Abstract:
Isochromans, isothiochromans, 2-benzoxepins, and 2-benzothiepins are described. The compounds possess hypotensive and anti-psychotic properties; methods and compositions using them are described.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application is a continuation-in-part of application Ser. No. 953,574, filed Oct. 23, 1978 now abandoned which is a divisional of Ser. No. 847,350 filed Oct. 31, 1977, also abandoned. 
    
    
     SUMMARY OF THE INVENTION 
     The present application relates to novel compounds which are amines of certain 2-benzoxepins. In particular the present invention relates to the novel 2-benzoxepins disclosed in U.S. Ser. No. 858,303, now a U.S. Pat. No. 4,153,612, the disclosure of which is incorporated hereby reference. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In particular, U.S. Ser. No. 858,303 now U.S. Pat. No. 4,153,612 describes the use of certain 2-benzoxepins as intermediates for preparing 2-benzoxepin amine type compounds. With respect to the specification of U.S. Ser. No. 858,303, now U.S. Pat. No. 4,153,612 particular reference is made to Examples 1 through 9, 10A through 10i, Example 11 for compounds in Table 8 and Example 18 for compounds in Table 10. 
     Moreover, the Examples 1 and 10A provide examples of preparation of amines according to formula of Examples 10b through 10i and of Example 11 in Table 8. Furthermore, Examples 13 through 17 provide examples of preparation of amines according to formula of Example 18 in Table 10. Accordingly, these are described: 
     1-(4-fluorophenyl)-4-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-piperazine in Example 1; 
     1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl]-4-(3-chlorophenyl)piperazine in Example 10A; 
     1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(2-methoxyphenyl)-piperazine in Example 13; 
     1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-hydroxy-4-(3-trifluoromethylphenyl)-piperidine in Example 14; 
     1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(4-fluorophenyl)-piperazine in Example 15; 
     1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(4-fluorophenyl)piperazine in Example 16; and 
     1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(2-pyridyl)-piperazine in Example 17. 
     As indicated in the text associated with Examples 1 through 9 in U.S. Ser. No. 858,303, now U.S. Pat. No. 4,153,612 the method of preparing amines of 1-methyl substituted 1,3,4,5-tetrahydro-2-benzoxepins is according to the procedure of Example 1 from 1-bromomethylbenzoxepin and HNR 9  R 10 . Likewise, certain additional 2-benzoxepin amine type compounds represent novel chemical entities comprising one aspect of the present invention. Moreover, these novel compounds are prepared by following procedures similar to those of Example 1 in U.S. Ser. No. 858,303, now U.S. Pat. No. 4,153,612 but substituting an appropriate HNR 21  R 22  for HNR 9  R 10  as follows: 
     
         __________________________________________________________________________ ##STR1##                 Anal. (Found)ExampleNR.sub.21 R.sub.22           M.P. (°C.)                 C  H  N  Cl Name__________________________________________________________________________9a ##STR2##  224-225°.sup.c                 62.57                    8.31                       4.06                          10.95                             1-[(1,3,4,5-tetrahydro- 7,8-dimethoxy-2-                             benzoxe- pin-1-yl)methyl]pyrroli-                             dine.9b ##STR3##  225-226°.sup.d                 54.60                    7.61                       7.05                          17.98                             1-methyl-4-[(1,3,4,5- tetrahydro-7,8-dim                             ethoxy- 2-benzoxepin-1-yl)methyl]-                             piperazine.9c ##STR4##  231-232°.sup.c                 59.30                    7.57                       3.87                          10.87                             1-[(1,3,4,5-tetrahydro- 7,8-dimethoxy-2-                             benzoxe- pin-1-yl)methyl]morpho- line.9d ##STR5##  188-189°.sup.d                              1-(N,Ndimethylamino)- methyl-1,3,4,5-te                             trahy- dro-7,8-dimethyl-2-benzo-                             xepin.9e ##STR6##                    1-(1-adamantylamino)- methyl-1,3,4,5-tet                             rahydro- 7,8-dimethoxy-2-benzoxepin.9f ##STR7##                    1-[N(1-n-butyl)amino]- methyl-1,3,4,5-te                             trahydro- 7,8-dimethoxy-2-benzoxe-                             pin.9g ##STR8##                    1-[N,Ndi(1-n-butyl)amino]- methyl-1,3,4,                             5-tetrahydro- 7,8-dimethoxy-2-benzoxe-                             pin.9h ##STR9##  180-183°.sup.c                 62.66                    8.27                       4.10                          10.48                             1-[(1,3,4,5-tetrahydro- 7,8-dimethoxy-2-                             benzoxe- pin-1-yl)methyl]piperi-__________________________________________________________________________                             dine. 
    
     Further, in the text associated with Examples 10A through 10i in U.S. Ser. No. 858,303, now U.S. Pat. No. 4,153,612 the method of preparing amines of 1-ethyl substituted-1,3,4,5-tetrahydro-2-benzoxepins is in the manner of Example 10A from 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl chloride and HNR 9  R 10 . Therefore, other 2-benzoxepin amine type compounds represent additional novel chemical compounds comprising the present invention. These compounds are again prepared following procedures nearly the same as those of Example 10A in U.S. Ser. No. 858,303 now U.S. Pat. No. 4,153,612 but substituting an appropriate HNR 21  R 22  for HNR 9  R 10  as follows: 
     
         __________________________________________________________________________ ##STR10##                   Anal. (Found)ExampleNR.sub.21 R.sub.22             M.P. (°C.)                   C  H  N  Cl Name__________________________________________________________________________10j ##STR11##   .sup. 221-222°.sup.c                   61.61                      7.00                         6.07                            15.12                               1-[2-(1,3,4,5-tetra- hydro-7,8-dimetho                               xy- 2-benzoxepin-1-yl)- ethyl]-4-(2-ch                               loro- phenyl)piperazine.10k ##STR12##   144.0-144.5                   76.22                      8.05                         3.47                            -- 1-[2-(1,3,4,5-tetra- hydro-7,8-dimetho                               xy-2- benzoxepin-1-yl)ethyl]-                               4-phenyl-1,2,3,6-tetra- hydropyridine.10l ##STR13##   107.5-108.0                   75.74                      8.35                         3.53                            -- 4-phenyl-1-[2-(1,3,4,5- tetrahydro-7,8                               -dimethoxy- 2-benzoxepin-1-yl)ethyl]-                               piperidine.__________________________________________________________________________ 
    
     Furthermore, as disclosed in Example 11 of U.S. Ser. No. 858,303, now U.S. Pat. No. 4,153,612 following the procedure used in Examples 1 through 10 but substituting the appropriate 1-haloalkylbenzoxepin novel compounds similar to those in Table 8 can be made (Table 8a and Table 8b): 
     
                                           TABLE 8a__________________________________________________________________________ ##STR14##                 Anal. (Found)ExampleNR.sub.21 R.sub.22           M.P. (°C.)                 C H N Cl                         Name__________________________________________________________________________ ##STR15## 248-250°.sup.c                         1-[(1,3,4,5-tetrahydro- 7,8-dimethoxy-4,4-di                         - methyl-2-benzoxepin-1- yl)methyl]piperidin                         e.2 ##STR16## 239-241°.sup.d                         4-methyl-1-[(1,3,4,5- tetrahydro-7,8-dimetho                         xy- 4,4-dimethyl-2-benzoxepin- 1-yl)methyl]p                         iperazine.3    NHButyl                  1-[N(1-n-butyl)amino]-                         methyl-1,3,4,5-tetra-                         hydro-7,8-dimethoxy-4,4-                         dimethyl-2-benzoxepin.4 ##STR17##               1-[(1,3,4,5-tetrahydro- 7,8-dimethoxy-4,4-di                         - methyl-2-benzoxepin-1-yl)- methyl]morpholi                         ne.5 ##STR18##               1-(N,Ndiethylamino)- methyl-1,3,4,5-tetra-                         hydro-7,8-dimethoxy-4,4- dimethyl-2-benzoxep                         in.6 ##STR19##               1-(1-adamantylamino)- methyl-1,3,4,5-tetra-                         ydro-7,8-dimethoxy-4,4- dimethyl-2-benzoxepi                         n.__________________________________________________________________________ 
    
     
                                           TABLE 8b__________________________________________________________________________ ##STR20##                       Anal. (Found)ExampleNR.sub.21 R.sub.22                M.P. (°C.)                       C  H  N  Cl Name__________________________________________________________________________ ##STR21##      210-212°.sup.d                       60.45                          7.18                             5.52                                13.90                                   4-(4-fluorophenyl)-1-[2- (1,3,4,5-                                   tetrahydro-7,8- dimethoxy-4,4-dime                                   thyl-2- benzoxepin-1-yl)ethyl]-                                   piperazine.2 ##STR22##      172-173°.sup.d                       58.57                          7.58                             5.04                                19.25                                   4-(3-chlorophenyl)-1-[2- (1,3,4,5-                                   tetrahydro-7,8- dimethoxy-4,4-dime                                   thyl-2- benzoxepin-1-yl)ethyl]-                                   piperazine.3 ##STR23##      186.5-187.5°.sup.c                       63.14                          7.39                             5.95                                14.29                                   4-(2-chlorophenyl)-1-[2- (1,3,4,5-                                   tetrahydro-7,8- dimethoxy-4,4-dime                                   thyl-2- benzoxepin-1-yl)ethyl]-                                   piperazine.4 ##STR24##      176-177°.sup.e                       59.72                          7.57                             5.17                                13.01                                   4-(2-methoxyphenyl)-1-[2-                                   (1,3,4,5-tetrahydro-7,8- dimethoxy                                   -4,4-dimethyl-2- benzoxepin-1-yl)e                                   thyl]- piperazine.5 ##STR25##      171-173°.sup.d                       63.56                          7.89                             6.10                                13.58                                   4-(2-methylphenyl)-1-[2- (1,3,4,5-                                   tetrahydro-7,8- dimethoxy-4,4-dime                                   thyl-2- benzoxepin-1-yl)ethyl]-                                   piperazine.6 ##STR26##      135.5-136.5°.sup.d                       65.70                          8.23                             2.59                                13.65                                   4-phenyl-1-[2-(1,3,4,5- tetrahydro                                   -7,8-dimethoxy- 4,4-dimethyl-2-ben                                   zoxepin- 1-yl)ethyl]piperidine.7 ##STR27##      203-204°.sup.d                       58.33                          7.45                             4.98                                19.21                                   4-(4-chlorophenyl)-1-[2- (1,3,4,5-                                   tetrahydro-7,8- dimethoxy-4,4-dime                                   thyl-  2-benzoxepin-1-yl)ethyl]-                                   piperazine.__________________________________________________________________________ .sup.e dihydrochloride monohydrate. 
    
     Finally, as disclosed in Example 18 of U.S. Ser. No. 858,303, now U.S. Pat. No. 4,153,612 following the procedure used in Example 12 through 17 but substituting the 1-[2-[(1,3,4,5,-tetrahydro-2-benzoxepin-1-yl)alkoxy]alkyl chlorides or benzene sulfonates and the appropriate amines the following novel compounds comprise an additional aspect of the present invention: 
     
                                           TABLE 10a__________________________________________________________________________ ##STR28##                  Anal. (Found)ExampleNR.sub.21 R.sub.22           M.P. (°C.)                  C  H  N  Cl Name__________________________________________________________________________ ##STR29##   210-212°.sup.f                  51.00                     7.85                        6.18                           16.12                              1-[2-[(1,3,4,5-tetrahydro- 7,8-dimethox                              y-2-benzoxepin- 1-yl)methoxy]ethyl]-4-m                              ethyl- piperazine.2 ##STR30## 118.5-119.5°.sup.g                  54.56                     7.91                        5.53                           -- 2-[2-[(1,3,4,5-tetrahydro- 7,8-dimethox                              y-2-benzoxepin- 1-yl)methoxy]ethyl]amin                              o- ethanol.__________________________________________________________________________ 
    
     In all of the above tables, the superscripts on the melting points are c-monohydrochloride; d-dihydrochloride; e-dihydrochloride monohydrate; and f-dihydrochloride dihydrate and g-cyclohexylsulfamate. 
     In accordance with the above disclosure of novel compounds of the present invention it has now been found that in addition to the preferred compounds of U.S. Ser. No. 858,303, now U.S. Pat. No. 4,153,612 Formula I&#39; additional amine type 2-benzoxepins are preferred. These additional amine type 2-benzoxepins are as disclosed in U.S. Ser. No. 858,303 now U.S. Pat. No. 4,153,612 but substituting for the group denoted (i) in the definition of A so that A is selected from the group consisting of: 
     (i) --(CH 2 ) n  NR 21  R 22  wherein n is one to five and R 21  and R 22  can be the same or different and are selected from the group consisting of H, alkyl of one through four carbons, and together with the N to which they are attached form heterocyclic rings of four to six ring atoms, morpholine, and NR 9  R 10 . 
     Also ##STR31## is herein added to the group from which NR 9  R 10  is selected. 
     Further, the present invention now comprises the unexpected discovery that certain 2-benzoxepin amine type compounds of U.S. Ser. No. 858,303 now U.S. Pat. No. 4,153,162 and the novel compounds of the present invention exhibit a split in activity between an antipsychotic and a hypotensive effect. In other words, such compounds have first, either a high antipsychotic and low cardiovascular effect or second, a low antipsychotic and high cardiovascular effect. For example, the effect of the first split recited above is exhibited by 1-[2-(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl-ethyl]-4-(2-chlorophenyl)-piperazine. The effect of the second split recited above is exhibited by 1-[2-(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)ethyl]-1,2,3,6-tetrahydro-4-(4-chlorophenyl)-pyridine and 1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl]-4-(2-pyridyl)piperazine which are disclosed as Examples 10f and 10i respectively in U.S. Ser. No. 858,303 now U.S. Pat. No. 4,153,162. 
     It has now also been discovered that certain 2-benzoxepin amine type compounds of the present invention exhibit antidiabetic effects. These compounds are disclosed herein in Examples 9a through 9h and in Examples 1 through 6 in Table 8a also of the present disclosure. 
     In the formulation of compounds in the present invention for pharmacological utility conventional techniques are used as fully disclosed in U.S. Ser. No. 858,303 now U.S. Pat. No. 4,153,162.