DE2551062A1 - 2-ANGULAR BRACKETS ON (SUBSTITUTED PIPERAZINYL) -ALKYL SQUARE BRACKETS FOR -1H-BENZ SQUARE BRACKETS ON SQUARE BRACKETS FOR ISOCHINOLINE-1,3 (2H) -DIONE - Google Patents

Description

"2- / X substituted piperazinyl) -alkyl7-1H-benz / de7isochiuoIin 1,3 (2H) -diones"

Priority: I3. November 197 ^, V.St.A., No. 523 293 January 23, 1975, V.St.A., No. 5 ^ -3 558

There are various naphthalimides as dyes and optical ones Known brightener. For example, in C-A. , 3d. 62, 1195Oc the N - ^ - Piperidinoäthyl / - ^ - methoxy-1,8-naphthaliiri.id, also as 6-methoxy-2- / 2- (1-piperidinyl) ethyl7-1K-benz / de7isoquinoline-

known
1,3 (2H) -diorvi is described as an optical brightener. In US Pat. No. 3,625,9 ^ 7, 2- / 2- (2- or ^ pyridyl) -ethyl7-1H-bens / de7isoquinoline-1,3 (2H) -diones are described as fluorescent brighteners.

In U.S. Patent 3,247,208, 1H-benz / de7isoquinoline-1,3 (2H) -diones are with a (1-substituted-4-piperidinyl) group in the "2" position described, which have anesthetic properties.

609822/1010

ORK3INAL INSPECTED

r _ ₂ ^? 5S1062 ~ ⁱ

From FR-PS 2 167 355 (4-phenyl) -piperidine-2,6-diones are with an alkylheteroalkyl radical in the 1-position with antidepressant Known effect. Imides with a nitroimidazolylethyl group as N-substituent and with action against bacteria and protozoa are in U.S. Patents 3,642,836 and 3,77,763. Certain Imidodicarboximides of those described in U.S. Patent 3,560,495 Kind have a wide variety of pharmacological properties.

From U.S. Patent 3,717,634 and J. Med.Chem., Vol. 15 (1972), pp. 477-479 are azaspirodecanediones with a / 4- (pyridyl or pyrimidinyl or triazinyl) -1-piperazinyl / alkylene group on the nitrogen atom known to have tranquilizer properties. Furthermore, U.S. Patents 3,398,151 and 3,558,777 and in J. Med.Chem., Vol. 12 (1969), pp. 876-881 azaspirodecanediones with a (4-phenyl ~ 1-piperazinyl) alkylene group on the nitrogen atom described, which have various pharmacological properties ", including muscle relaxant and anti-inflammatory Effect. Finally, U.S. Patent No. 3,541,098 discloses 1,2-cyclobutanedicarboximides with a / 4 "- (chi or phenyl) -1 ~ piperazinyl7-alkylene group described on the nitrogen atom, the CNS-suppressing effect as well as analgesic and sedating properties.

The invention relates to that characterized in the claims

1 2

Object. As halogen atoms for the radicals R and R are Fluorine, chlorine or bromine atoms are preferred. The pyridine, diazine or triazine radical R is attached to the 4-position of the piperazinyl group via a carbon atom. As a diazine and triazine residue the various isomeric forms come into question, namely

^L , ■ 60982 2/1010

Pyrimidine, pyridazine, pyrazine, s-triazine, a-triazine and v-triazine groups. These rings can be on one or both carbon atoms be substituted by a lower alkyl or alkoxy radical or a halogen atom.

The lower alkyl radicals are straight or branched radicals with 1 to 4 carbon atoms, such as the methyl, ethyl, propyl, Isopropyl and butyl group. The lower alkoxy and alkylthio radicals also contain 1 to 4 carbon atoms.

The substituted phenyl and phenyl-lower-alkyl radicals can be substituted by one or more substituents, for example by lower alkyl, alkoxy or alkylthio radicals, halogen atoms, preferably fluorine, chlorine or bromine atoms, trifluoromethyl, amino or nitro groups. Specific examples of these groups are the o-, m- and p-chlorophenyl, o-, m- and p-tolyl, 2,5-dibromophenyl, 3 _T 5-dimethylphenyl, o-, m- and p -Methoxyphenyl, o-, m- and p-r-chlorobenzyl, o-, m- and p-methoxybenzyl and o-, m- and p-bromophenethyl groups.

As a straight or branched alkylene radical with 1 to 8 carbon atoms comes for example the group of the general formula

in which η has the value 1 to 8, the group

-CH-CH ₂ -, -CH ₂ -CH- (CH ₂ ) ₂ - -CH-CH

CH, ix and CH

in question.

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In the preferred compounds of the invention, means at least

1 2
one of the radicals R and R is a hydrogen atom and the other is a hydrogen, fluorine, chlorine or bromine atom, a methyl or methoxy group. If the radical R is a heterocyclic ring, it means an optionally substituted 2-pyridinyl, 2-pyrimidinyl or 2,4,6-triazinyl group. The substituent is a methyl or methoxy group or a chlorine atom attached to one or both of the available carbon atoms. A denotes an unbranched or branched alkylene radical having 1 to 6 carbon atoms.

In the particularly preferred compounds, the radicals R are

and R are hydrogen atoms, the radical R is a 2-pyridiny group and A is a group of the general formula - (CHo) -, in which η is a whole Is a number with a value from 2 to 6.

The compounds of the general formula I are prepared according to the following reaction schemes. A means unbranched or branched alkylene radical with 2 to 8 carbon atoms.

The substituted naphthalic anhydride of the general formula II

is with an alkanolamine of the general formula III

H ₂ NA-OH (III)

L '-J

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55 OK62 ~ ¹

implemented. It becomes the corresponding alcohol of the general formula IV

A-OH

obtained by reaction with p-toluenesulfonyl chloride, Methanesulfonyl chloride, thionyl chloride, thionyl bromide or hydriodic acid into the intermediate of the general formula V

R ^J

is transferred, in which Y is a leaving group, such as a tosylate or methanesulfonate group or a halogen atom. That Intermediate "of the general formula V is then with the piperazine of the general formula VI

HN N-R

(VI)

implemented.

The substituted! ^. Phthalic anhydride of the general formula II can by reacting with a compound of the general formula VII

H ₂ NAN NO

(VII)

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? 5 5 1 O R 2

converted directly into the compounds of general formula I. will.

The reactions described above are represented by the following reaction scheme.

(ID R ¹

(III)

H ₀ NA-OH

i -} / NO

(VII)

(D

HN N-R

(VI)

A-OH

(IV)

A-Y

(V)

609822/1 010

2 5 5 1 O R 2

The intermediate of the general formula V can also be obtained by Um set a substituted naphthalimide of the general formula VIII

(VIII)

in an organic solvent with a solution of a base in a polar organic solvent, for example a Solution of potassium hydroxide in an alcohol and subsequent addition of a solution of a compound of the general formula IX

"Y ¹ -AT (IX)

in which Y ¹ and Y are identical or different and represent tosylate or methanesulfonate groups or halogen atoms and A is a straight or branched alkylene radical having 2 to 8 carbon atoms.

The compounds of general formula I in which A is an unbranched one or branched alkylene radical having 2 to 8 carbon atoms can also be obtained by reacting the anion of the substituted Naphthalimide of the general formula VIII with a solution of the compound of the general formula X

in which Y has a leaving group as described above is.

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2551 Q62 "" ¹

The compounds of general formula I in which A is an unbranched one or branched alkylene radical with 2 to 8 carbon atoms means, can also by reacting the intermediate of the general formula V with diethanolamine to form the intermediate of the general formula XI

/ -CH ₇ OH -N
• V-CH ₂ OH

XI

getting produced. This intermediate is then made by reacting with p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, Thionyl bromide, hydrogen bromide or hydrogen iodide into the corresponding intermediate of the general formula XlI transferred, in the Y one of the above-described leaving groups is. The intermediate of the general formula XII is then converted into the compounds of the following reaction scheme general formula I:

Cxii).

+ H ₀ NO

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r ~ \

Compounds of general formula I in which A is a methylene group are _{suspended by reacting the naphthalimide of general formula VIII f} in a polar organic solvent such as dimethylformamide (DMF) with a compound of general formula VI and a formaldehyde source such as aqueous formaldehyde solution or paraformaldehyde.

The various starting compounds, for example the substituted ones Anhydrides of the general formula II, the alcohols of the general formula IV, the substituted naphthalimides of the general Formula VIII and the 4-substituted piperazines of the general formulas VI, VII and X can be prepared according to methods known per se getting produced.

The compounds of general formula I in which one or two

Λ ?

de radicals R and R represent amino groups or R represents an amino-substituted one Phenyl or phenyl-lower-alkyl group means, are reduced by reducing the corresponding nitro compounds with a reducing agent such as hydrogen in the presence of a palladium catalyst or made with a chemical reducing agent. This is preferably done in the last stage of the above reaction schemes described carried out.

Depending on the reaction conditions and the starting compounds the compounds of general formula I are obtained either as free bases or in the form of their salts with acids. The salts can be converted into the free bases in a manner known per se, for example by reaction with a

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stronger base. Inorganic acids such as Hydrohalic acids, for example hydrochloric acid and hydrogen bromide acid, sulfuric acid, nitric acid and phosphoric acid, or organic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, benzoic acid, 2-acetoxybenzoic acid, Salicylic acid, succinic acid, nicotinic acid, methanesulfonic acid and cyclohexanesulfamic acid.

The compounds of the invention and their salts have ZKS activity. In particular, they show an antidepressant effect. This is shown in their antagonism to that induced by tetrabenzaine Ptosis (see Vernier et al., "The Pharmacοdynamics of Amitriptyline ", Psychosomatic Medicine, 1962, pp. 683-690) as well as their ability to block the reuptake of monoamines in vitro according to the method of Horn et al., Molecular Pharmacology, 7th edition, I97I, p. 66.

The compounds of general formula I are also anti-inflammatory drugs. They can be used in the same way as phenylbutazone or indomethacin.

The examples illustrate the invention.

example 1

2- / 2 - / ^ - (2-pyridinyl) -1-piperazinyl7-ethy3,7-1H-benzZda7isoquinoline-1,3 (2H) -dione hydrochloride (1: 2)
a) 2- (2-Hydroxyethyl) -1H ~ benz / d £ / isoquinoline-1,3 (2H) -dione 50 g (0.252 mol) ^ phthalic anhydride and 16 g (0.262 mol)

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Ethanolamine are refluxed for 3 hours in 200 ml V / water. After cooling to 25 ° C, the water is decanted and the residue crystallized from 95pi "ozentigem recrystallized ethanol. Yield 47.8 g of the title compound, melting at I72 to 173 ⁰ C.

b) 2- (2-Hydroxyethyl) -1H-benzZde7isoquinoline-1,3 (2H) -dione-4-methylbenzenesulfonate ester

600 ml of pyridine cooled to 5 ° C are mixed with 52 g (0.216 mol) 2- (2-Hydroxyethyl) -1H-benz / de7isoquinoline-1,3 (2H) -dione and 100 g (0.525 mol) of p-toluenesulfonyl chloride were added. The mixture will shaken briefly and then left to stand at 5 ° C for 15 to 18 hours. Then the reaction mixture is poured into 3OOO ^ l ice water, Stirred for 15 minutes and filtered. The filter residue is stirred with fresh water, filtered off again and 15 his Dried 18 hours at 25 ° C / 0.1 Torr. Yield 83 g of the title compound.

c) 2-Z2-Z4- (2-pyridinyl) -1-piperazinyl7-ethyl7-1H-benzZde.7-iso ~

quinoline-1,3 (2H) -dione hydrochloride (1: 2)

10 g (0.025 mol) of the compound obtained in (b), 4.1 g (0.025 mol) 1- (2-pyridinyl) piperazine and 3.27 g (0.0253 mol) diisopropylethylamine are refluxed in 3OO ml of toluene for 3 1/2 hours heated. The toluene is then distilled off, the residue is dissolved in chloroform and the solution is washed with water. All aqueous solutions are extracted with chloroform. The combined chloroform extracts are evaporated and the The residue is recrystallized from a mixture of chloroform and ethanol. The 2- / 2- / 4- (2-pyridyl) -1-piperazinyl7-

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r ■■ ■ 25-Ι062-Ι

Ethyl7-1H-benzZde7isoquinoline-1,3 (2H) -dione from mp 188 to 19O ⁰ C obtained. - -

The free base is dissolved in a mixture of hot chloroform and ethanol, and an excess solution of hydrogen chloride in ethanol is added. The hydrochloride precipitates and is dried from methanol and from a mixture of methanol and diethyl ether uiokr istall ized under reduced pressure at 80 ⁰ C. Yield 4.0 g of pure hydrochloride (1: 2) vom'F. 283 to 2SA- ⁰ G (decomp.)

Examples 2 to 12

According to Example 1, but using those listed in column 1 Alkanolamines, are the corresponding products of the general formula

obtained, in which A has the meaning given in column 2.

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2 ^ 1062- "

Example column I column II

H ₂ N- (CH ₂ ) ₃ -OH - (CH ₂ ) 3-

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H ₀ N- (CH ₀ ) --OH '- (CH ₀ ), -

Δ Δ D Δ Ο

H ₀ N- (CH ₀ ), - OH - (CH ₀ )

H ₂ N- (CH ₂ J ₈ -OH - (CH ₂ J ₈ -

H ₀ N-CH ₀ -CH-CH ₀ -OH -CH ₀ -CH-CH ₀ -

Δ Δ j Δ Δ ι Δ

vCH ₃ CH ₃

H ₀ N-CH- (CH ₀ ) ^ - OH -CH-

Δ J Δ ό ι

CH ₃ OH ₃

H ₀ N- (CH ₀ K-CH-OH - (CH ₀ J ₀ -CH-

Δ Δ i χ Δ ό ι

CH ₃ CH ₃

H ₀ N-CH ₀ -CH-XCH ₀ J ₀ -OH -CH ₀ -CH- (CH ₀ J ₀

^ Δ j Δ Δ * · \ Δ Δ

H ₀ N-CH-CH ₀ -CH-OH -CH-CH ₀ -CH-

² I ² II ² I.

CH ₃ CH ₃ CH ₃

2 5 5 1 O 6 2

Examples 13 to 44

■ As in Example 1, but using those listed in column 1 Compounds, the products indicated in column 2 are obtained. Het has the meaning given below.

Column I.

HN N-Het

Column II

CH ₀ CH ₀ N N-Het

^{2 2}

Example 13

Het

■ o

OC ₃ H ₅

^C 2 ^H 5

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2'5SiO62 ~ «

-Example Het

19th

20th

21

22nd

^ v

25th

26th

27

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- 1b - ^ ₁ ! 06

Example ·

28 Het

OCH-

OCH.

29

^C 2 ^H 5

30th 31

C ₃ H ₇

OCH,

Vi ⁵ N

CH-

32 Cl '

Cl

33 N—

34

Cl

35

, N

36

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V- ; 062 ~ »

example

Het

^CH

OCH.

OCH.

H,

N_N

OCH

3 • / CH-

CH.

: n

Cl

Cl

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When using the substituted piperazines of Examples 13 to 44 in the process of Examples 2 to 12, the corresponding Get connections.

Example 45 2- / / 4- (2- pyridinyl) -1 ~ piperazinyl7-methyl7-1H-benzZde.7isochino-

lin-1,3 ( 2H) -dione

An equimolar mixture of 1- (2-pyridinyl) piperazine, aqueous JFormaldehyde solution and 1,8-naphthalimide are used in a low Amount of dimethylformamide suspended and until completely dissolved heated. The solution is then left to stand at room temperature. The resulting precipitate is filtered off and dried. . The title compound is obtained.

Using the substituted piperazines of Examples 13 to 44 in the process described above, the corresponding compounds are prepared.

Example 46

2_ / zj: ./ 4_ (2-pyridinyl) -1-piperazinyl7-butyl7-1H-benzZde7isoquinoline-1,3 (2H) -dione hydrochloride (1; 2)

a) 2- (4-Bromobuty1) -1H-benz / de7isoquinoline ~ 1,3 (2H) -dione 100 g (0.5 mol) 1,8-naphthalimide are suspended in 2100 ml dimethylformamide. The mixture is ^{heated to 90 0} O until everything has gone into solution. A solution of 36.3 g (0.55 mol) of 85 percent potassium hydroxide in 100 ml of methanol is then added to the resulting solution. An instant is formed

L _l

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yellow precipitation. The resulting mixture is stirred for 1 hour at 90 ⁰ C and then cooled to 25 ° C. Then 245 g (1 * 0 mol) 1,4-dibromobutane are added, and the mixture is ^{heated again to 90 °} C. and stirred for a further hour. The reaction mixture is then cooled and the precipitate is filtered off and discarded. The filtrate is evaporated under reduced pressure and the residue is diluted with 500 ml of hexane. This precipitates crude 2- (4-bromobutyl) -1H-benz / de7isoquinoline-1,3 (2H) -dione. The precipitate is filtered off, washed with fresh hexane and dried for 2 hours at 50 ° C./0.1 torr. An analytically pure sample is obtained by dissolving the product in hot 95 percent ethanol and cooling it to 25 ° C. The precipitate is dried for 2 hours at 50 ⁰ C / 0.1 Torr. The pure compound melts at 113 to 115 ^° C

b) 2- / 4- / 4- (2-pyridinyl) -1-piperazinyl7-butyl7-1H-benz / de.7- isoquinoline-1,3 (2H) -dione hydrochloride (1: 2) 9.0 g (0.0271 mole) 2- (4-bromobutyl) -1H-benz / de7isoquinoline-1,3- (2H) -dione, 4.73 g (0.0276 mole) 1- (2-pyridinyl) -piperazine and excess sodium carbonate are refluxed in 200 ml of benzene for 48 hours. The sodium carbonate is then filtered off and washed out with hot chloroform. The organic solutions are combined and evaporated, the residue is dissolved in toluene and washed twice with 10 percent hydrochloric acid. The combined hydrochloric acid extracts are then washed with toluene and neutralized over potassium hydroxide pellets. The precipitate obtained is extracted with chloroform, and the chloroform extract is washed twice with water over sodium sulfate

L -I

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r. 2c -

dried and evaporated. The residue is recrystallized from ethanol. Yield 11.74 g of the title compound, melting at I50 to 152 ⁰ C.

The free base is dissolved in dioxane and with a 5N solution treated by hydrogen chloride in dioxane. The resulting hydro chloride (1: 2) is filtered off and dried. Yield 9 »4 · g from 280 to 282 ° C.

Example 47

nolin-1,3 (2H) -dione hydrochloride ( 1; 2)

a) 2- (5-Bromopentyl) -1H-benz / de7isoquinoline-1,3 (2H) -dione According to Example 46 Ca) ₁ but using 1,5-dibromopentane, the title compound is from F, II3 to 115 ° C received.

b) 2- / 5-Z ^ ~ (2-pyridinyl) -1-piperazinyl7-pentyl7 ~ 1H-benzZde7iso ~ quinoline-1,3 (2H) -dione hydrochloride (1: 2) according to Example 46 (b), however, using the compound obtained in (a), the title compound is obtained.

Example 48

2- / 6-Z5- (2-pyridinyl) -1-piperazinyl7-hexyl7-1H-benzZde7isochino lin-1,5 (2H) -dione hydrochloride (1: 2)

a) 2- (6-Bromohexyl) -1H-benzZda7isoquinoline-1,3 (2H ) -dione According to Example 46 Ca), but using 1,6-dibromo

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O ^! - \ i \ ^ r; 2 ~ 1 hexane, the title compound is obtained with a melting point of 95 to 96 ° C.

b) 2- / 6-Z4- (2 ~ pyridin; yl) -1-piperazine; yl7-hexyl quinoline-1,3 (2H) -dione hydrochloride (1: 2)

According to Example 46 (b), but using those obtained in (a) Compound, the title compound is obtained.

The procedures outlined in Examples 4-6 to 48 can be used
also for the preparation of the compounds of Examples 1 to
be applied.

Examples 49 to 74

According to Example 1, but using the information given in column I. The products indicated in column II are obtained from esters.

Column I.

Column II

(CH ₂ )

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IN8PECTEC

^Γ: ■ - '.. ??. 2 b β 1 O 6 2

Example χ ¹ χ ² χ ³ χ ⁴ χ ⁵ χ ⁶

49 .. H H Br H H H 50 H Cl H H H H 51 H Br H H H H 52 H F. H H H H 53 H I. H H H H 54 H Cl H H Cl H 55 Br H H H H H 56 H H Cl Cl . H H 57 H H CH ₃ H H H 58 H H ^C 2 ^H 5 H H H 59 H H 3 7 H H H 60 H H CH ₃ CH ₃ H H 61 H H OCH ₃ H H H 62 H H OC ₂ H ₅ H H H 63 H H OC ₃ H ₇ H H H 64 H H OCH ₃ OCH ₃ H H 65 H NO ₂ H H H H 66 H H NO ₂ H H H 67 H CF ₃ H H H H 68 H H CF ₃ H H H 69 Il CN H H H H 70 H H CN H H H 71 H H NH ₂ H H H 72 H NH ₂ H H H H 73 H SC ₃ H ₇ H H H . H 74 H H NS, H H H

L _J

. 6 0 9 8 2 2/1010

., ₂₇ _? O5! O62 ~ f

Using the esters of column I of Examples 49 to 7 ^ in the procedure of Examples I3 to 44, the corresponding compounds are prepared. According to Example 45, but using a substituted 1,8-naphthalimide of the general formula VIII, in which the substituents X ¹ , X ² , X ^, X ⁴ , X ^ _and X ^{6 have} the meaning given in Examples 49 to 74 v / earth the appropriate connections.

According to Example 2 to 12, but using a substituted 1,8-naphthalic anhydride of the general formula II, in which the substituents X ¹ , X ² , X ⁵ , X ⁴ , X ⁵ and X ⁶ in Examples 49 to 7 ^ Have given meaning, the corresponding compounds are made.

Example 75

2- / 2- (4-Fhenyl-1-piperazinyI) -äthyl7-1H-benz / de.7isoquinoline-1,5 (2H) -dione-hydrochloride (1: 2)

10 g (0.025 mol) of the ester obtained according to Example 1 (b), 4.3 g (0.026 mol) of N-phenylpiperazine and 3.27 g (0.025 mol) of diisopropylethylamine are refluxed for 4 hours in 500 ml of toluene. Thereafter, the reaction mixture with 5prozentiger Shaken sodium hydroxide solution, filtered and washed with water. All aqueous solutions are back-extracted with toluene. The reaction mixture is then reduced to 10 percent Shaken hydrochloric acid. The resulting precipitate is filtered

and
trated / washed with water and toluene. After recrystallization from aqueous ethanol, 3.0 g of the title compound with a melting point of 286 ° to 287 ° C. (decomp.) Are obtained.

-J 609822/1010

_ 2k - 2 5 5 ι Ο 6 2 -ί

Example 76

2- / 2- / 4- (4-methoxyphenyl) ~ 1-piperazinyl-7-ethyl-1H-benz / d £ 7iso quinoline-1,3 (2H) -dione hydrochloride (1: 2) According to Example 75, but under use of 5.1 e (0.026 mol) of 1- (p-methoxyphenyl) -piperazine are, 8.0 g of the title compound from P. 270-271 ⁰ C (dec.) was obtained.

Example 77

2- / 2- / 4- (2-methoxyphenyl) -1-piperazinyl7-ethyl7-1H-benz / da7isoquinoline-1,3 (2H) -dione hydrochloride (1: 2) According to Example 75 »but using 5 * 1 g (0.026 mol) 1- (o-methoxyphenyl) piperazine, 2.9 g of the title compound from Έ. 28A- G ⁰ (dec.) Was obtained.

Example 78

2- / 2- / 4- (4-chlorophenyl) -1-piperazinyl7-ethyl7-1H-benz / dQ7iso quinoline-1,3 (2H) -dione hydrochloride (1: 1) According to Example 75 »but using 5 »2 g (0.026 mol) of 1- (p-chlorophenyl) ~ piperazin be 3 * 0 g of the title compound, melting at 286-287 ° C (dec.) was obtained.

B e i s ρ i e 1 79

2- / 2- / 4- (2-chlorophenyl) -1-piperazinyl7-ethyl7-1H-benz / de7isoquinoline-1,3 (2H) -dione

According to Example 75, but using 5.2 g (0.026 mol) 1- (o-Chlorophenyl) piperazine, the hydrochloride of the title compound is obtained. The hydrochloride is neutralized with sodium hydroxide solution and the free base extracted with chloroform. Of the

-j 609822/1010

Chloroform extract is dried over sodium sulfate, evaporated to 200 ml and left to stand. Crystallization takes place slowly. The crystals are filtered off and dried at 50 ° C./60 torr for 15 to 18 hours. Yield 4 g of the title compound from 213 to 214 ° C.

Example 80

2- / 2- / 4- ^ 3 - (! Trifluoromethyl) -phenyl7-1-piperazinyl7-ethy ΐ7-1Η » benz / da7isoquinoline- 1,3 (2H) -dione hydrochloride (1: 1) According to Example 75, but using 6.1 g (0.026 Hol) 1/3 ~ (Trifluormeth; yl) -phen; yl / ~ piperazin be 6.53 S of the title compound 3 ?, 276-277 ⁰ C (dec.) obtain.

Example 81

2- / 2- / 4- (4-fluorophenyl) -1-piperazine; yl7-eth ^ nolin-1,3 (2H) -dione hydrochloride (1: 1)

According to Example 75, but using 4.8 g (0.026 mole) of 1- (p-fluorophenyl) -piperazine, 6.1g of the title compound, melting at 309-310 ⁰ C (dec.) Was obtained.

Example 82

2- / 2- / 4- (Pheny! Methyl) ~ 1-piperaziny l7-ethy: L7-1H-benz / d * a7isoquinoline-1,3 (2H) -dione-h7 / droch loride (1: 2)
According to Example 75, but using 4.7 g (0.026 mol) of 1- (phenylmethyl) piperazine, the title compound is 10.8 g, melting initially at 278-281 ⁰ C and finally at 284 ° C with decomposition .

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Examples 83 "to

According to Example 75, but using equivalent amounts of the following compounds: 1- (2-phenylethyl) ~ piperazine 1 ~ (3-phenylpropyl) piperazine 1- (4-phenylbutyl) ~ piperazine 1- (3,5-dichlorophenyl) piperazine 1- (4-Ethylphenyl) -piperazine 1- (4-Nitrophenyl) -piperazine 1- (2-Tliiopropylphenyl) -piperazine 1- (3-Trifluoromethyl-A-ch.lorph.enyl) -piperazine 1- (3- Trifluoromethyl-4-methylphenyl) piperazine 1 ~ / r4-bromophenyl) methyl / piperazine 1- / 2- (4-chlorophenyl) ethyl / piperazine 1- _j / ~ / "(3 ~ trifluoromethyl)" phenyl7- iaethyl7-piperazine 1- ₍ / 3- (4-methylphenyl) propyl7-piperazine or 1- / 0,5-dimethoxypheny 1) -inethyl7-piperazine gives the following compounds: 2- / 2- ^ 4- (2-phenylethyl ) ~ 1-piperazinyl7-ethyl7-1H-benz / de7isoquinoline-1,3 (2H) -dione hydrochloride; 2- / 2- / 4- (3-phenylpropyl) -1-p iperaziny l7-ethy l7-1H-benzZda7isoquinoline-1,3 (2H) -dione hydrochloride; ² ~ / 2- / 4- (4-phenylbutyl) -1-piperazinyl7-ethyl7-1H-benz ^ de7isoquinoline-1,3 (2H) -dione hydrochloride; 2- ₍ / 2- ₍ / 4- (3,5-dichlorophenyl) -1-piperazinyl7-ethyl7-1H-benz / 3e7 "isoquinoline-1,3 (2H) -dione hydrochloride; 2- / 2- / 4 - (4-Ethylphenyl) -1-piperazinyl7-ethyl7-1H-benz / dß7isoquinoline-1,3 (2H) -dione hydrochloride;

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; υ b I

2- / 2-A- (4-nitropheny 1) -1-ρ iperaziny l7-ethyl l7-1H-l) enzZda7isoquinoline-1,3 (2H) -dione hydrochloride;

2- / 2-Ä- (2-Thiopropylplieny l) -1-p iperazinyl / -äthyl7-'lH-benzZda7-isoquinoline-1,3 (2H) -dione hydrochloride; 2- / 2- / 4- (3-trifluoromethyl-4-chloroph.enyl) -1-piperazynyl / -äth.yl / -iH-benzZde7isoquinoline-1,3 (2II) -dione hydrochloride; 2- / 2- / 4-C 3-trifluoromethyl-4-me1: hylpheny l) -1-p iperazinyl7-ethyl7-IH-benz / d ^ isoquinoline-1, 3 (2H) -dione-hydrochloride ; 2- / 2- / 4 - / ^ 4-bromophenyl) methyl7-1-piperazinyl7-ethyl7-1H-benz- / de7isoquinoline-1,3 (2H) -dione hydrochloride; 2- / 2- / 4- / 2- (4-chlorophenyl) ethyl7-1-piperazinyl7-ethyl7-1H-benz - / de7isoch.inolin-1,3 (2H) -dione-hydrochloride; 2-Z2-Z4- / ~ / ^ 3-trifluoromethyl) phenyl7-methyl7-1-piperazinyl7-ethyl7-1H-benzZde / isoquinoline ~ '1,3 (2H) -dione-hydrochloride; 2- / 2-Z4-Z3- (4-methylplienyl) -prop: / l7-1-piperazinyl7-ethyl7-1H-benzZde7isoquinoline-1,3 (211) -dione hydrochloride. _: and 2- / 2- / 4 - / (3,5-dimethoxyphenyl) -me thy l7-1-piperaziny l7 ~ ethyl7-1H-benz / de7isoquinoline-1,3 (2H) -dione-byrochloride.

Example 97

2- / 3- (4-Phenyl-1-piperazinyl) -propyl7-1H-benz / ds / isoquinoline-1,3 (2H) -dione hydrochloride

a) 2- (3-hydroxypropyl) -1H-benz / de7isoquinoline-1,3 (2H) -dione- 4-methylbenzenesulfonate ester

According to Example 1 (a) and (b), but using 3-aminopropanol, the title compound is obtained.

60982 2/1010

2 5 S 1 η 6 2 -ι

b) 2- / 3- (4-Pheny 1-1 -piperazinyl) -propyl / -1H-benz / de. / isoquinoline 1,3 (2H) -dione hydrochloride

According to Example 75 »but using an equivalent Amount of the compound obtained in (a), the title compound is obtained.

Example 98

2- / 4- (4-Pheny1-1-piperazinyl) -buty! / - IH-benz / da / isoquinoline- 1,3 ( 2 H> -dione hydrochloride

a) 2- (4-Hydroxybutyl) -1H-benz _< / de7isoquinoline-1,3 (211) -d ion-4- methylbenzenesulfonate ester

According to Example 1 (a) and (b) ,. however, using 4-aminobutanol, the title compound is obtained.

b) 2- / 4- (4-phenyl-1-piperazinyl) -butyl / -1H-benz / d Q / isoquinoline- 1,3- (2H) -dione hydrochloride

According to Example 75 * but using an equivalent Amount of the compound obtained in (a), the title compound is obtained.

Examples 99 to IO7

According to Example 1 (a) and (b) and Example 75, but under Use of the alkanolamines listed in column I. the compounds of the general formula

60982 2/1010

2 h - I 0 R?.

rw- <2 /

A-

in which A has the meaning given in column II,

Ex. 99

Column 'I.

H ₀ N- (CH ₀ ), -OH JL Zb

- (CH ₂ ) ₇ -OH

-OH

H ₀ N-CH ₀ -CH-CH ₀ -OH 2 2 ι

H-

H ₂ N-CH-CH ₃

H ₂ N- (CH ₂ J ₃ -CH-OH CH ₃ '

C ₃ H ₇ column II - (CH ₂ J ₅ -

(CH ₀ ) -

-CH ₂ -CH-CH ₂ CH ₃

CH

-CH ₉ K-CH-2 3 ι

CH-,

-CH ₀ -CH- (CH ₀ ) _o -C ₃ H ₇

H ^ N-CH-CH ₀ -CH-OH

CH

CH ₃ CH ₃

-CH-CH ₀ -CH-

^{1 2} 1

CH ₃ CH ₃

609822/1010

₇ - j

When using those listed in Examples 2 to 22 substituted Piperazines in the procedure of Examples 23-33 can be used get the appropriate connections.

Example 108

1,3 (2H) ~ dione -h; hydrochloride (1: 1)

9.0 g (0.027 mol) of the 2- (4-bromobutyl) -1H-benz / dQ7isoquinoline-1,3 (2H) -dione obtained according to Example 46 (a) and 4.5 g (0.027 mol) of N-phenylpiperazine xverden Heated under reflux for 48 hours in the presence of excess anhydrous sodium carbonate. The reaction mixture is then washed with water / water and the aqueous solutions are back-extracted with toluene. The combined organic solutions are washed twice with water and shaken with 10 percent hydrochloric acid for 1 hour. The resulting Fällung'wird of the two phases filtered, washed with v / ater and toluene, and at 100 ⁰ C under reduced pressure for 1 hour dried. Yield 9 _S 33 g of the title compound from I \ 265 to 267 ° C (decomp.).

Example 109

2- / 6- (4-Pheny 1-1 -piperazinyl) -hexyl / -1H-benz / de / isoquinoline-1, 3 ~ (2H) -dione hydrochloride

a) 2- (6-Bromohexyl) -1H-benz / de7isoquinoline-1,3 (2H) -dione According to Example 46 (a), but using 1,6-dibromohexane, the title compound from Έ. 95 to 96 ° C obtained.

609822/1 010

b) 2- / 6- (4-Phenyl-1-piperazinyl) -hexyl7 ~ 1H-benz / de , 7isoquinoline- 1,5 (2Η) -dione hydrochloride

According to Example 108, but using the compound obtained in (a), the title compound is obtained.

Example 110

2- / 5- (4-Pheny1-1-piperazinyl) -pentyl7-1H-benz / da7isoquinoline -1,5 (2H) -dione hydrochloride

a) 2-C5-bromopentyl) -1H-benz / de7isoquinoline-1,5C2H) -dione According to Example 46 (a), but using 1,5-dibromopentane, the title ^{compound with a melting point of 113 to 115 °} O is obtained .

"b) 2- / 5 ~ (4-phenyl-1-piperazinyl) -pentyl7 ~ 1H-benz / da7isoquinoline- 1,3 (2H) -dione hydrochloride

According to Example 108, but using the compound obtained in (a), the title compound is obtained.

The preparation of the compounds of Examples 75 to 107 can be carried out also take place according to Examples 108 to 110.

Example 111

2- / X4-Phenyl-1-piperazinyl) -methyl7-1H-benz / de7isoquinoline-1,3- (2H) -dione

An equimolar mixture of N-phenylpiperazine, aqueous formaldehyde solution and 1,8-l-taphthalimide is used in a small amount Suspended dimethylformamide and heated until completely dissolved. The solution is then left to stand at room temperature.

L -I

609822/1010

7 .; y _

2 5 B 1 O 6 2 "·

sen. The resulting crystals are filtered off and dried. The title compound is obtained.

Using those described in Examples 76 "through 96 substituted piperazines, the corresponding compounds are prepared.

Example 112

3-chloro-2- / 2-C4-ph.enyl ~ 1-p-iperazinyl) -äthyl7-1H - benzZds7 is oquinoline-1,3 (2H) -dione hydrochloride (1: 1)

a) ^ -Chlor-2- (2-hydroxyethyl) -1H-benz / de7isoquinoline-1,5 (2H) - dione-4-methylbenzenesulfonate ester

According to Example 1 (a) and (b), but using 3-chloronaphthalic anhydride, the title compound is obtained.

b) 5-chloro-2-Z2- (4-phenyl-1-piperazinyl) -äthyl7-1H-benzZd "e.7-

Isoquinoline-1,3 (2H) -dione hydrochloride (1: 1) 10 g (0.023 mol) of the compound obtained in (a) and 7.6 g (0.04-9 mol) of N-phenylpiperazine are in 300 ml Toluene heated under reflux for 1 hour. The mixture is then cooled to 25 ° C. After 3 hours, the precipitate obtained is filtered off. The filtrate is shaken through with excess 10 percent hydrochloric acid. A smear that is insoluble in both layers forms. Crystallization occurs after a few minutes. The crystals are filtered off from the two liquid phases. The crude product is refluxed in 1 liter of 50 percent aqueous ethanol for 2 hours, then reduced to 25 ° C.

-I 609822/1010

r "" 25Β1Π62 "!

cooled, filtered and dried for 4 hours at 90 ° C / 0.1 Torr. Yield 5.2 g of the title compound. When heated to 284- ⁰ C, the crystals darken. At 286 to 290 ⁰ C, melting occurs with decomposition.

Example 113

6-chloro-2- / 2- (^ -phen: / l-1-piperazinyl) -eth: / 17-1H -benzZde.7isoquinoline-1,3 ( 2H) -dione-h; hydrochloride (1; 1)

a) 6-chloro ~ 2- (2-chloroethyl) ~ 1H-t> enzZda7isochinolin-1,3 (2H) -dione 25 g (0.108 mol) of A-Chlornaphthalimid are dissolved in 3OO ml heated to about 8O ⁰ C dimethylformamide. A solution of 7.1 g (0.108 mol) of 85 percent potassium hydroxide in 100 ml of ethanol is added to the solution. A precipitate forms. The mixture is ^{heated to about 90 °} C. for 30 minutes and then 4-5 g (0 _t 32 mol) of i-bromo-2-chloroethane in 100 ml of dimethylformamide are added. After stirring for 1 hour, the mixture is cooled, poured into 3 liters of water and extracted with chloroform. The chloroform extract is evaporated to dryness and placed on a column filled with 100 g aluminum oxide of activity I and eluted with chloroform. The eluate is evaporated under reduced pressure and the residue is digested in boiling ethanol for 30 minutes. The mixture is cooled to 25 ⁰ C. The resulting precipitate is filtered off and dried. Yield 13.6 g of the title compound.

b) 6-chloro-2- / 2- (4 - phenyl-1-piperazinyl) -eth; yl7-1H-benzZde7- isoquinoline-1,3 (2H) -dione hydrochloride (1: 1)

5 g (0.017 mol) of the compound obtained in (a), 6 g (0.037 mol

609822/1010

N-phenylpiperazine and 2.2 g (0.017 mol) of diisopropylethylamine are refluxed in 250 ml of toluene for 48 hours. After cooling to 25 ° C., the mixture is shaken through with excess 10 percent hydrochloric acid. A precipitate forms which is insoluble in both liquid phases. The precipitate is filtered off and extracted between 10 percent potassium hydroxide solution and chloroform and converted into the free base in the process. The chloroform extract is evaporated. The free base is then added to a column filled with aluminum oxide of activity I and measuring 50 × 170 mm and washed out with chloroform. The eluate is evaporated. 3 g of the free base remain. The free base is taken up in toluene and converted into the hydrochloride by shaking with 10 percent hydrochloric acid. The resulting precipitate is filtered off from the two liquid phases, recrystallized from 66 percent aqueous ethanol and dried for 12 hours at 70 ° C./0.1 torr. Yield 2.0 g of the title compound. The melting point of the salt is fuzzy. When heated rapidly (10 to 20 ° / minute) to 200 to 265 ° C, the color of the product changes from yellow to gray to black. At slower heating to 265 to 272 ⁰ C the black mass sinters together and becomes liquid ^{at 272 to 274 0 C.}

Examples 114 to 139

According to Example 75 but using the esters given in column I, the products given in column II obtain.

609822/1010

Column I.

■ i ^CH 2 ⁾ 2- ° 3 ^SC 6 ^H 4 ^CH 3

Example,

X "

114 H H Br H • OCH ₃ H H 115 H Cl H H H H H 116 H Br H H H H H 117 H F. H H H H H 118 H I. H H H H H 119 H Cl H H Cl H 12P Br H H H H H 121 H H . Cl Cl H H 122 H H CH ₃ H H H 123 H H C ₂ H ₅ H H H 124 H H 1-C ₃ H ₇ H H H 125 H H CH ₃ CH ₃ H H 1.26 H H OCH ₃ H H H 127 H H OC ₂ H ₅ H H H 128 H H OC ₃ H ₇ H H 129 H H OCH ₃ H H 130 H .NO ₂ H H H 131 H H NO ₂ H H 132 H CF ₃ H H H 133 H H cf ' H H

609822/1010

Ex. X ¹ · X ² X ³ X ⁴ ■ X ⁵ X ⁶

134 H CN H H H H 135 H H CN H H H 136 H H NH ₂ H H H 137 H NH ₂ H H H H 138 H ■ ^SC 3 ^H 7 H H H H 139 H H NS. H H H

Similarly, using the esters from Column I of Examples 114-139 in the process of Examples 76-107, the corresponding compounds were prepared. According to the example 108, but using a substituted 1,8-naphthalimide of the general formula VII, in which the substituents X,

O "Z f \ C Γ *

X% X, X, X and X are those given in Examples 114-139 Have meaning, the corresponding compounds are obtained.

609822/1010

Claims (1)

Claims "H 2- / X- substituted piperazinyl) -alkyl / -1H-benz / da7isoc] iinoline-1,3 (2H) -diones of the general formula I 1 2 in which R and R are hydrogen or halogen atoms, lower alkyl, alkoxy or alkylthio radicals, nitro, cyano, amino or trifluoromethyl groups, A is an unbranched or branched alkylene radical having 1 to 8 carbon atoms and R is optionally represented by halogen atoms, lower alkyl, alkoxy or alkylthio radicals, nitro, amino or trifluoroethyl groups substituted phenyl or phenyl-lower-alkyl group or R represents an optionally substituted by lower alkyl or alkoxy radicals or halogen atoms Pyridinyl, diazine or triazine group means, and their Salts with acids. 2, compounds according to claim 1 of the general formula I, in 1 2 of R and R hydrogen or halogen atoms, lower alkyl, alkoxy or alkylthio radicals, nitro, cyano, amino or trifluoromethyl groups and A is an unbranched or branched alkylene radical having 1 to 8 carbon atoms and R is a lower one, optionally through halogen atoms _l 609822/1010 γ "25ΒΊ062" » Represents alkyl, alkoxy or alkylthio radicals, nitro, amino or phenyl or phenyl- ^{lower alkyl groups substituted by 1} JIvI-fluoromethyl groups. 5. Compounds according to claim 2 of general formula I in which at least one of the radicals R and R is a hydrogen atom and the other radical is a hydrogen, fluorine, chlorine or bromine atom, a methyl or methoxy group and A an unbranched one or branched alkylene radical with 1 to 6 carbon atoms means. 4. 2- / r ^/ l - I'ti.enyl-1-piperazinyl) -iaethyl7-1H-benz _j / de7isOquinoline-1,3 (2H) -dione. 5. 5-chloro-2- / 2- (4-phenyl-1-piperazinyl) -ethyl7-1H-benz / d £ 7isoquinoline-1,3 (2H) -dione hydrochloride (1: 1). 6. 6-chloro-2- / 2- (4-phenyl-1 ~ piperazinyl) -ethyl7-1H-benz, / de7isoquinoline-1,3- (2H) -dione hydrochloride (1: 1). 7. Compounds according to claim 3 of the general formula I in which 1 2 R and R denote hydrogen atoms and A denotes an unbranched one Represents alkylene radical having 2 to 6 carbon atoms. 8. 2- / 2- (4-Phenyl-1-piperazinyl) -ethyl7-1H-benzZde7isoquinoline-1,3 (2H) -dione hydrochloride (1: 2). 609822/1010 9. 2- / 2- / 5- (4-methoxypheny 1) -1-piperazinyΐ7-αΐ1 ^ ΐ7-ΊΗ ^ βηζ / 5Θ7 ~ isoquinoline-1,3 (2H) -dione hydrochloride (1: 2). 10. 2- / 2- / 5- (2-meth.oxyphenyl) -1-piperazinyl7-ethyl7-1H-benz / d§7-isoquinoline-1,3- (2H) -dione hydrochloride (1: 2). 11. 2- / 2- / 5 - (^ - Chlorophenyl) -1-piperazinyl7-ethyl7-1H-benz / de7iso quinoline-1,3 (2H) -dione hydrochloride (1: 1). 12. 2 ~ / 2- / 5- (2-chlorophenyl) -1-piperazinyl7-ethyl7-1H-benz / ds7iso cMnolin-1,3 (2H) -dione hydrochloride (1: 1). 13. 2- / 2- / 5- / 3- (trifluoromethyl) phenyl7-1-piperazinyl7-ethyl7-1H-benz / de7isoquinoline-1,3- (2H) -dione hydrochloride (1: 1). 2- / 2- / 5- (4-fluoroplienyl) -1-piperazinyl7-ethyl7-1H-benz / de7iso quinolin-1 _i 3 (2H) -dione hydrochloride (1: 1). 2- / 2- / 5- (Phenylmetliyl) -1-piperazinyl7-eth.yl7-1H-benz / de7isoquinoline-1,3 (2H) -dione hydrochloride (1: 1). 16. 2- / 4- (4-Phenyl-1-piperazinyl) -butyl7-1H-benz / de7isoquinoline 1,3- (2H) -dione-hydrochloride (1: 1). 17. Compounds according to claim 1 of the general IOrmel I, in 1 2 where R and R are hydrogen atoms, A is unbranched th alkylene radical having 2 to 6 carbon atoms and R represents a 2-pyridinyl group. 609822/1010 - 4 € - 2 $ 5062 5 -. ^ 4_ (2-pyridinyl) -1-piperazinyl7-ethyl7-1H-benz ^ de7isoquinoline-1,3 (2H) -dione hydrochloride (1: 2). 19. 2- / 4- / 4- (2-pyridinyl) -1-piperazinyl7-butyl7-1H-benz / de7isoquinoline-1,3 (2H) -dione hydrochloride (1: 2). 20. Process for the preparation of the compounds according to claim 1, characterized in that one is carried out in a manner known per se a compound of the general formula V A-Y in which Y is a leaving group, preferably a tosylate or represents methanesulfonate group or a halogen atom, with a piperazine of the general formula VI HN ft-R (VI) converts and optionally the compound obtained through Reacting with an inorganic or organic acid converted into a salt. 21. Medicaments containing a compound according to claim 1 and customary carriers and / or diluents and / or auxiliary materials. 609822/1010