CA1058178A - 2-((substituted-piperazinyl)alkyl)-1h-benz(de)isoquinoline-1,3(2h)-diones - Google Patents
2-((substituted-piperazinyl)alkyl)-1h-benz(de)isoquinoline-1,3(2h)-dionesInfo
- Publication number
- CA1058178A CA1058178A CA239,072A CA239072A CA1058178A CA 1058178 A CA1058178 A CA 1058178A CA 239072 A CA239072 A CA 239072A CA 1058178 A CA1058178 A CA 1058178A
- Authority
- CA
- Canada
- Prior art keywords
- benz
- dione
- isoquinoline
- piperazinyl
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
Abstract
ABSTRACT
Compounds of the following formula and their acid addition salts wherein R1 and R2 are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro, cyano, amino and trifluoromethyl; A is a straight or branched chain alkylene of 1 to 8 carbons; and R is phenyl, phenyl-lower alkyl, substituted phenyl and phenyl-lower alkyl or a 6-membered unsaturated substituted or unsubstituted heterocyclic ring selected from pyridine, diazine and triazine are disclosed.
These compounds exhibit antidepressant activity. In addition these compounds are also useful as antiinflammatory agents.
Compounds of the following formula and their acid addition salts wherein R1 and R2 are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro, cyano, amino and trifluoromethyl; A is a straight or branched chain alkylene of 1 to 8 carbons; and R is phenyl, phenyl-lower alkyl, substituted phenyl and phenyl-lower alkyl or a 6-membered unsaturated substituted or unsubstituted heterocyclic ring selected from pyridine, diazine and triazine are disclosed.
These compounds exhibit antidepressant activity. In addition these compounds are also useful as antiinflammatory agents.
Description
10~8~78 MT96/85 various naphthalimide compounds have been developed for use as dyes and optical brightening agents. Kimura et al., for example, at Chem. Abst., Vol. 62, 11950c, disclose N-[2-piperidinoethyl]-4-methoxy-1,8-naphthalimide (i.e. 6-methoxy-2-[2-(1-piperidinyl)ethyl]-lH-benz[de]isoquino-line-1,3(2H)-dione under the current Chem. Abst. nomenclature) as an optical brightening agent. Noguchi et al. in U. S.
Pat. No. 3,625,947 disclose 2-~2-(2 or 4-pyridyl)ethyl]-lH-benz[de]isoquinoline-1,3(2H)-diones as fluorescent whitening agents.
Schenker et al. in U. S. Pat. No. 3,247,208 disclose that lH-benz[de]isoquinoline-1,3(2H)-diones having a (1-substituted-4-piperidinyl) group in the 2-position possess anesthetic properties. Carron et al. in French Pat. No.
Pat. No. 3,625,947 disclose 2-~2-(2 or 4-pyridyl)ethyl]-lH-benz[de]isoquinoline-1,3(2H)-diones as fluorescent whitening agents.
Schenker et al. in U. S. Pat. No. 3,247,208 disclose that lH-benz[de]isoquinoline-1,3(2H)-diones having a (1-substituted-4-piperidinyl) group in the 2-position possess anesthetic properties. Carron et al. in French Pat. No.
2,167,355 disclose that ~4-phenyl)piperidine-2,6-diones having an a~kylheteroalkyl substituent at the l-position possess antidepressant activity. Imides having a nitroimidazolyethyl group as an N-substituent and possessing anti-bacterial and anti-; protozoal activity are disclosed in U. S. Pat. Nos. 3,642,836 and 3,770,763 to Cusic et al. Certain imido dicarboxylic acid imides possessing various pharmacological properties are dis-closed in U. S. Pat. No. 3,560,495 to Frankus et al.
Wu et al. in U. S. Pat. No. 3,717,634 and in the Journal of Med. Chem., Vol. 15, p. 477-479 (1972) disclose azaspirodecanediones having a 14-(pyridyl or primidinyl or triazinyl)-l-piperazinyl~alkylene group attached to the N
atom which possess tranquilizing properties. Additionally, Wu et al. in U. S. Pat. Nos. 3,398,151 and 3,558,777 1058~7~
and in the Journal of Med. Chem., Vol. 12, p: 876-881 (1969) disclose azaspirodecanediones having a (4-phenyl-1-piperazinyl)-alkylene group attached to the N atom which possess various pharmacological activities incIuding muscle relaxant and antiinflamma~ory activity and Mennear in U. S. Pat. No.
Wu et al. in U. S. Pat. No. 3,717,634 and in the Journal of Med. Chem., Vol. 15, p. 477-479 (1972) disclose azaspirodecanediones having a 14-(pyridyl or primidinyl or triazinyl)-l-piperazinyl~alkylene group attached to the N
atom which possess tranquilizing properties. Additionally, Wu et al. in U. S. Pat. Nos. 3,398,151 and 3,558,777 1058~7~
and in the Journal of Med. Chem., Vol. 12, p: 876-881 (1969) disclose azaspirodecanediones having a (4-phenyl-1-piperazinyl)-alkylene group attached to the N atom which possess various pharmacological activities incIuding muscle relaxant and antiinflamma~ory activity and Mennear in U. S. Pat. No.
3,541,098 disclose 1,2-cyclobutanedicarboximides having a [4-(chlorophenyl)-1-piperazinyl]alkylene group attached to the N atom which possess central nervous system depressant activity and have useful analgesic and sedative properties.
This invention relates to new 2-[[4-(azine or diazine or triazine)-l-piperazinyl]alkyl]-lH-benz[de]isoquinoline-1,3(2H)-diones and their acid addition salts of the formula A-N N-R
I \
O ~ /0 Rl~ R2 The symbols have the following meaning in formula I and throughout this specification.
R1 and R2 are each independently selected from hydrogen, halogen (preferably Br, Cl, or F), CF3, lower alkyl, lower alkoxy, lower alkylthio, nitro, amino and cyano.
A is straight or branched chain alkylene of 1 to 8 carbons.
R is phenyl, phenyl-lower alkyl, substituted phenyl and phenyl-lower alkyl or a 6-membered substituted or unsubstituted unsaturated heterocyclic ring selected from pyridine, diazine, and triazine attached to the 4-position of the piperazinyl by way of a carbon atom. The terms diazine and triazine are meant to include the various isomeric forms, i.e., pyrimidine, ~0~8~78 M~96/85 pyridazine, pyrazine, s-triazine, a-triazine, and v-triaæine.
These rings can be substituted at one or two available carbon atoms by a lower alkyl, lower alkoxy, or halogen group.
The various groups represented ~y the symbols have the meanings defined below and these definitions are retained throughout this specification.
The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 4 carbons. Examples of the type of groups contemplated are methyl, ethyl, propyl, isopropyl, butyl, etc. The lower alkoxy groups include such lower alkyl groups attached to an oxygen, e.g., mèthoxy, ethoxy, propoxy, etc.
The lower alkylthio group include such lower alkyl groups attached to a sulfur, e.g., methylthio, ethylthio, etc.
The substituted phenyl and phenyl-lower alkyl groups include one or more substituents such as lower alkyl, lower alkoxy, lower alkylthio, halogen (preferably F, Cl, or Br), CF3, amino, nitro and the like. Examples of the type of groups contemplated are o-, m- or p-chlorophenyl, o-, m-, or p-tolyl, 2,5~dibromophenyl, 3,5-dimethylphenyl, o-, m-, or p-methoxyphenyl, o-, m-, or p-chlorobenzyl, o-, m-, or p-methoxybenzyl, o-, m-, or p-bromophenethyl, etc.
Straight or branched chain alkylene of 1 to 8 carbons is intended to include groups such as -(CH2)n~ wherein n is 1 to 8, -CH-CH2-, -CH2-,CH-(CH2)2 ~ C ~ CH-CH2-, etc.
Preferred embodiments of this invention are as follows:
At least one of Rl and R2 is hydrogen and the other is hydrogen, Cl, F, Br, CH3 or OCH3.
10~78 MT96/85 R, when a heterocyclic ring, is 2-pyridinyl, substituted 2-pyridinyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 2,4,6-triazinyl and substituted 2,4,6-triazinyl wherein said sub-stituent is a methyl, methoxy, or chlorine group attached to one or two available carbon atoms.
A is straight or branched chain alkylene of 1 to 6 carbons.
The most preferred compounds are:
Rl and R2 are both hydrogen.
R, when a heterocyclic ring, is 2-pyridinyl.
A is -(CH2)n~ wherein n is an integer from 2 to 6.
The new compounds of this invention are prepared by the following reactions where A is straight or branched chain alkylene of 2 to 8 carbons.
The substituted naphthalic anhydrlde of formula II
(II) O ~ ~ o R1~2 is reacted with an alkanolamine of formula III
(III) H2N-A-OH
to yield the alcohol of formula IV
(IV) I-OH
0~-~
~ .
_ The alcohol of formula IV is converted to the inter-mediate of formula V
~058178 MT96/85 (V) ~~Y
Rl ~ R2 where Y is a leaving group such as tosylate, methanesulfonate or halogen by treating the alcohol with p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, thionyl bromide or hydrogen iodide.
The intermediate of formula V is then converted to the final products of formula I by reactions with com-pounds of the formula . (VI) A
HN ~ N-R
The substituted naphthalic anhydride of formula II
can be converted directly to the final products of formula I by reacting the anhydride with compounds of formula VII
; (VII) H2N-A-N N-R
~J
The following schematic summarizes the reactions described above.
.
~ ~ . ~ ~
~-Z~ ~ P
1 0 ~d ~
,~ ~ ~ ~
~3 ~ p ri l¢
.o z~ .
~, o ' .;
ri I 1¢
H ) ~ H
H
r~
H
1~58~ 78 MT96/85 Also, the intermediate of formula V can be prepared by combining a substituted naphthalimide of formula VIII
(VIII) N
R~R2 in an organic solvent with a polar organic solvent solution of a base, as for example an alcohol solution of potassium hydroxide, followed by the addition of a solution of the compound of formula IX, (IX) Y'-A-Y
wherein Y' and Y are the same or different and are leaving groups selected from tosylate, methanesulfonate, or halogen and A is a straight or branched chain alkylene of 2 to 8 carbons.
Alternatively, the compounds of formula I wherein A
is straight or branched alkylene-of 2 to 8 carbons ban be pre~ared by combining the anion of the substituted naphthalimide of formula VIII, described above, with a solution of the compound of formula X, (X) Y-A-N N-R
\J
wherein Y is a leaving group as previously defined.
Also the compounds of formula I wherein A is straight or branched chain alkylene of 2 to 8 carbons can be prepared by reacting the intermediate of formula V with diethanolamine to form the intermediate -~o58~78 MT96/85 O~
. ~-N
o Rl ~R2 XI
This intermediate i5 then converted to the intermediate of formula XII where Y is a leaving group as defined previously by treating the alcohol with p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, thionyl bromide, hydrogen bromide or hydrogen iodide. The intermediate of formula XII can then be 1058~78 ~T96/85 reacted as shown below to yield the final products of ~ormula I
A-N ~-N N-R
Rl ~ + H2N-R ~ ~ 2 XII
Compounds of formula I where A is -CH2- are pre-pared by reacting the substituted naphthalimide of formula VIII suspended in a polar organic solvent such as dimethyl-formamide (DMF) with compounds of the formula VI and a source of formaldehyde such as aqueous formaldehyde or paraformaldehyde.
The various starting materials such as the substituted anhydrides of formula II, the alcohols of formula IV, the substituted naphthalimides of formula VIII, and the 4-substituted piperazines of formula VI, VII and X are known in the art re~dily obtainable by known procedures. Further process details are also provided in the illustrative examples.
The compounds of formula I wherein either or both Rl and R~ are amine or R is an amino subætituted phenyl or phenyl-lower alkyl group are prepared by reducing the corresponding nitro substituted compound with a reducing agent such as hydrogen over a palladium catalyst or a suitable chemical reducing agent. This is preferably done as the last stage in the reaction procedures described above.
Depending on the reaction conditions and the starting materials used, the new compounds are obtained _9_ in the free form or in the form of their acid addition salts. The salts thereof can be converted into the free compounds in a known manner such as by reaction with a basic agent. Free bases which may be obtained can be converted into pharmaceutically acceptable acid addition salts by reaction with a variety of acids. Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g. hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicyclic, succinic, nicotinic, methanesulfonic or cyclohexanesulfamic.
The new compounds of the present invention including the acid addition salts are capable of modifying the central nervous system. When administered to mice, cats, rats, dogs, and other mammalian species in amounts ranging from about 0.5 mg. to about 100 mg. per kg. of body weight per day, these compounds in particular exhibit antidepressant activity. A
preferred dosage regimen for optimum results would be from about 1 mg~ to about50 mg. per kg. of body weight per day, and such dosage units are employed so that a total of from about 35 mg. to about 3 g. of active ingredient in single or divided doses are administered in a 24 hour period.
The-antidepressant activity of the compounds of formula I is demonstrated by their ability to antagonize tetrabenzaine-i~duced ptosis according to the procedure of Vernier et al. ("The Pharmacodynamics of Amitriptyline", Psychosomatic Medicine, (1962), pages 683-690) and also by their ability to block the reuptake of monoamines in vitro lOS81713 MT 9 6/8 5 according to the procedure of Horn et al. (Molecular Pharma-colo~, 7th Ed., (1971), page 66).
The compounds of formula I are also useful as anti-inflammatory agents and may be used, for example, in a manner similar to phenylbutazone or indomethacin. They may be used to decrease joint swelling, tenderness, pain and stiffness in mammalian species, e.g., in conditions such as rheumatoid arthritis. The quantity administered ranges from about 1 mg.
to about 30 mg. per kg. of body weight per day.
For any of these pharmaceutical purposes a compound or mixture of compounds of ormula I or their pharmaceutically acceptable acid addition salts may be administered orally or parenterally in a conventional dosage form~such as tablet, caps~le, injectable or the like. These may be conventionally formulated in an oral or parenteral dosage form by com-pounding with a conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.
The following examples are illustrative of the invention and represent preferred embodiments. Other modifications may`be readily produced by suitable variations of the reactions. All temperatures are on the centigrade scale.
Example 1 2-~2-[4-(2-Pyridinyl)-l-piperazinyl]ethyl]-lH-benz[dellsoquino-line-1,3(2H)-dione, hydrochloride (1:2) a) 2-(2-Hydroxyethyl)-l~-benz[de]isoquinoline-1,3(2~)-dione 50 g. (0.252 mole) of naphthalic anhydride and 16 g.
(0.262 mole) of ethanolamine are refluxed for three hours in 200 ml. of water (the solution is never complete). After cooling to 25 the water is decanted off and the residue recrystallized from 9S~ ethanol to yield 47.8 g. of 2-(2-:
~ 10 hydroxyethyl)-lH-benz[de]isoquinoline-1,3(2H)-dione;
l~ m.p. 172-173.
b) 2-(2-Hydroxyethyl)-lH-benz[de]isoquinoline-1,3(2~)-dione, 1: ~
1 ,
This invention relates to new 2-[[4-(azine or diazine or triazine)-l-piperazinyl]alkyl]-lH-benz[de]isoquinoline-1,3(2H)-diones and their acid addition salts of the formula A-N N-R
I \
O ~ /0 Rl~ R2 The symbols have the following meaning in formula I and throughout this specification.
R1 and R2 are each independently selected from hydrogen, halogen (preferably Br, Cl, or F), CF3, lower alkyl, lower alkoxy, lower alkylthio, nitro, amino and cyano.
A is straight or branched chain alkylene of 1 to 8 carbons.
R is phenyl, phenyl-lower alkyl, substituted phenyl and phenyl-lower alkyl or a 6-membered substituted or unsubstituted unsaturated heterocyclic ring selected from pyridine, diazine, and triazine attached to the 4-position of the piperazinyl by way of a carbon atom. The terms diazine and triazine are meant to include the various isomeric forms, i.e., pyrimidine, ~0~8~78 M~96/85 pyridazine, pyrazine, s-triazine, a-triazine, and v-triaæine.
These rings can be substituted at one or two available carbon atoms by a lower alkyl, lower alkoxy, or halogen group.
The various groups represented ~y the symbols have the meanings defined below and these definitions are retained throughout this specification.
The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 4 carbons. Examples of the type of groups contemplated are methyl, ethyl, propyl, isopropyl, butyl, etc. The lower alkoxy groups include such lower alkyl groups attached to an oxygen, e.g., mèthoxy, ethoxy, propoxy, etc.
The lower alkylthio group include such lower alkyl groups attached to a sulfur, e.g., methylthio, ethylthio, etc.
The substituted phenyl and phenyl-lower alkyl groups include one or more substituents such as lower alkyl, lower alkoxy, lower alkylthio, halogen (preferably F, Cl, or Br), CF3, amino, nitro and the like. Examples of the type of groups contemplated are o-, m- or p-chlorophenyl, o-, m-, or p-tolyl, 2,5~dibromophenyl, 3,5-dimethylphenyl, o-, m-, or p-methoxyphenyl, o-, m-, or p-chlorobenzyl, o-, m-, or p-methoxybenzyl, o-, m-, or p-bromophenethyl, etc.
Straight or branched chain alkylene of 1 to 8 carbons is intended to include groups such as -(CH2)n~ wherein n is 1 to 8, -CH-CH2-, -CH2-,CH-(CH2)2 ~ C ~ CH-CH2-, etc.
Preferred embodiments of this invention are as follows:
At least one of Rl and R2 is hydrogen and the other is hydrogen, Cl, F, Br, CH3 or OCH3.
10~78 MT96/85 R, when a heterocyclic ring, is 2-pyridinyl, substituted 2-pyridinyl, 2-pyrimidinyl, substituted 2-pyrimidinyl, 2,4,6-triazinyl and substituted 2,4,6-triazinyl wherein said sub-stituent is a methyl, methoxy, or chlorine group attached to one or two available carbon atoms.
A is straight or branched chain alkylene of 1 to 6 carbons.
The most preferred compounds are:
Rl and R2 are both hydrogen.
R, when a heterocyclic ring, is 2-pyridinyl.
A is -(CH2)n~ wherein n is an integer from 2 to 6.
The new compounds of this invention are prepared by the following reactions where A is straight or branched chain alkylene of 2 to 8 carbons.
The substituted naphthalic anhydrlde of formula II
(II) O ~ ~ o R1~2 is reacted with an alkanolamine of formula III
(III) H2N-A-OH
to yield the alcohol of formula IV
(IV) I-OH
0~-~
~ .
_ The alcohol of formula IV is converted to the inter-mediate of formula V
~058178 MT96/85 (V) ~~Y
Rl ~ R2 where Y is a leaving group such as tosylate, methanesulfonate or halogen by treating the alcohol with p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, thionyl bromide or hydrogen iodide.
The intermediate of formula V is then converted to the final products of formula I by reactions with com-pounds of the formula . (VI) A
HN ~ N-R
The substituted naphthalic anhydride of formula II
can be converted directly to the final products of formula I by reacting the anhydride with compounds of formula VII
; (VII) H2N-A-N N-R
~J
The following schematic summarizes the reactions described above.
.
~ ~ . ~ ~
~-Z~ ~ P
1 0 ~d ~
,~ ~ ~ ~
~3 ~ p ri l¢
.o z~ .
~, o ' .;
ri I 1¢
H ) ~ H
H
r~
H
1~58~ 78 MT96/85 Also, the intermediate of formula V can be prepared by combining a substituted naphthalimide of formula VIII
(VIII) N
R~R2 in an organic solvent with a polar organic solvent solution of a base, as for example an alcohol solution of potassium hydroxide, followed by the addition of a solution of the compound of formula IX, (IX) Y'-A-Y
wherein Y' and Y are the same or different and are leaving groups selected from tosylate, methanesulfonate, or halogen and A is a straight or branched chain alkylene of 2 to 8 carbons.
Alternatively, the compounds of formula I wherein A
is straight or branched alkylene-of 2 to 8 carbons ban be pre~ared by combining the anion of the substituted naphthalimide of formula VIII, described above, with a solution of the compound of formula X, (X) Y-A-N N-R
\J
wherein Y is a leaving group as previously defined.
Also the compounds of formula I wherein A is straight or branched chain alkylene of 2 to 8 carbons can be prepared by reacting the intermediate of formula V with diethanolamine to form the intermediate -~o58~78 MT96/85 O~
. ~-N
o Rl ~R2 XI
This intermediate i5 then converted to the intermediate of formula XII where Y is a leaving group as defined previously by treating the alcohol with p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, thionyl bromide, hydrogen bromide or hydrogen iodide. The intermediate of formula XII can then be 1058~78 ~T96/85 reacted as shown below to yield the final products of ~ormula I
A-N ~-N N-R
Rl ~ + H2N-R ~ ~ 2 XII
Compounds of formula I where A is -CH2- are pre-pared by reacting the substituted naphthalimide of formula VIII suspended in a polar organic solvent such as dimethyl-formamide (DMF) with compounds of the formula VI and a source of formaldehyde such as aqueous formaldehyde or paraformaldehyde.
The various starting materials such as the substituted anhydrides of formula II, the alcohols of formula IV, the substituted naphthalimides of formula VIII, and the 4-substituted piperazines of formula VI, VII and X are known in the art re~dily obtainable by known procedures. Further process details are also provided in the illustrative examples.
The compounds of formula I wherein either or both Rl and R~ are amine or R is an amino subætituted phenyl or phenyl-lower alkyl group are prepared by reducing the corresponding nitro substituted compound with a reducing agent such as hydrogen over a palladium catalyst or a suitable chemical reducing agent. This is preferably done as the last stage in the reaction procedures described above.
Depending on the reaction conditions and the starting materials used, the new compounds are obtained _9_ in the free form or in the form of their acid addition salts. The salts thereof can be converted into the free compounds in a known manner such as by reaction with a basic agent. Free bases which may be obtained can be converted into pharmaceutically acceptable acid addition salts by reaction with a variety of acids. Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g. hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicyclic, succinic, nicotinic, methanesulfonic or cyclohexanesulfamic.
The new compounds of the present invention including the acid addition salts are capable of modifying the central nervous system. When administered to mice, cats, rats, dogs, and other mammalian species in amounts ranging from about 0.5 mg. to about 100 mg. per kg. of body weight per day, these compounds in particular exhibit antidepressant activity. A
preferred dosage regimen for optimum results would be from about 1 mg~ to about50 mg. per kg. of body weight per day, and such dosage units are employed so that a total of from about 35 mg. to about 3 g. of active ingredient in single or divided doses are administered in a 24 hour period.
The-antidepressant activity of the compounds of formula I is demonstrated by their ability to antagonize tetrabenzaine-i~duced ptosis according to the procedure of Vernier et al. ("The Pharmacodynamics of Amitriptyline", Psychosomatic Medicine, (1962), pages 683-690) and also by their ability to block the reuptake of monoamines in vitro lOS81713 MT 9 6/8 5 according to the procedure of Horn et al. (Molecular Pharma-colo~, 7th Ed., (1971), page 66).
The compounds of formula I are also useful as anti-inflammatory agents and may be used, for example, in a manner similar to phenylbutazone or indomethacin. They may be used to decrease joint swelling, tenderness, pain and stiffness in mammalian species, e.g., in conditions such as rheumatoid arthritis. The quantity administered ranges from about 1 mg.
to about 30 mg. per kg. of body weight per day.
For any of these pharmaceutical purposes a compound or mixture of compounds of ormula I or their pharmaceutically acceptable acid addition salts may be administered orally or parenterally in a conventional dosage form~such as tablet, caps~le, injectable or the like. These may be conventionally formulated in an oral or parenteral dosage form by com-pounding with a conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.
The following examples are illustrative of the invention and represent preferred embodiments. Other modifications may`be readily produced by suitable variations of the reactions. All temperatures are on the centigrade scale.
Example 1 2-~2-[4-(2-Pyridinyl)-l-piperazinyl]ethyl]-lH-benz[dellsoquino-line-1,3(2H)-dione, hydrochloride (1:2) a) 2-(2-Hydroxyethyl)-l~-benz[de]isoquinoline-1,3(2~)-dione 50 g. (0.252 mole) of naphthalic anhydride and 16 g.
(0.262 mole) of ethanolamine are refluxed for three hours in 200 ml. of water (the solution is never complete). After cooling to 25 the water is decanted off and the residue recrystallized from 9S~ ethanol to yield 47.8 g. of 2-(2-:
~ 10 hydroxyethyl)-lH-benz[de]isoquinoline-1,3(2H)-dione;
l~ m.p. 172-173.
b) 2-(2-Hydroxyethyl)-lH-benz[de]isoquinoline-1,3(2~)-dione, 1: ~
1 ,
4-methylbenzenesulfonate ester i , , i 52 g. (0.216 mole) of the 2-(2-hydroxyethyl)-lH-I benz[de]isoquinoline-1,3(2H)-dione and 100 g. (0.525 mole) 1~ ' .
of p-toluenesulfonyl chloride are added to 600 ml. of ~ pyridine previously cooled to 5. The mixture is shaken f~ . brie1y then allowed to stand overnight àt 5. The mixture ! is then poured into 3000 ml. of ice and water, stirred J ~
20~ for lS minutes and filtered. The insoluble material is stirred with fresh water, filtered off again and dried overnight at 25 (0.1 mm.) yielding 83 g. of 2-(2-hydroxyethyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, 1, 4-methylbenzenesulfonate ester.
~ cj 2-12-t4-(2-Pyridinyl)-l-piperazinyl]ethyll-lH-benz[de I isoquinoline-1,3(2H)-dione, hydrochloride (1:2) 10 g. (0.025 moles) of the ester from part (b), .~
~; 4.1 g. (0.025 moles) of 1-(2-pyridinyl)piperazine and 3.27 g.
(0.0253 moles) of diisopropylethylamine are refluxed in 300 ml.
1058~78 of toluene for 3.5 hours. The toluene is ev~porated and the residue is dissolved in chloroform and washed with water (all aqueous layers are backwashed). The chloroform is evaporated and the residue is recrystallized from chloroform/
ethanol to yield 2-[2-[4-(2-pyridyl)-1-piperazinyl]ethyl]-lH-benz~de]isoquinoline-1,3(2H)-dione; m.p. 188-190.
This free base is dissolved in hot chloroform/ethanol and treated with excess alcoholic HCl causing the salt to precipitate. Recrystallization of thi~s crude salt from methanol and methanol/ether followed by drying at 80 under a vac~um yields 4.0 g. of pure 2-[2-[4-(2-pyridinyl)-1-piperazinyll-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2); m.p. 283-284 (dec.).
Examples 2-12 Following the procedure of example 1 but substituting the alkanolamine shown in Col. I for the ethanolamine the following products are obtained wherein A is the radical shown in Col. II.
A-N\__/N-O N O
I
~) ' ~058178 Ex. Col. I Col. II
2 H2N-(CH2)3-OH -(CH2)3-3 H2N (CH2)4 . -(CH2)4-4 H2N-(CH2)5-OH -(CH2)5-H2N-(CH2)6-OH -(CH2)6-.
6 H2N-(CH2)7-OH -(CH2)7-' 7 H2N-(CH2)8-OH -(CH2)8-: CH3 CH3 9 H2N-ICH-(CH2)3-OH -CH-(CH2)3-H3 . 3 H2N-(CH2)3-CIH-OH -(CH2)3-CH-. CH3 CH3 20 11 H2N-CH2-CH-~CH2)2-OH -CH2-ClH-(cH2)2 12 H2N-CH-CH2-CH-OH .-CH-CH2-CH-~058~78 Examples 13-44 Following the procedure of example 1 but substituting for the 1-(2-pyridinyl)piperazine the compounds shown in Col. I one obtains the products shown in Col. II wherein Het represents the radical shown below.
Col. I Col. II
2CH2N N-Het - HN N-Het ~ ~ O ~ N ~ O
~
Ex. Het ~
~ 5 17 4 '>
& 3 18 ~
Ex. Het 19 ~1 ~?
21 ~N
F
,~1 22 ~\~C
23 ~/3 24.
.
,_N
N
26 ' ~/~
27 ~CH3 OCH
28 ~
--<OCH3 10~i8~7t3 MT 9 6/ 8 5 Ex. Het 29 ~)C2H5 =N
~\~
~<OC3H7 ~ N
31 ~CH
Cl' ~N
3 2 , N
~CC1 3 3 ~</ ~-Cl N
~Cl - Cl 3 5 4~N
N--3 6 ~N/~N
N
3 8 ~ `CNH3 NJ
1058~78 MT 9 6/8 5 Ex. Het : OCH3 39 ~/ ~ N
C~ 5 ~/ ~N
N--N N
N`~CH3 4 2~/ ~\N
43 ~ N
C
4 4 -X/~N
=<Cl Similarly, by employing the substituted piperazines of examples 13 to 44 in the procedure of examples 2 to 12, other compounds within the scope of the invention are obtained.
~058~78 MT96/85 xample 45 2-[[4-(2-(Pyridinyl?-l-piperazinyl]meth~l]-lH-benzIde]isoquino-line-1,3(2H)-dione ~ n equimolar mixture of 1-(2-pyridinyl)piperazine, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-lH-benz[de]isoquinoline-1,3(2H)-dione.
Similarly, b~ employing the substituted piperazines of examples 13 to 44 for the 1-(2-pyridinyl)piperazine in the above procedure, other compounds within the scope of the in-vention are obtained.
Example 46 2-[4-[4-(2-Pyridinyl)-l-piperazin~l]butyl]-lH-benz[de]isoquino-line-1,3(2O -dione, hydrochloride (1:2) a) 2-14-Bromobutyl)-lH-benz[de]isoquinoline-1,3(2H)-dione 100 g. (0.5 mole) of 1,8-naphthalimide is suspended 20 in 2100 ml. of dimethylformamide and the mixtrue is heated to 90 to form a complete solution. A solution of 36.3 g. (0.55 mole) of potassium hydroxide (85~) in 100 ml. of methanol is added resulting in the immediate formation of a yellow pre-cipitate. The resulting mixture is stirred for one hour at 90 and cooled to 25. 245 g. (1.0 mole) of 1,4-dibromobutane is added and the mixture is again heated to 90 and stirred for an additional hour. A precipitate remains in the mixture but is more granular than the initial material. ~he reaction mixture is cooled and the precipitate filtered off and discarded. The solvent is removed from the fil-trate under vacuum and the residue is diluted with 1~58178 MT9~85 500 ml. of hexane immediately precipitating crude 2-(4-bromo-butyl)-lH-benz[de]isoquinoline-1,3 (2H) -dione. The precipitate is filtered off, washed with fresh hexane and dried for 2 hours at 50 (0.1 mm.) to yield 2-(4-bromobutyl)-lH-benz[de]isoquinoline-1,3(2_)-dione. An analytically pure sample is prepared by dis-solving the above product in hot 95~ ethanol and recrystallizing by allowing the solution to cool to 25. The resulting pre-cipitate is dried for two hours at 50 (0.1 mm.) to yield pure 2-(4-bromobutyl)-1_-benz[de]isoquinoline-1,3(2H)-dione, m.p. 113-1150.
b) 2-[4-[4-(2-Pyridinyl)-l-piperazinyl]butyl]-lH-benz[de]-isoquinoline-1,3(2_)-dione, hydrochloride (1:2) 9.0 g. (0.0271 mole) of 2-(4-bromobutyl)-lH-benz[de]-isoquinoline-1,3(2H)-dione, 4.73 g. (0.0276 mole) of 1-(2-pyridinyl)piperazine, and excess sodium carbonate are refluxed in 200 mI. of benzene for two days. The sodium carbohate is filtered off and washed with hot chloroform. The organic portions are combined and evaporated and the residue is dis-solved in toluene and washed with 10~ HCl (twice). The com-bined acid washings are then washed with toluene and neutralizedwith KOH pellets. The resulting precipitate is extracted into chloroform, washed with water (twice), dried (Na2SO4), and evaporated. The residue is recrystallized from ethanol to yield 11.74 g. of 2-[4-[4-(2-pyridinyl)-1-piperazinyl]butyl]-lH-benz[de]isoquinoline-1,3(2~1)-dione; m.p. 150-152.
This free base is dissolved in dioxane and treated with 5N HCl in dioxane to precipitate 9.4 g. of 2-[4-[4-(2-pyridinyl)-l-lOS8~78 MT9~85 piperazinyl]butyl]-lH-benz[de]isoquinoline-1;3(2H)-dione, hydrochloride (i:2); m.p. 280-282.
Example 47 2- E5- [4-(2-~y~idiny~ -piperazinyl]pentyl]-lH-benz~de]isoquin line-1,3(2H)-dione, hydrochloride (1:2) a) 2-(5-Bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione Following the procedure of part (a) of example 46 but substituting l,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113~115.
b) 2-[5-[4-(2-Pyridinyl)-l-piperazinyl]pentyl]-lH--benz[de]i quinoline-1,3(2H)-dione, hydro~hloride (1:2) Following the procedure of part (b) of example 46 but sub-stituting 2-(5-bromopentyl)-lH-benzlde]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-lH-benz[de]lsoquinoline-1,3(2H)-dione, one obtains 2-[5-[4-(2-pyridinyl)-1-piperazinyl]pentyl]-l_-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2).
Example 48 2-[6-[4-~2-Pyridinyl)-l-piperazinyl]hexyl]-lH benz[de]isoquino-line-1,3(2H)-dione, hydrochloride (1:2) a) 2-(6-Bromohexyl)-lH-benz[de]isoquinoline-1,3(2~ -dione Following the procedure of part (a) of example 46 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-~6-bromohexyl)-lH-benz[de]isoquinoline-1,3(2_)-dione;
m.p. 95-96.
b) 2-[6-[4-(2-Pyridinyl)-l-piperazinyl]hexyl]-lH-benzEde]isoquino-line-1,3(2H)-dione, hydrochloride (1:2) _ Following the procedure of part (b) of example 4Ç but substituting 2-(6-bromohexyl)-lH-benz[de~isoquinoline-1,3(2H)-1058~78 MT96/85 , dione for the 2-(4-bromobutyl)-lH-benz~de]isoquinoline-1,3-(2H)-dione, one obtains 2-[6,-[4-~2-pyridinyl)-1-piperazinyl]-hexyl]-l_~benz~de]isoquinoline-1,3(2_)-dione, hydrochloride (1:2).
Alternatively, the procedure of examples 46-48 can be employed to prepare the compounds of examples 1-44.
Examples 49-74 Following the procedure of example 1 but substituting for the 2-(2-hydroxyethyl)-lH-benz~de]isoquinoline-1,3(2H)-lQ ' dione, 4-methylbenzenesulfonAte ester the ester shown in Col. I one obtains the product~shown in Col. II.
Col. I Col. II
~CH2) 2--03SC6H4CH3 (CH2) 2N'~3 O ~ N ~O O ~ ~ O
. . ..
Ex Xl x2 X3 X4 X5 X6 . .
49 H H Br - H H H
H Cl H H H H
Sl H Br H H H H
54 H Cl H H Cl H
Br H H H H H
56 H H Cl Cl H H
~ Ex. Xl x2 X3 X4 ~ X5 x6 .
59 H Hi-C3H7 H H H
H H CN H H H
Similarly, by employing the ester of Col. I of examples 49-74 in the procedures of examples 13 to 44, other compounds within ~he scope of this invention are prepared.
Similarly, by following the procedures of example 45 but employing a substituted 1,8-naphthalimide of formula VIII
wherein the substituents are those listed under the headings Xl, X2, X3, X4, X5, and x6 in examples 49 to 74, other compounds within the scope of this invention are prepared.
Also by following the procedure of examples 2-12, but employing a substituted 1,8-naphthalic anhydride of formula II
wherein the substituents are those listed under the headings Xl, X2, X3, X4, X5 and x6 in examples 49-74, other compounds within the scope of the invention are prepared.
~058~78 Example 75 2-[2-(4-Phenyl-l-piperazlnyl)ethy~_-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2) 10 g. (0.025 mole) of the ester from part (b) of Example 1, 4.3 g. (0.026 mole) of N-phenylpiperazine, and 3.27 g. (0.025 mole) of diisopropylethylamine are refluxed in 500 ml. of toluene for four hours. The reaction mixture is then shaken with 5 NaOH, filtered, washed with water (all aqueous layers are backwashed with toluene), and shaken with 10% HCl. The pre-cipitate that forms is filtered and washed with water and toluene.
Recrystallization from water/ethanol yields 3.0 g. of 2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (~1:2); m.p. 286-287 (dec.).
Example 76 2-[2-[4-~4-Methoxyphenyl)-l-piperazinyl]ethyl-lH-benz[de]isoquino-line-1,3(2_)-dione, hydrochloride (1:2) Following the procedure of example75 but substituting
of p-toluenesulfonyl chloride are added to 600 ml. of ~ pyridine previously cooled to 5. The mixture is shaken f~ . brie1y then allowed to stand overnight àt 5. The mixture ! is then poured into 3000 ml. of ice and water, stirred J ~
20~ for lS minutes and filtered. The insoluble material is stirred with fresh water, filtered off again and dried overnight at 25 (0.1 mm.) yielding 83 g. of 2-(2-hydroxyethyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, 1, 4-methylbenzenesulfonate ester.
~ cj 2-12-t4-(2-Pyridinyl)-l-piperazinyl]ethyll-lH-benz[de I isoquinoline-1,3(2H)-dione, hydrochloride (1:2) 10 g. (0.025 moles) of the ester from part (b), .~
~; 4.1 g. (0.025 moles) of 1-(2-pyridinyl)piperazine and 3.27 g.
(0.0253 moles) of diisopropylethylamine are refluxed in 300 ml.
1058~78 of toluene for 3.5 hours. The toluene is ev~porated and the residue is dissolved in chloroform and washed with water (all aqueous layers are backwashed). The chloroform is evaporated and the residue is recrystallized from chloroform/
ethanol to yield 2-[2-[4-(2-pyridyl)-1-piperazinyl]ethyl]-lH-benz~de]isoquinoline-1,3(2H)-dione; m.p. 188-190.
This free base is dissolved in hot chloroform/ethanol and treated with excess alcoholic HCl causing the salt to precipitate. Recrystallization of thi~s crude salt from methanol and methanol/ether followed by drying at 80 under a vac~um yields 4.0 g. of pure 2-[2-[4-(2-pyridinyl)-1-piperazinyll-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2); m.p. 283-284 (dec.).
Examples 2-12 Following the procedure of example 1 but substituting the alkanolamine shown in Col. I for the ethanolamine the following products are obtained wherein A is the radical shown in Col. II.
A-N\__/N-O N O
I
~) ' ~058178 Ex. Col. I Col. II
2 H2N-(CH2)3-OH -(CH2)3-3 H2N (CH2)4 . -(CH2)4-4 H2N-(CH2)5-OH -(CH2)5-H2N-(CH2)6-OH -(CH2)6-.
6 H2N-(CH2)7-OH -(CH2)7-' 7 H2N-(CH2)8-OH -(CH2)8-: CH3 CH3 9 H2N-ICH-(CH2)3-OH -CH-(CH2)3-H3 . 3 H2N-(CH2)3-CIH-OH -(CH2)3-CH-. CH3 CH3 20 11 H2N-CH2-CH-~CH2)2-OH -CH2-ClH-(cH2)2 12 H2N-CH-CH2-CH-OH .-CH-CH2-CH-~058~78 Examples 13-44 Following the procedure of example 1 but substituting for the 1-(2-pyridinyl)piperazine the compounds shown in Col. I one obtains the products shown in Col. II wherein Het represents the radical shown below.
Col. I Col. II
2CH2N N-Het - HN N-Het ~ ~ O ~ N ~ O
~
Ex. Het ~
~ 5 17 4 '>
& 3 18 ~
Ex. Het 19 ~1 ~?
21 ~N
F
,~1 22 ~\~C
23 ~/3 24.
.
,_N
N
26 ' ~/~
27 ~CH3 OCH
28 ~
--<OCH3 10~i8~7t3 MT 9 6/ 8 5 Ex. Het 29 ~)C2H5 =N
~\~
~<OC3H7 ~ N
31 ~CH
Cl' ~N
3 2 , N
~CC1 3 3 ~</ ~-Cl N
~Cl - Cl 3 5 4~N
N--3 6 ~N/~N
N
3 8 ~ `CNH3 NJ
1058~78 MT 9 6/8 5 Ex. Het : OCH3 39 ~/ ~ N
C~ 5 ~/ ~N
N--N N
N`~CH3 4 2~/ ~\N
43 ~ N
C
4 4 -X/~N
=<Cl Similarly, by employing the substituted piperazines of examples 13 to 44 in the procedure of examples 2 to 12, other compounds within the scope of the invention are obtained.
~058~78 MT96/85 xample 45 2-[[4-(2-(Pyridinyl?-l-piperazinyl]meth~l]-lH-benzIde]isoquino-line-1,3(2H)-dione ~ n equimolar mixture of 1-(2-pyridinyl)piperazine, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-lH-benz[de]isoquinoline-1,3(2H)-dione.
Similarly, b~ employing the substituted piperazines of examples 13 to 44 for the 1-(2-pyridinyl)piperazine in the above procedure, other compounds within the scope of the in-vention are obtained.
Example 46 2-[4-[4-(2-Pyridinyl)-l-piperazin~l]butyl]-lH-benz[de]isoquino-line-1,3(2O -dione, hydrochloride (1:2) a) 2-14-Bromobutyl)-lH-benz[de]isoquinoline-1,3(2H)-dione 100 g. (0.5 mole) of 1,8-naphthalimide is suspended 20 in 2100 ml. of dimethylformamide and the mixtrue is heated to 90 to form a complete solution. A solution of 36.3 g. (0.55 mole) of potassium hydroxide (85~) in 100 ml. of methanol is added resulting in the immediate formation of a yellow pre-cipitate. The resulting mixture is stirred for one hour at 90 and cooled to 25. 245 g. (1.0 mole) of 1,4-dibromobutane is added and the mixture is again heated to 90 and stirred for an additional hour. A precipitate remains in the mixture but is more granular than the initial material. ~he reaction mixture is cooled and the precipitate filtered off and discarded. The solvent is removed from the fil-trate under vacuum and the residue is diluted with 1~58178 MT9~85 500 ml. of hexane immediately precipitating crude 2-(4-bromo-butyl)-lH-benz[de]isoquinoline-1,3 (2H) -dione. The precipitate is filtered off, washed with fresh hexane and dried for 2 hours at 50 (0.1 mm.) to yield 2-(4-bromobutyl)-lH-benz[de]isoquinoline-1,3(2_)-dione. An analytically pure sample is prepared by dis-solving the above product in hot 95~ ethanol and recrystallizing by allowing the solution to cool to 25. The resulting pre-cipitate is dried for two hours at 50 (0.1 mm.) to yield pure 2-(4-bromobutyl)-1_-benz[de]isoquinoline-1,3(2H)-dione, m.p. 113-1150.
b) 2-[4-[4-(2-Pyridinyl)-l-piperazinyl]butyl]-lH-benz[de]-isoquinoline-1,3(2_)-dione, hydrochloride (1:2) 9.0 g. (0.0271 mole) of 2-(4-bromobutyl)-lH-benz[de]-isoquinoline-1,3(2H)-dione, 4.73 g. (0.0276 mole) of 1-(2-pyridinyl)piperazine, and excess sodium carbonate are refluxed in 200 mI. of benzene for two days. The sodium carbohate is filtered off and washed with hot chloroform. The organic portions are combined and evaporated and the residue is dis-solved in toluene and washed with 10~ HCl (twice). The com-bined acid washings are then washed with toluene and neutralizedwith KOH pellets. The resulting precipitate is extracted into chloroform, washed with water (twice), dried (Na2SO4), and evaporated. The residue is recrystallized from ethanol to yield 11.74 g. of 2-[4-[4-(2-pyridinyl)-1-piperazinyl]butyl]-lH-benz[de]isoquinoline-1,3(2~1)-dione; m.p. 150-152.
This free base is dissolved in dioxane and treated with 5N HCl in dioxane to precipitate 9.4 g. of 2-[4-[4-(2-pyridinyl)-l-lOS8~78 MT9~85 piperazinyl]butyl]-lH-benz[de]isoquinoline-1;3(2H)-dione, hydrochloride (i:2); m.p. 280-282.
Example 47 2- E5- [4-(2-~y~idiny~ -piperazinyl]pentyl]-lH-benz~de]isoquin line-1,3(2H)-dione, hydrochloride (1:2) a) 2-(5-Bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione Following the procedure of part (a) of example 46 but substituting l,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113~115.
b) 2-[5-[4-(2-Pyridinyl)-l-piperazinyl]pentyl]-lH--benz[de]i quinoline-1,3(2H)-dione, hydro~hloride (1:2) Following the procedure of part (b) of example 46 but sub-stituting 2-(5-bromopentyl)-lH-benzlde]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-lH-benz[de]lsoquinoline-1,3(2H)-dione, one obtains 2-[5-[4-(2-pyridinyl)-1-piperazinyl]pentyl]-l_-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2).
Example 48 2-[6-[4-~2-Pyridinyl)-l-piperazinyl]hexyl]-lH benz[de]isoquino-line-1,3(2H)-dione, hydrochloride (1:2) a) 2-(6-Bromohexyl)-lH-benz[de]isoquinoline-1,3(2~ -dione Following the procedure of part (a) of example 46 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-~6-bromohexyl)-lH-benz[de]isoquinoline-1,3(2_)-dione;
m.p. 95-96.
b) 2-[6-[4-(2-Pyridinyl)-l-piperazinyl]hexyl]-lH-benzEde]isoquino-line-1,3(2H)-dione, hydrochloride (1:2) _ Following the procedure of part (b) of example 4Ç but substituting 2-(6-bromohexyl)-lH-benz[de~isoquinoline-1,3(2H)-1058~78 MT96/85 , dione for the 2-(4-bromobutyl)-lH-benz~de]isoquinoline-1,3-(2H)-dione, one obtains 2-[6,-[4-~2-pyridinyl)-1-piperazinyl]-hexyl]-l_~benz~de]isoquinoline-1,3(2_)-dione, hydrochloride (1:2).
Alternatively, the procedure of examples 46-48 can be employed to prepare the compounds of examples 1-44.
Examples 49-74 Following the procedure of example 1 but substituting for the 2-(2-hydroxyethyl)-lH-benz~de]isoquinoline-1,3(2H)-lQ ' dione, 4-methylbenzenesulfonAte ester the ester shown in Col. I one obtains the product~shown in Col. II.
Col. I Col. II
~CH2) 2--03SC6H4CH3 (CH2) 2N'~3 O ~ N ~O O ~ ~ O
. . ..
Ex Xl x2 X3 X4 X5 X6 . .
49 H H Br - H H H
H Cl H H H H
Sl H Br H H H H
54 H Cl H H Cl H
Br H H H H H
56 H H Cl Cl H H
~ Ex. Xl x2 X3 X4 ~ X5 x6 .
59 H Hi-C3H7 H H H
H H CN H H H
Similarly, by employing the ester of Col. I of examples 49-74 in the procedures of examples 13 to 44, other compounds within ~he scope of this invention are prepared.
Similarly, by following the procedures of example 45 but employing a substituted 1,8-naphthalimide of formula VIII
wherein the substituents are those listed under the headings Xl, X2, X3, X4, X5, and x6 in examples 49 to 74, other compounds within the scope of this invention are prepared.
Also by following the procedure of examples 2-12, but employing a substituted 1,8-naphthalic anhydride of formula II
wherein the substituents are those listed under the headings Xl, X2, X3, X4, X5 and x6 in examples 49-74, other compounds within the scope of the invention are prepared.
~058~78 Example 75 2-[2-(4-Phenyl-l-piperazlnyl)ethy~_-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2) 10 g. (0.025 mole) of the ester from part (b) of Example 1, 4.3 g. (0.026 mole) of N-phenylpiperazine, and 3.27 g. (0.025 mole) of diisopropylethylamine are refluxed in 500 ml. of toluene for four hours. The reaction mixture is then shaken with 5 NaOH, filtered, washed with water (all aqueous layers are backwashed with toluene), and shaken with 10% HCl. The pre-cipitate that forms is filtered and washed with water and toluene.
Recrystallization from water/ethanol yields 3.0 g. of 2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (~1:2); m.p. 286-287 (dec.).
Example 76 2-[2-[4-~4-Methoxyphenyl)-l-piperazinyl]ethyl-lH-benz[de]isoquino-line-1,3(2_)-dione, hydrochloride (1:2) Following the procedure of example75 but substituting
5.1 g. (0.026 mole) of l-(~-methoxyphenyl)piperazine for the N-phe~ylpiperazine in the example, one obtains 8.0 g. of 2-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride (1:2); m.p. 270-271 (dec.).
Example 77 2-[2-l4-(2-Methoxyphenyl)-l-piperazinyl]ethyl]-l~-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride (1:2) Following the procedure of example75 but substituting 5.1 g. (0.026 mole) of l-(o-methoxyphenyl)piperazine for the N-phenylpiperazine in the example, one obtains 2.9g. of 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2); m.p. 284 (dec.).
1058~78 MT9~/85 Example 78 2-[2-[4-(4-Chlorophenyl)-l-piperaz~nyl]ethyl]-lH-benz[de]isoqulno-line-1,3(2H)-dione, hydrochloride (1 1) Following the procedure of example75 but substituting 5.2 g. (0.026 mole) of l-(p-chl~rophenyl)piperazine ~or the N-phenylpiperazine in the example,one obtains 3.0 g. of 2-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1); m.p. 286-287 (dec.).
Example ?9 2-[2-[4-(2-Chlorophenyl)-l-piperazinyl]ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione Following the procedure of example75 but substituting 5.2 g. (0.026 mole) of l-(o-chlorophenyl)piperazinefor the N-phenylpiperazine in the example, one obtains the hydrochloride salt - of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-lH-benz[de]-i~oquinoline-1,3(2H)-dione. This salt is neutralized with aqueous sodium hydroxide and extracted with chloroform. The chloroform solution is dried (Na2SO4), concentrated to 200 ml.
and allowed to stand open to the air. The product slowly crystalllzes and is removed by filtration. Drying at 50 (60 mm.) overnight yields 4 g. of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione;
m.p. 213-214.
Example 80 2-[2-[4-[3-(Trifluoromethyl)phenyl]-l-piperazinyl]ethyl]-lH
benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1) Following the procedure of example75 but substituting
Example 77 2-[2-l4-(2-Methoxyphenyl)-l-piperazinyl]ethyl]-l~-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride (1:2) Following the procedure of example75 but substituting 5.1 g. (0.026 mole) of l-(o-methoxyphenyl)piperazine for the N-phenylpiperazine in the example, one obtains 2.9g. of 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2); m.p. 284 (dec.).
1058~78 MT9~/85 Example 78 2-[2-[4-(4-Chlorophenyl)-l-piperaz~nyl]ethyl]-lH-benz[de]isoqulno-line-1,3(2H)-dione, hydrochloride (1 1) Following the procedure of example75 but substituting 5.2 g. (0.026 mole) of l-(p-chl~rophenyl)piperazine ~or the N-phenylpiperazine in the example,one obtains 3.0 g. of 2-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1); m.p. 286-287 (dec.).
Example ?9 2-[2-[4-(2-Chlorophenyl)-l-piperazinyl]ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione Following the procedure of example75 but substituting 5.2 g. (0.026 mole) of l-(o-chlorophenyl)piperazinefor the N-phenylpiperazine in the example, one obtains the hydrochloride salt - of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-lH-benz[de]-i~oquinoline-1,3(2H)-dione. This salt is neutralized with aqueous sodium hydroxide and extracted with chloroform. The chloroform solution is dried (Na2SO4), concentrated to 200 ml.
and allowed to stand open to the air. The product slowly crystalllzes and is removed by filtration. Drying at 50 (60 mm.) overnight yields 4 g. of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione;
m.p. 213-214.
Example 80 2-[2-[4-[3-(Trifluoromethyl)phenyl]-l-piperazinyl]ethyl]-lH
benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1) Following the procedure of example75 but substituting
6.-1 g. (0.026 mole) of 1-[3-(trifluoromethyl)phenyl]piperazine for the N-phenylpiperazine inthe example, one obtains 6.53 q. of 1058~78 MT96/85 2-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1);
m.p. 276-277 (dec.).
Example 8 2-[2-[4-(4-Fluorophenyl)-l-p ~ ]ethyl]-lH,benz[de]isoquino-line-1,3(2H)-dione, hydrochlorld _ ) Following the procedure of example75 but substituting 4.8 g. (0.026 mole) of l-(~-fluorophenyl)piperazine for the N-phenylpiperazine in the example,one obtains 6.1 g. of 2-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]-lH-benzEde~isoquinoline-1,3(2T~)-dione, hydrochloride (~:1); m.p. 309-310 (dec.).
_ Example 82 2-[2-[4-(Phen~lmethyl)-l-pi~_razinyl]ethyl]-lH-benz[de]isoqulno-line-1,3(2H)-dione, hydrochloride (1:2) Following the procedure of example 75 but substituting 4.7 g. (0.026 mole) of l-(phenylmethyl)piperazine for the N-phenylpiperazine in the example, one obtains 10.8g. of 2-[2-[4-(phenylmethyl)-l-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2_)-dione, hydrochloride (1:2); preliminary melting at 278-281 and final melting with decomposition at 284.
Exam~les 83-96 Following the procedure of example 75 but substituting for the N-phenylpiperazine in the example an equivalent amount of one of the following:
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 -~o5~178 MT96/85 1-(2-thiopropylphenyl)piperazine 1-(3-trifluoromethyl-4-chlorophenyl)piperazine 1-(3-trifluoromethyl-4-methylphenyl)piperazine 1-[(4-bromophenyl)methyl]piperazine 1-[2-(4-chlorophenyl)ethyl]piperazine 1-[[(3-trifluo~omethyl)phenyl]methyl]piperazine 1-[3-(4-methylphenyl)propyl]piperazine . 1-[(3,5-dimethoxyphenyl)methyl]piperazine one obtains 2-[2-[4-(2-phenylethyl)-1-piperazinyl]ethyl]-lH-benz[de]-10isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(3-phenylpropyl)-1-piperazinyl~ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(4-phenylbutyl)-1-piperazinyl]ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride;
2-[.2-[4-(3,5-dichlorophenyl)-1-piperazinyl]ethyl]-lH-benzEde]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(4-ethylphenyl)-1-piperazinyl]ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(4-nitrophenyl)-1-piperazinyl]ethyl]-lH-benz[de]-: isoquinoline-1,3(~H)-dione, hydrochloride;
2-[2-[4-(2-thiopropylphenyl)-1-piperazinyl]ethyl]-lH-benz~de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(3-trifluoromethyl-4-chlorophenyl)-1-piperazinyl]-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(3-trifluoromethyl-4-methylphenyl)-1-piperazinyl]-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-[(4-bromophenyl)methyl]-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-[2-(4-chlorophenyl)ethyl]-1-piperazinyl]ethyl]-lH-30benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
M~96/85 lOS~3178 2-[2-[4-[[(3-trifluoromethyl)phenyl]methyl]-1-piperazinyl]-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-[3-(4-~ethylphenyl~propyl].l-piperazinyl]ethyl-lH-benz[de]isoquinoline-1,3( 2H) -dione, hydrochloride;
and 2-[2-[4-[(3,5-dimethoxyphenyl)methyl]-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
respectively.
Example 97 2-[3-(4-Phenyl-l-piperazinyl)propyl]-l_-benz[de]iso~uinoline-1,3(2H)-dione, hydrochloride a) 2-(3-Hy~rox~propyl)-lH-benz`[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester Following the procedure of example l(a~ and (b) but substituting 3-aminopropanol for the ethanolamine in part (a) one obtains 2-(3-hydroxypropyl)-lH-benz[de~isoquinoline-1,3(2H)-dione, 4-methylben2enesulfonate ester.
b) 2-[3-(4-Phenyl-l-piperazinyl)propyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride Following the procedure of example 75 but substituting an equivalent amount of 2-(3-hydroxypropyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester for the ester in example 75 , one obtains 2-[3-(4-phenyl-1-piperazinyl)propyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride.
Example 98 2-[4-(4-Phenyl-l-piperazinyl)butyl]-lH-benz[de]isoquinoline-1,3-(2H)-dione, hydrochloride a) 2-(4-Hydroxybutyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, - 4-methylben~enesulfonate ester Following the procedure of example l(a) and (b) but substituting 4-aminobutanol for the ethanolamine in part (a) one 30 obtains 2-(4-hydroxybutyl)-1_-benz[de]isoquinoline-1,3(2H)-~QS8~78 dione, 4-methylbenzenesulfonate ester.
b) Z-[4-(4-Phenyl-l-piperazi;nyl)butyl]-lH-~enz[de]isoquinoline-1,3-(2_)-dione, hydrochloride Following the procedure of example 75 but substituting an equivalent amount of 2-(4-hydroxybutyl)-lH-benz[de]iso~uinolin~
1,3(2H)-dione, 4-methylbenzenesulfonate ester for the ester in example 75, one obtains 2-[4-(4-phenyl-1-piperazinyl)-butyl]-lH-benz[de]isoquinoline-1,3(2 )-dione, hydrochloride.
Examples 99-107 Following the procedure of example l(a),l(b) and 75,but substituting the alkanolamine shown in Col. I for the ethanolamine the following products are obtained wherein A is the radical shown in Col. II.
- ~ N
. ~ N ~
; Ex. Col. I Col. II
9~ H2N-(cH2)5-OH -(CH2)5-100 H2N-(CH2)6-OH -(CH2)6-.. 101 H2N (CH2)7 OH .-(CH2)7-102 H2N-(CH2)8-QH (CH2)8 103 H2N-CH2-CH-CH2-OH -CH2-~H-CH2-10~ H2N-ICH-(CH2)3-OH -CIH-(CH2)3-105 H2N-(CH2)3-1CH-OH -(CH2)3-1CH-10~ H N-cH2-cH-(cH2)2-OH -CH2-ClH-(cH2)2 Ex. Col. I Col. II
107 H2N-CH-CH2~lH-OH -CH-CH2-CH-Similarly, by employing the substituted piperazines of examples 2 to 22 in the procedures of examples of 23 to 33, other compounds within the scope of this invention are prepared pared.
Example 108 2-[4-(4-Phenyl-l-piperazinyl)butyl]-lH-benz[de]isoquinoline-1,3(2_)-dione, hydrochloride (l:l) 9.0 g. (0.027 mole)of 2-(4-bromobutyl~lH-benz[de]isoquinoline 1,3(2H)-dionefrom part (a) of Example 46 and 4.5 g. (0.0~7 mole) of N-phenylpiperazine are refluxed for two days over excess anhydrous sodium carbonate. The reaction mixture is washed with water and backwashed with toluene. The combined organic layers are washed with water twice and shaken with 10% HCl for one hour. ~he resulting precipitate is filtered from the two phases, washed with water and toluene, and dried in vacuo at 100 for one hour to yield 9.33 g. of 2-[4-(4-~henyl-1-pipera-zinyl)butyl]-lH-benz[de]isoquinoline-1,3t2_)-dione, hydrochloride (1:1); m.p. 265-267 (dec.).
~058~78 Example 109-2-[6-(4-Phenyl-l-piperazinyl)hexyl]-lH-benz[de]isoquinoline-1,3-(2H)-dione, hydrochloride a) 2-(6-Bromohexyl)-lH-benz[de]isoquinoline-1,3~2H)-dione Following the procedure of part (a) of example 46 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-lH-benzlde]isoquinoline-1,3(2H)-dione;
m.p. 95-96.
b) 2-[6-(4-Phenyl-l-piperazinyl)hexyl]-lH-benz~de3isoquinoline-- 1,3(2H)-dione, hydrochloride Following the procedure of example 108 but ,substituting 2-(6-bromohexyl)-lH-benz[de]isoauinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-lH-b,enz[de]isoquinoline-1,3-(2H)-dione, one obtains 2-~6-(4-phenyl-1-piperazinyl)hexyl]-lH-benz[de3isoquinoline-1,3(2H)-dione, hydrochloride.
MT96/~
1()58~78 Example 110 2-[5-(4-Phenyl-l-piperazinyl~pent~l]-lH-benz[de]isoquinoline-1,3( 2H) -dione, hydrochloride a) 2- ~5-Bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione Following the procedure of part (a) of example 46 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113-115.
b) 2-[5-(4-Phenyl-l-piperazinyl)`pentyl]-l~-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride Following the procedure~of example 108 but sub-stituting 2-(5-bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-(4-phenyl-1-piperazinyl)pentyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride.
Alternatively, the procedure of examples 108-110 can ~e employed to prepare the compounds of examples7S-107.
Example 111 2-[(4-Phenyl-l-piperazinyl)methyl]-lH-benz[de]isoquinoline-1,3-(2H)-dione An equimolar mixture of N-phenylpiperazine, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[(4-phenyl-1-piperazinyl)methyl]-lH-benz-[de]isoquinoline-1,3t2H)-dione.
Similarly, by employing the various substituted pipera-zines of examples76 to 96 in the above procedure, other compounds within the scope of the invention are prepared.
~05~3~78 Example 112 5-Chloro-2-[2-(4- hen 1-1- i erazin ljeth l]-lH-benz[de]iso-P Y P P Y Y
quinoline-1,3(2H)-dione, hydrochloride (1:1) a) 5-Chloro-2-(2-hydroxyethyl)-lH-benzlde] isoyuinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester Following the procedure of example l(a) and (b) but substituting 3-chloronaphthalic anhydride for the naphthalic anhydride one obtains 5-chloro-2-(2-hydroxyethyl)-lH-benz-[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate 10 ester.
b) 5-Chloro-2-E2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloxide (1:1) 10 g. (0.023 mole) of the ester from part (a) and 7.6 g.
(0.049 mole) of N-phenylpiperazine are refluxed in 300 ml. of toluene for one hour. The mixture is then cooled to 25 and after three hours the resulting precipitate is removed by fil-tration. The filtrate is shaken with excess 10% HCl (aqueous) producing a gum that is insoluble in both layers. After several minutes the gum crystallizes and is filtered from 20 the two liquid phases. This crude material is digested for ~wo hours at reflux temperature in 1000 ml. of 50% aqueous ethanol, cooled to 25, filtered, and dried at 90 (0.1 mm.) for four hours to yield 5.2 g. of 5-chloro-2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]isoquinoline-1,3 (2H)-dione, hydrochloride (1:1); preliminary darkening at 284 followed by melting with decomposition at 286-290.
1~58178 ~T96/85 Example 113 6-Chloro-2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]isoquino-line-1,3(2H)-dione, hydrochloride (1:1) a) 6-Chloro-2-(2-chloroethyl)-lH-benz[de]isoquinoline-1,3(2H)-dion~
25 g. (0.108 mole) of 4-chloronaphthalimide is dissolved in 300 ml. of warm dimethylformamide (ca. 80). 7.1 g. (0.108 mole) of potassium hydroxide (85%) in 100 ml. of ethanol is added resulting in the formation of a precipitate. The resulting mixture is heated at about 90 for 30 minutes and 45 g. ~0.32 mole) of 1-bromo-2-chloroethane in 100 ml. of dimethylformamide is added. After stirring for one hour, the mixture is cooled, poured into three liters of water and extracted with CHC13. The solution is evaporated to dryness and washed through a short (100 g.) column of alumina (Act. I) with CHC13. The solvent is removed under vacuum and the residue is digested for 30 minutes in boiling ethanol. The mixture is cooled to 25 and the pre-cipitate is filtered off and dried to yield 13.6 g. of 6-chloro-2-(2-chloroethylj-lH-benz[de]isoquinoline-1,3(2H)-dione.
b) 6-Chloro-2-~2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]-isoquinoline-1,3(?H)-dione, hydrochloride (1:1) 5 g. (0.017 mole) of 6-chloro-2-(2-chloroethyl)-lH-benz[de]isoquinoline-1,3(2_)-dione, from part (a), 6 g.
(0.037 mole) o N-phenylpiperazine, and 2.2 g. (0.017 mole) of diisopropylethylamine are refluxed in 250 ml. of toluene for 48 hours. After cooling to 25, the mixture is shaken with excess 10% HCl producing a precipitate that is insoluble in both liquid phases. The precipitated crude product is filtered o~f and purified by converting it back to the free base (parti-tion between 10% KOH and CHC13 and evaporating off the CHC13) and then washing it through a short column of alumina (50 x 170 mm ~058~78 Act. I) with CHC13. The soIvent is removed ~o give 3 g. of free base. This is again taken up in toluene and converted to the salt by shaking with 10% HCl (aqueous). The resulting precipitate is filtered from the two liquid phases, recrystallized from 66% aqueous ethanol, and dried for 12 hours at 70 (0.1 mm.) to yield 2.0 g. of 6-chloro-2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[delisoquinoline-1,3(2H)-dione, hydrochloride (1:1).
The melting point of the salt is indistinct. On rapid heating (10-20/minute), from 200-265 the material changes color from yellow to gray to black. On slower heating from 265-272 the black material collapses and at 272-274 becomes fluid.
Examples 114-139 Following the procedure of example75 but substituting for the 2-(4-hydroxyethyl)-lH= benz[de]isoquinoline-1,3(2_)-dione, 4-methylbenzenesulfonate ester the ester shown in Col. I one obtains the product shown in Col. II.
Col. I Col. II
(~ 2~2 O3SC6H4CH3 (fH2)2-~
20Q ~ N ~ o O ~N~o X6 ~ ~ ' xl x6~/v~ xl xS ,l~ X2 xS ~"r l ~1"1~ X2 Ex. Xl x2 X3 X4 X5 x6 .
114 H H Br H H H
115 H Cl H H H H
116 H Br H H H H
J
~058178 Ex Xl X2 3---~ X X5 ~-~- 6 119 H Cl H H Cl H
120 Br H H H H H
121 H H Cl Cl H H
lZ9 H H OCH3 OCH3 H H
131 H H No2 H H H
13~ H H NH2 H H H
Similarly, by employing the ester of Col. I of examples 114-139 in the procedures of examples 76 to 107, other compounds within the scope of this invention are prepared.
Similarly, by following the procedures of example .108 but employing a substituted 1,8-naphthalimide of formula VII
wherein the substituents are those listed under the headings Xl, X2, X3, X4, X5, and x6 in examples 114 to 139, other compounds within the scope of this invention are prepared.
m.p. 276-277 (dec.).
Example 8 2-[2-[4-(4-Fluorophenyl)-l-p ~ ]ethyl]-lH,benz[de]isoquino-line-1,3(2H)-dione, hydrochlorld _ ) Following the procedure of example75 but substituting 4.8 g. (0.026 mole) of l-(~-fluorophenyl)piperazine for the N-phenylpiperazine in the example,one obtains 6.1 g. of 2-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]-lH-benzEde~isoquinoline-1,3(2T~)-dione, hydrochloride (~:1); m.p. 309-310 (dec.).
_ Example 82 2-[2-[4-(Phen~lmethyl)-l-pi~_razinyl]ethyl]-lH-benz[de]isoqulno-line-1,3(2H)-dione, hydrochloride (1:2) Following the procedure of example 75 but substituting 4.7 g. (0.026 mole) of l-(phenylmethyl)piperazine for the N-phenylpiperazine in the example, one obtains 10.8g. of 2-[2-[4-(phenylmethyl)-l-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2_)-dione, hydrochloride (1:2); preliminary melting at 278-281 and final melting with decomposition at 284.
Exam~les 83-96 Following the procedure of example 75 but substituting for the N-phenylpiperazine in the example an equivalent amount of one of the following:
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 -~o5~178 MT96/85 1-(2-thiopropylphenyl)piperazine 1-(3-trifluoromethyl-4-chlorophenyl)piperazine 1-(3-trifluoromethyl-4-methylphenyl)piperazine 1-[(4-bromophenyl)methyl]piperazine 1-[2-(4-chlorophenyl)ethyl]piperazine 1-[[(3-trifluo~omethyl)phenyl]methyl]piperazine 1-[3-(4-methylphenyl)propyl]piperazine . 1-[(3,5-dimethoxyphenyl)methyl]piperazine one obtains 2-[2-[4-(2-phenylethyl)-1-piperazinyl]ethyl]-lH-benz[de]-10isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(3-phenylpropyl)-1-piperazinyl~ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(4-phenylbutyl)-1-piperazinyl]ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride;
2-[.2-[4-(3,5-dichlorophenyl)-1-piperazinyl]ethyl]-lH-benzEde]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(4-ethylphenyl)-1-piperazinyl]ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(4-nitrophenyl)-1-piperazinyl]ethyl]-lH-benz[de]-: isoquinoline-1,3(~H)-dione, hydrochloride;
2-[2-[4-(2-thiopropylphenyl)-1-piperazinyl]ethyl]-lH-benz~de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(3-trifluoromethyl-4-chlorophenyl)-1-piperazinyl]-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-(3-trifluoromethyl-4-methylphenyl)-1-piperazinyl]-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-[(4-bromophenyl)methyl]-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-[2-(4-chlorophenyl)ethyl]-1-piperazinyl]ethyl]-lH-30benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
M~96/85 lOS~3178 2-[2-[4-[[(3-trifluoromethyl)phenyl]methyl]-1-piperazinyl]-ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
2-[2-[4-[3-(4-~ethylphenyl~propyl].l-piperazinyl]ethyl-lH-benz[de]isoquinoline-1,3( 2H) -dione, hydrochloride;
and 2-[2-[4-[(3,5-dimethoxyphenyl)methyl]-1-piperazinyl]ethyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride;
respectively.
Example 97 2-[3-(4-Phenyl-l-piperazinyl)propyl]-l_-benz[de]iso~uinoline-1,3(2H)-dione, hydrochloride a) 2-(3-Hy~rox~propyl)-lH-benz`[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester Following the procedure of example l(a~ and (b) but substituting 3-aminopropanol for the ethanolamine in part (a) one obtains 2-(3-hydroxypropyl)-lH-benz[de~isoquinoline-1,3(2H)-dione, 4-methylben2enesulfonate ester.
b) 2-[3-(4-Phenyl-l-piperazinyl)propyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride Following the procedure of example 75 but substituting an equivalent amount of 2-(3-hydroxypropyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester for the ester in example 75 , one obtains 2-[3-(4-phenyl-1-piperazinyl)propyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride.
Example 98 2-[4-(4-Phenyl-l-piperazinyl)butyl]-lH-benz[de]isoquinoline-1,3-(2H)-dione, hydrochloride a) 2-(4-Hydroxybutyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, - 4-methylben~enesulfonate ester Following the procedure of example l(a) and (b) but substituting 4-aminobutanol for the ethanolamine in part (a) one 30 obtains 2-(4-hydroxybutyl)-1_-benz[de]isoquinoline-1,3(2H)-~QS8~78 dione, 4-methylbenzenesulfonate ester.
b) Z-[4-(4-Phenyl-l-piperazi;nyl)butyl]-lH-~enz[de]isoquinoline-1,3-(2_)-dione, hydrochloride Following the procedure of example 75 but substituting an equivalent amount of 2-(4-hydroxybutyl)-lH-benz[de]iso~uinolin~
1,3(2H)-dione, 4-methylbenzenesulfonate ester for the ester in example 75, one obtains 2-[4-(4-phenyl-1-piperazinyl)-butyl]-lH-benz[de]isoquinoline-1,3(2 )-dione, hydrochloride.
Examples 99-107 Following the procedure of example l(a),l(b) and 75,but substituting the alkanolamine shown in Col. I for the ethanolamine the following products are obtained wherein A is the radical shown in Col. II.
- ~ N
. ~ N ~
; Ex. Col. I Col. II
9~ H2N-(cH2)5-OH -(CH2)5-100 H2N-(CH2)6-OH -(CH2)6-.. 101 H2N (CH2)7 OH .-(CH2)7-102 H2N-(CH2)8-QH (CH2)8 103 H2N-CH2-CH-CH2-OH -CH2-~H-CH2-10~ H2N-ICH-(CH2)3-OH -CIH-(CH2)3-105 H2N-(CH2)3-1CH-OH -(CH2)3-1CH-10~ H N-cH2-cH-(cH2)2-OH -CH2-ClH-(cH2)2 Ex. Col. I Col. II
107 H2N-CH-CH2~lH-OH -CH-CH2-CH-Similarly, by employing the substituted piperazines of examples 2 to 22 in the procedures of examples of 23 to 33, other compounds within the scope of this invention are prepared pared.
Example 108 2-[4-(4-Phenyl-l-piperazinyl)butyl]-lH-benz[de]isoquinoline-1,3(2_)-dione, hydrochloride (l:l) 9.0 g. (0.027 mole)of 2-(4-bromobutyl~lH-benz[de]isoquinoline 1,3(2H)-dionefrom part (a) of Example 46 and 4.5 g. (0.0~7 mole) of N-phenylpiperazine are refluxed for two days over excess anhydrous sodium carbonate. The reaction mixture is washed with water and backwashed with toluene. The combined organic layers are washed with water twice and shaken with 10% HCl for one hour. ~he resulting precipitate is filtered from the two phases, washed with water and toluene, and dried in vacuo at 100 for one hour to yield 9.33 g. of 2-[4-(4-~henyl-1-pipera-zinyl)butyl]-lH-benz[de]isoquinoline-1,3t2_)-dione, hydrochloride (1:1); m.p. 265-267 (dec.).
~058~78 Example 109-2-[6-(4-Phenyl-l-piperazinyl)hexyl]-lH-benz[de]isoquinoline-1,3-(2H)-dione, hydrochloride a) 2-(6-Bromohexyl)-lH-benz[de]isoquinoline-1,3~2H)-dione Following the procedure of part (a) of example 46 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-lH-benzlde]isoquinoline-1,3(2H)-dione;
m.p. 95-96.
b) 2-[6-(4-Phenyl-l-piperazinyl)hexyl]-lH-benz~de3isoquinoline-- 1,3(2H)-dione, hydrochloride Following the procedure of example 108 but ,substituting 2-(6-bromohexyl)-lH-benz[de]isoauinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-lH-b,enz[de]isoquinoline-1,3-(2H)-dione, one obtains 2-~6-(4-phenyl-1-piperazinyl)hexyl]-lH-benz[de3isoquinoline-1,3(2H)-dione, hydrochloride.
MT96/~
1()58~78 Example 110 2-[5-(4-Phenyl-l-piperazinyl~pent~l]-lH-benz[de]isoquinoline-1,3( 2H) -dione, hydrochloride a) 2- ~5-Bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione Following the procedure of part (a) of example 46 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113-115.
b) 2-[5-(4-Phenyl-l-piperazinyl)`pentyl]-l~-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride Following the procedure~of example 108 but sub-stituting 2-(5-bromopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-lH-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-(4-phenyl-1-piperazinyl)pentyl]-lH-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride.
Alternatively, the procedure of examples 108-110 can ~e employed to prepare the compounds of examples7S-107.
Example 111 2-[(4-Phenyl-l-piperazinyl)methyl]-lH-benz[de]isoquinoline-1,3-(2H)-dione An equimolar mixture of N-phenylpiperazine, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[(4-phenyl-1-piperazinyl)methyl]-lH-benz-[de]isoquinoline-1,3t2H)-dione.
Similarly, by employing the various substituted pipera-zines of examples76 to 96 in the above procedure, other compounds within the scope of the invention are prepared.
~05~3~78 Example 112 5-Chloro-2-[2-(4- hen 1-1- i erazin ljeth l]-lH-benz[de]iso-P Y P P Y Y
quinoline-1,3(2H)-dione, hydrochloride (1:1) a) 5-Chloro-2-(2-hydroxyethyl)-lH-benzlde] isoyuinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester Following the procedure of example l(a) and (b) but substituting 3-chloronaphthalic anhydride for the naphthalic anhydride one obtains 5-chloro-2-(2-hydroxyethyl)-lH-benz-[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate 10 ester.
b) 5-Chloro-2-E2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]-isoquinoline-1,3(2H)-dione, hydrochloxide (1:1) 10 g. (0.023 mole) of the ester from part (a) and 7.6 g.
(0.049 mole) of N-phenylpiperazine are refluxed in 300 ml. of toluene for one hour. The mixture is then cooled to 25 and after three hours the resulting precipitate is removed by fil-tration. The filtrate is shaken with excess 10% HCl (aqueous) producing a gum that is insoluble in both layers. After several minutes the gum crystallizes and is filtered from 20 the two liquid phases. This crude material is digested for ~wo hours at reflux temperature in 1000 ml. of 50% aqueous ethanol, cooled to 25, filtered, and dried at 90 (0.1 mm.) for four hours to yield 5.2 g. of 5-chloro-2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]isoquinoline-1,3 (2H)-dione, hydrochloride (1:1); preliminary darkening at 284 followed by melting with decomposition at 286-290.
1~58178 ~T96/85 Example 113 6-Chloro-2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]isoquino-line-1,3(2H)-dione, hydrochloride (1:1) a) 6-Chloro-2-(2-chloroethyl)-lH-benz[de]isoquinoline-1,3(2H)-dion~
25 g. (0.108 mole) of 4-chloronaphthalimide is dissolved in 300 ml. of warm dimethylformamide (ca. 80). 7.1 g. (0.108 mole) of potassium hydroxide (85%) in 100 ml. of ethanol is added resulting in the formation of a precipitate. The resulting mixture is heated at about 90 for 30 minutes and 45 g. ~0.32 mole) of 1-bromo-2-chloroethane in 100 ml. of dimethylformamide is added. After stirring for one hour, the mixture is cooled, poured into three liters of water and extracted with CHC13. The solution is evaporated to dryness and washed through a short (100 g.) column of alumina (Act. I) with CHC13. The solvent is removed under vacuum and the residue is digested for 30 minutes in boiling ethanol. The mixture is cooled to 25 and the pre-cipitate is filtered off and dried to yield 13.6 g. of 6-chloro-2-(2-chloroethylj-lH-benz[de]isoquinoline-1,3(2H)-dione.
b) 6-Chloro-2-~2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[de]-isoquinoline-1,3(?H)-dione, hydrochloride (1:1) 5 g. (0.017 mole) of 6-chloro-2-(2-chloroethyl)-lH-benz[de]isoquinoline-1,3(2_)-dione, from part (a), 6 g.
(0.037 mole) o N-phenylpiperazine, and 2.2 g. (0.017 mole) of diisopropylethylamine are refluxed in 250 ml. of toluene for 48 hours. After cooling to 25, the mixture is shaken with excess 10% HCl producing a precipitate that is insoluble in both liquid phases. The precipitated crude product is filtered o~f and purified by converting it back to the free base (parti-tion between 10% KOH and CHC13 and evaporating off the CHC13) and then washing it through a short column of alumina (50 x 170 mm ~058~78 Act. I) with CHC13. The soIvent is removed ~o give 3 g. of free base. This is again taken up in toluene and converted to the salt by shaking with 10% HCl (aqueous). The resulting precipitate is filtered from the two liquid phases, recrystallized from 66% aqueous ethanol, and dried for 12 hours at 70 (0.1 mm.) to yield 2.0 g. of 6-chloro-2-[2-(4-phenyl-1-piperazinyl)ethyl]-lH-benz[delisoquinoline-1,3(2H)-dione, hydrochloride (1:1).
The melting point of the salt is indistinct. On rapid heating (10-20/minute), from 200-265 the material changes color from yellow to gray to black. On slower heating from 265-272 the black material collapses and at 272-274 becomes fluid.
Examples 114-139 Following the procedure of example75 but substituting for the 2-(4-hydroxyethyl)-lH= benz[de]isoquinoline-1,3(2_)-dione, 4-methylbenzenesulfonate ester the ester shown in Col. I one obtains the product shown in Col. II.
Col. I Col. II
(~ 2~2 O3SC6H4CH3 (fH2)2-~
20Q ~ N ~ o O ~N~o X6 ~ ~ ' xl x6~/v~ xl xS ,l~ X2 xS ~"r l ~1"1~ X2 Ex. Xl x2 X3 X4 X5 x6 .
114 H H Br H H H
115 H Cl H H H H
116 H Br H H H H
J
~058178 Ex Xl X2 3---~ X X5 ~-~- 6 119 H Cl H H Cl H
120 Br H H H H H
121 H H Cl Cl H H
lZ9 H H OCH3 OCH3 H H
131 H H No2 H H H
13~ H H NH2 H H H
Similarly, by employing the ester of Col. I of examples 114-139 in the procedures of examples 76 to 107, other compounds within the scope of this invention are prepared.
Similarly, by following the procedures of example .108 but employing a substituted 1,8-naphthalimide of formula VII
wherein the substituents are those listed under the headings Xl, X2, X3, X4, X5, and x6 in examples 114 to 139, other compounds within the scope of this invention are prepared.
Claims (34)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R1 and R2 are each independently selected from hydrogen and halogen; A is a straight or branched chain alkylene of 1 to 8 carbons; and R is selected from phenyl which may be substituted by lower alkoxy, halogen and CF3, benzyl and pyridyl and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting a compound of the formula wherein Y is a leaving group such as tosylate, methanesulfonate or halogen, with an amine of the formula .
2. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(2-pyridinyl)piperazine to form 2-(2-(4-(2-pyridinyl)-1-piperazinyl)ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
3. A process according to claim 1 wherein 2-(4-bromo-butyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(2-pyridinyl)piperazine to form 2-(4-(4-(2-pyridinyl)-1-piperazinyl)butyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
4. A process according to claim 1 wherein 2-(5-bromo-pentyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(2-pyridinyl)piperazine to form 2-(5-(4-(2-pyridinyl)-1-piperazinyl)pentyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
5. A process according to claim 1 wherein 2-(6-bromo-hexyl)-1H-benz[d,e]isoquinoline-1,2(2H)dione is reacted with 1-(2-pyridinyl)piperazine to form 2-(6-(4-(2-pyridinyl)-1-piperazinyl)hexyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
6. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with N-phenylpiperazine to form 2(2-(4-phenyl-1-piperazinyl)ethyl)-lH-benz[d,e]isoquinoline-1,3(2H)dione.
7. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(p-methoxyphenyl)piperazine to form 2-(2-(4-(4-methoxyphenyl)-1-piperazinyl)ethyl-1H-benz[d,e]isoquinoline-1,3(2H)dione.
8. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(o-methoxyphenyl)piperazine to form 2-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
9. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(p-chlorophenyl)piperazine to form 2-(2-(4-(4-chlorophenyl)-1-piperazinyl)ethyl)-lH-benz[d,e]isoquinoline-1,3(2H)dione.
10. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(3-(trifluoromethyl)phenyl)piperazine to form 2-(2-(4-(3-(trifluoromethyl)phenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione.
11. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(p-fluorophenyl)piperazine to form 2-(2-(4-(4-fluorophenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
12. A process according to claim 1 wherein 2-(2-hydroxy-ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with 1-(phenylmethyl)piperazine to form 2-(2-(4-(phenylmethyl)-1-piperazinyl)ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
13. A process according to claim 1 wherein 2-(4-bromo-butyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with N-phenylpiperazine to form 2-(4-(4-phenyl-1-piperazinyl)butyl)-lH-benz[d,e]isoquinoline -1,3(2H)dione.
14. A process according to claim 1 wherein 2-(6-bromo-hexyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with N-phenylpiperazine to form 2-(6-(4-phenyl-1-piperazinyl)-hexyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
15. A process according to claim 1 wherein 2-(5-bromo-pentyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with N-phenylpiperazine to form 2-(5-(4-phenyl-1-piperazinyl)-pentyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione.
16. A process according to claim 1 wherein 5-chloro-2-(2-hydroxyethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione, 4-methylbenzenesulfonate ester is reacted with N-phenylpiperazine-to form 5-chloro-2-(2-(4-phenyl-1-piperazinyl)ethyl)-1H-benz-[d,e]isoquinoline-1,3(2H)dione.
17. A process according to claim 1 wherein 6-chloro-2-(2-chloroethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione is reacted with N-phenylpiperazine to form 6-chloro-2-(2-(4-phenyl-1-piperazinyl)ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)-dione.
18. A compound of the formula wherein R1 and R2 are each independently selected from hydrogen and halogen; A is a straight or branched chain alkylene of 1 to 8 carbons; and R is selected from phenyl which may be substituted by lower alkoxy, halogen and CF3, benzyl or pyridyl and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 1.
19. A compound according to claim 18 having the name 2-(2-(4-(2-pyridinyl)-1-piperazinyl)ethyl)-1H-benz]d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 2.
20. A compound according to claim 18 having the name 2-(4-(4-(2-pyridinyl)-1-piperazinyl)butyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 3.
21. A compound according to claim 18 having the name 2-(5-(4-(2-pyridinyl)-1-piperazinyl)pentyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 4.
22. A compound according to claim 18 having the name 2-(6-(4-(2-pyridinyl)-1-piperazinyl)hexyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 5.
23. A compound according to claim 18 having the name 2-(2-(4-phenyl-1-piperazinyl)ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 6.
24. A compound according to claim 18 having the name 2-(2-(4-(4-methoxyphenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 7.
25. A compound according to claim 18 having the name 2-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 8.
26. A compound according to claim 18 having the name 2-(2-(4-(4-chlorophenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 9.
27. A compound according to claim 18 having the name 2-(2-(4-(3-(trifluoromethyl)phenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 10.
28. A compound according to claim 18 having the name 2-(2-(4-(4-fluorophenyl)-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 11.
29. A compound according to claim 18 having the name 2-(2-(4-(phenylmethyl)-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 12.
30. A compound according to claim 18 having the name 2-(4-(4-phenyl-1-piperazinyl)butyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 13.
31. A compound according to claim 18 having the name 2-(6-(4-phenyl-1-piperazinyl)-hexyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 14.
32. A compound according to claim 18 having the name 2-(5-(4-phenyl-1-piperazinyl)-pentyl)-1H-benz[d,e]isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 15.
33. A compound according to claim 18 having the name 5-chloro-2-(2-(4-phenyl-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 16.
34. A compound according to claim 18 having the name 6-chloro-2-(2-(4-phenyl-1-piperazinyl)ethyl)-1H-benz[d,e]-isoquinoline-1,3(2H)dione, whenever prepared by the process of claim 17.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/523,293 US3940397A (en) | 1974-11-13 | 1974-11-13 | 2-[(Substituted-piperazinyl)alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones |
| US05/543,558 US3940398A (en) | 1975-01-23 | 1975-01-23 | 2-[[4-(Azine or diazine or triazine)-1-piperazinyl]alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1058178A true CA1058178A (en) | 1979-07-10 |
Family
ID=27061097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA239,072A Expired CA1058178A (en) | 1974-11-13 | 1975-11-05 | 2-((substituted-piperazinyl)alkyl)-1h-benz(de)isoquinoline-1,3(2h)-diones |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS51125293A (en) |
| CA (1) | CA1058178A (en) |
| DE (1) | DE2551062A1 (en) |
| FR (1) | FR2290903A1 (en) |
-
1975
- 1975-11-05 CA CA239,072A patent/CA1058178A/en not_active Expired
- 1975-11-13 DE DE19752551062 patent/DE2551062A1/en not_active Withdrawn
- 1975-11-13 FR FR7534615A patent/FR2290903A1/en active Granted
- 1975-11-13 JP JP13711575A patent/JPS51125293A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE2551062A1 (en) | 1976-05-26 |
| FR2290903A1 (en) | 1976-06-11 |
| JPS51125293A (en) | 1976-11-01 |
| FR2290903B1 (en) | 1978-11-10 |
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