WO1993005036A1

WO1993005036A1 - N-substituted carbazole derivative

Info

Publication number: WO1993005036A1
Application number: PCT/JP1992/001129
Authority: WO
Inventors: Satoshi Hibino; Shigeru Okuyama; Atsuro Nakazato; Yutaka Kawashima
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1991-09-06
Filing date: 1992-09-03
Publication date: 1993-03-18
Also published as: AU2511192A

Abstract

An N-substituted carbazole derivative represented by general formula (I) and a salt thereof, wherein R?1 and R3¿ may be the same or different from each other and each represents hydrogen, halogen, hydroxy or C¿1? to C5 alkoxy; R?2¿ represents hydrogen or methyl; R4 represents C¿1? to C5 alkyl; and n represents an integer of 1 to 4. This compound is useful for treating schizophrenia without causing extrapyramidal disorder and for treating problematic behaviors accompanying cerebrovascular disorder or senile dementia.

Description

Description N-substituted rubazole derivative

Technical field

The present invention relates to an N-substituted rubazole derivative having an antipsychotic effect. Background art

Psychotic drugs are used not only in the treatment of schizophrenia but also in the treatment of problematic behaviors (aggression, mental agitation, wandering, delirium, etc.) in cerebrovascular disorders and senile dementia. Are severely affected by extrapyramidal disorders, which is a major problem. In order to solve this problem, the development of antipsychotic drugs in recent years has been approached from a completely different aspect than the mechanism of action of conventional drugs. One of them is a sigma receptor antagonist. The sigma receptor is considered to be a receptor involved in mental disorders such as hallucinations, and compounds having a specific affinity for this receptor show antipsychotic effects without causing extrapyramidal disorders.

As a compound of this type, for example, Limizole (Rimcazoe) is known, but the affinity and specificity for sigma receptor are not sufficient. An object of the present invention is to provide a compound having an antipsychotic effect without causing extrapyramidal disorders. Disclosure of the invention

Means for Solving the Problems The present inventors have conducted intensive studies on a compound having a carbazole skeleton, and as a result, have found a novel carbazole compound that is specific and has high affinity for sigma receptor and has completed the present invention.

Hereinafter, the present invention will be described.

The present invention is based on the formula 1

(Wherein, R ¹ and R ³ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, R ² is a hydrogen atom or a methyl group, and R ⁴ is An alkyl group having 1 to 5 carbon atoms, and n is an integer of 1 to 4. N-substituted carbazonole derivatives represented by the following formulas and salts thereof.

In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The alkoxy group is a linear or branched one, for example, a methoxy group, an ethoxy group, a broboxy group, an isopropoxy group, a butoxy group. Alkyl groups are straight-chain or branched-chain, such as methyl, ethyl, bromo, isopropyl, butyl, and benzyl.

Further, the salt of the compound represented by the formula 1 of the present invention means a pharmacologically acceptable salt, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, lactic acid, tartaric acid, and fumaric acid. Salts with organic acids such as sulfonic acid, maleic acid, trifluoroacetic acid, and methanesulfonic acid.

The compound of the present invention of the formula 1 has optical isomers (D-form and L-form), and the present invention includes both of them.

The compound of Formula 1 has the formula

(Wherein, RR ² and R ³ are as defined above.) One-

Or a protected form thereof [for example, manufactured by the method described in Journal of Chemical Society (J. Chem. Soc.), 1962, p. ] And expression

(Wherein, R ⁴ and n are as defined above, and X is an arbitrary halogen atom.) Or a salt thereof (e.g., hydrochloride). .

This reaction is carried out in a solvent inert to the reaction (for example, benzene, chloroform, methylene chloride, tetrahydrofuran, Ν, Ν-dimethylformamide, dimethylsulfoxide, water, or a mixture thereof) or in a solvent-free solvent. In the presence of a basic compound (for example, pyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, carbonated carbonate, sodium hydride, etc.) or in the presence of a basic compound and a phase transfer catalyst (sulfuric acid) Hydrogen tetrabutylammonium) is stirred under ice-cooling to the reflux temperature of the solvent used.

After completion of the reaction, water is usually added to precipitate crystals, and the desired product can be obtained by filtration. If no crystals are precipitated, the desired product can be obtained by extracting with an appropriate solvent (for example, benzene, chloroform, ethyl acetate, methanol, etc.) and treating it by a conventional method.

In order to use the compound of the present invention as a medicine, the compound of the present invention is mixed with a solid or liquid carrier and prepared into a pharmaceutical preparation suitable for oral or parenteral administration. Pharmaceutical preparations include solid preparations such as tablets, pills, capsules and granules, liquid preparations such as injections, syrups and emulsions, and external preparations such as ointments and suppositories, which are commonly used. It is manufactured according to formulation technology.

Each of the above preparations may contain commonly used additives such as excipients, binders, lubricants, stabilizers, wetting agents, emulsifiers and the like. For example, injectables include dissolving agents such as distilled water for injection, physiological saline, Ringer's solution, methyl paraoxybenzoate, and Palau. --

Preservatives such as propyl xyloxybenzoate may be included. In addition, syrups and emulsions include sorbitol syrup, methylcellulose, glucose, sucrose tablets, hydroxyethyl cellulose, cooking oil, glycerin, ethanol, water, etc., as well as gum arabic and lecithin? It may contain an activator such as a preservative, a twin, or a span. Solid preparations include excipients such as crystalline cellulose, lactose, corn starch, mannitol, lubricating agents such as magnesium stearate, talc, binders such as hydroxybutyl vircellulose and polyvinyl vilolidone, and calcium carboxymethyl cellulose. A disintegrant, a fluid ft improver such as light gay anhydride, or the like can be used.

The dose of the compound of the present invention to a treated patient may vary depending on the patient's age, disease type and condition, etc., but usually 0.5 to 20 mg per day can be administered to an adult in one or several divided doses. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples.

Example 1

Under a nitrogen stream, 60% sodium hydride (0.264 g) was washed with petroleum ether. After drying, dimethylsulfoxide (4.4 ml) was added, and the mixture was stirred at 60 for 1 hour. g, 0.01 mol) in anhydrous tetrahydrofuran (20 ml) and stirred at room temperature for 15 minutes. To this was added a solution of N-methyl 2- (2-chloroethyl) pyrrolidine hydrochloride (0.92 g, 0.005 mol) in dimethyl sulfoxide (2 ml), and the mixture was stirred for 15 hours. After the reaction, ammonium chloride water (50 ml) was added, extracted with ethyl acetate, washed with saturated saline, and dried with anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, and crystals were obtained from a 2% methanol-form-form stream, which was recrystallized from ethanol to give 9- (N-methylvinyl 0.60 g of dino-2-ethyl) 16-methoxycarbazole was obtained. '.

mp 86-88. C Example 2

6-Acetoxycarbazole was used instead of 6-methoxycarbazole, and reacted with N-methyl-2- (2-chloroethyl) pyrrolidine hydrochloride in the same manner as in Example 1. By hydrolyzing with sodium water and treating in a conventional manner, 2-hydroxy-91 (N-methylpyrrolidinone 2-ethyl) carbazole was obtained.

m.p. 1 32-134. C (recrystallized from ethanol)

In the same manner as in Example 1 or 2, the following compounds were obtained from the corresponding starting materials.

7-Black mouth _9-1- (N-methyl bilolidinol 2-ethyl) 1-1,4-dimethyl

m.p. 102-104 ° C (recrystallized from ethanol)

9-1- (N-methylbirolidino 2-ethyl) 1,4-dimethylcarbazole m.p. 76-78 ° C (recrystallized from benzene / hexane)

9-1- (N-methylbirolidino-2-ethyl) -1,4-dimethylcarbazol NMR (60 MHz, CDC ") 6 (p pm);

1.23 (9H, s),

1.40 to 3.30 (9H, m),

4.27 (2H, t, J = 7.4H z),

6.93 to 7.60 (9H, m),

8.02 (2H, t, J = 7.0H z)

MS m / e;

278 (M +), 180 (100%)

2-Hydroxy-91 (N-methylbiberidino 2-ethyl) potassium lvazol m.p. 165-167. C (recrystallized from benzene-hexane)

2-Hydroxy-91 (N-n-Provirbiberidino-1-ethyl) carbazol

m.p. 159-163 ° C (recrystallized from benzene / hexane)

Test example [Receiver binding experiment] One €

The animals used were male Wistar rats.

(+) C ³ H] 3—PPP [3- (3-hydroxyphenyl) -N-n-propylpyperidine] as a [ ³ H] -labeled ligand for the sigma receptor, and (1-) for the D ₂ receptor ) [ ³ H] sulpiride was used respectively.

Binding reactions using [ ³ H] -labeled ligands are described in Molecular Pharmacology, Vol. 32, p. 772 (1987), Journal of Pharmaceuticals and Pharmacology, Vol. 32, p. 820 (1987), respectively. Year)), the following methods (1) to (3) were used.

(1) (+) [ ³ H] 3—PPP binding: Membrane preparation obtained from rat striatum. (1) [ ³ H] 3—PPP and test drug were combined with 5 OmM Tris-HCl buffer (pH 8). . 0)

The reaction was carried out at 21 for 90 minutes.

(2) (—) [ ³ H] sulviride bond: A membrane preparation obtained from rat striatum. (1) [ ³ H] sulpiride and the test drug were prepared in 5 OmM Tris-HCl buffer (pH 7.7).

The reaction was performed at 37 ° C for 10 minutes.

After each reaction, the solution was suction-filtered through a glass filter (GFZB), and the radioactivity of the filter paper was measured with a liquid scintillation vector meter.

The 10 βΜ (+) 3-ΡΡΡ 10 μΜ ( I) Kino combined with Surubirido were reacted in the presence, respectively ^{(+) [3 Η] 3-} ΡΡΡ, ( I) ^[3 Eta] Non-specific binding of Surubiri de And the difference between total binding and non-specific binding was defined as specific binding. Constant concentration

^[3 Eta] labeled ligand and a test drug concentrations were varied to obtain the inhibition curves by reacting under the conditions of the above (1) to (2), the concentration of each of the coupling from the inhibition curve 50% inhibition of the test drug (IC ₅₀ ) was determined and the results are shown in Table 1.

[Figures IC _5. Value (nM). ] One one

(Note 1)

A; 2-Hydroxy-91 (N-methyl bilolidinol 2-ethyl) carbazole

B; 9— (N-methylbi-lidino-1-ethyl) 1-6—Methoxycarbazole C; 2-Hydroxy 91- (N-methylbiberidino 2-ethyl) carbazo

D; 2-Hydroxy-91 (N-n-Brovirbiberidino 2-ethyl) Carbazole

(Note 2)

The values of rimcasole were quoted from those described in the Journal of the Bian Journal of Pharmaco, Vol. 155, p. 345 (1988).

The value of D ₂ Resebuta is that is shown by the value for ^[3 H] Subiberon bond. Industrial applicability

The compounds of the present invention are specific for sigma receptors and show high affinity. Therefore, the compound of the present invention exhibits an antipsychotic effect without causing extrapyramidal dysfunction, and thus is useful as a therapeutic agent for schizophrenia, cerebrovascular disorders, and problematic behavior associated with senile dementia.

Claims

1 set

blue

Example

(Wherein, R ¹ and R ³ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, R ² is a hydrogen atom or a methyl group, and R ⁴ Is an alkyl group having from 5 to 5 carbon atoms, and n is an integer from 1 to 4. N-substituted benzyl derivative represented by the following formula: