JPS61152671A - Dibenzo(b,e)oxepine derivative and antiallergic agent - Google Patents

Abstract

NEW MATERIAL:Dibenzo[b,e]oxepine derivative of formula I [R' is O-(CH2)m- NR<3>R<4> (m is 1-6; R<3> and R<4> are lower alkyl), NHR<5> (R<5> is lower alkyl, OCH2 CH(OR<6>)CH2OCH2CH3 (R<6> is H or acetyl) or OCH2CH2OCH2CH2OH; R<2> is S-NR<7>R<8> (R<7> and R<8> are lower alkyl) or 4-(lower alkyl)piperazino] or its salt. EXAMPLE:N-Hexyl-11-(2-dimethylaminoethyl)thio-6, 11- dihydrodibenzo[b, e]oxepi ne-2-carboxamide. USE:It has anti-allergic activity and is useful as a medicinal drug such as antiasthmatic, etc. Administered preferably by oral administration or by injection. PREPARATION:The compound of formula I can be prepared according to the reaction formula, by reacting the compound of formula II with thionyl chloride, and reacting the reaction product with the compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a dibenz(b,e)oxepin derivative and an antiallergic agent containing the same as an active ingredient.

BACKGROUND OF THE INVENTION Dibenz(b,e)oxepin derivatives are used as anti-inflammatory agents (see JoMed, Cheap, Vol. 23, p. 633, 1978) or for use in the treatment and control of allergic symptoms (U.S. Pat. 282.3
65) is known as prior art.

There is also an application filed by the present applicant regarding dibenz (b, e) oxepin derivatives and anti-allergic agents containing these as active ingredients (Japanese Patent Application No. 118-009-1982).

Problems to be Solved by the Invention There is a constant need for compounds that have novel and useful antiallergic effects.

[In the formula, R' is 0-(CH*)ill-NR3R'
(In the formula, m represents an integer of 1 to 6, and R3 and R4 represent the same or different lower alkyl groups.), NHR'
(In the formula, R5 represents a lower alkyl group.), 0CH2C
H (R') CHiOCHtCHs (In the formula, R" represents a hydrogen atom or an acetyl group.) or QC)
l*cHJcHiCH,OH, R2 is SA/NR
Dibenz (b, e) represented by 'R'' (wherein R7 and Rs represent the same or different lower alkyl group) or 4-lower alkylpiperazino group
Oxepin derivative [hereinafter referred to as compound (1)]. The same applies to other large-numbered compounds] or a pharmacologically acceptable acid addition salt thereof, and an antiallergic agent containing at least one of these compounds as an active ingredient.

The present invention will be explained in detail below.

In the definition of each group in formula (I), the lower alkyl group includes an alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, etc. (the lower of the 4-lower alkylpiperazino group) The same applies to alkyl groups).

Compound (1) can be obtained by the following manufacturing method.

Manufacturing method A (n)
(I) (In the formula, RI and R2 represent the same meanings as in the previous example.) Compound (II) and 1 to 2 equivalents of thionyl chloride are mixed in the presence of pyridine, if necessary, with methylene chloride, ethyl ether, benzene, or toluene. etc.+7) React in an inert solvent at an appropriate temperature from ice cooling to room temperature for 1 to 3 hours. Next, add 1 to 3 equivalents of the compound to compound (n) to the reaction solution itself, or if thionyl chloride is used in excess, distill off the excess thionyl chloride and add a solvent as necessary. Compound (1) is obtained by adding (III) and carrying out the reaction at an appropriate temperature from water cooling to room temperature for 1-3 hours.
to be generated.

Production method B (II)) Compound (Ia') and 1-3 equivalents of acetic anhydride are heated in the presence of pyridine in an inert solvent such as methylene chloride, ethyl ether, benzene, toluene, etc., from water cooling to room temperature. Compound (Ib) is produced by reacting for 1 to 5 hours at an appropriate temperature between

The final target products in each of the above production methods are isolated and purified using known methods, such as filtration, extraction with an organic solvent such as ethyl acetate or methylene chloride, drying, concentration, and then, if necessary, purification by recrystallization or column chromatography. It can be done by etc. Moreover, the compound (I[) used as a starting material can be obtained, for example, by the method disclosed in Japanese Patent Application No. 118.009/1983.

When obtaining a salt of compound (I), if compound (1) is obtained in the form of a salt, it may be purified as it is, or if it is obtained in a free form, the salt may be purified by a conventional method. That's fine.

The pharmacologically acceptable acid addition salts of compound (I) include:
Examples include inorganic acid salts such as hydrochloride, sulfate, and phosphate, and organic acid salts such as acetate, maleate, fumarate, tartrate, and citrate.

Next, specific examples of the present invention are shown in Table 1, and their structures are shown in Table 2.
Moreover, its physical and chemical properties are shown in Table 3.

Table 1 Table 2 Table Q2 Next, the antiallergic effect and acute toxicity test of this compound will be explained.

Anti-allergic effect test Anti-allergic effect is 48 hours homologo
usPCA (passive cutaneous
The results were investigated using the anaphylaxis test. In addition, as experimental animals, the body weight should be between 180 and 22 mm for antiserum collection.
Male Wistar rats weighing 0 g were used for the PCA test, and male Wistar rats weighing 120-140 g were used for the PCA test.

A) Preparation of anti-EW^rat serum 5totland and 5hare method (Can
ad, J, Physiol.

Anti-ovalbumin (Ew^) rat serum was prepared by Pharmacol, 52.1114.1974). In other words, aluminutnh EW^ of IIQg
The mixture was mixed with 20 mgl of ydroxide gel and 5ml of pertussis-diphtheria-tetanus combination vaccine Q, and administered subcutaneously to the paw of the rat in four divided doses. After 14 days, blood was collected from the carotid artery, and serum was separated and stored frozen at -80°C. 48 hours of this antiserum hoa + ologous P
The titer of C^ was 1:32.

B) 48-hour homologous PCA test on rats Using 3 rats per group, anti-EWA rat serum diluted 8 times with physiological saline was injected into two areas within the skin of the hair-removed back.
(Passive sensitization was performed by injecting 15 ml each.

After 47 hours, the compound of the present invention or its solution (physiological saline or CMC solution) was orally administered, and 1 hour later, the antigen εI
1% Evans blue saline containing IA 2■ 0.5
+I11/100 g was administered intravenously in the tail vein. After 30 minutes, the animals were bled to death, the skin was peeled off, and the amount of dye leaked from the blue-stained area was measured using the method of Katayama et al.
ol, Imrnunol.

22, 89 (1978) 3. That is, cut out the blue dyed part with scissors and add 1ml of IN KOH.
and incubated at 37°C for 24 hours.

Add 9 ml of 0.6N phosphoric acid/acetate:/(5:13) mixture, shake, centrifuge for 250 Orpm% 10 minutes, measure the absorbance in 620 μl of the supernatant, and calculate the amount of leaked dye using a calibration curve prepared in advance. was quantified. The average value of the two locations was taken as the value for one individual, and the inhibition rate for each individual was calculated using the following formula.

Suppression rate (%) = When the suppression rate was 50% or more, it was considered to be a positive PC^ suppression effect, and the minimum dose at which a positive case was observed in at least one out of three animals was defined as the minimum effective dose (MHO). The results are shown in Table 4.

Acute toxicity test A group of 3 male and female DD mice weighing 20±1 g was used to administer the compound of the present invention orally (PO: 300 μ/kg).
) or intraperitoneally (ip: 100 μ/kg). Observe the mortality status 7 days after administration and determine MLD
(minimum mortality) value was determined. The results are shown in Table 4.

Table 4 As is clear from Table 3, Compound (I) has an anti-allergic effect and is of great use as a pharmaceutical such as an anti-asthma drug.

Compound (I) can be used in various pharmaceutical forms for administration purposes in view of its pharmacological action.

The pharmaceutical composition of the present invention can be prepared by homogeneously mixing an effective amount of Compound (1) or its acid addition salt as an active ingredient with a pharmacologically acceptable carrier. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form suitable for administration orally or by injection. In the preparation of compositions in oral dosage form,
Any useful pharmaceutically acceptable carrier can be used.

Oral liquid preparations, such as suspensions and syrups, can be prepared using water, sugars such as shakerose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, alkyl para It can be manufactured using preservatives such as hydroxybenzoate and flavors such as strawberry flavor and peppermint. Powders, capsules, and tablets contain excipients such as lactose, glucose, shakerose, and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, and talc, polyvinyl alcohol, hydroxypropyl cellulose, It can be manufactured using a binder such as gelatin, a surface active agent such as a fatty acid ester, and a softening agent such as glycerin. Tablets and capsules are the most useful oral dosage units because of their ease of administration. Solid pharmaceutical carriers are used in the manufacture of tablets and capsules. Injectable solutions can also be prepared with carriers consisting of saline glucose solutions or mixtures of saline and glucose solutions.

The blind dose of compound (1) is 1 to 20 mg/kg/day
The number of administrations is preferably 3 to 4 times a day.

Examples and reference examples are shown below.

In addition, the physicochemical properties of the target compounds obtained in the examples are as follows.
shown in the table.

Example 1゜1l-(2-dimethylaminoethyl)thio-6,11-
1.8 g of dihydrodibenz (b, e) oxepine-2-carboxylic acid hydrochloride was dissolved in a mixed solvent consisting of methylene chloride 2Qa+1 and pyridine 5o1, and thionyl chloride Q,7+1 was added dropwise under water cooling, and the mixture was heated at room temperature for 1 hour. Stir.

The reaction solution was immersed in a solution consisting of 2.3 g of n-hexylamine and 1 Q ml of methylene chloride under water cooling at room temperature.
Stir for an hour. After adding ice chips and stirring for 30 minutes, the mixture was concentrated to dryness under reduced pressure. To the residue, add 100 f of IN-hydrochloric acid aqueous solution.
After adding 15 Qml of methylene chloride and shaking, the aqueous layer was discarded. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate: triethylamine = 10210
:1), and the main fraction was concentrated under reduced pressure to give an oily N-hexyl-11-(2-dimethylaminoethyl)thio-6
,11-dihydrodibenz(b,e)oxepin-2-
1.7 g of carboxamide (compound 1) is obtained.

Compound 11 thus obtained. 7 g was dissolved in 5 Q ml of gamma setone, 460 ml of fumaric acid was added, and the mixture was stirred for 1 hour. Concentration to dryness under reduced pressure yields the fumarate salt of Compound 1 (Compound 1'>1.9 g) as an amorphous powder.

Example 2゜In the same manner as in Example 1, 1l-(4-methylpiperidino)
-6,11-dihydrodibenz(b,e)oxepin-
3.0 g of 2-carboxylic hydrochloride and 1.5 m of thionyl chloride
The corresponding acid chloride was prepared using l followed by n
-N-hexyl-
11-(4-Methylpiperazino)-6,11-dihydrodibenz (b, e) Oxepin-2-carboxamide (
3 g of compound 2N are obtained.

Example 3 In the same manner as in Example 1, 11-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz (b) was prepared.

e] 3.2 g of oxepin-2-carboxylic acid is converted into acid chloride using 1.3 i1 of thionyl chloride. The obtained acid chloride was dissolved in 3Qml of methylene chloride, and this was dissolved in 2Qml of methylene chloride.
- It was added dropwise to a solution consisting of 5.4 g of diethylaminoethanol and 5 Qa+1 methylene chloride under water cooling, and the mixture was stirred at room temperature for 1 hour. After adding ice chips and stirring for 30 minutes, the mixture was concentrated to dryness under reduced pressure. Add 10 Qml of water to the residue, x-
After adding Chill 80IIll and further adding 4N aqueous hydrochloric acid to adjust the pH to 1.2, the mixture was shaken. Separate the aqueous layer and use IQN-sodium hydroxide aqueous solution to
Adjust to H12.5. Methylene chloride tQ 0111
1 was added and shaken, the aqueous layer was discarded, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and an oily 1l-2(2-dimethylaminoethyl)thio 2.0 g of -6,11-dihydrodibenz[b,ε]oxepin-2-carbo7ic acid (2-diethylaminoethyl) ester (Compound 3) is obtained.

31.9 g of the compound thus obtained was mixed with 5 Qm of acetone.
Add 0.4 g of fumaric acid and stir for 1 hour.

The obtained residue was concentrated to dryness under reduced pressure, and the resulting residue was crystallized using ether. The generated crystals were collected by filtration and dried under reduced pressure and heat to give 0.7% of the fumarate of compound 3 (compound 3').
Obtain 5g.

Example 4゜In the same manner as in Example 3, 1l-(4-methylpiperazino)
-6,11-dihydrodibenz(b,e)oxepin-
2.9 g of 2-carboxylic acid was converted to acid chloride using 1.2 ml of tiniol chloride, and then reacted with 5.0 g of 2-diethylaminoethanol to form an oily 1-carboxylic acid.
1-(4-Methylpiperazino)-6,11-dihydrodibenz(b,e)oxepin-2-carboxylic acid (2-diethylaminoethyl) ester (compound 4N, 6 g is obtained.

Example 5 In the same manner as in Example 1, 11-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz (b) was prepared.

C] 3.5 g of oxepine-2-carboxylic acid is converted into acid chloride using 1.5 ml of thionyl chloride. The obtained acid chloride was dissolved in 3Q, ml of methylene chloride, and 3-
A solution of 3.2 g of ethoxy-2-hydroxypropatol dissolved in 2 Q ml of methylene chloride was added dropwise under water cooling. The mixture was stirred for 1 hour under water cooling and further stirred for 3 hours at room temperature. After adding ice chips and stirring for 30 minutes, the mixture was concentrated to dryness under reduced pressure.

Add methylene chloride 200+I11 to the residue. water 1001+11
After adding and shaking, discard the aqueous layer. AII was washed with saturated sodium chloride solution and then with water, and dried over anhydrous sodium sulfate. The crude product obtained was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (elution solvent: hexane:
The main fraction was concentrated under reduced pressure to obtain oily 1l-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz (b, e). Oxepin-2-carboxylic acid (3-ethoxy-2-hydroxypropyl) ester (compound 5)1.
Obtain 0g.

51.0 g of the compound thus obtained was mixed with 59 ml of acetone.
0.21 g of fumaric acid was added, stirred for 1 hour at room temperature, and then concentrated to dryness under reduced pressure to obtain 1.2 g of the amorphous fumarate of Compound 5 (Compound 5').
get.

Example 6 In the same manner as in Example 5, 3.7 g of 1l-(4-methylpiperazino)-6,11-dihydrodibenz(b,e)oxepin-2-carboxylic acid was added to thionyl chloride L, 2+11
1 to the acid chloride and then reacted with 6.6 g of 3-ethoxy-2-hydroxyprono(nol) to give an oily 1l-(4-methylpiperazino)-6,11-
Dihydrodibenz (b, e) oxepine-2-carboxylic acid (3-ethoxy-2-human o-4-dipropyl) ester (compound 6) L, Tg is obtained.

Example 7゜ 1l-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e) oxy7pine-2-carboxylic acid (3-ethoxy-2-hydroxypropyl) obtained in Example 5 ) Add 1.60 g of ester (compound 5) to a mixed solution consisting of 5 ml of pyridine and 1 ml of acetic anhydride, and stir at room temperature for 4 hours. After adding ice chips and stirring for 1 hour, the mixture was concentrated to dryness under reduced pressure. After adding 100 ml of methylene chloride and 50 ml of IN-hydrochloric acid aqueous solution to the residue and shaking, the aqueous layer was discarded. The nurturing layer is washed with water, dried over anhydrous sulfuric acid, and then concentrated to dryness under reduced pressure to obtain a crude product. This was subjected to silica gel column chromatography (eluent: hexane:
The main fraction was concentrated under reduced pressure to obtain oily 1l-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz (b, e). -Oxepine-2-carboxylic acid (2-acetoxy-3-ethoxypropyl) ester (compound?)
Obtain 0.38 g.

70.38 g of the compound thus obtained was added to 501 g of acetone.
1, add 90+ag of fumaric acid, stir at room temperature for 1 hour, and concentrate under reduced pressure to obtain crude crystals. This was recrystallized from isopropyl ether to obtain 0.37 g of fumarate of compound 7 (compound?').

Example 8゜1l-(4-methylpiperazino)-6,11-dihydrodibenz(b,e) oxepin-2-carvone[12(3-ethoxy-2-hydroxypropyl)ester ( Compound 6) 1.7g was acetylated in the same manner as in Example 7 to give oily 1l-(4-
Methylpiperazino)-6,11-dihydrodibenz(b
, e) Oxepin-2-carboxylic acid (2-acetoxy-
3-ethoxypropyl) ester (compound 8) 0.
Obtain 6 g.

80.6 g of the compound thus obtained was mixed with 40 μg of acetone,
Stir with 0.13 g of fumaric acid at room temperature for 1 hour. The resulting residue was crystallized by tritination with isopropyl ether, collected in an oven, and dried under reduced pressure and heating to obtain the 7-malate salt of compound 8, A water. 0.29 g of compound 8' is obtained.

Example 9 In the same manner as in Example 1, 2.5 g of 1l-(4-methylpiperazino)-6,11-dihydrodibenz(b,e)oxepin-2-carboxylic acid was added using gml of thionyl chloride Q. converted into acid chloride, which was then reacted with 7.84 g of diethylene glycol to form an oily 1l-(4
-methylpiperazino)-6,11-dihydrodibenz(
b, e] Oxepin-2-carboxylic acid (2-(2-hydroxyethoxy)ethyl) ester (compound 9) 1.4
get g.

91.4 g of the compound thus obtained was mixed with 10.0 g of acetone.
ml, fumaric acid 0.3 g for 1 hour, and concentrated to dryness under reduced pressure to obtain the fumarate salt of compound 9 (compound 9
') 1.35 g are obtained as an amorphous powder.

Example 10. Tablets Tablets having the following composition are prepared by a conventional method.

1l-(4-Methylpiperazino)-6,11-dihydrodibenzo(b,e)oxepin-2-carboxylic acid (2-
Acetoxy-3-ethoxypropyl) ester l fumarate extrahydrate (compound 8') 0 mg Lactose 60 ■ Potato starch 30 ■ Polyvinyl alcohol 2 ■ Magnesium stearate 1 ■ Tallis pigment
Micro-amount Example 11. A powder having the following composition was prepared by a conventional method.

1l-(2-diethylaminoethyl)thio-6,11-
Dihydrodibenzo (b, e) oxepine-2-carboxylic acid (3-ethoxy-2-hydroxypropyl) ester (compound 5') 30 ■ Lactose
270 ■ Example 12. Syrup A syrup having the following composition was prepared by a conventional method.

1l-(4-Methylpiperazino)-6,11-dihydrodibenzo(b,e)oxepin-2-carboxylic acid (2-
(2-Hydroxyethoxy)ethyl]ester dihydrochloride (compound 9') 300mg refined white sugar
40g Methyl paraoxybenzoate 40mg Propyl paraoxybenzoate
10 ■Strawberry flavor 0
．． Add 1 cc of water to make a total volume of 100 cc.

Effects of the Invention Compound (I) and its acid addition salts have antiallergic effects.

Claims (2)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is O-(CH_2)_m-NR^3R^
4 (in the formula, m represents an integer from 1 to 6, R^3 and R^4
represent the same or different lower alkyl groups. ), N
HR^5 (in the formula, R^5 represents a lower alkyl group),
OCH_2CH(OR^6)CH_2OCH_2CH_
3 (in the formula, R^6 represents a hydrogen atom or an acetyl group) or OCH_2CH_2OCH_2CH_2OH, and R
^2 is S■NR^7R^8 (in the formula, R^7 and R^8
represent the same or different lower alkyl groups. ) or represents a 4-lower alkylpiperazino group. ] or a pharmacologically acceptable acid addition salt thereof. (2) An antiallergic agent containing Compound (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.