Patent Publication Number: US-3875166-A

Title: 3-(Aminoalkoxy)-2,3-dihydroquinobenzoxa(or thia) zepine derivatives

Description:
United States Patent [191 Yale et a1.  
 [ 3-(AMlNOALKOXY)-2,3-  
 DIHYDROQUINOBENZOXMOR THIA) ZEPINE DERIVATIVES [75] Inventors: Harry L. Yale, New Brunswick,  
 NJ.; Ramesh B. Petig&#39;ara, Lansdale,  
 [73] Assignee: E. R. Squibb &amp; Sons, Inc.,  
 Princeton, NJ.  
 [22] Filed: Oct. 29, 1973 [21] Appl. No.: 410,860  
  Related U.S. Application Data [62] Division of Ser. No. 222,286, Jan. 31, 1972, Pat. No.  
 Primary Examiner-Donald G. Daus Assistant Examiner-Mary C. Vaughn Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith; Donald J. Barrack Apr. 1, 1975 [5 7] ABSTRACT 3-(Aminoalkoxy)-2,3-dihydroquinobenzoxa(or thia) zepine derivatives are provided having the structures H A-CH wherein A is O or S; and X, Y, R, R n, n and n&#34; are as defined hereinafter. These compounds are useful as anti-inflammatory agents, and central nervous system stimulants 0r depressants depending on dosage.  
 4 Claims, N0 Drawings 1 3-(AMINOALKOXY)-2,3- Dll-IYDROQUINOBENZOXA(OR THIA) ZEPINE DERIVATIVES This is a divisional application of Ser. No. 222,286, f led Jan. 31, 1972, now U.S. Pat. No. 3,809,698.  
  The present invention relates to 3-aminolkyloxy-2,3- dihydroquinobenzoxa(or thia)zepine derivatives of the structure A-CH o 7 a 1 or -12 n N CH wherein X and Y are the same or different and can be halogen. trifluoromethyl, lower alkyl, cycloalkyl, lower alkylmercapto, lower alkyloxy, cyano, isocyanido or di-lower alkylsulfamoyl, A is O or S, n is 0, l or 2, n is 0, l or 2 an n&#34; is l to 10, and pharmaceutically acceptable acid-addition salts thereof.  
  The term &#34;lower alkyl&#34; as employed herein includes both straight and branched chain radicals of up to and including eight carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, pentyl, hexyl, isohexyl. heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like. The lower alkyl group can include substituents such as aryl.  
 The term halogen includes F, Cl, Br or I.  
  The lower alkylmercapto groups contain up to eight carbon atoms and include methylmercapto, ethylmercapto. propylmercapto and mercapto radicals containing any of the lower alkyl groups mentioned hereinbefore.  
  The terms lower alkyloxy and lower alkoxy are interchangeable and refer to groups containing up to eight carbon atoms and which include any of the lower alkyl groups mentioned hereinbefore attached to an oxygen atom.  
  The term cycloalkyl includes saturated ring systems contain from three to seven carbons such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.  
  The term alkenyl includes mono-unsaturated straight chain or branched chain radicals of less than eight carbons corresponding to lower alkyl as defined above.  
  ln the above Formulae l and Il, each of the carbocyclic aromatic rings can include 0, l or 2 substituents, other than hydrogen. The nature and position of the substituents in the starting materials will determine which isomer, Type 1 and/or Type II, is obtained.  
  R and R may be the same or different and represent hydrogen, lower alkyl, aralkyl and alkenyl; NRR  
 taken together is a heterocyclic radical having the formula v -N I X&#39; l (c11 a in which X represents NR, 0, S or CH r represents 1, 2 or 3; R represents hydrogen, lower alkyl, hydroxylower alkyl, lower alkanoyloxy-lower alkyl, hydroxylower alkoxy-lower alkyl, di(lower alkyl)amino-lower alkoxy-lower alkyl, lower-alkylamino-lower alkyl, dilower alkyl amino-lower alkyl, amino -lower alkyl; and R represents any of the R groups. These may be exemplified by piperidinyl; (lower alkyl)piperidinyl [e.g., 2-, 3- or 4-(lower alkyl)piperidinyl]; (lower alkoxy)- piperidinyl; pyrrolidinyl; (lower alkyl)-pyrrolidinyl; (lower alkoxy)pyrrolidinyl; piperazinyl; (lower alkyl)- piperazinyl (e.g-, N -methylpiperazinyl); di(lower alkyl)piperazinyl; (lower alkoxy)piperazinyl; (hydroxylower alkyl)piperazinyl [e.g., N*-(2-hydr0xyethyl)- piperazinyl]; (lower alkanoyloxyalkyl)piperazinyl [e.g., N -(2-acetoxyethyl)piperazinyl]; (hydroxy-lower alkoxy-lower&#39; alkyl)piperazinyl [e.g., N*-[2-(2 hydroxyethoxy)ethyl]piperazinyl]; di-(lower alkyl- )amino-(lower alkoxy-lower alkyl)piperazinyl [e.g., N -[2-(2-dimethylaminoethoxy)ethyl]piperazinyl]; homopiperazinyl; amino(lower alkyl) piperidinyl [e.g., 3-(aminoethyl)piperidinyl], lower alkylamino (lower alkyl)piperidinyl[e.g., 2-[(methylamino)ethyl]- piperidinyl], di-lower alky|amino(lower alkyl) piperidinyl[e.g.,4-[dimethylamino(methyl)]piperidinyl].  
  The salts of the compounds of this invention include the acid-addition salts, particularly the non-toxic acidaddition salts. Acids useful for preparing the acidaddition salts, include inter alia, organic acids, such as oxalic, maleic, fumaric, tartaric, citric, pamoic. acetic, and succinic acid.  
  As will be seen hereinafter, the compounds of the invention are prepared from starting materials of the structure 5 it ii I In 00 6:; or)  
 ca cit N g l CH CH COOH Where in the starting material III, 11 is l or 2 and X includes a strongly electronegative group like trifluoromethyl, cyano, isocyanido or di-lower alkylsulfamoyl substituent at the 7-position,&#39; and n is 0, or Y is a substituent at a position other than 3 and 4 in the starting material, cyclization is directed to the 4-position so that the Type II isomer is subsequently formed. However, where X is an ortho-para orienting group like halogen, especially chlorine, and n is l or 2 and at least one halogen is at the 7-position of starting material III, or is lower alkyl, lower alkyloxy, cycloalkyl or lower alkylmercapto at any position or a strongly electronegative group at a position other than 3, or when n is 0, a mixture of the Type I and Type II isomers is obtained.  
  Where in the starting material 111, n is l or 2 any Y includes a strongly electronegative group like trifluoromethyl, cyano or di-lower alkylsulfamoyl at the 3- position, and n is O, or X is a substituent at a position other than 7 in the starting material, cyclization is di-- rected to the 6-position so that the Type I isomer is subsequently formed.  
  Where in the starting material III, n is l or 2 and Y includes an ortho-para orienting substituent at the 3- position, and n is 0, or X is a substituent at a position other than 7 in the starting material, cyclization is directed to the 6-position so that the Type I isomer is subsequently formed.  
  Where n and n&#39; are 0, that is where there are no substituents on either aromatic ring, the Type I isomer is obtained, that is Where the starting material does not include substituents at the 3 and/or 7 positions, but does include substituents such as lower alkyl, lower alkyloxy, cycloalkyl or lower alkylmercapto at the 2,8 and/or 9 positions, the Type I isomer is obtained.  
  Where the starting material does no include substituents at the 3 and/or 7 positions, but does include strongly electronegative groups at the 1 and/or 9 positions, the Type I isomer is obtained. However, where the starting material includes a strongly electronegative group at the 2 and/or 8 positions, then a mixture of the Type I and Type II isomers is obtained.  
  Where X represents a strongly electronegative group like trifluoromethyl, cyano or di-lower alkylsulfamoyl and n is l or 2 at least one X being at the 7-position of the starting material and Y is lower alkyl, lower alkylmercapto, cycloalkyl or lower alkoxy at any position or any of the above strongly electronegative groups at a position other than 3 in the starting material and n is O, l or 2, the Type II isomer is obtained.  
  Where X is lower alkyl, lower alkyloxy, cycloalkyl, or lower alkylmercapto and n is l or 2 and Y is halogen, trifluoromethyl, cyano, isocyanido or di-lower alkylsulfamoyl, and n is l or 2 at least one Y being at the 3- position of the starting material, the Type I isomer is obtained. In this case, X can be trifluoromethyl or other strongly electronegative group so long as it is not in the 7-position of the starting material as will be seen hereinafter.  
  Where X is lower alkyl, lower alkyloxy, cycloalkyl or lower alkylmercapto. and n is l or 2 and n in (Y),,, is 0, the Type I isomer is obtained.  
  Where Y is lower alkyl, lower alkyloxy, cycloalkyl or lower alkylmercapto and n is l or 2 and the n in (X),, is 0, the Type II isomer is obtained.  
  Where both X and Y represent lower alkyl, lower alkoxy and/or lower alkylmercapto, at least one of said groups being at the 3 and 7 positions of the starting material, the Type I isomer is obtained.  
  Preferred are those compounds of Formula I wherein and n&#39;=O and n&#34; is 2 or 3 and A=0, those compounds of Formula I wherein n=O, n=l and Y is Cl at the l l-position, and n=l, n&#39;=0 and n&#34; is 2 or 3 and X is Cl at 4-position and A=0 and those compounds of Formula II wherein n=l, X is CF or C] at the 11- position, n&#39;=0, and A=0.  
  Compounds of the Formulae I and II can be prepared from VII or VIII obtained by reducing a 3-one of the structure Ib-CH (xi by reacting it with any of the reducing agents, like lithium aluminum hydride and preferably sodium borohydride, to form the corresponding 3-hydroxy compound of the structure VIII  The 3-hydroxy compound (VII or VIII) is treated with a base such as sodium hydride or potassium hydride, in the presence of an aromatic hydrocarbon solvent such as benzene, toluene or xylene, at a temperature within the range of from about 10 to about 130C and preferably from about 30 to about 1 10C and the resulting reaction mixture is reacted with a compound of the structure to form compounds of structures I or II.  
  The 3-one starting materials can be prepared by reacting a compound of the structure IO A-CHZ- I III l H CH 11 l CHZCHZCOOH The 3-chloro compounds of structures X and XI can be converted to compounds of formula I or II of the in- I vention by reacting them with a hydroxy alkyleneamine Where&#34;! 1 and A are 115 defined hefelnbefore,  
 of the structure X&#34; with a phosphorus pentahalide, such as phosphorus l 2 pentachloride, in a molar ratio of lll:pentahalide of 2)n NR R within the range of from about 0.911 to about 1:1, in the XII absence of oxygen, and in the presence.of an inert solvent, such as benzene, toluene, xylene, etc., at a tem- Compounds of formula [or II can also be prepared perature within the range of from about 0 to about by treating a 3-hydroxy compound (VII or VIII) with 50C, to f rm an acyl halide of th str tur a base such as an alkali metal hydride, such as sodium hydride or potassium hydride, in the presence of an aromatic hydrocarbon solvent, such as benzene, toluene or xylene at a temperature within the range of from (X) (y) about 10 to about 130C and preferably from about XVII CH CH n 30 to about 1 10C; the reaction mixture is treated with N a dihaloalkane of the structure Z Z fi L Hal(CH- Hal 0 The acyl haldie XVII 1s reacted with anhydrous stannic chloride in a molar ratio of acyl halide XVIIzstannic chloride within the range of from about 0.4:1 to about 1:1, at a temperature within the range of from about 20 to about 30C to form the formulae V and VI,3 or  
 wherein Hal and Hal are different and can bel, Br, C1, or F. to form a compound of the structure I 3-one compounds depending upon the nature and the position of the X and Y substituents. m (Yi or N CH XIV  
 XV O u H Compound XIV or XV is then reacted with an amine of the structure 5 HNRIR2 The compounds of formula V and/or VI can also be XVI prepared by reacting the starting material 7 A-cn III IL 1% (W cu N c l CH CH COOH with trifluoroacetic anhydride (preferred) or phosphorus pentoxide, in a molar ratio of lllztrifluoroacetic anhydride, or phosphorus pentoxide of within the range of from about 0.9:1 to about 1:1, in the presence of an inert solvent such as benzene, toluene, xylene, pentane, hexane, etc., at a temperature within the range of from about to about 80C, or with polyphosphoric acid (PPA) in a molar ratio of lllzPPA of Within the range of from about 1:10 to about 1:25.  
  The starting materials of formula III are prepared by a sequence of reactions. First step comprises reacting compounds having the formula XVIII:  
 with acrylonitrile to yield compounds of formula XIX I CH CH CN wherein n, n, X, Y and A are as defined herein.  
  This reaction is carried out by employing an excess of the acrylonitrile as the solvent. The temperature utilized in the reaction can be varied from about 0 to about l0OC with the preferred range being between about 0 and about 75C. This reaction proceeds expeditiously when a small amount (up to about 1%) of a strong base like sodium hydroxide, sodium methoxide, potassium t-butoxide, or preferably benzyl trimethylammonium hydroxide (Triton B) is used as the catalyst.  
  The next step for preparing compounds of formula III is to treat the compounds of structure XXV with alcoholic hydrogen halide, such as hydrogen chloride in methanol, ethanol, and so forth, at room temperature whereby esters of the structure XX are formed.  
 . zx-cn (x) 2 xx n J (W CH ca clude, but are not limited to, the following wherein A can be 0 or S.  
 CH CH COOH ca ca cooa CH &#39;CH COOH CH2CH.,COOH&#39; O A-Cl-L, ca  
 CH CH COOH CH Cl \ca v ea CN I ca cn coofi ctr cn coon car Compounds of this invention are therapeutically active compounds which are useful as central nervous system stimulants or depressants depending upon dosage employed, or as anti-inflammatory agents. For these purposes, they may be administered orally or parenterally in such form as tablets, capsules, injectables, or the like by incorporating the appropriate dosage of the compound with carriers according to accepted pharmaceutical practices.  
  When the compounds of the invention are employed as central nervous system depressants, the dose for humans would be initially about 200 mg., administered two or three times daily. This level would be maintained for 4 to 6 days, and would then be increased to about 400 mg., 2 or 3 times daily, for complete therapeutic maintenance. When the compounds of the invention are employed as stimulants, the dose for humans would be initially about mg., administered 2 to 3 times daily. This level would be maintained for 4 to 6 days, and would then be increased to about 40 mg., 2 or 3 times daily for complete therapeutic maintenance.  
  The compounds of this invention are also useful as anti-inflammatory agents in warm blooded animals in a manner similar to indomethacin. They may be used to decrease joint swelling, tenderness, pain and stiffness, in mammalian species, e.g., in conditions such as rheumatoid arthritis. A compound of formula I or a physiologically acceptable salt (when applicable) of the character described above may be compounded according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about mg to 1 gm per day in two to four divided doses.  
  They may also be used as surface disinfectants. About 0.01 to 1 percent by weight of any of these substances may be dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. They may be incorporated also, for example, in a soap or other cleansing agent, e.g., a solid or liquid detergent, detergent composition, for example, in general cleaning, in cleaning dairy barns or equipment or cleaning food handling or processing equipment.  
  The following examples illustrate the present invention without, however, limiting the same thereto. All temperatures are expressed in C.  
 EXAMPLE 1 2,3-Dihydro-3-[3-(4-methyl)-lpiperazinyl)propoxy]-l l-(trifluoromethyl)- ll-l,7l-l-quino[8,l-cd][1,5]benzoxazepine Maleate salt 1:2) A. 5,1 l-Dihydro-7- trifluoromethyl )dibenzl b,e][ 1,4]oxazepine-5- propionic acid To 50.0 g of 5,1l-dihydro-7- trifluoromethyl)dibenz[b,e][1,4]oxazepine in 60 ml of redistilled acrylonitrile is added in 5 minutes 0.80 ml of Triton B. Subsequently, the mixture is heated for one hour under reflux and the product isolated by extraction with benzene to give 5,1 1-dihydro-7- (trifluoromethyl)dibenz[b,e][1,4]oxazepine-5- propionitrile, m.p. about l6ll63.  
  7-(Trifluoromethyl )-5 ,l ldihydrodibenz[ b,e][ 1,4 ]oxazepine-S-propionitrile, 15.0 g, is dissolved in 240 ml of dry dioxane and to this 140 ml of 30% methanolic hydrogen chloride is added. The solution is stirred for 36 hours; 6 ml of H 0 is added, stirred 0.5 hour, and then concentrated in vacuo to ml. The solid is filtered, and the filtrate is concentrated to dryness in vacuo. The residual liquid is taken up in 200 ml of diethyl ether, treated with Darco and Hyflo, the diethyl ether solution concentrated and the residue distilled in vacuo to give 13.1 g. 5,1 l-dihydro-7- (trifluoromethyl)dibenz[b,e][1,4]oxazepine-5- propionic acid, methyl ester, b.p. about l66l 68 (0.08 mm.), m.p. about 70.07l.5.  
  7-(Trifluoromethyl)-5,1 ldihydrodibenz[b,e][ l,4]oxazepine-5-propionic acid, methyl ester, 3.15 g, is dissolved in 315 ml of methanol and to this 0.5 g of potassium hydroxide dissolved in 25 ml of water is added. The mixture is refluxed for 2.5 hours and then concentrated in vacuo. The residue is taken up in 250 ml of water and this solution is aciditied with 2% aqueous HCl to give 5,1 l-dihydro-7- (trifluoromethyl)dibenz[b,e&#39;r[ 1,4]oxazepine-5- propionic acid, m.p. about l05l07C. B. 1,2-Dihydro-l l-(trifluoromethyl)-3H,7H- quino[8,1-c,d][ l ,5]-benzoxazepin-3-one A solution of 6.86 g of 5,1l-dihydro-7- (trifluoromethyl)dibenz[b,e][1,4]oxazepine-5- propionic acid in 50 ml of benzene is cooled to 5l0. To this is added dropwise with stirring a solution of 4.6  
 g of PCl in 25 ml of benzene over a period of 15 minutes. The solution is stirred at 25 for 40 minutes and then at 40-50 for another 20 minutes. The reaction mixture is then heated at 55 for minutes, cooled to 10 and to this is added dropwise with stirring a solution of 12.0 g anhydrous stannic chloride in 20 ml of benzene. After stirring 20 minutes at 10 and 20 minutes at room temperature, 100 ml of ether are added, followed by 10 ml of concentrated hydrochloric acid, and then 100 ml of water. After stirring vigorously for 10 minutes, the organic phase is separated, and the aqueous phase is extracted with 100 ml of ether. The combined organic extracts are washed, dried, filtered, and concentrated to dryness to give 6.9 g of residue; this is crystallized from 2-propanol to give 4.3 g of product, m.p. about l40l42. C. 2,3-Dihydro-l l-trifluoromethyl)-11-1,7H-quino- [8,l-cd][1,5]benzoxazepin-3-ol A solution of 9.6 g of 1,2-dihydro-l l- (tn&#39;fluoromethyl)3 H ,7H-quino[8,1 -cd][1 ,5]benzoxazepin-3-one in 200 ml of dioxane is cooled to 10, and to this is added a cold solution of 1.2 g of sodium borohydride in 60 ml of 25% aqueous dioxane, within 3 minutes. After the addition, the reaction mixture is stirred for 1 hour at room temperature, and then heated on a steam bath. When the temperature reaches 60-65, the color of the reaction mixture fades and becomes colorless. lt is cooled to 10 and to this is added 1000 ml of cold 2% aqueous hydrochloric acid while stirring. The resultant white solid is filtered, washed with 200 ml of water, and dried to give 9.3 g. of an offwhite solid, mp. about l20-l24. It is recrystallized twice from a mixture of 50 ml of benzene and 150 ml of cyclohexane, to give 8.6 g of the desired carbinol, which melts at about l27l29. D. 2,3-Dihydro-3-l3-(4-methyl-1- piperazinyl)propoxy]-l l-(trifluoromethyl)-lH,7H- quino[8.l-cd][1,5]benzoxazepine, maleate salt (1:2)  
  To a solution of 5.8 g of 2,3-dihydro-1l- (trifluoromethyl)-lH,7H-quino[8,1-cd][1,5]benzoxazepin-3-ol in 100 ml of toluene while stirring, is added 1.0 g of NaH (50% suspension in mineral oil). Vigorous effervescence of H is noticed. The reaction mixture is gently heated under reflux for 45 minutes, then cooled to 10 and to this, is added dropwise, a solution of 3.9 g of l-(3-chloropropyl)-4-methylpiperazine in 20 ml of toluene. The reaction mixture is heated under reflux for 5 hours. Next day, it is filtered and the filtrate concentrated to dryness in vacuo. This gives 9.0 g of viscous liquid that is dissolved in 200 ml of warm absolute EtOH, and to this is added a solution of 4.6 g of maleic acid in ml of absolute EtOH. Spontaneous precipitation occurs; the mixture is treated with 600 ml of anhydrous Et O and the solid filtered with suction to give 12.1 g of product, m.p. about 165l70. This is recrystallized from 1100 ml of absolute EtOH, to give 8.3 g (66% yield) of the product, m.p. about 170.5-l72.5.  
 EXAMPLE 2 3-[ 2-(Dimethylamino)ethoxy]-2,3-dihydro-l l- (trifluoromethyl)-1l-l,7H-quino[8,lcd][ 1,5]benzoxazepine, oxalate salt (1:1)  
  The procedure described in Example 1 is followed in this preparation, using 6.4 g of 2,3-dihydro-11- (trifluoromethyl)-lH,7H-quinol8.l-cd][1,5]benzoxazepin-3-ol.. 120 ml of toluene, 1.5 g of NaH and a solution of about 4.3 g of 2-(dimethylamino)ethyl chloride in 20 ml of toluene. Work up of the reaction mixture gives 8.3 g of viscous liquid residue of the base that does not solidify. This residue is dissolved in a mixture of 25 ml of absolute EtOH and 50 ml of anhydrous EtOH and 50 ml of anhydrous Et O and to the solution is added a solution of 2.0 g of oxalic acid in a mixture of 7 ml of absolute EtOH and 40 ml of anhydrous Et- O(ethyl ether). The solid is filtered and dried to give 6.6 g of a product, m.p. about 8695dec. This is recrystallized from a mixture of EtOH-Et O to give 4.4 g of the product, m.p. about 8896. This 4.4 g of the product is dissolved in 130 ml of boiling 2-butanone, the solution treated with 1.0 g of Darco and filtered; the filtrate concentrated under reduced pressure to 40 ml and cooled. The crystalline solid is filtered, and dried in vacuo at over P 0 for about 6 hours to give 2.6 g of the product, m.p. about l40143dec (sintering at EXAMPLE 3 3-[3-(Dimethylamino)propoxy]-2,3-dihydro-l 1- (trifluoromethyl)-lH,7H-quino[8,1- cd][1,5]benzoxazepine, maleate salt (1:1)  
  The procedure of Example 1 is employed substituting 3-(dimethylamino)propyl chloride for 3-(4-methyl-1- piperazinyl)propylchloride to prepare the title compound m.p. about l11-1l3(dec).  
 EXAMPLE 4 1 l-Chloro-2,3-dihydro-3-[3-(piperidinopropoxy)]- 1H, 7H-quino[8,1-cd][1,5]benzoxazepine Maleate salt 1:1)  
 A. 7-Chloro-5,l 1-dihydro-dibenz[b,e][1,4]oxazepine- 5-propionic acid To 50.0 g of 7-chloro-5,l1-dihydro-dibenz[b,e][1,- 4]oxazepine in 60 ml of redistilled acrylonitrile is added in 5 minutes 0.80 ml of Triton B. Subsequently, the mixture is heated for one hour under reflux and the product isolated by extraction with benzene to give 7- chloro-5,l 1-dihydro-dibenz[b,e][1,4]oxazepine-5- propionitrile, m.p. about 131l32.  
  7-Chloro-5,l l-dihydrodibenz[b,e][ l,4]oxazepine-5- propionitrile, 15.0 g, is dissolved in 240 ml of dry dioxane and to this ml of 30% methanolic hydrogen chloride is added. The solution is stirred for 36 hours; 6 ml of H 0 is added, stirred 0.5 hour, and then concentrated in vacuo to 120 ml. The solid is filtered, and the filtrate is concentrated to dryness in vacuo. The residual liquid is taken up in 200 ml of diethyl ether, treated with Darco and l-lyflo, the diethyl ether solution concentrated and the residue distilled in vacuo to give 7-chloro-5,1 l-dihydro-dibenz[b,e][1,4]oxazepine-5- propionic acid, methyl ester, m.p. about 7072.  
  7-Chloro-5,l l-dihydrodibenz[b,e][ 1,4]oxazepine-5- propionic acid, methyl ester, 3.15 g, is dissolved in 3 15 ml of methanol and to this 0.5 g of potassium hydroxide dissolved in 25 ml of water is added. The mixture is refluxed for 2.5 hours and then concentrated in vacuo. The residue is taken up in 250 ml of water and this solution is acidified with 2% aqueous HCl to give 7-chloro- 5,1 1-dihydro-dibenz[b,e][1,4loxazepine-5-propionic acid, m.p. about -157. B. ll-Chloro-l,2-dihydro-3H,7H-quino[8,1- c,d][ 1,5]benzoxazepin-3-one A solution of 6.86 g of 7-chloro-5,l l-dihydrodibenz[b,e][l,4]oxazepine-5-propionic acid in 50 ml of benzene is cooled to 5l0. To this is added dropwise with stirring a solution of 4.6 g of PCl in 25 ml of benzene over a period of 15 minutes. The solution is stirred at 25 for 40 minutes and then at 40-50 for another 20 minutes. The reaction mixture is then heated at 55 for 10 minutes, cooled to 10 and to this is added dropwise with stirring a solution of 12.0 g anhydrous stannic chloride in 20ml of benzene. After stirring 20 minutes at 10 and 20 minutes at room temperature, 100 ml of ether are added, followed by 10 ml of concentrated hydrochloric acid, and then 100 ml of water. After stirring vigorously for 10 minutes, the organic phase is separated, and the aqueous phase is extracted with 100 ml of ether. The combined organic extracts are washed, dried, filtered, and concentrated to dryness to give 6.9 g of residue; this is crystallized from 2- propanol to give 4.3 g of product, m.p. about 140142.  
 C. l1-Chloro-2,3-dihydro- 1 l-l7l-l-quino-[ 8,1- cd][1,5]benzoxazepin-3-ol A solution of 9.2 g of 1 l-chloro-l,2-dihydro-3H,7H- quino[8,l-cd][1,5]benzoxazepin-3-one in 200 ml of dioxane is cooled to 10, and to this is added a cold solution of 1.2 g of sodium borohydride in 60 ml of 25% aqueous dioxane, within 3 minutes. After the addition, the reaction mixture is stirred for 1 hour at room temperature, and then heated on a steam bath. When the temperature reaches 6065, the color of the reaction mixture fades and becomes colorless. It is cooled to 10 and to this is added 1000 ml of cold 2% aqueous hydrochloric acid while stirring. The resultant white solid is filtered, washed with 200 ml of water, and dried to give 8.5 g of an off-white solid. lt is recrystallized&#39;twice from a mixture of 50 ml of benzene and 150 ml of cyclohexane, to give 7.7 g of the desired carbinol.  
 D. 3,] l-Dichloro-2,3-dihydro-lH,7H-quino-[8,lcd][ 1 ,5]benzoxazepine To a solution of 6.0 g of l l-chloro-2,3-dihydro- 1H7H-quino[8,l-cd][ 1,5]benzoxazepin-3-ol, in 100 ml of benzene is added 4.0 g of anhydrous calcium chloride and into this is slowly bubbled dry hydrogen chloride. The mixture is filtered and the filtrate is concentrated to dryness under reduced pressure to give 5.86 g of solid. This is recrystallized from petroleum ether (3060), to give 4.6 g of the product.  
 E. ll-Chloro-2,3-dihydro-3-[3-(piperidinopropoxy)]- 1H,7H-quino[8,1-cd][ 1,5]benzoxazepine, maleate salt (1:1)  
  To a solution of 2.86 g of 3-piperidinopropanol in 100 ml oftoluene is added 1.1 g of NaH (50%) and the mixture is heated under reflux for 30 minutes. This is then cooled to 10 and to it is added dropwise a solution of 3.4 g of 3,1 1-dichloro-2,3-dihydro-lH.7H- quino-[8,l-cd][ 1,5]benzoxazepine in 34 ml of toluene. The mixture on similar work up as in Example 1 gives the desired product.  
 EXAMPLE 5 4-Chloro-2,3-dihydro-3-[3-(4-hydroxyethyl)-lpiperazinyl)propoxy]-1H,8H-quino[1,8- ab][4,l ]benzothiazepine, maleate salt (1:1) A 4-Chloro-l,2-dihydro-3H,8H-quino[ 1,8- ab][4,1]benzothiazepin-3-one To a suspension of 18.0 g of 7-chloro-5,l1- dihydrodiben2o[b,e][1,4]thiazepine in 35 ml ofacrylonitrile, cooled to 05, is added with stirring 0.2 ml of Triton B. The suspension becomes homogeneous, the temperature rises to 10, and a red solution results. This is allowed to come to 20 and is then heated under reflux for 1 hour. The excess of acrylonitrile is removed by distillation and the residue is extracted with 5-400 ml portions of diethyl ether. The diethyl ether extracts are dried and concentrated to about 250 ml, and the colorless product is filtered. The filtrate is concentrated and the resulting solid is again filtered. The yield of the combined solids, 7-chloro-5,1 ldihydrodibenzo[b,e 1,4]thiazepine-S-propionitrile, is about 22.0 g.  
  The 7-ch1oro-5,l 1- dihydrodibenz[b,e][ 1,4 ]thiazepine-S-propionitrile, 71.0 g, is dissolved in 1200 ml of dry dioxane and to this 800 ml of 30% methanolic hydrogen chloride is added. The solution is stirred at 20 for 72 hours, 30 ml of water is added, the mixture is stirred for 0.5 hour, concentrated in vacuo to about 400 ml, filtered, and the filtrate concentrated to dryness in vacuo to yield 67.5 g of methyl,7-chloro-5,l dihydrodibenzo[ b,e l,4]thiazepine-S-propionate.  
  The methyl, 7-chloro-5 ,1 dihydrodibenzo[b,e 1,4]thiazepine-S-propionate, 25.0 g, is dissolved in 2200 ml of methanol and to this is added a solution of 5.6 g of potassium hydroxide in 300 ml of water. The solution is heated under reflux for.  
 4 hours, concentrated in vacuo, the residue is dissolved in 600 ml of water, the solution cooled, and then acidified with 2% aqueous hydrochloric acid. The solid is filtered and dissolved in 600 ml of benzene. The solution is decolorized and then extracted with 600 ml of 2% aqueous sodium hydroxide solution. The aqueous extract is acidified with 2% aqueous hydrochloric acid. The solid is filtered and recrystallized from benzene. The yield of 7-chloro-5,l ldihydrodibenzo[b,e][ 1,4]thiazepine-5-propionic acid is about 22.0 g.  
  A solution of 7.55 g of 7-chloro-5,11- dihydrodibenzo[b,e][ l,4]thiazepine-S-propionic acid in 40 ml of warm benzene is slowly cooled to 35 and while stirring 5.3 g of trifluoroacetic anhydride is added dropwise. The reaction mixture is heated under reflux for 5 minutes, 50 ml of benzene is added, and the solution is poured into cold water. The benzene layer is separated, the aqueous phase is extracted with 50 ml of benzene, and the combined benzene extracts are concentrated to dryness in vacuo. The residue, 7.0 g, m.p. about ll0l20, is dissolved in 325 ml of a boiling mixture of 2-propanol and cyclohexane (2:3), and then kept at 20 to give two different types of crystals. These are filtered and the yellow transparent rhombic crystals (compound 1) are separated from the darker yellow flat needles (compound 11).  
  Compound I is recrystallized from 2-propanolcyclohexane (1:4) to give 2.2 g of 1 l-chloro-l,2- dihydro-3 H,7H-quino-[8,1-cd][1,5]benzothiazepin- 3-one.  
  Compound 11 is recrystallized from 2-propanolcyclohexane (1:4) to give about 2.6 g of 4-chloro-l ,2- dihydro-3H,8l-l[1,8-ab][4,1]benzothiazepin-3-one.  
  4-Chloro-2,3-dihydrol H,8H-l l,8-ab][4,l ]benzothiazepin-S-ol.  
  By following the procedure described in Example 4-C, using 10.0 g of 4-chloro-2,3-dihydro-1H,8H-[1,8- ab][4,1]benzothiazepin-3-one, and 1.3 g of NaBH there is obtained 8.2 g of the desired benzothiazepin-3- o1 4-Chloro-2,3-dihydro-3-[ 3-(4-hydroethyll piperazinyl )propoxyll l-l,8l-l-quino[ l ,8- ab][4,l ]benzothiazepine, maleate salt (1:1)  
  To a solution of 5.5 g of 4-chloi&#39;o-2,3-dihydrolH,8H-quino-[ l,8-ab][4,l ]benzothiazepin-3-ol in 100 ml of toluene is added l.0 g of NaH (50%), and the mixture is heated under reflux for 45 minutes, then cooled to 10. To this is added dropwise, a solution of 3.9 g of l-bromo-3-chloropropane and the mixture is heated under reflux for 6 hours. This is cooled, filtered and concentrated to dryness in vacuo to give 5.7 g of the crude 4-chloro-2,3-dihydro-3-(3-chloropropoxy)lH,8H-quino[ l,8-ab][4,l lbenzothiazepine, as a viscous oil. This oily residue is dissolved in I30 ml of 2- Table I Column A column 3 Ex. No. $tartinn Matarlal 3 Or 3v H CH COOH s-crr I ,s-cn  
  2 L chic? 2-0 Q iq g .231:  
 PrOH and to it are added 3.0 g of Nal and 5.2 g of lpiperazineethanol. The reaction mixture is heated under reflux for about 20 hours, washed and then concentrated to dryness in vacuo. The residue is converted to the maleate salt and is recrystallized from 2-PrOH.  
 Examples 6 to 20 Employing the procedure described in Example 1A, 1B, 1C but substituting the starting material shown in column A of Table 1 below, the 3-ol is column B is ob tained; employing the procedure of -lD but substituting the 3-ol shown in column B and the haloalkylene amine shown in column C, the product shown in column D is obtained.  
 Column C Column D 1 2 H n R g oduet cn you: a 10 c n fl m no 5 C .1 CH CH 2 L 3 CZ&#39;HS C2145 CHZCHZCOOH s-cu 13 Q 2 O II n CH CH COOH Ho y S-CH  
 N- (CH 0 S-CH  Employing the procedure described in Example 4A. 4B, 4C, 4D, but substituting the starting material shown Table l-Continued Hal (cn .,-NR R Product a n c s-cn H c a H c ca 5 2 CH 2 3 5 cn 3 m a s O Startin Material Examples 2] to 30 in column A ofTable ll below, the 3-chloro compound in column B is obtained; by reacting the 3-chloro compound with the hydroxyalkylene amine shown in column C. the product shown in column D is obtained.  
 Column A Column B Column C Column D Startinn Material 3 &#39;or 3&#39;-ch1oro Derivative H0-(cii ;-l-in i1 Product 3 -cn o- 2 O no-(cn -n(cn CH3 O 2 O i: N CH c1 m CH N c1 i H I c c1 ca ca coon i 2 2 x (cI-l N (cn o I I s -c foik 50 I C; I HO-(CH2)5N(CH3)C2H5 N l gj c1 CH N CH c1 c H c1 :1 ca coon 2 2 c H (cH )N(cH o I CH c1 N l-l cu coor-r&#39; r H r 2 2 I I a Dr (Cy- 69 c H -ca c H 5-CH 2 5 2 2 5 25 O 2 O 1m: t O CH H 2 3 c n E 7 a 7 5 3 5 eH CI-I COOH I c1 te n t n-lcn l Q HO-CH -mrc a 1 2 29 O 2 5 C H O/CIQIT NC (1 1-1 0 CH NC a CZHSO m NC 2 5 R crr cn codi-l Cl r {5 11 f&#39;2?&#34; I v e I r I l I v 5 c loves an ap m 3 m H0-(cH -nnc rr c ri 1 4 v c a s c rr s H tlr C cl 5 11 H r 2 cn cu cqoa s s z lll z Examples 31 to 45 them with the following reactants, as per Example 5 B, Employing the procedure of Example 5, substituting set out in Table III below, the products of Examples 31 the starting materials of Examples 6 to and reacting to are obtained.  
 &#39; Table III EX- 1 l 2 E12. Hal(CH ,,Hal HNR R 31 Br (CH C1 ENC] 32 I (CH C1 HN 33 Br (CH -Cl HN: 0CH  
 &#39; Table III Continued BX. Hal (CH2) ilal H&#39;NR R 34 I (CH2) Br n uc n 36 Br (CH C1 rm I l u- 37 I(CH 8? RN n-cn ocn l t, t H 3 CH 38 F(CH2) Cl HN CH 1 39 Br (CH c1 n:n(c n )cH 40 B r (CH Cl HN y l 41 I(CH Cl HN V l 4 2 Br (CH c1 nutcn c fi lcn 43 BI (CH Cl 7 RN 0 &#39;44 &#39;ncn B1.- rm N(CH CCH 45 I(CH Br mum Example 46 Following the procedure of Examples 31 to 45, employing as the starting materials 4 N N F C O-CH (CH n 2 2 3 NCH CH OH g z 3 and r&#39;\ HN N- CH CH OH I Example 47 Following the procedure of Examples 31 to 45. cmthe product obtained has the structure ploying as starting materials group consisting of hydrogen and lower alkyl having up to eight carbon atoms; n&#34; is 2 or 3; and a pharmaceutically acceptable acid-addition salt thereof.  
  N 2. A compound having the structure F C 5 O-CH Br (CH C1 2 wherein X is selected from the group consisting of trifluoromethyl and chloro; R and R are the same or dif- 2 Z Z &#39;Z ferent and are selected from the group consisting of hydrogen and lower alkyl having up to eight carbon atoms; n&#34; is 2 or 3; and a phannaceutically acceptable acid-addition salt thereof. the Product Obtained has the Smmmre 3. The compound in accordance with claim 2 having the structure OQH CH OCH CH OH o-cn, E c N F C What is claimed is:  
  A compolmd having the Structure 4. The compound in accordance with claim 2 having the structure 1 2 F c v R R N-(Cll ,,0 3 N wherein X and Y are the same or different and are selected from the group consisting of hydrogen and chlorine, at least one of X and Y being hydrogen; R and R are the same or different and are selected from the o(cn s (c11