DE2623215A1 - NEW 3-ARYL-2-PIPERAZINYL PROPIONIC ACIDS, THE PROCESS FOR THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM - Google Patents

Description

Godfather ^ tanwfiit

8 Munich 80

Lucile-Grahn-Str. 33

A 13 245

Applicant: LABORATOIRES BIOSEDRA

42, Avenue Augustin Dumont 92240 MALAKOFF (France)

New 3-aryl ~ 2-piperazinyl ~ propionic acids, process for their Manufacture and pharmaceutical preparations containing them

The invention relates to new 3-aryl-2-piperazinyl-propionic acids, a process for their preparation and the pharmaceutical containing them Preparations (preparations).

It has been found that those described below are certain 3-Aryl-2-piperazinyl-propionic acids an interesting (advantageous

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adhesive) have pharmaceutical activity (effect), in particular as anaigetics.

The invention therefore relates to new 3-aryl-2-piperazinylpropionic acids the general formula

CH -CH- CO ₂ R

where mean:

R ^]

R.
X

a phenyl or naphthyl group,

a hydrogen atom or an alkyl group, a hydroxyalkyl group, an acetylated hydroxyalkyl group, the group -CH ₂ -CO ₂ -At or a phenyl group,

a hydrogen atom or a methyl group and a hydrogen or halogen atom or a Alkyl, alkoxy, alkylthio, trifluoromethyl or substituted or unsubstituted phenyl group,

as well as the acid addition salts thereof, especially those with pharmaceutically acceptable acids ₀

8098-51 / 1051

In Table I below, a number of compounds according to the invention are listed which have been prepared. In this, the "Process" column gives the number of the general process used for the preparation of the respective compound, which is used in the examples below
is described in more detail. The value ¹¹ LDc _n "is
around the LD ₁ . in the case of a mouse in mg / kg on oral administration of the compound according to the invention.

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Connect ..
application no. ■ Ar R. R ¹ R ² X F. (as Dihydro
chloride) ~ -
( ⁰ C) Procedure
ren ^ω 50 1 Phenyl -CH.-CH-CH,
I ³
OH H H 187 4th 2 1! It -CH ₂ -CH ₂ -OH H H 171 4th 3 ! I It -CH ₀ -CH ₀ -OH H p-Cl 190 1 1000 4th 11 Il -CH.-CH-CH,
I ³
OH H P-Cl 177 1 1260 5 η η ■ * ^H 2 ^ ° 2 * 2 ^H 5 H H 155 4th > 1000 6th Il ti Phenyl H H 223 4th , '' ■■■ ·. · '■; 7th It It - ^CH 2- ^{<; O} 2 ^C 2 ^H 5 H H 160 4th -,, 8th It ti -CH ₂ -CH ₂ OH H m-CF, 196 1 TABLEI "r. 9 ti It -CH.-CH-CH.
2 I 3
OH H SU-CF ₄
· - ύ 206 1 10 η ti -CH ₉ ^ CH-CH ₉ -Ch '
· ..- ■, OH "■ ν,;:. ¹ · '- · ■ Vr H P ^ -Cl .201-202
. ·, · *. '■■ ■ ■' *. j ■ ■., ',, ■' ■ '
', v' · ■■ "■ '*: ■ ■ * * SHO 11 -
'- », η
■ J " ft
-ι
* f * -CH ₉ -CH-CH-V
, \ . · ■. :. ■ "; .. ■ '■ ■., -
';■>' ■ [? ■ 0H '^;;, ν: ■> ■:, "■■■ ·. ; _: ; .Hv, - ·> ■: ■ '■ - ■ \ ■■:. · ■
'ff * ¹ ', V ■ '* ■';>; . "■ ', ■ ': «■!: ■, 185 ■ - ■ -""■■ ■, ■ ■■: ■.
^ JiIi '. . ■.,: ■■; - ^ ■■; '/;"■■;
¹ '' ■■■ ~ ^ιΡ ",," I ¹ - '''.■''''' ⁿ ':.'^; ':■'.'■'"
, '■ ■.'., / , ■ ■■ ·. '■ ^: ', - ·; ■ '■> ■

GD K) CO K)

1. Continuation of Table I Ar R. 11 R ¹ R ² X F. (as DiHydro-
chloride)
( ⁰ C) Procedure
ren .> o Connect
application no. Phenyl Il 2! 3rd
OH H ^ ^CH 3 188 1 12th H It -CH ₂ -CH ₂ OH H £ - ^CH 3 200 1 13th ti π -CH ₂ -CH ₂ OH H £ ^ 0CH ₃ 182 1 14th £ -naphthy] η -CH ₂ -CH ₂ OH H H 204 1 15th I! ° 2 ^Η 5 -CH ₀ -CH-CH ₉ -CH,
2 ι 2 3
OH H H 208 1 16 Phenyl ^0Η 3 -CH ₂ -CH ₂ OH H mf-SCH, 187 1 17th π η -CH ₀ -CH-CH.
OH H £ -Cl 199 1 > 1000 18th α «naphthy β. -CH ₉ -CH ₉ OH
U it H H 163 3 19th η
• -CH ₉ -CH-CH ₉ -CH-
2 j 2 3
OH H H 205 3 20th Phenyl -CH ₉ -CFI-CH ₉ -CII.
² I ^2? :
OH ■■ ' \ i ::' ■ '■ H £ * «C1 198 ... 2 . _. . 385 .: 21

2. Continuation of Table I Ar R. R ¹ R ² X F. (as dihydro
chloride)
( ⁰ C) Ver
fah
ren 300
ΐ Connect
application no. Phenyl ^0Η 3 -CH ₉ -CIi-CH ₉ -CH.
OH H m «-Cl 192 2 > 1ΟΟΟ 22nd η It CH ₉ -CH ₉ OH H ρ-phenyl 200-202 3 > 1000 23 IT O ₄ H ₉ CH ₉ -CH-CH ₉ -CH.
2 ι 2 3
OH H £ -Cl 203 2 830 24 It ^0Η 3, -CH ₉ -CH-CH ₉ -CH ₀
0 CO CH ₃ H £ r-Cl 191 2 22 ^c
f 25th »I. It -CH-CK-CH ₉ -CH ₁ .
OH H 0 ^ CF ₃ 192 2 S30 26th π. It -CH ₂ ^ M ₄ H ₉
011 H J5-C1 180 2 7S0 27 tr Il -CH _O -CH-CH, -CH "
it X 3
OH H 192 2 720 28 N H -CH ₉ -CH-CH ^ -CH,
OH H £ »~ Br 2. 29

Ν3 CT) Ni CO KJ

: ■ '■' ■ '■>''.' ^: '' ■■ "■' ■ '■■ i. ... ^: 3. Continuation of Table I Ar R. R ¹ R ² X F. (as dihydro
chloride)
( ⁰ C) Ver
fah
ren > 1000 I. link
No. Phenyl ^CH 3 H 2-Cl 188 2 ί
i 30th It Il -CH ₀ -CH-CH ₀ -CH ₀
Zj δ j
OH CH ₃ £ -Cl 198 1 31 Il H OH H 2-Cl 158-160
(a) 2 32 π ^0H 3 -CH ₂ -CH-CH £ CH ₃
OH H jwChloro-
phenyl 199 3 σ
C.
te
cc
C. ; 33
< η η 2 j 6 13
OH H £. Cl 201 2 O ι 34

(a) Melting point (F.) of the "-free base

σ?

N) co

cn

Particularly preferred compounds according to the invention are compound no. 4, methyl 3- (p-chlorophenyl) -2- [4 '- (2 "-hydrox3rpropyl) -piperazine-1 ^f -yl] propionate, compound no. 28, methyl -3- (p-fluorophenyl) -2- [4 ^t - (2 "-hydroxybutyl) piperazin-1 ^l yl propionate and the compound no. 3O ₁ methyl-3- (p-chlorophenyl) -2- [4 '- ( 4 "-hydroxybutyl) pipera2in-I ¹ -ylJpropionat, and the corresponding free acids, ethyl esters and acetylated derivatives thereof.

A preferred class of compounds of the invention are those of the general formula

Shark

where mean:

CH ₂ -CH-CO ₂ R

II

Hal a halogen atom, in particular a chlorine or fluorine atom, R is a hydrogen atom or an alkyl group, in particular

a methyl or propyl group, and R "is a hydroxyalkyl group, or an acetylated hydroxyalkyl group, especially a hydroxypropyl or hydroxy-butyl group (eg. as a 2-hydroxypropyl, 2-hydroxybutyl or 4-hydroxybutyl group) or an acetylated derivative thereof.

When the compounds according to the invention are in the form of the acid addition salts present, it can be

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their salts with inorganic acids, such as

acid or sulfuric acid, or salts with organic ones

Acids, such as succinic acid, act.

The compounds of the formula I according to the invention can according to a further object of the invention forming process be prepared, which is characterized in that a suitably substituted piperazine of general formula

HN NR ¹ _τι1

with a 3-aryl-2-bro: n-propionic acid derivative of the general Formula implements

R ²

CH - CH - CO_R IV

J Br

whererAr> R, R, R and X have the meanings given above.

The compounds of the formula IV can be prepared according to the Meerwein reaction ("J. Org. Chem.", 34 (1969), page 774) or according to the malonic ester synthesis ("Indian J. Chem.", 4 (1966), page 177) getting produced. The compounds of the formula IV can thus be prepared by reacting an aryldiazonium bromide of the general formula

609851/1057

Ar \ μ + τ,

with an alkyl acrylate of the general formula

R ² -CH _o = CH-C0,

with formation of a compound of the general formula

TJ ¹
Ar \ CI ^ -CH-CO Jl ³

Br

2
wherein Ar, X and R have the meanings given above

and R is an alkyl group, preferably a methyl group,

which is then reacted with the compound of formula III.

Alternatively, the compound of the formula IV can also be prepared by reacting an I-halogenoalkylaryl compound of general formula

.2

R'ar \ CH - shark

VI

with diethyl mabnate to form a diester of the general formula

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VII

Hydrolyze this diester, for example with a aqueous potassium hydroxide solution, with the formation of a dicarboxylic acid the general formula

COOH

COOH

VIII

Bromination of this dicarboxylic acid to form a bromodicarboxylic acid the general formula

COOH

IX

Decarboxylation of this bromodicarboxylic acid to form a bromonocarboxylic acid of the general formula

and esterification of this bromonocarboxylic acid, for example with an alkanol ROH in the presence of sulfuric acid, with formation an ester of the general formula

609851/1057

CH-CH- COOR χι Br

where in the above forms In (Ar ^ R, R, Hai and X the further Have the meanings given above.

The compound of the formula III in which R is a hydroxyalkyl group can be prepared by reacting Piperazine with an epoxy compound of the general formula

4th
wherein R is a hydrogen atom or an alkyl group, e.g. B. a methyl or ethyl group, means, forming a compound of the general formula

OH N - CII - CH - R ⁴ IHa

The compounds of the formula I in which R is a hydrogen atom, can conveniently be prepared by hydrolysis of a corresponding ester where R is an alkyl group. The compounds of formula I in which R is a different alkyl group as a methyl group can be conveniently prepared from the corresponding methyl ester by transesterification. the

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Compounds of the formula I in which R is an acetylated hydroxyalkyl group can be obtained by acetylating corresponding compounds in which:
means to be produced.

corresponding compounds in which R is a hydroxyalkyl group

The invention further relates to a pharmaceutical preparation or a pharmaceutical preparation which is characterized in that it consists of or contains at least its compound of the general formula I given above or a salt thereof in combination with a pharmaceutical carrier or diluent _{or the like}

The invention is explained in more detail by the following examples, but without being limited to it.

609851/1057

Example 1 (method 3.) Establishing the connection no. 4th

10 mg potassium iodide was added to a solution of 155 g (1.08 mol) 1- (2'-hydroxypropyl) piperazine in 400 ml of methanol was added. The solution was cooled to 0 C and then a solution of 150 g (0.54 mol) of methyl 2-bromo-3- (p-chlorophenyl) propionate became added dropwise in 100 ml of alcohol. The solution was kept at 0 C for 1 hour, then warmed to ambient temperature left and finally left to stand overnight.

The solution was then refluxed for 1/2 hour and the methanol was evaporated. The residue was in water taken up and then extracted with ether. The ethereal solution was washed with water and then with 10% Hydrochloric acid extracted. The hydrochloric acid extract was made alkaline by adding a 25% ammonium hydroxide solution, extracted with ether and the organic Phase was washed with water. The oil obtained after evaporation of the solvent was taken up in 500 ml of ether, the solution was decolorized over activated charcoal and then the product was made by adding hydrogen chloride containing Ether precipitated in the form of the hydrochloride. The hydrochloride was recrystallized from methanol and 44 g of the hydrochloride, mp 177 ° C., were obtained after drying.

Example 2 (Method 2) Preparation of Compound No. 10

17.5 g (0.165 mol) dry sodium carbonate and 100 mg potassium iodide were to a solution of 26 g (0.165 mol) of 1- ^ '- hydroxybutyl) piperazine added in 180 ml of methanol. The solution was cooled to a temperature between 0 and 5 C and below

609851/1057

A solution of 45.5 g (0.165 mol) of methyl 2-bromo-3- (p-chlorophenyl) propionate was stirred added in 50 ml of methanol. Stirring was continued for an additional 4 hours at 0-5 ° C and the reaction mixture was left overnight at ambient temperature ditched. Then the solids were filtered off and the solvent was evaporated in vacuo. Of the The residue was taken up in ethyl acetate and then extracted with 15% hydrochloric acid. The aqueous phase was made alkaline with an ammonium hydroxide solution, extracted with methylene chloride, and the extract was left to neutrality washed with water. After drying and evaporation of the solvent, 11 g of an oil were obtained, from which after when taken up in a very small amount of diisopropyl ether in the cold, 4.3 g of white crystals, mp 54 to 56 ° C., precipitated.

The dihydrochloride could by adding the hydrogen chloride containing diisopropyl ether to a solution of the base in diisopropyl ether. The hydrochloride was recrystallized from methanol, a product having a melting point (F.) of 201 to 2O2 ° C. being obtained.

Example 3 (Method 3) Preparation of Compound No. 23

100 ml of potassium iodide were added to a solution of 39 g (0.03 mol) l- (2'-Hydroxyethyl) piperazine in 260 ml of benzene was added. After cooling the solution to 5 to 10 C was over a period of time a solution of 48 g (0.15 mol) of methyl 2-bromo-3- (p-biphenylyl) propionate for 1 hour added dropwise in 150 ml of benzene. The reaction mixture was stirred at 5 to 10 ° C. for 6 hours and then allowed to stand at ambient temperature for 72 hours. The reaction mixture was then added by adding

609851/1057

made alkaline by ammonium hydroxide and the organic phase was washed with water. The organic phase was extracted with hydrochloric acid and the hydrochloride of the product formed, which was sparingly soluble (hardly soluble) in water, precipitated. A large volume of water was added to dissolve all of the product and the aqueous phase was washed several times with methyl acetate. The aqueous phase was made alkaline and the product formed was extracted again with chloroform, "ach washing, drying and evaporation 3.5 g _eihielt} product F. 93 ° C.

The base was redissolved in Atltylacetat and at the Addition of ethyl acetate containing hydrogen chloride fell

HydrochL received.

Hydrochloride, 3.6 g of product, F. 200 to 202 ⁰ C ,,

Example 4 (Method 4) Preparation of Compound No. 1

105 g of N- (2'-hydroxypropyl) piperazine were added at ambient temperature added to a solution of 89 g of methyl 2-bromo-3-phenylpropionate in 470 ml of benzene. The reaction mixture became 3 Heated to 50 C for hours and then filtered. The filtrate was washed with water and 2N hydrochloric acid. The aqueous phase was washed with a sodium hydroxide solution and the ether was extracted, whereby 43 g of a yellow oil received. The addition of ether containing hydrogen chloride gave the dihydrochloride, mp 187 C.

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Example 5

Establishing connection no.24

100 mg of sodium were dissolved in 250 ml of n-butanol. To the solution, 9 g (0.0254 mol) of methyl 3- (p-clilorphenyl) -2- [4 ^l (2 "-hydroxybutyl) -piperazin-l'-yl] propionate (Compound No. 10) were added and the reaction mixture was kept for 3 hours at 70 ° C. The solvent was then evaporated off under reduced pressure, the residue was taken up in water and then extracted with methylene chloride. After the organic phase had been washed until neutral, the solvent was evaporated to give an oil. which was dissolved in diisopropyl ether and adding hydrogen chloride in diisopropyl ether, the hydrochloride of the hydrochloride, mp 203 ⁰ C ₁ was precipitated _o the hydrochloride was then recrystallized from n-butanol to give 5 g received.

Example 6

Establishing the connection ^ No. 25th

13.5 g (0.038 mol) of methyl 3- (p-chlorophenyl) -2-] 4 ^f - (2 "-hydroxybutyl) piperazin-l'-yl] propionate (Compound No. 10) were added to a 1 liter Flask was dissolved in 360 ml of anhydrous tetrahydrofuran, 7.7 g (0.038 mol) of dicyclohexylcarbodiimide and then 6.8 g (0.114 mol) of acetic acid were added to the solution, and the reaction mixture was left to stand in a refrigerator at 0 ° C. for 72 hours insolubles were filtered off and the product was taken up in water and ethyl acetate and then extracted with 15% hydrochloric acid, the aqueous phase was made alkaline by the addition of ammonium hydroxide and extracted again with methylene chloride, after evaporation of the solvent an oil was obtained was dissolved in diisopropyl ether, and by adding chlorine

609851/1057

The hydrochloride was precipitated using hydrogen in diisopropyl ether. The hydrochloride was then recrystallized from absolute ethanol, 8.3 g of product, mp 191 ° C., were obtained.

Example 7

Establishing connection no.32

1.7 g (0.033 mol) of potassium hydroxide were in 50 ml of absolute Ethanol was dissolved, then 5.8 g (0.0165 mol) of methyl 3- (pchlorophenyl) -2- [4 '- (2 "-hydroxybutyl) piperazin-1'-yl / propionate were added (Compound No. 10) was added. The reaction mixture was left for 3 days at ambient temperature in; Left in the dark. The solution was then neutralized to pH 7 by adding 10% hydrochloric acid.

The solvents were evaporated in vacuo and the residue was taken up in methylene chloride. The insoluble inorganic salts were filtered off and the solvent was dried over sodium sulfate and the solvent became The residue was taken up again in methylene chloride and traces of inorganic salts were removed again. After drying and evaporation, a light colored one was obtained crystalline product, which after recrystallization from isopropyl alcohol 3 g of a white crystalline product, F. 158 bis 160 ° C.

As indicated above, the compounds of the invention are interesting (advantageous) analgesics, especially because because they do not lead to habituation or addiction.

The pharmaceutical which forms a further subject of the invention Preparation contains or consists of at least one

609851/1057

Compound according to the invention in combination with a pharmaceutical Carrier or diluent.

The pharmaceutical carrier can be a liquid, in which case the preparations according to the invention in the form of solutions for injection, in the form of syrups, elixirs, suspensions and the like. The carrier but can also be a solid, in which case the preparations according to the invention in the form of tablets, capsules, Fills, coated tablets and the like. May be present.

The toxicities of the compounds according to the invention are given in Table I above.

The most interesting (most advantageous) compounds according to the invention are those for which in Table II below the results of specific oral analgesic tests Administration, their activity being compared with that of noramidopyrine and propoxyphene.

3 Table II test Randall Sellito
(Rat)
ED ₅₀ mg / kg 4th Heating plate
(Mouse)
ED ₅₀ mg / kg 200 10 Benzoquinone
(Mouse)
ED ₅₀ mg / kg 80 26th Noramidopyrine 25th 50 78 Propoxyphene 28 30th 74 84 Connection no. 30th 50 46 94 Connection no. 15th 25th 150 Connection no. 49 24 80 "Connection no. 18th 30th 100 Connection no. 14th 300 Connection no ₀ 54 609851/1057

In the hot plate test changed nalorphine the analgesic / ktivität (efficacy) of the compounds of the invention Nos. 4, IG, 13, 25, 28 and 30 (which were administered in an ED, _r) does not. This result shows that the compounds according to the invention do not lead to any habituation or dependency. The results are given in Table III below.

dose Verb. Table III Verb. Verb. Verb. Verb. Morphine mg / kg No. Verb. Mr. No. No. No. (p.o.) 75 4th No. 18th 25th 28 30th acceptance 10 the anal table 100 85 50 50 150 Activity ₆ -, 45 according to ver submission from 0 0 0 0 0 Nalorphine 0 (in %)

Patent claims:

609851/1057

Claims (1)

Claims where mean: / Ar \ ei a phenyl or naphthyl group, a hydrogen atom or an alkyl group a hydroxyalkyl group or an acetylated hydroxy alkyl group, the group -GH ₂ CO ₂ At or a phenyl group a hydrogen atom or a methyl group and X is a hydrogen or halogen atom or an alkyl, alkoxy, alkylthio, trifluoromethyl or substituted one or unsubstituted phenyl group, as well as the acid addition salts thereof, especially those with pharmaceutically acceptable acids. 609851/1 057 -zT- 2. Compounds according to claim 1, characterized by the general formula Shark where mean: shark is a calogen atom, R represents a hydrogen atom or an alkyl group and R ^{11 is} a hydroxyalkyl group or an acetylated hydroxy alkyl group, as well as the acid addition salts thereof, especially those with pharmaceutically acceptable acids. 3 «methyl 3- (p -chlorophenyl) -2- [4 ^l - (2" -hydroxypropyl) -piperazin-l'-yl] propionate and the acid addition salts thereof. 4. Methyl 3- (pf luophenyl) -2- [4 ^l - (2 ^ll -hydroxybutyl-piperazin-l'-yl] propionet and the acid addition salts thereof. 5. Methyl 3- (p -chlorophenyl) -2- [4 '- (4 "-hydroxybutyl) -piperazin-1'-yljpropionate and the acid addition salts thereof .. 6. Process for the preparation of the 3-aryl-2-piperazinyl-propionic acids and their acid addition salts according to at least one of Claims 1 to 5, characterized in that one 609851/1057 - 4> - Piperazine of the general formula wherein R "has the meanings given in claim 1, with a 3-aryl-2-bromopropionic acid derivative of the general formula R ² CH-CH-CO ₀ R (IV) I wherein ( Ar}, X, R and R have the meanings given in claims 1 and 2, and if necessary, in a manner known per se in their Acid addition salts, especially those with pharmaceutically acceptable acids, converted. 7. A process for the preparation of a compound of the general formula (i) given in claim 1, wherein R is a Denotes hydrogen atom, characterized in that a corresponding connection in which R denotes an alkyl group, hydrolyzed. 8. A process for the preparation of a compound of the general formula (I) given in claim 1, wherein R is a different alkyl group as a methyl group, characterized in that that a corresponding compound of the formula (I) in which R is a meth) rl group is transesterified. 6 09851/1057 9ο Method for producing a connection of the in claim 1 given general formula (I), in which R is an acetylated hydroxyalkyl group, characterized in that that a corresponding compound in which R is a hydroxyalkyl group is acetylated. 10. Pharmaceutical preparation, characterized in that it contains or consists of at least one compound according to at least one of claims 1 to 5 in combination with a pharmaceutical carrier or diluent. 609851/1057