JPH0128756B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to bicyclocyclic dicarboxylic acid imide derivatives substituted with piperazinyl alkyls at the N-position. More specifically, the present invention discloses the general formula [] which has an anxiolytic effect and is useful as an anxiolytic drug. [In the formula, A represents a methylene chain, an ethylene chain or an oxygen atom, n represents an integer of 3 or 4, and R represents a 2-pyrimidinyl group. Further, the dotted line () in the bicyclo ring system indicates a single bond or a double bond. ] The present invention relates to a cyclic imide derivative represented by the above and a pharmaceutically acceptable acid addition salt thereof. The present invention includes all stereoisomers of the compound represented by the general formula [] and mixtures thereof. In the compound of general formula [], two isomers exist unless A is a methylene chain and the dotted line portion ( ) of the bicyclo ring system is a single bond. The distinction between isomers is determined by the mutual position between the imide group and the bridging group attached to the 2- and 3-positions of the bicyclo ring system. That is, if the imide group is on the same side as the bridging group, the general formula [a] [In the formula, A' has the same meaning as A' above, but when the dotted line () in the bicyclo ring system is a single bond, it represents something other than a methylene chain. n, R and the dotted line of the bicyclo ring system have the same meanings as above. ] If it is an exo isomer represented by the general formula [b] and the imide group is on the opposite side of the bridging group, [In the formula, A', n, R and the dotted line ( ) of the bicyclo ring system have the same meanings as above. ] It is an endo isomer represented by Pharmaceutically acceptable acid addition salts of compounds of general formula [] include inorganic or organic acids commonly used for this purpose, such as hydrogen chloride, hydrogen bromide, sulfuric acid,
It is formed together with phosphoric acid, acetic acid, butyric acid, propionic acid, tartaric acid, citric acid, maleic acid, fumaric acid, etc. The compound of the present invention can be synthesized by various methods, for example, by the following method. [In the reaction formula, A, n and R have the same meanings as above. ] According to the method of route A, the acid anhydride of the general formula [A] and the compound of the general formula [] are reacted to obtain the compound of the general formula [A]. If desired, it can be converted into a compound of general formula [B] by reducing the double bond. On the other hand, in the method of route B, the compound of general formula [A] is first reduced to form an acid anhydride derivative of general formula [B], and then the compound of general formula [B] is reacted with the compound of general formula A compound of formula [B] is obtained. The reaction between the acid anhydride of general formula [A] or [B] and the amine of general formula [] is generally carried out by heating in an inert organic solvent. A preferred solvent is pyridine. Depending on the compound, general formula [A] or [
The general formula [] that is first produced by the reaction of the acid anhydride of B] and the amine of the general formula [] [In the formula, A, n, R and the dotted line ( ) of the bicyclo ring system have the same meanings as above. ] It may take a long time to cyclize the half amide derivative represented by. In such a case, the half amide of the general formula [] can be easily converted into a cyclized compound of the general formula [] by heating in acetic anhydride. For the reduction of the compound of general formula [A] or [A], a wide range of conditions can be employed that normally reduce double bonds. Among these, it is advantageous to use catalytic reduction, which is carried out by hydrogenation in a solvent in the presence of a catalyst. Catalysts that are commonly used for hydrogenation reactions include platinum catalysts such as platinum black, platinum oxide, and colloidal platinum, palladium catalysts such as palladium black, palladium carbon, and colloidal palladium, rhodium catalysts, and nickel catalysts such as Raney nickel and nickel oxide. Can be mentioned. Examples of the solvent used include lower alcohols such as methanol, ethanol, and isopropanol, water, acetic acid, acetic acid ester, tetrahydrofuran, and dioxane. The hydrogenation reaction easily proceeds at room temperature under normal pressure in a hydrogen stream, but the reaction can also be carried out under increased pressure or heating. Specific examples of the compounds of the present invention include the following. N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide hydrochloride N-[3-{4-(2 -pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide hydrochloride N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl] Bicyclo[2.2.1]heptane-2,3-di-endo-carboximide hydrochloride N-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]heptane-2, 3-di-endo-carboximide hydrochloride N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.2]octane-2,3-dicarboximide hydrochloride N-[ 4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]-7-oxabicyclo[2.2.1]heptane-2,3-di-exo-carboximide hydrochloride N-[4-{4-( 2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]hepta-
5-ene-2,3-di-exo-carboximide hydrochloride N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]hepta-
5-ene-2,3-di-endo-carboximide hydrochloride N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.2]octa-
5-ene-2,3-di-endo-carboximide hydrochloride N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]-7-oxabicyclo[2.2.1]hepta-5- En-2,3-di-exo-carboximide hydrochloride The anxiolytic effects of the compounds of the present invention can be demonstrated by anti-conflict tests in rats. For example, one of the compounds of the present invention N-[4-{4-(2
-pyrimidinyl)-1-piperazinyl}butyl]
Bicyclo[2.2.1]heptane-2,3-di-exo-carboximide showed an anti-conflict effect, that is, an anxiolytic effect, comparable to that of the known anxiolytic drug diazepam, and both had little effect on general behavior. . On the other hand, when looking at the hexobarbital anesthesia enhancing effect, which is an indicator of central depressant side effects such as drowsiness, the above-mentioned compound of the invention showed almost no enhancing effect, unlike diazepam. Based on these facts, it can be said that the above-mentioned compound of the invention is a selective anxiolytic drug with weak central depressant side effects. In addition, in comparison with the known anxiolytic drug buspirone, the above-mentioned inventive compound has the same anti-conflict effect, but when looking at the anti-dopamine effect, which is thought to cause extrapyramidal side effects, it exhibits anti-apomorphine stereotypy. In terms of action, the above-mentioned inventive compounds exhibited much less action. Due to these, the above-mentioned invention compound has the following properties:
It can be said that it is an anxiolytic drug that has a more selective anxiolytic effect. Next, the method of the present invention will be explained with reference to examples, but these are merely examples, and it goes without saying that the method is not limited thereto. Example 1 N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]heptane-2,3-di-endo-carboximide hydrochloride norbornane-2,3-di -Endo-carboxylic anhydride 500 mg (3 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine
A mixture of 708 mg (3 mmol) and 12.1 ml of pyridine was refluxed for 5 hours. Then, the reaction solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel using chloroform as an eluent. The resulting oil was treated with 6% hydrochloric acid/isopropyl alcohol to give the hydrochloride. After distilling off the solvent, recrystallization was performed with isopropyl alcohol to obtain 920 mg (yield 67.2%) of the title compound. Melting point 202-203°C Example 2 N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide hydrochloride norbornane- 2,3-di-exo-carboxylic anhydride 636 mg (3.8 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine
A mixture of 900 mg (3.8 mmol) and 15.4 ml of pyridine was refluxed for 11 hours. Subsequently, the same post-treatment as in Example 1 was carried out to obtain the title compound having a melting point of 227-229°C (recrystallization solvent isopropyl alcohol). Example 3 N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.2]octane-2,3-dicarboximide hydrochloride Bicyclo[2.2.2]octane-2, A mixture of 541 mg (3 mmol) of 3-dicarboxylic anhydride, 708 mg (3 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 12.1 ml of pyridine was refluxed for 10 hours. Then, the reaction solvent was distilled off under reduced pressure, and the residue was extracted with chloroform and water. Dilute the chloroform layer with magnesium sulfate (anhydrous)
After drying, the solvent was distilled off under reduced pressure to obtain 1 g of crude crystals. The obtained crude crystals were treated with 6% hydrochloric acid/isopropyl alcohol to form a hydrochloride. The solvent was distilled off under reduced pressure to obtain the title compound. Melting point 198-200°C (recrystallization solvent ethyl alcohol) Example 4 N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]-7-oxabicyclo[2.2.1]heptane-2,3 -di-exo-carboximide hydrochloride 7-oxabicyclo[2.2.1]heptane-2,
3-di-exo-carboxylic anhydride 1 g (5.95 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine 1.4 g (5.95 mmol)
and 23.9 ml of pyridine was refluxed for 12 hours. Next, the same post-treatment as in Example 1 was carried out, and the melting point
210-213℃ (reconsolidation solvent isopropyl alcohol)
The title compound was obtained. Example 5 N-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboximide hydrochloride bicyclo[2.2 .1] Hepta-5-ene-2,3
-di-exo-carboxylic acid anhydride 2.2 g (13.56 mmol), 1-(3-aminopropyl)-4-(2-
3 g (13.56 mmol) of pyrimidinylpiperazine
and 53 ml of pyridine was refluxed for 7 hours.
Next, the reaction solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and filtered through silica gel. The filtrate was distilled off under reduced pressure to obtain 3.91 g (78% yield) of crystals. The obtained crystals were treated with 5% hydrochloric acid/isopropyl alcohol to form a hydrochloride. After distilling off the solvent, recrystallization was performed with isopropyl alcohol to obtain the title compound having a melting point of 209-212°C. Example 6 N-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide hydrochloride N-[3-{4 2.7 g (7.35 mmol) of -(2-pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboximide, 270 mg of 5% palladium on carbon and 27 ml of tetrahydrofuran. The mixture was hydrogenated for 2 hours. Next, the reaction solution was filtered, and the filtrate was distilled off under reduced pressure to obtain crude crystals. The obtained crude crystals were converted into hydrochloride with 5% hydrochloric acid/isopropyl alcohol. After distilling off the solvent, recrystallization was performed with ethyl alcohol/isopropyl alcohol to obtain the title compound having a melting point of 216-217°C. Example 7 N-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]hept-5-ene-2,3-di-endo-carboximide hydrochloride Bicyclo[2.2 .1] Hepta-5-ene-2,3
A mixture of 1.76 g (11 mmol) of -di-endo-carboxylic acid anhydride, 2.37 g (11 mmol) of 1-(3-aminopropyl)-4-(2-pyrimidinyl)piperazine and 43 ml of pyridine was refluxed for 13 hours. Then, the reaction solvent was distilled off under reduced pressure, and the residue was subjected to the same post-treatment as in Example 1 to obtain the title compound having a melting point of 244-245.5°C (recrystallization solvent isopropyl alcohol). Example 8 N-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]heptane-2,3-di-endo-carboximide hydrochloride N-[3-{4 -(2-pyrimidinyl)-1-piperazinyl}propyl]bicyclo[2.2.1]hept-5-ene-2,3-di-endo-carboximide 3.4 g (9.25 mmol), 5% palladium on carbon 340 mg and tetrahydrofuran 34 ml The mixture was hydrogenated for 3 hours. Subsequently, the same post-treatment as in Example 6 was carried out to obtain the title compound having a melting point of 228 to 230°C (recrystallization solvent isopropyl alcohol). Example 9 The following compound was synthesized in the same manner as in Example 5. N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]hepta-
5-ene-2,3-di-exo-carboximide hydrochloride mp.259-260°C Test Example 1 Anti-conflict effect test Compound of the present invention N-[4-{4-(2-pyrimidinyl)-1-piperazinyl} The effective anti-conflict effect dose of butyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide hydrochloride (compound A) was determined. Conflict testing is Geller and Seifter
Rats were trained to develop conflict behavior based on the method of Psychopharmacollogia, 1 , 482 (1960), and diazepam and buspirone were used as control drugs. The results are as follows.

[Table] Test Example 2 Hexobarbital anesthesia enhancing effect test The effective dose of hexobarbital anesthesia enhancing effect of the compound A of the present invention was determined. The exam was conducted by Nakamura, et al. [Archives internationales
Pharmacodynamie et de Therapie, 229 ,
163 (1977)] using mice and using diazepam as a control drug. The results are as follows.

[Table] Test Example 3 Antidopamine Effect Test As an antidopamine effect test of Compound A of the present invention, the ED ₅₀ value of the stereotypic behavior suppressing effect (anti-Apomorphine stereotypic behavior effect) induced in rats by Apomorphine was measured. . The test was carried out by Yamamoto et al. [Arzneim-Forst., 24 , 1248]
(1947)] using buspirone as a control drug. The results are as follows.

【table】

Claims (1)

[Claims] 1. General formula [In the formula, A represents a methylene chain, an ethylene chain or an oxygen atom, n represents an integer of 3 or 4, and R represents a 2-pyrimidinyl group. Further, the dotted line () in the bicyclo ring system indicates a single bond or a double bond. ] A cyclic imide derivative represented by or a pharmaceutically acceptable acid addition salt thereof. 2 A is a methylene chain or an ethylene chain and n is 4
or a pharmaceutically acceptable acid addition salt thereof, which is an integer of . 3. The compound according to claim 1, wherein A is a methylene chain and n is an integer of 4, or a pharmaceutically acceptable acid addition salt thereof. 4 N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide according to claim 1 A compound or a pharmaceutically acceptable acid addition salt thereof. 5 N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.1]heptane-2,3-di-endo-carboximide according to claim 1 A compound or a pharmaceutically acceptable acid addition salt thereof. (6) General formula [In the formula, A represents a methylene chain, an ethylene chain, or an oxygen atom, and the dotted line () in the bicyclo ring system represents a single bond or a double bond. ] The compound represented by and the general formula [In the formula, n represents an integer of 3 or 4, and R represents a 2-pyrimidinyl group. ] A general method characterized in that when the dotted line ( ) of a bicyclo ring system requires a single bond, it can also be obtained by reducing the double bond. formula [In the formula, A, n, R and the dotted line ( ) of the bicyclo ring system have the same meanings as above. ] A method for producing a cyclic imide derivative represented by or a pharmaceutically acceptable acid addition salt thereof.