DE1695410A1 - Process for the preparation of 1- (thiazolyl-5-alkyl) -4- (pyridyl-2) -piperazines - Google Patents

Description

Process for the production of 1- (Thiazolyl-5-alkyl) -4- (pyridyl-2) -piperazines

It has been found that 1 - (! Ethiazolyl-5-alkyl) ~ 4- (pyridyl-2) -piperazines of formula I.

wherein

R ⁵ R ¹ , R ² and R ^{5 are the} same or A— Ή N— (/ ^) are different and H

j carbon atoms, and

A linear or branched alkylene with 2-6 carbon atoms means,

and their acid addition salts have valuable pharmacological properties. If well tolerated, the substances show remarkable effects on the circulatory system and the central nervous system. In particular, blood pressure-lowering, furthermore anesthesia-prolonging, anesthesia-potentiating, tranquilling and / or neuroleptic effects occur. For example, the N - /, 4 "- (2,4-dimethyl-thiazolyl-5) -butyl-17- ^NI -". (Pyridyl-2) -piperazine was found both in conscious rats with experimental hypertension and in dogs' with renal hypertension

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Already in very low doses strongly lowering blood pressure without significant influence on the other circulatory functions with good tolerance at the same time.

The invention relates to a process for the preparation of 1- (thiazolyl-5-alkyl) -4- (pyridyl-2) piperazines of the formula I as well as their acid addition salts, which consists in the fact that a compound of the formula II

A - X ^WOrin ■

X Cl, Br, J or a halogen

R analogous, through an amino group

yj means replaceable remainder

with a (pyridyl-2) piperazine of the formula III

- ^{/ r} "~ ^X " in

or that one thiazolylalkyl-piperazine of the formula IV

S- j "A-Xi ίΐίί JY

R ²

with a pyridyl derivative of the formula VX— < ^/ ^) V

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or that a thiazolylalkylamine of the formula YI

YI
n. - χι

with an aminopyridyl derivative of the formula YII

wherein the two groups X next to

■ jr prr / trr Ώ?

λ. OH ₂ -UH ₂ / T ^ C of ^{the ol3en an} given meaning

/ \ sz / also together mean an oxygen-X-CH _{2 -GH 2 or} sulfur atom

YII can,

or that a compound of the formula YIII

wherein the two groups X

. _T ^ CH ₂ -CH ₂ -X besides that given above

S ri— A - Jn \

L. II CH ₂ -CH ₂ -X meaning also together

^RR oxygen or sulfur

_. atom can mean

with an aminopyridine of "Formula IX

or that an ethylenediamine derivative of the formula X

_R 1- ^ R ₂

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with an ethane derivative of the formula XI

Σ - CH ₂ - CH ₂ - X XI

or that a Mtrile of the formula XII

R wherein

R ' R ²

η means 1 to 4

XII

with an organometallic compound of the formula XIII

wherein

_R 4 _ _M M MgT, CdR ^ »ZnR ⁴ or an alkali metal, preferably lithium,

XIII R ⁴ - alkyl with 1 - 4 carbon atoms and

Γ Cl, Br or J means

but the sum of η and the number of carbon atoms in R ^ are not greater than 5 may be,

or that a compound of the formula I in which one or more groups which can be replaced by hydrogen and / or C-C multiple bonds are present with hydrogen donating funds

or that a thioamide of the formula XIY R ¹ - CS - NH ₂ XIV

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with a carbonyl compound of the formula XV

2 / - \ / T ^

R-CO-CHX -AN N- ('^ S XV

or that compounds of the formula XVI

wherein

B and D sulfur

i / ^ - \ 2 mean

it MR

XVI

with HgS-releasing agents

or that compounds of the formula XVI in which B and D are acidic substance or one of the two radicals B and D as well. Mean sulfur can, implemented with sulfur-releasing agents

and that optionally a compound of formula I by Treating with acid converts it into a physiologically compatible acid addition salt

or that a base of the formula I is obtained from its acid addition salt sets in freedom.

In formulas II-XVI, R ¹ , R ² , R ³ , A, B, D and X have the
given meaning.

The alkyl groups in the radicals R ¹ _f R ² »K ^ and R * come in
Question “Methyl, ethyl, n-propyl, isopropyl, n-> butyl, ieobutyl, also sec-butyl and tert-butyl.

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1B 95410.

The group A preferably means -CH ₂ GH ₂ -, -GHCH ₅ -, -, -CH (CH ₅ ) CH ₂ -, -GH ₂ CH (CH ₅ ) -, -

-CH ₂ CH ₂ CH (CH ₅ ) -, - (GH ₂ ) ₅ -, - (CH ₂ ) ₆ - _? it can also have the following meaning, for example, -GH (C ₂ H ₅ ) CH ₂ -, -CH ₂ CH (C ₂ H ₅ ) -, -GHCn-O ₅ H ₇ -) -, -CH (IsO-G ₅ H ₇ ) -, -GH (OH ₅ ) CH ₂ CH ₂ GH ₂ -, -GH ₂ CH (CH ₅ ) GH ₂ CH ₂ -, -CH ₂ CH ₂ CH (CH ₅ ) GH -CH (C ₂ H ₅ ) CH ₂ CH ₂ -, -CH ₂ CH (G ₂ H ₅ ) GH ₂ -, -CH (nC ₅ H ₇ ) GH ₂ -, -CH ₂ GH ^ -C ₅ H ₇ ) -, -GH (XSO -C ₅ H ₇ ) CH ₂ -, -CH ₂ CH (IsO-C ₅ H ₇ ) -, -CH (nG ₄ H ₉ ) -, -CHCiSO-G ₄ H ₉ ) -, -CH (sec.- C ₄ H ₉ ) -, -GH (tert-C ₄ H ₉ ) -, -CH (CH ₅ ) CH ₂ GH ₂ Ch ₂ CH ₂ -, -CH ₂ CH (CH ₅ ) CH ₂ Ch ₂ CH ₂ -, -CH ₂ CH ₂ CH (CH ₅ ) CH ₂ Ch ₂ -, -GH ₂ Gh ₂ CH ₂ GH (CH ₅ ) CH ₂ -, -CH ₂ CH ₂ CH ₂ GH ₂ CH (Gh ₅ ) -.

In the definition of X are under halogen analogous, by a Amino group-replaceable radicals are understood to mean those which, when reacted with an amine, are in the same way as halogen atoms can be replaced by an amino group, preferably the following! Hydroxy, acyloxy, such as acetoxy, methanesulfonyloxy, p-toluene sulfonyl oxy or lower alkoxy, such as Methoxy. It is also possible to work under reducing conditions with starting compounds which correspond to the formulas II, VII, VIII, XI or XV, but instead of one or two CHX Reete aldehyde, ester or other analogues Contain groups that are reduced to groups such as CHOH under the reaction conditions.

The term "replaceable by hydrogen groups" are understood above all halogen atoms are preferably chlorine barren bromine atoms, further carbonyl _r hydroxy or Benaylgruppen.

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Double bonds in particular are used as C-C multiple bonds lrage, but also triple bonds can be eliminated by the treatment converted into saturated bonds with hydrogen-releasing agents "

The following are the individual manufacturing options the piperazines of the formula I explained in more detail »

The starting compounds of formula II are mainly the following in embossing 1- (thiazolyl-5) -2-chloroethane? 1- (Thiazolyl-5) -3-chloro-propane? 1- (Thiazolyl-5) -4-chloro-butane? ^ j 1- (thiazolyl-5) -5-ehlor-pentane? 1- (Thiazolyl-5) -6-chloro-hexane? 1- (2-methyl-thiazolyl-5) -2-chloroethane? 1- (2-methyl-thiazolyl-5) -3-chloro-propane; 1- (2-methyl-thiazolyl-5) -4-chloro-butane; 1- (2-methyl-thiazolyl-5) -5-chloropentane; 1- (2-methyl-thiazolyl-5) -6-chlorohexane; 1- (4-methyl-thiazolyl-5) -2-chloroethane? 1- (4-methyl-thiazolyl-5) -3-chloropropane; 1- (4- -Methyl-thiazolyl- ■ 5) -4-chloro-butanj 1- (4-methyl-thiazolyl-5) -5-chloropentane; 1- (4-methyl-thiazolyl-5) -6-chloro-hexane, 1- (2,4-dimethylthiazolyl-5) -2-chloro-ethane? 1- (2,4-Dimethyl-thiazolyl-5) -3-chloro-propane? 1- (2,4-Dimethyl-thiazolyl-5) -4-chloro-butane? 1- (2,4-Dimethyl-thiazolyl-5) -5-chloropentane? 1- (2,4-dimethylthiazolyl-5) -6-chloro-hexane; 1- (2-Ethyl-4-methyl-thiazolyl-5) -3-chloropropane 1- (2-ethyl-4-methyl-thiazolyl-5) -4-chloro- { butane? 1- (2-ethyl-4-methyl-thiazolyl-5) -5-chloropentane? 1 - / 7- (Propyl-3) -4-methyl-thiazolyl-57-4-chloro-butane? 1 - / 2 ~ - (Propyl-2) -4-methyl-thiazolyl-57-4-chloro-butane? 1 - /? - (Butyl-4) -4-methyl-thiazolyl-57-4-chloro-butane? 1- (2-methyl-4-ethylthiazolyl-5) -4-chloro-butane? 1- / 5-methyl-4- (propyl-3) -thiazolyl-57-4-chlorobutane? 1 - /? - methyl-4- (propyl-2) -thiazolyl-57-4-chloro-butane. Instead of the chlorides, it is also possible to use the corresponding bromides, iodides or alcohols and their esters, in particular their methane and p-toluenesulfonates.

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The following piperazines, for example, are suitable as compounds of the formula III: 1- (pyridyl-2) piperazine, 1- (3-methylpyridyl-2) piperazine, 1 ~ (4-methyl-pyridyl-2) -piperazine, 1 - (5-methyl-pyridyl-2) -piperazine, 1 - (6-methyl-pyridyl-2) piperazine, 1- (3-A "thyl-pyridyl-2) -piperazine, 1- (4-ethylpyridyl-2) -piperazine, 1 ~ (5-ethyl-pyridyl-2) -piperazine, 1 - (6-ethyl-pyridyl-2) -piperazine. ·

The straight-chain piperazines of the formula I are preferably obtainable by reacting the compounds of the formula II with the 1- (pyridyl-2) piperazines of the formula III. Some of these compounds of the formula II are known, such as, for. B "1- (4-methyl-thiazolyl-5) -2-chloro-ethane, or can easily be prepared analogously to known compounds. For example, the 7-chlorheptanone (2) known from the literature can be chlorinated with SO 2 Cl 2 to give 3,7-dichloro-heptanone (2), the thiazole ring closure of which, carried out by known methods, with thioamides of the formula XIV (cf. B. Elderfield, Heterocyclic Compounds , Volume I (1957), John Wiley & Sons, Inc., Few York, page 496) leads to compounds of the formula II in which RH or alkyl with 1-4 carbon atoms, R ² CH ₅ , A (OH ₂ J ₄ and X are Cl * The 2-chloroethyl or the ^ -chloro-n-butyl-thiazole side chain can be extended by a methylene group in a manner known per se if the halogen is exchanged for the nitrile group, this in the ester converts, reduces the ester with LiAlH ^ to the alcohol and converts this into the halide by treatment with thionyl chloride. An extension by two methylene groups is achieved by reacting the halide with sodium malonic ester, saponification, decarboxylation, re-esterification, reduction of the ester to alcohol and its conversion to Halogeni d. In general, therefore, primary alcohols (II, X = OH) are e.g. B. by reduction of the corresponding carboxylic acids or their esters, secondary and

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tertiary from · corresponding ketones through. Reduction or implementation available with organometallic compounds. Treat with thionyl chloride, hydrogen bromide, phosphorus tribromide or Similar halogen compounds yield the corresponding halides (II, X = Cl or Br), the corresponding iodine compounds you get z. B. by exposure to potassium iodide the associated p-toluenesulfonic acid esters. The suIfonyloxy compounds can be obtained in the usual way from the alcohols S-rr-A-OH

by reaction with the corresponding acid chlorides _e The "piperazines III are obtainable from piperazine and pyridyl derivatives of the formula V", preferably 2-chloro- or 2-bromopyridines, or by reacting aminopyridines of the formula IX with diethanolamine, morpholine or bis- (2-chloroethyl ) -amine.

The reaction of the compounds II and III proceeds according to methods known for the alkylation of amines (cf. Houben-Weyl, Methods of Organic Chemistry, Volume Xl / 1, Georg-Thieme-Verlag, Stuttgart, 1957t especially pages 24 and 205-224). You work without a solvent by fusing the components with one another, if necessary in a closed manner Tube or in an autoclave, optionally also in the presence of an inert solvent such as benzene, Toluene, xylene, acetone, butanone or other ketones, methanol, ethanol or other alcohols, tetrahydrofuran or dioxane, optionally also in mixtures of these solvents with one another or mixed with water. It is beneficial to add an acid-binding agent, for example a hydroxide, Carbonates, bicarbonates or another salt of a weak acid of the alkali or alkaline earth metals, vorzugswelae of potassium, sodium or calcium or the addition of a

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organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the piperazine derivative of the formula III. The reaction time, depending on the conditions used, between a few minutes and 14 days, the reaction temperature is between 0 and 200 ° _t usually at 100-130 ⁰ C. If the reaction without solvent at about 120 ° C, the reaction is within approximately 1 / 2- Finished 2 hours. When using solvents, heating for 12 to 24 hours is sometimes necessary * to achieve good yields.

In a variant of the above method, one can use a Aldehyde of formula XVII

XVII

wherein

m 1 - 5 means

react with piperazines of the formula III under the conditions of a catalytic hydrogenation. The reaction conditions correspond to those customary in reductive alkylations (cf. Organic Reactions, Volume IV, John Wiley & Sons, Inc., New York (1948), pages 174-255). The aldehydes XVII are accessible by oxidation of the corresponding primary alcohols of the formula TI (X * OH) or by hydrogenation of the corresponding acid chlorides in the presence of Pd / BaSO ^ catalysts.

The compounds of the formula I can also be obtained by reaction of a thiazolylalkylpiperazine of the formula IV with a pyridyl * derivative of the formula V.

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The thiazolylalkyipiperazines of the formula IV are obtainable either by reacting thiazolyialkyl halides of the formula II with 1-benzyl-piperazine and subsequent reductive elimination of the benzyl group or by reacting thiazolylalkylamines of the formula TI with diethanoiamine, morpholine or bis (2-chloroethyl) amine. The following thiazolylalkyipiperazines of the formula IV can mainly be used: 1- (Thiazolyl-5) -2-N-piperazino-ethane; 1- (thiazolyl-5) -3-8-piperazino-propane; 1- (thiazolyl-5) -4-N-piperazino-butane; 1- (thiazolyl-5) -5- N -piperazino-pentane 1- (thiazolyl-5) -6-N-piperazino-hexane; 1- (2-methyl-thiazolyl-5) -2-N-piperazinoethane; 1- (2-methyl-thiazolyl-5) -3- N -piperazino-propanj 1- (2-methyl-thiazolyl-5) -4-N-piperazino-1) utane; 1- (2-methylthiazolyl-5) -5-li-piperazino-pentani 1- (2-methyl-thiazolyl-5> 6-N-piperazino-hexane 1- (4-methyl-thiazolyl-5) -2-N -piperazinoethane 1- (4-methyl-thiazolyl-5) -3-N-piperazino-propanj 1 - (4-methyl-thiazolyl-5) -4-N ~ piperazino-butanj 1- (4-methylthiazolyl-5) - 5-N-piperazino-pentane? 1- (4-methyl-thiazolyl-5) -6-li-piperazino-hexane; 1 - (2,4-dimethyl-thiazolyl-5) -2-N-piperazino-ethane 1 - (2,4-Dimethyl-thiazolyl-5) -3-N-piperazinopropane ; 1- (2 i 4-Dimethyl-thiazolyl-5) -4-N-piperazino-ljutane; 1- (2,4-dimethyl- thiazolyl-5) -5-N-piperazino-pentane; 1- (2,4-dimethyl-thiazolyl-5) -6-N-piperazino-hexane; 1- (2-ithyl-4-methyl-thiazolyl-5) -3-N-piperazino-propane; 1- (2-ethyl-4-methylthiazolyl-5) -4-N-piperazino-butane; 1- (2-ethyl-4-methylthiazolyl-5) -5-N-piperazino -pentane; 1- £ 2- (Propyl-3) -4-methylthiazolyl- ^ 7-4-N-piperazino-butane; 1- / 5- (Propyl-2) -4-methylthiazolyl-57-4-N- piperazino-butane; 1 - /? - (Butyl-4) -4-methylthiazolyl-57-4-N-piperazino-butane; 1- (2-methyl-4-ethylthiazolyl-5) -4-N-piperazino-butane ; 1- £ 2-M ethyl-4- (propyl-3) -thiazolyl-57-4-N-piperazino-butane; 1- / 2-diethyl-4- (propyl-2) -thiazolyl-57-4-N-piperazino-butane,

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169-541 above

The pyridyl derivatives of the formula V are either known or they can according to the usual methods of synthesis of 2-halopyridines can be easily obtained (cf. e.g. Erwin Klingsberg, Pyridine and its Derivatives, Volume 2 (1961), pages 299 - 371, Interscience Publishers, Inc., New York). The compounds IV and V are reacted by the abovementioned methods the N-alkylation.

The compounds of formula I are also by the structure of Piperazine rings available from suitable precursors. So you can either obtain thiazolylalkylamines of the formula VI ( from the compounds II with phthalimide potassium or by reducing the corresponding nitriles) with nitrogen Lo implement st compounds of the formula VII (produced about by reacting 2-halopyridines of the formula V with diethanolamine or of aminopyridines of the formula IX with ethylene oxide and subsequent conversion of the hydroxyl groups into halogen atoms, for example with thionyl chloride); or the nitrogen mustard compounds thiazolylalkylated on the nitrogen atom can be used of the formula VIII and the aminopyridines of the formula IX (cf., for example, Erwin Klingsberg 1. c. »Volume 2, (1962), page 3 66) react with one another under conditions similar to those mentioned above for the N-alkylation. The connections VIII are e.g. B. from the amines VI by reaction with ethylene chlorohydrin or from the compounds II and diethanolamine and, if desired, by further reaction with thionyl chloride available. The following are preferably possible starting compounds for these reactions?

Formula VIs

1- (Thiazolyl-5) -2-amino-ethane 1- (Thiazolyl-5) -3-amino-propane 1- (thiazolyl-5) -4-aminobutane 1- (thiazolyl-5) -5-aminopentane; 1- (thiazolyl-5) -6-amino-hexane; 1- (2-methyl-thiazolyl-5) -2-amino-ethane; 1- (2-methyl-thiazolyl-5) -3-amino-propanj 1- (2-

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Methyl ~ thiazolyl ~ 5) - ~ 4-amino-butanj 1- (2-methyl-thiazolyl-5) -5-amino-ρ ent an j 1- (2-methyl-thiazolyl-5) -6-amino-hexane; 1 - (4-methyl-th.iazolyl-5) -2-aaiino-etiian; 1 - (4-methyl-thiazolyl-5) -3-aminopropane 1- (4-methyl-thiazolyl-5) -4-aminobutane 5i 1- (4-methyl-thiazolyl-5) -5-amino-pentane 1- (4-methyl-thiazolyl-

5) -6-amino-hexane ; 1 ■ - (2,4-dimethyl-th, iazolyl-5) -2-amino-ethane; 1 - (2,4-dimethyl-thiazolyl-5) -3-aminopropane 1- (2,4-dimethylthiazolyl-5) -4-aminobutane; 1- (2 ₁ 4-Dimethyl-thiazolyl-5) -5-amino-pentanj 1- (2,4-dimethyl-thiazolyl-5) -6-amino-nexanj 1- (2-ethyl-4-methyl-thiazolyl -5) -3 ^to amino-propani 1- (2-ithyl-

4-methyl-thiazolyl-5) -4-aminobutane? 1- (2-ethyl-4-methyl- Λ

thiazolyl-5) -5-aminopentane 1/2 "- (propyl-3) -4 ~ methyl-thiazolyl-5 / -4-aminobutane j 1 - / 2 ~ - (Propyl-2) -4-methyl-thiazolyl - ^ / - 4-amino-butanj 1 - / 2- (butyl-4) -4-methyl-thiazolyl -5 / -4-aminobutane; 1- (2-methyl-4-ethyl-thiazolyl-5) -4-aminobutane; 1 - /? - methyl-4- (propyl-3) -thiazolyl -5 / -4-aminobutane 1 - / 2 ~ - Methyl-4- (propyl-2) -thiazolyl -jj / ^ - amino-butane.

Formula VII:

2- / bis- (2-chloroethyl) -amino / - and 2- / bis- (2-bromoethyl) -amino / -pyridine and their 3- »4-» 5- or 6 ~ methyl and their 3-, 4- » 5- or 6-ethyl derivatives.

Amines of the formula VIII are preferably the corresponding bis (2-chloroethyl) - or bis (2-bromoethyl) amines or morpholine or thiomorpholine derivatives _$ such. B. 2> 4-dimethyl-5- (4- / I-morpholino / - (butyl-1) -thiazole or 2-ethyl-4-methyl-5- (4 - ^ - thiomorpholino / - (butyl-1) -thiazole.

Compounds of formula IX are, for. B. 2-aminopyridine and its 3-, 4-, 5- or 6-methyl and its 3- »4- _f 5- or • 6-ethyl derlvate.

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Furthermore, the compounds of the formula I can be obtained by using the Bischoff see piperazine synthesis (reports of the German Chemical Society, Volume 22, page 1777 (1889); Volume 23-, page 1977 (1890) - Volume 25, Page 2949 (1892)) N-2-pyridyl-N '- (thiazolyl-5-alkyl) ethylenediamines of the formula X with ethylene chloride, ethylene dibromide or analogous compounds of the formula XI, advantageously in the presence of acid-binding agents. Me compounds X can be obtained by reacting aldehydes of the formula XVII with a corresponding N- (2-pyridyl) ethylenediamine to give the Schiff base and catalytically hydrogenating it. Examples of compounds of the formula X that may be mentioned are? N- / 5- (4-methyl-thiazolyl-5) propyl-17-N ^t - (pyridyl-2) ethylenediamine; N- ^ J- (2,4-Dimethylthiazolyl-5) -butyl-17'-N ^f - (pyridyl-2) -ethylenediamine N- / T- (2-methyl-4-ethyl-thiazolyl-5) -propyl -27-N - (pyridyl-2) ethylenediamine; Ί5- / Έ- (2-ethyl-4-methyl-thiazolyl-5) -hexyl-T / -KT '- (4-methyl-pyridyl-2) -ethylenediamine.

The Bischoffshe synthesis also takes place under the conditions the N-alkylation, however, one generally applies something more vigorous conditions. For example, heating is carried out, if necessary in the presence of a higher-boiling inert solvent and a strong base such as sodium hydroxide or carbonate Stir for 6-8 hours at temperatures between 120 and 160 °

A reaction of nitriles of the formula XII with an organometallic compound of the formula XIII, preferably a Grignard compound of the formula H ^ -Mg-X, also leads to the desired compounds of the formula I. Nitriles of the formula XII are obtained according to the following reaction scheme: one sets the 1,4-dicarbonyl compounds of the formula XVIII known from the literature

R ² - 00 - CH ₂ CH ₂ CHO XVIII

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after conversion into the bisulfite adducts with (pyridyl-2) piperazines of formula III and an alkali metal cyanide are preferred Potassium cyanide, according to Strecker (cf. Houben-Weyl, methods of Organic chemistry, 4th edition, Georg-Thieme-Verlag, Stuttgart, Volume 8 (1952), page 279) "and receives the ketonitrile piperazines of Formula XIX

R ² -C0-CH ₂ -CH ₂ -CH-N Ν - (/ <*) XIX CN

which one with halogens, preferably with bromine, to the halogen compounds of the formula XX halogenated.

3 R ² -CO-CH-CHp-CH-N N- V ^ f XX

X CN

The thiazole ring closure carried out by known methods (cf. e.g. Elderfield, Heterocyclic Compounds, Volume V. (1957), John Wiley & Sons, Inc., New York, page 496) of XX with thioamides of the formula XIV leads to the nitrile piperazines XII. As starting compounds for the synthesis of substances | of the formula XII are preferably used Suceindialdehyd, ß-acetyl-, ß-propionyl- or ß-butyryl-propionaldehyde as 1,4-diketo compounds of the formula XVIII, (pyridyl-2) -piperazine and its 3-, 4-, 5- or 6-methyl and its 3-, 4-, 5- or 6-ethyl derivatives as piperazines of the formula III.

Suitable organometallic compounds of the formula XIII are above all methylmagnesium;) odide, ethylmagnesium chloride, ethyl bromide and -iodide, n-propyl magnesium chloride, bromide and iodide, iso-

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propyl magnesium chloride, bromide and iodide, n-butyl magnesium chloride, bromide and iodide, also methyl, ethyl, n-propyl, Isopropyl and n-butyllithium as well as dimethyl and diethyl zinc or cadmium.

The reaction of the nitriles XII with the organometallic compounds XIII is usually carried out by the nitrile in solution or in solid form to a solution of the organometallic compound slowly, optionally with cooling, and then added the mixture obtained until the end of the

Q) Settlement warms or boils. As solvents are above all Ether, diisopropyl ether or tetrahydrofuran, also anisole, dibenzyl ether, dioxane, benzene, toluene or methylene chloride suitable, as well as higher ethers or hydrocarbons and mixtures of these solvents with one another. In some In cases, it is advisable to add inorganic salts such as magnesium bromide or copper (I) chloride. Response time and temperature are not critical? as a rule, however, the reaction takes place at temperatures between 0 ° and the boiling point of the solvent used and is after 1/2 to 48 hours, preferably after 4 to 6 hours of boiling, completed. Working up is carried out in a manner known per se by hydrolysis of the mixture, for example with water,

P dilute acids or magnesium chloride solution, and subsequent Isolation of the bases or their salts.

Finally, it is possible to obtain a compound of the formula I by starting from a precursor which is additionally or one or more atoms instead of hydrogen atoms groups that can be replaced by hydrogen and / or C = C double bond, fertilize and / or contains CSC triple bonds, and this with treated hydrogen-emitting agents. For example, can chlorine or bromine atoms on the heterocyclic rings or in the chain by catalytic hydrogenolysis or by treatment with chemical reducing agents through hydrogen

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substitute. You can z. B · N- / 4 * - (2,4-Mmethyi-thiazolyl-5) -butyl-j7-N ^f - (4-hydroxymethylpyridyl-2) -piperazine with catalytically excited hydrogen to the corresponding N "* - (4- It is also possible to hydrogenate methylpyridyl-2) derivative, for example (pyridyl-2) -piperazines of the formula III with an acid or thioacid of the general formula XXI

^{S rT} ~ "° m ^H 2m" ^Z m 1 - 5 and

wherein m 1 _R 1 y ^ EK ^ 2 Z COOH or OSOH

XXI mean M

or to react with functional derivatives of such carboxylic acids or thiocarboxylic acids to give corresponding amides or thioamides, which then by reducing the carbonyl function with complex hydrides, such as lithium aluminum hydride, can be converted into compounds of the formula I. The acids of Formula XXI, in which Z is GOOH, can be prepared by Oxidation of the corresponding primary alcohols of the formula II (X = OH) or the corresponding aldehydes of the formula XVII or by replacing the halogen in compounds of the formula II by the nitrile group and saponifying it. Acid derivatives, Thiocarboxylic acids and thiocarboxylic acid derivatives are obtained from the acids of the formula XXI, in which Z denotes COOK, according to known methods Methods. In addition, one can use ethylenediamine derivatives of the formula X with oxalic acid or haloacetic acids or their functional derivatives or sulfur analogues to form compounds of general formula XXII,

■ j where

_A _. g jj (/ ^ y ^H E and FH ₂ , 0 or S,

but E and F do not

S.

¹ la

R ¹ R * f \ at the same time H ₂ be

can interpret XXII

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■ - 13 -

, 1t> 9b41U

realize. Compounds of formula XXII can also be reductive, e.g. B. with lithium aluminum hydride or catalytically Compounds of J Formula I are reduced.

Reactions with lithium aluminum hydride are preferably in Ether, tetrahydrofuran or di-n-butyl ether, preferably in the boiling point. It is sometimes an advantage to extract poorly soluble starting materials continuously with the boiling solvent. Basically can according to the methods described in Organic Reactions, Volume 6 (Mew York, John Wiley ft Sons, 1951), pages 4-63-509 work.

For catalytic ^ hydrogenation and / or hydrogenolysis are as Catalysts such as noble metal, nickel and cobalt catalysts suitable. The noble metal catalysts can be on supports (e.g. palladium on charcoal, calcium carbonate or Strontium carbonate), as oxide catalysts (e.g. platinum oxide), or as finely divided metal catalysts. Nickel- and cobalt catalysts are expediently used as Raney metals, Nickel also used on kieselguhr or pumice stone as a carrier »The hydrogenation can take place at room temperature and normal pressure or can also be carried out at elevated temperature and / or elevated pressure. It is preferable to work between printing 1 and 100 at and at temperatures between -80 and + 150 ° »in primarily between room temperature and + 100 °. The implementation is expedient in the presence of a solvent such as water, Methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dioxane, Acetic acid or tetrahydrofuran can also be used Use mixtures of these solvents with one another. To the Hydrogenation can use the free bases or the corresponding Salts, for example the hydrochlorides, are used. The hydrogenation conditions must be chosen so that

109815/2193

the phenyl and thiazole rings are not also attacked. In the hydrogenation of multiple bonds and in the hydrogenolysis of benzyl groups is therefore preferably carried out at normal pressure in such a way that the Hydrogenation stops after the calculated amount of hydrogen has been absorbed.

The reaction of the thioamides of the formula XIV known from the literature with carbonyl compounds of the formula XV, preferably α-halogen ketones, to compounds of the formula I is carried out by the customary methods (cf., for example, ELderfield, Ie, page 496 ff and Organic Reactions, Volume VI, page 369 ff, John Wiley & Sons, Inc., New York).

The reaction components XIV and XV are with or without addition of inert solvents such as water, methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran, dimethylformamide, Benzene, toluene, xylene at temperatures between 10 and 200 °, preferably between 40 and 100 °, brought to reaction, wherein Often external cooling is necessary to keep the exothermic Control reactions.

^ -Halogen ketones of the formula XV are for example according to the following Accessible reaction scheme, compounds of formula XXIII known from the literature are used,

CH ₃ - CO - CH ₂ - A - X XXIII

wherein

X is halogen, preferably bromine,

with (pyridyl-2) piperazines of the formula III to give ketopiperazines of the formula XXIV '.

109815/2193

CH ₅ -GO-CH ₂ -AN Ν - ('- *> χχ _ΐν

to, their halogenation, preferably bromination, c <-halogen ketones the formula XV result.

It is also possible to thermally convert compounds of the formula XYI, in which B and D are sulfur, into compounds of the formula I by splitting off HoS. One works at temperatures between 60-250 ° with or without the addition of solvents, optionally in the containment tube. The following solvents can preferably be used: benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetone. In addition, substances can be added that are _{capable of promoting H 2} S elimination, such as? 2 ^ 5 »lead tetraacetate, alkali or alkaline earth metal oxides and carbonates, ΡρΟς» aluminum oxide.

Finally, compounds of the formula XVI in which B and D can be oxygen or one of the two radicals B and D can also be sulfur can be reacted with sulfur-releasing, thiazole ring-closing agents to give compounds of the formula I. _{P 2} Sc, optionally with the addition of K ₂ S, alkaline earth carbonates or oxides, and reaction conditions as described, for example, in Elderfield Ie, page 503, are preferably used as the sulfur-releasing agent. But you can also use arsenic, antimony and aluminum sulfides, the latter often with the addition of a hydrated salt such as Na ₂ SOj · 6H ₂ O, furthermore thioformamide, thioacetamite, mixtures of P2O5 and sulfur and other sulfur-releasing agents. The reaction partners can be merged or in solution

1098 15/2193

16954IU

agents such as benzene, toluene, xylene, tetrahydrofuran, dioxane, Dimethylformamide, ethanol, isopropanol, n- * butanol, if necessary in the containment tube, at temperatures between 60 and 280 ° bring to reaction.

Compounds of formula XVI are for example according to the following Reaction scheme accessible: 1-chloro-6-bromo-hexanone known from the literature ~ (5) According to Gabriel, it becomes the 6-phthalimido derivative with phthalimide potassium and further with (pyridyl-2) piperazines of formula III to compounds of formula XXY

| T ^ N-Ch ₀ -CO-CH ₀ -CH ₀ -OH ₀ -NN ML / £ c- 2 2 \,

N N

XXV

The primary amino group is set free by acid hydrolysis. Reactions with acid or thioic acid derivatives then lead to compounds of the formula XVI in which R ¹ and R ^ have the meaning given, RH, A (GH ₂ ) j, B oxygen or sulfur and D can mean oxygen. In order to exchange the oxygen for sulfur in compounds of the formula XVI, in which B is sulfur and Β I is oxygen, solvents such as benzene , toluene, diozane or tetrahydrofuran are reacted under mild conditions with? 2% * ^n! Other © compounds of structure XVI can be established in the same way.

The obtained according to one of the above methods, products of the formula I are administered in "a customary manner, eg., By extraction, isolated from reaction mixtures and AEEN by distillation

109815/219: 3:

Ib 9541 Ü

or crystallization of the bases or their salts, mainly the hydrochloride, purified. Ehromatographic methods too can be used for isolation and cleaning.

A piperazine derivative of the formula I obtained by the process of the invention can be treated with an acid in a customary manner be converted into the associated acid addition salt. For this reaction, those acids come into consideration which provide physiologically harmless salts. So can organic and inorganic acids, such as. B. aliphatic, alicyclic,

f) araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid t propionic _f pivalic "Mäthylessigsäure, oxalic» malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid »aminocarboxylic acids, SuIfaminsäure, benzoic acid acid, salicylic acid, phenylpropionic acid, citric acid, (muconic acid, ascorbic acid, isonicotinic acid, Methaneulfonsäure, Ithandisulfonsäuren ß-HydroxyäthaEgulfonsäure _p p-folxtolsulfonsäure, naphthalene-mono- and -dismlfonsäure acid ₉ sulfuric acid, nitric acid, hydrogen halide such as hydrochloric acid or Bromwasserstoffsäur © ₈ or phosphoric acids such as orthophosphoric Satire * Me free bases of the formula I can, if desired,

w from iron salts. Treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate - are obtained «__" ...

According to the invention, compounds of the formula I can be prepared in which R * R and R ^, identically or differently, Bind nad H _r OH ^ or C ₂ H ^ ttacl A are alkylene with 3 - 5 carbon atoms.

109815/2193

1Ü95410

The new compounds can be mixed with conventional drug carriers be used in human or veterinary medicine. The carrier substances used are organic or inorganic substances in question, which are used for parenteral, enteral or topical application are suitable and those with the new compounds do not react, such as water, vegetable oils, polyethylene glycols, gelatine, Lactose, starch, magnesium stearate, talc, petroleum jelly, Cholesterol, etc. For ρ ar ent er al application are in particular solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. For enteral application, tablets or dragees, for topical application ointments or creams, which may be sterilized or with auxiliaries such as preservatives, Stabilizing or wetting agents or salts for influencing osmotic pressure or mixed with buffer substances are to be applied.

The substances according to the invention are preferably administered in a dosage of 0.1 to 50 mg per dosage unit.

Example 1 ,

20.4 g of 1- (2,4-dimethyl-thiazolyl-5) -4-chloro-butane (boiling point 98-100 ° / 0.05 mm) and 40 g of N- (pyridyl-2) piperazine are used 1 hour to 120 ° -130 ° C. After cooling, aqueous ammonia is added and the mixture is extracted with ether. The ether residue is distilled in vacuo, giving 23.3 g of N - /? - (2,4-dimethyl-thiazolyl-5 ) -butyl- tf-E * - (pyridyl-2) -piperazine of bp 192-195 ° / 0.5 mm. The trihydrochloride monohydrate melts at 223-225 °.

10 9 8 15/2193

1 b 9 5 A Ί ü

Analogously, from N- (pyridyl-2) -piperazine: with 1- (4-methyl-thiazolyl-5) -2-chloroethane (boiling point 104-106 ° / 8 mm.): N- / T- (4-methyl-thiazolyl-5) -ethyl-2) -N ^f - (pyridyl-207-piperazine, b.p. 196-198 ° / 0.1 mm, trihydrochloride P. 274-276 °;

with 1- (4-methyl-thiazolyl-5) -5-chloropropane (b.p. 120-122 ° / 9 mm): Ν- / ΊΓ- (4-methyl-thiazolyl-5) -propyl-37-N * - (Pyfidyl-2) -piperazine, b.p. 208-210 ° / 0.1 mm, trihydrochloride F. 272 »275 ⁰ J

with 1- (4-methyl-thiazolyl-5) -4-chloro-butane (b.p. 140-142 ° / 9 mm): N- / 4 "- (4-methyl-thiazolyl-5) -butyl-Jj- K ^r - (pyridyl-2) piperazine, bp 190-194 ° / 0.01 mm, trihydrochloride mp 255-258 °;

with 1- (2,4-dimethyl-thiazolyl-5) -5-chloropentane (b.p. 103-106 ° / 0.05 mm):

N- / 5- (2,4-Dimethyl-thiazolyl-5) -pentyl-17-N ^f - (pyridyl-2) -piperazine, b.p. 190-194 ° / 0.50 mm;

with 1- (4-methyl-thiazolyl-5) -6-chlorohexane (bp 98-100 ° / 0.05 mm):

N- / F- (4-methyl-thiazolyl-5) -hexyl-i / -N - (pyridyl-2) -piperazine, Bp 193-196 ° / 0.05 mm;

with 1- (2,4-dimethyl-thiazolyl-5) -6-chloro-hexane (b.p. 120 - 122 ° / 0.05 mm):

Έ- / Έ- (2,4-dimethyl-thiazolyl-5) -hexyl-17-N '- (pyridyl-2) -piperazine, boiling point ^: 218-220 ° / 0.5 mm;

with 1- (2-ethyl-4-methyl-thiazolyl-5) -4-chloro-butane (boiling point 105 107 ° / 0.01 mm):.

N- / T- (2-ethyl-4-methyl-thiazolyl-5) -butyl-Jj-K - (pyridyl-2) piperazine, 192-194 ° / O.0.5 mm, trihydrochloride monohydrate M.p. 215-218 °;

109815/2193

1Ö9541U

with 1 - / 2- (Propyl-3) ^ -methyl-thiazolyl - ^^ - chlorobutane (Ep. 1T5 - 117 ° / 0.01 mm): '.

N- / 4- (2- (Propyl-3) -4-methyl-thiazolyl-5) -butyl-17-ΪΤ * - (pyridyl-2) -piperazine, Ep. 195-2OO ° / O, 0.5 mm, trihydrochloride monohydrate 1. 214-217 °;

with 1 - /? - (Butyl-4 -) - 4-methyl-thiazolyl-57-4-chloro-t) UtarL (Ep.

134 - 137 ° / O, O5 mm):

N - /? - (2- (Butyl-4) -4-methyl-thiazolyl-5) -butyl -Υ / -Ή »- (pyridyl-2) -piperazine, ep. 200-2O5 ° / 0, 05 mm , Trihydrochloride mono-

hydrate P. 225-227 °. |

The following connections are also established in an analogous manner:

N- / 5- (4-methyl-thiazolyl-5) -pentyl-27-Ιί ^f - (pyridyl-2) -piperazine; N - /? - (2,4-Mmethyl-thiazolyl-5) -ethyl- ^ 7-N ^f - (pyridyl-2) -piperazine;

N- / 2 "- (2-methyl-4-ethyl-thiazolyl-5) -ethyl-17-N * - (pyridyl-2) -piperazinj

N- / 2- (2-methyl-4- (propyl-3) -thiazolyl-5) -ethyl-17-N * - (pyridyl-2) -piperazine;

N- / 2- (2-methyl-4- (butyl -4) -thiazolyl-5) -ethyl-t / -! * - (pyridyl-2) -piperazine;

N- / 5- (2-methyl-4-ethyl-thiazolyl-5) -propyl-27-N »- (pyridyl-2) - i piperazine;

N- / 5- (2-Methyl-4- (propyl-3) -thiazolyl-5) -propyl-17-N ^f - (pyridyl-2) -piperazine; ·

N- / 5- (2-Methyl-4- (butyl-4) -thiazolyl-5) -propyl-17-N '- (pyridylaO-piperazine;

109815/2193

1 b 9 b A Ί ü

N- / 4- (2-methyl-4-ethyl-thiazolyl-5) -butyl-1 / -H • - (pyridyl-2) piperazine

N - / ^ - (2-Methyl-4-ethyl-thiazolyl-5) -pentyl-iJ-N • - (pyridyl-2) piperazine

N- / 2- (2,4-diethyl-thiazolyl-5) -ethyl-iJ-N »- (pyridyl-2) piperazine;

N- / 2- (2-ethyl-4-methyl-thiazolyl-5) -ethyl-17-N.- (pyridyl-2) piperazine;

N- / 2- (2- (Propyl-3) -4-methyl-thiazolyl-5) -ethyl-17-N · -

(pyridyl-2) -piperazinj.

¥ - /? - (2- (Butyl-4) -4-methyl-thiazolyl-5) -ethyl-17-ΪΓ · - (pyridyl-2) -piperazine?

N- £ 5- (2-ethyl-4-methyl-thiazolyl-5) -propyl -Ij-Ή * - (pyridyl-2) piperazinj

N-Z5- (2- (Propyl-3 ■) -4-methyl-thiazolyl-5) -propyl-JJ-W * - (pyridyl-2) -piperazinj

N- ^ J- (2,4-dimethylthiazolyl «5) -butyl -Ij-H" * - (3-methyl-

pyriayl-2) -piperazine f ..._ ■ _

1- / T- (2,4-Dime thyl-thiazolyl-5) -butyl-IJ-IT ^r - (4-methylpyridyl-2) piperazine;

N - /? - (2 _f 4-3) imethyl -thi azolyl-5) -butyl- Ij-S ^f - (5-methyl-pyridyl-2) -piperazine 5

N- / 2f- (2,4-dimethyl-thiazolyl-5) -butyl-17-l r ^f - (6 * methyl-

pyridyl-2) piperazine. '.

Example 2

25f3 g of U- / 4 "- (2 _r 4 ~ dimethyl-thiazolyl-5) -butyl-17-piperazine (bp. 152-155 ^o / 0 _t Q1 mm) and 8 g of 2-bromopyridine are heated to 100 ° for 1 hour After cooling, aqueous ammonia is added and the mixture is extracted with ether. The base mixture remaining after evaporation of the ether is distilled

1098 15 / 219.3

7 b 9 5 A1 Ü

N- / 4- (2,4-Dimethyl-thiazolyl-5) -butyl- Ij-E »- (pyridyl-2) -piperazine distilled at 190 - 95 ° / ö, 0.5 mm, ϊ ¹ . 48 - 50 °. The trihydrochloride monotydrate melts at 223-225 °, the dimaleate at 95 °.

Example 3

18.4 g of 1- (2,4-dimethyl-t-mazolyl-5) -4-aminobutane (boiling point 103105 ° / 0.05 mm), obtainable in a known manner from 1- (2,4-Dimeth.yl-thiazolyl-5) -4-ehlorbutane, and 22 g of 2-bis (ß-chloroethyl) aminopyridine (obtainable from 2-bromopyridine by reaction with diethanolamine and subsequent chlorination of the reaction product with thionyl chloride) are refluxed for 24 hours in a mixture of 600 ml of acetone and 600 ml of water. It is then concentrated, made alkaline with sodium hydroxide solution and extracted with benzene. After drying and evaporation of the Benzene solution, the residue is fractionated in vacuo.

The N- ^ T- (2,4-dimethyl-thiazolyl -5) - butyl-1 / -! T ^f - (pyridyl-2) piperazine boils at 192-195 ° (0.05 samV

Example 4

3 g of N- (pyridyl-2) -N · - /? - (2 ^f , 4'-dimethyl-thiazolyl-5 *) -butyl-7-ethylenediamine, obtainable from 1- (2,4-dimethyl-thiazolyl-5 ) -4- A amino-butan and ethyleneimine in the presence of τοη aluminum chloride and conversion of the ethylenediamine derivative with 2-bromopyridine, are stirred in 500 ml of boiling xylene in the presence of 2 g of ethylene bromide and 25 g of anhydrous powdered sodium carbonate for 10 hours. After the reaction product has been worked up by chromatography, N - // f- (2,4-dimethyl-t-mazolyl-5) -butyl-17 »is obtained. N ¹ - (pyridyl-2) -piperazinj bp 190-195 ° / 0.50 mm, ¥. 48 - 50 °.

109815/2193

Example 5

12 g of 5N- / N- (pyridyl-2) -piperazino7-pentanone- (2), available from 5-chloropentanone (2) ethyl ketal and pyridyl pip he az in after subsequent ketal cleavage, are in 50 ml of 2N hydrogen bromide acid dissolved and added dropwise according to the 8 g of bromine are added to the decolorization. Then neutralize with sodium bicarbonate and take the released bromoketone in ether. After drying and evaporation of the solution, the crude residue is treated with 50 ml of alcohol and 4 g of thioacetamide for 2 hours refluxed. After the alcohol has evaporated, the semi-solid residue is mixed with water and extracted with ether. The aqueous phase is then made alkaline with soda and then extracted thoroughly with ether. This extract is dried over sodium sulfate and evaporated, the residue is fractionated in vacuo. N- / 3 "- (2,4-dimethyl-thiazolyl-5) -propyl-17-N - (pyridyl-2) -piperazine is obtained, 190-192 ° / O, 0.1 mm. Trihydrochloride, m.p. 263 - 265 °

Example 6

3 g of N- (pyridyl-2) -N ^f - / J- (2,4-dimethyl-thiazolyl-5) -allyl7-piperazine (obtainable by malonic acid condensation of 2,4-dimethyl-thiazol-5-aldehyde to the corresponding Thiazolylacrylic acid, esterification of the acid, reduction of the ester with lithium aluminum hydride to thiazolyl-allyl alcohol, conversion of the alcohol into the mesylate and conversion of the mesylate with N * (pyridyl-2) -piperazine) with the addition of 0.5 g of 5-tiger palladium carbon -Catalyst hydrogenated to a standstill in 40 ml of methanol at normal pressure and room temperature. After the catalyst has been filtered off with suction, the solution is concentrated. Ethereal hydrochloric acid is added to the residue. After recrystallization from absolute alcohol, N- / 5- (2,4-dimethylthiazolyl-5) propyl-17-N ^f - (pyridyl-2) piperazine trihydrochloride is obtained. F. 263-265 °.

109815/2193

Example 7

3.3 g of 3 ~ C4-methyl-thiazolyl-5) -butyric acid-F ^f - (pyridy-1-2) -piperazid (obtainable from 3- (4-methyl-thiazolyl-5) -butyric acid ethyl ester "and N- ( Pyridyl-2) -piperazine) are refluxed in 100 ml of absolute tetrahydrofuran with 1 g of Mthiumaluminiumhydrld for 24 hours under nitrogen Precipitate is washed off with absolute alcohol and the filtrates are evaporated. The residue is distilled in vacuo. N - /? - (4-Methyl-thiazolyl-5) -butyl -Yf- N ¹ - (pyridyl-2) is obtained piperazine, bp 190-194 ⁰ / Q * 01 mm, trihydrochloride, m.p. 255-258 °.

Example 8

3.3 g of 2-acetylamino-7-N- (N ^f -pyridyl-2-piperazino) -heptanone- (3) (obtainable from 7-N- (N ^f -pyridyl-2-piperazino) -heptanone- (3 ) by oximation and acetylating reduction of the oxime group) and 2.2 g of diphosphorus pentasulphide are intimately mixed and heated to 110-120 °, with a reaction occurring with evolution of ^ S. After 15 minutes the mixture is cooled, taken up with dilute hydrochloric acid, filtered and made alkaline with ammonia. The precipitated bases are taken up in ether. The ether residue is separated by chromatography. N- / 4 "- (2,4-dimethyl-thiazolyl-5) -butyl-Ij-N · - (pyridyl-2) -piperazine. Bp. 190-195 ° / 0.50 mm,> 48 The trihydrochloride monohydrate melts at 223-225 °, the dimaleate at 95 °.

109815/2193

Claims (1)

Claims 1. Process for the preparation of 1- (thiazolyl-5-alkyl) -4- (pyridyl-2) -piperazines from iOrmel I. wherein / -ν / r ~ S ^ R ¹ , R ² and R ^{5 are the} same or S -—— ι—— A TO \ j / / - ^ TV Y T ^ / are different and H j carbon atoms and P A linear or branched tes alkylene with 2-6 carbon atoms mean ..- ■ '■ as well as their acid addition salts, characterized in that that a compound of the formula II wherein S — Tj — A ~ X ϊ Cl, Br, J or a halogen _Ώ 1 - ^^ H '^ vt »2 analogous, by an amino xi -K group replaceable remainder means ¹¹ , > '■■■■■ ~ with a (fyridyl-2) piperazine of the formula III HN N- < ^/ ^) III 1098 15/2193 No. 1 sentence 3 31 1 b 9 5 4 t above or that one thiazolylalkyl-piperazine of the formula IV S η - A - N NH IV with a pyridyl derivative of the formula V or that a 3-hiazolylalkylamine of the formula VI VI with an aminopyridyl derivative of the formula VII X-GH -GH / - * - v R ^ where the two groups X j ^{> Sv} N ^ ^ in addition to the above N— ^ ^ y in addition to the above-mentioned X-GH ₂ -CH ₂ ^ ¹¹ ^^ meaning also together Oxygen or sulfur VII atom can mean or that a compound of the formula VIII 109815/2193 16954 1U AT
Γ C. VIII in which the two groups X, in addition to the meaning given above, also together Can mean oxygen or sulfur atom, with an aminopyridine of the formula IX IX or that an ethylenediamine derivative of the formula X S j-A-NH-CH ₀ -CH ₀ -NH- ^ with an ethane derivative of the formula XI X - CH ₂ - CH ₂ - X XI or that a nitrile of the formula XII R ¹ (C ₂ H _2n ) -CH-R ^{2 CN} wherein η 1 to 4 means XII 109815/2193 with an organometallic compound of the formula XIII . wherein ^R '" ^M Iff: MgY, CdR ⁴ , ZnR ⁴ or an alkali metal, preferably lithium, R ^{4 is} alkyl with 1 - 4 carbon atoms and Y is Cl, Br or J, but the sum of η and the number of carbon atoms in R ^{4 must} not be greater than 5, or that a compound of the formula I in which one or more groups which can be replaced by Fassstoff are additionally used and / or C-C multiple bonds are present with hydrogen donating funds or that a thioamide of the formula XIV R ¹ - CS - NH ₂ with a carbonyl compound of the formula XV R ² - CO - CHX - A - NN - (f - ^ V XV R ³ or that compounds of the formula XVI He in what f, "V" ^A - \ __ / \ ^ J B and D sulfur 1 / ^ nA. 2 mean Jx U It XVI 109 815 721 93 3H IbEl54 I U with HpS splitting agents or that compounds of the formula XVI, in which B and I) Oxygen or one of the two radicals B and D can also mean sulfur, with sulfur-releasing agents implements and that, if appropriate, a compound of the formula I by treatment with acid into a physiologically compatible acid addition sal or that one. Base of the formula I from its acid eadditi onssalz sets in freedom. 2. Compounds of the formula I A - R ¹ R ^fi wherein R ¹ , R ² and R ^{5 are} identical or different and are H or alkyl with 1-4 carbon atoms and A linear or branched alkylene with 2-6 carbon atoms means. 3. IT-ZT- (4-methyl-thiazolyl-5) -ethyl-27-N · - (pyridyl-2) -piper azin. 4. N- / T- (4-methyl-thiazolyl-5) -propyl-37-liV- (pyridyl-2) piperazine. 5. Ητ / Ϊ- (^ -Methyl-thiazolyl -?) - butyl-IJ-N - (pyridyl-2) -piperazine 10 981 5/2193 1U95A1Ü 6. NZ? - (4- piperazine 7. NZ & - (4-J «ethyl-thiazolyl-5) -hexyl-TJ-N ^f - (pyridyl-2) -piperazine. 8. ΪΓ- / Ζ- (2,4-dimethyl-thiazolyl-5) -ethyl-17-li ^t - (pyridyl-2) -piperazine. 9. N- / J- (2,4-Dimethyl-thiazolyl-5) -PrOPyI-Ij-Ii * - (pyridyl-2) -piperazine. 10. N- / T- (2,4-Mmetiiyl-'thiazolyl-5) - 'butyl-17-N ^t - (pyridyl-2) -piperazine. 11. N- / 5-C2,4-3) ime-fciiyl-thiazolyl-5) -pentyl-t7-li ^f - (pyridyl-2) -piperazine. 12. N- / F- (2,4-Mmethyl-thiazolyl-5) -liexyl-i7-li * - (pyridyl-2> piperazine. 15. N-Z? - (2-Methyl-4-ethyl-thiazolyl-5) -ethyl-Ij-II "- (pyridyl-2) piperazine. - 14. K-Z ^ - (2-Methyl-4- (propyl-3 ■) -thiazolyl-5) -ethyl-iJ-F * (pyridyl-2) -piperazine. 1 5 . H-Z2- (2-methyl-4- (dutyl-4) -thiazolyl-5) -ethyl-ij-ii * (pyridyl-2) -piperazine. 16. N-ZT- (2-methyl-4-ethyl-thiazolyl-5) -propyl-IJ-N »- (pyridyl-2) piperazine. 109815/2193 17. N - /? - (2-Methyl-4- (propyl-3) -thiazolyl-5) -propyl-Ji7 ~ ir ^f - (pyridyl-2) -pxperazine. 18.N- / 5- (2-Methyl-4- (butyl-4) -thiazolyl-5) -propyl-17-N · - (pyridyl-2) piperazine. 19. N- / 4 "- (2-methyl-4-ethyl-thiazolyl-5) -butyl -! / - Ν» - (pyridyl-2) -piperazine. 20.N- / 5- (2-Metb.yl-4-ethyl-thiazolyl-5) -pentyl-17-N - (pyridyl-2) piperazine 21. N-Z2 "- (2 _t 4-diethyl-thiazolyl-5) -ethyl-i7-N '- (2-pyridyl) piperazine. 22. N - /? - (2-Ethyl-4-methyl-thiazolyl-5) -ethyl-IJ-N · - (pyridyl-2) ■ piperazine. 23. N-Z2- (3- (Propyl-3) -4-methyl-tliiazolyl-5) -ethyl-i7-N - (pyridyl-2) piperazine. 24. N- / 2 "- (2- (Butyl-4) -4-methyl-thiazolyl-5) -ethyl-17-N · - (pyridyl-2) piperazine. 25. N- / 5- (2-ethyl-4-methyl-thiazolyl-5) -propyl-17-N - (pyridyl-2) -piperazine, 26. N- / 5- (2- (Propyl-3) -4-aetb.yl-thiazolyl-5) -propyl-17-N · - (pyridyl-2) piperazine. 27.N- / i- (2- (Butyl-4) -4-methyl-thiazolyl-5) -butyl-i7-N - (pyridyl-2) piperazine. 10 9 8 15/2193 28. N- / 4- (2-Ä (pyridyl-2) piperazine. 29. Ή- / J- (2- (Propyl-3) ^ - methyl-thiazolyl-i) -butyl-1 / -N • (pyridyl-2) -piperazine. 30. N-ZT- (2,4-bimethyl-1; hiazolyl-5) -butyl-iJ-N ^f - (3-methylpyridyl-2) -piperazine. 31. N- / T- (2,4-Bimethyl-thiazolyl-5} -buΐyl-17-l · r '- (4-methylpyridyl-2) -piperazine. 32. N- / 4 "- (2,4-Dimethyl-thiazoiyl-5) -butyl-17-N * - (5-methyl pyridyl-2) piperazine » 33. F - / ^ - (2,4-Dimethyl-thiazolyl-5) '- l) utyl-t7-N ^f - (6-methyl-pyridyl-2ϊ-piperazine. 109815/2193