JPH0558998A - Carbazole derivative - Google Patents

Abstract

PURPOSE:To obtain the subject safe and readily usable derivative, containing a carbazole skeleton, having hyperactivity suppressing action on intracerebral dopamine- based nervous systems, having excellent improving ratio for problem behaviors caused by schizophrenia, cerebrovascular disorder and jeriafoic dementia and useful as medical products, etc. CONSTITUTION:A 4-alkoxyphenethylamine expressed by formula I (Ra' is H or 1-5C alkyl; (n) is 1-3) is reacted with an acid chloride expressed by the formula RbCOC1 (Rb is 1-5C alkyl) to provide an acid amide derivative, which is then reduced to afford an amine derivative. The resultant amine derivative is subsequently reacted with an acid chloride expressed by the formula RcCOC1 (Re is the same kind as that of Rb) to provide an acid amide derivative, which is then nitrated with concentrated nitric acid and reduced to produce amino group. The produced amino group is acetylated and subsequently reacted with o-nitrobromobenzene to afford a compound expressed by formula II (Ac is acetyl). The nitro group is then reduced and treated with sodium nitrite to carry out cyclizing reaction. Thereby, a carbazole ring is produced to provide a compound expressed by formula III. The acid amid group in the resultant compound is reduced and the protecting group of the hydroxyl group, as necessary, is removed to afford the objective compound expressed by formula IV (Ra is H or Ra').

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a carbazole derivative having an activity of suppressing hyperactivity of brain dopamine nervous system.

[0002]

2. Description of the Related Art Among the neuropsychiatric symptoms associated with cerebrovascular disorders and senile dementia, problematic behaviors such as aggressive behavior, nervous excitement, loitering, and delirium are caused by overactivity of the dopaminergic nervous system in the brain, and are considered in terms of patient care. It is the most problematic condition in clinical practice. Cerebral metabolism stimulants (such as calcium fopatate) and cerebral circulation improvers (such as ifenprodil) have been developed as drugs for these symptoms.
The effect of suppressing problem behavior is still insufficient. Therefore,
In clinical settings, antipsychotic drugs (chlorpromazine, sulpiride, etc.) have been substituted. However, since antipsychotics were originally developed for the purpose of treating schizophrenia,
Optional symptoms including effects and side effects (especially extrapyramidal disorders, oversedation, excessive muscle relaxation, induction of secondary delirium, cardiovascular disorders)
However, its use in clinical situations must be restricted. Under these circumstances, there is a demand for the development of a drug that exhibits a high improvement rate for problem behavior, is highly safe, and is easy to use.

Thiabrid is known as a drug for suppressing hyperactivity of the dopaminergic system in the brain [Medical care and new drugs, Vol. 24 (3), p. 19 (1987)].

On the other hand, 9-benzyl-1,4-dimethylcarbazole is known as a compound having a structure similar to that of the compound of the present invention, but no inhibitory effect on the hyperactivity of the dopaminergic nervous system in the brain has been reported. ..

[0005]

An object of the present invention is to provide a compound having an action of improving problem behavior associated with cerebrovascular disorder and senile dementia.

[0006]

Means for Solving the Problems As a result of intensive investigations on a compound having a carbazole skeleton, the present inventors have found a novel carbazole derivative having an inhibitory effect on hyperactivity of the dopaminergic nervous system in the brain, and completed the present invention. .. The invention has the formula

[0007]

[Chemical 2]

(Wherein Ra is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, Rb and Rc are the same or different and are alkyl groups having 1 to 5 carbon atoms,
n is an integer of 1 to 3. ) Are carbazole derivatives and salts thereof.

In the present invention, the alkyl group is a linear or branched alkyl group such as a methyl group,
Examples thereof include ethyl group, propyl group, isopropyl group, butyl group and pentyl group. Further, the salt of the compound of the present invention of Chemical formula 2 means a pharmacologically acceptable salt, for example, sulfuric acid,
Examples thereof include salts with mineral acids such as hydrochloric acid and phosphoric acid, salts with organic acids such as acetic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid and methanesulfonic acid.

The compound of Chemical formula 2 can be synthesized according to the reaction formulas of Chemical formula 3 and Chemical formula 4 (Chemical formula 3 and Chemical formula 4)
Wherein Rb, Rc and n have the same meanings as described above, and Ra ′
Is Ra excluding hydrogen atom. ).

[0011]

[Chemical 3]

[0012]

[Chemical 4]

That is, 4-alkoxyphenethylamine (1) is reacted with an acid chloride of the formula (2) to form an acid amide compound (3), which is then subjected to ordinary reduction using lithium aluminum hydride or the like to give the amine compound (4). To Then, after reacting with the acid chloride of the formula (5) to form the acid amide form (6) in the same manner as above, nitration is performed with concentrated nitric acid to obtain the nitro form (7). After reducing the nitro group to an amino group by catalytic reduction and then performing normal acetylation to give an acetanilide compound (9), N-phenylation was carried out by reacting with o-nitro-bromobenzene to obtain a diphenylamine compound (10). With a small amount of deacetylated product (11)
To get (10) is obtained by hydrolysis with a base (1
Can lead to 1). Diphenylamine body (1
The nitro group of 1) is catalytically reduced to give an amino compound (12) and then diazotized with sodium nitrite to obtain a benzotriazole compound (13). The benzotriazole body (13) is thermally decomposed in phenanthrene to obtain a carbazole body (14). The carbazole compound (14) is reduced with lithium aluminum hydride to give (15) of the present invention.
Can be obtained. By demethylating the compound of (15) with boron tribromide, the compound of (16) of the present invention can be obtained.

[0014]

INDUSTRIAL APPLICABILITY According to the present invention, a compound having an excellent action of improving schizophrenia and problem behavior associated with cerebrovascular disorder and senile dementia is provided.

Next, a test example will be shown. Test Example [Receptor Binding Experiment] Male Wistar rats were used as animals. As a [ ³ H] -labeled ligand, the sigma receptor has (+) [ ³ H] 3
-PPP [3- (3-hydroxyphenyl) -Nn-
Propylpiperidine], the D ₂ receptor has (-)
[ ³ H] sulpiride was used, respectively. The binding reaction using [ ³ H] -labeled ligand is described in Molecular Pharmacology, Vol. 32, p. 772 (1987), Journal of Pharmacy and Pharmacology, Vol. 32, p. 820 (1987), respectively. The following methods (1) to (3) were performed.

[0016] ^{(1) (+) [3} H] 3-PPP binding: Rat striatum than obtained membrane ^{preparation, (-) [3 H]} 3-PPP
And a test drug were treated with 50 mM Tris-HCl buffer (pH 8.
In (0), the reaction was performed at 21 ° C. for 90 minutes. (2) (-) [ ³ H] sulpiride bond: Membrane preparation obtained from rat striatum, (-) [ ³ H] sulpiride and test drug were added to 50 mM Tris-HCl buffer (pH 7.7) at 37
The reaction was carried out at 0 ° C for 10 minutes.

After completion of each reaction, a glass filter (GF
/ B) by suction filtration, and the radioactivity of the filter paper was measured with a liquid scintillation spectrometer. 10 μM (+)
The binding when reacted in the presence of 3-PPP and 10 μM (−) sulpiride was (+) [ ³ H] 3-PP, respectively.
Nonspecific binding of P and (−) [ ³ H] sulpiride was defined as the specific binding, and the difference between the total binding and the nonspecific binding was defined as the specific binding. An inhibitory curve was obtained by reacting a constant concentration of [ ³ H] -labeled ligand and a test drug with varying concentrations under the conditions (1) and (2) above, and a test was performed to inhibit 50% of each binding from this inhibitory curve. The drug concentration (IC ₅₀ ) was determined, and the results are shown in Table 1.

[0018]

[Table 1]

(Note 1) A: 4- (N, N-dipropylamino) ethyl-1-methoxycarbazole B: 4- (N, N-dipropylamino) ethyl-1-hydroxycarbazole hydrochloride

(Note 2) The value of rimcazole is as shown in European Journal of Pharmacology, No. 155.
Vol., Page 345 (1988). The value of the D ₂ receptor is shown as the value for [ ³ H] spiperone binding.

[0021]

EXAMPLES The present invention will be specifically described below with reference to examples.

Example 1 Synthesis of 4- (N, N-dipropylamino) ethyl-1-methoxycarbazole (1) Pyridine (10.5 g) was added to a chloroform solution (100 ml) of 4-methoxyphenethylamine (3 g, 66 mmol). , 132 mmol) was added, and a chloroform solution (100 ml) of propionyl chloride (9.2 g, 99 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. 2-3 drops of ethanol was added to the reaction solution, washed with 4-fold diluted hydrochloric acid and then with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 12.68 g of N-propionyl-4-methoxyphenylethylamine. m. p. 74-76 ° C

(2) anhydrous tetrahydrofuran (200 m
l) lithium aluminum hydride (LAH) (9 g)
Was added and stirred, and a solution of N-propionyl-4-methoxyphenylethylamine (9 g, 43.5 mmol) in anhydrous tetrahydrofuran (100 ml) was added dropwise under ice cooling, followed by stirring at 60 ° C. for 3 hours. 20% Sodium hydroxide (about 50 ml) was added dropwise under ice cooling, the mixture was filtered through Celite, the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by vacuum distillation, and N-propyl-
7.37 g of 4-methoxyphenylethylamine was obtained. b. p. 130-131 ° C / 5mmHg

(3) N-propyl-4-methoxyphenylethylamine (10.5 g, 56.5 mmol) was treated in the same manner as in (1), and the chloroform solution (60 ml) of the example was added, and the mixture was stirred at room temperature. It was stirred for 14 hours. 2-3 drops of ethanol was added to the reaction solution, washed with 4-fold diluted hydrochloric acid and then with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by vacuum distillation,
12.96 g of N-propyl-N-propionyl-4-methoxyphenylethylamine was obtained. b. p. 163-164 ° C / 2mmHg

(4) 18 to 22 in nitric acid (150 ml)
N-Propyl-N-propionyl-4-methoxyphenylethylamine (19.16 g, 52 mmol) at ° C.
, And after stirring for 20 minutes at room temperature, ice water (about 500 ml)
I opened it. After extraction with chloroform, the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (1
80 g) and 5% methanol-chloroform: hexane (1: 9) fraction was obtained to obtain 9.83 g of N-propyl-N-propionyl-3-nitro-4-methoxyphenylethylamine. m. p. 57-58 ° C

(5) N- in ethanol (150 ml)
Propyl-N-propionyl-3-nitro-4-methoxyphenylethylamine (6.37 g, 21.7 mmol) was subjected to catalytic reduction (hydrogen gas about 1500 ml) under 5% palladium carbon (1.0 g). The reaction solution was filtered through Celite, the filtrate was concentrated, and recrystallized from benzene-hexane to give N-propyl-N-propionyl-3-amino-4-.
5.5 g of methoxyphenylethylamine was obtained. m. p. 60 ~ 61 ℃

(6) N-propyl-N-propionyl-
3-amino-4-methoxyphenylethylamine (6.
76 g, 25.6 mmol) was diluted with dilute hydrochloric acid (3 → 80, 30).
(Mmol) dissolved. Acetic anhydride (3 m
1, 30 mmol) was added, and a sodium acetate aqueous solution (2.5 → 20, 30 mmol) prepared immediately was added, and the mixture was stirred for 30 minutes under ice cooling. The reaction mixture was poured into ice water, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was evaporated.
It was washed with ter-hexane, the crystals were collected by filtration and N-propyl-N.
6.5 g of -propionyl-3-acetamino-4-methoxyphenylethylamine was obtained. m. p. 72-73 ° C

(7) N-propyl-N-propionyl-3-acetamino-4-methoxyphenylethylamine (5.18 g, 17 mmol) and o-nitrobromobenzene (6.90 g, 34 mmol) in xylene (100 ml). ), Potassium carbonate (4.70 g, 34 mmol), cuprous chloride (1.0 g, 10.2 mmol) and tris [2- (2-methoxy) ethyl] amine (0.
(83 g, 2.6 mmol) was added, and the mixture was heated under reflux for 4 days in a nitrogen stream. The reaction solution was filtered through Celite, washed with ethyl acetate, the organic layer was washed with 4-fold diluted aqueous ammonia and then with saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (75 g), and 0.47 g of a deacetylated product was obtained from a 10% ethyl acetate-benzene stream. Furthermore, from the 30% ethyl acetate-benzene stream fraction, the target N-propyl-N-
4.19 g of propionyl-3- (2-nitrophenyl) acetamino-4-methoxyphenylethylamine was obtained.

(8) N-propyl-N-propionyl-
3- (2-Nitrophenyl) acetamino-4-methoxyphenylethylamine (4.66 g, 10.99 mmol) was dissolved in ethanol (200 ml), 50% aqueous potassium carbonate solution (200 ml) was added, and the mixture was heated under reflux for 4 days. , Ethanol was concentrated and extracted with chloroform. After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (60 g), and the target N-propyl-N was collected from a 5% ethyl acetate-benzene stream. -Propionyl-
1.97 g of 3- (2-nitrophenyl) amino-4-methoxyphenylethylamine (deacetylated product) was obtained.
In addition, the raw material was obtained from the 30% ethyl acetate-benzene stream as 2.
01 g was recovered and the reaction was repeated.

(9) N- in ethanol (200 ml)
Propyl-N-propionyl-3- (2-nitrophenyl) amino-4-methoxyphenylethylamine (2.
44 g, 6.3 mmol) was subjected to catalytic reduction (hydrogen gas about 380 ml) under 5% palladium carbon (1.0 g). The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and
Propyl-N-propionyl-3- (2-aminophenyl) amino-4-methoxyphenylethylamine was added to 2.
12 g was obtained. Since the compound obtained here was easy to be colored and unstable, it was used in the next reaction without being purified.

(10) N-propyl-N-propionyl-3- (2-aminophenyl) amino-4-methoxyphenylethylamine (130 mg, 0.37 mmol)
Was dissolved in acetic acid (1 ml), and an aqueous solution (1 ml) of sodium nitrite (30 mg, 0.44 mmol) was added dropwise under ice cooling. The reaction mixture was gradually returned to room temperature, stirred for 1 hour, and extracted with chloroform. The chloroform layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (20 g), and 20% ethyl acetate-N-propyl-benzene was taken from a benzene stream. 120 mg of N-propionyl-3- (1-benztriazole) -4-methoxyphenylethylamine was obtained.

(11) N-propyl-N-propionyl-3- (1-benztriazole) -4-methoxyphenylethylamine (1.40 g, 3.8 mmol) was heated under reflux in phenanthrene (15 g) for 1 hour. .. After cooling, the reaction solution was washed with hexane to remove phenanthrene to some extent and then subjected to silica gel column chromatography (30 g) to remove phenanthrene by benzene outflow, and 1-methoxy-from 5% ethyl acetate-benzene stream. 0.30 g of 4- (N-propyl-N-propionyl) aminoethylcarbazole was obtained.

(12) Anhydrous tetrahydrofuran (20 m
LAH (1 g) was added to l) and stirred, and 1-methoxy-4
An anhydrous tetrahydrofuran solution (20 ml) of-(N-propyl-N-propionyl) aminoethylcarbazole (0.79 g, 2.3 mmol) was added dropwise under ice cooling,
The mixture was stirred at room temperature for 14 hours. 20% sodium hydroxide (about 10 ml) was added dropwise to this under ice-cooling, then filtered through Celite and washed with ethyl acetate. The filtrate was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (25
Then, 0.71 g of 4- (N, N-dipropylamino) ethyl-1-methoxycarbazole was obtained from the chloroform stream.

0.4 g of this was dissolved in ether (2 ml), hydrochloric acid saturated ether (20 ml) was added, and the precipitated crystals were collected by filtration, and 4- (N, N-dipropylamino) ethyl-1-methoxycarbazole hydrochloric acid was added. 335 mg of salt crystals
(75.4%) was obtained. m. p. 210 ~ 212 ℃

Example 2 Synthesis of 4- (N, N-dipropylamino) ethyl-1-hydroxycarbazole 4- (N, N-dipropylamino) ethyl obtained in Example 1 (12) under nitrogen stream. Anhydrous methylene chloride solution (20 ml) of -1-methoxycarbazole (0.20 g, 1.23 mmol) was cooled to -80 ° C, and boron tribromide (0.93 g, 3.69 mmol) in anhydrous methylene chloride solution was added. (30 ml) was added, and the mixture was gradually returned to room temperature and stirred for 14 hours. The reaction solution was poured into a large amount of water (about 250 ml), and the precipitated crystals were collected by filtration. This was subjected to iatro beads column chromatography, and the crystals obtained from the 5% methanol-chloroform flow fraction were recrystallized from chloroform-benzene to obtain 160 mg of the desired product.

M. p. 165-168 ° C

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yutaka Kawashima 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. The formula: (In Chemical Formula 1, Ra is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, Rb and Rc are the same or different and are alkyl groups having 1 to 5 carbon atoms, and n is an integer of 1 to 3. And a salt thereof.