JPH04288072A - Alkylenedioxybenzene derivative and antianxiety agent containing the same as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new compound, having the ability to bind to 5-HT receptors and useful as an antianxiety agent. CONSTITUTION:A compound expressed by formula I [(m) is 2-5; (n) is 1-3], e.g. 5-[3-{(2S)-(1,4-benzodioxan-2-ylmethyl)amino} propoxy]-1,3-benzodioxole hydrochloride. Furthermore, the compound expressed by formula I is obtained by reacting a compound expressed by formula II with 0.5-10equiv. compound expressed by formula III in the presence of 0.5-10equiv. organic base such as triethylamine in a solvent such as benzene.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to a specific optically active alkylene dioxybenzene derivative or an acid addition salt thereof, and an anxiolytic drug containing the same as an active ingredient.

0002

[Prior Art and Problems to be Solved by the Invention] In recent years, with the rapid diversification of social environments, interest in mental anxiety has been increasing. Benzodiazepine compounds are known as conventional anti-anxiety drugs. In addition, in recent years, buspirone has been developed as a new anxiolytic drug with a different mechanism of action than benzodiazepine compounds.
) [N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,1-cyclopentane diacetamide hydrochloride], but there are also new anxiolytic drugs. It is hoped that it will appear.

On the other hand, as an alkylene dioxybenzene derivative, a compound of the following formula (II) is used.

[Formula 2] (wherein, R represents a hydrogen atom or a lower alkyl group,
X represents an oxygen atom or a methylene group, p represents an integer of 1 to 3, and q represents an integer of 3 or 4. ) and the same compound is known to have a good blood pressure lowering effect. (Unexamined Japanese Patent Application No. 57-108088, 58-21
9114). However, the existence of its optical isomers was not known, and furthermore, the anxiolytic effects of such compounds were not known at all.

0004

[Means for Solving the Problem] As a result of repeated studies focusing on alkylenedioxybenzene derivatives, the present inventors found that among the same compounds, a specific optical isomer or its acid addition salt has extremely good anti-anxiety properties. It was discovered for the first time that this method has an effect, and the present invention was completed. That is, the gist of the present invention is that the following general formula (I)

An alkylene dioxybenzene derivative or an acid addition salt thereof represented by the formula (wherein, m represents an integer of 2 to 5, and n represents an integer of 1 to 3), and the same as an active ingredient. Existing in anti-anxiety drugs.

To explain the present invention below, the alkylene dioxybenzene derivative used in the present invention has the general formula (I
). Among the compounds of the present invention, preferred compounds are those in which m represents 3 to 5 and n represents 1 to 5 in the above formula (I).
3 or an acid addition salt thereof. A more preferred compound of the present invention is a compound in which n represents 1 or an acid addition salt thereof.

Specific examples of preferred compounds of the present invention are shown in Tables 1 and 2 below. Examples of the acid in the acid addition salt of the compound of the present invention include hydrochloric acid, hydrooxalic acid, sulfuric acid,
Examples include inorganic acids such as phosphoric acid and nitric acid, and organic acids such as acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, and methanesulfonic acid. It will be done.

[0007]

[Table 1]

[0008]

[Table 2]

Next, the method for producing the compound of the present invention will be explained. The compound of the present invention can be produced by any suitable method, for example, by the following synthetic route.

[C4]

The starting material (III) can be prepared using conventional primary amine synthesis methods, such as Angewandte Chemie,
80,986 (1968), and the other starting material (IV) was synthesized according to the method described in
Of Medicinal Chemistry (Journal)
of Medicinal Chemistry)
, 20, 880, 1977. From these starting materials (III) and (IV), a conventional secondary amine synthesis method is used, for example, starting material (IV) is synthesized without a solvent or with an aromatic hydrocarbon solvent such as benzene, toluene, or xylene; ether, Tetrahydrofuran (THF),
Ether solvent such as dioxane; saturated hydrocarbon solvent such as n-hexane; acetonitrile; dimethylformamide; N-methylpyrrolidone; or dimethyl sulfoxide, preferably 0.5 to 10 equivalents of potassium carbonate or sodium carbonate. , 0.5 to 10 equivalents of amine derivative (III) in the presence of an inorganic base such as potassium hydroxide, sodium hydroxide, or sodium hydride, or an organic base such as triethylamine, pyridine, diisopropylethylamine, and -10 to 150 Compound (I) is produced by reacting at ℃ for 30 minutes to 2 days and purifying by a conventional method such as silica gel chromatography or recrystallization.

The compound of the present invention binds to the 5-HT1A receptor, which is one of the 5-hydroxytryptamine (5-HT) receptors, as shown in the Examples below. Conventionally, 5-
Compounds that bind to HT1A receptors, such as buspirone (
Buspirone) [N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,1-cyclopentane diacetamide hydrochloride] [Naunin-Sumi-
Doberx Achieve Fur Pharmacology (Na
unyn-Schmiedeberg's Arch
．． Pharmakol. ) 328, 467, 1985]
, or Ipsapirone [2
-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazole-3-(
2H)one-1,1-dioxydehydrochloride] and SM-3997 [3aα,4β,7β,7aα-hexahydro-2-(4-(4-(2-pyrimidinyl)-1-
Piperazinyl)-butyl)-4,7-methano-1H-isoindole-1,3(2H) dione citrate dihydrogen salt] [Naunyn-Schmied
eberg's Arch. Pharmakol. )
328, 467, 1985; Japanese Journal of Pharmacology (Japan.J.Phar
macol. ), 45, 493, 1987] are known to exhibit anxiolytic effects, and the compounds of the present invention can also be used as anxiolytic drugs with similar effects.

Namely, panic disorder with or without agoraphobia, agoraphobia, social phobia, simple phobia,
It is useful for the treatment or prevention of chronic and acute anxiety disorders (neurosis) such as obsessive-compulsive disorder (or obsessive-compulsive neurosis) and post-traumatic stress disorder; schizophrenia; manic depression; migraine, etc. When the compound of the present invention is used as an anxiolytic drug, it can be administered by any method, but it is preferably administered by the following method.

[0013] Namely, it is administered by parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or oral administration. The dosage depends on the patient's age, health condition, weight,
This is determined by the type of concurrent treatment, if any, the frequency of treatment, the nature of the desired effect, etc. In general, the daily dosage of the active ingredient is 0.001-10.0 mg/kg body weight, usually 0.001 to 10.0 mg/kg body weight.
05-3 mg/kg body weight, administered in one or more doses.

When the compound of the present invention is administered orally, tablets,
It is used in the form of capsules, powders, liquids, elixirs, etc., and in the case of parenteral administration, it is used in sterile liquid forms such as liquids or suspensions. When used in such forms, solid or liquid non-toxic pharmaceutical carriers can be included in the composition. As an example of a solid carrier, conventional gelatin type capsules are used. Alternatively, the active ingredient may be tabletted or packaged as a powder with or without adjuvants.

These capsules, tablets and powders generally contain from 5 to 95% by weight of active ingredient, preferably from 25 to 90%. i.e. 0.5 to 500 m for these forms of administration.
g, preferably 1 to 100 mg of active ingredient. As the liquid carrier, water or oil of animal or vegetable origin, such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, or synthetic oil, is used.

[0016] In general, physiological saline, dextrose or similar sucrose solutions, and glycols such as propylene glycol and polyethylene glycol are preferred as liquid carriers, and in particular, in the case of injections using physiological saline, the concentration is usually 0.5 ~20%, preferably 1-10% by weight of active ingredient. For liquid preparations for oral administration, 0.
Suspensions or syrups containing 5-10% by weight of active ingredient are preferred. In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers.

[0017]

[Examples] The present invention will be explained in more detail with reference to examples below, but the present invention is not limited to the following examples unless it exceeds the gist thereof. Example 1 5-[3-{(2S)-(1,4-benzodioxane-
Synthesis of 2-ylmethyl)amino}propoxy]-1,3-benzodioxole hydrochloride (Compound No. 1 in Table 1) 5-(3-aminopropoxy)-1,3-benzodioxole 5. 86 g and (2R)-2-tosyloxymethyl-1,4-benzodioxane (Journalof
Medicinal Chemistry, 20
, 880, 1977) was dissolved in 100 ml of acetonitrile, and triethylamine 2
．． Add 77 ml and stir under heating under reflux for 12 hours. After the reaction is complete, water is added and extracted with chloroform. The extract was washed with water and then dried over anhydrous sodium sulfate. The chloroform layer was concentrated and purified by silica gel column chromatography (chloroform-methanol) to give 5-[3-{
2.68 g of (2s)-(1,4-benzodioxan-2-ylmethyl)amino}propoxy]-1,3-benzodioxole was obtained.

Dissolve this in ethyl acetate and add 26% hydrochloric acid/
Add isopropanol. The generated crystals were collected by filtration to obtain 2.37 g of the title compound. Melting point 212-218℃
. 1H-NMR (DMSO-d6) δ9.16 (2H
, m), 6.89 (5H, m), 6.63 (1H, d,
J=2.4Hz), 6.37(1H, dd, J=7.5
, 2.5Hz), 5.95 (2H, s), 4.65 (1
H, m), 4.37 (1H, dd, J=12.5, 2.
3Hz), 4.02 (3H, m), 3.25 (4H, m
), 2.10 (2H, m) The obtained optically active form and the separately synthesized racemic form (synthesized according to the method described in USP 4,684,739) were respectively dissolved in pyridine.
After amidation with (S)-methoxytrifluoromethylphenylacetic acid chloride, it was analyzed by high-performance liquid chromatography (column: Waters Nova Pack C18), and the optical purity was determined by comparison. 99%e. It was more than e.

Example 2 5-[4-{(2S)-(1,4-benzodioxane-
In Synthesis Example 1 of 2-ylmethyl)amino}butoxy]-1,3-benzodioxole hydrochloride (Compound No. 4 in Table 1), 5-(3-aminopropoxy)-1
The title compound was synthesized in the same manner except that 5-(4-aminobutoxy)-1,3-benzodioxole was used instead of ,3-benzodioxole. Melting point 169-171
°C 1H-NMR (DMSO-d6) δ9.20 (2
H, m), 6.89 (5H, m), 6.61 (2H, d
, J=2.5Hz), 6.35 (2H, dd, J=8.
5, 2.5Hz), 5.94 (2H, s), 4.65 (
1H, m), 4.36 (1H, dd, J=11.8,2
．． 3Hz), 4.05 (1H, m), 3.90 (2H,
m), 3.10 (4H, m), 1.75 (2H, m)

[
Example 3 5-[5-{(2S)-(1,4-benzodioxane-
2-ylmethyl)amino}pentyloxy]-1,3-
Benzodioxole hydrochloride (Compound No. 7 in Table 1)
) (in Example 1, 5-(3-aminopropoxy)-1
The title compound was synthesized in the same manner except that 5-(5-aminopentyloxy)-1,3-benzodioxole was used instead of ,3-benzodioxole. Melting point 169-
173°C 1H-NMR (DMSO-d6) δ9.10 (2H
, m), 6.88 (4H, m), 6.78 (1H, d,
J=8.5Hz), 6.60(2H, d, J=2.5H
z), 6.34 (1H, dd, J=8.3, 2.5Hz
), 5.93 (2H, s), 4.65 (1H, m), 4
．． 36 (1H, dd, J=11.5, 2.3Hz), 4
．． 04 (1H, m), 3.88 (2H, t, J = 6.2
Hz), 3.20 (2H, m), 2.98 (2H, m)
, 1.71 (4H, m), 1.44 (2H, m)

00
Example 4 8-Hydroxy-2-(di-n-propylamino)tetralin ([
Binding using 3H]8-OH-DPAT)
Assay [Neuropharmacology (Neurop)
harmacol. ), 26, 139, 1987], the affinity of the compounds of the present invention for the 5-HT1A receptor was determined. Specifically, a rat brain is homogenized with Tris buffer, centrifuged, and then the precipitate is homogenized again with Tris buffer and incubated at 37° C. for 10 minutes. This is centrifuged again, and the precipitate is homogenized with Tris buffer containing pargyline, calcium chloride, and ascorbic acid, and subjected to a binding assay. (membrane specimen). The assay was performed by combining the membrane specimen with [3H]8-OH-DPAT and the test drug and incubating at 37°C for 10 minutes. Thereafter, it was immediately filtered using a Whatman GF/B filter, and the radioactivity remaining on the filter was measured by liquid chromatography. The binding ability of the test compound to the 5-HT1A receptor is determined by the following formula:

[0022]

[Formula 1] (In the above formula, [L] is the concentration of [3H]8-OH-DPAT, kd is the dissociation constant, and IC50 is [3H]8-OH-DPAT.
- the concentration of test compound required to inhibit DPAT binding by 50%. ) is expressed as the ki value calculated by That is, a compound with a lower ki value has a higher binding ability to the 5-HT1A receptor, and is therefore considered to be useful for application as an anxiolytic drug. The results are shown in Table-3. In addition, the table -
Compound No. 3 in is Compound No. 1 in Tables 1 and 2.
corresponds to

[0023]

[Table 3] Example 5 Vogel et al.
An anti-conflict effect test was conducted to evaluate the anxiolytic activity using the method of [Pharmacology] 21, 1, 1971]. Rats that had been deprived of water for 38 hours were placed in an anti-conflict effect measuring device, and the number of times they drank water was measured for 10 minutes without applying an electric shock. Rats that drank water 100 times or more were deprived of water for another 24 hours, placed back into the apparatus, and then
The number of shocks received was measured for 3 minutes under conditions in which an electric shock was given once each time the subject licked the drinking nozzle. Rats whose values were suppressed to 25 times or less were subjected to experiments as rats in a conflict state.

The test drug was orally administered, and one hour later, the number of shocks received was measured again for 3 minutes under the same conditions. Anti-conflict effects are evaluated by how much the test drug increases the number of shocks received compared to the number of shocks received by the control group. The results are shown in Table 4. In addition, compound No. in Table-4 is compound No. in Table-1. corresponds to

[Table 4]

Example 6 Acute toxicity test The compound of the present invention was administered to SD male and female rats at 0.5% CMC-N.
A suspension in an aqueous solution was orally administered, and symptoms were observed for 7 days. The ALD value (approximate lethal dose) of the compound of Example 1 was 100 mg/kg body weight. Example 7 Formulation Example (1) Tablet The following ingredients were mixed according to a conventional method and tableted using a conventional device. Compound no. 1
10 mg crystalline cellulose
21 mg cornstarch 33
mg lactose
65 mg Magnesium stearate 1.3 mg (2) Soft capsules The following ingredients were mixed according to a conventional method and filled into soft capsules. Compound no. 1
10 mg olive oil
105 mg lecithin
6.5mg (
3) Injection preparation The following ingredients were mixed according to a conventional method to prepare a 1 ml ampoule. Compound no. 1
0.7mg sodium chloride
3.5mg distilled water for injection
1.0mg

[0026]

EFFECT OF THE INVENTION The compound of the present invention has a higher ability to bind to 5-HT1A receptors than buspirone, a known anxiolytic drug, and is therefore expected to be used as an excellent anxiolytic drug.

Claims (2)

[Claims] Claim 1: An alkylene dioxybenzene derivative represented by the following general formula (I): (wherein m represents an integer of 2 to 5, and n represents an integer of 1 to 3); Acid addition salts. 2. An anxiolytic drug containing the compound according to claim 1 as an active ingredient.