NO136841B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PHENYLIMIDAZOLIDINONES. - Google Patents

Description

This invention relates to the preparation of compounds of the formula

In this formula I and in the following formulas means

R a hydrogen atom, a lower alkyl or alkoxy group

or a halogen atom,

R' one of the following groups in the m or p position

-CHR^Q-A

-CHR2-A

-0-CHR2-CHR1-Q-A

where

A means the rest

and

Q means an unbranched or branched alkylene chain with

1-4 carbon atoms,

a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group or a lower alkylaminocarbonyloxy group,

a hydrogen atom or a methyl group,

R 3 and R 3 , which may be the same or different, a hydrogen atom,

a lower alkyl or alkoxy group, a halogen atom or a trifluoromethyl group or together also a condensed aliphatic or aromatic 5- or 6-ring,

Z a pyridyl or quinolyl group,

R" a hydrogen atom or a linear or branched alkyl radical with 1-4 carbon atoms.

To the extent that the new bases can appear in the form of optical isomers, e.g. as antipodal pairs or as diastereomer pairs, the pure forms and also the mixtures resp. the racemates and acid addition salts of the above formula I.

With "alkyl and olefin residues" resp. with "lower alkyl-

and lower olefin residues" shall be understood as such residues with usually 1-4, preferably 1-2 carbon atoms. Preferred halogen atoms are chlorine and bromine.

For the production of the new compounds i

according to the invention the following methods:

1. Reaction of an amine with the formula

where A has the meaning given above, with a compound of the formula where R Cl means one of the following groups in the m- or p-position -CHR2-X, 136841

-CHR1-Q-X and

-0-CHR2-CHR1-Q-X,

where X means a residue which together with the hydrogen atom in the compound HA can be split off as HX, e.g. a halogen atom, an -O-SO2~alkyl or -O-SO2~aryl group, in the presence of an HX binding agent, e.g. potassium carbonate, sodium carbonate or excess of amine. 2. For the preparation of such compounds of formula I where R^ denotes a hydrogen atom, a hydroxy or a lower alkoxy group:

Circularization of the corresponding compound with the formula

where X is as indicated in 1.

by heating with strong bases such as potassium or sodium hydroxide. 3. For the preparation of such new compounds of formula I where R^ does not mean a hydroxy group or a monoalkylaminocarbonyloxy group:

Cyclization of ethylenediamine derivatives with formula

with N,N'-carbonyldiimidazole.

4. For the preparation of such new compounds where A represents the residue

reductive amination of compounds of formula

where Rtø means one of the following groups in the m or p position

-CHO

-CHR1-<C>2<H>2n-1° °9

-0-CHRo-CHR., -C H..0

• 2 ch 2n-l

(n means 1, 2, 3 or 4)

with an amine of formula H-A under the influence of hydrogen and hydrogenation catalysts.

5. For the preparation of such compounds of formula I where R' means the radical -CHOH-Q-A: Reduction of ketones with the formula

preferably with suitable hydrides, e.g. sodium borohydride, or also with hydrogen and hydrogenation catalysts. 6. For the preparation of such compounds of formula I where • R^ means hydrogen and R" means a residue • '* Removal of the OH group from compounds of formula $

where R^" means an alkyl residue with 1-4 carbon atoms, and Rc means a residue in the m- or p-position with the formula

-CR2OH-A,

-CHOH-Q-A or

-0-CHR2-CHOH-Q-A preferably by first using a chlorinating agent, e.g. S0C12 or PCl^, replaces the OH group with chlorine and then removes the chlorine by hydrogenation. 7. For the preparation of compounds of formula I, where R^ denotes a hydroxy group:

Turnover of compounds with formula

where R^ means a residue in m- or p-position with the formula where Rg and R^ mean hydrogen atoms or alkyl residues with a total of up to 3 carbon atoms, with amines of formula H-A. 8. For the preparation of such compounds of formula I, where R^ denotes a hydrogen atom, a lower alkoxy group, a lower alkanoyloxy group or a di-lower alkylaminocarbonyloxy group: Introduction of a corresponding residue R" by a compound of the formula

where R' has the above limited meaning for R^, and Me<+ >means an alkali cation, is reacted with a corresponding compound R"X. The compound X can be prepared from the corresponding NH compound by metallation, e.g. with sodium hydride, lithium amide or potassium tert-butylate.

9. For the preparation of compounds of formula I, where R' means the radical

-0-CHR2"CH2-Q-A:

Reaction of a phenol with the formula

where the phenolic OH group is in the m- or p-position, with a compound of formula X-CHR2-CH2~Q-A in the presence of an acid-binding agent, e.g. sodium or potassium carbonate. 10. For the preparation of compounds of formula I where R 1 denotes an alkoxy group or a lower alkanoyloxy or lower alkylaminocarbonyloxy group:

Reaction of compounds with the formula

where Rg means the following residue in the m- or p-position

-CHOH-Q-A or -0-CHR2-CHOH-Q-A,

with a means to replace the OH hydrogen with an alkyl group or a lower alkanoyl or lower alkylaminocarbonyl group.

Ether formation can be carried out below with common alkylating agents, e.g. alkyl halides, dialkyl sulfates or sulfonic acid esters in the presence of alkali under conditions of ether formation. One can also first replace the OH group with chlorine using a chlorinating agent such as PCl^ or SOC12, and react the resulting compound with alkali alcoholate.

To the extent that the new compounds form racemates

or diastereomeric antipode pairs, these can be separated in the usual way into the diastereomeric racemates or in the individual optical antipodes.

The starting materials for the method of manufacture

of the new compounds have been partly described earlier and can otherwise be prepared by usual synthesis methods.

The new compounds are particularly useful as pharmaceuticals. They act as central nervous system depressants, neuroleptics, analgesics, antiphlogistic, spasmolytic, broncholytic, blood pressure-lowering and cholesterol-lowering effects.

They are used in the form of ordinary, galenic preparations with ordinary aids and carriers, e.g. in the form of tablets, dragées, capsules, aerosols, drop and injection solutions. Single dose is approx. 2 to 100 mg, preferably 5-50 mg (per 75 kg).

Particularly suitable compounds have, among other things, proved to be 1-(4-imidazolidinone-(2)-ylphenethyl)-4-(2-ethylphenyl)-piperazine and 1-(4-imidazolidinone-(2)-ylphenethyl)-4-(2-methylphenyl)- piperazine, and more generally those compounds where R" means hydrogen and R^ means hydrogen or hydroxy.

The following examples shall serve to further illustrate the invention.

EXAMPLE 1: 1-(4-imidazolidinone-(2)-ylphenethyl)-4-(3-chlorophenyl)-piperazine (Me 446)

19.6 g (0.1 mol) of N-3-chlorophenylpiperazine and 23.0 g (0.1 mol) of 2-(4-nitrophenyl)-ethyl bromide are boiled in the presence of 20 g of potassium carbonate in 150 ml of acetonitrile for 2 hours under reflux cooling. The hot solution is suctioned off, the residue is washed out with acetonitrile, and the combined solutions are evaporated. Treatment of the residue with iso-propanol gives 19 g of 1-(4-nitrophenethyl)-4-(3-chlorophenyl)-piperazine (m.p. 87°C), and from the mother liquor a further 4.5 g is obtained.

The total yield is 23.5 g (70% of the theoretical).

The nitro compound is dissolved in 240 ml of methanol and hydrogenated in the presence of 1 g of PtO 2 at 20°C and 5 ato of hydrogen until the nitro group is reduced. After separation of the catalyst, 21 g of amine are obtained as a distillation residue, which without further purification is reacted with 8.5 g of [3-chloroethyl isocyanate in 150 ml of benzene during 3 hours of heating to 50°C, to form the compound

(yield 27 g (96% of theoretical), decomposition point >200°C). 27 g of this compound are dissolved while warm in 360 ml of ethanol and then a solution of 4.0 g of potassium hydroxide in 40 ml of ethanol is added. The mixture is boiled for a further 3-5 minutes under reflux, filtered with suction after cooling, and inorganic material is removed from the residue by leaching with water. You get 17 g

as a base. For transfer to the salt, the base is heated to boiling in 500 ml of ethanol and an equivalent of methanesulfonic acid is added in the form of an ethanolic solution. You get 20.5 methanesulfonate, m.p. 239°C (from ethanol).

In the same way as described in example 1, the following compounds are prepared:

Furthermore, it is produced in the same way as in example 1:

In the following examples, y denoted the residue 28.4 g (0.1 mol) of 2-(4-imidazolidinone-(2)-ylphenyl)-ethyl-methylsulfonal which is prepared from 2-(4-imidazolidinone-(2)-yl- phenyl)-ethanol and methanesulfochloride in pyridine, is reacted with 17.5 g of N-2-methylphenylpiperazine in 120 ml of acetonitrile in the presence of 21 g of soda, and the mixture is boiled for 1 hour under reflux. Compound A is isolated as a base and has a melting point of 195°C. 10 g of 1-(4-imidazolidinon-2-yl-phenyl)-2-oxo-propane is hydrogenated with 8.1 g of 2-methylphenylpiperazine in 100 ml of methanol in the presence of 1 g of PtO2 at 60°C and 5 ato until the calculated amount of hydrogen is occupied. After removing the catalyst, the methanol is distilled off, and the residue is crystallized with acetonitrile. From the base, the hydrochloride of B is prepared in a little methanol by adding concentrated hydrochloric acid, and the hydrochloride has a melting point of 299-301°C and crystallizes as monohydrate. EXAMPLE 4 15.5 g (0.05 mol 1-[2-(4-aminophenyl)-ethyl]-4-(2-ethylphenyl)-piperazine are mixed in 85 ml of glacial acetic acid with 1.6 g of paraformaldehyde and a solution of 4 .1 g of potassium cyanide in 7 ml of water at 15-20°C, and the reaction is allowed to complete by standing at room temperature overnight. The product formed has a melting point of 137-138°C and is hydrogenated in methanol with Pt02 as a catalyst

and the calculated amount of N,N<1->carbonyldiimidazole dissolved in tetrahydrofuran is added to benzene. The mixture is allowed to stand overnight at room temperature, boiled for a further 2 hours under reflux cooling, and the product C formed is isolated as a base (m.p. 178-181°C).

EXAMPLE 5

4-Methoxy-3-nitroacetophenone is reduced to 4-methoxy-3-aminoacetophenone, reacted with 3-chloroethyl isocyanate to (m.p. 149°C), which with the help of potassium hydroxide in ethanol is converted to the imidazolidinone derivative with formula (m.p. 186-188°C). The reaction with bromine in chloroform gives the compound which, as a crude product (85 g), is reacted with 105 g of N-2-ethylphenyl-piperazine in 1500 ml of acetonitrile to give the compound

(m.p. 170-172<W>C). 32 g of this compound in 250 ml of methanol is added 5 g of NaBH^ in portions, and the mixture is allowed to stand overnight unprocessed. The compound D is obtained with a yield of 32.5 g as hydrochloride (m.p. 234°C).

EXAMPLE 6

35 g of 3-aminopropiophenone is reacted in 250 ml of benzene with 27 g of 3-chloroethyl isocyanate to the compound (m.p. 114°C), cyclization with potassium hydroxide to 3-(faidazolidinone (2)-yl)-propiophenone (m.p. 162 °C) and reacted with bromine in chloroform to the bromoketone 33 g of the bromoketone, boiled with 39 g of 2-methylphenylpiperazine in 660 ml of acetonitrile for 30 minutes, gives after working up

40 g of the compound

with melting point 157°C.

To 6 g of the amino ketone in 60 ml of ethanol, 1 g of NaBH^ is added, and then the mixture is heated to 50°C, and after cooling, a further 1 g of NaBH^ is added. After approx. 1 hour, 5 g of the threo form of E crystallize out, m.p. 204°C, methanesulfonate m.p. 241°C.

To prepare the erythroform of E, 6 g of aminoketone are dissolved in methanol and hydrogenated with palladium/charcoal at 60°C and 5 at. The preparation in the erythro form of E with a melting point of 161°C

EXAMPLE 7

5 g of the compound are introduced in portions into 20 ml of thionyl chloride, whereby the solution turns red after a while. Excess thionyl chloride is distilled off, and the residue is crystallized with acetonitrile and then boiled off. You thus get 3.3 g of the compound

which in the presence of 1.67 g of dimethylaniline and Raney nickel as catalyst is hydrogenated for so long in methanol that hydrogen absorption ceases. After distilling off the dimethylaniline, compound F is isolated

as the hydrochloride from the residue. The compound has m.p. 256-257°C.

EXAMPLE 8

4-Aminoacetophenone is transferred with S-chloroethyl isocyanate and subsequent treatment with potassium hydroxide to 4-(imidazolidinone-(2)yl)-acetophenone (m.p. 208°C). With 1 mole of bromine is extracted in chloroform

The <w-bromoketone

Sm.p. 175°C.

14.2 g of bromoketone in 200 ml of ethanol are added slowly

and under ice-cooling 2 g of sodium borohydride and then stirred for 2 hours at room temperature. Precipitated sodium bromide is suctioned off. 0.5 ml of water and 17.6 g of N-2-methylphenylpiperazine are added to the solution, the mixture is allowed to stand overnight at room temperature, boiled for a further 2 hours under reflux, and then the compound (G) is isolated. It has a melting point of 221-223°C.

EXAMPLE 9

4-benzyloxy-aniline is reacted with B-chloroethyl isocyanate to the compound i (m.p. 176°C) and transferred with potassium hydroxide in ethanol to the imidazolidinone derivative

(m.p. 226°C).

The catalytic hydrogenation gives the compound

seam has sm.p. 180°C. /'

14.2 g of this compound is reacted in ethanol with 2.6 g of N-3-chloropropyl-N<1->2-methylphenylpiperazine in the presence of 3.1 g of potassium hydroxide while boiling to compound H (m.p.; 171 °C).

in 1

EXAMPLE 10

1-(4-imidazolidinoh-(2)-ylphenylmethyl)-4-phenylpiperazine

From 4-nitrobenzyl bromide and 1-phenylpiperazine, 1-phenyl4-(4-nitrobenzyl)-piperazine is prepared by boiling in acetonitrile under reflux. The reduction of this compound with hydrogen/PtO 2 in methanol leads to 1-phenyl-4-(4-aminobenzyl)-piperazine, m.p. 105°C, from which the compound is obtained by reaction with B-chloroethyl isocyanate in benzene

21 g of this compound in 160 ml of ethanol is added to 2.4 g of NaOH

and boil for 10 minutes under reflux. One obtains 16 g of the compound indicated in the title, m.p. 218°C (from ethanol). The methanesulfonate, m.p. 210°C, is obtained from the base with the calculated amount of methanesulfonic acid in ethanol.

EXAMPLE 11

1-(4-imidazolidinone-(2)-ylphenylmethyl)-4-phenylpiperazine

4-aminobenzaldehyde and B-chloroethyl isocyanate are converted in chloroform to the corresponding B-chloroethylurea derivative. The imidazolidinone ring is then closed by treatment with NaOH in ethanol.

The aldehyde obtained is reductively aminated in methanol with 1-phenylpiperazine under the influence of hydrogen/Pt02 until the theoretical amount of hydrogen is taken up. The compound given in the title is obtained with a melting point of 218°C (from ethanol).

EXAMPLE 12

1-(4-imidazolidinone-(2)-ylphenylmethyl)-4-phenylpiperazine

20 g of the 1-(4-formylphenyl)-imidazolidinone (2) prepared according to example 11 is reduced in ethanol with sodium borohydride to the corresponding 1-(4-hydroxymethylphenyl) compound. The hydroxy group is then replaced by chlorine by reaction with thionyl chloride in methylene chloride with the addition of pyridine. The thus obtained 1-(4-chloromethylphenyl)-imidazolidinone (2) is then reacted in acetonitrile with 1-phenylpiperazine, whereby the title compound is obtained, m.p. 218°C (from ethanol).

EXAMPLE 13

1-(4-imidazolidinone-(2)-ylphenylmethyl)-4-phenylpiperazine

13.35 g of 1-phenyl-4-4 (4-aminobenzyl)-piperazine is brought into 85 ml of glacial acetic acid together with 1.6 g of paraformaldehyde and a solution of 4.1 g of potassium cyanide in 7 ml of water at 15 to 20°C. After standing for several hours at room temperature, the cyanomethylamino compound is formed, and this is hydrogenated in methanol over PtC^ • The obtained ethylenediamine derivative with the formula

is dissolved in benzene and the calculated amount of N,N<1->carbonyldiimidazole dissolved in tetrahydrofuran is added. The mixture is first allowed to stand for a few hours at room temperature and is then boiled for a further 2 hours under reflux cooling. You get the connection stated in the title with sm.p. 218°C (from ethanol). EXAMPLE 14 1-(4-Imidazolidinone-(2)-ylphenethyl)-4-(2-quinolyl)-piperazine (Me 482) 9 g N-(2-quinolyl)-piperazine and 9.7 g p-nitrophenethyl bromide refluxed in the presence of 12 g of soda ash in 125 ml of acetonitrile for 4 hours. The hot solution is suctioned off, and the residue is washed out with acetonitrile. On cooling the mother liquor, 1-(2-quinolyl)-4-(4-nitrophenethyl)-piperazine crystallizes out.

After suction and recrystallization from acetonitrile

the yield is 11 g, m.p. 162°C. 20 g of the nitro compound, dissolved in 1 liter of methanol, is hydrogenated in the presence of 1 g of PtO 2 at 20°C and 5 ato until the theoretical amount of hydrogen is taken up. After filtering off the catalyst and evaporating the solvent, the crystalline distillation residue is recrystallized in acetonitrile, and 18 g of the amino compound is isolated, m.p. 133°C. 10 g of this is reacted with 3.8 g of S-chloroethyl isocyanate in 200 ml of chloroform by heating for 1 hour to 50°C to the compound

sm.p. 233°C. For ring closure, 11 g of this compound are suspended in 165 ml of methanol, and at boiling temperature, 1.05 g of NaOH dissolved in 15 ml of H 2 O are added. A solution is formed, and after 2 minutes crystallization occurs. After cooling and suction the crystals are washed with water and acetonitrile. 7 g of the title compound are formed, m.p. 230°C (from dimethylformamide). In alcohol, the base is transferred with the calculated amount of methanesulfonic acid to the dimethanesulfonate and recrystallized from methanol. The dimethanesulfonate contains 1 mol of crystal water, m.p. 197°c.

EXAMPLE 15

1-[1-(4-imidazolidinone-(2)-ylphenyl)-1-hydroxyethyl]-4-(2-pyridyl)-piperazine

14.15 g of 4-(inidazolidinone-(2)-yl)-oo-bromoacetophenone,

sm.p. 175°C, refluxed with 16.3 g of α-pyridylpiperazine in 150 ml of acetonitrile for 45 minutes. After separation of the precipitated α-pyridylpiperazine hydrobromide, the compound is isolated

the compound is isolated as a base (76% of the theoretical), m.p. 214°C (from ethanol).

Reduction of the ketone in 90% methanol with NaBH^ gives

the corresponding hydroxy compound in 88.5% yield, m.p. 218°C (from ethanol).

EXAMPLE 16

1-(4-imidazolidinone-(2)-ylphenethyl)-4-(2-pyridyl)-piperazine

14.1 g of 1-(4-aminophenethyl)-4-(2-pyridyl)-piperazine in

85 ml of glacial acetic acid are brought together with 1.6 g of paraformaldehyde and a solution of 4.1 g of potassium cyanide in 7 ml of water at 15 - 20°C, and the reaction is terminated by standing at room temperature overnight. The cyanoethylamino compound formed is hydrogenated in methanol with hydrogen, PtC^ as catalyst, to the corresponding ethylenediamine derivative. To this is added the calculated amount of N,N'-carbonyldiimidazole, dissolved in tetrahydrofuran, in benzene. After standing overnight at room temperature, boil for a further 2 hours under reflux, and the compound

isolated as a base, m.p. 200°C.

The dihydrochloride has m.p. 299-302°C.

EXAMPLE 17

1-[4-(3-methylimidazolidinone-(2)-yl)-phenethyl]-4-(2-methylphenyl)-piperazine ( Me 451 )

14.5 g of 1-(4-imidazolidinone-(2)-ylphenethyl)-4-phenylpiperazine is added to 1.82 g of NaH (50% in oil) in 250 ml of diglyme. After 1 hour of stirring at 60°C, the theoretical amount of hydrogen has been formed. To the solution, which has been cooled to 20°C, 5.7 g of methyl iodide dissolved in 20 ml of absolute diglyme are added dropwise, whereby sodium iodide is precipitated.

After stirring for 1 hour at 50°C, the precipitated sodium iodide is removed by suction, and the solvent is distilled off. The crystalline residue is washed with ethanol, filtered off and after recrystallization from ethanol has a melting point of 129°C. Yield: 12 g of the compound stated in the title as base.

The methanesulfonate is prepared from the base and the calculated amount of methanesulfonic acid in ethanol, m.p. 196°C (from ethanol).

According to this example, the following compound is prepared:

Sm.p. 286°C.

EXAMPLE 18

1-[4-(3-n-butylimidazolidinone-(2)-yl)-phenethyl]-4-(2-methylphenyl)-piperazine (Me 463)

28.5 g of the compound of the formula

dissolve in hot in 400 ml of ethanol and add an ethanolic solution of 4.0 g of potassium hydroxide. One boils for 5 minutes under reflux and then isolates the compound indicated under the title:, which in the form of hydrochloride has m.p. 283 C (from ethanol).

EXAMPLE 19

1-[1-(4-imidazolidinone-(2)-ylphenyl)-1-acetyloxyethyl]-4-(2-methyl-phenyl)-piperazine (Me 474)

7.6 g (0.02 mol) 1-[1-(4-imidazolidinone-(2)-ylphenyl)-1-hydroxyethyl]-4-(2-methylphenyl)-piperazine, 2.5 ml acetic anhydride and 76 ml chloroform is boiled for 2 hours under reflux.

After distilling off the solvent, the residue dissolves as

is crystallized from ethanol, in chloroform and shaken with potassium carbonate solution and steam. The organic phase is dried with sodium sulphate, and the chloroform is distilled off. A residue remains which can be crystallized from ethanol. From the base, the hydrochloride is prepared in hot ethanol by adding concentrated hydrochloric acid. After recrystallization from ethanol, the salt shows a m.p. at 310°C (decomposition). The yield is 5.5 g.

EXAMPLE 20

1-[1-(4-imidazolidinone-(2)-ylphenyl)-1-methylcarbamoyloxy-ethyl]-4-(2-methylphenyl)-piperazine (Me 473)

7.6 g (0.02 mol) 1-[1-(4-imidazolidinone-(2)-ylphenyl)-1-hydroxyethyl]-4-(2-methylphenyl)-piperazine, 1.1 ml methyl isocyanate and 114 ml chloroform is shaken in a pressure vessel at 60 - 70°C for 1 hour. After distilling off the chloroform, a residue remains which is brought to crystallization with ethanol. From the base, the hydrochloride is prepared in hot ethanol by adding ethanolic hydrochloric acid.

After recrystallization from ethanol, the salt has a m.p. at 159°C.

(fission). The yield is 7.5 g.

EXAMPLE 21

1-[1-(4-imidazolidinone-(2)-ylphenyl)-1-ethoxyethyl]-4-(2-methylphenyl)-piperazine

To a solution of 1.84 g (0.08 mol) sodium in 200 ml absolute ethanol is added 8.7 g (0.02 mol) l-[l-(4-imidazolidinone-(2)-yl-phenyl)- 1-Chloroethyl]-4-(2-methylphenyl)-piperazine hydrochloride prepared from the corresponding hydroxy compound by chlorination with PCI5 in acetonitrile. After stirring for 1 hour at 40°C, the calculated amount of ethanolic hydrochloric acid is added, the precipitated NaCl is suctioned off, and the ethanol is distilled off to a volume of 20 ml. From the residue you get the base. The base gives in ethanol with the calculated amount of methanesulfonic acid the methanesulfonate of the compound indicated in the title, m.p. 187°C (dec.).

EXAMPLE 2 2

1 g of 1-(4-imidazolidinone-(2)-ylphenyl)-2-bromo-ethanol and

1.2 g of N-(2-methylphenyl)-piperazine is stirred in 30 ml of acetonitrile

for 3 hours at room temperature and then boiled for 8 hours under reflux. The formed imidazolidinone-(2)-ylphenylethyl-enoxide is converted by boiling with N-(2-methylphenyl)-piperazine present to 1-(4-imidazolidinone-(2)-ylphenyl)-2-[4-(2-methyl- phenyl)-piperazino]-ethanol. The compound 1-(4-imidazolidinone-(2)-ylphenyl)-2-[4-(2-methylphenyl)piperazino]-ethanol, as isol-

eres after evaporation of the solvent, has a melting point of 223°C (from ethanol). The methanesulfonate has a melting point of 191°C.

Claims (1)

Analogous method for the preparation of therapeutically active compounds of the general formula where <\ > R means hydrogen, a lower alkyl or alkoxy group or a halogen atom, R' means one of the following groups in m- or p-position -CHR1-Q-A, -CHR2~A, and -0-CHR2- CER1-Q-A, where A means the rest J Q means an unbranched or branched alkylene chain of 1 to 4 carbon atoms, R1 means hydrogen, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group or a lower alkylaminocarbonyl oxy group, R 2 means hydrogen or a methyl group, R 3 and R 4 , which may be the same or different, mean a hydrogen atom, a lower alkyl or alkoxy group, a halogen atom or a trifluoromethyl group or together also a condensed ali phatic or aromatic 5- or 6-ring, Z represents a pyridyl or quinolyl group, R" means a hydrogen atom or an unbranched or branched alkyl residue with 1-4 carbon atoms, and acid addition salts thereof, characterized in that a) an amine with the formula is reacted with a compound with the formula where R 3.represents one of the following groups in m- or p-position -CHR2-X, -CHR1-Q-X, and -0-CHR2 -CHR^ -Q-X where X means a residue which together with the hydrogen atom from the compound HA, can be cleaved off as HX, in the presence of an HX-binding agent, or b) for the preparation of such compounds of formula I where R^ means a hydrogen atom, a hydroxy or a lower alkoxy group, a corresponding compound with the formula is ring-closed where X is as indicated in a), or c) for the preparation of such compounds of formula I where R^ does not mean a hydroxy group, or a monoalkylaminocarbonyloxy group, a cyclization of ethylenediamine derivatives with the formula with N,N'-carbonyldiimidazole, or d) for the preparation of such compounds of formula I where A represents the residue is reductively aminated a compound with the formula where Rb means one of the following groups in m- or p-position -CHO, -CHR, -C H_ ,0 ',and 1 n 2n-l ^ -O-CHR.-CHR., -C H„ .0 2 ln 2n-l (n is 1, 2, 3 or 4), with an amine of formula HA, under the influence of hydrogen and a hydrogenation catalyst, or e) for the preparation of such compounds of formula I, where R<1> means the residue -CHOH-Q-A, ketones are reduced by the formula preferably with suitable hydrides or also with hydrogen and hydrogenation catalysts, or f) for the preparation of such compounds of formula I where R-^ means hydrogen and R" means a residue Rj"f the OH group is removed from IN a compound with formula where R^" means an alkyl residue with 1-4 carbon atoms, and Rc means a residue in the m- or p-position with the formula -CR2OH-A, -CHOH-Q-A, or -0-CHR2-CHOH-Q-A, preferably by first replacing the OH group with chlorine using a chlorinating agent and then removing the chlorine by hydrogenation, or g) for the production of such compounds with the general formula I, where R^ denotes a hydroxy group, a compound with the formula is reacted where R^ means a residue in the m- or p-position with the formula where Rg and R^ mean hydrogen or alkyl radicals with a total of up to 3 carbon atoms, with an amine of the formula H-A, or h) for the preparation of such compounds of formula I, where R 1 means hydrogen, a lower alkoxy group, a lower alkanoyloxy group or a di- lower-alkylaminocarbonyloxy group, a compound of the formula is reacted where R' has the above limited meaning for R^, and Me means an alkali cation, with a corresponding compound R"X, or i) for the preparation of compounds of formula I, where R<1 >means the residue a phenol with the formula is reacted where the phenolic OH group is in the m- or p-position, with a compound of the formula X-CHR2-CH2~Q-A in the presence of an acid-binding agent, or k) for the preparation of compounds of the formula I, where R^ means an alkoxy group or a lower alkanoyloxy or lower alkylaminocarbonyloxy group, reacts a compound with the formula where Re means one of the following residues in the m- or p-position -CHOH-Q-A, or -0-CHR2-CHOH-Q-A, with a means to replace the OH hydrogen atom with an alkyl group or a lower alkanoyl or lower alkylaminocarbonyl group, and that according to the methods a) to k) primarily obtained bases are optionally transferred to acid addition salts, primarily obtained acid addition salts are optionally transferred to free bases, and/or optionally a separation is made into diastereomers or optical antipodes.