JPH0296580A - Novel condensed 4-aminoquinoline derivative - Google Patents

Abstract

NEW MATERIAL:A condensed 4-amionoquinoline derivative of formula I (R1 is H or lower alkyl; R2 is H, lower alkyl or forms a cyclic alkylene chain together with R6; R3 and R4 are H or form a quinoline ring or tetrahydroquinoline ring together with the ring A; X is O, S, N-R5; R5 is H or lower alkyl; Y is O or N-R6; R6 is H, lower alkyl or forms a cyclic alkylene together with R2; n is 0 or 1; m is 0-4). EXAMPLE:4'-Aminoquinolino[2,3-b]-4-methyl-5,6-dihydro-1,4-oxazine. USE:The compound of formula I has excellent memory learning-accelerating action and cerebral function-improving action and is useful as a medicine. PREPARATION:A compound of formula II (R<7> and R<8> are H, etc.; Z is halogen) is reacted with a compound of formula III and the reaction product is subjected to an intramolecular ring-closing reaction and subsequently to the reaction of the nitro group at the 4-position of the produced compound to provide the compound of formula I.

Description

Detailed Description of the Invention The present invention provides - form (I) (C) (λ) (wherein R1 is a hydrogen atom or a lower alkyl group, and R2 is independently a hydrogen atom or a lower alkyl group) Show or R6
together with indicates a cyclic alkylene chain. R3 and R
4 independently represents a hydrogen atom, or together with ring A constitutes a quinoline ring or a tetrahydroquinoline ring. X is an oxygen atom, a sulfur atom, or N-
R5 represents a hydrogen atom or a lower alkyl group. Y represents an oxygen atom or N-RG, RG independently represents a hydrogen atom or a lower alkyl group, or together with R2 represents a cyclic alkylene chain, and m represents an integer of 0 to 4. , n represents O or 1. ) is related to a novel compound represented by

In recent years, with the transition to an aging society, the aging population has also increased, and the number of diseases affecting the elderly is rapidly increasing. In particular, the mechanism of pharyngeal syndrome is not yet clearly understood, and in severe cases, it can even lead to death.As such, it has become an important social problem, and excellent therapeutic agents are desired. ing.

Many studies are currently being conducted regarding dementia in old age. Until now, in patients with senile dementia, central cholinergic nerve function has been affected due to a decrease in the synthesizing enzyme (choline acetyltransferase, CAT) and degrading enzyme (acetylcholinesterase, AChE) of acetylcholine, which is a neurotransmitter for cholinergic neurons. decline [British Medical Journal (Br
itish Medical Journal), i:
1457-1459゜1978; Play 7 (B r
a i n) + −[Ω1-:507-518.1
984; Journal of the Neurological Science
logical 5 sciences), iL:4
07-417.1982; Lancet
, i: 1403.1978, etc.] Decreased central noradrenergic system nerve function [British Medical Jour
nal), 282:93-94.19811, etc., and research is being carried out on therapeutic agents to treat these symptoms.

In view of these circumstances, the present inventors have conducted extensive research in order to develop an excellent therapeutic agent that activates the neurological function deteriorated due to senile dementia.As a result, the compound represented by the -form (I) The present invention was based on the discovery that this compound exhibits a specific pharmacological effect of activating nerve function and promoting memory learning function in animals.

The compound represented by general formula (I) is a new compound,
For example, it can be obtained as follows.

General formula (II) (In the formula, R7 and R8 each independently represent a hydrogen atom, or together with ring A, constitute a quinoline ring. Z represents a halogen atom.) Using the compound shown as a starting material, react it with the compound shown in (wherein R11R2, X% YN ms n has the same meaning as above) to obtain general formula (IV) (CI-Lz) , (wherein R1, R2, R7, R8, L YN m1n is,
Indicates the same meaning as above. ) is obtained.

This reaction is carried out in a single solvent such as tetrahydrofuran, alcohols, dimethylformamide, acetonitrile, chloroform, methylene chloride, or a mixture thereof. The reaction temperature is between room temperature and 100°C,
It can be completed in half a day to 2 days. Further, depending on the compound, the reaction may proceed to intramolecular ring closure to give a compound represented by -form (V). (Compound No. 11) Then the general formula (
By intramolecularly closing the compound represented by IV),
- A compound represented by the formula (V) (wherein R11R2, R7, R8, and LYlmln have the same meanings as above) is obtained. This ring-closing reaction is carried out by adding an amount of an inert solvent such as dimethylformamide, acetonitrile, or tetrahydrofuran, and an anhydride such as acetic anhydride, and the reaction temperature is from room temperature to 150°C, preferably 100°C. When X is a sulfur atom, the reaction proceeds at room temperature without adding anhydride.

When the nitro group at the 4-position of the compound represented by the general formula (V) is reduced, the target compound of the general formula Cl1) (C)lz) (where R11R2, R7, R8, X% Y% m1n is ) is obtained. This reduction reaction is a commonly performed reaction in which palladium-
It is carried out by hydrogenation under a catalyst such as carbon, nickel, Raney nickel, or Raney cobalt. The reaction is carried out in an inert solvent such as an alcohol or tetrahydrofuran, and preferably proceeds at room temperature. The obtained general formula (Vl
), in which R7 and R8 together form a quinoline ring with ring A, are further subjected to a reduction reaction under a catalyst such as platinum dioxide, Raney nickel, etc. Formula (■) (C City).

The compound shown is obtained. This reaction is carried out in a solvent such as acetic acid or trifluoroacetic acid.

The reaction temperature is 10 to 50°C, preferably room temperature.

The compound represented by the general formula (I) obtained in this way exhibits excellent memory learning promoting action, brain function improving action, etc. even in a small amount, and is effective as a medicine.

EXAMPLES The present invention will be explained in more detail below with reference to Examples and Experimental Examples, but the present invention is not limited thereto.

Example I (In the formula, R1, R2, R7, R8, L Ylmsn have the same meanings as above.) Oxide 2g (0,0074 mol) and N-methylethanolamine 1.12g (0,015 mol) was dissolved in 12 mΩ of tetrahydrofuran and stirred at room temperature for days.

The whole is concentrated under reduced pressure, 10% potassium carbonate solution is added to the residue, and after stirring, the crystals are collected by filtration and washed with water. The crystals are redissolved in chloroform, washed with water, and the chloroform layer is dried over anhydrous sodium sulfate. The chloroform layer was compressed under reduced pressure,
The residue is washed with ethanol to obtain 1.5 g of 3 sites (yield 77%).

1.1 g (98% yield) of rho-oxazine is obtained.

1 g (0,0041 mol) of 9L is dissolved in 30 ml of a mixture of equal amounts of methanol and tetrahydrofuran, and 0.35 g of 10% palladium-carbon is added thereto for reduction. After removing the palladium-carbon by filtration, it was concentrated, separated and purified by alumina column chromatography (developing solvent: chloroform), and 1.2 g (0,0046 mol) of the main dioxide was dissolved in 10 ml of dimethylformamide, and 2 ml of acetic anhydride was added. Add and heat to 100'C on an oil bath. After heating for about 30 minutes,
The whole is concentrated under reduced pressure and extracted with chloroform-10% sodium bicarbonate solution. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue n-
Washing with hexane gives '-nitroquinolinomethyl-dihyde g (yield 80%).

Example 2 °-a5noquinolino obtained in Example I-(c)
- -Methyl--dihyro-oxazine 0.2g (0,0009
Platinum oxide (IV mole) was dissolved in trifluoroacetic acid and platinum oxide (IV
) 0.15g and reduce.

After removing platinum oxide (TV) by filtration under reduced pressure, the mother liquor is concentrated under reduced pressure.

The whole is dissolved in chloroform and the trifluoroacetic acid is neutralized with 10% sodium bicarbonate solution. After washing the chloroform layer with water, dry it with anhydrous sodium sulfate. When chloroform is concentrated under reduced pressure, crystals precipitate.

Wash with ether and add '-amino'$1 table 0.17 g (85% yield) of monooxazine is obtained.

The general formula (I) thus obtained is shown in Table 1 below.
The compound represented by is shown below.

In addition, Q in the R3 and R4 columns in Table 1 constitutes a quinoline ring together with ring A, T constitutes a tetrahydroquinoline ring together with ring A, and P means that R3 and R4 are each a hydrogen atom. shows.

1 Experimental Example I Acetylcholinesterase Acetylcholinesterase activity was determined by S. H. Sterry (S@H@5terri) and F.
European Journal of Biochemistry (European Jou)
RNA Biochemistry), 91:2
15-222.1978). That is, in 20mM sodium phosphate buffer (pH 7,4), 1.3mM (1-Il')acetylcholine (0,025μCi) was used as a substrate, and acetylcholinesterase (EC3,1,1°7) was used. 0.5 μU of enzyme preparation (Jig? No. C-2888) was heated at 30°C for 15 minutes.
After incubation for minutes, activity was measured. 1 μM of each compound was added to this reaction solution, and the influence on enzyme activity was examined.

The results were obtained as the average of the two-sided constant values, the activity value in the absence of the drug was taken as 100%, and the value when each compound was added was expressed as a percentage.

The results are shown in Table 2.

As shown in Table 2, the compounds of the present invention have a strong inhibitory effect on acetylcholinesterase activity, and are expected to have the effect of activating the function of the cholinergic system in the central nervous system. This indicates that a disorder specific to central corinary neurons [B.J. Whitehouse (P-J-W
Science
), 2''j, 1237-1239.1 were measured. The drug administration method was as follows: Physiological saline was administered during the habituation trial, and 10μg/kg of the sample was administered at 1ml/100g body weight during the acquisition trial.
For the control group, the same liter of physiological saline was intraperitoneally administered 60 minutes before the start of the trial. The results are shown in Table 3. 1'3L 5tep Through Latency in the table
is expressed as mean±S,E.

Mann-Whisotony (Mann Wh)
Itney) U-test showed significant difference *p<0.0
5**p<0.01 5tep'rrough Latency of control group as shown in Table 4
was 41.9±10.2 seconds, whereas the compound of the present invention can be said to be useful for the treatment of Alzheimer's type dementia.

Experimental Example 2 Four groups of 10 male ICR mice (10 to 14 weeks old) were used; one group was used as a control, and the remaining three groups were administered the compound of the present invention. As an experimental device, an experimental box consisting of a bright area and a dark area is used, and an electrical stimulation device is connected to a floor grid provided in the dark area.

The experiment consisted of habituation trials, acquisition trials, and reproduction trials, one per day.
The trial was conducted for a total of 3 days. In the habituation trial, the subject was first placed in the light part of the experimental box and left for 5 minutes to become accustomed to the apparatus. 2
In the sun/moon acquisition trial, the subject was placed in the light part of the experimental box, and upon entering the dark part, was confined there and an electric shock of 1 mA AC was applied for 10 seconds through the floor grid. The playback attempt is
Another 24 hours after the acquisition trial, the subject was placed in the light part of the device and the time until entering the dark part (Step Through
It is clear that it intentionally increases the latency (Latency) and has the effect of promoting memory and learning.

Claims (1)

[Claims] 1) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R1 represents a hydrogen atom or a lower alkyl group, and R2 independently represents a hydrogen atom or a lower alkyl group, or
Alternatively, together with R6, it represents a cyclic alkylene chain. R
3 and R4 each independently represent a hydrogen atom, or together with ring A constitute a quinoline ring or a tetrahydroquinoline ring. X represents an oxygen atom, a sulfur atom or N-R5, and R5 represents a hydrogen atom or a lower alkyl group. Y represents an oxygen atom or N-R6, and R6 independently represents a hydrogen atom or a lower alkyl group, or together with R2 represents a cyclic alkylene. n represents 0 or 1, and m represents an integer of 0 to 4. ). 2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R1 is a hydrogen atom or a lower alkyl group, R2
independently represents a hydrogen atom or a lower alkyl group, or together with R6 represents a cyclic alkylene chain. X represents an oxygen atom, a sulfur atom or N-R5, and R5 represents a hydrogen atom or a lower alkyl group. Y represents an oxygen atom or N-R6, R6 independently represents a hydrogen atom or a lower alkyl group, or together with R2 represents a cyclic alkylene chain, m is an integer of 0 to 4, n represents 0 or 1. ) The compound according to claim 1, which is represented by: 3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R1 represents a hydrogen atom or a lower alkyl group, and R2 independently represents a hydrogen atom or a lower alkyl group, or
Alternatively, together with R6, it represents a cyclic alkylene chain. X represents an oxygen atom, a sulfur atom, or N-R5, and R5 represents a hydrogen atom or a lower alkyl group. Y is an oxygen atom,
or N-R6, R6 independently represents a hydrogen atom or a lower alkyl group, or together with R2 represents a cyclic alkylene chain, m is an integer of 0 to 4, and n is 0
Or indicates 1. ) The compound according to claim 1, which is represented by: 4) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R1 represents a hydrogen atom or a lower alkyl group, R2 independently represents a hydrogen atom or a lower alkyl group, or R6
together with indicates a cyclic alkylene chain. X represents an oxygen atom, a sulfur atom, or N-R5, and R5 represents a hydrogen atom or a lower alkyl group. Y is an oxygen atom or N-R6
, R6 independently represents a hydrogen atom or a lower alkyl group, or together with R2 represents a cyclic alkylene chain, m represents an integer of 0 to 4, and n represents 0 or 1. ) The compound according to claim 1, which is represented by: