BE556791A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
 



   The present invention relates to new pharmacologically active piperazine derivatives and methods for their preparation therein.



   It is known that some asymmetrically substituted piperazine derivatives have an antihistamine effect. For example, some representatives of the latter type of compounds show a very strong and long-lasting antihistamine effect. As a side effect, a rather important sedating effect occurs. As a result, these compounds are also used as sedatives.



   The main object of the present invention is to disrupt compounds which have antihistamine and sedative action and have low toxicity. Another object of the invention is to separate the anti-effect from the sedative side effect as much as possible.

 <Desc / Clms Page number 2>

 
 EMI2.1
 



  Since this side effect in itself is also n, attie; antihistamines with a little sedative effect as well as sedatives with a low level of antimycotic effects were sought. It was now found that an enhancement or weakening of the sedative effects compared to the antihistamine effect in a certain group of piperazine. .3 ".Tivatives could easily promote.

   Was caught after ': seem that connection
 EMI2.2
 gene of the general formula:
 EMI2.3
 
 EMI2.4
 where: Y is a wu, iirs4 <: is.f, aoi :; or 1 L'e, :): yl, T ('OP.1' X is a -Cl, 2-cf a., C-m-e.) and R 1, R 2, and R 3 are hydrogen ci halogen atom, or an alkoxy or alkyl group containing not more than 5 carbon or alloys, active antihistamines, with weak sedative activity, then X is equal to -CH2- "and highly active sedatives with only low activity. * have anti-histamine effect when X is equal to wCU--.



  Some of the anti-histaroinic drugs exhibit a terl-1: ferkz3.arity comparable to the efficacy of [beta] -ch] dryl-4-m-methylbenzylpiperazine, and / or have a very long duration of action. The sedative effect chains have a calming effect on laboratory animals, but no cause for drowsiness for a while, not even in the high doses. The sedative effect is here understood to mean the rerc .rflNl of the spcntr, .ne r.io til3t.it of laboratory animals. In their operation, third: chains are still the best to be compared; uJu, et reserpine, the well-known calstering recognized R, 1T \ Iolf: ï.aa ] h, J.oid (these types of compounds are also called t: w, rcuil.ir; z agents The strength of this effect is ri, -t in numbers from tue: ro.ï:, rr .., All compounds are very little toxic.

   A clear effect h. drove? to be obtained with small fractions of the toxic dose (in the order of 1/100).



  In the npvoL '' '' nth table, disrr¯: -, "; clp ::: f 'the connection obtained from \' 1lY1: Ll1E ', 1-n, p <¯t their chewJ fd -) f; .rF ':',:. '; ",' ', J oe-L :: C! lf) r ;: C' (!" '. ms veY "Jelc.

 <Desc / Clms Page number 3>

   'TABLE
 EMI3.1
 Ri N '> 1 - OH OH fi-R2 Y - NN -: K - CH = CH j R.2 R3 Melt #eid o ------------------- -------------- Salt (Th iele ..Jcrkz & .mheJ.a Ft, 3 in C) Anti-Sedat. R1 R2 R3 hist. Sedate 1 H CH2 HHH base 20 + + bpt 191 at 18.5 mm 2 H CO HHH base 68 + ++ 3 COOC2H5 CH2 H "b-C4H9 H base 1190 0 + 4 C6H5-CH = CH Cl H t-C4H9 H HG1 250-255 + -t + 5 C6H5-CH8-C = 0 H t-CH9 H base 128-129 + ++ 6 (CIS) 2CH-C = O HHH base 1680 "+ ..



  7 (C6H5) 2Cli- CH2 HHH HCl 192 (De) fldd- + 8 (06H5) 20H- 0 = 0 H Cl H base z5 + +++ 9 (C6H5) 2 CH- CH2 H Cl H HCl 160-162 + + t- + 10 (C6H5) 2CH- 0 = 0 H t-C4H9 H base 183-185 + + F + 11 (C6H5) 2CH-0H2 H t-C4H9 H base 130.5-133 +++ + 12 s (CgIiS) 2CH-Cl) H OCH3 H Hei 221 (Ont) + +++ 13 (C6Hr) 2CH-CEs H OCH3 H base 126-132 ++ - + + 14 (C6H5) 2eH- C = 0 OCH3 00H3 00H3 base 178- 1795 + -H4 15 p-Cl-C (, H4-CH2 HHH HOI 200-201 -H- + + CH-C6H5 16 'id. C = O H CH3 H HCl 150-153 + +++ 17 id. CH2 H CH3 H HCl 177-17co -HH + 18 id. C = 0 CH3 HH H01 155-173 + + F + 19 id. CH2 CH3 HH HCl 176-200 +++ + (De) 20 id. CO H i-C3H7 H base 14995 + +++ 21 id C = O H 1 -C 3 H 7 H HCl 153 + +++ 22 p-C 1 -C 6 H 4 -CH 2 H 1 -C 3 H 7 H HCl 16/1 + F + CH-C 6 H 5 23 id. C = O H t-C4 H 9 H base 170.5-171 + 8 + F 2 fi id.

   CH2 H t-C-4 H 9 H HCl 167-175 -H- + 25 id. 0 = 0 H OCH3 H base 131-133 + +++ 26 id. OH2 H OCH3 H HCl 179-180 -H- +

 <Desc / Clms Page number 4>

 
 EMI4.1
 Melting point Efficacy N Y X RI R2 R3 salt (Thiele Anti-Sedat. In C) hist. Sedat.



  27 p-OH 3C6H4-C = O H- -t :: -C 4 H9 H base 144-) 45 + +++ CH-C6H5 28 id. CH2 H id. - H - - HCl 188-201 ++ + 29 p -1 - C3H7C6H4 - H id. H base 169-172 + -F4 "CH-C6H5 C = O 30 id. CH2 H id. H H01 195-198 ++ + (Ont) 31 p-CH3 OC6H4 - C - O H id. H base 139-142 + +++ CH-C6H5 32 id, CH2 H id H HCl 163-165 + 1- + 33 p-CH3-OC6H CO H id, 1 base 139 + +++ PC, 1-C6H4 34 id, CH2 H id, H HCl 157-158 -1+ + 35 p-CH 3 C 11 H C "- O H id. H base 100-102 + + 4- + p-C 1 -C 6 H 4 36 id. CH2 H id. H01 HCl 205-206 ++ + 37 p-1-CaH7C6-CO H id. H base 158-1600 + ++ H-CH-Cl-C61, 38 id. CH2 H id.

   H HCl 201-2050 ++ + The compounds according to the invention can be obtained by reaction of piperazine with halides
 EMI4.2
 in any order, in the presence of a hydrogen halide binder, the symbols X, Y, R1, R and R3 having the meanings indicated, while Hal represents a halogen atom.



  In the following examples, only the second phase of the process is indicated, since the first phase proceeds in an analogous manner.



  However, it is preferred to use an excess of piperazine in this first phase in order to favor the formation of the monosubstituted compound.

 <Desc / Clms Page number 5>

 



   Furthermore, the compounds wherein X is a -CO group can be converted in a simple manner by reduction with lithium aluminum hydride into the corresponding compounds wherein X represents a -CH 2 group without affecting the double bond.



   The invention is now further illustrated by the following examples:
EXAMPLE I 36.5 g (0.165 mol) of tert, butyl-4-cinnamic acid chloride in 400 ml of anhydrous benzene are mixed with 93 g of 1- (chloro-4-benzhydryl) piperazine in 600 ml of anhydrous benzene and at reflux for 30 minutes cooked. The reaction mixture is then allowed to stand overnight at about 20 DEG C. The benzene is then evaporated in vacuo, the residue is taken up in chloroform and washed with 50-000 ml of dilute hydrochloric acid. The unreacted "1- (chlor-", benzhydryl) piperazine can be recovered from the resulting aqueous layer by rendering it alkaline.



   The chloroform layer is washed with dilute sodium hydroxide solution, then with water, and finally dried with K2CO3. The residue, which is obtained after evaporating the solution to dryness, is then dissolved in a mixture of 25% toluene and 75% heptane by heating. On cooling the solution to about 20 DEG C., the 1- (tort. Butyl-4-cinnamoyl) -4- (chloro-4-benzhydryl) piperazine precipitates. Yields of 66 to 81 g are obtained. (70-86%). The melting point is 170.5-171 ° C, the ultraviolet spectrum in isopropanol shows a maximum at 287.5 mu with an extinction of about 27,900.

   The calculated mole. wt. is 473.04 (C30H33N2OCI), 478.6 and 477.2 were found, the chlorine content was 9.50% (theoretically also 9.50%)
EXAMPLE 2
To 0.04 mole of 1- (methyl-4-cinnamoyl) -4- (chloro-4-benzhydryl) piperazine in 50 ml of ether is slowly added 0.03 mole of lithium aluminum hydride in 250 ml of ether. Sufficient heat is developed to bring the ether to a boil.

   After 30 minutes, the mixture is refluxed for several hours and the excess lithium aluminum hydride is decomposed with water, in which preferably some sodium potassium tartrate is dissolved. After shaking the basic material with ether, the hydrochloride is formed with sodium chloride gas in the known manner, which is further purified by crystallization.

 <Desc / Clms Page number 6>

 
 EMI6.1
 All other reductions with lithiutrium sodium hydrate are carried out in an analogous manner. The yields are 50-90%.



   EXAMPLE 3
A solution of 0.07 mol of chloro-4-benzhydryl chloride and 0.14 mol of 1-einnamyl piperazine in 500 ml of toluene is boiled for 2 days, optionally in the presence of 0.15 mol of K2CO3. The toluene is evaporated and the residue extracted with ether, this solution filtered and the residue. ether evaporates again. Acetone is now extracted, which is then added with
 EMI6.2
 hydrochloric acid saturates. The chlorohydrate of the 1- (chloro-1,1-benzhydryl) piperazine precipitates, is filtered and purified by crystallization.



   If desired, the base can also be purified directly by fractional distillation.



   All similar compounds can be prepared in this way, including those where X = C-O. The yields are 60-85.%
 EMI6.3
 SUMMARY - REVINDICATIONS 1. New pharmacologically active piperazine derivatives of the general formula:
 EMI6.4
 wherein: Y is a hydrogen atom or an aralkyl group.
 EMI6.5
 X is a -chez group or a -CO group, and R1, R2 and R3 represent a hydrogen or halogen atom, or an alkoxy or alkyl group having no more than 5 carbon atoms.



  2. New pharmacologically active piperazine derivatives according to revindication. 1, wherein X represents a -CO- group.
 EMI6.6
 



  3- (4-tertiary butyl cinnamoyl) -4- (4-chlorobenzhydryl) piperazine. 4. New pharmacologically active piperazine derivatives according to recovery
1, wherein X represents a -CH2 group.
 EMI6.7
 



  5. 3- (4-isethoxy cinnamyl) -4-benzhydryl piperazine.



  6. 1- (4-ethyl-cinnam-1) -1,1-chloro-nzhydr; 1) piprazine.

 <Desc / Clms Page number 7>

 



  7. 1-cinnamyl-4-beznhdryl piperazine.



  8. Process for the preparation of new pharmacologically active piperazine derivatives of the general formula according to Revindication 1, characterized in that piperazine is reacted with halides of the formulas:
 EMI7.1
 in any desired order, in the presence of a halogen hydrogen bonding agent, the symbols x, y, R1, R2 and R3 being as defined above, while Hat represents a halogen atom. 9. The method of revindication 8, comprising the kennm that is a halide of the formula
 EMI7.2
 is reacted with a monosubstituted piperazine of the formula
 EMI7.3
   in the presence of a halogen hydrogen bonding agent.



  Process according to revindication 8, characterized in that a halide of the formula Hal - Y is reacted with a monosubstituted piperazine of the formula:
 EMI7.4
 
 EMI7.5
 in the presence of a halogen material binding agent, 11. Process according to Fig. 8, for the preparation of compounds wherein X represents a -CO2 group, characterized in that the corresponding compound wherein X represents a -CO- group is reduced with lithium aluminum hydride.