JPH03120283A - Dioxynoquinoline derivatives and pharmaceutical compositions containing the compounds as active ingredients - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 and R2 are H, lower alkyl or phenyl). EXAMPLE:2,2-Dimethyl-1,3-dioxino[3,2-f]quinoline-7-(8H)-one. USE:It has platelet coagulation inhibiting action, phosphodiesterase inhibiting action and blood flow increasing action and is useful as an antithrombotic agent, cerebral circulation improving agent, hypotensor, antiasthmatic agent, anti-inflammatory agent and antiulcer agent. PREPARATION:The objective compound can be produced by condensing 6- hydroxyquinolin-2-one of formula II and formaldehyde and reacting the resultant 6-hydroxyquinoline-5-hydroxymethyl-2-one of formula III with a ketone (or aldehyde) of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel dioxynoquinoline derivatives, more specifically, compounds of the general formula I: [wherein R3 and R2 independently represent a hydrogen atom, a lower alkyl group, or a phenyl group] The present invention relates to a dioxynoquinoline derivative represented by: and a pharmaceutical composition containing the compound as an active ingredient.

As a result of various studies, the present inventors found that the above-general formula (I)
The compound of the present invention represented by has a platelet aggregation inhibiting action, a phosphogesterase inhibiting action, and a blood flow increasing action,
It has been found to be useful as an antithrombotic agent, a cerebral circulation improving agent, an antihypertensive agent, an antiasthmatic agent, an antiinflammatory agent, and an antiulcer agent.

In the above general formula (1), lower alkyl groups R1 and R
, and includes, for example, methyl, ethyl, isopropyl, butyl, tert-butyl groups, and the like. The phenyl group may have a substituent that does not inhibit the pharmacological action aimed at in the present invention.

Representative examples of the compounds of the present invention include the following, but the present invention is not limited thereto.

1.1.3-Dioxine [3,2-fl quinoline-7-
(8H)-one 2.2-Methyl-1,3-dioxin[3,2-f]quinolin-7-(8H)-one 3.2.2-dimethyl-1,3-dioxin[3,2-f]
fl Quinolin-7-(8H)-one 4,2-ethyl-2-methyl-1,3-dioxin [
3,2-i'l Quinoline-7-(8)])-one 2-isopropyl-1,3-dioxin[3,2-f]
Quinolin-7-(8H)-one 5゜6.2-phenyl-1,3-dioxin [3゜2-f
]Quinoline-7-(8H)-one 7.2-methyl-2-
Phenyl-1,3-dioxin[3,2-f]quinolin-7-(8H)-one 8,2-butyl-2-methyl-1,3-dioxin [
3,2-f) Quinolin-7-(8H)-one 9,2-tertbutyl-2-methyl-1,3-dioxin [3,2-'fl Quinolin-7-(8H)-one of the present invention The compound can be produced by various methods, but an example is the method shown in Reaction Formula 1 below.

Reaction formula-1 [In the formula, R1 and R2 are the same as above 1 Reaction formula-1 above
As shown, the dioxynoquinoline derivative of the present invention represented by -M formula CI) is obtained by condensing 6-hydroxyquinolin-2-one represented by formula (II) and formalin by a conventional method, 6-hydroxyquinolin-5-hydroxymethyl-2-one represented by formula (TII) was obtained, and the obtained compound (III) and a ketone (or aldehyde) represented by formula (IV) were treated in a conventional manner. It can be produced by reacting with

The above condensation reaction is carried out using an aqueous solution of a basic compound as a condensing agent, but in addition to this, a wide variety of known condensing agents used in this type of reaction can be used, such as sodium hydroxide. , potassium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, calcium oxide, barium oxide, zinc oxide, lead oxide, sodium acetate,
Examples include zinc dust and potassium cyanide.

The ratio of 6-hydroxyquinolin-2-one (II) and formalin used in the above method is preferably equivalent to -1.5 times the molar amount of the latter to the former. Further, the reaction temperature is not particularly limited, but is 0°C to 5°C.
The zero reaction time, which is carried out at 0°C, preferably 20°C to 30°C, is usually 1 to 24 hours, preferably 3 to 12 hours.

The starting material 6-hydroxyquinolin-2-one (II) used in the above method is a known compound, for example, Journal of Organic Chemistry, 1968.
Volume 33, page 1089, Volume 36, 1971
It can be produced by the method described on page 3490.

In addition, 6-hydroxyquinoline-5-hydroxymethyl-2-one (111) and ketone (or aldehyde) (
The ketal (or acetal) forming reaction with IV) is
It is carried out using an acid as a catalyst. As a catalyst, a wide range of known catalysts used in this type of reaction can be used, such as hydrochloric acid, sulfuric acid, calcium chloride, ammonium chloride,
Examples include hydrogen bromide, p-toluenesulfonic acid, trifluoroboric acid etherate, carboxylic acid, selenium oxide, phosphoric acid, aluminum chloride, zinc chloride, titanium tetrachloride, and the like.

Any inert solvent that does not affect the reaction can be used as the reaction solvent, such as dimethyl ether,
Diethyl ether, dioxane, tetrahydrofuran (
THF) and the like.

The reaction temperature is not particularly limited, but is usually 0°C to 15°C.
The zero reaction time, which is carried out at 0°C, preferably from 0°C to room temperature, is usually 0.5 to 12 hours, preferably 0.5 to 5 hours.

The compound of general formula (r) produced in this manner can be easily isolated and purified by conventional separation means after the completion of the reaction.

Examples of the separation means include recrystallization, solvent extraction, column chromatography, and liquid chromatography.

When preparing the compound of the present invention into a pharmaceutical, general formula (I,)
It includes embodiments containing the compound represented by the formula in a mixture with a pharmaceutically acceptable diluent. The diluent herein means a material other than the compound represented by the general formula (I), and may be solid, semi-solid, liquid, or an ingestible capsule, and includes various materials. For example, lactose, starch, crystalline cellulose, polyethylene glycol, glycerin, medium chain fatty acids, triglycerides (miglyol:
(registered trademark), etc.

The medicament of the present invention can be applied by a conventional method in the field. For example, for improving cerebral circulation due to cerebrovascular disorder, 50 to 200 mg/day is orally administered.

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

1. Production Example 1 of the Compound of the Present Invention 80 g of 6-hydroxyquinolin-2-one was suspended in 200 ml of 35% formalin, and while cooling with ice water and stirring, it was added dropwise little by little to 50 g of a 50% aqueous sodium hydroxide solution at room temperature. Stir for 3 hours.

After the reaction is complete, add 1! of the reaction solution! ! Pour into ice water and add 20% MC.
Neutralize with I solution and filter off the precipitated white crystals. The crude crystals collected by filtration were recrystallized with methanol to give 6-hydroxy-
85 g of 5-hydroxymethylquinolin-2-one was obtained.

8 g of the obtained 6-hydroxy-5-hydroxymethylquinolin-2-one was dissolved in 12 ml of acetone, 1-THF 4
Suspended in 0 ml of the mixed solution, 12 ml of BFs-OfCJs) was added dropwise while stirring while cooling with ice water, and the solution was stirred at room temperature for 3.
Stir for 0 minutes. After the reaction is complete, pour the reaction solution into 500 ml of ice water and filter off the precipitated white crystals. The crude crystals were recrystallized from methanol to give 2,2-dimethyl-1,3-dioxin[3°2-f]quinolin-7-(8H)-one 6
I got g.

Example 2 The compounds shown in Table 1 were synthesized in the same manner as in Example 1.

- In the 椴 type (engineering), Table 1 Example 1 R2 yield Hl-NMR (CDC1s+DMSO]CH
, - - CH, - C*Hs- CHs-62% 5.02 (2H,s, -CHz-
1+1,55 (6H,s, -CH5) H-71% 5.14 (2H,s, -CHs-115
, 24 (6H,s, -CHal H-83% 5.17 2H,q, J: 5.2Hz.

-CL-) + 5.15 (2H+ 5rCH*-1
, 1,53(3H,d, J=5,2)1z, -CH
5) CHs-33% 5.05 (2H,s, -CHz-)+
(CH312CH- aHs- aHs- C4H, - - - CHs- C1, - 60% 58% 15% 90% 1.81 (2H, q, J・7°6Hz.

-CH2-111-47C3H131-CH, ], 1.
01f3H,t, J=7,6Hz, -cu31 5,16 (2H,s, ArCH20).

4.76 (IH, d, J = 4.6Hz.

0-C)[-01 6,00(IH,s, -GHz-1.

5.41 (IH, d, J = 15Hz -CH, -1, 5,41 (IH, d, J = 15Hz,
-CH2-1,5,28 flH, d, J: 15Hz, -CH2-) 5.05 (IH, d, J=15.IHz-C1,-),
4.74(LH, d, J=15.1Hz, -(:Hl
-1,1,82(3H,s, -CHx) 5.03f2H,s, -CH21,1 8~1.9 f9H+ m, -C4H9) 11.46
f3H,s, -CHll (CH313C-C1, -64% 5.05(2H,d
, J=4.64Hz-C1,-), 1.12(9H,s
, -CHs) s l + 1-38 (3Hr 3
+ -C)r, 1 Aggregation Table 2 2. Pharmacological Test: The compounds obtained in the above examples were evaluated for their medicinal efficacy.

Test Example 1 Platelet aggregation inhibitory effect As an evaluation of the platelet aggregation inhibitory effect of the compound of the present invention, AD
The inhibitory effects of P, PAF, arachidonic acid (AA), and collagen on each aggregating agent were investigated in vitro (rabbit platelets). The results are shown in Table 2.

6 45 10 12 35 8 10 18 9 21 41 12 9 39 6 47 91 24 200<200< 18880
140 100 49 78 48 Test Example 2: Blood Pressure Lowering Effect To evaluate the blood pressure lowering effect of the compound of the present invention, the compound was dissolved in dimethyl sulfoxide and a fixed amount was intravenously injected to a dog.

The results are shown in Table 3. In the table, the numerical values indicate the dose (ED*.: mg/kg) required to lower blood pressure by 30%.Table 3 Compound EDso: (mg/kg).

1. v.

) Example l 〃 2 〃 3 〃 4 〃 5 0, 050 0, 070 0.116 0, 170 0, 200 Table 4 Compound E D so (mg/kg+ 1.V,)004
8 0053 0110 0050 0062 ED,. : Dose required to increase carotid artery blood flow by 30% Test Example 3: Carotid artery blood flow increasing effect In order to evaluate the effect on the circulatory system, each of the compounds of the example was dissolved in dimethyl sulfoxide, and a certain amount was administered to dogs. was injected intravenously, and changes in carotid blood flow were measured. The results are shown in Table 4.

3. Toxicity test Acute toxicity of the compounds obtained in the above examples was evaluated.

Test Example 1 In order to evaluate the acute toxicity of the compound of the present invention, the compound was administered at 0.
The suspension was suspended in 5% CMC and orally administered to ddY mice, and the presence or absence of survival or death was examined 3 days after oral administration.

Table 5 Compound The results are shown in Table 5.

LDsa: (mg・ kg.

p・0゜) Weigh out the above ingredients, mix them uniformly, and then mix them by a conventional method.
1000 tablets of if 132 mg were obtained.

Claims (3)

[Claims] (1) General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 and R_2 are independently hydrogen atoms,
lower alkyl group or phenyl group] A dioxynoquinoline derivative represented by: (2) General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 and R_2 are independently hydrogen atoms,
lower alkyl group or phenyl group] A pharmaceutical composition comprising a dioxynoquinoline derivative represented by the following as an active ingredient. (3) The pharmaceutical composition according to claim 2, which is an antithrombotic agent, a cerebral circulation improving agent, an antihypertensive agent, an anti-asthma agent, an anti-inflammatory agent, and an anti-ulcer agent.