JPH0259575A - Benzoxazolone derivative or salt thereof - Google Patents

Abstract

NEW MATERIAL:The benzoxazolone derivative of formula I (A is 5- or 6-membered heterocyclic group containing 1-3 N atoms and optionally having one or more substituents selected from 1-5C alkyl, cyano, carboxyl, 1-5C alkoxycarbonyl, hydroxyl, 1-5C alkoxy, amino, 1-5C alkylamino, 2-6C dialkylamino, 2-5C acylamino and carbamoyl group on the ring) and its salt. EXAMPLE:6-(4-Pyridylamino)-2(3H)-benzoxazolone. USE:Useful as a cardiotonic. It can be administered orally or parenterally and exhibits persistent effect. PREPARATION:The compound of formula I can be produced according to the reaction formula (X is halogen) by reacting a compound of formula II with a compound of formula III in an inert solvent at 50-200 deg.C for 0.5-10hr.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a novel benzoxazolo/
It relates to derivatives or salts thereof.

[Problems to be solved by conventional technology and invention]

Cardiotropes have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used to treat heart failure.

However, many of these inotropic agents have disadvantages, such as having an extremely narrow safety margin, causing arrhythmia, or having a transient inotropic effect, making them unsuitable for oral administration.

The present inventors have searched for a compound that is highly active as a cardiotonic agent and can exhibit a sufficiently long-lasting effect, and as a result of intensive studies, they have arrived at the present invention.

[Means to solve the problem]

That is, the gist of the present invention is the following general formula (I): (In the above formula, A represents a !-membered or ot-membered heterocyclic group containing 7 to 3 nitrogen atoms, and on the ring, C1 to C5 alkyl group, cyano group, carboxyl group, C+ to C5 alkoxycarbonyl group, hydroxyl group, 01 to C5 alkoxy group,
Amino group, alkylamino group of CI-C5, C2-C6
may have at least one substituent selected from a dialkylamino group, a C2-C5 acylamino group, and a carbamoyl group. ) Benzoxasilone derivatives or salts thereof.

The present invention will be explained in detail below.

Specific examples of A in the above general formula (1) include a pyridyl group, a pyridazinyl group, a picimidyl group, a pyrazinyl group,
Contains 7 to 3 nitrogen atoms such as δ-triazinyl group, ω-triazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group! Examples include a heterocyclic group having a membered ring or a membered ring, and may have at least one substituent on the ring.

The substituents include methyl group, ethyl group, propyl group,
C1-C6 straight chain or branched alkyl group such as butyl group; cyano group; carboxyl group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
C1-C5 straight-chain or branched alkoxycarbonyl group such as butoxycarbonyl group; Hydroxyl group: C1-C5 straight-chain or branched alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group; Amino group: Straight chain or branched alkylamino groups of CI-Cs such as methylamino group, ethylamine group, propylamino group, butylamino group; C2 to C6 straight chain such as dimethylamino group, diethylamino group, dipropylamino group, etc. or a branched dialkylamine group; a C2-C5 straight-chain or branched acylamino group such as an acetylamino group, a propionylamino group, a butyrylamino group; and a carbamoyl group.

Furthermore, specific examples of the benzoxacylone derivative represented by the above general formula (1) include the compounds shown below.

The benzoxacilone derivative according to the present invention is produced, for example, by the following route.

Also included within the scope of the present invention are pharmaceutically acceptable salts of the above compounds. Examples of the above salts include salts of mineral acids such as hydrochloric acid and phosphoric acid, and salts of organic acids such as lactic acid and acetic acid. All of these compounds are useful as cardiotonic agents.

Next, the method for producing the compound of the present invention will be explained (In the above formula, A is as defined above, and X represents a halogen atom.) That is, the above compound (n) and compound (DI) are combined with N, N
- The desired benzoxacylone derivative (1
) can be synthesized.

Note that triethylamine and l,! are used as bases. -Diazabisilo (z, 4t, o) - An organic base such as -7-undecene or an inorganic base such as potassium carbonate and sodium carbonate may be added.

Further, a copper compound may be used as a catalyst.

The above compound (II) used as a starting material is synthesized according to a conventional method, for example, by the route shown below.

(IV) (V) (II) (Vl) (■) When the compound of the present invention is used as a cardiotonic agent, it can be administered by an appropriate oral or parenteral administration method.

In this case, the forms to be provided include, for example, powders, granules, tablets, dragees, pills, capsules, liquids, etc. for oral administration, and wastes, suspensions, solutions, emulsions, etc. for parenteral administration. Examples include ampoules and injection solutions. Of course, a combination of these can also be provided.

For formulation, conventional methods in this field can be used.

In addition, the amount of the compound of the present invention to be administered as a cardiotonic drug depends on age, sex, body weight, sensitivity differences, administration method, administration timing/interval, severity of disease, physical condition, nature/preparation/type of pharmaceutical preparation, etc.
This will be determined by your doctor, taking into account the type of active ingredient.

For example, in the case of oral administration, 9t/day per body weight, 0,/
-/Om9tkf or so is selected, but of course it is not limited to this.

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following examples unless it exceeds the gist thereof.

Reference example/, +-amino-2(3)()-benzo(1)
≦−Nitro2 (j)()−Benzoxazoλ−
Amino! -nitrophenol 10. ♂1 and/ ,/'
-Carbonyldiimidazole//Jj1 N,N-dimethylformamide θrnl solution was heated on a 20°C oil bath for 7 hours.
The mixture was heated and stirred for hours. After cooling the reaction mixture with water, methanol 7
0θml was added and the precipitated crystals were collected and dried to obtain the above crude product ♂, 94tS' (yield 7/%).

(2) O-amino-λ(3H)-benzoxazo After the crude product ♂ obtained in the above synthesis reaction (1) was subjected to θθ1, the reaction was stopped and the catalyst was removed from the furnace. Add 1 rotnl of water to the furnace liquid,
100 g of methanol was distilled off under reduced pressure, and the precipitated crystals were collected. After drying, the above target object 2. j9f (yield 36cm)
I got it.

Reference example 2. teramino-2(JH)-benzo(1)j
- Nitro 2 (3H) - Benzoxazo reference collapse (1
10.) By the same treatment as 10. From ♂2 to the above crude product io, t31 (yield,
r4t%) was obtained.

(2)! -Amino, z(3H)-benzoxazo The same treatment as in reference (2) was performed to obtain the target compound 7.7-2F ( 〇Example/, t-
(¥-pyridylamino)-1(3H)-benzoxacilone ≦-amino, 2(J'H)-benzoxacilone 〇! Dissolve 7 g of N-methyl-2-pyrrolidone and
0.419 m of triethylamine under heating and stirring on an oil bath
1 and chlorpyridine hydrochloride/, 0 and 1 were added sequentially. After stirring at the same temperature for 2 hours, the reaction mixture was ice-cooled, acetone jjvtl was added, and the precipitated solid was collected. Dissolve the separated solid in warm water 2θ0 and cool on ice.
J- Sodium hydroxide was added to neutralize. The precipitated solid was collected and purified by silica gel column chromatography (solvent: chloroform/methanol eco theta//-+///; 0.2% acetic acid added). Fractions containing the target product were collected and concentrated, and the residue was treated with N,N-dimethylformamide 3.
0mg was added and dissolved, and after cooling on ice, N-hydrochloric acid/dioxane,
Add 2 ml, then add 100 ml of acetone and 1 ether
00ml was added. The precipitated solid was sold commercially and dried to obtain the hydrochloride salt of the target product as a pale yellow powder with the following physical properties.

Yield: 1. 3t゛ (yield? 3t), melting point: >3oo℃
IR: / 67! cm-' Example λ, r-(4t-pyridylamino)-2(3H)
- By treatment similar to Benzoxacilone Example/! -Amino 2 (JH
) - Benzoxacilone/,! From θV, a hydrochloride salt of the target product was obtained as a pale yellow powder with the following physical properties.

Yield: 2.06? (yield 7♂chi), melting point: 2F! ~IR
: 1670cm-'2J'
7°C (Degradation) Test Example The usefulness of the compound of the present invention as a cardiotonic agent was demonstrated by causing a significant increase in the contractile force of isolated guinea pig right atrium and isolated papillary muscle. The test method using isolated papillary muscle and its results are described.

O test method (a) Method using isolated guinea pig right atrium Weight: 20
A male guinea pig weighing 0 to 3 oy was hit on the back of the head, and the right atrium was immediately removed.

The right atrium ventricle ostium, 3! The organ was fixed at the bottom of an organ bath filled with 30 g of Krebs-Henslide solution kept at 0.degree. 9 for the Kreps-Henslide solution in the organ bath! A mixed gas consisting of 5% O2 and 5% CO2 was bubbled through. A thread was attached to the atrial appendage of the right atrium, the other end of the thread was connected to a transducer, and the isometric tension was measured.

The specimen has 0. ! A resting tension of 1 was applied. 30 days after specimen preparation
After stabilizing for a minute, the compound obtained in the above Examples/and λ dissolved in a solvent was added into the organ bath and one reaction was recorded.

(b) Method using isolated guinea pig papillary muscle Guinea pig right ventricular papillary muscle is used in the same manner as in (a) using isolated guinea pig right atrium; in this case, the specimen is
It was electrically driven via a platinum electrode with a square wave lasting 1 millisecond and having a voltage of j times the threshold, twice every 7 seconds.

O test results The rate of increase in contractile force of guinea pig right atrium and papillary muscle is shown in the table below.

Table 1

Claims (1)

[Claims] (1) The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) (In the above formula, A represents a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms. and C_1 to C_ on the ring
5 alkyl group, cyano group, carboxyl group, C_1~
C_5 alkoxycarbonyl group, hydroxyl group, C_1 to C
_5 alkoxy group, amino group, C_1 to C_5 alkylamino group, C_2 to C_6 dialkylamino group,
It may have at least one substituent selected from C_2 to C_5 acylamino groups and carbamoyl groups. )
A benzoxazolone derivative or a salt thereof represented by: