FI60006B - PROCEDURE FOR THE PHARMACOLOGICAL PROPERTIES OF VARIABLE N- (1- (3,4-METHYLENDIOXIPHENYL) -ROPYL (2)) - N '- (SUBSTITUTED PHENYL) PIPERAZINER OCH DERAS SYRAADDITIONSSALTER - Google Patents

Description

ESr ^ l ΓβΊ «« advertisement publication, πηπ LBJ (11) UTLÄGGNINCSSKRIFT 600 06 c (45) iri ·: ^ v ^ (51) Kv.ik.Wci.3 C 07 D 405/06 ENGLISH I —FI N LAN D ( 21) Pit.nttihtk.mui-Ptnttnrfkninj 752288 (22) Hakamitpilvl - An * eknlr> gsdk (13 * 08.75 (23) AlkupUvt - Gllti | h «tsda | 13.08.75 (41) Tullut JulklMlul - Bllvlt offantllg 0U. 03.76

Patents · and Registry Administrators ...., „. . ,.

\ (44) NthUvikalpano and moon outdoor date. -

Patent and registration authorities Amökan utlajd och utl »krift« n pubik «r» d 31.07.8l (32) (33) (31) Fyy ^ etty «Tuoikaut —Begird prlorltat 03.09.71+

Federal Republic of Germany-Förbundsrepubliken lyskland (DE) P 21 + 1 + 2158.7 (71) C.H. Boehringer Sohn, Ingelheim am Rhein, Federal Republic of Germany (DE) (72) Ernst-Otto Renth, Ingelheim, Anton Mentrup, Ingelheim, Kurt Schromm, Ingelheim, Wilhelm Frölke, Ingelheim, Federal Republic of Germany (Förbundsrep) ) Leitzinger Oy (5I +) Process for the preparation of pharmacologically valuable N- [1- (3 '+ -methylenedioxyphenyl) -propyl (2) 7-N' - (substituted phenyl) piperazines and their acid addition salts - Förfarande för framställning av farraa-kologiskt vardefulla Ν- / Ϊ- (3,1 + -methylenedioxyphenyl) propyl (2) 7-N '- (substituted phenyl) piperazine and derivative salt

The invention relates to a process for the preparation of pharmacologically valuable N- [1- (3,4-methylenedioxyphenyl) -propyl (2- [7 '- (substituted phenyl) piperazines] having the general formula I

CHq wherein either R 2 represents chlorine or R 1 represents methyl and R 2 represents methoxy, and for the preparation of their physiologically acceptable acid addition salts.

According to the invention, the novel compounds can be prepared as follows: a) (2,4-substituted phenyl) -piperazine of the general formula III h- * 1 H -R 2 111 R 1 in which and have the same meaning as above, is reacted with 1- (3,4 -methylenedioxyphenyl) propanone (2) -chloride, -bromidine mesylate or tosylate in the presence of an acid scavenger such as potassium carbonate, b) reacting (2,4-substituted phenyl) -piperazine of general formula III with 1- (3,4-methylenedioxyphenyl) ) with propanone (2) in the presence of a reducing agent such as catalytically activated hydrogen or metal hydrides (e.g. lithium aluminum hydride or sodium borohydride), or that c) is treated with catalytically activated hydrogen according to the formula 1-halogen-1-. methylenedioxyphenyl] -2-phenyl-piperazino-propane CH 2 I / N / y X 1 Ha.

wherein R 1 and R 6 are as defined above, and Hal is a chlorine, bromine or iodine atom, or that d) 1- (3,4-methylenedioxyphenyl) -2- (bis (N-substituted ethyl)) of general formula V -amino / propane 3 60006 CHo (° ^ X "CH2 ~ ™ ~ N ~ ICH2 ~ CH2 ~ x> 2 (V) wherein R1 and R2 have the same meaning as above and X is an easily anionically cleavable group such as a halogen atom or alkyl or arylsulfonyloxy group is reacted with an aniline of general formula VI r2-NH2 (VI) wherein and R2 are as defined above or that e) a secondary diamine of general formula VII CHo 1 -J ~ \ _ ch-nh-ch2-ch2- nh-v 7 - r 2 '0 ^ R, (VII) wherein R 1 and R 2 are as defined above, is reacted with an ebane compound of general formula VIII x - ch 2 - ch 2 - X (VIII) wherein X is as defined above, or that f) reducing 1- (phenyl) -4- (3,4-methylenedioxyphenylisopropyl) -piperazinedione 2,3 of the general formula IX

ch3 I I

I / —c \ f \ o ^ w h R! 4 60006 wherein and R2 are as defined above or that g) N- [1- (3,4-dihydroxyphenyl) -propyl-2J-N'-phenyl-piperazine of the general formula X s wherein R 1 and R 2 are as defined above is reacted with a methane compound of general formula XI

X - CH2 - X

(31) wherein X is as defined above, and if desired, the compound obtained by any of the above methods is converted into its physiologically acceptable acid addition salts by reacting the substances of the invention with the appropriate acids in the usual manner. Suitable acids for this include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, succinic acid, and tartaric acid.

It is already known from DT-PS 16 70 144 that CH3 compounds of general formula II

Ar ch-LQq ^ 'm wherein Ar is an aromatic group having two rings attached to each other, wherein the ring not attached to the rest of the molecule may be an iso- or heterocyclic saturated or aromatic ring, and R 1 and r 2 represent hydrogen, halogen, CFg groups or alkyl or alkoxy groups having 1 to 4 carbon atoms, and their acid addition salts 60006 5 have valuable central nervous system depressant properties.

It has now been found that the compounds of the above-mentioned formula I and their acid addition salts have, in addition to a central nervous system depressant effect, an excellent blood lipid and cholesterol lowering effect, and thus can be used in preparations for lowering blood lipids.

In this respect, they are even better than the compounds known from DT-OS 21 36 929. A suitable daily dose is 25 to 75, preferably 40 to 60 mg. Thus, a single dose administered 1-5 times a day is 5-75 mg.

The compounds of the general formula I have a very low toxicity and therefore a very favorable therapeutic index.

The active compounds of the general formula I for the prophylactic treatment of coronary thrombosis can also be combined with a coronary dilator, for example dipyridamole (= 2,6-bis- (diethanolamino) -4,8-dipiperidino- / 5,4-d7'-pyrimidine) in a daily dose of 50 - 150 mg (single dose 10 - 150 mg) for coronary dilators.

Pharmacological comparative tests.

The following are pharmacological comparative experiments using compounds known from the prior art and prepared according to the invention according to the following designations: I. Background Art

Me 358 = N / 1- (3,4-methylenedioxyphenyl) propyl (2) -7 '- (2-chlorophenyl) piperazine, GB-PS 1,176,672

Me 317 = N / 1- (3,4-methylenedioxyphenyl) -propyl (2) R '-N' - (2-methoxyphenyl), DT-OS 16 70.144

Me 318 = N / 1- (3,4-methylenedioxyphenyl) -propyl (2) -7-N '- (2,6-dimethylphenyl), DT-OS 16 70 144 6 60006 II. Made according to the invention

Ren 88: N- [1- (3,4-methylenedioxyphenyl) propyl (2) J-N '- (2,4-dichlorophenyl) piperazine

Ren 89: N-Cl- (3,4-methylenedioxyphenyl) -propyl (2) J-N '- (methyl-4-methoxyphenyl) -piperazine

The experiments used NMRI mice placed on a sloping glass plate and observed the amount of test compound at which the test animals began to slide, i.e., their holding reflex began to deteriorate. The ataxia test determined the amount of dose at which atactic, ie non-coordinated, movement occurred. Experiments, the results of which have been evaluated by the so-called "Probif method", show that the compounds according to the invention have a lower central nervous system effect than the compounds of the prior art. The experimental results are given in the following Table 1:

table 1

Sliding tissue Ataxia ED50 (mg / kg) ED50 (mg / kg)

Me 358 2.2 2.2

Me 317 14 39

Me 318 25 105

Ren 88 190 160

Ren 89 690 120 2. Cholesterol lowering effect of compounds

The experiments used 85 male rats weighing about 250 g as experimental animals. The experimental animals were kept separate and had free access to water and food, except for blood sampling days. The test compound was administered to the experimental animals via a gastric tube. The experimental animals used were a group of experimental animals given saline alone and the experimental animals used a group of animals given the lipid-lowering preparation Clofibrate. The compounds were administered as follows: 7 60006

Compound _Dose _Number of animals

Fysio1.

NaCl solution Comparison 15

Me 317 50 mg / kg 15

Me 318 25 mg / kg 15

Me 358 25 mg / kg 10

Ren 88 25 mg / kg 10

Ren 89 25 mg / kg 10 "Clofibrate" 300 mg / kg 10 "Clofibrate" = 2- (4-chlorophenoxy) -2-methyl-propionic acid ethyl ester. The experimental period was 3 weeks with weekly measurement of serum cholesterol, which was analyzed with an auto-analyzer (Liebermann-Burchard, Lit .: J. Levine et al. Technicon-Symposium, 1967, Vol. 1, S 25).

At the beginning of the experiment (day 0), the total cholera persistence of all animals in the blood was measured, as well as on days 8, 14, and 21 of the experiment.

The values obtained in the experiments are shown in Table 2.

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The values obtained show that all the test compounds have a serum cholesterol-lowering effect, so that the potency of the reference compounds can be expressed as follows:

Me 317 ^ g | Me 318 ^ g | Clof ibrate ^ Me 358. ^ * Ren 89. «* · Ren 88.

The following examples illustrate the invention:

Example 1 N- [1- (3,4-methylenedioxyphenyl) propyl (2) -7-N '- (2-methyl-4-methoxyphenyl) piperazine (method variant a) - 29.0 g (0.14 mol) (2 methyl 4-methoxy) phenylpiperazine, 41.5 g (0.16 mol) of 1- (3,4-methylenedioxyphenyl) propanol (2) -methanesulfonate (prepared by esterification of propanol with mesyl chloride) and 44 g of anhydrous potash are refluxed for 7 hours. 250 ml of xylene and the solvent are distilled off in vacuo, the residue is recrystallized from aqueous methanolic hydrochloric acid, and the melting point of the title compound hydrochloride is 235-259 °.

Example 2 N- [1- (3,4-methylenedioxyphenyl) propyl (2) -N- (2,4-dichlorophenyl) piperazine (method variant b)) - 32.5 g (0.14 mol) of 2,4- dichlorophenylpiperazine, 41.5 g (0.16 mol) of 1- (3,4-methylenedioxyphenyl) -propanol (2) -methanesulfonic acid ester and 44 g of anhydrous potash are refluxed for 7 hours in 250 ml of xylene. Further processing is carried out according to Example 1. Melting point of the title compound hydrochloride: 259-263 ° C.

Example 3 N- [1- (3,4-methylenedioxyphenyl) -propyl (2 H -N '- (2-methyl-4-methoxy) phenylpiperazinyl (method variant b)) 1.78 g of 1- (3,4-methylenedioxyphenyl) ) -propanone- (2) and 1.76 g of N- (2-methyl-4-methoxy) phenylpiperazine were hydrogenated in 20 ml of methanol in the presence of 0.2 g of platinum oxide at 60 [deg.] C. After the theoretical amount of hydrogen had been consumed, the title compound was separated off. compound having a melting point of monohydrochloride of 256-259 ° C.

ίο 6 0 0 0 6

Example 4 N- [1- (3,4-methylenedioxyphenyl) -propyl- (2) -7 '-N' - (2,4-dichloro) phenylpiperazine (method variant b) -

As described in Example 3, the hydrochloride of the title compound having a melting point of 261-263 ° C can be prepared.

Example 5 N- [1- (3,4-methylenedioxyphenyl) propyl (2)] -N '- (2-methyl-4-methoxyphenyl) -piperazine (method variant c) - 10 g of 1-chloro-1- 4-Methylenedioxyphenyl-2 - [(4-methoxy-2-methyl) -phenylpiperazino-17-propane hydrochloride (m.p. = 189-193 °) was dissolved in 150 ml of methanol and hydrogenated by the addition of 20 g of N, N-dimethylaniline and Raney nickel at normal pressure until consumption was complete. The catalyst was separated and 1N hydrochloric acid was added at boiling temperature until a weakly acidic reaction was achieved. After cooling, the precipitate was collected and recrystallized once more from aqueous methanol. The yield was 50% of the hydrochloride of the title compound, m.p. = 256 - 259 ° C.

Example 6 N- [1- (3,4-methylenedioxyphenyl) propyl (2) -7-N '- (2,4-dichlorophenyl) piperazine (method variant d) - 8.5 g of 1- (3,4- methylenedioxyphenyl) -2- (E- is- (8-chloroethyl) -amino] -propane hydrochloride (m.p. 177 ° C), 4.1 g of 2,4-dichloroaniline and 10.3 g of potassium carbonate were boiled in 50 ml of methyl glycol at the same time. stirring for 10 hours using a reflux condenser.

After stirring, 100 ml of water were added and the pH was adjusted to 5 with concentrated hydrochloric acid. Stirring was continued for about an hour, at which time the hydrochloride of the title compound precipitated.

Example 7 N- [1- (3,4-methylenedioxyphenyl) propyl (2) -7-N '(2,4-dichlorophenyl) piperazine (method variant e) - 11 60006 20.3 g of N- (2,4-dichlorophenyl ) -N '- [α-Methyl-3,4-methylenedioxy-phenethyl] -ethylenedicunine hydrochloride was boiled together with 10 g of 1,2-dibromoethane and 20 g of potash in 150 ml of n-butanol for 10 hours under reflux. Finally, the mixture was weakly acidified with aqueous hydrochloric acid and the product was filtered off with suction. The precipitate was washed well with water and chloroform and recrystallized from methanol. The hydrochloride of the title compound had a melting point of 259-263 ° C.

Example 8 N- [1- (3,4-methylenedioxyphenyl) propyl (2] -7 “N '- (2-methyl-4-methoxy-phenyl) -piperazine (Process Option f) - 9.5 g of LiAlH4 was boiled in 400 ml of absolute THF with stirring and reflux was used to extract 39.6 g (0.1 mol) of 1- (4-methoxy-2-methylphenyl) -4- [3,4-methylenedioxyphenylisopropyl] 7-piperazinedione 2 over 2 hours. 3 and (m.p. 144-145 ° C) from the extraction tank of the hot extractor was refluxed for a total of 24 hours, cooled and decomposed by adding dropwise excess LiAlH 2 in 36 ml of CH 2 Cl 2 in 200 ml of THF The product was filtered off with suction, washed thoroughly with THF, solvent was distilled in vacuo and the residue was recrystallized from methanol to give 33.7 g of base, mp = 95-96 ° C.

The HCl salt was obtained by dissolving the base at reflux in methanol and a calculated amount of 1N aqueous hydrochloric acid was added. Cooled and separated by suction and dried in a convection oven. The yield was 90% of theory,

Sp. = 256 - 259 ° C.

Example 9 N- [1- (3,4-methylenedioxyphenyl) propyl (2) -7-N '- (2,4-dichlorophenyl) piperazine (method variant g))

A mixture of 9.5 g of N- [1- (3,4-dihydroxyphenyl) -propyl-27-N '- / 2,4-dichlorophenyl] -piperazine (m.p. = 141-143 ° C), 5 g of methylene bromide, 7 g of potash and 1 g of Cu powder and 50 ml of dimethylformamide were refluxed for 24 hours. The solution contained in the product was separated at 12 ° C by suction filtration by suction and aqueous hydrochloric acid was added to effect a weakly acidic reaction. On cooling, the title compound slowly crystallized as the hydrochloride. The product was filtered off with suction, recrystallized from aqueous methanol and dried in a convection oven.

Claims (1)

60006 13 Method for the preparation of pharmacologically valuable N-ε- (3,4-methylenedioxyphenyl) -propyl (2) J-Ν '- (substituted phenyl) -piperazine of the general formula I CH-s 1. f ~ \ (° y ^ z * 2 ~ CH ~ N ^ ~) == / R 2 (I) wherein either R 1 and R 2 both represent chlorine or R 2 represents methyl and R 2 represents cations, and for the preparation of their physiologically acceptable acid addition salts, characterized in that a) (2,4-substituted phenyl) -piperazine H-N 2 -As, OH) of the general formula III in which R 1 and R 2 have the same meaning as above, reacting ΙΟ (4-methylenedioxyphenyl) propyl (2) -chloride, -bromide, - with a mesylate or tosylate in the presence of an acid scavenger such as potassium carbonate, b) reacting (2,4-substituted phenyl) -piperazine of general formula III with 1- (3,4-methylenedioxyphenyl) propanone (2) in a reducing agent in the presence of a substance such as catalytically activated hydrogen or metal hydrides (for example lithium aluminum hydride or sodium borohydride), or that c) treating with catalytically activated hydrogen 1-halo-2- [3,4-methylenedioxyphenyl] -2-phenylpiperazinopropane of the general formula IV? R \ XJ> hQt H f wherein R1 and R2 are as defined above and Hal is a chlorine, bromine or iodine atom, or that d) 1- (3,4-methylenedioxyphenyl) -2-Cbis- {β -substituted ethyl) -amino] propane 14 60006 ch3 / ° ^^ i ^ / CH2 "CH ~ N-1 CH2_CH2" XI? <Xf wherein R1 and R2 have the same meaning as above and X is an easily anionically cleavable group such as a halogen atom or an alkyl or arylsulfonyloxy group is reacted with an aniline of general formula VI r2- ^ 3 ”nh2 (VI) R1 wherein R1 and R2 means the same as above or that e) a secondary diamine of general formula VII CH 3 NH-CH 2 -CH 2 -NH- / JVr 2 wherein R 1 and R 2 are as defined above is reacted with an ethane compound of general formula VIII x - ch 2 - ch 2 - X ( VIII) wherein X is as defined above, or that f) reducing 1- (phenyl-4- (3,4-methylenedioxyphenylisopropyl) -piperazinedione-2,3 of the general formula IX 0 0 h3 III / C- CN / - (IX) <0xt y is 60006 wherein R1 and R2 are as defined above or that g) N- [1- (3,4- * dihydroxyphenyl) -propyl-2H-phenyl 'of general formula X -piperazine ch3 l jT \ H ° YYCH2-CH-Vv ~ yJ "R2 R 'wherein R1 and R are as defined above, may be reacting with a methane compound of the general formula XI X - CH 2 - X (XI) wherein X has the same meaning as above, and if desired, the compound obtained by any of the above methods is converted into its physiologically acceptable acid addition salts by reaction with suitable acids. 60006 16 For the preparation of pharmacologically active compounds N- / 1- (3,4-methylenedioxyphenyl) -propyl (2) J-n1- (substituted phenyl) -piperazine with the formula I and R23 for the addition of chlorine or R In the case of methyl and R2 methoxy, but also with physiologically acceptable hydrogenated solvents / compounds, a) (2,4-substituted phenyl) -piperazine with the formula III Hv> P "R; Rt (III) for R the same is reacted with 1- (3,4-methylenedioxyphenyl) propyl (2) -chlorides, bromides, mesylates or tosylates under a nerve bond to give a potassium carbonate, b) (2,4 -substituted phenyl) -piperazine with formula III Fär reagera with 1- (3,4-methylenedioxyphenyl) propanone (2) is used to reduce the use of metal hydrides, i.e. lithium aluminum hydrides or sodium borohydride, c) 1 -halogen-1- (3,4-methylenedioxyphenyl) '- 2-phenyl-piperazinopropane med; i7 6 000 6 CH3 / 0n ^ / i "cm" O O'Rj <"xj" «y där och R 2 of the same mixture are selected from the group consisting of chlorine, bromine and iodine, with the aid of catalytic activation, or (d) 1- (3,4-methylenedioxyphenyl) -2- [bis (β-substituted ethyl) amino] / propane with all the formulas V CH3 / “CH_ N ~, CH2 ~ ch2 ~ X> 2 \ XJ of R1 and R2 are the same as the group of the anionic group, and then halogen or alkyl- or arylsulfonyloxy, the ring is reacted with Aniline with the formula VI κ2 ~ ^ Λ — nh2 St,, vi) is R ^ och R2 is the same as above, or e) en secondary diamine with the formula VII CH3 / 0S ^ VCHj * CH "NH'CHrCHrNH ~ \ VR2 <VII) <" Xj, r