JPH02262578A - Isoindolinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [X is H, halogen or nitro; Ar is (substituted) phenyl or (substituted) naphthylidinyl; one of Z<1> and Z<2> is H and the other is lower alkanoyloxy or OH, or the both are equally lower alkoxy] or salt of said compound. EXAMPLE:5-chloro-3-(4-hydroxypiperidine-1-yl)carbonylmethyl-2-(4-metho xyphenyl) isoindoline-1-one. USE:Used as antianxiety agent. Especially affect to central nervous system and has a slight side-effect such as hypnogenetic action of hypomyotonic action. PREPARATION:For instance, a compound expressed by formula II (Y' is hydroxy, etc.) is subjected to condensation with a compound expressed by formula III to afford the compound expressed by formula I (in a case of basic).

Description

[Detailed Description of the Invention] “Saku Retired Emperor and Momme! The present invention relates to novel inindolinone derivatives useful as medicines and the like.

BACKGROUND ART Among drugs that act on the central nervous system, research on various new compounds has been advanced in the field of anxiolytics.

Regarding isoindolinone derivatives, many reports have already been made (for example, JP-A-47-12322, JP-A-48-76892, JP-A-49-93392, JP-A-58-189163, etc.).

Problems to be Solved by the Invention Drugs that act on the central nervous system, such as anxiolytics, are required to be able to be administered orally and to have no side effects such as muscle relaxing effects.However, from these viewpoints, there are still no compounds that are satisfactory. has not been found.

Means for Solving the Problems The present invention provides compounds of the formula [wherein X is hydrogen, halogen or nitro, and Ar is optionally substituted phenyl or naphthyridinyl] that act on the central nervous system and are particularly useful as anxiolytics. , Zl and Z'' indicate that one is hydrogen and the other is lower alkanoyloxy or hydroxy, or both are lower alkoxy] and salts thereof.

Regarding the formula (1), examples of the halogen represented by X include fluorine, chlorine, bromine, and iodine, with chlorine being preferred.

Phenyl or naphthyridinyl represented by "A" may have one or two substituents, such as halogen (e.g. fluorine, chlorine, bromine,
iodine), hydroxy, lower (CI-4) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl)
, lower 7th (C,-,)alkoxy (eg, methoxy, ethoxy, propoxy, impropoxy, butoxy), nitro, amino, methylenedioxy, phenoxy, benzyloxy.

Lower (Cl-8) alkanoyloxy (acetyloxy, propionyloxy, butyryloxy), α- or ω-hydroxy lower (CI-)alkyl (e.g., hydrocarbon dimethyl, hydroxyethyl), benzoyl, amido, cyanogen, trifluoro Methyl, lower (C+-)alkylthio (
Examples, methylthio, ethylthio, propylthio, butylthio), lower (CI-)alkanoyl-lower (C,,) alkyl (e.g., acetyloxymethyl, acetyloxymethyl, propionyloxymethyl), lower (C, *> alkanoylamino) L-acetylamino/, propionylamino), alkoxycarbonyl (e.g., methoxycarbonyl).

methoxycarbonyl, methoxycarbonyl, impropoxycarbonyl, propoxycarbonyl), etc.

The above-mentioned substituents may be substituted at any position on the benzene ring or the naphthyridine ring, but especially at the 4-position on the benzene ring, the naphthyridine ring, for example 1
．． A compound having a substituent at the 5th or 7th position on the 8-naphthyridine ring is preferred. Further, 1,8-naphthyridine preferably has a bond at the 2-position.

As Ar, naphthyridinyl is preferable, and 1,8-naphthyridinyl substituted with a halogen at the 7-position is particularly preferable.

zl and Z! Regarding lower (C,-,)alkanoyloxy, formyloxy, acetoxy.

Probionyloxy, inpropionyloxy.

Examples include butyryloxy, and examples of lower (CI-,) alkoxy include methyloxy and ethyloxy.

Examples include propyloxy and isopropyloxy.

When the compound <r> of the invention is basic, it may form acid addition salts, especially physiologically acceptable acid addition salts, such as inorganic acids (e.g. hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (e.g. acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid,
Examples include salts with malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).

A compound represented by the formula [wherein X and Ar have the same meanings as above, and Y' represents hydroxy or a reactive derivative thereof] and a compound represented by the formula [wherein Zl and Zl have the same meanings as above] It can be produced by subjecting it to a condensation reaction.

Regarding compound (II), the reactive derivative as Y' is a halogen (for example, fluorine, chlorine, bromine, chlorine, etc., with chlorine or bromine being preferred).

Lower (C,-,)alkoxy (e.g., methoxy, ethoxy.

propoxy, impropoxy, butoxy), N-hydroxydiacylimide esters (e.g., N-hydroxysuccinimide ester, N-hydroxyphthalic imide ester, N-hydroxy-5-norbornene-2,3-
dicarboximide ester), etc.

Compounds where Y' is halogen, i.e. acid halides, are
Compounds in which Y' is hydroxy, ie, carboxylic acids, can be treated by methods known per se, for example with halidating agents (eg, phosphorus oxychloride, phosphorus oxybromide).

Halogenation with phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, cyanuric acid chloride, boron tribromide, hydrogen iodide) It can be manufactured by

The solvent used for halogenation may be any commonly used solvent, and for example, inert solvents such as chloroform, dichloromethane, dichloroethane, benzene, and toluene are preferred.

The reaction between compound (IF) and compound (I[I) is carried out by a method known per se. For example, compound (II: Y'=
hydroxy) to a compound (If: Y
' = halogen) and react with compound (III), or the compound (n: Y' = hydroxy) is directly reacted with an acid-activated side such as carbonyldiimidazole, dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide, etc. The following can be produced by reacting with compound (■) or directly reacting compound (II: Y'=lower alkoxy) with compound (III). These reactions are typically carried out using hydrocarbon solvents (e.g., pentane, hexane, benzene, toluene),
Halogenated hydrocarbon solvents (e.g. dichloromethane, chloroform, dichloroethane).

carbon tetrachloride), ether solvents (e.g. ethyl ether,
tetrahydrofuran, dioxane, dimethoxyethane)
, ester solvents (e.g. ethyl acetate, butyl acetate, ethyl propionate), amide solvents (e.g. dimethylformamide, dimethylacetamide).

hexamethylphosphonotriamide), in an organic solvent such as dimethyl sulfoxide, under cooling (-10°C to lO°C),
At room temperature (11'C~40℃) or under heating (41'C~
120°C), and the reaction time is usually 10
minutes to 12 hours. Moreover, compound (III) is compound (
It is preferable to use 1.0 to 3.0 equivalents based on (2). Furthermore, in this reaction τ, if necessary, organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylamine, triethylenediamine, and tetramethylethylenediamine, and sodium bicarbonate, potassium bicarbonate, and sodium carbonate are added.

It is carried out in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide.

When the reactive derivatives of the above-mentioned compound (II: Y'=hydroxy) are N-hydroxy diacylimide esters, the reaction of these reactive derivatives with the compound (■) is usually carried out using, for example, dichloromethane.

The reaction is carried out in a solvent such as tetrahydrofuran, chloroform, dimethylformamide, acetonitrile or water, but any solvent can be used as long as it does not inhibit the reaction. The reaction is carried out in the presence of the above-mentioned organic amine base or inorganic base, if necessary. The reaction temperature is usually -
10°C to 100°C, preferably 0°C to 30°C.

Regarding compound (II), the compound in which Y' is hydroxy is a compound in which Y' is lower alkoxy, that is, the ester form, by a method known per se, for example, an alkali metal hydroxide (e.g., sulfur hydroxide, sulfur hydroxide, Lithium hydroxide, potassium hydroxide), alkali metal carbonates (e.g. potassium carbonate, sodium carbonate).

lithium carbonate) or mineral acids (e.g. hydrochloric acid, sulfuric acid).

(nitric acid, phosphoric acid, hydroiodic acid), organic acids (eg, acetic acid).

It can be easily obtained by hydrolysis with propionic acid, trifluoroacetic acid, monochloroacetic acid, trichloroacetic acid, methanesulfonic acid, toluenesulfonic acid).

The solvent used for hydrolysis may be any commonly used solvent, such as water, lower (c 1-4) alkanols (eg, methanol, ethanol, propatool, butyl).

Dioxane, dimethylformamide and the like are preferred. Moreover, when using an organic acid, there is no particular need to use a solvent. The reaction is usually carried out at a temperature of about -5°C to 120°C, preferably 0°C to 80°C.

Compound (II: Y'='=alkoxy) can be produced by the following reaction.

(■) (VT) (It/) (II) [
In the formula, X, Ar, and Y' have the same meanings as above.] The compound of general formula (VI) serving as a starting material is J, Org.

Chege, -2Lko5-, 2273 (1961
) or Chew.

It can be produced according to the method described in Coma+un, + 245 (1968), but for example,
m, Ber, +40r 4850 (1907),
Bull, Soc, Chill, France.

26+ 749 (1959), 11 Farmac
o Ed, Sc, 23+448 (1968), A
rzneim, Forsch, +12+12
07 (1962) or according to these, compound (■) is reacted with an amine represented by the formula % formula % () [wherein Ar has the same meaning as above] to form compound (V). After manufacturing, J, Org.

Chat 26. 2273 (1961) or Chem.

Compound (Vl) can be easily produced according to the method described in Coa+sun, + 245 (1968).

Compound (II: Y'='=alkoxy) can be produced by reacting compound (VI) with a compound having the formula %(2) [wherein Y'=lower lower alkoxy]. The reaction between compound (Vl) and compound (■) is carried out in an organic solvent such as toluene, benzene, xylene, ethyl acetate, dimethoxyethane, dichloromethane, etc., but any other solvent may be used as long as it does not inhibit the reaction. Organic solvents may also be used. The reaction temperature is usually 10℃
- About 160℃.

Preferably it is 25°C to 120°C. The reaction time is usually about 10 minutes to 12 hours, preferably 30 minutes to 2 hours.

Compound (III) is known per se (Tetrahedron
+ 27 + 411 (1971), J. Che
ta, Soc,, (B), l O87 (1971
), J, Ches, Soc,, (B), l 2
7 (1970)) or can be easily produced according to the methods described therein.

Compound (1) of the present invention has optical isomers, and both of these isomers and racemates are naturally included within the scope of the present invention. Compound (1) of the present invention is usually obtained as a racemate, but if necessary, it can be divided into optically active forms by a method known per se to obtain each optically active form. For example, compound (I
I: Y'='=roxy) is optically resolved by a method known per se to obtain optically active (II), and then reacted with compound (I[) by the method described above to obtain the optically active compound of the present invention. (
1) can be manufactured. Compound (II: Y'
An example of an optical resolution agent for hydrochloride is cinchonine.

Examples include optically active amines such as prusin, quinine, and amino acids.

The compound (1) of the present invention acts on the central nervous system of mammals and has a strong specific binding ability to benzodiazepine receptors,
It shows strong anxiolytic effects in the anti-conflict test in U./T. The compound of the present invention has a minimum lethal dose (MLD) of 1000 mg/kg (P,
0. ), which is much larger than the minimum effective dose (MED) and has an extremely wide drug safety margin. For example, the compound (
■: However, Ar is 7-chloro-1,8-naphthyridine-2
The MED of the above anxiolytic effect in rats is 2
0 mg/kg (P, O,) or less.

The compound (I) of the present invention has a wider drug safety range than the above-mentioned known inindolinone derivatives and benzodiazepine drugs currently on the market as anxiolytics, and has a hypnotic or muscle relaxing effect as a side effect. It is useful as an anxiolytic agent for mammals including humans because it is very well separated from its effects, has extremely minimal side effects such as so-called drowsiness and light-headedness, and is highly effective when administered orally.

Examples of useful target diseases for the compounds of the present invention include various psychosomatic diseases such as autonomic nervous system imbalance, neurogenic emesis, neurodermatitis 2 alopecia areata, neurogenic angina, and neurogenic dyspnea. , anxiety neurosis, and can be used to prevent or treat these diseases. The compounds of the present invention also exhibit anticonvulsant activity. So, for example, epilepsy.

It can also be used to treat traumatic convulsions.

The compounds of the present invention are administered orally or parenterally to mammals including humans in various dosage forms such as tablets, granules, capsules, injections, and skewers. The dosage varies depending on the type of disease, symptoms, etc., but in the case of oral administration, 0.01 mg per day for adults who use boat fishing.
~200 tag, preferably O,la+g~20mg
It is.

1-Biochemical Test Example The affinity of the compound (1) of the present invention for benzodiazepine receptors was investigated using radioactive [3H] diazepam.

The specific binding ability to benzodiazepine receptors is described in the literature (
Nature+ 266 + 732 (1977)
;EuropeanJ, pharmacol,,
48, 263 (1978)). That is, the crude mitochondrial fraction obtained from the cerebral cortex of SD male and female rats aged 9 to 10 weeks was mixed with 5QmMT.
Suspended in ris-HC (l buffer (pH 7,4), test drug at several concentrations and 3H-diazepam (final concentration 2n)
M) was incubated for 20 minutes at 4°C. This suspension was then filtered through a Whatman GF/B glass fiber filter, and the radioactivity of sH-diazepam on the filter was measured using a liquid scintillation counter. The concentration of the test drug that inhibits the binding of 3H-diazepam by 50% is I.
Cs. value.

The results are shown in Table 1.

Table 1 Compound (1) I.C.I.

[Pharmacological test example]

The anxiolytic, muscle relaxing and hypnotic effects of the compound (1) of the present invention were investigated.

(1) Anxiolytic effect Vogel et al.'s method (Psychophara + acolo
gia+ 21.

1 (1970)), the anxiolytic effect was measured as follows. In an apparatus consisting of a large transparent box with a stainless steel grid floor and a small, opaque, dark box fitted with a water inlet, one electric stimulation was applied to the legs through the grid floor every 20 times the animal drank water. It was set to The test compound was orally administered to male rats (SD/JCL) that had been deprived of water for 48 hours, and 30 minutes later, they were placed in a recording device and the frequency of anti-hydration was measured for 3 minutes. The rate of increase was determined, and this was taken as the strength of the anxiolytic effect, and the minimum effective dose was determined.

(2) Muscle relaxation effect Using 6 rats per group, place the rats on a rotating rod with a diameter of 3.5c plow that rotates at a speed of 8 times per minute, and the animals fall from the rotating rod within 1 minute. We measured whether or not. The amount of test compound required for half of the rats to fall was calculated by dividing the amount by ED (J, Am, Pharma-ceutic
al As5ocation, 1dan, 208
(1957)).

(3) Hypnosis-inducing effect Using 8 mice per group, 30 minutes after oral administration of the test drug
25 sag/kg of bendoparbital was administered intraperitoneally in 30 minutes, and sleep enhancement was defined as a loss of righting reflex that lasted for 2 minutes or more within 30 minutes.

ED, the amount of test compound that shows sleep enhancement in half of the mice.

It was calculated by dividing the

Table 2 shows the anxiolytic, muscle relaxing and hypnotic effects of representative compounds (1).

Compound (1) Anxiolytic action 111 action Hypnosis-inducing action Minimally effective t EDs. EDs.

EXAMPLES The present invention will be explained in more detail by Examples, Formulation Examples, and Reference Examples below, but the present invention is not limited thereto.

Reference Example 1 5-ChloI=l-3-(1,4-dioxa-8-azaspiro[4,5]]decane-8-ylcarbonylmethyl-
2-(4-Methoxyphenyl)isoindolin-1-one To a solution of 3.32 g of 6-chloro-2-(4-methoxyphenyl)-3-oxoisoindoline-1-acetic acid in dimethylformamide 30, under water cooling, While stirring, 1.
4-dioxa-8-azaspiro[4,5]decane 1.5
7 g), 2.3 g of ethylamine, and 2.12 g of diethyl cyanophosphate were sequentially added. The reaction solution was further cooled with water for 1
Stir for hours. When 150 g of ice water was added to the reaction solution and left to stand, crystals precipitated. The crystals were taken out of the oven, washed with water, and then dried. This was recrystallized from ether with a melting point of 156-157°C.
4.13 g of colorless crystals were obtained.

Elemental analysis value Ct4H*sCQN! Calculated value: C63,08: H5,52: N
6.13 Experimental value: C63,26; H5,54:
N 5.92 Example 1 In the same manner as in Reference Example 1, 5-chloro-3-(4-hydroxypiperidin-1-yl)carbonylmethyl-2-(
4-methoxyphenyl)isoindolin-1-one was obtained.

That is, 6-chloro-2-(4-methoxyphenyl)
-3-Oxoisoindoline-1-acetic acid (4.50 g) was added to a solution of 3.5 g of dimethylformamide under stirring under water cooling, and 1.72 g of 4-hydroxypiperidine was added, and 3.) ethylamine was added. i, 3.21 g of diethyl cyanophosphate
were added sequentially. The reaction solution was further stirred for 2 hours under water cooling. When 160 d of ice water was added to the reaction solution and left to stand, crystals precipitated. The crystals were taken out of the oven, washed with water, and then dried. This was recrystallized from ether to give colorless crystals with a melting point of 180-182°C.
．． 69'g was obtained.

Calculated value as elemental analysis value C*tHtsN -0:
C63,69: H5,59; N 6.75 Experimental value: C63,12; H5,53; N 6
．． 71 Example 2 In the same manner as in Reference Example 1, 3-(4-hydroxypiperidin-1-yl)carbonylmethyl-2-(4-methoxyphenyl)-5-nitroisoindolin-1-one (melting point 204- 205°C) was obtained.

Elemental analysis value C□H,,N,0. Calculated value as:
C62,11; H5,45; N 9.88 Experimental value: C62,33: H5,53; N 9.
90 Reference Example 2 2-(7-chloro-1,8-naphthyridin-2-yl)
-3-(1,4-dioxa-8-azaspiro[4,5codecan-8-yl)carbonylmethylisoindoline-
1-one 2=(7-chloro-1,8-naphthyridin-2-yl)
-3-oxoisoindoline-1-acetic acid 20.4 g,
Triethylamine 16-. 1.4-dioxa-8-azaspiro[
10.4 g of 4,5 codecane and 16-diethyl cyanophosphate were added and stirred for 20 minutes. Water was added, and the crystals were collected in a furnace, washed with water, and dried to obtain 26.4 g of crude crystals. Methylene chloride - Recrystallized from ethyl acetate, melting point 238-
27.1 g of colorless crystals at 239°C were obtained.

Elemental analysis value: Calculated value as CtsHtsCfN+O:
C62,70; H4,84; N 11.7
0 Experimental value: C62,84; H4,90; N
11.67 Example 3 In the same manner as in Reference Example 2, 2-(7-chloro-1°8-cathyridin-2-yl)-3-(4,4-dimethoxypiperidin-1-yl)carbonylmethylisoindoline -1-one was obtained.

That is, 2-(7-chloro-1,8-naphthyridine-
2-yl)-3-oxoisoindoline-1 to acetic acid 1.
63 g, 1.7 dl of triethylamine in a mixture of 16°0-dimethylformamide, 1.20 g of 4,4-dimethoxypiperidine, and 1 diethyl cyanophosphate.
．． 3- was added and stirred for 40 minutes.

Water was added, and the crystals were collected, washed with water, and dried to obtain 1.71 g of crude crystals. Recrystallization from methylene chloride-ether gave 1.48 g of colorless crystals with a melting point of 207-208°C.

Elemental analysis value C,,H,,C12N 40. Calculated value: C62,43, H5,24; N 11.6
5 Experimental value: C62,66; )! 5.19;
N 11.77 Example 4 In the same manner as in Example 3, the compounds shown in Table 3 were obtained.

Formulation Example 1 (1) 2-(7-chloro-1,8-naphthyridine-2-
yl)-3-(4,4-dimethoxypiperidin-1-yl)carbonylmethylisoindolin-1-one
1g (2) Lactose 89g (3) Corn starch 29g (4)
Magnesium stearate Ig (1), (2
) and 15 g of corn starch and granulated with a paste made from 8 g of corn starch;
To this, 6 g of corn starch and (4) were added, and the mixture was compressed using a compression tablet machine to produce 1000 tablets with a diameter of 5 am containing 1 mg of (1) per tablet.

Reference example 3 2-(7-chloro-1,8-naphthyridin-2yl)-
3-oxoisoindoline-1-acetic acid (1) 2-(7-
A mixture of 46.0 g of chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one, 8 g of t-butyloxycarbonylmethylenetriphenylphosphorane, and 800 g of toluene was heated under reflux for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 2-(7-chloro-1,8-naphthyridine-2
-yl)-3-oxoisoindoline-1-acetic acid t-
54.5 g of butyl ester was obtained. Recrystallization from toluene-ether gave colorless crystals with a melting point of 210-211°C.

Elemental analysis values C,,H,. Calculated value as Cl2N303: C64,47; H4,92; N 10.
25 Experimental value: C64,66; H4,87,N
10.27(2) t-Butyl ester obtained above 54.
5g is trifluoroacetic acid 270? The reaction mixture was concentrated, ether was added, and the precipitated crystals were collected in a furnace. Crystal 47.0 with melting point 225-226℃
I got g.

Reference example 4 6-chloro-2-(4-methoxyphenyl)-3-oxoisoindoline-1 = acetic acid (1) 5-chloro-2-(4-methoxyphenyl)3-
A solution of 20 grams of hydroxyisoindolin-1-one and 27 grams of ethoxycarbonylmethylenetriphenylphosphorane in 200 grams of dry toluene was heated to 110 DEG C. for 3 hours. After cooling, the generated triphenylphosphine oxide is removed and the resulting crude crystals are recrystallized from ether.
6-chloro- as colorless crystals with melting point 129-131'C
19.6g of 2-(4-methoxyphenyl)-3-oxoisoindoline-t-acetic acid ethyl ester? It was.

Elemental analysis value Calculated value as C1, H18CQNo4:
C63,42; H5,04; N 3.89 Experimental value: C63,47; H5,06; N 3
．． 87(2) To a methanol solution of 16 g of the ester obtained in (1) above, add 50 d of water and 27 ml of potassium carbonate.
g was added. The reaction solution was stirred at 80°C for 3 hours.

After cooling, excess methanol was distilled off, and 3N hydrochloric acid was added to the residue.
50- was added. After collecting the precipitated crystals in a furnace, washing them with water, and drying them,
Recrystallization from methanol gave 14.2 g of the title compound, melting point 250-251°C.

Elemental analysis value Calculated value as C,,H,,CQNO,:
C61,54; H4,25, N 4.22 Experimental value: C61,53; H4,26; N 4.
30 Effects of the Invention The compound (I) of the present invention acts on the central nervous system and has few side effects such as hypnotic effects and muscle relaxant effects, so it can be particularly advantageously used as an anxiolytic drug.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X is hydrogen, halogen or nitro, Ar is optionally substituted phenyl or naphthyridinyl, Z^1 and Z^2 indicates that one is hydrogen and the other is lower alkanoyloxy or hydroxy, or both are lower alkoxy] or a salt thereof.