Piperazine Substituted Carboxamide Derivatives, Compositions and Method of Use

1. Field of the Invention

The present invention relates to novel carboximide derivatives having excellent medicinal effects, to processes for their production and to medicines containing same.

More particularly, this invention relates to carboximide derivatives of the formula: ##STR4## and acid addition salts thereof; wherein X represents a group of the formula: ##STR5## Z represents a hydrogen atom or a group of the formula: ##STR6## wherein R represents an alkyl group, an aralkyl group, an aryl group, a cycloalkyl group, an alkenyl group, an arylalkenyl group, a pyridyl group or a substituted amino group; Y represents an alkyl group, an aralkyl group, an aryl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidyl group or a benzothiazolyl group; and m represents an integer of 2 or 3, to processes for their production, and to medicines containing same.

The carboximide derivatives provided by the present invention are novel compounds which have not yet been disclosed in any literature, and it has now been discovered that these compounds unexpectedly have hypoglycemic activity and are useful as treating agents for diabetes. In other words, the carboximide derivatives provided by the present invention are remarkably different in structure from the conventionally and widely employed sulfonyl urea agents, biguanide agents, etc.

Accordingly, an object of the present invention is to provide novel carboximide derivatives useful as treating agents for diabetes.

Another object of the present invention is to provide processes for the production of novel carboximide derivatives useful as treating agents for diabetes.

Still another object of the present invention is to provide novel treating agents for diabetes.

In the definition of X in the formula above, where X represents a group of the formula: ##STR7## these groups may exist in stereoisomeric forms, and often exist as exo and endo forms, and cis and trans forms, and therefore, the present invention encompasses all such stereoisomers.

Further, the compounds of the present invention may easily form acid addition salts by reacting with a pharmaceutically acceptable inorganic acid or organic acid. Examples of such an inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfulic acid etc., and examples of such an organic acid include maleic acid, fumaric acid, succinic acid, acetic acid, malonic acid, citric acid, benzoic acid etc.

The compounds of the present invention may be produced by various routes, among which some representative examples commonly employed are described below:

[Preparative Process 1]

Where Z is a hydrogen atom: ##STR8## wherein X, Y and m are as defined above.

That is, a compound of the formula (II) and a compound of the formula (III) are reacted to obtain a compound (IV) of the present invention.

This reaction may be carried out by appropriately selecting a solvent which does not participate in the reaction from, e.g., lower alcoholic solvents such as methanol, ethanol, propanol, isopropanol, butanol etc., 2-butanone, methyl isobutyl ketone etc.

In this process, the compound of the formula (II) employed as one starting material may be produced by, for example, the following process: ##STR9## wherein X is as defined above, and Hal represents a halogen atom.

That is, a compound of the formula (V) and a compound of the formula (VI) are reacted to obtain a compound of the formula (II).

This reaction may be carried out by appropriately selecting a solvent which does not participate in the reaction from e.g. lower alcoholic solvents such as methanol, ethanol, propanol, isopropanol, butanol etc., benzenic solvents such as benzene, toluene, xylene etc., etheric solvents such as dioxane, tetrahydrofuran etc., dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl ethyl ketone, methyl isobutyl ketone, water etc. On reaction, it is also possible to add an acid removing agent such as potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine etc. to the reaction system.

[Preparative Process 2]

Where Z is other than a hydrogen atom, and R represents an alkyl group, an aralkyl group, an aryl group, a cycloalkyl group, a pyridyl group, an alkenyl group or an arylalkenyl group:

In this case, the desired compound may be obtained by esterifying the hydroxyl group of a compound of the formula: ##STR10## wherein X, Y and m are as defined above; which has been produced by either the [Preparative Process 1] or other process.

As a representative process, the above compound of the formula (IV) is reacted with a carboxylic acid of the formula: RCOOH (VII) or a reactive derivative thereof, wherein R represents an alkyl group, an aralkyl group, an aryl group, a cycloalkyl group, a pyridyl group, an alkenyl group or an arylalkenyl group in conventional manner to obtain the desired compound, ester (I).

The most preferred and conventionally employed process comprises reacting with RCOCl, i.e. an acid halide (VII), to readily obtain the desired compound (I). At this time, preferred results may be obtained by employing an acid removing agent such as triethylamine, potassium carbonate, sodium carbonate etc. As the solvent in this case, e.g. chloroform, dichloroethane, dioxane, tetrahydrofuran, dimethylformamide etc. may be employed.

[Preparative Process 3]

Where Z is other than a hydrogen atom, and R represents a substituted amino group:

The desired compound may be obtained by converting the hydroxyl group of the compound of the formula: ##STR11## wherein X, Y and m are as defined above, which has been produced by either the [Preparative Process 1] or other process, to a urethane group.

One representative process comprises reacting the above compound of the formula (IV) with an isocyanate of the formula R.sub.1 NCO wherein R.sub.1 represents an alkyl group or a cycloalkyl group in conventional manner to obtain the desired compound (I). As the solvent in this case, e.g. toluene, xylene, cumene, cymene etc. may be employed.

Representative compounds of the present invention are illustrated below, but it should be understood that the present invention is not restricted thereto. Although the compounds set forth below are expressed as free forms, it should of course be understood that they include acid addition salts formed with a pharmaceutically acceptable inorganic acid or organic acid.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2-d icarboximide;

N-[2-acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2-d icarboximide;

N-[2-propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide;

N-[2-isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide;

N-[2-n-butanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide;

N-[2-n-hexanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide;

N-[2-n-heptanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-en e-1,2-dicarboximide;

N-[2-n-octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide;

N-[2-n-nonanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide;

N-[2-n-decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide;

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-n-undecanoyloxypropyl]cis-cyclohex-4-e ne-1,2-dicarboximide;

N-[2-n-dodecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-e ne-1,2-dicarboximide;

N-[2-n-tridecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4- ene-1,2-dicarboximde;

N-[2-n-tetradecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex- 4-ene-1,2-dicarboximide;

N-[2-n-pentadecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex- 4-ene-1,2-dicarboximide;

N-[2-n-hexadecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4 -ene-1,2-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycloh ex-4-ene-1,2-dicarboximide;

N-[2-cyclopentylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclo hex-4-ene-1,2-dicarboximide;

N-[2-(3-phenylpropionyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclo hex-4-ene-1,2-dicarboximide;

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]cis-cyclohex- 4-ene-1,2-dicarboximide;

N-[2-(trans-2-nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycloh ex-4-ene-1,2-dicarboximide;

N-[2-benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1, 2-dicarboximide;

N-[2-(4-methylbenzoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohe x-4-ene-1,2-dicarboximide;

N-[2-(2-methoxybenzoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycloh ex-4-ene-1,2-dicarboximide;

N-[2-n-butylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide;

N-[2-cyclohexylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-c yclohex-4-ene-1,2-dicarboximide;

N-[2-nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide;

N-[2-n-decylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide;

N-[2-cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dicarbox imide;

N-[2-acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dicarbox imide;

N-[2-isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-di carboximide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dic arboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cycohexane -1,2-dicarboximide;

N-[2-n-decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-di carboximide;

N-[2-palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dic arboximide;

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]cyclohexane-1 ,2-dicarboximide;

N-[2-nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dic arboximide;

N-[2-propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dic arboximide;

N-[2-n-butylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohex ane-1,2-dicarboximide;

N-[2-benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dicar boximide;

N-[2-(trans-2-nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexan e-1,2-dicarboximide;

N-[2-cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-dic arboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimid e;

N-[2-n-decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]succinimide;

N-[2-(trans-2-nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimid e;

N-[2-benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-n-octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide;

N-[2-n-decylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinim ide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1]hept- 5-ene-2,3-dicarboximide;

N-[2-acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1]hept- 5-ene-2,3-dicarboximide;

N-[2-propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[2-isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyc lo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[2-(trans-2-nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyc lo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-butylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bic yclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-cyclohexylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo- bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[2-n-decylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bic yclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[2-n-octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]endo-bicyclo[ 2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[2-n-butanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[2-n-hexanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[2-n-heptanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2, 1]hept-5-ene-2,3-dicarboximide;

N-[2-n-octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[2-n-nonanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[2-n-decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[2-n-undecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2 ,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-dodecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2 ,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-tridecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-tetradecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[ 2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-pentadecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[ 2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-hexadecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2 ,2,1]hept-5-ene-2,3-dicarboximide;

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]endo-bicyclo[ 2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1]he pt-5-ene-2,3-dicarboximide;

N-[2-(3-phenylpropionyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicy clo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-(4-methoxybenzoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyc lo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-(2-chlorobenzoyloxy)-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]endo-bicy clo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]exo-bicyclo[2,2,1]hept-5 -ene-2,3-dicarboximide;

N-[2-benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]exo-bicyclo[2,2,1]hep t-5-ene-2,3-dicarboximide;

N-[2-hexanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]exo-bicyclo[2,2,1]he pt-5-ene-2,3-dicarboximide;

N-[2-acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]exo-bicyclo[2,2,1]hept-5 -ene-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimid e;

N-[2-n-decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]phthalimide;

N-[2-(trans-2-nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimid e;

N-[2-nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-n-octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-n-butylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalim ide;

N-[2-cyclohexylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phtha limide;

N-[2-benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,2]oct-5 -ene-2,3-dicarboximide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,2] oct-5-ene-2,3-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyc lo[2,2,2]oct-5-ene-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1]hepta ne-2,3-dicarboximide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] heptane-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-7-oxabicyclo[2,2,1] heptane-2,3-dicarboximide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-7-oxabicyclo[2 ,2,1]heptane-2,3-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-7-oxa bicyclo[2,2,1]]heptane-2,3-dicarboximide;

N-[2-n-hexadecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-7-oxabicy clo[2,2,1]heptane-2,3-dicarboxyimide;

N-[2-n-hexadecanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-bicyclo[2 ,2,1]heptane-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2 -dicarboximide;

N-[2-isobutyryloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-e ne-1,2-dicarboximide;

N-[2-n-caproyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-en e-1,2-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide;

N-[2-acetoxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2 -dicarboximide;

N-[2-benzoyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide;

N-[2-propionyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-en e-1,2-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cyclohexane-1,2-dicarb oximide;

N-[2-acetoxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cyclohexane-1,2-dicarb oximide;

N-[2-isobutyryloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cyclohexane-1,2- dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cyclohex ane-1,2-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1]hep t-5-ene-2,3-dicarboximide;

N-[2-acetoxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1]hep t-5-ene-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]exo-bicyclo[2,2,1]hept -5-ene-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]phthalimide;

N-[2-benzoyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[2-n-hexadecanoyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex -4-ene-1,2-dicarboximide;

N-[3-{4-(2-benzothiazoyl)piperazin-1-yl}-2-hydroxypropyl]endo-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide;

N-[3-{4-(2-benzothiazoyl)piperazin-1-yl}-2-hydroxypropyl]cis-cyclohex-4-ene -1,2-dicarboximide;

N-[2-benzoyloxy-3-{4-(2-benzothiazoyl)piperazin-1-yl}propyl]cis-cyclohex-4- ene-1,2-dicarboximide;

N-[2-acetoxy-3-{4-(2-benzothiazoyl)piperazin-1-yl}propyl]cyclohexane-1,2-di carboximide;

N-[2-n-hexadecanoyloxy-3-{4-(2-benzothiazoyl)piperazin-1-yl}propyl]succinim ide;

N-{2-hydroxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2-dicarb oximide;

N-{2-n-caproyloxy-3-(4-methylpiperazin-1-yl)propyl}cyclohexane-1,2-dicarbox imide;

N-{3-(4-methylpiperazin-1-yl)-2-nicotinyloxypropyl}endo-bicyclo[2,2,1]hept- 5-ene-2,3-dicarboximide;

N-{2-n-caproyloxy-3-(4-methylpiperazin-1-yl)propyl}endo-bicyclo[2,2,1]hept- 5-ene-2,3-dicarboximide;

N-{2-hydroxy-3-(4-methylpiperazin-1-yl)propyl}endo-bicyclo[2,2,1]hept-5-ene -2,3-dicarboximide;

N-{3-(4-methylpiperazin-1-yl)-2-nicotinyloxypropyl}cis-cyclohex-4-ene-1,2-d icarboximide;

N-{2-isobutyryloxy-3-(4-methylpiperazin-1-yl)propyl}cyclohexane-1,2-dicarbo ximide;

N-{2-n-caproyloxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2-d icarboximide;

N-{2-isobutyryloxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2- dicarboximide;

N-{2-hydroxy-3-(4-methylpiperazin-1-yl)propyl}cyclohexane-1,2-dicarboximide ;

N-{2-cyclohexylcarbonyloxy-3-(4-n-hexylpiperazin-1-yl)propyl}cyclohexane-1, 2-dicarboximide;

N-{2-cyclohexylcarbonyloxy-3-(4-n-hexylpiperazin-1-yl)propyl}phthalimide;

N-{2-benzoyloxy-3-(4-ethylpiperazin-1-yl)propyl}phthalimide;

N-{2-hexadecanoyloxy-3-(4-propylpiperazin-1-yl)propyl}endo-bicyclo[2,2,2]oc t-5-ene-2,3-dicarboximide;

N-{2-benzoyloxy-3-(4-n-hexylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2-di carboximide;

N-{2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl}exo-bicyclo[2,2,1]hept-5-ene- 2,3-dicarboximide;

N-[2-acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]phthalimide;

N-[2-acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]cyclohexane-1,2-dic arboximide;

N-[2-acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide;

N-[2-acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]exo-bicyclo[2,2,1]h ept-5-ene-2,3-dicarboximide;

N-[2-benzoyloxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]endo-bicyclo[2,2 ,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-caproyloxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]endo-bicyclo[2 ,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[3-{4-(3-chlorophenyl)piperazin-1-yl}-2-hydroxypropyl]exo-bicyclo[2,2,1]h ept-5-ene-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-methoxyphenyl)piperazin-1-yl}propyl]exo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[3-{4-(3-chlorophenyl)piperazin-1-yl}-2-hydroxypropyl]exo-bicyclo[2,2,1]h eptane-2,3-dicarboximide;

N-[3-{4-(3-chlorophenyl)piperazin-1-yl}-2-hydroxypropyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(4-methylphenyl)piperazin-1-yl}propyl]endo- bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-hexadecanoyloxy-3-{4-(3-trifluoromethylphenyl)piperazin-1-yl}propyl]en do-7-oxabicyclo[2,2,1]heptane-2,3-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-phenylpiperazin-1-yl}propyl]cis-cyclohex-4- ene-1,2-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(3,4-dimethylphenyl)piperazin-1-yl}propyl]e ndo-bicyclo[2,2,2]oct-5-ene-2,3-dicarboximide;

N-[2-benzoyloxy-3-{4-(2-methoxyphenyl)piperazin-1-yl}propyl]phthalimide;

N-[2-n-hexadecanoyloxy-3-{4-(4-chlorophenyl)piperazin-1-yl}propyl]endo-bicy clo[2,2,1]hept-5-ene-2,3-dicarboximide,

N-[3-{4-<2-(4,6-dimethyl)pyrimidyl>piperazin-1-yl}-2-hydroxypropyl]cis-cycl ohex-4-ene-1,2-dicarboximide;

N-[3-{4-<2-(4,6-dimethyl)pyrimidyl>piperazin-1-yl}-2-hydroxypropyl]endo-bic yclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-hexanoyloxy-3-{4-<2-(4,6-dimethyl)pyrimidyl>piperazin-1-yl}propyl]ci s-cyclohex-4-ene-1,2-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-<2-(4-methoxy-6-methyl)pyrimidyl>piperazin- 1-yl}propyl]endo-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-hexanoyloxy-3-{4-<2-(3-methyl)pyridyl>piperazin-1-yl}propyl]cis-cycloh ex-4-ene-1,2-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-(4-pyridyl)piperazin-1-yl}propyl]endo-bicyc lo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-propanoyloxy-3-{4-<2-(4-methoxy)pyridyl>piperazin-1-yl}propyl]phthalim ide;

N-[2-propanoyloxy-3-{4-<2-(4-chloro)pyridyl>piperazin-1-yl}propyl]phthalimi de;

N-[2-cyclohexylcarbonyloxy-3-{4-(4-pyridyl)piperazin-1-yl}propyl]succinimid e;

N-[2-hydroxy-3-{4-(2-pyrimidyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]cis-cy clohex-4-ene-1,2-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyrimidyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]endo-b icyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]endo-bic yclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]cis -cyclohex-4-ene-1,2-dicarboximide;

N-{2-hydroxy-3-(4-phenylhexahydro-1H-1,4-diazepin-1-yl)propyl}cis-cyclohex- 4-ene-1,2-dicarboximide;

N-{2-hydroxy-3-(4-phenylhexahydro-1H-1,4-diazepin-1-yl)propyl}endo-bicyclo[ 2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]end o-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-methyl-hexahydro-1H-1,4-diazepin-1-yl}propy l]phthalimide;

N-[2-cyclohexylcarbonyloxy-3-{4-phenyl-hexahydro-1H-1,4-diazepin-1-yl}propy l]succinimide;

N-[2-nicotinoyloxy-3-{4-(3,4-dimethylphenyl)-hexahydro-1H-1,4-diazepin-1-yl }propyl]cyclohexane-1,2-dicarboximide;

N-[2-cyclohexylcarbonyloxy-3-{4-<2-(4,6-dimethyl)pyrimidyl>-hexahydro-1H-1, 4-diazepin-1-yl}propyl]endo-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-butylaminocarbonyloxy-3-{4-ethyl-hexahydro-1H-1,4-diazepin-1-yl}prop yl]exo-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-[2-n-hexadecanoyloxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propy l]cis-cyclohex-4-ene-1,2-dicarboximide;

N-[2-(2-benzylcarbonyloxy)-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}p ropyl]cis-cyclohex-4-ene-1,2-dicarboximide;

2-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]-1H-benz[d,e]isoquinolin e-1,3(2H)dione;

2-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]-1H-benz[d,e]isoqui noline-1,3(2H)dione;

2-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]-1H-benz[d ,e]isoquinoline-1,3(2H)dione;

N-{2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2-dicarb oximide;

N-[2-hydroxy-3-{4-(2-methylphenyl)piperazin-1-yl}propyl]endo-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide;

N-[3-{4-<2-(4,6-dimethyl)pyrimidyl>piperazin-1-yl}-2-hydroxypropyl]phthalim ide;

N-[2-n-caproyloxy-3{4-<2-(4,6-dimethyl)pyrimidyl>piperazin-1-yl}propyl]phth alimide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-methylphenyl)piperazin-1-yl}propyl]endo- bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide;

N-{2-cyclohexylcarbonyloxy-3-(4-phenylpiperazin-1-yl)propyl}cis-cyclohex-4- ene-1,2-dicarboximide;

N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]2,2-dimethylsuccinimide;

N-[2-cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]2,2-dimeth ylsuccinimide;

N-[2-n-caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]2,2-dimethylsuccini mide.

In order to explain the effect of the present invention in more detail, experimental examples on hypoglycemic activity are given below.

Male Sprague-Dawley rats (weighing 300-350 g) were maintained on rat chow and water adlibitum in a constant temperature room (22.degree.-24.degree. C.) for at least a week prior to use in studies. Sub-diabetic rats*.sup.1 were obtained by intrevenous injection of 20 mg/kg of streptozotocin (STZ). The compounds were orally administered in 5% gum arabic suspension in sub-diabetic rats. 3 g/kg of glucose was administered intraperitoneally an hour later. Blood samples were taken from the tail vein, and the blood sugar was measured by the anthrone method [Ui. M., Am. J. Physiol. 209, 353-358 (1965)]. The results are shown in Table 1, in which the numerical values are the improvement percentages of the blood sugar value of each group treated with compounds relative to those of the control group expressed as 100%.

Compound A: N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimi de maleate;

Compound B: N-[2-n-Decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-en e-1,2-dicarboximide dimaleater;

Compound C: N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide dimaleate;

Compound D: N-[2-(trans-2-Nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclo hex-4-ene-1,2-dicarboximide dimaleate;

Compound E: N-[2-Nicotinoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-en e-1,2-dicarboximide maleate

Compound F: N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis- bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide dimaleate;

Compound G: N-[2-Palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide dimaleate;

Compound H: N-[2-Nicotinoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide maleate;

Compound I: N-[2-Propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide maleate; and

Compound J: N-{2-n-Caproyloxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2- dicarboximide dimaleate.

From Table 1 it can be seen that the compounds of the present invention obviously possess extremely excellent improvement ability of glucose tolerance and therefore they are useful as agents for diabetes.

For toxicity of the compounds of the present invention, they are extremely safe drugs as demonstrated by the following experiment.

More specifically, when an experiment was carried out in DDY strain mice, there was no case of death at a dosage of 1,000 mg/kg, as shown below.

DDY strain mice (weighing 20-25 g) maintained on mice chow and water adlibitum in a constant temperature room (22.degree.-24.degree. C.) for at least a week were used.

An acute toxicity test was carried out by oral administration of the compounds at two dosage levels of 500 mg/kg and 1,000 mg/kg. Observation of dead cases were made within one week. In table 2, the denominator of each value indicates the number of cases tested and the numerator indicates the number of dead cases. Compounds A, B, C, D, E and F correspond to Compoounds A-F in Experiment 1 respectively.

When the compounds of the present invention are used as agents for diabetes, they are administered either orally or parenterally (e.g. intramuscularly, subcutaneously, intravenously, as suppositories etc.). Although the dosage depends on the severity of the condition of the patient, it is generally in the range of 100-1,000 mg, preferably 250-500 mg, per day for a human adult.

For preparations of the compounds of the present invention, they are made in the form of tablets, granules, powders, capsules, injectable compositions, suppositories etc. in accordance with conventional pharmaceutical practice.

More specifically, for preparing oral solid preparations, the main drug is mixed with an excipient and further, if necessary, a binder, disintegrantor, lubricant, cooling agent, flavoring agent etc. and made into tablets, coated tablets, granules, powders, capsules etc. in conventional manner.

As the excipients, there can be used, for example, lactose, corn starch, white sugar, glucose, sorbitol, microcrystalline cellulose etc. As the binders, there can be used, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone etc. As the disintegrantors, there can be used, for example starch, agar, gelatin powder, microcrystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin etc. As the lubricants, there can be used, for example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oils etc. As the colorants, there can be used those allowed as additives to medicine such as cocoa butter, menthol, aromatic acids, mint oil, camphol, cinnamon powder etc. These tablets, granules etc. may of course be suitably coated with sugar, gelatin or the like, if necessary.

For preparing injectable solution, the main drug is mixed with a pH adjusting agent, buffer, stabilizer, preservative etc., if necessary, and made into compositions for subcutaneous, intramuscular, intravenous injections etc. in conventional manner.

One liter of 2-butanone was added to 65.2 g of endo-cis-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide, 70 g of epichlorohydrin and anhydrous potassium carbonate, and the mixture was heated under reflux for 5 hours. The inorganic matters were filtered while hot, the filtrate was concentrated, and the separated crystals were filtered to obtain 70.9 g of the title compound, yield 81%, m.p. 112.degree.-114.degree. C.

200 ml of ethanol was added to 10.95 g of the N-(2,3-epoxypropyl)endo-cis-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide obtained by the process (1) and 8.2 g of 1-(2-pyridyl)piperazine, and the mixture was heated under reflux for 3 hours. The desired compound separated on standing to cool, and this was filtered to obtain 17.8 g (yield 93%) of the title compound.

Melting point: 142.degree.-144.degree. C.

2.2 g of N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2- dicarboximde was dissolved in 1,2-dichloroethane, and 0.8 g of acetyl chloride was added to the solution, which was then heated under reflux for about 30 minutes. Thereafter, this was cooled to 0.degree. C., a 5% aqueous sodium carbonate solution was added to adjust the pH to 9, and the organic layer was separated. This was washed with water and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated. Then, ethyl acetate was added to the residue to dissolve. Then, a solution of 0.69 g of maleic acid dissolved in a mixed solvent of ethyl acetate and methanol was added to the solution, which was then heated under reflux for 5 minutes. The desired compound separated on standing to cool, and this was filtered to obtain 2.9 g (yield 93%) of the title compound.

Melting point: 144.degree.-147.degree. C.

1.86 g of N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2-dic arboximide was dissolved in 50 ml of 1,2-dichloroethane, and 1.2 g of n-decanoyl chloride was added to this solution, which was heated under reflux for an hour. Thereafter, 1,2-dichloroethane was distilled off under reduced pressure, ether and dilute hydrochloric acid were added with ice cooling and the mixture was stirred. The aqueous layer was separated, adjusted to pH 9 by adding a 5% aqueous sodium carbonate solution with ice cooling, and extracted with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. This was filtered, and the filtrate was concentrated, after which ethyl acetate was added to the residue to dissolve, and a solution of 1.16 g of maleic acid dissolved in a mixed solvent of ethyl acetate and methanol was added to the solution, which was then heated under reflux for 5 minutes. The desired compound separated on standing to cool, and this was filtered to obtain 3.4 g (yield 90%) of the title compound.

Melting point: 125.degree.-128.degree. C.

1.84 g of N-{2-hydroxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2-dicar boximide and 2.6 g of triethylamine were dissolved in 50 ml of 1,2-dichloroethane, and 1.4 g of nicotinyl chloride hydrochloride was added to this solution, which was heated under reflux for 2 hours. After cooling to 0.degree. C., water was added, the mixture was stirred, and then the organic layer was separated. This was washed with water, and then dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, 1.4 g of maleic acid and ethanol were added to the residue, and the mixture was heated under reflux for 5 minutes. The desired compound separated on standing to cool, and this was filtered to obtain 3.5 g (yield 91%) of the title compound.

Melting point: 165.degree. C. (dec.)

25 ml of toluene was added to 1.9 g of N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide, 1.5 g of n-butyl isocyanate and 1 ml of pyridine, and heated at 160.degree. C. using a sealed tube for 6 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, after which a solution of 1.16 g of maleic acid dissolved in a mixed solvent of ethyl acetate-methanol was added to the resulting solution, and heated under reflux for 5 minutes. The desired compound separated on standing to cool, and this was filtered to obtain 3.1 g (yield 87%) of the title compound.

Melting point: 144.degree.-146.degree. C.

25 ml of xylene was added to 1.85 g of N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2- dicarboximide and 2 g of cyclohexyl isocyanate, and heated at 180.degree. C. using a sealed tube for 8 hours. The xylene was distilled off under reduced pressure, and the residue was then dissolved in ethyl acetate, after which a solution of 1.16 g of maleic acid dissolved in a mixed solvent of ethyl acetate and methanol was added to this solution, and heated under reflux for 5 minutes. The desired compound separated on standing to cool, and this was filtered to obtain 3.2 g (yield 88%) of the title compound.

Melting point: 151.degree.-153.degree. C.

3.82 g of N-[2-hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]-endo-cis-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide was dissolved in 100 ml of 1,2-dichloroethane. To the solution was added 1.8 g of cyclohexanecarbonyl chloride. The whole was heated under reflux for 5 hours. The 1,2-dichloroethane was distilled off under reduced pressure. To the residue was added under ice-cooling a mixture of ether and diluted hydrochloric acid. The whole was stirred. The aqueous layer was recovered by separation. To the recovered solution was added under ice-cooling 5% aqueous sodium hydroxide solution, thereby making its pH to 10. The mixture was extracted with chloroform. The extract was washed with water, followed by dried over anhydrous magnesium sulfate. It was filtered, the filtrate was concentrated, the residue was recrystallized from ethanol to obtain 4.4 g of free amine compound, that is, N-[2-cyclohexylcarbonyloxy-3{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-b icyclo[2,2,1]hept-5-ene-2,3-dicarboxamide (melting point: 149.degree.-151.degree. C.). The resulting crystalline mass was dissolved in ethanol while hot. To the solution was added a solution which was previously prepared by diluting 2 g of concentrated hydrochloric acid with 100 ml of ethanol. The desired compound separated on standing to cool, and this was filtered to obtain 4.8 g (yield 85%) of the title compound.

Melting point: 241.degree.-243.degree. C. (dec.)

The above-mentioned compound was administered to 6 rats in a dosage of 39 mg/kg. The experimental method was carried out in a similar manner as described in Experiment 1. Improvement percent of glucose tolerance was thus obtained at 23% after 1 hour; 33% after 2 hours; and 37% after 3 hours, respectively.

The following compounds were obtained by procedures similar to those in Example 1.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2-d icarboximide fumarate

Melting point: 170.degree.-172.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2-dica rboximide maleate

Melting point: 159.degree.-161.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 146.degree.-148.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]exo-cis-bicyclo[2,2,1]he pt-5-ene-2,3-dicarboximide

Melting point: 191.degree.-192.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide

Melting point: 147.degree.-149.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2,2,2]o ct-5-ene-2,3-dicarboximide

Melting point: 156.degree.-158.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2,2,1]h eptane-2,3-dicarboximide

Melting point: 156.degree.-158.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-7-oxabicyclo[2, 2,1]heptane-2,3-dicarboximide maleate

Melting point: 179.degree.-181.degree. C.

N-{2-Hydroxy-3-(4-phenylhexahydro-1H-1,4-diazepin-1-yl)propyl}cis-cyclohex- 4-ene-1,2-dicarboximide

Melting point: 134.degree.-136.degree. C.

N-[2-Hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2 -dicarboximide maleate

Melting point: 172.degree. C. (dec.)

N-[2-Hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2-di carboximide maleate

Melting point: 191.degree. C. (dec.)

N-[2-Hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide

Melting point: 147.degree.-150.degree. C.

N-[2-Hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]exo-cis-bicyclo[2,2,1] hept-5-ene-2,3-dicarboximide

Melting point: 180.degree.-182.degree. C.

N-[2-Hydroxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]phthalimide

Melting point: 114.degree.-118.degree. C.

N-[3-{4-(2-benzothiazoyl)piperazin-1-yl}-2-hydroxypropyl]endo-cis-bicyclo[2 ,2,2]hept-5-ene-2,3-dicarboximide

Melting point: 160.degree.-163.degree. C.

N-[3-{4-<2-(4,6-Dimethyl)pyrimidyl>piperazin-1-yl}-2-hydroxypropyl]endo-cis -bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide

Melting point: 135.degree.-137.degree. C.

N-[3-{4-(3-Chlorophenyl)piperazin-1-yl}-2-hydroxypropyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide

Melting point: 134.degree.-135.degree. C.

N-[3-{4-(2-Benzothiazolyl)piperazin-1-yl}-2-hydroxypropyl]cis-cyclohex-4-en e-1,2-dicarboximide maleate

Melting point: 177.degree. C. (dec.)

N-[3-{4-<2-(4,6-Dimethyl)pyrimidyl>piperazin-1-yl}-2-hydroxypropyl]cis-cycl ohex-4-ene-1,2-dicarboximide maleate

Melting point: 157.degree.-159.degree. C.

N-[3-{4-(3-Chlorophenyl)piperazin-1-yl}-2-hydroxypropyl]exo-cis-bicyclo[2,2 ,1]heptane-2,3-dicarboximide

Melting point: 154.degree.-156.degree. C.

N-{2-Hydroxy-3-(4-phenylpiperazin-1-yl)propyl}exo-cis-bicyclo[2,2,1]hept-5- ene-2,3-dicarboximide maleate

Melting point: 179.degree.-180.degree. C.

N-[3-{4-(3-Chlorophenyl)piperazin-1-yl}-2-hydroxypropyl]exo-cis-bicyclo[2,2 ,1]hept-5-ene-2,3-dicarboxamide

Melting point: 152.degree.-154.degree. C.

N-[2-Hydroxy-3-{4-(2-methoxyphenyl)piperazin-1-yl}propyl]exo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide hemioxalate

Melting point: 220.degree. C. (dec.)

N-{2-Hydroxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2-dicarb oximide dimaleate

Melting point: 159.degree.-161.degree. C.

N-{2-Hydroxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohexane-1,2-dicarboxi mide dimaleate

Melting point: 156.degree.-159.degree. C.

N-{2-Hydroxy-3-(4-methylpiperazin-1-yl)propyl}endo-cis-bicyclo[2,2,1]hept-5 -ene-2,3-dicarboximide dimaleate

Melting point: 158.degree.-161.degree. C.

N-[2-Hydroxy-3-{4-(2-pyrimidyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]cis-cy clohex-4-ene-1,2-dicarboximide maleate

Melting point: 153.degree.-156.degree. C.

N-[2-Hydroxy-3-{4-(2-pyrimidyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]endo-c is-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide maleate

Melting point: 171.degree.-173.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide dimaleate

Melting point: 142.degree.-145.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]endo-cis -bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 152.degree.-155.degree. C.

N-{2-Hydroxy-3-(4-phenylhexahydro-1H-1,4-diazepin-1-yl)propyl}endo-cis-bicy clo[2,2,1]hept-5-ene-2,3-dicarboximide

Melting point: 124.degree.-126.degree. C.

N-[2-Hydroxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]-2,2-dimethylsuccinimide

Melting point: 131.degree.-132.5.degree. C.

N-[2-Hydroxy-3-(4-phenylpiperazin-1-yl)propyl]cis-cyclohex-4-ene-1,2-dicarb oximide

Melting point: 153.degree.-157.degree. C.

N-[2-Hydroxy-3-{4-(2-methylphenyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide

Melting point: 120.degree.-125.degree. C.

N-[3-{4-<2-(4,6-Dimethyl)pyrimidyl>piperazin-1-yl}-2-hydroxypropyl]phthalim ide

Melting point: 137.degree.-140.degree. C.

The following compounds were obtained by procedures similar to those in Example 2.

N-[2-Acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2-dica rboximide dimaleate

Melting point: 142.degree.-145.degree. C.

N-[2-Propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide dimaleate

Melting point: 139.degree.-142.degree. C.

N-[2-Acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 134.degree.-136.degree. C.

N-[2-Propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 152.degree.-154.degree. C.

N-[2-Acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2,2,1]h ept-5-ene-2,3-dicarboximide dimaleate

Melting point: 167.degree. C. (dec.)

N-[2-Propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 153.degree.-156.degree. C.

N-[2-Acetoxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dimaleate

Melting point: 173.degree.-176.degree. C.

N-[2-Acetoxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1,2 -dicarboximide maleate

Melting point: 175.degree. C. (dec.)

N-[2-Propionyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-en e-1,2-dicarboximide maleate

Melting point: 178.degree. C. (dec.)

N-[2-Acetoxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2-di carboximide maleate

Melting point: 189.degree. C. (dec.)

N-[2-Acetoxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2,2,1 ]hept-5-ene-2,3-dicarboximide maleate

Melting point: 169.degree. C. (dec.)

N-[2-Acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide

Melting point: 127.degree.-130.degree. C.

N-[2-Acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]exo-cis-bicyclo[2,2 ,1]hept-5-ene-2,3-dicarboximide oxalate

Melting point: 112.degree. C. (dec.)

N-[2-Acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide oxalate

Melting point: 160.degree. C. (dec.)

N-[2-Acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2 -dicarboximide oxalate

Melting point: 143.degree. C. (dec.)

N-[2-Propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide maleate

Melting point: 176.degree.-178.degree. C.

N-[2-Acetoxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]phthalimide

Melting point: 141.degree.-144.degree. C.

The following compounds were obtained by procedures similar to those in Example 3.

N-[2-Isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide dimaleate

Melting point: 136.degree.-139.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide dimaleate

Melting point: 146.degree.-148.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycloh ex-4-ene-1,2-dicarboximide dimaleate

Melting point: 157.degree. C. (dec.)

N-[2-n-Decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide dimaleate

Melting point: 122.degree.-125.degree. C.

N-[2-Palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide dimaleate

Melting point: 119.degree.-122.degree. C.

N-[3-{4-(2-Pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]cis-cyclohex- 4-ene-1,2-dicarboximide dimaleate

Melting point: 118.degree.-120.degree. C.

N-[2-(trans-2-Nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycloh ex-4-ene-1,2-dicarboximide dimaleate

Melting point: 123.degree.-126.degree. C.

N-[2-Benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene-1, 2-dicarboximide dimaleate

Melting point: 147.degree. C. (dec.)

N-[2-n-Octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene -1,2-dicarboximide dimaleate

Melting point: 116.degree.-119.degree. C.

N-[2-Cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide dimaleate

Melting point: 114.degree.-117.degree. C.

N-[2-Isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohexane-1, 2-dicarboximide dimaleate

Melting point: 145.degree.-147.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2 -dicarboximide dimaleate

Melting point: 146.degree.-148.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycloh exane-1,2-dicarboximide dimaleate

Melting point: 156.degree.-158.degree. C.

N-[2-Palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2 -dicarboximide dimaleate

Melting point: 128.degree.-131.degree. C.

N-[3-{4-(2-Pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]cis-cyclohexa ne-1,2-dicarboximide dimaleate

Melting point: 124.degree.-127.degree. C.

N-[2-Isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide maleate

Melting point: 164.degree.-165.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 149.degree.-150.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimid e maleate

Melting point: 167.degree.-169.degree. C.

N-[2-n-Decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 136.degree.-138.degree. C.

N-[2-Palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 133.degree.-135.degree. C.

N-[3-{4-(2-pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]succinimide dimaleate

Melting point: 135.degree.-136.degree. C.

N-[2-(trans-2-Nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimid e dimaleate

Melting point: 147.degree.-149.degree. C.

N-[2-Benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 174.degree.-177.degree. C.

N-[2-n-Octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]succinimide dimaleate

Melting point: 130.degree.-131.degree. C.

N-[2-Isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2 ,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 147.degree.-150.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 146.degree.-148.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-b icyclo[2,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 173.degree.-175.degree. C.

N-[2-n-Decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2 ,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 112.degree.-116.degree. C.

N-[2-(trans-2-Nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-b icyclo[2,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 130.degree.-132.degree. C.

N-[2-n-Octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2 ,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 106.degree.-110.degree. C.

N-[2-Cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 120.degree.-123.degree. C.

N-[2-Isobutyryloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide maleate

Melting point: 174.degree.-175.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dimaleate

Melting point: 165.degree.-166.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimid e maleate

Melting point: 135.degree.-137.degree. C.

N-[2-n-Decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dimaleate

Melting point: 138.degree.-140.degree. C.

N-[2-Palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dimaleate

Melting point: 134.degree.-136.degree. C.

N-[3-{4-(2-Pyridyl)piperazin-1-yl}-2-(10-undecenoyloxy)propyl]phthalimide maleate

Melting point: 157.degree.-159.degree. C.

N-[2-(trans-2-Nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimid e maleate

Melting point: 138.degree.-140.degree. C.

N-[2-Benzoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dimaleate

Melting point: 195.degree. C. (dec.)

N-[2-n-Octanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dimaleate

Melting point: 135.degree.-137.degree. C.

N-[2-Cinnamoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dimaleate

Melting point: 159.degree.-162.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,2]oct-5-ene-2,3-dicarboximide dimaleate

Melting point: 138.degree.-140.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-b icyclo[2,2,2]oct-5-ene-2,3-dicarboximide dimaleate

Melting point: 150.degree.-152.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]heptane-2,3-dicarboximide dimaleate

Melting point: 132.degree.-134.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-7-oxabicyc lo[2,2,1]heptane-2,3-dicarboximide dimaleate

Melting point: 157.degree.-158.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-7 -oxabicyclo[2,2,1]heptane-2,3-dicarboximide dimaleate

Melting point: 175.degree.-177.degree. C.

N-[2-Isobutyryloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-e ne-1,2-dicarboximide maleate

Melting point: 178.degree. C. (dec.)

N-[2-n-Caproyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-en e-1,2-dicarboximide maleate

Melting point: 145.degree.-147.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide maleate

Melting point: 173.degree.-174.degree. C.

N-[2-Benzoyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide maleate

Melting point: 193.degree. C. (dec.)

N-[2-Isobutyryloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cyclohexane- 1,2-dicarboximide maleate

Melting point: 154.degree.-155.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyrimidyl)piperazin-1-yl}propyl]cis-cycl ohexane-1,2-dicarboximide

Melting point: 169.degree.-171.degree. C.

N-[2-n-Caproyloxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]endo-cis-bicyc lo[2,2,1]hept-5-ene-2,3-dicarboximide oxalate

Melting point: 154.degree. C. (dec.)

N-[2-Benzoyloxy-3-{4-(3-chlorophenyl)piperazin-1-yl}propyl]endo-cis-bicyclo [2,2,1]hept-5-ene-2,3-dicarboximide oxalate

Melting point: 190.degree. C. (dec.)

N-{2-Isobutyryloxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2- dicarboximide dimaleate

Melting point: 178.degree.-180.degree. C.

N-{2-n-Caproyloxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohex-4-ene-1,2-d icarboximide dimaleate

Melting point: 181.degree. C. (dec.)

N-{2-Isobutyryloxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohexane-1,2-dic arboximide dimaleate

Melting point: 174.degree. C. (dec.)

N-{2-n-Caproyloxy-3-(4-methylpiperazin-1-yl)propyl}cis-cyclohexane-1,2-dica rboximide dimaleate

Melting point: 176.degree. C. (dec.)

N-{2-n-Caproyloxy-3-(4-methylpiperazin-1-yl)propyl}endo-cis-bicyclo[2,2,1]h ept-5-ene-2,3-dicarboximide dimaleate

Melting point: 180.degree.-182.degree. C.

N-{2-n-Caproyloxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]cis -cyclohex-4-ene-1,2-dicarboximide dimaleate

Melting point: 98.degree.-101.degree. C.

N-[2-(3-Phenylpropionyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis- bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 122.degree.-124.degree. C.

N-[2-(3-Phenylpropionyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclo hex-4-ene-1,2-dicarboximide dimaleate

Melting point: 124.degree.-127.degree. C.

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]end o-cis-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 110.degree.-113.degree. C.

N-[2-n-Caproyloxy-3{4-(2-(4,6-dimethyl)pyrimidyl<piperazin-1-yl}propyl]phth alimide maleate

Melting point: 166.degree.-167.5.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-methylphenyl)piperazin-1-yl}propyl]endo- cis-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide maleate

Melting point: 206.5.degree. C. (dec.)

N-{2-Cyclohexylcarbonyloxy-3-(4-phenylpiperazin-1-yl)propyl}cis-cyclohex-4- ene-1,2-dicarboximide maleate

Melting point: 167.degree.-169.degree. C.

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]2,2-dimeth ylsuccinimide dimaleate

Melting point: 150.degree.-154.degree. C.

The following compounds were obtained by procedures similar to those in Example 4.

N-{3-(4-Methylpiperazin-1-yl)-2-nicotinyloxypropyl}endo-cis-bicyclo[2,2,1]h ept-5-ene-2,3-dicarboximide dimaleate

Melting point: 178.degree. C. (dec.)

N-[2-Nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide maleate

Melting point: 189.degree. C. (dec.)

N-[2-Nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide maleate

Melting point: 203.degree. C. (dec.)

N-[2-Nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohexane-1,2 -dicarboximide maleate

Melting point: 193.degree. C. (dec.)

N-[2-Nicotinyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cyclohex-4-ene- 1,2-dicarboximide maleate

Melting point: 183.degree. C. (dec.)

The following compounds were obtained by procedures similar to those in Example 5.

N-[2-n-Butylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide dimaleate

Melting point: 138.degree.-141.degree. C.

The following compounds were obtained by procedures similar to those in Example 6.

N-[2-n-Decylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cis-cycl ohex-4-ene-1,2-dicarboximide dimaleate

Melting point: 124.degree.-127.degree. C.

N-[2-n-Decylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis -bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide dimaleate

Melting point: 105.degree.-108.degree. C.

N-[2-Cyclohexylaminocarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo- cis-bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide maleate

Melting point: 147.degree.-151.degree. C.

The following compounds were obtained by procedures similar to those in Example 7.

N-[2-Propionyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dihydrochloride

Melting point: 240.degree.-242.degree. C. (dec.)

N-[2-n-Caproyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]endo-cis-bicyclo[2, 2,1]hept-5-ene-2,3-dicarboximide dihydrochloride

Melting point: 242.degree.-244.degree. C. (dec.)

N-[2-Cyclohexylcarbonyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]-cis-cyclo hex-4-ene-1,2-dicarboximide dihydrochloride

Melting point: 237.degree.-239.degree. C. (dec.)

N-[2-n-Decanoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]cyclohexane-1,2-di carboximide dihydrochloride

Melting point: 191.degree.-196.degree. C.

N-[2-Palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl)}propyl]endo-cis-bicyclo[2 ,2,1]hept-5-ene-2,3-dicarboximide dihydrochloride

Melting point: 186.degree.-190.degree. C.

N-[2-Palmitoyloxy-3-{4-(2-pyridyl)piperazin-1-yl}propyl]phthalimide dihydrochloride

Melting point: 184.degree.-188.degree. C.

N-[2-(trans-2-Nonenoyloxy)-3-{4-(2-pyridyl)piperazin-1-yl}propyl]-endo-cis- bicyclo[2,2,1]hept-5-ene-2,3-dicarboximide dihydrochloride

Melting point: 164.degree.-168.degree. C.

Examples of preparations containing representative compounds of the present invention are illustrated below.

According to conventional manner, the above respective ingredients were mixed into a granular form, and compression molded to give tablets, each containing 200 mg.

Using the above formulation and according to conventional manner, capsules, each containing 100 mg, were produced.