US3501483A

US3501483A - Novel 11-(4-piperidyl)dibenz(b,f)(1,4) oxazepines and thiazepines

Info

Publication number: US3501483A
Application number: US677012A
Authority: US
Inventors: Charles Frederick Howell; Paul Ramirez; Robert Allis Hardy Jr
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1966-04-15
Filing date: 1967-10-23
Publication date: 1970-03-17
Anticipated expiration: 1987-03-17
Also published as: US3532702A; FR1602883A; FR7194M; CH496727A; BE697032A; NL155830B; GB1184251A; NL6705298A; DE1645964A1

Description

United States Patent ABSTRACT OF THE DISCLOSURE The preparation of ll-substituted dibenz[b,f] [1,4]- oxazepines and thiazepines from intermediates, such as, substituted 2-aryloxy or 2-arylthio-1-substituted isoni-pecotanilides, is described. These compounds are physiologically active on the central nervous system and therefore useful as tranquilizers, hypnotics etc.

This application is a continuation-in-part of our application Ser. No. 542,738, filed Apr. 15, 1966, now abandoned.

Summary of the invention This invention relates to new organic compounds. More particularly, it relates to ll-substituted dibenz[b,f] [1,4]- oxazepines and thiazepines, intermediates, and methods of preparing the same.

The novel compounds of the present invention may be illustrated by the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, carbo(lower)alkoxy, carbobenzyloxy and ar(lower alkyl); R is selected from the group consisting of hydrogen and lower alkyl; R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower alkylmercapto, halogen, trifiuoromethyl, nitro, di(lower alkyl) sulfamoyl and lower alkanoyl; X is selected from the group consisting of oxygenand sulfur; Y is selected from the group consisting of methylene and ethylene; and nontoxic acid addition salts.

The compounds of the present invention possess valuable central nervous system (CNS) properties at nontoxic doses. As such, they show one or more of the following CNS actions: tranquilizer, hypnotic and/ or muscle relaxant type actions, and anti-depressant activity. The compounds have been tested pharmacologically and found to have the above properties which show a desirable wide spread between doses producing depressant or sedative actions or anti-depressant actions and toxic symptoms such as paralysis or lethality. They are also analgesics.

The CNS depressant properties, such as tranquilizer, hypnotic and muscle relaxant type activity, are indicated by several procedures. For example, a test which indicates hypnotic and/or muscle relaxant type activity is represented by the following rod walking test. Groups of 3,501,483 Patented Mar. 17, 1970 6 mice each are tested for their ability to walk across a horizontal rod in a normal manner after receiving graded intraperitoneal doses of a test compound. A median effective dose, rod walking dose (RWD) is estimated.

A test which indicates tranquilizing activity is represented by a measure of the reduction in motor activity. One half of the rod walking dose (RWD); see above, is given to a group of 5 mice and a 5 minute count of motor activity is recorded (actophotometer). Counts of 5250 are considered to indicate a specific reduction (more than two standard deviations) of activity at a dose causing only minimal impairment of neurological function as measured by "rod walking ability. Compounds that appeared to reduce motor activity (5250 count) are administered to additional groups of 5 mice at graded doses and tested similarly. The motor depressant dose (MDD) which causes a 50% reduction of motor activity (A count of 250) is estimated. The use of reduced motor activity as a measure of tranquilizing activity has been described by W. D. Gray, A. C. Osterberg and C. E. Rauh, Archives Internationales et de Therapie, vol. 134, p. 198 (1961) and by W. J. Kinnard and C. J. Carr, Journal of Pharmacology and Experimental Therapeutics, vol. 121, p. 354 (1957).

When tested by the above procedures, the following compounds of this invention show activity indicated in the table.

The anti-depressant properties of the compounds of the present invention are determined by measuring their ability to counteract a depression induced in animals by the administration of tetrabenazine hexamate. Graded doses of the active compounds of this invention are administered to groups of 5 mice each, and this is followed by administering a dose of tetrabenazine which is known to markedly depress the exploratory behavior of normal mice. The anti-depressant treated groups show normal exploratory behavior, while the control groups, and groups treated with an ineffective anti-depressant agent, do not show normal exploratory behavior, but show the well known profound depression induced by tetrabenazine. When tested by this procedure at an intraperitoneal dose of 1.6 mg./kg. the following compounds of this invention show anti-depressant activity: 2-chloro-11-(4-piperidyl)dibenzo- [b,f][1,4]thiazepine and l1-(4-piperidyl)dibcnz[b,f]- [1,4] oxazepine.

The compounds of this invention are, in general, oils or low melting solids only slightly soluble in water, but soluble in organic solvents such as methanol, ethanol and the like. They are basic substances which are usually soluble in aqueous minerals acids at room temperature. They form substantially insoluble acid addition salts such as the hydrochloride, sulfate, phosphate, citrate, tartrate, maleate, fumarate, etc. The present compounds, generally in the form of their salts, may be administered orally or parenterally and when so administered, are effective central nervous system agents. For oral administration the new compounds of this invention may be incorporated with the usual pharmaceutical excipients and used, for instance, in the form of tablets, capsules, dragees, liquids to be administered in drops, emulsions, suspensions and syrups, and in chocolate, candy, chewing gum and the like. They may also be administered in suppositories, and in aqueous solutions for parenteral injection.

ring Rig @313 X/ closure J h ,Nit

wherein R, R R R Y and X are as previously described.

By this method appropriately substituted isonipecotanilides are treated with acid condensing agents such as phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acid, zinc chloride, aluminum chloride and the like either alone or in combination or in the presence of an inert solvent such as benzene, Xylene, o-dichlorobenzene and the like. This reaction is generally carried out at an elevated temperature but the temperature may range from about 90 C. to about 240 C. The reaction is usually complete within several hours but may take as long as 2 to 4 days with mild reagents at low temperatures. The required substituted isonipecotanilides nipecotanilides, pipecolinanilides, etc. (H) are readily prepared by acylation of known o-aryloxyanilines and o-arylthioanilines with the desired substituted acid halide hydrohalide. This reaction is generally eifected in an inert solvent such as acetone, benzene, dimethylformamide and the like in the presence of an alkaline reagent such as triethylamine, pyridine, dimethylaniline, and the like.

By another method, a 2 (o aminophenoxy)phenyl l-substituted piperidyl ketone (III) is cyclized as follows:

MET;

R1 NH2 I ring R R closure \X/ (III) N it wherein R, R R R Y and X are previously described. This cyclization is generally effected in an inert solvent such as benzene, toluene, xylene and the like in the presence of an acidic catalyst. Reagents such as zinc chloride, sulphuric acid, p-toluene sulfonic acid, phosphorus pentachloride and the like are suitable for this purpose. A suitable temperature range is from about to C. A preferred embodiment of this method illustrates the synthesis of novel 2-substituted-11-(1-substituted-4-piperidyl)dibenz[b,f][1,4]oxazepines and thiazepines of this invention:

wherein R, R and X are as previously described. The requisite ketone (IIIa) are products of the reduction of nitroketones (IV), obtained by condensing o-nitrohalobenzenes with 2-hydroxyor 2-mercapto 5 substituted phenyl l-substituted 4 piperidyl ketone (V) which, in turn, are preparable from p-substituted phenols or thiophenols (VI) and isonipecotoyl halide hydrohalides (VII) in the presence of Friedel-Crafts catalysts such as zinc chloride, aluminum chloride, hydrogen fluoride and the like. This sequence may be illustrated as follows:

wherein R, R and X are as hereinbefore described and A represents a halogen atom of atomic weight less than 80.

Another general method applicable to the synthesis of these 11 substituted dibenz[b,f] [1,4]oxazepines and thiazepines involves cyclization at the diphenyl ether or diphenyl sulfide bridge as the terminal step. This process may be illustrated as follows:

wherein R, R R R Y and X are as hereinbefore described, and W and Z are reactive groups including mercapto, hydroxyl, halogen, nitro and diazonium, one of which is hydroxyl or mercapto.

Other methods for the synthesis of the novel ll-(lsubstituted 4 piperidyl)dibenz[b,f] [l,4]oxazepines and thiazepines of this invention involve transformations on suitably substituted dibenz[b,f] [l,4]oxazepines and thiazepines. One such general sequence may be illustrated as follows:

1 wherein R, R R and X are as hereinbefore described and E is a suitably reactive group such as halogen or arylsulfonyloxy (such as tosyloxy), and the like. Moreover, certain of the substituents R (Formula I) may be transformed to other substituents R as defined hereinbefore. Illustrative of such sequences are the conversion of carbethoxy to hydrogen (by hydrolysis), or to methyl (by reduction) and the conversion of hydrogen to 2- hydroxyethyl (by reaction with ethylene oxide) or to acyloxy lower alkyl (by reaction with ot-acetoxypropyl chloride). Alternatively, a variety of substituents on the aromatic rings such as amino, nitro, diazonium, and halogen groups may be converted to the R and R groups either directly or sequentially by methods well known to those skilled in the art.

Detailed description The following examples illustrate in detail the preparation of representative ll-substituted dibenz[b,f][l,4] oxazepines and thiazepines and intermediates.

EXAMPLE 1 Preparation of 2-chloro 1l-(l-methyl-4-piperidyl) dibenz[b,f] [1,4] oxazepine The hydrochloride salt of 2'-(p-chlorophenoxy)-l'- methylisonipecotanilide is prepared by dissolving 0.7 g. of the base in ethanol containing an excess of hydrochloric acid. The resulting solution is concentrated to dryness. To the residue is added 1.4 g. of phosphorus pentoxide and 5 ml. of phosphorus oxychloride. The mixture is refluxed for 48 hours, after which it is quenched with ice and made alkaline with potassium hydroxide. The semi-solid product is collected, and is dried in a vacuum over phosphorus pentoxide. This semi-solid product is purified by adsorption chromatography on an alumina column. The purified product is eluted from the column using an ethyl acetatehexane solvent system. Removal of the solvent then gives 2 chloro ll (1-methyl-4-piperidyl)dibenz[b,f][1,4] oxazepine as a clear, colorless oil. The ultraviolet absorption spectrum of this material shows xCHKOH 300, 325 my. @5200, 5500, respectively) 6 EXAMPLE 2 Preparation of 2'-(p-chlorophenoxy)-1-methylisonipecotanilide A slurry of l-methylisonipecotoyl chloride hydrochloride is prepared by the reaction of thionyl chloride (25 ml.) and 9.7 g. of l-methylisonipecotic acid, hydrochloride at 25 C. After the evolution of gas ceases, the excess thionyl chloride is removed by distillation under reduced pressure. The crystalline residue is triturated with 250 ml. of anhydrous hexane. The resulting suspension is concentrated to dryness under reduced pressure (thereby removing solvent and residual thionyl chloride). This residue is then taken up in 200- ml. of anhydrous acetone. To this slurry is added 10.4 g. of 2-(pchlorophenoxy)aniline in 50 ml. of acetone. After 20 minutes, 10 g. of triethylamine is added, with the immediate formation of a heavy slurry. After stirring for 2 hours at room temperature, the reaction mixture is filtered and the filtrate is concentrated to dryness. The residue is dissolved in a benzene-water mixture and the aqueous phase is made basic wtih potassium carbonate. The product is extracted into benzene and the benzene layer is dried over potassium carbonate and concentrated under reduced pressure. Recrystallization from hexane then gives 2'-(p-chlorophenoxy)-1-methylisonipecotanilide, melting point l4ll43 C.

EXAMPLE 3 Preparation of 2-chloro-l l-( l-methyl-4-piperidyl)dibenzo[b,f] [1,4] thiazepine hydrochloride The hydrochloride salt of 2- p-chlorophenylthio)-lmethylisonipecotanilide is prepared with ethanolic hydrochloric acid as in the procedure of Example 1.

This compound is treated with polyphosphoric acid (30:1 by weight) and is heated to about C. for approximately 8 hours. After which it is quenched on ice and made alkaline. The product is extracted into ether, dried with potassium carbonate and concentrated to dryness. The oily residue is dissolved in ethanol containing an equivalent amount of hydrochloric acid and the addition of ether precipitates 2-chloro-11(1-methyl- 4 piperidyl)dibenzo[b,f] [1,4]thiazepine hydrochloride, melting point 234-237 C.

EXAMPLE 4 Preparation of 2- (p-chlorophenylthio) -1-methylisonipecotanilide To a suspension of l-methylisonipecotoyl chloride hydrochloride, prepared by the procedure used in Example 2, in acetone is added 2-(p-chlorophenylthio)aniline. After 20 minutes, two equivalents of dimethylaniline is added with the immediate formation of a heavy precipitate. After stirring overnight the dimethylaniline hydrochloride is removed by filtration. The filtrate is concentrated to dryness and the residue is recrystallized from hexane to give 2 (p-chlorophenylthio)-l-methylisonipecotanilide, melting point l26l28 C.

EXAMPLE 5 Preparation of 11-( l-methyll-piperidyl) dib ,f] [1,4] oxazepine The compound o-phenoxyaniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 4 to give 1-methyl-2'-phenoxyisonipecotanilide.

This compound is cyclized With phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to give ll-(l-methyl-4-piperidyl.)dibenz- [b,f][1,4]oxazepine. Hydrogenolysis of Z-chloro-ll-(lmethyl-4-piperidyl)dibenz [b,f] [1,4] oxazepine with palladium in ethanol gives ll-(l-methyl-4-piperidyl)dibenz- [b,f][1,4]oxazepine hydrochloride, melting point 230- 35 C.

7 EXAMPLE 6 Preparation of 11 1-methyl-4-piperidyl)dibenzo- [b,f] [1,4] thiazepine The compound o-phenylthioaniline is reacted with l-methylisonipecotoyl chloride hydrochloride as in Example 4 to give l-methyl-2-(phenylthio)isonipecotanilide.

The latter compound is cyclized wtih polyphosphoric acid according to the procedure of Example 3 to give 11- 1-methy1-4-piperidyl) dibenzo [b,f] [1,4] thiazepine.

EXAMPLE 7 Preparation of 2-chloro-11-(4-piperidyl) dib i] [1,4] oxazepine 1 carbobenzyloxy-2'-(p-chlorophenoxy)isonipecotanilide is prepared by treating a solution of l-carbobenzloxyisonipecotic acid in tetrahydrofuran with carbonyldiimidazole at 10 C., followed by the addition of o-(pchlorophenoxy)aniline.

This compound is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to give 2-chloro-1l(4-piperidyl)dibenz- [b,f] [1,4] oxazepine. 2-chloro 11 (4-piperidyl)dibenz- [b,f] [1,4]oxazepine is also prepared by cleavage of 11-(1- carbobenzyloxy-4-piperidyl) 2 chlorodibenz[b,f] [1,4]- oxazepine wtih' hydrobromic acid in glacial acetic acid. The hydrochloride has melting point 2735 C.

EXAMPLE 8 Preparation of 11-(4-piperidyl)dibenzo[b,f] [1,4] thiazepine 1 carbobenzyloxy-2'-(phenylthio)isonipecotanilide is prepared by treating a solution of l-carbobenzyloxyisonipectic acid in tetrahydrofuran with carbonyldiimidazole at C. followed by the addition of o-(phenylthio) aniline. The mixture is refluxed for 1 hour and the product is isolated.

This compound is cyclized with polyphosphoric acid according to the procedure of Example 3 to give 11-(4- piperidyl -dibenzo [b,f] [1,41thiazepine.

EXAMPLE 9 Preparation of 2-chloro11(4-piperidyl)dibenzo- [b,f] [1,4] thiazepine 1 carbobenzyloxy 2' (p chlorophenylthio)isonipecotanilide is prepared as described in the procedure of Example 7. This compound is cyclized with polyphosphoric acid as in Example 3 to give 2-chloro- 11- (4 piperidyl) dibenzo [b,f] [1,4]thiazepine hydrochlorlde, melting point 302 C.

EXAMPLE 10 of 2-chloro-1 1-[ 1-(2-hydroxyethyl) -4-piperidyl] dibenz [b,f] [1,4] oxazepine 2-(p-chlorophenoxy) aniline is treated with the a-lactone of a-hydroxy-u-(Z-hydroxyethyl)butyric acid to give 2'-(p-chlorophenoxy) -4-hydroxy-2 (2 hydroxyethyl)butyranilide. This compound is refluxed with phosphorus pentoxide and phosphous oxychloride according to the procedure of Example 1 to give 2-chloro-11-[bis(2-chloroethyl) methyl] dibenz [b,f] [1,4] oxazepine hydrochloride. Treatment of 2-chloro-1 1- [bis (2-chloroethyl methyl] dibenz[b,f] [l,4]oxazepine hydrochloride with amino-ethanol yields the desired compound 2-chloro-ll-[1-(2-hydroxyethyl) -4-piperidyl] dibenz [b,f] 1,4] oxazepine.

Treatment of 2 chloro 11-(4-piperidyl)dibenz[b,f] [1,4] oxazepine with ethylene oxide gives the same com- Preparation pound 2 chloro 11-[1-(2-hydroxyethyl)-4-piperidyl]dibenz [b,f] [1,4] oxazepine.

EXAMPLE 11 Preparation of 1 1-[ 1-(2-hydr'oxyethy1)-4-piperidyl] dibenzo [b,f [1,4] thiazepine l1-(4-piperidyl)dibenzo[b,f] [1,4] thiazepine (Example 8 is treated with ethylene oxide in ethanol to give 11- l- 8 (Z-hydroxyethyl) 4 piperidyl] dibenzo [b,f] [l,4]thiazepine.

EXAMPLE 12 Preparation of 11-[ l-(2-acetoxyethyl)-4-piperidyl] dibenzo [b,f] [1,4] thiazepine.

ll -[1 (2 hydroxyethyl) 4 piperidyl]dibenzo[b,f] 1,4]thiazepine (Example 11) is treated with acetic anhydride and 11 [l (2 acetoxyethyl)-4-piperidyl] dibenzo [b,f] [l,4]thiazepine is thereby obtained.

EXAMPLE 13 Preparation of l1-(1-carbethoxy-4-piperidyl)-2-chlorodibenzo[b,f] [-,4]thiazepine is treated with ethyl chlorocarbonate in the presence of pyridine to yield 11-( 1-carbethoxy-4-piperidyl) -2-chlorodibenzo[h,f] [1,4] thiazepine.

EXAMPLE 14 Preparation of 1 1- (4-piperidyl)dibenz[b,f] [1,4] oxazepine A solution of 1-carbobenzyloxyisonipecotic acid in tetrahydrofuran at 10 C. is treated with carbonyldiimidazole followed by o-phenoxyaniline. The mixture is refluxed and the 1 carbobenzyloxy 2'-phenoxyisonipecotanilide which forms, is isolated. This compound is cyclized with phosporus pentoxide in phosphorus oxychloride according to the procedure of Example 1 to give 11-(4-piperidy1)dibenz[b,f] [1,4] oxazepine hydrochloride, melting point 259-262 C.

EXAMPLE 15 Preparation of 1 1-( 1-carbobenzy1oxy-4-piperidyl)dibenz [b,f] [1,4] oxazepine 11 (4 piperidyl)dibenz[b,f] [1,4]oxazepine, prepared according to the procedure of Example 14, is treated with carbobenzyloxy chloride to give 1l-(1-carbobenzy1oxy-4- piperidyl) dibenz [b,f] [1,4] oxazepine.

EXAMPLE 16 Preparation of 1 1-( 1-methyl-4-piperidyl) -2-trifluoromethydibenz [b,f] [1,4] oxazepine 2-(u,a,a-trifluoro-ptolyloxy)aniline is treated with 1- methylisonipecotoyl chloride hydrochloride by the procedure of Example 4 to give 1-methyl-2'-(a,a,a-trifluorop-tolyloxy)isonipecotanilide. This compound is treated with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to give 11-(1- methyl-4 piperidyl) 2 trifiuoromethyldibenz [-b,f] [1,4] oxazepine.

EXAMPLE 17 Preparation of 2-bromo-11-(1-methyl-4-piperidyl)dibenzo [bi] [1,4] thiazepine The methods of Examples 4 and 3 are repeated. Thus, 2-(p-bromophenylthio)aniline is acylated with l-methylisonipecotoyl chloride hydrochloride to give 2'-(p-bromo phenylthio)-l-methylisonipecotanilide, as in Example 4. This compound is cyclized in hot polyphosphoric acid, as in Example 3, to give 2-bromo-11-(1-methyl-4-piperidyl) dibenzo [b,f] [1,4] thiazepine.

EXAMPLE 18 Preparation of 2-fluoro-1 1-( 1-methyl-4-piperidyl dibenzo i] [1,4] thiazepine The methods of Examples 4 and 3 are repeated. Thus, Z-(p-fluorophenylthio)aniline is acylated with l-methylisonipecotoyl chloride hydrochloride to give 2'-(p-fluorophenylthio)-1-methylisonipecotanilide, as in Example 4. This compound is cyclized in hot polyphosphoric acid, as in Example 3, to give 2-fluoro-l1-(1-methyl-4-piperidyl) dibenzo [b,f] 1,4] thiazepine.

9 EXAMPLE 19 Preparation of 2-(N,N-dimethylsulfamoyl)-1 1-( l-methyl- 4-piperidyl) dibenz b,f] [1,4 oxazepine o [p (N,N dimethylsulfamoyl)phenoxy]aniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 4 to give 2-[p-(N,N-dimethylsulfamoyl)phenoxy] 1 methylisonipecotanilide. This compound is cyclized with phosphorus oxychloride according to the procedure of Example 1 to yield 2-(N,N- dimethylsulfamoyl) 11 (1 methyl 4 piperidyl) dibenz[b,f] [1,4] oxazepine.

EXAMPLE 20 Preparation of 3-acetyl-l1-(l-methyl-4-piperidyl)dibenz i] 1,4] oxazepine The compound o-(m-acetylphenoxy)aniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 4 to give 2'-(m-acetylphenoxy)-lmethylisonipecotanilide. This compound is cyclized with phosphorus pentoxide and phosphorous oxychloride according to the procedure of Example 1 to yield 3-acetyl- 11-(1-methyl-4-piperidyl)dibenz[b,f] [1,4] oxazepine.

EXAMPLE 21 Preparation of 2-methoxy-11-(1-methyl-4-piperidyl)dibenz[b,f] [1,4] oxazepine Hydroquinone monomethyl ether is acylated with 1- methylisonipecotic acid under Friedel-Crafts conditions in the presence of anhydrous hydrogen fluoride. The resulting 2-hydroxy-5-methoxyphenyl 4-piperidyl ketone is condensed with o-chloronitrobenzene in the presence of potassium carbonate and copper powder, and the resulting nitro compound is hydrogenated over palladium on charcoal in ethanol to give 2-(o-aminophenoxy)-5-methoxyphenyl 1- methyl-4-piperidyl ketone. This compound is heated in xylene in the presence of zinc chloride to give Z-methoxy- 11-( 1-methy1-4-piperidyl)dibenz [b,f] [1,4] oxazepine.

The same compound is obtained when o-(p-methoxyphenoxy)-aniline is heated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 4 to give 2'-(p-rnethoxyphenoxy) 1 methylisonipecotanilide which is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to yield Z-methoxy-ll-(1-methyl-4-piperidyl)dibenz[b,f] [1,4] oxazepine.

EXAMPLE 22 Preparation of 11-( l-methyl-4-piperidyl)-2methylthiodibenz[b,f] [1,4] oxazepine o-(p-Methylthiophenoxy)aniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 4 to give 2-(p-methylthiophenoxy)-1-methylisonipecotanilide. This compound -is cyclized with phos phorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to yield 11-(1-methyl-4- piperidyl) -2-methylthiodibenz[b,f] [1,4] oxazepine.

EXAMPLE 23 Preparation of 2-chloro-8-methyl-l1-(1-methyl-4- piperidyl)dibenzo [b,f] [1,4] thiazepine The methods of Examples 4 and 3 are repeated. Thus, 4-(p-chlorophenylthio) m toluidine is acylated with l-methylisonipecotoyl chloride hydrochloride to give 4'- (p-chlorophenylthio -1-methyl-m-isonipecotoluidide as in Example 4. This compound is cyclized in hot polyphosphoric acid as in Example 3 to give 2-chloro-8-methyl- 11-(1-methy1-4-piperidyl)dibenzo[b,f] [1,4] thiazepine.

EXAMPLE 24 Preparation of 8-methyl-11-(1-methyl-4-piperidyl) dibenzo [bi] [1,4] thiazepine 2-chloro-8-methyl-l1 (1 methyl-4-piperidyl)dibenzo- [b,f] [1,4]thiazepine, prepared as in Example 23, is dissolved in ether and added to a suspension of magnesium in ether previously activated by treatment with a little ethylene dibromide. The resulting Grignard reagent is decomposed by cautious addition of water to yield 8-methyl-11-(l methyl 4 piperidyl)dibenzo[b,f] [1,4] thiazepine.

EXAMPLE 25 Preparation of 2-chloro-1 1-(1-methyl-4-propy1-4- piperidyl dibenzo [b,f] [1,4] thiazepine Preparation of Z-chloro-l 1-(1-methy1-3-pyrrolidinyl) dibenz[b,f] [1,4] oxazepine The methods described in Examples 1 and 2 are used, and 2-(p-chlorophenoxy)aniline is treated with l-methyl- 3-pyrrolidinecarbonyl chloride hydrochloride, by the procedure of Example 2, to give 2-(p-chlorophenoxy)-1- methyl-3-pyrrolidinecarboxanilide. This compound is cyclized with phosphorus pentoxide in phosphorus oxychlo ride to give 2-chloro-l1-(1-methy1-3-pyrrolidiny1)dibenz- [b,f] [1,410xazepine.

EXAMPLE 27 Preparation of 2-chloro-11-(1-methyl-3-piperidy1) dibenzo [b,f] [1,4] thiazepine The methods of Examples 4 and 3 are repeated. Thus, Z-p-chlorophenylthio)aniline is acylated with l-methylnipecotoyl chloride hydrochloride to give 2'-(p-chlorophenylthio)-lmethylnipecotanilide as in Example 4. This compound is cyclized in hot polyphosphoric acid, as in Example 3, to give 2-chloro-l1-(1-methyl-3-piperidyl) dibenzo [b,f] [1,4] thiazepine.

EXAMPLE 28 Preparation of 2-chloro-1 1-(1-methyl-2-piperidyl) dibenzo['b,f] [1,4] thiazepine The methods of Examples 4 and 3 are repeated. Thus, 2-(p-chlorophenylthio)aniline is acylated with l-methylpipecoloyl chloride hydrochloride to give 2'-(p-chlorophenylthio)-1-methylpipecolanilide as in Example 4. This compound is cyclized in hot polyphosphoric acid as in Example 3 to give 2-chlor0-l1-(1-methyl-2-piperidyl) dibenzo[b,f] [1,4] thiazepine.

EXAMPLE 29 Preparation of 11-(6-methy1-3-piperidyl)dib [b,f] [1,4]oxazepine A solution of 1-car-bobenzyloxy-S-methylnipecotic acid in tetrahydrofuran at 10 is treated with carbonyldiimidazole followed by p-phenoxyaniline. The mixture is refluxed and 1-carbobenzyloxy-6-methyl-2'-phenoxynipecotanilide which forms, is isolated. This compound is cyclized With phosphorus pentoxide in phosphorus oxychloride according to the procedure of Example 1 to give 11-(6-methyl-3-piperidyl)dibenz[b,f] [l,4]oxazepine EXAMPLE 30 Preparation of 11-( 1-methyl-4-piperidyl)-2-nitrodibenz [b,f] [1,4]oxazepine The compound o-(p-nitrophenoxy)aniline is treated with l-methylisopecotoyl chloride hydrochloride by the procedure of Example 4 to give 1-methy1-2-(p-nitrophenoxy) isonipectanilide.

This compound is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to give 11-(1-methyl-4-piperidy1)-2-nitrodibenz [b,f] [1,4]oxazepine.

What is claimed is:

1. An ll-substituted dibenz[-b,f][1,41heteroazepine of the formula:

Y La where R is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, carbo(lower)alkoxy, and carbobenzyloxy; R is selected from the group consisting of hydrogen and lower alkyl; R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, methylthio, halogen, trifluoromethyl, di(lower) alkylsulfamoyl, lower alkanoyl and nitro; X is selected from the group consisting of oxygen and sulfur; Y is selected from the group consisting of methylene and ethylene; and non-toxic acid addition salts.

2. The 11-substituted dibenz[-b,f] [1,4]heteroazepine according to claim 1; 2-chloro-11-(1-methyl-4-piperidyl)di- 'benz[b,f] [1,4] oxazepine.

3. The ll-substituted dibenz[ b,f] [1,4]heteroazepine ac- 12 cording to claim 1; 11-(1-methyl-4-piperidyl)dibenz[b,f] [1,4] oxazepine.

4. The ll-substituted dibenz [13,1] [1,4]heteroazepine according to claim 1; 2-chloro-,11-(1-methyl-4-piperidyl)dibenzo [b,f] [1,4]thiazepine.

5. The ll-substituted dibenz[-b,f] [1,4]heteroazepine according to claim 1; 2-chloro-11-(4-piperidyl)di-benz[b,f] [1,4] oXaZepine.

6. The ll-substituted dibenz[b,f] [1,41heteroazepine according to claim 1; 2-chl0ro-1 1- (4-piperidyl) dibenzo b,f] [1,4] thiazepine.

7. The ll-substituted dibenz[-b,f] [1,4]heteroazepine according to claim 1; 2-chloro-11-[1-(2-hydroxyethyD-4- piperidyl] dibenz[b,f] [1,4] oxazepine.

8. The ll-substituted di-benz ['b,f] [1,4]heteroazepine according to claim 1; 11- (4-piperidyl) dibenz [b,f] [1,4] oxazepine.

9. The ll-substituted dibenz[-b,f] [1,41heteroazepine according to claim 1; 2-bromo-11-(1-methy1-4-piperidyl)dibenzo [b,f] [1,4] thiazepine.

References Cited UNITED STATES PATENTS U.S. Cl. X.R.