins the compound of formula III by reduction with a metal hydride into the corresponding 3-benzyl-1,2,3,4,5,6hexahydroazepine (4,5-b) indole of the formula
EMI1.5
 transferred and the compound obtained in this way hydrogenated in the presence of a catalyst.



   The alkyl groups with 1 to 3 carbon atoms are methyl, ethyl, propyl or isopropyl groups; Alkoxy groups are methoxy, ethoxy, propoxy or isopropoxy groups.



   The compounds of the formula V obtainable according to the invention can be used to make compounds of the formula
EMI2.1
 as well as their acid addition salts. In the formula VII given above, R and R 'have the meanings already given and R "is an alkyl group with 1-3 carbon atoms or the benzyl group. The new compounds of the formula VII can be prepared by adding a compound of the formula V with corresponding alkyl bromides or iodides or with benzyl chloride or bromide in the presence of a base, preferably sodium hydride.The compounds of the formula VII can often be isolated as the hydrochloride, hydrobromide or hydroiodide.



   The compounds of formula V obtainable according to the invention and also the compounds of formula VII can be converted into their corresponding acid addition salts, e.g. B. in -the hydrochlorides, hydrobromides, hydroiodides, perchlorates, fluosiiicate, thiocyanates, sulfates, cyclohexanesulfamates, acetates, propionates, laurates, palmitates, maleates, tartrates, lactates, citrates, oxalates, trifluoroacetates, chloroacetates u. Ä.



   It is also possible to convert the new compounds of the formula V to compounds of the formula
EMI2.2
 to acylate. In these compounds, R and R 'have the meaning given above and R'R "' is hydrogen or an alkyl group with 1-2 C atoms or phenyl. Benzoic anhydride, acetic anhydride, acetic anhydride and formic acid, propionic anhydride, acetyl in particular are used as acylating agents , Propionyl or benzoyl chloride or bromide.



   The compounds of the formulas II and III are valuable intermediates for the preparation of the active compounds of the formulas V and VII which have an amino group in the 3-position. The new amino compounds of the formulas V and VII, as well as the compounds of the formula VI, are active tranquilizers (Ataractica) and sedatives and act as antidepressants and appetite suppressants. At a dose of 1 to 3 mg / kg 1,2,3,4,5,6-hexahydroazepino (4,5-b] indole, the cats lost interest in the mice that were in the cages together, and the cats hissed and no longer attacked other cats they came into contact with.

  Anti-aggressive behavior was also shown in rats and mice that were under the influence of 9-methoxy-HHAI **), 6-methyl HHAI and unsubstituted HHAI, which were administered in the form of hydrochlorides. Antiag ** For 1,2,3,4,5,6-hexahydroazepino (4,5-b) indole, the abbreviation HHAI is used in the following for the sake of simplicity and greater clarity.



  Gressive behavior was also noted in mice treated with 7-, 8- and 10-methoxy-HHAI hydrochlorides, 9-fluoro-HHAI, 7-methyl-HHAI hydrochloride and with 9-methyl-HHAI. Optionally, the amino compounds can be used as pharmacologically acceptable acid addition salts, such as. B. hydrochlorides, cyclohexanesulfamates, maleates, tartrates, citrates and the like. Ä. Supplied. Because of their calming effect, these compounds are suitable for administration to animals that are by ship, train, truck or the like or zoo animals on long journeys in amounts between 3 and 4 mg / kg body weight, so the animals are calmer and the Loss of valuable animals, which occurs as a result of overexcitation and fighting among the captured animals, is reduced.



  These amino compounds are also of great importance for the treatment of obesity and agitation in humans. The new amino compounds of the formulas V and VIII can be administered to mammals, birds and humans both orally and parenterally in order to achieve the stated pharmacological effects. Dosage forms such as tablets, capsules, powders, granules, syrups, elixirs and the like are particularly suitable for oral administration. Ä. Containing appropriate amounts of the active agent. In tablets, commonly used pharmaceutical carrier materials such as starch, lactose, kaolin, dicalcium phosphate and the like are also used. Ä .; Powders can be filled into gelatin capsules, with or without other fillers such as methyl celium, magnesium stearate, calcium stearate, talc and the like. Ä.



  For liquid dosage forms, the compounds can be dissolved or suspended in aqueous alcoholic carriers, with buffering agents or flavorings also being able to be added if necessary.



     Acid addition salts of the amino compounds of the formulas V and VIII, which as such are unsuitable for therapy, are suitable for various other purposes. So form z. B. the fluosilicates of these compounds moth repellants of the type described in US Pat. No. 1,915,334 and US Pat. No. 2,075,359. The thiocyanic acid addition salts of the same compounds can form resinous polymers after condensation with formaldehyde (cf. USA- Patents 2,425,320 and 2,606,155), which are useful as etch inhibitors.



  The addition salts of the amino compounds of the formulas V and VIII with trichloroacetic acid are herbicides which are effective, for example, against Johnson grass (Sorghum halepense), yellow foxtail grass, green foxtail grass, Bermuda grass and field mercury.

 

   The starting compounds (I) for the process according to the invention are known phenylhydrazines.



  The 1-benzoylhexahydro-4H-azepin-4-one is usually prepared as indicated in the preparation below. To carry out the inventive method, for. B. the selected phenylhydrazine of the formula I with 1-benzoylhexahydro4H-azepin-4-one in a solvent such as ethanol, benzene, toluene and the like. Ä. Heated to reflux. According to a preferred embodiment of the process according to the invention, an acid catalyst such as acetic acid is also used in an amount of 0.25 to 1.58 / o, calculated on the amount of solvent, in order to achieve higher yields. The total duration of the reaction can range from half an hour to four hours at the reflux temperature of the solvent. After the reaction has ended, the product can be used in a customary and known manner, e.g. B.



  by crystallization, filtration, extraction and the like ä can be isolated.



   The 1-benzoylhexahydro-4H-azepin-4-one-phenylhydrazone (II) obtained in this way is then usually heated with 88 to 995 / above formic acid, generally for about 10 minutes to two hours; in this way crude 3-benzoylFHHAI (III) is obtained, which can be isolated and purified in the usual way, e.g. B. by pouring the reaction mixture into ice water, filtering off and recrystallizing the solid substance and chromatographing or extracting the product to obtain the pure 3-benzoyl-HHAI (III).



   The 3-benzoyl-HHAI obtained in this way is reduced with a metal hydride, preferably lithium aluminum hydride in tetrahydrofuran solution. The reaction is generally carried out initially under nitrogen; the reaction time is usually half an hour to 8 hours at about room temperature; H. about 20 to 30 ° C. In the initial phase, higher or lower temperatures can also be used. The temperature is then generally increased to the reflux temperature of the mixture; the mixture can then be held at this temperature for 6 to 24 hours.

  The desired end products are usually obtained by decomposing the reaction mixture after cooling with water and a base such as sodium hydroxide or potassium hydroxide and filtering the solution. The desired 3 BenzylrHHAI is obtained in particular by concentrating the filtrate. (IV).



   The removal of the benzyl group from the 3-benzyl-HHAI is achieved by hydrogenation in the presence of a catalyst, e.g. B. a palladium or platinum catalyst (5 to 100 / o platinum or palladium on carbon as a support material). The hydrogenation can be carried out at a hydrogen pressure between 0.7 and 5.3 kg / cm2 and is generally completed in 1 to 8 hours at room temperature. After the reaction has ended, the catalyst is usually filtered off, the filtrate is concentrated and the crude product is conventionally removed, e.g. B. by recrystallization, salt formation and treatment of the salt with a base u. cleaned.



   The HHAI (V) obtained in this way can be acylated with an acid anhydride such as benzoic anhydride, acetic anhydride, propionic anhydride or - in the case of the preparation of 3-formyl-HHAI - with formic anhydride (formed in situ from 980% formic acid and acetic anhydride) at room temperature. Instead of acid anhydrides, acyl chlorides or acyl bromides can also be used, e.g. B. acetyl chloride, propionyl chloride, benzoyl chloride or the corresponding bromides. The acylation can be carried out at temperatures between 0 and 35 ° C. and usually takes about 6 to 48 hours.



  After the reaction has ended, the mixtures are generally poured into water, and the solid substances are filtered off and purified, usually by recrystallization or chromatography; in this way one can obtain the desired 3-acyl-HHAI (VI).



   As will be readily apparent to those skilled in the art, many of the various indicated reactions can be interchanged; H. the conversions do not have to be carried out in the specified order. For example, an HHAI (V) can first be alkylated in the 6-position, so that a compound of the formula VIII is obtained and then acylated in the 3-position.



   Preparation: 1-Benzoylhexahydro-4H-azepin-4-one
A. 1-Benzoylhexamethyleneimine (1 -B enzoylhexahydro-4H-azepine)
60 ml of benzoyl chloride in 200 ml of Skellysolve B hexanes were added with stirring to a cooled (ice bath) solution of 200 mol of hexamethyleneimine in 800 ml of Skellysolve B hexanes. This mixture was then washed several times with 1N hydrochloric acid and with water and then filtered through anhydrous sodium sulfate. After evaporation of the SkellysolveB hexanes and distillation of the oily residue, 40.5 g of 1-benzoylhexamethyleneimine with a boiling point of 150-160 C / 1 Torr were present.



   Analysis for Cl3Ht, NO:
Calculated: N 6.89
Found: N 6.54
B. Fermentation of 1-Benzoyihexamethyleneimine
A fermentation medium was first prepared from 200 g of corn plasticizer (60 / o solids content), 100 g of commercially available dextrose and 10 l of tap water.



  The pH of the medium was adjusted to 4.8-5; in addition, 10 ml of pork oil was added as a tree preventive agent. This medium was sterilized and then inoculated with a 72 hour old vegetative strain of Sporotrichumsulfurescens, ATCC 7159, and incubated for 24 hours at about 280 ° C. and an aeration rate of 0.5 liters per minute and a stirring speed of 300 rpm; then 2 g of 1-benzoylhexamethyleneimine, which was dissolved in the smallest possible amount of acetone (about 20 ml), were added to the base. After a further 72 hours of incubation at the same temperature and ventilation rate, the fermentation broth and mycelium were separated by filtration. The mycelium was washed with water; the wash water was added to the fermentation broth filtrate.

 

  The expanded filtrate obtained in this way was extracted four times with an amount of methylene chloride corresponding to about a quarter of the amount of the filtrate. The combined extracts were washed with a quarter of their volume of distilled water; the solvent was then distilled off so that a residue remained.



   The residue obtained in this way was chromatographed over Florisil and eluted with Skellysolve B (technical hexanes), which contained increasing amounts of acetone. About 250 mg of 1 benzoylhexahydro-4H-azepin-4-one could be obtained from the 25 / o acetone 750/0 Skellysolve B eluate; 1 benzoyl-4-hydrohexahydro-4H-azepine (determined by thin layer chromatography) could be obtained from the acetone product.



   C. Oxidation of 1-Benzoyl
4-hydroxyhexahydro-4H-azepine
The 1 -B-enzoyl-4-hydroxyhexahydro-4H-azepine obtained as described above is dissolved in acetone and treated at room temperature by adding a visible excess of Jones reagent (2.67 m chromic acid reagent, prepared from 26.7 g of chromium trioxide and 23 ml of sulfuric acid and diluted to 100 ml with water) oxylated. The excess oxidizing agent is destroyed by adding isopropyl alcohol; then the mixture is evaporated to dryness. 20 ml of water are added to the residue and the product thus obtained is extracted with 20 ml of methylene chloride. The extract is evaporated to dryness.

  The 1 -Bezoylhexahydro-4H-azepin-4-one obtained as a residue in this way was combined directly with the same product which had been obtained in the bioconversion. The combined products were chromatographed on a Florisil column (anhydrous magnesium silicate). The column was eluted with Skellysolve B, which contained increasing amounts of acetone; the fractions containing the desired product (determined by thin layer chromatography) were combined and evaporated to dryness. In this way, 770 mg of 1-benzoylhexahydro-4H-azepin-4-one were obtained in the form of an oil with a boiling point of 170-174 C / 0.3 Torr, which slowly crystallized.



   Analysis for C15Ht5NO2:
Calculated: C 71.86 H 6.96 N 6.45
Found: C 71.51 H 7.25 N 6.46
example 1
Phenylhydrazone of 1-benzoylhexahydro
4H-azepin-4-one
A mixture of 20 g (0.092 mol) of 1-benzoylhexahydro-4H-azepin4-one, 10.5 g of phenylhydrazine (0.097 mol). 200 ml of absolute ethanol and 1.5 ml of acetic acid were refluxed for one hour and then cooled in an ice bath. The crystals then formed were filtered off, washed with ethanol and dried; in this way 20.8 g (740 / of the compound mentioned in the title with F .: 185-190 C.



   Example 2 p-Methoxyphenylhydrazone of 1-Benzoylhexahydro-4H-azepin-4-one
A solution of 120.1 g (0.869 mol) of p-methoxyphenylhydrazine, 172.0 g (0.792 mol) of l-benzoylhexahlydro-4H-azepin-4-one and 12.9 ml of glacial acetic acid in 1725 ml of absolute ethanol was under a nitrogen atmosphere Heated at reflux for an hour. The reaction mixture was cooled and concentrated under reduced pressure. The product which had crystallized out was filtered off from the solution, washed with ethanol and dried; 108.9 g of the compound mentioned in the title with F .: 155.5-166.5 "C were obtained in this way. A second yield could be obtained by concentrating the mother liquors; this second yield was 32.9 g; the total yield was 530/0.



   Example 3 m-Methoxyphenylhydrazone of 1 -Benzoylhexahydro-4H-azepin-4-one
62.7 g (0.360 mol) of m-methoxyphenylhydrazine hydrochloride were added to 300 ml of a 3N aqueous sodium hydroxide solution and 300 ml of ether. This mixture was stirred until the material went into solution; then the ether layer was separated and the aqueous layer extracted with further ether. The ether layer and the extracts were washed with brine, dried over anhydrous potassium carbonate} and concentrated under reduced pressure at about 250 ° C .; in this way a residue was obtained.



  A solution of 1-benzoylhexahydro-4Hazepin-4-one (65 g; 0.3 mol) in 300 ml of ethanol and 5 ml of acetic acid was added to a solution of the residue in 500 ml of ethanol. The resulting solution was refluxed under nitrogen for one hour and then concentrated under reduced pressure. The product which crystallized out of the partially concentrated reaction mixture was filtered off, washed with ethanol and dried; in this way 54.2 g (44.70 / o) of the compound mentioned in the title with F .: 153-1590 C.



   Example 4 o-Methoxyphenylhydrazone of 1-Benzoylhexahydro-4H-azepin-4-one
62.7 g (0.360 mol) of o-methoxyphenylhydrazine hydrochloride were added to a mixture of 300 ml of 3N aqueous sodium hydroxide and 300 ml of Safe with stirring. Once solution had entered, the aqueous layer was saturated with sodium chloride, separated from the ether layer, and extracted with ether.



  The ether layer and the extracts were combined and washed with brine, dried over potassium carbonate and concentrated under reduced pressure at 25 C; in this way a residue was obtained. The residue was dissolved in 500 ml of ether and added to a solution of 65 g (0.300 mol) of 1-benzoylhexahydro-4H-azepin-4-one in 300 ml of ethanol and 5 ml of acetic acid. The mixture was refluxed for one hour and then concentrated under reduced pressure. The residue obtained in this way was recrystallized from ethanol: a total of 34.3 g of the compound mentioned in the title with F .: 145-1540 C were then present.



   Example 5 p-Fluorophenylhydrazone of 1-Benzoylhexahydro-4H-azepin-4-one
58.3 g (0.360 mol) of p-fluorophenyl hydrazine hydrochloride were added to a solution of 300 ml of 3N sodium hydroxide and 300 ml of ether with stirring. Once solution had entered, the aqueous layer was extracted with ether. The ether layer and the extracts were combined, washed with brine, dried over anhydrous potassium carbonate and concentrated in vacuo (at about 25 ° C.). The residue thus obtained was dissolved in 500 ml of ethanol. solved; this solution was added to a solution of 65 g (0.3 mol) of 1-benzoylhexahydro-4H-azepin-4-one in 300 ml of ethanol and 50 ml of acetic acid.

  The solution thus obtained was refluxed for one hour in a nitrogen atmosphere and then concentrated under reduced pressure. The product, which crystallized from the concentrated mixture, was filtered off, washed with ethanol and dried; in this way, 32.7 g (33.3 / n) of the compound mentioned in the title with F .: 150-162 C.



   Example 6 o-Tolylhydrazone of 1-Benzoylhexahydro-4H-azepin-4-one
79.3 g (0.5 mol) of o-tolylhydrazine hydrochloride were added to a solution of 400 ml of 3N sodium hydroxide and 400 ml of ether, with stirring. As soon as solution had occurred, the aqueous layer was saturated with sodium chloride, separated from the Sither layer and extracted with ether. The ether layer and the extracts were combined, washed with brine, dried over anhydrous potassium carbonate and concentrated under reduced pressure at 25 ° C.

  The residue obtained in this way was dissolved in 700 ml of ethanol and mixed with a solution of 108.6 g (0.5 mol) of 1-benzoylhexahydro-4H-azepin-4-one in 400 ml of ethanol and 6.95 ml of acetic acid. The solution thus obtained was refluxed for one hour in a nitrogen atmosphere and then concentrated under reduced pressure. The residue obtained in this way was recrystallized from ethanol; 29.7 g of the compound mentioned in the title with F .: 135-141 C. were obtained. A further yield of 4.85 g could be obtained, so that the total yield was 21.5 / o.



   Example 7 p-Tolylhydrazone of 1 -Benzoylhexahydro-4H-azepin-4-one
In the manner described in Example 6, a freshly prepared ethanol solution of p-tolylhydrazine (from 58.5 g of p-tolylhydrazine hydrochloride) was reacted in the presence of acetic acid with 160 g of 1-benzoylhexahydro-4H-azepin-4-one in ethanol solution; 26.9 g of the compound mentioned in the title with F .: 145-155 C could be obtained in two yields.



   Example 8 p-Sithylphenylhydrazone of 1-Benzoylhexahydro-4H-azepin-4-one
In the manner described in Example 1, l-benzoylhexahydro-4H-azepin-4-one was heated with p-ethylphenylhydrazine in absolute ethanol in the presence of acetic acid; in this way the compound mentioned in the title was obtained.



   Example 9 p-Propoxyphenylhydrazone of i -Benzoylihexahydro-4H-azepin-4-one
In the manner described in Example 1, p-propoxyphenylhydrazine was heated with 1-benzoylhexahydro-4Hazepin-4-one in absolute ethanol in the presence of acetic acid; in this way the compound mentioned in the title was obtained.



   Example 10 () -chlorophenylhydrazone of 1-benzoylhexahydro-4-azepin-4-one
In the manner described in Example 1, o-chlorophenylhydrazine was reacted with 1-benzoylhexahydro-4H azepin-4-one in absolute ethanol in the presence of acetic acid; in this way the compound o-chlorophenylhydrazone of 1-benzoylhexahydro-4H-azepin-4-one was obtained.



   In the manner described in Example 1, other substituted phenylhydrazones of 1-benzoylhexahydro-4H-azepin-4-one can be prepared by adding a correspondingly substituted phenylhydrazine with 1-benzoylhexahydro-4H-azepin-4-one, which is dissolved in ethanol , in the presence of acetic acid. Typical compounds which can be obtained in this way are: m- or o-ethyl, p- or o- or m-ethoxy, p-isopropoxy, o-propoxy, 3,4-dichloro, 2,3 difluoro -, 2,3-dibromo, 3,4-dimethyl, 2,3-dimethyl, 2,3-diethoxy, 2-ethoxy-3-fluoro, 2-bromo-4-propoxy, 2- Methyl 4-chlorophenyl hydrazone and the like; Ä. of 1-Benzoylhexahydro-4H-azepin-4-one.



   Example 11
3-benzoyl HHAI
A mixture of 5 g (16.3 mol) of phenylhydrazone of 1-benzoylhexahydro-4H-azepin-4-one * and 35 ml of 970 / above formic acid was heated on a steam bath in a nitrogen atmosphere for 20 minutes. It was then poured into ice water, a dark brown solid substance forming which was filtered off, washed with water and dried in vacuo; A yield of 4.5 g of crude product was then obtained. This material was chromatographed over 300 g of silica gel with mixtures containing 15-30 / o acetone with the remainder cyclohexane. The product thus obtained was evaporated and recrystallized from methanol-water.



  This gave 1.9 g (40%) of the compound mentioned in the title with F .: 169-170 C.



   Analysis for Ct9Ht8N2O:
Calculated: 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-HHAI
3.37 g (0.010 mol) of p-methoxyphenylhydrazone from BHHAO were added to a solution of 100 ml of 3N hydrogen chloride in absolute ethanol.



  This mixture was heated over a steam bath for 7 minutes and then poured into ice water.



  The solid substance was collected by filtration, washed with water and dissolved in methylene chloride. The methylene chloride solution was dried over anhydrous magnesium sulfate, concentrated to 10 ml and poured over a column containing 250 g of neutral aluminum oxide. The column was eluted with 80% ethyl acetate-200/0 Skellysolve B; the product thus obtained was recrystallized from ethyl acetate.

 

  A yield of 0.3 g (9.37 / o) of the compound mentioned in the title with F .: 129.5-133 C (dec.) Was obtained.



   Example 13 3-Benzoyl-8-methoxy-HHAI (13) and
3-benzoyl-10-methoxy-HHAI
A mixture of 43.9 g (0.130 mol) of m-methoxyphenylhydrazone from BHHAO and 195 ml of 880% formic acid was heated in a nitrogen atmosphere over a steam bath for 30 minutes. It was then cooled and poured into ice water. The mixture thus obtained was extracted with chloroform. The Chlo * for the verb. L-Benzoylhexahydro-4H-azepin-4-one is used in the following the abbreviation BHHAO.



  Form extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue obtained in this way was chromatographed over 2.2 kg of silica gel with a mixture containing 60% ethyl acetate - 400/0 cyclohexane. 25 fractions were collected. The first band obtained from fractions 8-11 was recrystallized from methylene chloride-ethyl acetate. In this way, 2.66 g of compound (14) with F .: 263.5-267 C. A second crop of this material with 0.185 g (total yield 6.82 / o) could be obtained. After recrystallization from methylene chloride-methanol, the product gave the pure compound mentioned in the title with F .: 264.5-266.5 C.



   Analysis for C2oH2oN202
Calculated: 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 recrystallized from methylene chloride-ethyl acetate; 5.86 g of the compound mentioned in the title with F .: 201.5-203 C. were obtained in this way. A second fraction of 3.98 g of the same material was also obtained. Recrystallization of the product from methylene chloride-methanol gave the pure compound with F .: 202-203.5 C.



   Analysis for C20H20N2O2:
Calculated: C 74.97 H 6.29 N 8.74
Found: C 74.77 H 6.50 N 8.62
Example 14
3-Benzoyl-7-methoxy-HHAI
A mixture of 29.9 g (0.0888 mol) of o-methoxyphenylhydrazone from BHHAO and 880% formic acid (120 ml) was heated in a nitrogen atmosphere over a steam bath for 30 minutes and then poured into 2.5 l 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. The residue obtained in this way was chromatographed over silica gel (1.5 kg) and extracted with 60% ethyl acetate 40% cyclohexane.

  The product thus obtained was recrystallized from methylene chloride-ethyl acetate.



  1.15 g of the compound mentioned in the title with F .: 203-204.5 C. were obtained in this way. A second crop of 0.754 g was obtained from the same material with a total yield of 6.69 / o.



   Analysis for C2oH2oN202
Calculated: C 74.97 H 6.29 N 8.74
Found: C 75.00 H 6.45 N 8.92
Example 15 3-B enzoyi-9-fluoro-HHAI
A mixture of 3.25 g (0.01 mol) of p-fluorophenylhydrazone from BHHAO in 880% formic acid (15 ml) was refluxed under nitrogen for 30 minutes; the reaction mixture was poured into ice water. The dark semi-solid mixture thus obtained was extracted with chloroform. The chloroform extracts were washed with water, dried over anhydrous magnesium sulfate, treated with 10 g of silica gel and concentrated under reduced pressure.



  The granular solid substance obtained in this way was carefully poured onto a column of 200 g of silica gel and chromatographed with 60% ethyl acetate - 40% cyclohexane. The eluates were combined and concentrated, and the product thus obtained was recrystallized from ethyl acetate-Skellysolve B. In this way, 1.072 g (34.80 / o) of the desired compound with F .: 131-133 C. This material was recrystallized from Athylace tat-Skellysolve B, after which the melting point of the compound (16) was 165-167 C.



   Analysis for CtgHt7N2OF:
Calculated: 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 16 3 -B enzoyl, 7 -methyl-HHAI
A mixture of 31.3 g (0.0975 mol) of o-tolylhydrazone from BHHAO in 290 ml of 880 / above formic acid was heated to reflux in a nitrogen atmosphere for 30 minutes. The reaction mixture was poured into ice water and extracted several times with methylene chloride; the methylene chloride extracts were combined, dried (over anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue thus obtained was chromatographed over 1.5 kg of silica gel using 600/0 ethyl acetate 400/0 cyclohexane.

  The fractions were combined, recrystallized and concentrated. A solid substance was obtained which was recrystallized from ethyl acetate skeleton B. The yield was 10.0 g of Compound (17) having a melting point of 187-188.50C.



  A second fraction of 1.26 g of the same material was obtained, increasing the yield to 37.9%. Recrystallization of this material from ethyl acetate gave the pure compound mentioned in the title with F .: 189-1900 C.



   Analysis for Q0H20N2O2:
Calculated: 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-HHAI
A mixture of 26.9 g (0.0837 mol) of p-tolylrhydrazone from BHHAO was heated to reflux for 30 minutes while stirring with 125 ml of 880% formic acid in a nitrogen atmosphere. The reaction mixture was poured into ice water and then extracted several times with chloroform.



  The chloroform extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained in this way was chromatographed on a column containing 1 kg of silica gel using a mixture of 60% ethyl acetate-40% cyclohexane. The combined eluates were concentrated. This gave a yield of 10.33 g of a product (40.6% yield) which was recrystallized from methylene chloride-methanol. The pure desired compound had a melting point of 210-211 ° C.



   Analysis for C20H20N2O:
Calculated: C 78.92 H 6.62 N 9.20
Found: C 78.30 H 6.80 N 9.10
Example 18
3-Benzoyl-7-chloro-HHAI
Using the procedure described in Example 11, the o-chlorophenyl hydrazone from BHHAO was heated in formic acid; the connection mentioned in the title is thus obtained.



   Example 19
3-benzoyl-9-ethyl-HHAI
Using the procedure described in Example 11, the p-ethylphenyihydrazone of BHHAO was heated in formic acid; the desired compound was thus obtained.



   Example 20 3-Benzoylw9-propoxy-HHAI
Using the procedure described in Example 11, the p-propoxyphenylhydrazone from BHHAO was heated in formic acid; 3 -B enzoyl-9-propoxy-HHAI was obtained in this way.



   Using the procedure described in Example 11, other 3-benzoyl substituted HHAIs were also obtained by heating a substituted phenylhydrazone of BHHAO with formic acid. Examples of compounds that can be obtained in this way are as follows:
EMI7.1


<tb> 3-Benzoyl-8-ethyl
<tb> 3-B <SEP> enzoyl-1 <SEP> 0-ethyl- <SEP>
<tb> 3-Benzoyl-1 <SEP> 0-ethyl
<tb> 3-Benzoyk7-ethyli <SEP>
<tb> 3-Benzoyl-9-propyl
<tb> 3-Benzoyl-7-propyl
<tb> 3-Benzoyl-8-propyi- <SEP> 1,2,3,4,5,6-hexahydro
<tb> 3-Benzoyi-1 <SEP> 0-propyl- <SEP> azepine [4,5-b] indole
<tb> 3 <SEP> -B <SEP> enzoylL9 <SEP> -isopropyl- <SEP>
<tb> 3 <SEP> -Benzoyl-7-isopropyl- <SEP>
<tb> 3 <SEP> -B <SEP> enzoyl-9-chloro- <SEP>

   
<tb> 3-Benzoyl-7-bromo
<tb> 3-B <SEP> enzoyl-8-fluoro <SEP>
<tb> 3 <SEP> -Benzoyl104luoro- <SEP>
<tb> 3 <SEP> -Benzoyl-7-alkoxy
<tb> 3-Benzoyl-8-ethoxy
<tb> 3-Benzoyl-9-isopropoy
<tb> 3-Benzoyi-8,9-dichloro <SEP>
<tb> 3-Benzoyl-9-10-dichloro
<tb> 3-Benzoyl-7,8-difluoro
<tb> 3-benzoyl-7,8-dibromo
<tb> 3-Benzoyl-8,9-dimethyl- <SEP> HHAI
<tb> 3-Benzoyl-9, <SEP> 10-dimethyl- <SEP>
<tb> 3 <SEP> -Benzoyl-7, <SEP> 8-dimethyl- <SEP>
<tb> 3-Benzoyle7,8-diethoxy- <SEP>
<tb> 3-Benzoyls7-ethoxy-8-fluoro- <SEP>
<tb> 3-Benzoyl-7-bromo-9-propoxy
<tb> 3 <SEP> -Benzoyi4-methyl-9-chloro- <SEP>
<tb> u. <SEP> a.
<tb>



   Example 21
3-benzyl-HHAI
A solution of 6 g (20.6 mmol) of 3-benzoyl HHAI in 150 ml of tetrahydrofuran was added to a mixture of 6 g of lithium aluminum hydride in 400 ml of dry tetrahydrofuran with stirring. The addition was carried out in a nitrogen atmosphere over a period of one hour. The mixture thus obtained was stirred for four hours at room temperature (about 250 ° C.) 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 a 15% sodium hydroxide solution and then with 18 ml of water. This mixture was stirred for two hours and then filtered. The filtrate was concentrated under reduced pressure. A residue was obtained which was recrystallized from ethyl acetate SkellysolveB.

  3.37 g (59O / o) of the desired compound with mp .: 116-117 ° C. were obtained.



   Analysis for C19H20N2:
Calculated: C 82.57 H 7.30 N 10.14
Found: C 82.34 H 7.52 N 10.04
Example 22 3 -B enzoyl-9-methoxy-HHAI
1 g (0.00312 mol) of 3-benzoyl-9-methoxy-HHAI was added to an ice-cold suspension of 1 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. The mixture was refluxed for 18 hours in a nitrogen atmosphere. The mixture was then cooled in an ice bath and treated successively with 1 ml of water, 1 ml of 150% aqueous sodium hydroxide solution and 3 ml of water. The mixture thus obtained was filtered. The filtrate was concentrated in vacuo; a solid substance was obtained, which was recrystallized from ethyl acetate.

  0.773 g (81%) of a product were obtained, which in turn was recrystallized from ethyl acetate-Skellysolve B. The pure desired compound had a melting point of 127.5-129.5 ° C.



   Analysis for C20H22N2O:
Calculated: C 78.40 H 7.24 N 9.14
Found: C 78.54 H 7.35 N 9.42
Example 23 3 -Benzyl-8-methoxy-HHAI
8.93 g (0.0279 mol) of 3-Benzoyi-8-methoxy-HHAI were added with stirring to an ice-cold suspension of 9 g of lithium aluminum hydride in 900 ml of tetrahydrofuran. The mixture was heated to reflux in a nitrogen atmosphere for 18 hours, cooled in an ice bath and treated successively with 9 ml of water, 9 ml of 150% aqueous sodium hydroxide and 27 ml of water. The mixture was filtered.

  The filtrate was evaporated and the residue was recrystallized from ethyl acetate; In this way, 6.62 g (77.4%) of product were obtained, which, after recrystallization from ethyl acetate, gave the compound mentioned in the title and having F .: 146.5-1470 ° C.



   Analysis for C20lI, 2N2O:
Calculated: C 78.40 H 7.24 N 9.14
Found: C 78.25 H 7.44 N 9.33
Example 24
3-benzyl-10-methoxy-HHAI
To an ice-cold suspension of lithium aluminum hydride (3 g) in 300 ml of tetrahydrofuran was added 2.35 g (7.26 mmol) of 3-benzoyl-10methoxy-HHAI with stirring. This mixture was refluxed for 18 hours in a nitrogen atmosphere, then cooled, in an ice bath and treated successively with 3 ml of water, 3 ml of 150% aqueous sodium hydroxide and 9 ml of water. The mixture was filtered, the filtered solid substance was washed with tetrahydrofuran, and the washing waters and the filtrate were combined and concentrated.



  The solid crude product obtained in this way was recrystallized from ethyl acetate Skellysolve B. 1.85 g (83.30 / a) of the desired compound were obtained, which after repeated recrystallization from the same solvent mixture had F .: 163.5-164.5 ° C.



   Analysis for C20H22N2O:
Calculated: 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-HHAI hydrochloride
1.85 g (5.77 mmol) of 3-benzoyl-7-methoxy-HHAI were added with stirring to an ice-cold suspension of 2 g of lithium aluminum hydride in 200 ml of tetrahydrofuran. The mixture thus obtained was refluxed in a nitrogen atmosphere for 18 hours and then decomposed by the successive addition of 2 ml of water, 150% aqueous sodium hydroxide (2 ml) and 6 ml of water. The mixture thus obtained was filtered; the filtrate was recrystallized under reduced pressure. A residue was obtained.

  A solution of this residue in ethyl acetate was acidified with methanolic hydrogen chloride; the crystalline hydrochloride thus obtained was filtered off and dried; the yield was 1.81 g (91.5 / o) of the compound given in the title with F .: 251-252.50 C. The recrystallized material from methanol-ethyl acetate melted at 247-2480C (dec.).



   Analysis for C20H23ClN2O:
Calculated: C 70.06 H 6.76 N 8.17 ct 10.34
Found: C 70.15 H 6.94 N 8.12 Cl 10.32
Example 26 3-Benzyl 9-fluoro-HHAI
6.94 g (0.0225 mol) of 3-benzoyl9-fluoro-HHAI were added with stirring to an ice-cold suspension of 8 g of lithium aluminum hydride in 800 ml of dry tetrahydrofuran. The resulting mixture is refluxed under nitrogen for 10 hours, cooled in an ice bath and treated successively with 8 ml of water, 8 ml of 150% aqueous sodium hydroxide and 24 ml of water. The mixture is filtered, the solid substance is washed with tetrahydrofuran and the filtrate, which has been combined with the washing waters, is concentrated in vacuo. The residue obtained in this way is recrystallized from ethyl acetate.

  This gives a yield of 5.53 g (83.60 m) of the product which, after additional recrystallization from ethyl acetate, gave the desired compound with F .: 143-144 ° C.



   Analysis for CjgHtgN2F
Calculated: 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-HHAI hydrochloride
A solution of 11.6 g (0.0376 mol) of 3-benzoyl7-methyl-HHAI in 300 ml of tetrahydrofuran was added with stirring in a nitrogen atmosphere to an ice-cooled suspension of 11 g of lithium aluminum hydride in 700 ml of tetrahydrofuran. The mixture obtained in this way was refluxed for 18 hours, cooled in an ice bath and treated successively with 11 ml of water, 11 mol of 150% sodium hydroxide and 33 ml of water. The mixture was filtered and the filtrate was concentrated under reduced pressure.



  A solution of the oily residue in ethyl acetate was acidified with methanolic hydrogen chloride; a yield of 5.15 g (41.9 / o) of the compound indicated in the title, which, after recrystallization from methanol-ethyl acetate, had a melting point of 210.5-212 ° C. was obtained.



   Analysis for C20lI, 2N2Cl:
Calculated: C 73.49 H 7.09 N 8.57 Cl 10.85
Found: C 73.09 H 7.27 N 8.18 C1 10.60
Example 28
3-benzyl-9-methyl-HHAI
A solution of 9.56 g (0.0310 mol) of 3-benzoyl9-methyl-HHAI in 300 ml of tetrahydrofuran was added with stirring in a nitrogen atmosphere to an ice-cooled suspension of 10 g of lithium aluminum hydride in 700 ml of tetrahydrofuran. The resulting mixture was refluxed for 16 hours, cooled in an ice bath and treated with 10 ml of water, 10 ml of 150% aqueous sodium hydroxide and 30 ml of water.

  The mixture was stirred for one hour and then filtered; the filtrate was concentrated in vacuo; an oil was obtained which was crystallized in three parts of ethyl acetate: Yield of compound (29) 7.27 g with F .: 140.5-142 C, 0.702 g with F .: 12Q136 C and 0.395 g with F. : 123.5-134 C. Recrystallization of this material from ethyl acetate Skellysolve B gives a pure product with F .: 142.5-143.5 C.



   Analysis for C20H22N2:
Calculated: C 82.72 H 7.64 N 9.65
Found: C 82.38 H 7.91 N 9.96
Example 29
3-benzyl-7-chloro-HHAI
If 3-benzoyl-7-chloro-HHAI is reduced with lithium aluminum hydride in the manner described in Example 21, the compound 3-benzyl is obtained; 7-chloro-HEIAI.



   Example 30
3-benzyl-9-ethyl-HHAI
If 3-benzoyl-9-ethyl-HHAI is reduced with lithium aluminum hydride in the manner described in Example 21, the desired compound is obtained.



   Example 31 3 -Benzyl-9-propoxy-HHAI
If 3-benzoyl-9-propoxy-HHAI is reduced with lithium aluminum hydride in the manner described in Example 21, the compound 3-benzyl-9-propoxy-HHAI is obtained.



   If, in the manner described in Example 21, other 3-benzoyl-substituted HHAIs are reduced with a metal hydride such as lithium aluminum hydride, then 3-benzyl-substituted HHAIs are obtained accordingly.



  The following connections can be obtained:
EMI9.1


<tb> 3-Benzyl-8-ethyl
<tb> 3-Benzyl-10-ethyl
<tb> 3-Benzyl-7-ethyl
<tb> 3-Benzyl-9-propylw <SEP>
<tb> 3-Benzyl-7-propyl
<tb> 3-Benzyl-8-propyi- <SEP>
<tb> 3-Benzyl-10-propyl <SEP>
<tb> 3-Benzyl-9-isopropyl- <SEP>
<tb> 3-Benzyl-7-isopropyl
<tb> 3-Benzyl-9-chloro
<tb> 3-Benzyl-7-bromo
<tb> 3-Benzyl-8-fluoro
<tb> 3-benzyl-10-fluoro
<tb> 3-Benzyl-7-ethoxy
<tb> 3-Benzylk8-ethoxy- <SEP> HHAI
<tb> 3-Benzyl-10-ethoxy
<tb> 3-Benzyl-9-isopropoxy
<tb> 3-Benzyl-8,9-dichloro
<tb> 3-Benzyl-9,10-dichloro <SEP>
<tb> 3-Benzyl-7,8-difluoro- <SEP>
<tb> 3-Benzyl-7,8-dibromo
<tb> 3-Benzyl-8,9-dimethyl
<tb> 3-Benzyl-9, <SEP> <RTI

    ID = 9.15> -dimethyl- <SEP>
<tb> 3-B <SEP> enzyl-7 <SEP>, <SEP> 8-dimetlyl- <SEP>
<tb> 3-Benzyl-7,8-diethoxy
<tb> 3-Benzyl-7-ethoxy-8-fluoro
<tb> 3-Benzyl-7-bromo-9-propoxy
<tb> 3-B <SEP> enzyl-7-methyl-9-chloro- <SEP>
<tb> u. <SEP> Ä.
<tb>



   Example 32
HHAI (33) and its cyclohexane sulfamate
A solution of 3-benzyl-HHAI (1 g; 3.61 mmol) in 150 ml of ethanol was treated with 100 mg of 100 / o palladium carbon catalyst and placed in a Parr apparatus at an initial hydrogen pressure of 3.52 kg / cm2 hydrogenated. After a period of 1/2 hour, the reaction was complete and the catalyst was removed by filtration. The filtrate was concentrated in vacuo; the residue thus obtained was dissolved in 100 ml of benzene; the solution was concentrated to give solid crude HHAI Compound V.



  This material was dissolved in 10 ml of ethyl acetate and treated with a solution of cyclohexanesulfamic acid (0.5 g) in 3 ml of ethanol. The crystalline salt formed was recrystallized from isopropyl alcohol Skellysolve B; in this way 0.17 g (13.2 / o) of the desired compound with F .: 164-165 C.



   Analysis for 8H27N3O3S:
Calculated: 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
HHAI hydrochloride
A solution of 7.58 g (0.0407 mol) of HHAI in methanol-ethyl acetate (obtained in the manner described in Example 32) was acidified with methanolic hydrogen chloride. If the mixture is allowed to crystallize, 6.74 g (74.4 / o) of the compound (35) with F .: 250.5-251.50 ° C. are obtained. After recrystallization from methanol / sithyl acetate, the material had a melting point from 247.5-248.5 C.



   Analysis for C12Ht5N2C1:
Calculated: C 64.71 H 6.79 N 12.58 C1 15.92
Found: C 64.93 H 7.08 N 12.70 Cd 16.10
Example 34
9-methoxy-HHAI and its hydrochloride
A solution of 3-benzyl-9-methoxy-HHAI (5.21 g; 0.017 mol) in a mixture of 47 ml acetic acid and 100 ml 950% ethanol was treated with 100% palladium-carbon catalyst (1 g) ; the mixture was hydrogenated in a Parr apparatus for two hours at an initial pressure of 2.8 kg / cm2.



  The reaction mixture was then filtered through Celite (diatomaceous earth); the filtrate was concentrated under reduced pressure. The residue so obtained was dissolved in water, cooled in an ice bath and made alkaline with sodium hydroxide solution. The crystalline solid was collected by filtration, washed with water and dried in vacuo. 3.53 g of the desired compound with F .: 174-1760 C.

 

   A solution of this material in methanol was acidified with methanolic hydrogen chloride. The salt thus obtained was recrystallized from methanol.



  3.96 g (92.30 / o) of the compound mentioned in the title with F .: 234-236 C. After recrystallization from methanol, F .: 235-235.5 C.



   Analysis for C13H17ClN2O:
Calculated: C 61.77 H 6.78 Cl 14.013 N 11.09
Found: C61.30 H 6.85 Cm 14.11 N10.99
Example 35
8-methoxy-HHAI and its hydrochloride
A mixture of 6.34 g (0.0207 mol) of 3-benzyl 8-methoxy-HHAI, 950 / o strength ethanol (200 ml) and 1 g of 100% palladium-carbon catalyst was at an initial pressure of 2.78 kg / cm2 hydrogenated for 8 hours. The resulting mixture was filtered through Celite (diatomaceous earth); the filtrate was concentrated in vacuo. The residue thus obtained was recrystallized from methanol-ethyl acetate. The yield was 3.24 g (72.4 O / o) 8-methoxy-HHAI with a melting point of 158-160.5 C.



   Analysis for Cl3HX7ClN2O:
A solution of the base in methanol was acidified with methanolic hydrogen chloride; the salt was recrystallized from water; this gave the hydrochloride of 8-methoxy-HHAI with a melting point of 276-276.50 C. (decomp.).



   Analysis for CX3Hl7ClN2O:
Calculated: C 61.77 H 6.78 N 11.09 Cl 14.03
Found: C 62.03 H 6.87 N 11.17 Cl 14.12
Example 36
10-methoxy-HHAI and its hydrochloride
A mixture of 3-benzyl-10-methoxy-HHAI (1.66 g; 5.42 mmol), 200 ml of 950 / above ethanol and 0.5 g of 10% palladium-carbon catalyst was at an initial pressure of 2.88 kg / cm2 hydrogenated for seven hours. The catalyst was removed by filtration through Celite (diatomaceous earth); the filtrate was concentrated under reduced pressure.



  This gave 10-methoxy-HHAI as an oil.



   The oil was dissolved in methanol and acidified with methanolic hydrogen chloride. The salt thus obtained was recrystallized from methanol-ethyl acetate; one received 1.04 g (75.60 / s) of the hydrochloride of 10 methoxy-HHAI, which had a melting point of 236 ° C. after additional recrystallization from methanol-ethyl acetate.



   Analysis for Ct3Ht7CIN20:
Calculated: C 61.77 H 6.78 N 11.09 Cl 14.03
Found: C 61.95 H 6.49 N 10.98 Cl 14.06
Example 37
7-methoxy-HHAI hydrochloride
A mixture of 1.61 g (4.70 mmol) of 3-benzyl7-methoxy-HHAI hydrochloride, 100 ml of 950 / & gem ethanol and 200 mg 100 / o palladium-carbon catalyst was 2.75 hours at an initial pressure of 2s67 kg / cme hydrogenated. The mixture thus obtained was filtered; the filtrate was concentrated under reduced pressure. The residue thus obtained was recrystallized from methanol.

  0.782 g of a material with an F .: 275-2770C and 0.233 g of a material with an F .: 278-279C (yield = 85.4 / o) were obtained.



  This material was recrystallized from methanol to give compound (42) with m.p .: 275-275.5 C.



   Analysis for C13H17ClN2O:
Calculated: C61.77 H 6.78 N11.09 Cl 14.03
Found: C 61.83 H 6.71 N 10.92 Cl 13.85
13.77
Example 38
9-fluoro-HHAI
A mixture of 5.58 g (0.0190 mol) 3-benzyl9-fluoro-HHAI, 250 ml 950 / o strength ethanol and 100 / o palladium-carbon catalyst was 170 minutes at an initial pressure of 2.04 kg / cm2 in a Parr device. The reaction mixture was then filtered through Celite (diatomaceous earth) and the filtrate was concentrated in vacuo.

  The residue thus obtained, recrystallized from ethyl acetate, gave 3.36 g (86.7%) of the desired compound which, after additional recrystallization from ethyl acetate, had a melting point of 179-180 ° C.



   Analysis for Ct2HtSN2F:
Calculated: C 70.56 H 6.41 N 13.72 F 9.30
Found: C 70.70 H 6.09 N 13.60 F 9.09
Example 39
7-methyl-HHAI hydrochloride
A mixture of 4.84 g (0.0148 mol) of 3-benzyl7-methyl-HHAI hydrochloride, 200 ml of 95 0 / above ethanol and 1 g of 100 / o palladium-carbon catalyst was 2.5 hours with a Hydrogenated initial pressure of 2.88 kg / cm2. The catalyst was removed by filtration through Celite (diatomaceous earth); the filtrate was concentrated under reduced pressure.

  The crystalline residue thus obtained was recrystallized from methanol; 2.64 g (750/0) of the compound given in the title were obtained which, after additional recrystallization from methanol, had a melting point of 2710 ° C. (decomp.).



   Analysis for C13H17N2Cl:
Calculated: C 65.95 H 7.24 N 11.84 Cl 14.98
Found: C 65.93 H 7.26 N 11.53 Cl 14.90
Example 40 9-methyl-HHAI
A solution of 7.89 g (0.0272 mol) of 3-benzyl; 9-methyl-HHAI in 200 ml of 950 / above ethanol and 10 ml of glacial acetic acid was treated with 1 g of 10010 palladium-carbon catalyst and hydrogenated at an initial pressure of 2.11 kg / cm2 for a period of 1.5 hours. The reaction mixture was then filtered through Celite (diatomaceous earth), and the filtrate was concentrated in vacuo. A solution of the residue thus obtained in water was decolorized with activated charcoal (Darco G60). The solution was cooled in an ice bath and made alkaline with sodium hydroxide.

  The resulting crystalline product was collected by filtration, washed with water and dried in vacuo. 5.18 g (95.2 / o) of the desired compound were obtained, which had a melting point of 243.5-2450 ° C. after recrystallization from methylene chloride-methanol. (Dec.).



   Analysis for CtsHN2:
Calculated: C 77.96 H 8.05 N 13.99
Found: C 77.76 H 8.38 N 13.93
Example 41
7-chlorine-HHAI
In the manner described in Example 32, 3-benzyl-7-chloro-HHAI was hydrogenated in the presence of a palladium-carbon catalyst; 7Xhlor-HHAI was obtained in this way.



   Example 42 9-Ethyl-HHAI
In the manner described in Example 32, 3-benzyl-9-ethyl-HHAI was hydrogenated in the presence of a palladium-carbon catalyst; 9-l2ithyl-HHAI was obtained in this way.



   Example 43
9-propoxy-1,2,3,4,5,6 hexahydroazepine (4,5-b) indole
In the manner described in Example 32, 3-benzyl-9-propoxy-HHAI was hydrogenated in the presence of a palladium-carbon catalyst; the desired compound was obtained in this way.



   In the manner described in Example 32, other substituted HHAI were also prepared from 3-benzyl-substituted HHAI by hydrogenation in the presence of a noble metal catalyst, preferably palladium on a support material, e.g.

  B. the following connections:
EMI11.1


<tb> 8 <SEP> -Ethyl- <SEP>
<tb> 1 <SEP> 0-ethyl- <SEP>
<tb> 7ethyl- <SEP>
<tb> 9-propyl
<tb> 7-propyl
<tb> 8-propyl
<tb> 10-propyl
<tb> 9-isopropyl
<tb> 7-isopropylw <SEP>
<tb> 9-chlorine
<tb> 7-bromine
<tb> 8-fluoro
<tb> 10-fluorine
<tb> 7-ethoxy- <SEP>
<tb> <SEP> 8-ethoxy- <SEP> HHAI
<tb> 1 <SEP> 0-ethoxy- <SEP>
<tb> 9-isopropoxy
<tb> 8,9-dichloro <SEP>
<tb> 9.1 <SEP> 0-dichloro <SEP>
<tb> 7,8-difluoro
<tb> 7,8-dibromo
<tb> 8,9-Dimethyli <SEP>
<tb> 9,10-dimethyl
<tb> 7,8-dimethyl
7,8-diethoxy
<tb> 7-bromo-9-propoxy
<tb> 7-methyl-9-chloro <SEP>
<tb>

   <SEP> u. <SEP> a.
<tb>



   Example 44
A mixture of 9.45 ml icic acid anhydride
3-Formyl-HHAI and 3.98 ml of 980% formic acid were stirred and then switched off at 25 ° C. for one hour. The mixture was then cooled in an ice bath and treated with 5.58 g (0.03 mol) of HHAI. After the indole went into solution, a second precipitate formed. Then 25 ml of ether were added to the mixture thus prepared, which was left to stand for 18 hours in a nitrogen atmosphere, and then boron in water. The solid substance thus obtained was collected by filtration, washed with water and dried in vacuo. A crude product of 6.27 g with F .: 220-221.5 C.

  By recrystallizing this material from methanol-ethyl acetate there were three yields of the desired compound: 4.24 g with F .: 221-222.5 C, 1.19 g with F .: 220.5-221.5 C and 0.282 g with F .: 219.5-221 C; the overall yield was 89%. Another recrystallization from methylene chloride-methanol gives the desired compound with F .: 22im222.5 "C.



   Analysis for Ct3H14N2O:
Calculated: C 72.87 H 6.59 N 13.08
Found: C 72.90 H 6.74 N 12.84
Example 45
3-acetyl-8-methoxy-HHAI
A solution of 2 g of 8-methoxy-HHAI in 25 ml of pyridine and 10 ml of acetic anhydride was left to stand for 20 hours at room temperature in a nitrogen atmosphere. The reaction mixture was poured into water, the solid substance was collected on a filter and recrystallized from methanol-ethyl acetate; it resulted in 3-acetyl-8-methoxy-HFAI.



   Example 46
3-Propionyl-9-fluoro-HHAI
In the manner described in Example 45, 9-fluoro-HHAI is reacted with propionic anhydride in pyridine; the desired connection results.



   Example 47 3-Acetyli-7-methyl-HHAI
In the manner described in Example 45, 7-methyl-HHAT is reacted with acetic anhydride in pyridine; the connection given in the title results.



   Example 48
3-propionyl; 9-methylwHHAI
In the manner described in Example 45, 9-methyl-HHAI is reacted with propionic anhydride in pyridine; 3-propionyl-9-methyl-NHAI is obtained.

 

   Example 49 3-Acetyl; 9-methoxy-HHAI
In the manner described in Example 45, 9-methoxy-HHAI is reacted with acetic anhydride in pyridine; 3-acetyl-9-methoxy-HHAI is obtained.



   Example 50 3 -Formyb7-chloro-HHAI
In the manner described in Example 44, 7-chloro-HHAI is reacted with acetic anhydride and formic acid and the desired compound is obtained.



   Example 51
3-Acetyl-7,8-dibromo-HHAI
In the manner described in Example 45, 7,8-dibromo-HHAI is reacted with acetic anhydride in pyridine and the compound given in the title is obtained.



   Example 52
3-acetyl-7-methyl-9-chloro-HHAI
In the manner described in Example 45, 7-methyl-9-chloro-HHAI is reacted with acetic anhydride in pyridine and 3-acetyl-7-methyl} 9-chloro-HHAI is obtained.



   In the manner described in Examples 44, 45 and 46, other 3-acyl derivatives of substituted HHAI according to Examples 32 to 43, including the compounds shown in the list after Example 43, can be prepared by treating the compounds with acetic anhydride, acetic anhydride and formic acid, propionic anhydride, acetyl chloride, propionyl chloride, benzoyl chloride or the corresponding bromides.



   Example 53 6-methyl-HHAI and its hydrochloride
To an ice-cold solution of HHAI (3.73 g; 0.02 mol) in 200 ml of dry dimethylformamide was added 0.960 g of a 550% sodium hydride suspension in mineral oil (0.022 mol of the sodium hydride) in a nitrogen atmosphere with stirring. The mixture was heated to 250 ° C. and turned off for two hours.



  It was then cooled, in an ice bath, and treated with a methyl iodide solution (1.37 ml; 0.022 mol) in 25 ml of ether for 30 minutes. The solution obtained in this way was stored at 25 ° C. for 18 hours. 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 were combined, washed with brine, dried over anhydrous potassium carbonate and concentrated under reduced pressure. 6-methyl-HHAI was obtained.

  The residue thus obtained was redissolved in ethyl acetate and acidified with methanolic hydrogen chloride; the hygroscopic salt thus obtained was recrystallized from methanol-ethyl acetate. 3.19 g (75.3O / o) of material, which was again recrystallized from methanol-ethyl acetate, resulted. In this way, the hydrochloride of 6-methyl-HHAI with a melting point of 214-2150 C.



   Analysis for CtSHt, N2CI:
Calculated: C 65.95 H 7.24 N 11.84 Cm 14.98
Found: C 66.35 H 6.99 N 11.78 Cd 14.90
Example 54 6-Ethyl HHAI Hydrochloride
A cold solution of 7.45 g of HHAI in 400 ml of dry dimethylformamide in a nitrogen atmosphere was treated with 1.92 g of 550% sodium hydride suspension in mineral oil. The mixture was stirred for three hours at room temperature, then cooled and treated with a solution of 3.54 ml of ethyl iodide in 50 ml of water. The addition took 15 minutes. The mixture was then stirred at room temperature for 18 hours. Thereafter, the mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in 250 ml of water.

  The aqueous mixture was extracted three times with ether and three times with methylene chloride.



  The two extracts were worked up separately; H. they were washed with brine, then with water, and finally dried over anhydrous potassium carbonate. The two extracts were then combined and concentrated. The residue obtained in this way was suspended with 30 g of silica gel and chromatographed over 450 g of silica gel using 20 / o ethylamine 48 / o methanol-500 / o ethyl acetate for the elution. Fractions of 150 ml were collected. The first band (A) consisted of fractions 6-9. The product was in fractions 14-21 (Volume B). The B fractions were combined and concentrated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate, cooled and acidified with methanolic hydrogen chloride.

  The precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo. This gave 7.67 g of material which was recrystallized from methanol and three times from methanol-ethyl acetate. The result was 6-ethyl-HHAI hydrochloride with mp .: 253-2540 ° C. (dec.).



   Analysis for Ct4Ht9N2Cl:
Calculated: C67, O5 H7.64 N11.17 Carl 14.14
Found: C67.10 H7.90 N 11.47 Cd 14.38
Example 55 6-methyl-9-methoxy-HHAI hydrochloride and 3,6-dimethyl-9-methoxy-HHAI hydrochloride
In the manner described in Example 54, 9-methoxy-HHAI was treated with sodium hydride and then with methyl iodide, so that a mixture of amines was obtained. This mixture was separated by chromatography on silica gel using a mixture of 2 o / o diethyl-15 O / o methanol-830 / o ethyl acetate as the eluate. Fractions 14-24 contained 3,6-dimethyl-9-methoxy-HHAI, which was converted to its hydrochloride with methanolic hydrogen chloride.

  Recrystallization of this salt from methanol gave 3,6 dimethyl 9-methoxy-HHAI hydrochloride with melting point: 2700 ° C. (dec.).



   Analysis for CH2tClN2O:
Calculated: C 64.16 H 7.54 N 9.98 Cd 12.63
Found: C 64.20 H 7.73 N 9.82 Cd 12.78
The fractions 28-49 of the chromatography column contained 6-methyl-9-methoxy-HHAI, which was converted into its hydrochloride with methanolic hydrogen chloride. Recrystallization of this salt from methanol gave the corresponding hydrochloride with mp .: 2720 ° C. (dec.).

 

   Analysis for Ct4HtgCIN2O
Calculated: C 63.03 H 7.18 N 10.50 C113.29
Found: C62.89 H7.25 N10.36 Cd 13.25
Example 56
6-Benzyl-HHAI and its hydrochloride and 3,6-dibenzyl-HHAI
In the manner described in Example 54, 5.59 g of HHAI in 300 ml of dimethylformamide were reacted with 1.44 g of a 550% sodium hydride suspension in mineral oil and, after standing for 3 hours and cooling, with 4.18 g of benzyl chloride in 37 mk of dry ether. The mixture was stirred at room temperature for 18 hours. The solution was then concentrated under reduced pressure. The residue obtained in this way was dissolved in 300 ml of water and extracted with methylene chloride.

  The methylene chloride extracts were washed with water, dried over potassium carbonate and concentrated under reduced pressure. The residue was redissolved in ethyl acetate. A small amount of crystallized material was collected by filtration. The mother liquors were chromatographed over 450 g of silica gel using a solvent mixture of 20 / o diethylamine, 28 / o ethyl acetate and 700/0 cyclohexane. 100 ml fractions were collected. Fractions 13-19 contained 3,6-dibenzyl-HHAI with F .: 85.5-86.5 C.



   Analysis for C26H2GN2:
Calculated: 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 20 / o trimethylamine and 98 / o methanol. The methanolic solution of the product thus obtained was converted into its hydrochloride. Recrystallization of this salt from methanol / ethyl acetate gave the hydrochloride of 6-benzyl-HHAI with F .: 212-213 C.



   Analysis for C10H21N2Cl:
Calculated: C 72.95 H 6.77 N 8.96 Cl 11.35
Found: C 72.51 H 6.75 N 9.21 Cl 11.41
Example 57 6-Propyl-9-fluoro-HHAI and its hydrochloride
In the manner described in Example 54, 9-fluoro-HHAI was treated successively with sodium hydride and propyl iodide. This gave 6-propyl9-fluoro-HHAI, which was obtained as the hydrochloride from a methanolic chlorine hydrogen solution.



   Example 58 6-Isopropyl-9-methyl-HHAI and its hydrochloride
In the manner described in Example 54, 9-methyl-HHAI in dimethylformamide was treated successively with sodium hydride and isopropyl iodide; the compound mentioned in the title resulted, which was obtained as the hydrochloride.



   PATENT CLAIM 1
Process for the preparation of 1,2,3,4,5,6-hexahydroazepino (4,5-b) indoles of the formula
EMI13.1
 and their acid addition salts, in which R and R 'are hydrogen, an alkoxy or alkyl group having 1-3 C atoms or halogen, characterized in that a phenylhydrazine of the formula
EMI13.2
 while warming 1-benzoylhexahydro-4H-azepin-4-one to the corresponding phenylhydrazone of 1 benzoylhexahydro-4H-azepin-4-one of the formula
EMI13.3
 wherein a phenyl group is reacted and then, by heating the compound thus obtained with formic acid, the 3-benzoylA1,2,3,4,5,6-hexahydroazepine (4,5-b) indole of the formula
EMI13.4
 wins,

   the compound of formula III by reduction with a metal hydride into the corresponding 3-benzyl-1,2,3,4,5,6hexahydroazepine (4,5-b) indole of the formula
EMI13.5
 transferred and the compound obtained in this way hydrogenated in the presence of a catalyst.



   SUBCLAIMS
1. The method according to claim I, characterized in that the hydrogenation catalyst used is palladium-carbon.



   2. The method according to claim I, characterized in that the compounds of the formula V obtained are converted into the corresponding acid addition salts.



   3. The method according to claim I, characterized in that the compounds of formula V obtained by reaction with acetic anhydride, acetic anhydride and formic acid, propionic anhydride, benzoic anhydride, acetyl, propionyl

** WARNING ** End of DESC field could overlap beginning of CLMS **.



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. stirs. The solution was then concentrated under reduced pressure. The residue obtained in this way was dissolved in 300 ml of water and extracted with methylene chloride. The methylene chloride extracts were washed with water, dried over potassium carbonate and concentrated under reduced pressure. The residue was redissolved in ethyl acetate. A small amount of crystallized material was collected by filtration. The mother liquors were chromatographed over 450 g of silica gel using a solvent mixture of 20 / o diethylamine, 28 / o ethyl acetate and 700/0 cyclohexane. 100 ml fractions were collected. Fractions 13-19 contained 3,6-dibenzyl-HHAI with F .: 85.5-86.5 C. Analysis for C26H2GN2: Calculated: 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 20 / o trimethylamine and 98 / o methanol. The methanolic solution of the product thus obtained was converted into its hydrochloride. Recrystallization of this salt from methanol / ethyl acetate gave the hydrochloride of 6-benzyl-HHAI with F .: 212-213 C. Analysis for C10H21N2Cl: Calculated: C 72.95 H 6.77 N 8.96 Cl 11.35 Found: C 72.51 H 6.75 N 9.21 Cl 11.41 Example 57 6-Propyl-9-fluoro-HHAI and its hydrochloride In the manner described in Example 54, 9-fluoro-HHAI was treated successively with sodium hydride and propyl iodide. This gave 6-propyl9-fluoro-HHAI, which was obtained as the hydrochloride from a methanolic chlorine hydrogen solution. Example 58 6-Isopropyl-9-methyl-HHAI and its hydrochloride In the manner described in Example 54, 9-methyl-HHAI in dimethylformamide was treated successively with sodium hydride and isopropyl iodide; the compound mentioned in the title resulted, which was obtained as the hydrochloride. PATENT CLAIM 1 Process for the preparation of 1,2,3,4,5,6-hexahydroazepino (4,5-b) indoles of the formula EMI13.1 and their acid addition salts, in which R and R 'are hydrogen, an alkoxy or alkyl group having 1-3 C atoms or halogen, characterized in that a phenylhydrazine of the formula EMI13.2 while warming 1-benzoylhexahydro-4H-azepin-4-one to the corresponding phenylhydrazone of 1 benzoylhexahydro-4H-azepin-4-one of the formula EMI13.3 wherein a phenyl group is reacted and then, by heating the compound thus obtained with formic acid, the 3-benzoylA1,2,3,4,5,6-hexahydroazepine (4,5-b) indole of the formula EMI13.4 wins, the compound of formula III by reduction with a metal hydride into the corresponding 3-benzyl-1,2,3,4,5,6hexahydroazepine (4,5-b) indole of the formula EMI13.5 transferred and the compound obtained in this way hydrogenated in the presence of a catalyst. SUBCLAIMS 1. The method according to claim I, characterized in that the hydrogenation catalyst used is palladium-carbon. 2. The method according to claim I, characterized in that the compounds of the formula V obtained are converted into the corresponding acid addition salts. 3. The method according to claim I, characterized in that the compounds of formula V obtained by reaction with acetic anhydride, acetic anhydride and formic acid, propionic anhydride, benzoic anhydride, acetyl, propionyl or benzoyl chloride or bromide in compounds of the formula EMI14.1 converted in which R "'denotes hydrogen, an alkyl group with 1-2 C atoms or phenyl. PATENT CLAIM II Use of the compounds of the formula V obtained by the process according to claim I for the preparation of compounds of the formula EMI14.2 and their acid addition salts, in which R and R 'have the meaning given in claim I and R "is an alkyl group with 1-3 carbon atoms or the benzyl group, characterized in that a compound of the formula V with corresponding alkyl bromides or iodides or with benzyl chloride or bromide in the presence of a base. SUBCLAIMS 4. Use according to claim II, characterized in that the compounds obtained are converted into the corresponding acid addition salts. 5. Use according to claim II, characterized in that the reaction is carried out in the presence of sodium hydride. 6. Use according to claim II, characterized in that the alkyl halide used is methyljo- did.