Patent Publication Number: US-4093630-A

Title: Diazabicycloalkane derivatives

Description:
The present invention relates to a novel diazabicycloalkane derivative and a process of producing the same. More particularly, the present invention relates to a novel pyrrolo[1,2-a][1,4] diazepine derivative which is useful as an antihistamic agent, and a process for producing the same. 
     The diazabicycloalkane derivative in accordance with the present invention is represented by the formula I: ##STR2## wherein R represents a hydrogen atom or a halogen atom. 
     Examples of the halogen atoms in the formula above are chlorine, bromine, iodine, etc. 
     The diazabicycloalkane derivative of the present invention, represented by the formula I, is prepared by reacting pyrrolo [1,2-a] [1,4] diazepine represented by the formula II: ##STR3## with a benzhydryl halide derivative represented by the formula III: wherein R has the same meaning as defined above and X represents a halogen atom. 
     It is advantageous to carry out the reaction in a solvent. Any solvents are usable as far as they do not prevent the reaction. Typical examples of these solvents include benzene, toluene, xylene, methanol, ethanol, isopropanol, n-butanol, dimethylformaide, dimethylsulfoxide, etc. The reaction advantageously proceeds in the presence of an acid acceptor such as a tertiary amine, sodium carbonate, potassium carbonate, sodium alkolate, sodium hydride, sodium amide, sodium iodide, etc. If an excess amount of the compound represented by the formula II is used, the compound can be the acid acceptor. 
     The reaction temperature should preferably be at about boiling point of the solvent used. 
     Pyrrolo [1,2-a][1,4] diazepine represented by the formula II is synthesized in accordance with the following method. The products are both optically active since L-proline is used herein as a starting material. ##STR4## 
     The compound represented by the formula I may be converted to acid addition salts thereof, e.g., hydrochloride, hydrobromide, sulfate, oxalate, maleate, citrate, fumarate, etc. 
     The compound represented by the formula I is useful as an antihistamic agent. The compound is administered orally in the form of a capsule or tablet or parenterally, with a pharmaceutically acceptable carrier, in an effective amount usually varying between about 5 to about 100 mgs. 
     Comparison of the compound represented by the formula I with a known compound has been made with respect to antihistamic activity, the results of which are as follows. 
     EVALUATION OF ANTIHISTAMIC ACTIVITY 
     Antihistamic effect was examined in accordance with the Magnus method, using the ileum extracted from a mongrel dog. The effect was evaluated by determining the PA 2  value by the Takayanagi method. Comparison with a known compound is shown in the table below. Known Compound: 
     Diphenhydramine hydrochloride Compounds of Invention: 
     I: 2-benzhydryloctahydro-1H-pyrrolo[1,2-a][1,4]diazepine dihydrochloride (Compound of Example 1) 
     Ii: 2-(p-Chlorobenzhydryl) octahydro-1H-pyrrolo[1,2-a][1,4]diazepine (Compound of Example 2) 
     
                       Table                                                       
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Compound              PA.sub.2                                            
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Diphenhydramine hydrochloride                                             
                      8.15 + 0.04                                         
Compound I            8.25 + 0.05                                         
Compound II           8.42 + 0.12                                         
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     As can be seen from the results above, the compounds of the present invention are sufficiently comparable with the known compound and even better. 
     The present invention will be explained in more detail with reference to the examples herebelow. 
    
    
     EXAMPLE 1 
     2-Benzhydryloctahydro-1H-pyrrolo[1,2-a][1,4]diazepine dihydrochloride 
     A mixture of 2.8 g. of octahydro-1H-pyrrolo[1,2-a][1,4]diazepine, 4.9 g. of benzhydryl bromide and 4.1 g. of anhydrous potassium carbonate in 40 ml. of distilled benzene was stirred for 16 hrs. under reflux. The reaction mixture was washed with 50 ml. of a 5% potassium carbonate solution and the benzene layer was dehydrated. After evaporating the solvent off, the residue was converted to the dihydrochloride in a conventional manner. After recrystallizing from isopropanol, the product having a melting point of 183°-185° C. was obtained (yield 4.8 g.; [α] D  = -15.9° (C=1, water)). 
     
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Elemental Analysis: C.sub.21 H.sub.26 N.sub.2.2HCl                        
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Calcd.  C: 80.78    H: 7.44     N: 7.38                                   
Found   C: 80.72    H: 7.48     N: 7.33                                   
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     EXAMPLE 2 
     2-(p-Chlorobenzhydryl) octahydro-1H-pyrrolo[1,2-a][1,4]diazepine: 
     The same procedures as in Example 1 were repeated except that 2.1 g. of octahydro-1H-pyrrolo[1,2-a][1,4]diazepine, 4.2 g. of p-chlorobenzhydryl bromide and 3.0 g. of anhydrous potassium carbonate were employed. The product having a boiling point of 190°-191° C./1.5 mmHg was thus obtained in an amount of 3.6 g. [α] D  = -16.7° (C=1, chloroform).