JPH0687854A - New piperdine derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound, having antidement, antiischemic and antidepressant actions and useful as an antidepressant agent and a therapeutic agent for sequelae of cerebral angiopathy. CONSTITUTION:The piperidine derivative of formula I (X<1> and X<2> are lower alkyl, lower alkoxy or halogen), e.g. 1-[3-{4-(3,4-dichlorophenyl)piperidin-1- yl}propylcarbamoyl]-2-oxopyrrolidine. This compound of formula I is obtained by reducing a compound of formula II (R is amino-protecting group), etc., providing a compound of formula III and then reacting the resultant compound of formula III with 1-{3-(chloropropyl)carbamoyl}-2-oxopyrrolidine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel piperidine derivative having antidepressant action, antiischemic action and the like and a method for producing the same.

[0002]

2. Description of the Related Art In order to improve consciousness disorder, memory disorder, cognitive decline and various dementia symptoms caused by cerebral dysfunction or organic organ disorder, conventional consciousness disorder improving drug, psychotropic drug or anti-dementia Many medicines have been developed. Further, the present applicant has already disclosed a carbamoylpyrrolidone derivative useful in senile dementia in JP-A-1-131155, and a tetrahydropyridine derivative having psychoactive activity in Japanese Patent Application No. 3-47656. Disclosure.

[0003]

The present inventors have found that (1) it has a strong serotonin reuptake inhibitory action, and (2) it strongly suppresses delayed neuronal necrosis due to intracerebral ischemia. ) I aimed to create a compound with a low enzyme-inducing action and a method for producing the same. These actions will be described in more detail below.

(1) It has been conventionally known that compounds that inhibit the reuptake of serotonin show antidepressant action (J.
Clin. Psychiatry 55; 3, March 1992). That is, known antidepressants such as imipramine and amitriptyline inhibit the amine pump that takes in serotonin released from the serotonin-acting nerve endings of the central nervous system to the nerve terminal side, and thus increases serotonin concentration in the synaptic cleft. .

(2) Intracerebral ischemia is a particularly strong local anemia found in the brain, in which brain tissue suffering from ischemia shows dysfunction and, if sustained for a long time, the cells become degenerated and necrotic. Fall.

(3) In addition, depending on the drug, an increase in liver weight may be observed after administration. This is due to an increase in smooth endoplasmic reticulum (SER) of liver microsomes. In this SER, there is a system of drug-metabolizing enzymes, and the administration of drugs enhances the activity of enzymes involved in metabolism. ,
Induction of drug-metabolizing enzymes occurs, which reduces the duration of action of the drug. With respect to this inducing action, no pharmacological or structural correlation of the compound has been found, but the compound of the present invention is a useful compound having a small enzyme inducing action.

[0007]

DISCLOSURE OF THE INVENTION As a result of earnest research in consideration of the above-mentioned circumstances, the inventors of the present invention have obtained formula ( b ):

[Chemical 6] (In the formula, X ¹ and X ² each independently represent lower alkyl, lower alkoxy or halogen. R represents an amino protecting group.) Or a compound represented by the formula ( c ′ ) :

[Chemical 7] (In the formula, X ¹ , X ² and R have the same meanings as described above.) After reacting the compound in the presence of a Lewis acid,
If necessary deprotection formula ( d ):

[Chemical 8] (Wherein, X ¹ and X ² have the same meanings as described above), and the compound is represented by 1- {3- (chloropropyl).
A compound of formula (I) by reacting with carbamoyl} -2-oxopyrrolidine:

[Chemical 9] (Wherein, X ¹ and X ² are as defined above) or a pharmaceutically acceptable acid addition salt thereof is obtained, and the compound of the formula (I) or pharmaceutically acceptable salt is obtained. The acid-addition salt tolerated by the above-mentioned target (1) has a strong serotonin reuptake inhibitory effect, and (2) strongly suppresses delayed neuronal necrosis due to intracerebral ischemia, (3) The present invention has been completed by finding that the enzyme-inducing action is small. That is, the present invention provides an excellent compound which is extremely useful as an antidepressant drug, an anti-dementia drug, a therapeutic drug for sequelae of cerebrovascular accidents, and does not show a decrease in pharmacological activity even after long-term continuous use, and a method for producing the same. To do. Furthermore, the compound of the present invention is particularly excellent in antidepressant action and cerebral nerve cell necrosis inhibitory action during ischemia.

In the present specification, lower alkyl means C ₁ -C ₆ linear or branched alkyl, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, tert
-Pentyl, 2-methylbutyl, n-hexyl, isohexyl and the like.

The lower alkoxy means C ₁ -C ₆ alkoxy, and specific examples thereof include methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy. Halogen means fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and acetic acid, formic acid, propionic acid, succinic acid, fumaric acid, maleic acid, tartaric acid and citric acid. , And salts with organic acids such as oxalic acid, but salts with oxalic acid and maleic acid are particularly preferable.

The method for producing the compound of the present invention is shown below.

[Chemical 10] (In the formula, X ¹ , X ² and R have the same meanings as described above.) (1) Compound a is reacted with a suitable reagent in the presence of a base in a suitable organic solvent to form an amino group of tetrahydropyridine. Protecting gives compound b . This reaction is 10
It is preferable to carry out the reaction at ˜150 ° C., preferably near room temperature for 1 to 20 hours, preferably 3 to 7 hours. Examples of the organic solvent include alcohols such as methanol and ethanol,
Ethers such as diethyl ether and tetrahydrofuran, dimethylformamide, acetonitrile, methylene chloride and the like are used. As the base, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, pyridine, triethylamine and the like are used. As the amino-protecting group, as long as it can be removed without catalytic reduction, those usually used, for example, benzoyl, acetyl, formyl, acyl derivatives such as trifluoroacetyl, benzyloxycarbonyl, tert-butoxycarbonyl, etc. Examples thereof include urethane-type derivatives such as isopropoxycarbonyl, methoxycarbonyl and ethoxycarbonyl, and alkyl derivatives such as allyl, benzyl, trityl and tetrahydropyranyl, and tert-butoxycarbonyl is particularly preferable.

(2) Compound c is obtained by hydrogenating compound b in a suitable organic solvent, preferably in the presence of a catalyst.
To get This reaction is carried out at 10 to 150 ° C., preferably around room temperature. The same organic solvent as that used in (1) is used. As the catalyst, a commonly used hydrogenation catalyst, that is, platinum, iron, nickel,
Oxides such as copper and sulfides are used, but platinum oxide is particularly preferable in this reaction.

[0013] (3) The compound c trifluoroacetic acid - anisole - presence of Le, the ordinary process to obtain a compound d by subjecting the deprotection reaction. This reaction is carried out at 10 to 100 ° C., preferably around room temperature.

The compound d can also be synthesized as follows.

[Chemical 11] Compound c ′ (synthesized by the method described in JP-B-45-5266) is added to a suitable solvent in the presence of a Lewis acid such as AlCl ₃ at −50 to 150 ° C., preferably around ice-room temperature. in to give the compound c by treating with trialkyltin halides such as Et ₃ SnH, obtain more suitable organic solvent c, and compound d by heating in the presence of a base. The same organic solvent and base as in (1) are used.

(4) Compound (I) is obtained by reacting compound d with 1-{(3-chloropropyl) carbamoyl} -2-oxopyrrolidine in the presence of a base in a suitable solvent.
To get This reaction is 50 to 300 ° C., preferably 90 to 1
It is carried out at 20 ° C. for 1 to 20 hours, preferably 5 to 8 hours. As the suitable solvent, the same solvent as in (1) is used, but dimethylformamide is preferable in this reaction. As the base, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, pyridine, triethylamine and the like are used, but potassium carbonate is most preferable in this step.

The compound of the present invention can be administered orally or parenterally. In the case of oral administration, the compound of the present invention is in the form of a usual preparation, for example, a solid preparation such as tablet, powder, capsule or granule, or liquid preparation such as aqueous or oily suspension, syrup or elixir. Can also be used as For parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection. In its preparation, any of the conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents and the like can be used, and other additives such as preservatives, It may contain a stabilizer or the like.

The dose of the compound of the present invention varies depending on the administration method, age, weight, condition of patient and kind of disease, but usually 5 to 10 per day orally for adults.
The amount is 00 mg, preferably 20 to 200 mg, and parenterally, it is 1 to 500 mg, preferably 5 to 50 mg per day, which may be administered in 1 to 5 divided doses.

The present invention will be described in more detail below with reference to Examples and Reference Examples, but the scope of the present invention is not limited by these. The abbreviations used in the examples have the following meanings. Boc: tert-butoxycarbonyl DMF: dimethylformamide

EXAMPLE 1 Example 1 1- [3- {4- (3,4-dichlorophenyl) piperi
1-yl} pro Pi] -2- oxo
Pyrrolidine (I)

[Chemical 12] (1) 4- (3,4-dichlorophenyl) -1-tert-
Butoxycarbonyl-1,2,3,6-tetrahydropyri
Gin 2 compound 1 1.49 g (6.36 mM), a mixture of di-tert-butoxycarbonylanhydride 1.61 ml (7.0 mM) and triethylamine 0.89 ml (6.36 mM) in methylene chloride solution (13 ml) at room temperature. Stir for hours. The reaction mixture is poured into ice-cooled hydrochloric acid, the organic layer is separated, and the remaining aqueous layer is extracted with methylene chloride. The organic layers thus obtained are combined, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 24/1) to give compound 2 2.
057 g (yield: 98.6%) is obtained as a pale yellow oil. IR (CHCl ₃ ) cm ⁻¹ : 1680, 1550, 1423, 1364 NMR (CDCl ₃ ) δ: 1.491 (s, 9H); 2.38-2.54 (m, 2
H); 3.629 (t, J = 6Hz, 2H); 4.073 (q, J = 3Hz, 2H); 6.0
55 (brs, 1H); 7.173, 7.215 (ABq, J = 2Hz, 1H); 7.391
(d, J = 8Hz, 1H); 7.442 (d, J = 2Hz, 1H)

(2) 4- (3,4-dichlorophenyl)
-1-tert-Butoxycarbonyl-1 -piperidine 3 50 ml of a solution of 3.331 g (10.15 mM) of compound 2 obtained in methanol are hydrogenated in the presence of 398 mg of platinum oxide at room temperature. After removing the catalyst and solvent, the residue is poured into aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer is dried over magnesium sulphate and evaporated under reduced pressure. Silica gel column chromatography of the residue
Purification with (toluene / ethyl acetate = 24/1) gives 2.70 g (yield: 76.2%) of compound 3 as a colorless oil. IR (CHCl ₃ ) cm ⁻¹ : 1673, 1471, 1463, 1437, 1422, 1
361 NMR (CDCl ₃ ) δ: 1.480 (s, 9H); 1.592 (td, J ₁ = 1
3Hz, J ₂ = 4Hz, 2H); 1.797 (d, J = 11Hz, 2H); 2.51-2.71
(m, 1H); 2.783 (td, J ₁ = 12Hz, J ₂ = 2Hz, 2H); 4.244
(d, J = 13Hz, 2H); 7.013,7.054 (ABq, J = 2Hz, 1H); 7.2
87 (d, J = 2Hz, 1H); 7.369 (d, J = 8Hz, 1H)

(3) 4- (3,4-dichlorophenyl)
Piperidine 4 2 ml of the compound 3 obtained (8.20 mM), 5 ml of a mixture of 5 ml of trifluoroacetic acid and 0.5 ml of anisole in 5 ml of methylene chloride are stirred at room temperature for 55 minutes. After removing the reagents and solvent, the residue is poured into sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride-methanol-ammonia = 128/12 / 1-128 / 16/1).
To obtain 1.12 g (yield: 59.2%) of a maleic acid salt of compound 4 as a colorless oil. The maleate salt is recrystallized from methanol-ether to obtain colorless plate crystals. Melting point: 154.0-155.5 ° C Elemental analysis value (%) Calculated as C ₁₁ H ₁₃ C ₁₂ N ・ C ₄ H ₄ O ₄ C: 51.84; H, 4.96; N, 4.13; Cl, 20.40 Actual measurement Value: C, 52.04; H, 4.95; N, 4.05; Cl, 20.48 IR (Nujol) cm ^-1 : 3261, 2770, 2710, 2575, 2485, 1
701, 1638, 1618, 1574, 1556 (sh), 1522, 1478, 1463,
1448, 1378 NMR (CD ₃ OD) δ: 1.72-2.00 (m, 2H); 2.081 (d, J =
14Hz, 2H); 2.81-3.03 (m, 1H); 3.130 (td, J ₁ = 13Hz,
J ₂ = 3Hz, 2H); 3.507 (d, J = 12Hz, 2H); 6.259 (s, 2H);
7.196, 7.237 (ABq, J = 2Hz, 1H); 7.453 (d, J = 2Hz, 1
H); 7.487 (d, J = 8Hz, 1H)

(4) 4- (3,4-dichlorophenyl)
Separate synthesis of piperidine 4

[Chemical 13] 2.56 g (22 mM) of Et ₃ SiH was dissolved in 5 ml of methylene chloride under ice cooling, and 2.1 g of AlCl ₃ was added to the solution.
Add (15.7 mM) and stir for 10 minutes. Compound 3 ' (described in JP-B-45-5266, Raw Material Preparation Example 2) 1 g (3.1 mM) methylene chloride 20 ml
The solution is added dropwise under ice cooling, stirred at the same temperature for 50 minutes, then returned to room temperature and stirred for 5 hours. The reaction solution is poured into an aqueous solution of sodium carbonate, the precipitate (Al (OH) ₃ ) is filtered off with Celite, washed with water and saturated brine in that order, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl ₃ / MeOH /
It was purified by NH ₄ OH = 128/16/1) to obtain 0.4 g (55%) of compound 4 in crystalline form.

(5) 1- [3- {4- (3,4-dichloro)
Phenyl) piperidin-1-yl} pro Pirukarubamoi
Lu] -2-oxopyrrolidine (I) Obtained compound 4 1.062 g (4.61 mM), 1-{(3
-Chloropropyl) carbamoyl} -2-oxopyrrolidine 9
44 mg (4.61 mM), potassium carbonate 1.238 g (9.
22 mM), 1.037 g NaI (6.92 mM) and 15 ml DMF and stir at 105 ° C. for 6.5 hours.
The reaction mixture is poured into ice water and extracted with ethyl acetate.
The organic layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. Silica gel column chromatography of the residue
(Methylene chloride-methanol-ammonia water = 128 /
12 / 1-128 / 16/1) to obtain 1.415 g (yield: 77.0%) of the hydrochloride of compound (I). The obtained hydrochloride is recrystallized from methanol-ether to obtain colorless plate crystals. Melting point: 225.0 to 231.0 ° C. Elemental analysis value (%) Calculated as C ₁₉ H ₂₅ C ₁₂ N ₃ O ₂ .HCl: C, 52.32; H, 6.00; N, 9.77; Cl, 24.54 Measured value: C, 52.49; H, 6.03; N, 9.66; Cl, 24.46 IR (Nujol) cm ^-1 : 3303, 2635, 2575, 2538, 2507, 2
420, 1713, 1619, 1541, 1483, 1462, 1442 (sh), 1411,
1400, 1378 NMR (CDCl ₃ ) δ: 1.52-1.90 (m, 6H); 1.90-2.15
(m, 4H); 2.35-2.55 (m, 1H); 2.435 (t, J = 7Hz, 2H);
2.614 (t, J = 8Hz, 2H); 3.036 (d, J = 12Hz, 2H); 3.34
6, 3.409 (ABq, J = 7Hz, 2H); 3.865 (t, J = 7Hz, 2H);
7.044, 7.086 (ABq, J = 2Hz, 1H); 7.345 (d, J = 2Hz, 1
H); 7.348 (d, J = 8Hz, 1H)

[Pharmacological Test] (1) Action on Neurotransmission System [ ³ H] Serotonin (5-HT) Uptake Inhibition Experiment 12-week-old male Slc: Wistar rats (Japan SLC) were used in the experiment. After decapitation and sacrifice, the whole brain except the cerebellum was promptly taken out, 20 times volume of ice-cold 0.32 M sucrose solution was added thereto, and the suspension was suspended in a Potter-type homogenizer. Minute centrifugation was performed. The supernatant was spun down at 40,000 xg for 20 minutes, and 20 times the amount of Krebs-Hens was added to the pellet.
eleit buffer (1 mM-ascorbate, 0.17 mM-
EDTA and 0.08 mM-pargline) and then resuspended with Polytron and 40,000 xg
The operation of centrifugation for 10 minutes was repeated 3 times. 20 times the amount of ice-cold Krebs-He was added to the finally obtained pellet.
nseleit buffer and resuspend with Polytron,
This was further diluted 10-fold with the same buffer to give a synaptosome preparation. 5 nM [ ³ H] 5-HT (10
μl) and a synaptosome preparation (480 μl), and a test drug solution or a solvent thereof having an arbitrary concentration (the volume is 1
After incubating with 0 μl) at 37 ° C. for 5 minutes, the reaction was stopped by dilution with 2.5 ml of ice-cold Krebs-Henseleit buffer and suction filtration.
Whatman GF / C filter paper with 2.5 ml ice-cold Kreb
After washing 3 times with s-Henseleit buffer and allowing it to stand in 5 ml of Cleasol-1 for about 18 hours, its radioactivity was measured with a liquid scintillation counter. It should be noted that 5 nM [ ³ H] 5-HT (10 μl), synaptosome preparation (480 μl) and drug-dissolving solvent (10 μl) were incubated at 0 ° C. for 5 minutes and then obtained by the same procedure as above. The radioactivity obtained was taken as the blank value. The vertical axis represents the amount of [ ³ H] 5-HT incorporated into the synaptosome (radioactivity), and the horizontal axis represents the concentration of the test drug (lo).
The concentration (IC ₅₀ ) at which [ ³ H] 5-HT uptake is suppressed by 50% was determined from the graph in which the (g concentration) was plotted, and Table 1
It was shown to.

[Table 1] (A): Compound (I) of the present invention (b): Compound (1- [3
-{4- (3,4-dichlorophenyl) piperidine-1
-Yl} propylcarbamoyl] -2-oxopyrrolidine) As described above, the compound of the present invention exhibits a much stronger serotonin uptake inhibitory action than the compound described in JP-A-1-131155, and therefore exhibits antidepressant action. It is considered to indicate.

(2) Cerebral ischemia experiment Delayed hippocampal CA1 pyramidal cell necrosis-preventing action For experimental animals, 11 to 12-week-old MGD / Sea male sand rats (Mongolian gerbil, Seiwa Institute of Experimental Animal Research; Group 3-) 8 examples) were used. The test drug (compounds (a) and (b)) was dissolved in distilled water, and the control group was intraperitoneally administered with 0.2 ml per 100 g of body weight of distilled water. Under halothane anesthesia, the bilateral common carotid arteries of the sand rat were separated from the surrounding tissues and ligated with the Sugita arterial clamp for 5 minutes (the anesthesia was interrupted simultaneously with the occlusion of the common carotid artery). On the 4th day after the operation, pentobarbital Na (45
(mg / kg, intravenous administration) The brain was taken out after perfusion of the brain with 4% paraformaldehyde solution under anesthesia. Then, a small piece of brain containing hippocampus was prepared, fixed in Carnoy's solution overnight, and then embedded in paraffin. After staining a coronal brain section with a thickness of 10 μm with hematoxylin-eosin, parame
The degree of injury (%) of the pyramidal cell layer extending from dian to CA4 was examined with a two-dimensional image analyzer (Cosmozon 1S, Nikon).

[Table 2] From the above test results, the compound (a) of the present invention significantly inhibits delayed neuronal necrosis of sand mice due to cerebral ischemia at doses of 12.5 and 25 mg / kg, as compared with the compound (b). Further, at the time of administration of 50 mg / kg, complete prevention of neuronal necrosis was observed.

(3) Enzyme induction test [Experimental method] Compound (a) (the compound of the present invention) or compound (c) (1-
[3- {4- (3,4-dichlorophenyl) -1,2,5,
A 5% gum arabic suspension of 6-tetrahydropiperidin-1-yl} propylcarbamoyl] -2-oxopyrrolidine) was intraperitoneally administered once a day for 3 days (100 mg / kg). Twenty-four hours after the final administration, the liver was collected and the liver microsome was adjusted by the centrifugal fractionation method. Phenobarbital (dissolved in physiological saline) or β-naphthoflavone (suspended in sesame oil), which are typical enzyme inducers, were similarly intraperitoneally administered to mice to prepare liver microsomes.
The drug-metabolizing enzyme activity of liver microsomes was determined using 7-alkoxycoumarin-O-dialkylase activity as an index.

[Table 3] From the above results, an increase in drug enzyme activity was observed in the livers of mice to which compound (c) was administered for 3 days, but demethylation activity was 1.61 times that of the control group, whereas deethylation, The increase in depropylation activity was 1.99 to 2.20 times, and the increase in deethylation and depropylation activity was remarkable. This tendency was also observed during the treatment with β-naphthoflavone, which is a typical inducer. On the other hand, the drug-metabolizing enzyme activity in the liver of the compound (a) -administered mouse showed almost the same value as the activity in the mouse liver of the control group, and no induction phenomenon was observed. Therefore, the compound (c) exhibits a carcinogenic β-naphthoflavone type (3-methylcholanthrene type) enzyme-inducing action, while the compound (a) does not show an enzyme-inducing action. As described above, the compound of the present invention provides a compound having antidepressant action and cerebral nerve cell necrosis inhibitory action with few serious side effects such as enzyme induction.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI technical display location C07D 207: 00 211: 00) (72) Inventor Teruo Shiomi 5298 Kataitaya, Sekika-gun, Mie Prefecture

Claims (4)

[Claims] 1. Formula (I): (In the formula, X ¹ and X ² each independently represent lower alkyl, lower alkoxy or halogen.) A pharmaceutically acceptable acid addition salt. 2. An antidepressant containing the compound according to claim 1 as an active ingredient. 3. A therapeutic agent for sequelae of cerebrovascular disorders, which comprises the compound according to claim 1 as an active ingredient. 4. Formula ( b ): (In the formula, X ¹ and X ² each independently represent lower alkyl, lower alkoxy or halogen. R represents an amino protecting group.) Or a compound represented by the formula ( c ′ ) : [Chemical 3] (In the formula, X ¹ , X ² and R have the same meanings as described above.) After reacting the compound in the presence of a Lewis acid,
If necessary, deprotect and formula ( d ): (Wherein, X ¹ and X ² have the same meanings as described above), and the compound is represented by 1- {3- (chloropropyl).
By reacting with carbamoyl} -2-oxopyrrolidine of formula (I): (In the formula, X ¹ and X ² have the same meanings as described above.) A method for producing the compound represented by the formula.