DE2824764A1 - NEW PYRIDYL PIPERAZINE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

HOECHST AKTIENGESELLSCHAFT HOE 78 / F 109 Dr.MD/hka

Ο5.θ6.'ΐ97δ

New pyridylpiperazine derivatives and processes for their preparation

The invention relates to new substituted pyridylpiparazane derivatives and methods of making them.

It concerns particularly new 4-pyridylpiperazines / the valuable ones pharmacological properties, especially cardiac, Have circulatory and psychotropic effects and are suitable as medicinal products.

The invention therefore relates to piperazine derivatives of the formula I

3 x, ^

N N

¹⁵ "Ύ ^ viorin mean:

X is a CH - group or a CH, group which is connected to the O position of the phenyl radical by a single bond,
R hydrogen or C. - C _ß -alkyl,

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R is hydrogen, C ₁ - Cg-alkyl, phenyl, C ₁ - Cg-alkyloxy, C ₁ - C ^ -dialkylamino, hydroxy, cyano or halogen,

R hydrogen, C ₁ -Cg -alkanoyl

and their physiologically compatible salts. 5 Possible preferred substituents are:

for R ¹ hydrogen, methyl,

2 for R hydrogen, methyl, phenyl, methoxy, cyano, chlorine, for R hydrogen, C ₁ -C alkanoyl, for example acetyl, propionyl, trimethylacetyl.

The invention also relates to a process for the preparation of compounds of the formula I, which is characterized is that one 15

a) a compound of the formula II in which X and R are as defined above,

^x Ti ^) - och cn-cn Ii

O = O ^ Jl ^ ^ i

J.1

with a pyridylpiperazine of the formula III 25

^ (T ² in

wherein R has the meaning of formula I, converts, or

b) a compound of the formula IV in which X, R and R are as defined above and Hal is a halogen atom means 35

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^Χ '"" ΓΓ "JL OCH ₂ CII-CH Hal

IV

with a piperazine derivative of the formula III, or

c) a phenolic compound of the formula V, wherein X and R have the meaning given above,

o = c.

with a compound of the formula VI or VII,

H _£ C CH-CH ₂ NN

OR ³

• / ^ fi HaICH ₂ CH-CH ₂ NN — Η T- ^R

d)

2 3

wherein R, R and Hai have the abovementioned meaning

have, implements, or

a compound of the formula VIII, in which X, R and R are as defined above,

0 = (

OR

IL · OCH ₉ CH-CK_N NH

VIII

l

with a compound of the formula IX

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- U-

HaI-J-> ^ _IX

where R and Hal have the meaning given above,

5 implements, or

e) a compound of the formula X, in which X, R, R and Hal have the meanings given above,

10 χ.

O = c _v

with a compound of the formula XI,

H ₂ N J- _XI

wherein R has the meaning given above, converts,
or

f) a compound of the formula XIx,

3
OCH "CHCH" NH "XII

25 ^0R

wherein X, R and R have the meaning given above, with a compound of the formula XIII,

HaICH CH

N -4 λ " ^K XIII

35 HaICH CH. / ^N

where R and Hai have the meaning given above,

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-ft-

implements.

In process a) , the reaction of an epoxy compound of the formula II, which is obtained in a manner known per se from a phenolic compound of the formula V and epichlorohydrin, with a pyroxide of the formula III can be carried out in the absence of a solvent. If solvents are used, ethers such as dioxane or tetrahydrofuran, glycol ethers such as diglyme, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, aprotic solvents such as N, N, -dimethylformamide, dimethylacetamide or the like and alcohol such as ethanol, isopropanol or isoamyl alcohol are possible . The reaction is carried out at a temperature in the range from 30.degree. To 200.degree. C., preferably between 60.degree. And 160.degree. C., using preferably equimolar amounts of the amine of the formula III.

In method b) , the reaction of a 3-halopropoxy compound of the formula IV, which in turn is obtained in a manner known per se, for example from an epoxide of the formula II with salts of tertiary bases, for example pyridine hydrochloride, with an amine of the formula III, is preferred in the presence of a base, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, or tertiary amines, such as triethylainin or pyridine, but it is also possible to work in the absence of a base. The reaction is generally carried out at temperatures between 50.degree. And 200.degree. C., preferably between 60.degree. And 160.degree. If they are used for the reaction, the solvents mentioned above come into consideration as solvents. The amine of the formula III is used in at least equimolar amounts up to a five-fold molar excess.

According to process n c) , the reaction of the phenolic compound of the formula V with pyridylpiperazine derivatives of the formula VI or VII is carried out in a manner known per se,

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where those described above for process variants a) and b) Reaction conditions are applied. A preferred variant of the method is that one first the phenolic compound V into the corresponding alkali salt by means of an alkali alcoholate or alkali hydride convicted.

In process d) , the monosubstituted piperazine derivatives of the formula VIII, which in turn are obtained from the compounds of the formula II or IV and piperazine according to processes a) or b), are condensed with halopyridines IX. The reaction is carried out either in a polar solvent with a high boiling point, for example alcohols such as isoamyl alcohol or pentanol, or preferably in an aprotic solvent such as dimethylacetamide or in a non-polar solvent, for example an aromatic hydrocarbon such as toluene or chlorobenzene. The reaction is preferably carried out between 80 ° and 150 ° C in the presence of ej.net; Acceptor for the hydrohalic acid formed in the course of the reaction, such as potassium carbonate or pyridine, for example.

In process e) , the condensation of the compounds X with aminopyridines of the formula XI is carried out in a suitable solvent at a temperature between 80 ° and 160 ° C. in the presence of an acceptor for the hydrohalic acid formed during the reaction. Suitable solvents are, as in process d) above, higher-boiling alcohols, glycol ethers such as diglyme, tertiary amides such as dimethylformamide or aromatic hydrocarbons such as chlorobenzene or xylene. Suitable hydrogen halide acceptors are salts such as potassium bicarbonate, sodium bicarbonate, or organic bases such as triethylamine or pyridine.

According to process f) , aminopropanol compounds of the formula XII, which in turn are derived from the compounds of the formula

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mel II or IV, e.g. from the epoxides of the formula II with alcoholic ammonia solution can be obtained with Halogenäthylaminopyridinderivaten of the formula XIII implemented in a manner known per se, the above for the process variants d) and e) described reaction conditions are used.

The compounds of the formula I with R = hydrogen are in a manner known per se, for example with an acid chloride or acid anhydride, acylated, and so in compounds of

3
general formula I with R = C _{1 -C g} -alkanoyl converted.

The compounds of the general formula I are isolated in free form or as salts, depending on the reaction conditions used. The free bases can react with inorganic or organic acids in their pharmacological compatible salts are transferred. Such acids are e.g. hydrochloric acid, sulfuric acid, phosphoric acid, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids such as Acetic acid, tartaric acid, lactic acid, maleic acid, fumaric acid, citric acid, oxalic acid, methanesulfonic acid, hydroxyethanesulfonic acid, or synthetic resins containing acidic groups.

The compounds according to the invention are new compounds which are useful as pharmacological agents. They show various effects, in particular antihypertensive and neuroleptic effectiveness.

The new compounds can either be mixed alone or with physiologically acceptable auxiliaries or carriers can be applied. They can be administered orally, parenterally, or intravenously. For oral use the active compounds are mixed with the substances customary for this purpose and converted into by customary methods suitable dosage forms, such as tablets,

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Push-fit capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. as inert carriers can e.g. magnesium carbonate, lactose or corn starch with the addition of other substances such as magnesium stearate, be used. The preparation can take place either as dry or moist granules. as Oily carriers or solvents are particularly suitable vegetable and animal oils, such as sunflower oil or cod liver oil.

As a solvent of the corresponding physiologically acceptable salts of the active compounds for an intravenous Applications come into question, for example: water, physiological saline solution or alcohols such as ethanol, Propanediol or glycerine, as well as sugar solutions such as glucose or mannitol solutions, or a mixture from the various solvents mentioned.

The invention is illustrated, but not limited, by the following examples.

Example 1:

5- [3- <C 4- (2-pyridyl) -i-piperazinyl ^ -2-hydroxypropyloxi] -1-methyl-2-indolinone
25th

-OCH ₂ CHCH ₂ -N N- / \

OH

Method a):

A mixture of 6.6 g (0.03 mol) of 5- (2,3-epoxypropyloxi) -1-methyl-2-indolinone and 4.9 g (0.03 mol) 1- (2-Pyridyi) -piperazine is heated to 110 ° C for 1 hour. The residue is dissolved in 50 ml of methylene dichloride and 40 ml of solvent is distilled off. The oily residue is in 50 ml Dissolved diethyl ether, the precipitating crystalline

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Sucked off precipitate after 3 hours and washed with ether. Melting point 128 ° -130 ° C., yield 11.1 g (97% of theory) The base is dissolved in hot acetone, mixed with a small excess of ethanolic hydrochloric acid, the Trihydrochloride precipitates.

It is filtered off with suction, washed with acetone and dried, melting point 270 ° C. with decomposition, quantitative yield.

Method b):

0.26 g (0.01 mol) 5- (3-chloro-2-hydroxy-propyloxi) -1-methyl-2-indolinone, 0.24 g (0.015 mol) of 1- (2-pyridyl) piperazine and 1 g of potassium carbonate are dissolved in 5 ml of N'N-dimethylformamide Boiled under reflux for 48 hours. After cooling, it is diluted with 20 ml of water and the precipitate is filtered off with suction and after dissolving in a little methylene chloride, crystallized with ether. The substance has a melting point of 127 ° -129 ° C identical to the compound obtained above.

Procedure c):

To 1.63 g (0.01 mol) of 5-hydroxy-1-methyl-2-indolinone in 20 ml of dioxane add 0.01 mol of sodium hydride and afterwards the evolution of gas 2.4 g (0.01 mol) of 1-chloro: o-2-hydroxy-3- [4- (2-pyridyl) -1-piperazinyl] propane given. The mixture is refluxed for 10 hours after cooling diluted with water and extracted with methylene dichloride. After concentration, the title compound is with Ether pleases. It is identical in all properties to that obtained above.

Method d):

3 g (0.01 mol) 5- [3- (1-piperazinyl) -2-hydroxipropyloxi] -1-methyl-2-indolinone, 1.74 g (0.011 mol) of 2-bromopyridine and 5 g of potassium carbonate are dissolved in 50 ml of N'N-dimethylformamide Heated under reflux for 3 hours. The solvent is removed in vacuo and the residue is triturated with water. The undissolved is sucked off and the crude product like

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cleaned as described above. The compound is identical to that obtained according to method 1 in all properties.

Method e);

3.5 g (0.01 mol) of 5- [3- <bis- (2-chloroethyl) -amino> -2-hydroxipropyloxi] -1-methyl-2-indolinone and 2.8 g (0.03 mol) of o-aminopyridine are dissolved in 30 ml of diglyme for 10 hours Heated to 150 ° C. The mixture is diluted with water, extracted with methylene dichloride and the solvent in vacuo removed. The resinous residue is triturated with ether and the brown-colored crystalline product formed is filtered off and washed with ether. It is identical in all properties to the compound described above.

Procedure f):

A mixture of 2.2 g (0.01 mol) 2- [bis (2-chloroethyl) amino] pyridine, 2.4 g (0.01 mol) 5- (3-araino-2-hydroxipropyloxi) -1-methyl-2-indolinone, 5 g of anhydrous Kaliumcarbo'.at and 30 ml of N, N-dimethylformamide is heated to 130 ° C. for 10 hours. It is diluted with water, extracted with methylene chloride and purified as above by crystallization with ether. The crystalline compound obtained is identical in all properties to that obtained above by method a. \.

The compounds in the following table are shown in analogy to Example 1 using the processes specified there.

OH

N N-Het

jj ^X ^ - OCH ₂ C

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-Λ5-

Ex.
No. R ¹ 2 H 3 CH ₃ 4th CH ₃ 5 CH ₃ 6th CH ₃ 7th CH ₃ 8th CH ₃ 9 CH ₃ 10 CH ₃ 11 CH ₃

Indolinone Isctneres *)

Het

5 4 6

7 5

5 5

2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 4-pyridyl

-Cu

¹ CH-

^H 3
6 ^H 5

^CN ö

Melting point

3HCl 207
3HCl 236
3HCl 264
3HCl 225
3HCl 236

209 ° C 238 ° C 266 ° C 227 ° C 238 ° C

3HCl 210-212 ° C

3HCl 198-200 ° C

3HCl 205-207 ° C

3HCl 247-248 ° C

3HCl 235-237 ° C

20 *) Position of the -OCH ₂ CH (OH) CH ₂ -N N-Het group on the benzene ring

Example 12:

25 5- [3- <4- (2-pyridyl) -1-piperazinyl> -2-pivaloyloxipropyloxi j -1-ethyl-2-indolinone

CIi-CH

NN- ^ y

CH.

OCOC (CH ₃ )

A mixture of 2.0 g (5 mmol) 5- [3- <4- (2-pyridyl) -1-piperazinyl ^? -2-hydroxipropyloxi] -1-methyl-2-indolinone, 5 g of pivalic acid and 5 g of pivalic anhydride are stirred for 4 hours at room temperature. The volatile components are removed in vacuo, the residue triturated with ether, the crystalline precipitate filtered off with suction and with

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Ether washed. Yield 2.2 g (91% of theory), melting point 123 ° C.

The trihydrochloride is shown in analogy to Example 1. Mp. 230 ° C (decomp.), Quantitative yield. 5

Example 13:

1- (N-methyl-'i-acetamidophenoxy) -3- [4- (2-pyridinyl) -1 - piperazinyl] propan-2-ol

/ \\

CH

N- ^ V-OCH ₀ CIICIr N N- / -

CH N—

A mixture of 4.4 g (0.02 mol) of N-methyl-4- (2,3-Epoxipro pyloxi) acetanilide and 3.2 g (0.02 mol) 1 - (2-pyridyl) piperazine are heated to 100 ° C. for 1 hour. The received The melt is dissolved in 50 ml of hot acetone. When cooling down a crystalline precipitate separates out. It is filtered off with suction and washed with acetone. 6.7 g (87% of theory), Mp. 136 ° C.

Trihydrochloride: produced with ethanolic hydrochloric acid in acetone / chloroform, melting point 137 ° - 139 ° C with decomposition.
25th

Example 1 4:

1- (2-7iceta mi dophenoxi ) -3- [A- (2-pyridiny 1) -1 -piperazinyl] -propan- 2-ol

OH . ι /

η-OCH ₂ CIICH ₂ N X- / \ ^ -NHCOCH ₃ " ^K ~ - ^/ X '" - ^J

A mixture of 4.2 g (0.02 moles) of 2- (2,3-epoxypropyloxi) acetariilide and 3.2 g (0.02 mol) 1- (2-pyridyl) -piperazine are heated to 100.degree. C. for 1.5 hours. The cooled down Melt is dissolved in 50 ml of hot acetone, an excess

a O 9 8 51/0051

added to ethanolic hydrochloric acid, the precipitate formed is filtered off with suction, washed with acetone and dried. Yield 8.0 g (84% of theory) of hydrochloride of the title compound with a melting point of 205 ° C. (decomposition).

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Claims (1)

HOE 78 / F 109 Patent claims: Λ / piperazine derivatives of the formula I OR ³ where mean: 10 X is a CH ^ group or a CH ~ group linked to the O-position of the phenyl radical is connected by a single bond, R is hydrogen or C ₁ - C, - alkyl, R hydrogen, C ₁ - Cg-Alkyl, Phenyl, C. - Cg-AlkyI- 15 oxy, C ₁ -Cg dialkylamino, hydroxy, cyano or Halogen,
3
R is hydrogen, C ₁ - Cg-alkanoyl and their physiologically acceptable salts. 20 2. Process for the preparation of piperazine derivatives of the formula I, characterized in that one a) a compound of the formula II in which X and R are as defined above, ^ / 0 ocii cn— cii _o Ii with a pyridylpiperazine of the formula III wherein R 'has the meaning of formula I, converts, 909851/0051 ORIGINAL INSPECTED - 2 - HOE 78 / f 109 or 282 ^ 764 b) a compound of the formula IV in which X, R and R ³ are as defined above and Hal is a halogen atom, OR
Γ'JP ^ ⁰⁰ VHCH Hal IV with a piperazine derivative of the formula II, or c) a phenolic compound of the formula V, in which X and R have the meaning given above, i '^' iPV ⁰ " ^ with a compound of the formula VI or VII, H ₂ C CH-CH ₂ N N- "- ^R OR ³ ρ ¹ -.OC " have, implements, or 2 3
wherein R, R and Hai have the abovementioned meaning d) a compound of the formula VIII, wherein X, R and 3
R have the meaning given above, Ö09851 / 0051 - 3 - HOE 78 / F OR ³ γ / ν ;. I / \ - "^ ZL- OCHpCH-CH N NH VIII with a compound of the formula IX IX II 2 in which R and Hal have the meaning given above, implements, or 1 15 e) a compound of the formula X, wherein X, R, R and Shark have the meaning given above, ³ CHCH OCH ₀ CH-CH ₀ N ^{2 2} ^ with a compound of the formula XI 25 2 in which R has the meaning given above, converts, or 30 f) a compound of the formula XII, OR ³ x, / ^ I Fl " ^1-0CIJ 2 ^CHCH 2 ^NH 2 ^ΧΙ1 35 ^N. 909851/0051 - 4 - HOE 78 / f 109 wherein X, R and R have the meaning given above, with a compound of the formula XIII, HaICH ₀ CH ₀ wherein R and Hai are as defined above. 3. piperazine derivatives according to claim 1 for use in a therapeutic procedure. 4. Process for the preparation of medicaments, characterized in that compounds according to claim 1, optionally together with customary pharmaceutical carriers and / or stabilizers in one for therapeutic Brings appropriate dosage form for purposes. 5. Medicament, characterized by a content of a compound according to claim 1 or consisting of such a connection. 6. Use of compounds according to claim 1 in combating high blood pressure and as a neuroleptic. 909851/0051