JPS6016425B2 - carbostyril derivatives - Google Patents

Description

[Detailed description of the invention] Industrial applications The present invention relates to novel carbostyril derivatives.

Conventional technology The compound of the present invention is a novel compound described in the literature.

Problems to be Solved by the Invention As will be described later, the object of the invention is to provide a compound useful as a therapeutic agent for end-of-breath breathing.

Means to solve problems According to the invention, the general formula [In the formula, RI represents a lower alkyl group.

R2 represents a lower alkenyl group or a lower alkyl group having one substituent selected from a hydroxyl group, a halogen atom, a cyano group, and a cycloalkyl group. Further, the bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ]
Provided are carbostyril derivatives represented by: and acid addition salts thereof.

The compound of the present invention represented by the above general formula (1} has 3-
It has an adrenergic nerve stimulant effect and is useful as a therapeutic agent for acute breathing.

In particular, of the 31 autonomic nerve receptors present in the body, the compound has little effect on 8, which is mainly distributed in the heart, and selectively acts on 82, which is mainly distributed in the bronchus. 8, which may cause side effects when used as a treatment for acute asthma.
, there is very little risk of inducing cardiac dysfunction, angina pectoris, arrhythmia, etc. due to the effects of the drug, and from this point of view it is very useful as an agent for treating asthma. This will be explained in detail in the pharmacological test examples below. The lower alkyl group represented by RI in the above general formula {1} is a mirror or branched alkyl group having 1 to 4 carbon atoms, specifically a methyl, ethyl, propyl, isopropyl, butyl, ten-butyl group. etc. can be exemplified.

The lower alkenyl group represented by R2 has 1 to 1 carbon atoms.
straight-chain or branched alkenyl group of 4, specifically vinyl, allyl, 1-methylvinyl, 2-putenyl, 3-
Examples include butenyl and 1-methylallyl groups. Also R
Examples of the halogen atom substituted on the lower alkyl group represented by 2 include a chlorine atom, bromine atom, iodine atom, and fluorine atom, and examples of the cycloalkyl group include a cycloalkyl group having 3 to 7 carbon atoms, specifically a cycloalkyl group having 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclobentyl, cyclohexyl, and cycloheptyl groups. Representative compounds of the present invention are listed below.

0 8-hydroxy-5-[1-hydroxy-2-(2
-Hydroxyethylamino)propyl] Rubostyril 0 8-Hydroxy-5-[1-Hydroxy-2-(2
-hydroxy-1-methylethylamino)butyl]carbostyryl o 8-hydroxy-5-[1-hydroxy-2-(4-hydroxybutylamino)butyl]carbostyryl 0 8-hydroxy-5-[1-hydroxy-2-( 2-hydroxyethylamino)propyl]-3,
4-dihydrocarpostyril o 8-hydroxy-5-[1-hydroxy-2-(2-hydroxy-1.1 dimethylethylamino)ethyl] Rubostyryl o 5-[
1-hydroxy-2-(2-cyanoethylamino)propyl]-8-hydroxycarpostyryl 0 8-hydroxy-5-[1-hydroxy-2-(3-cyanopropylamino)propyl]-3,4-dihydrocarpostyryl o 5-[1-Hydroxy-2-(2-chloroethylami/)propyl]-18-hydroxycarbostyryl o 5-{1-hydro.

xy2-(3-fluoropropylamino)butyl)-8
-Hydroxycarbostyryl 0 5-[1-Hydroxy-2-(2-chloro-1-methylethylamino)ethyl-8-hydroxycarbostyryl o 5-[1-Hydroxy-2-(2-chloroethylami/)bropyru-8-Hydroxy-3 ,4-dihydrocarbostyryl o 5-(2-allylamino-1-hydroxypropyl)-8-hydroxycarbostyryl o 5-[1-hydroxy-2-(3-butenylamino)butyl]-8-hydroxycarbostyryl o 5-(2 -Alylamino-1-hydro.

xypropyl)-8-hydroxy-3,4-dihydrocarbostyryl 0 5-[2-cycloheptyl-1-methylethylamino)-1-hydroxypropyl]-8-hydroxycarbostyryl o 5-[2-(2-cyc.

hexylethylamino)-1-hydroxybutyl)-8
-Hydroxycarbostyryl o 5-[2-(3-hexylpropylamino)-1-hydroxypropyl]-8-hydroxy-3,4-dihydrocarbostyryl of the present invention represented by the general formula [1] The compound can be synthesized by various methods, and a typical synthesis method includes the method shown in the following formula.

[In the formula, RI and R2 are the same as above] The compound of general formula (0) used as a starting material is known.

The reaction between the compound of general formula (b) and the compound of general formula (m) can be carried out without a solvent or in a solvent such as water, methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc. It will be held in The ratio of the compound of general formula (b) and the compound of general formula (m) to be used is not particularly limited and can be appropriately selected within a wide range, but when the reaction is carried out without a solvent, the former is usually used in proportion to the latter. It is best to use a molar to large excess amount, preferably a large excess amount, and when the reaction is carried out in the above solvent, the latter is usually used in an equimolar to large excess amount, relative to the former.
It is preferable to use a molar amount of 1.2 to 15,000 qC, and the reaction temperature is usually room temperature to about 15,000 qC, preferably room temperature to 50 qC, and the reaction is usually completed within 1 to 2 carp lifespans. A compound represented by formula (W) is easily produced. For the reduction reaction of the compound of general formula (W), conventionally known reduction methods such as palladium black, palladium carbon,
Catalytic reduction methods using platinum oxide, platinum black, Raney nickel, etc. as catalysts, ring element methods using sodium borohydride, lithium aluminum hydride, etc., reduction methods using metals such as zinc, iron, tin, etc. and acids, etc. can be widely used.

When performing reduction by the straw catalytic reduction method, water, methanol, ethanol, isopropanol, acetic acid, dioxane,
Using a conventional solvent such as tetrahydrofuran, in the presence of the above-mentioned catalyst, in a hydrogen atmosphere, usually at normal pressure to 2 p atm, preferably at normal pressure to 5 atm, at a temperature usually from room temperature to 100°C, preferably from room temperature to 50 pm. It is better to react with The amount of catalyst used is usually 0.1 to 40% by weight, preferably 5 to 2% by weight, based on the compound of general formula (W). The reaction time is usually 1 to 1 hour. In addition, when reduction is carried out using a reducing agent such as sodium borohydride, the reducing agent is used in an amount equivalent to 20 times the molar amount of the compound of general formula (W), preferably 1.5 to 3 times the molar amount. The reaction may be carried out in a conventional solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, acetic acid, etc., usually at -30 to 70 qo, preferably at 0°C to room temperature, for about 30 minutes to 1 hour. The compounds of the present invention can be easily obtained by these reduction reactions. The compound of general formula (1) can be easily converted into an acid addition salt by reacting with a pharmacologically acceptable acid.

Such acids include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, hydrobrodic acid, phosphoric acid, acetic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, and mandelic acid. Examples include organic acids such as methanesulfonic acid, p-tosylic acid, and benzoic acid. Furthermore, the present invention naturally includes optical isomers and stereoisomers of the carbostyryl derivative represented by general formula (1).

Examples To further clarify the present invention, the general formula (W) is shown below.
Examples of the production of compounds of the present invention (Reference Examples) and production examples of the compounds of the present invention (Examples) are listed below.

Reference example 1 25 g of 5-(Q-promopropionyl)-8-hydroxycarbostyryl and 1 part of 2-hydroxythylethylamine
5' was added to form a homogeneous phase, then 50% of isopropanol was added, monkey hydrochloric acid was added to adjust the pH to ±1, and acetone-ethyl ether was added to re-precipitate.

The precipitate was dissolved in water, treated with activated carbon, the aqueous layer was concentrated to dryness, reprecipitated twice from methanol-acetone and ethyl alcohol, crystallized by adding acetone, washed with methanol-isopropanol, and dissolved in methanol. -Neutralized with potassium hydroxide, 8-hydroxy-5-[Q-(2-hydroxyethylamine)propionyl)carbostyryl 1 methanolate2. Get a squad. Melting point 164-165qo (decomposition) Example 10 5-[Q(2-hydroxyethylamino)propionyl]-8-hydroxycarbostyryl 1
Suspend 1 night of methanol hydrate in 50 drops of methanol, and add 1 g of sodium sewage hydride cooled in ice water little by little.

After the reaction is complete, concentrated hydrochloric acid is added to adjust the pH to 1, the precipitate is removed from the furnace, methanol-concentrated hydrochloric acid is added to the furnace solution, and the mixture is concentrated to dryness under reduced pressure. Add a small amount of water to the residue, leave it to stand, collect the precipitate in a furnace, wash with water-acetone, acetone, and ether in that order, and recrystallize the crude crystals from water to obtain 5-[1-hydroxy-2-hydroxyethylamine)propyl-8- Hydroxycarbostyril hydrochloride 1/Z pyrohydrate 0.3 is obtained. Melting point 2
16-2170 (Decomposition) Example 2 1 g of 5-[Q-(2-hydroxyethylamino)propionyl]-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride was suspended in 50 methanol and dissolved in potassium hydroxide. Adjust the pH to 9 with methanol, and add 0.5 g of sodium borohydride little by little under ice-water cooling.

After the reaction is complete, concentrated hydrochloric acid is added to adjust the pH to 1, the precipitate is removed from the furnace, methanol concentrated hydrochloric acid is added to the furnace solution, and the mixture is dried under reduced pressure. A small amount of water was added to the resulting residue and left to stand, the precipitate was collected in an oven, washed with water, acetone, acetone, and ether in that order, and recrystallized from water to give 5-[1-hydroxy-2-(
0.4 g of 2-hydroxyethylaminopropyl]8-hydroxy-3,4-dihydrocarbostyryl hydrochloride is obtained. Melting point 194-196oo (decomposition) reference example 25-
(Q-Bromop.

pionyl) -3 to 20g of 8-hydroxycarbostyryl
- Add 25 g of aminopropionitrile, incubate at room temperature for 2 hours, adjust the pH to ±1 with isopropanol-concentrated hydrochloric acid, add acetone, and collect the crystals. Add water and remove impurities in a furnace, concentrate the aqueous layer to dryness, add a small amount of water to crystallize it, recrystallize from methanol and ethyl ether, and obtain 51 [
Q-(2-cyanoethylamino)propionyl]-8-hydroxycarbostyryl hydrochloride monohydrate is obtained. The obtained crystals were neutralized with methanol-potassium hydroxide to give 5-
[Q-(2-cyanoethylamino)propionyl]-8
-Hydroxycarbostyryl monomethanolate 3.2 is obtained.

Melting point 150-151qo (decomposition) Example 3 5-[Q-(2-cyanoethylamino)propionyl]
1 g of -8-hydroxycarbostyril hydrochloride was suspended in 50 ml of methanol, potassium hydroxide-methanol was added to adjust the pH to 9, and the mixture was cooled with ice and water. Add the rudder little by little.

After the reaction is complete, add concentrated hydrochloric acid to make the pH≠1, remove the precipitate from the oven, add methanol concentrated hydrochloric acid to the solution, concentrate to dryness under reduced pressure, extract the residue with methanol, and remove methanol under reduced pressure. After concentrating to dryness, dissolve in a small amount of water and leave to stand. The precipitate is removed by furnace,
Wash with water-acetone, acetone, and ether in this order.
-[2-(2-cyanoethylamino)-1-hydroxypropyl]-8-hydroxycarbostyryl hydrochloride 11
/Zk 0.2 chicks are obtained. Melting point 204-207qC (
Decomposition) Reference Example 32-chloroethylamino hydrochloride 5 was dissolved in 100 g of water, a solution of 25.3 g of potassium hydroxide dissolved in water was added while cooling with ice and water, and then 5-( Q-promopropionyl)-18-hydroxycarbostyryl (3).

After the reaction mixture was stirred at room temperature for 1 hour, a 48% aqueous solution of hydrobromic acid was added to make it strongly acidic, and a large amount of water was added to remove impurities. The aqueous layer was concentrated under reduced pressure, and before drying, acetone was added and the precipitate was taken out in an oven. 200 M of water was added to remove the hardly soluble substances, which were then washed with water and acetone in that order.
6 g of 2-chloroethylamino)propionyl]-8-hydroxycarbostyryl hydrobromide are obtained. Melting point 15
9-161°C (Decomposition) Example 45 3 g of Q-(2-chloroethylamino)propionyl/-8-hydroxycarbostyryl hydrobromide was suspended in 100 methanol and dissolved in potassium hydroxide-methanol under cooling with ice water. pH〒9
and add sodium borohydride grade.

After the reaction is completed, concentrated hydrochloric acid is added to adjust the pH≠1, the precipitate is removed in an oven, the mother liquor is concentrated to dryness, and methanol and concentrated hydrochloric acid are added and the concentration to dryness is repeated. Add water to the residue, leave it to crystallize, take it out in a furnace, wash it (water, acetone, 7 liters of ethyl ether) and give 5
1-[2-(2-chloroethylamino)-1-1-lyhydroxypropyl]-8-hydroxycarbostyryl hydrochloride. 1
/ZK sum 2. Get the following. Melting point 156-159 0 (decomposition) Reference example 4 Allylamine 50' was added to 50 g of 5-(Q-furomopropionyl)-8-hydroxycarbostyryl, left at room temperature for 3 hours, and then concentrated to dryness under reduced pressure. , dissolved in isopropanol, adjusted to pH=1 with concentrated hydrochloric acid, reprecipitated three times from isopropanol-acetone-ether, dissolved the resulting precipitate in water, treated with activated carbon, and concentrated the aqueous layer under reduced pressure. After drying and crystallizing the residue with isopropanol, the crude crystals were recrystallized from methanol-acetone.
5-(Q-allylaminopromopropionyl)-8-hydroxycarbostyryl hydrochloride7. Get connected.

Melting point 253-254oo (decomposition) Example 5 5-(Q-allylaminopropionyl)-8-hydroxycarbostyryl hydrochloride 1. Suspend the crab in 50% methanol, adjust to pH≠9 with potassium hydroxide-methanol under ice-water cooling, and add sodium borohydride little by little overnight.

After the reaction is complete, concentrated hydrochloric acid is added to adjust the pH to 1, the precipitate is removed in an oven, and the mother liquor is concentrated to dryness. Concentrated hydrochloric acid-methanol was added to the residue to remove poron, a small amount of water was added to crystallize it, and the mixture was filtered and washed with water-acetone, acetone, and ether.
-(2-allylamino-1-hydroxypropyl)-8
-Hydroxycarpostyril hydrochloride 0. gain berth; Melting point 155-1570 (decomposition) 2 Reference example 55
Add 30 g of 2-amino-1-cyclobentylpropane to 30 g of 1-(Q-furomopropionyl)-8-hydroxycarbostyryl and mix thoroughly at room temperature.

After standing for 3 hours, excess amine was extracted and removed with ethyl ether, 300% water was added, and 47% hydrobromic acid was added to make it strongly acidic.

The aqueous layer is removed by decantation and extracted by adding two drops of water. Concentrate the aqueous layer, dissolve the precipitated oil in acetone,
Leave it to stand, remove the precipitated crystals in a furnace, wash with acetone, and rinse with 35-[Q
-(2-Cyclobenyl-1-methylethylamino)propionyl]-8-hydroxycarbostyryl hydrobromide6. Get a mallet. Melting point 221-22400 (decomposition) Example 6 35-
Q-(2-benzene-1-methylethylamino)
Add 100ml of methanol to 18-hydroxycarbostyryl hydrobromide (propionyl) and cool with ice water.
Add caustic soder methanol solution to pH≠8 and add 1.5 g of sodium boron hydrthalide in small portions.

After the reaction is complete, add concentrated hydrochloric acid to make it strongly acidic and remove the precipitate in the furnace.
The mother liquor was concentrated to dryness, concentrated hydrochloric acid-methanol was added to the residue, and the concentration and dryness was repeated to remove boron. The residue was crystallized from acetone and recrystallized from water to give 5-[2-(2-cyclobentyl-1-methylethylamino)-1-hydroxypropyl]-8-hydroxycarpostyryl hydrochloride.
11'Z pyrohydrate 0. get a place Enemy Ta points 173-176
00 Reference Example 6 5-chloroacetyl-8-hydroxycarbostyryl 1
Add 100% allylamine to the bamboo under ice-water cooling, and add 2% allylamine at room temperature.
After standing for a while, concentrate at low temperature.

The residue was dissolved in approximately 500 methanol, ethanol, and isopropanol, and concentrated hydrochloric acid was added under cooling with ice water to make it strongly acidic and allowed to stand. After concentrating the mother liquor to about half its volume, it is cooled, and the precipitated crystals of 9.0% are collected in a furnace. Dissolved in water-methanol, treated with activated carbon, concentrated to dryness, and recrystallized from water-atacetone to obtain 5-allylaminoacetyl-8-hydroxycarbostyryl hydrochloride (4.8%), melting point 277-279°C.
(Decomposition) Example 7 5-Alylaminoacetyl-8-hydroxyl 0 Rubostyryl Hydrochloride 4.0% methanol 50% was added, potassium hydroxide-methanol solution was added under ice-water cooling, and p
The pH is adjusted to 8.5, and sodium shelchloride hydride is added little by little. After the reaction is complete, concentrated hydrochloric acid is added to make it strongly acidic, and the precipitate (including the target product) is taken out in a furnace and washed several times with water.

After concentrating the mother liquor and removing shelf elements using a conventional method, it was extracted with methanol, concentrated to dryness, and combined with the previously obtained crystals and recrystallized from water (treated with activated carbon) to obtain 5-(2-allylamino-
1-Hydroxyethyl)-8-hydroxycarpostyril hydrochloride2. Get the key. Melting point 232-23yo (decomposition)
Reference example: 25 g of 75-(Q-fromoptyril)-8-hydroxycarpostyril and 200 g of allilamine under cooling with ice water.
After leaving at room temperature for 3 hours in the dark, concentrate at room temperature, add 500 ml of water and mix well, and add concentrated hydrochloric acid while cooling with ice water to make it strongly acidic. Insoluble matter is removed in an oven, treated with activated carbon, and the mother liquor is concentrated at a low temperature. When the amount of water becomes low, the acetone washing is repeated, a small amount of isopropanol is added to the residue and mixed, and acetone is further added and left to stand, and 12.5 g of precipitated crystals are collected in a furnace. Suspend this in a small amount of water, make it alkaline by adding an aqueous potassium hydroxide solution, collect the precipitated crystals, suspend in methanol, add concentrated hydrochloric acid to make it strongly acidic, and add ethyl ether until it is saturated. put. The precipitated crystals were collected in a furnace to obtain 7.6 g of 5-(Q-allylaminobutyryl)-8-hydroxycarbostyryl hydrochloride. Melting point 250-253°C (decomposition) Example 8
51 (Q-allylaminobutyryl)-8-hydroxycarbostyryl hydrochloride 7
100 g of methanol is added to the solution, a potassium hydroxide-methanol solution cooled in ice water is added to adjust the pH to 9, and 10.5 g of sodium shelf hydride is added little by little.

After the reaction is completed, concentrated hydrochloric acid is added to make it strongly acidic, the precipitate is removed from the oven, and the methanol layer is concentrated. Shelf elements are removed by a conventional method, and salt is removed by methanol extraction. The ethanol layer was concentrated to dryness, the residue was crystallized by adding acetone, and recrystallized from methanol-ethyl ether (removal of Z salt and treatment with activated carbon) to obtain 5-(2-allylamino-1-hydroxybutyl). 18-Hydroxycarbostyril hydrochloride 2.
Get 8 evenings. Melting point 141-145L. ○
-Reference Example 8 Add allylamino 40' to 25-(Q-bromobentanoyl)-8-hydroxycarbostyryl and heat at 40 q○ in an argon gas atmosphere for 1 hour to dry the reaction solution. The residue was dissolved in methanol, adjusted to pH 1 with concentrated acid, and concentrated to dryness. The residue is dissolved in water 2, and the insoluble matter is removed in an oven. Add an aqueous sodium hydroxide solution to adjust the pH to 11 and remove the precipitated oil. The aqueous solution was adjusted to pH 1 with concentrated hydrochloric acid and concentrated to dryness. The residue is dissolved in a small amount of water, left to stand for one day to crystallize, and taken out in a furnace. The crude crystals were recrystallized from ethanol-3-ether to give 1/2 of 5-(Q-allylaminobentanoyl)-8-hydroxycarbostyryl hydrochloride.
5.3 g of hydrate are obtained. Melting point 242.5-243.50
0 (disassembly) Example 9
35-(Q-allylaminobentanoyl)-8-hydroxycarbostyryl hydrochloride was diluted with 40% methanol.
Dissolve the solution in water, adjust the pH to 9-10 with sodium hydroxide-methanol, and gradually add sodium chloride hydride.
Boil at room temperature for 5 hours.

Concentrated hydrochloric acid is added to the reaction solution to adjust the pH to 1-2 and remove the precipitate. The mother liquor was concentrated to dryness, methanol was added to the residue, and poron was removed by drying. The residue is crystallized with methanol-acetone ether and filtered. The crude crystals were recrystallized from water to obtain 5-(1-hydroxy-2-allylaminobentyl)-8-hydroxycarbostyryl hydrochloride quarter hydrate. Get thighs. Melting point 154-15600
Reference Example 9 Allylamine 40' was added to 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyryl 1 female,
Incubate for 1 hour at 20 qo under an argon gas atmosphere.

The reaction solution was concentrated to dryness, the residue was dissolved in methanol, and concentrated hydrochloric acid was added to adjust the pH to ≠1, followed by concentration to dryness. Add inpropyl alcohol to the residue to crystallize it and remove the tears. The crude crystals were recrystallized from water-acetone to obtain 7.0 g of 5-allylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride. Melting point 2I. 0~256.0q
○(Decomposition) Example 105-allylaminoacetyl-8
-Hydroxy-3,4-dihydrocarbostyril hydrochloride was dissolved in 50% sodium hydroxide, adjusted to pH≠10 with sodium hydroxide-methanol, and gradually added sodium hydroxide, and dissolved at room temperature. Time reacts.

After adding methanol-hydrochloric acid to the reaction solution and adjusting the pH to 2, the impurities were removed in an oven. The mother liquor is concentrated to dryness (below 40°C), methanol is added to the residue, and boron is removed by concentrating to dryness, and the residue is crystallized with methanol-acetone and filtered.
The crude crystals were recrystallized from methanolacetone to obtain 1.1 g of 5-(1-hydroxy-2-allylaminoethyl)-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride 1/Z pyrohydrate. Examples of pharmacological tests conducted on compounds of the present invention with a melting point of 179 to 180 points are listed below.

Pharmacological test example A Extracted guinea pig bronchus test Male Hartley guinea pig (weight 450-600 g
), and the trachea was removed using Constantin's method [J. W.
Constantine, J. Phann. Phann
acol. 17, 384 (1965).

3 specimens, 9500 carbon dioxide - 5% oxygen gas 0
Aerated lock solution (154 mmol of common salt, 5.6 mmol of potassium chloride, 2.2 mmol of calcium chloride, 2.4 mmol of sodium bicarbonate, 5.6 mmol of dextrose)
The pressure transducer (Sanei side device,
45072).

Acetylcholine (10-
Fetolamine (3×
10-Mo/()15I solution was added. Van Rossum's method [J. M. Va Nagi ossum. , AJch. lnt
．． Phannacodyn. Ther, 143,
299 (1963)], the test drug was administered cumulatively into the interstitial fluid. The response is expressed as a percent change relative to 100% of the maximum response of relaxation caused by isoproterenol. ED5 of test drug. The value was determined and compared with that of isoproterenol. Isoproterenol was used as a control compound. B. Total output guinea pig atrial test Performed using the same apparatus as Test A above.

The minimum load tension is set at 1 g and the number of spontaneous contractions is determined. The dose of the test drug is gradually increased and the response is measured by single administration. At least 5 washes and equilibration were performed between each dose before the next dose. The ED medical value of test drug 2 was determined and compared with that of isoproterenol. Isoproterenol was used as a control compound. Tests A and B above were conducted on the compounds listed in Table 1, and the results obtained were calculated according to the following formula, based on the results for isoproterenol, and are also listed in the same table.

Test A: 82 effect = ED5 of isopterenol.

E Hiroshi of the offering compound. Test B: 8, Effect = ED25 of isoproterenol ED25 of test compound Table 1 From the above Table 1, it is clear that the compounds of the present invention have very little effect on 8, and have high selectivity for 82. .

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a lower alkyl group. R^2 is a lower alkenyl group or hydroxyl group, a halogen atom,
It represents a lower alkyl group having one substituent selected from a cyano group and a cycloalkyl group. Furthermore, the bonds at the 3rd and 4th positions of the carbostyril skeleton do not show single or double bonds.
] Carbostyryl derivatives and acid addition salts thereof.