JPS6019310B2 - Benzoxepine derivatives and their production method - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a penzoxepine derivative represented by the following general formula (1) (wherein, R is hydride, represents an xy group or an amino group, Y represents CH or N, and x represents an oxygen atom or two hydrogen atoms). and its manufacturing method. The present inventor has been synthesizing many penzoxepine compounds over a long period of time and studying their pharmacological effects, and has discovered that the penzoxepine derivative represented by the above general formula has an outstanding anti-inflammatory effect, and has completed the present invention. . Therefore, the present invention provides compounds of the general formula (1) having excellent pharmacological effects.
Our objective is to provide a novel compound represented by Another object is to provide a method for producing the compound of general formula (1). The compound of formula ○ of the present invention can be further subdivided into the following eight compound groups depending on the structure. (In the formula, R is the same as above.) The compound of general formula (1) of the present invention is produced by any of the following methods. Method 1: (In the formula, Y represents the same as above) That is, 21[(QHcyanoethyl)phenoxy]phenylacetic acid or 21[(Q-cyanoethyl)phenoxy]-3-pyridylacetic acid (0) as a condensing agent The dihydroxobenzoxepine propionic acid amide derivative (m) is produced by a heating reaction in the presence of . As the condensing agent, polyphosphoric acid, polyphosphate ester, etc. are used. Although the reaction can be carried out without a solvent, benzene, toluene,
It can also be carried out in a solvent such as xylene. The reaction temperature is 8
Preferably, the reaction time is 0 to 200 q○ and the reaction time is 0.5 to 2 hours. The compound of the (old) formula as a raw material is produced, for example, as follows. (In the formula, R2 is an ester residue, A and B
One of them is a halogen atom, the other is an OH group, Z is a halogen atom, "Y is the same as above), that is, 2
- [(Q-cyanoethyl)fe/xy]phenylacetic acid or 2-hydroxy (or halogeno) phenylacetic acid is reacted with halogeno (or hydroxy) acetophenone to form 2-(acetylphenoxy)phenylacetic acid;
This is esterified to form 2-(acetylphenoxy)phenylacetate, which is reduced to 2-[(Q-
Hydroxyethyl) phenoxy] phenyl acetic acid ester is produced by halogenation, cyanation, and further deesterification. Also, 2-[(Q-cyanoethyl)phenoxy]-3-
Pyridylacetic acid is 2-hydroxy (or halogeno)-3
- Pyridyl acetate is reacted with halogeno (or hydroxy) acetophenone to form 2-(acetylphenoxy)-3-pyridylacetate, which is reduced to 2-[(Q-hydroxyethyl)phenoxy]-3
-pyridylacetate, which is then halogenated, cyanated, and further deesterified. Method 2: (In the formula, Y is the same as above.) That is, the dihydroxobenzoxoxepine propionic acid amide derivative (m) is hydrolyzed to produce the dihydroxobenzoxoxepine propionic acid derivative (W). This reaction is carried out by conventional hydrolysis, for example by heating under reflux for 5 to 8 hours in water or a water-containing organic solvent in the presence of an acid or base. Method 3: (In the formula, Y is the same as above) That is, the dihydroxobenzoxepine propionic acid amide derivative (m) is reacted with hydrazine to form hydrazine (V), and then this is reacted with an alkali agent. Dihydrobenzoxepine propionic acid derivative (
W) is manufactured. To produce a compound of formula (V) from a compound of formula (m), the compound is heated under reflux for 1 to 3 hours in an inert organic solvent such as an alcohol such as methanol or ethanol, or an ether such as dioxane or tetrahydrofuran. is preferred.
In order to produce a compound of formula (V) from a compound of formula (V), an alkali agent is added at a temperature of room temperature to 200 qo in a solvent such as ethyl alcohol, t-butanol, diethylene glycol, dioxane, or tetrahydrofuran. Make it react. As the alkaline agent, for example, potassium hydroxide, sodium hydroxide, metal alkoxide, etc. are used, and the reaction is
It is preferable to carry out the treatment for 4 hours. Method 4: (In the formula, R and ' represent a ester residue, and Y is the same as above.) That is, dihydroxobenzoxoxepine propionic acid amide derivative (m) is reacted with a mineral acid in alcohol to form dihydroxobenzo Oxepine propionate derivative (blood) is obtained, which is then subjected to Clemensen reduction to obtain dihydrobenzoxepine propionate derivative (skin), which is further hydrolyzed to dihydrobenzoxepine propionate. Acid derivative (W) is produced. To produce a compound of the (skin) formula from a compound of the (m) formula, the compound of the (blood) formula is mixed in an alcohol such as methanol, ethanol, or propanol in the presence of sulfuric acid, hydrochloric acid, etc. for 3 to 4 hours.
This is done by heating under reflux for a period of time. In order to produce a compound of the (wind) formula from a compound of the (skin) formula, the (blood) compound is subjected to the so-called Clemensen reduction. Specifically, if reduction is performed using zinc amalgam and concentrated hydrochloric acid, a compound of formula (Kaze) can be obtained. Hydrolysis of compounds of the (skin) formula is carried out in conventional manner with acids or bases. The compound of the present invention represented by general formula (1) has an excellent anti-inflammatory effect. The pharmacological results of the compound of the present invention investigated using the carrageenan edema method are shown below in comparison with the effects of known typical anti-inflammatory agents. That is, the compound of the present invention or a known representative anti-inflammatory agent is orally administered to male sterling rats weighing approximately 100 kg each consisting of 5 to 6 animals per group, and 1 hour later, 0.1% of a 1% carrageenan saline solution is administered.

[/ Rats were injected subcutaneously into the hind limbs, and the volume of the hind limbs was measured by Volmmedifferenti.
It was measured over time using an al meter. The results obtained are shown in Tables 1 and 2. - Compound 1: 2-(10,11-dihydro-11-oxodibenzo[b,f]oxepin-3-yl)-propionamide Compound 2: 2-(5,6-dihydro-6-oxobenzo[b]pyrido[3,2-yl) f] Oxepin-9-yl)-propionamide compound 3: 2-(10,11
-dihydro-11-oxodibenzo[b,f]xepin-3-yl)-propionic acid compound 4:2-(5,6
-dihydro-6-oxobenzo[b]pyrido[3,2-f]oxepin-9-yl)-propionic acid compound 6:
2-(10,11-dihydrodibenzo[b,f]oxepin-3-yl)-f. opi. onic acid compound 6:2-(10,11-dihydro-11-oxodibenzo[b,f]oxepin-2-yl)-propionamide compound 7:2-(10,11-dihydro-11-oxodibenzo[b, f) Oxepine-
2-yl)-propionic acid compound 8:2-(10,11
-dihydrodibenzo[b,f]oxepin-2-yl)
-Bropionic acid compound 9:2-(5,6-dihydro6
-Oxobenzo[b]pyrido[3,2-f]oxepin-8-yl)-propionamide compound 10:2-(1
0,11-dihydrobenzo[b,f]oxepin-2-
When the compound of the present invention is used as a medicine, it can be used as such or in the form of a salt thereof. The salt is preferably a non-toxic salt such as sodium, potassium, calcium or aluminum. The compound of the present invention exerts its action in both oral and parenteral administration, and can be formulated into dosage forms for oral, injection, rectal, and topical administration. Solid dosage forms for oral administration include capsules, tablets, pills,
Available in powder form and granule form. As additives for these dosage forms, in addition to excipients such as white rice bran, lactose, and starch, a lubricant such as magnesium stearate can be used. Moreover, it can also be made into an enteric-coated and sustained-release dosage form. Liquid dosage forms for oral administration include emulsifiers, solutions,
There are suspensions, syrups, elixirs, etc. As additives for these dosage forms, in addition to solvents such as purified water and alcohols, auxiliary agents such as wetting agents, emulsifiers, and suspending agents can be added. Preparations for parenteral administration of the compound of the present invention include injections, suppositories, and the like. For injections and the like, sterile aqueous or non-aqueous solutions can be prepared.
Examples of the solvent include propylene glycol, polyethylene glycol, vegetable oil, organic acid ester, and the like. It may also be in the form of a powder filling which can be dissolved in a solvent before use. In the case of suppositories, excipients such as cocoa, butter or suppository wax are added.
The dosage of the compound of the present invention varies depending on the symptoms, administration route, administration period, etc., but in general, for humans, the dosage is 200 mg/day.
9 out of 1000 is preferred. Next, an example will be given and explained. Example 1 2-(10,11-dihydro-11-oxodibenzo'
[b・f] Oxepin-3-yl)-propiosoamide: Add 22 parts of polyphosphoric acid to 1.1 parts of 2-[3-(Q-cyanoethyl)-phenoxy]-phenylacetic acid, 100~
I prayed for 1 hour at 105 pm. After cooling, ice water was added and extraction was performed with ethyl acetate, washed with a saturated aqueous sodium carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was removed to obtain a brown oil, which was subjected to silica gel column chromatography, and from the eluate of n-hexane acetone (5/1 to 1/1),
2-10,11-dihydro-11-oxobenzo [b
・f] Oxepin-3-yl)-propionamide was obtained as a pale brown oil (680 o (yield: 62%)). This was further crystallized from chloroform and washed with a mixed solvent of n-hexane/acetone (2/1) to give a melting point of 159-16.
0oo colorless crystals were obtained. IR〃S Guy 13 Enemies - 1:35
00, 3400 (CON day 2), 1600 (C=〇)N
MR (CDC13) 6:1.50 (group, d, J = 7HZ
,=CHCH3)3.67(IH,q,J=7HZ,
=CHCH3) 4.03 (2 days, s, -CO-CH2
-) 6.186.48 (spot, b, s, -CON day 2) 7
．． 04-7.48 (thin, m, aromatic protoso)7. Group (
IH, d, J〒8HZ, C, H) Example 2 2-(10,11-dihydro-11-oxobenzo [b
・f]Oxepin-3-yl)propionic acid: 2-(1
A mixture of 340 parts of 0,11-dihydro-11-oxobenzo[b·f]oxepin-3-yl)propionamide, 3 parts of ethanol, 9 parts of potassium hydroxide, and 3 parts of water was heated under reflux for 8 hours. After cooling, ethanol was removed, an aqueous IN sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. After washing with a saturated brine solvent, it was dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil, 380-9, which was purified by silica gel column chromatography to give 2-(10,11-dihydro-11-oxodibenzo[b/f]oxepiso 3-
yellow oil of propionic acid (Yield: 46)
%) was obtained. mre three skins 13 enemies-1: 17151680
(C=○) NMR (CDCW6:1-52 (Chihichi, d,
J=7Hz,=CHCH3)3.76(IH,q,J
=7HZ, =CHC) 4.00 (2 days, s, 1 CO-
CH2 −) 7.01-7.04 (Pongee, m, aromatic proton) 7.92 (IH, d, J = 8Hz, C.H) 10
．． 36 (IH,, b.s, COOH) MSm/e: 28
2(M+) Example 3 Methyl 2m(10,11-dihydro-11-oxodibenzo[b/f]oxepin-3-yl)-propionate: 2-(10,11-dihydro-11-oxodibenzo[b/f]oxepin-3-yl) ) - 100% of propionamide was suspended in 2 parts of methanol, and 0.2 parts of concentrated sulfuric acid was added.
was added to the mixture, and the mixture was heated under reflux for 4 hours. After cooling, the solvent was distilled off, ice pieces were added, and the mixture was extracted with ethyl acetate. After washing with saturated brine, it was dried over anhydrous sodium sulfate. The solvent was distilled off and methyl 2-(10.]1-dihydro-11-oxodibenzo[b・f]oxepin-3-
A pale yellow oil of yl)-propionate 95p (yield 90%) was obtained. IR S side is c-1:1730, 1
Trout 0 (C=0) Example 4 Methyl 2-(10,11-dihydrodibenzo[b,f]oxepin-3-yl)-propionate: Methyl 2-(10,11-dihydro-1
1-oxodibenzo[b・f]oxepin-3-yl)
- 95 mg of fropionate was dissolved in 1 volume of toluene, a small amount of zinc amalgam, 0.3 M of concentrated hydrochloric acid and 0.2 volumes of water were added, and the mixture was heated under reflux for 1 hour. After wrapping, the reaction solution was filtered, extracted with benzene, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oil, which was fractionated by thin layer chromatography to obtain a pale yellow oil of methyl 2-(10,11-dihydrodibenzo[b·f]oxepin-3-yl)-propionate 30 Females (yield 33%) were obtained. NMR(C
〇CI3) 6:1.44 (milk day, d, J=7Hz, =C
HCH3) 3.14 (Misaki, s, one CH2 -CH2 -
) 3.56 (Spot, s, -COOCH3 ) 3.60 (I
H, q, J = 7 days 2, = CHCH3) 6.72-7.1
4, m, aromatic proton) Example 52-(10・11
-dihydrodibenzo[b・f]oxepin-3-yl)
-Propionic acid: A mixture of 30 parts of methyl 2-(10,11-dihydrodibenzo[b,f]oxepin-3-yl)-propionate, 1 part of ethanol, 200 parts of potassium hydroxide and 1 part of water at room temperature for 18 minutes. I lost my respects. The solvent was distilled off, acidified with hydrochloric acid, and extracted with ethyl acetate.
After washing with saturated brine, it was dried over anhydrous sodium sulfate. The solvent was removed to obtain 28.4:9 of 2-(10,11-dihydrodibenzo[b·f]oxepin-3-yl)-propionic acid as a slightly yellow oil (yield: 100%). IR
Les Ax Dance Fox - 1:1705 (C=○) NMR (CDC13) 6:1.42 (Mother's Day, d, J=7
HZ,=CHCH3)2.99■day,S,1CH2C
H2 −) 3.56 (IH, q, J=7HZ, =CHC
H3) 6.70-7.14 (7 days, m, aromatic proton) MSm/e: 268 (M 10) Example 6 2-(5,6-dihydro 6-oxobenzo[b]pyrido[3,2 1f] Oxepin-9-yl)p. Pionamide: 1.3% of 2-[3-(Q-cyanoethyl)-phenoxy]-3-pyridylacetic acid and 30% of polyphosphoric acid
The mixture was heated at 150 ohms for 2 hours. After cooling, polyphosphoric acid was decomposed by adding ice water, made basic with 10% aqueous ammonia, and extracted with chloroform. After washing with saturated brine, it was dried over anhydrous sodium sulfate. The solvent was removed to obtain a citron-like substance, which was subjected to silica gel column chromatography and chloroform/ethanol (50/1).
2-(5,6-dihydro-6-oxobenzo[b]pyrido[3,21f]oxepin-9-yl)
A solid substance of mountain propionamide was obtained. This was further recrystallized from methanol to give pale yellow powder 2 with a melting point of 89-90 oo.
Got 50 o. IR 13 Foxes - 1:3 Iu Breasts 2
0 (NH), 1 job 0 (C=〇) MSm/e: 282 (M
+) Example 7 2-(5,6-dihydro-6-oxobenzo[b]pyrido[3,2-f]oxepin-9-yl)-propionic acid: 2-(5,6-dihydro-6-oxobenzo[b]
Virid [3.2-f)oxepin-9-yl)-propionamide 40/9, potassium hydroxide 180 female, water 1.
A mixture of 5' and ethanol 5' was heated under reflux for 5 hours under simulated aeration. After cooling, the solvent was distilled off, ice water was added, acidified with acetic acid, and extracted with chloroform. After washing with saturated brine, it was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an oily substance,
It was subjected to silica gel column chromatography, eluted with chloroform-ethanol, and purified to produce 2-(5,6-dihydro-6-oxobenzo[b]pyrido(3,21f)).
Pale yellow powder of oxepin-9-yl)-propionic acid 2
I got a 9 out of 0. IR〃Purified c-1:1710, 1 porridge 0 (C=○) MS
m/e: 283 (M 10) Example 8 21 (10,11-dihydro 11-oxodibenzo [
b・f] Oxepin 2-yl)-propionamide:
Add 15 parts of polyphosphoric acid to 730 parts of 2-[4'-(Q-cyanoethyl)phenoxy]-phenylacetic acid, and heat at 100°C.
At 0. I lost track of the song time. After the reaction, ice pieces were added and extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a yellow oil, which was subjected to column chromatography using silica gel 15 mm and eluted with chloroform to obtain 2-(10.
Yellow oil of 11-dihydro-11-oxodibenzo[b・f]oxepin-2-yl)-pionamide 3
78 samples (52% yield) were obtained. Furthermore, this was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give a melting point of 15.
4 to 15,500 pale yellow crystals were obtained. IR general support arc-1
:3400, 3200 (N ratio), 1670 (C=〇)N
r4R (CDC13) 8:1.42 (thin, d, J=7H
Z,=CHCH3)3. Insects (IH, q, J=7HZ,
=CHC ratio) 4.02 (2 days, s, COCH2)6.
0 & 6.52 (spot, b.s, -CON day 2) 6.8
4-7.62 (fine, m, aromatic proton) 7.92 (I
H, d, J = 3HZ, C, H) MSm/e: 281 (M
10) Example 9 2-(10,11-dihydrodibenzo[b・f]oxepin-2-yl)-propionic acid: 2-(10,11-dihydro 11-oxodibenzo[b・f]oxepin-2-yl)-propionamide 145 parts of ethanol was dissolved in 5 parts of ethanol, 1 part of hydrazine hydrate was added, and the mixture was heated under reflux for 3 hours. After the reaction, the solvent was distilled off, 10 parts of diethylene glycol and 50 parts of sodium hydroxide were added, and the mixture was heated at 132 to 13 parts for 1 hour. The reaction solution was acidified with hydrochloric acid, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution. The alkaline washing solution was acidified with hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and then dried with turbid sodium sulfate. The solvent was distilled off to obtain a brown oil, which was subjected to column chromatography using silica gel, filtered with old chloroform, and purified with 21 (10.
11-dihydrodibenzo[b・f]oxepin-2-yl)-puropionic acid as pale yellow oil 65/9 (yield 4
7%). IR anti-black arc-1:1710 (C=0) NMR (CDC13) 6:1.44 (fine, d, J=7H
Z, CHCH3 ) 3.10 (4 days, s, one CH2CH
2 -) 3.63 (IH, q, J = 7Hz, =CHCH
3) 6.80-7.28 (7 days, m, aromatic proton)
MSm/e: 268 (M+) Example 10 2-(10,11-dihydro 11-oxodibenzo
b・f] Oxepin-2-yl)-propionic acid: 2-(10,11-dihydro 11-oxodibenzo[b・
f] Oxepin-2-yl)-propionamide was treated in the same manner as in Example 2 to obtain pale yellow crystals having a melting point of 156-157°C. IR Lebe Ura Kite - 1:1700 (shoulder), 1680 (C=○
) NMR (CDCl3) 6:1.48 (fine, d, J: 7
Day 2, = CHCH3 ) 3.72 (IH, q, J = 7H
Z, CHC ratio) 4.04 (phantom, s, = CH2) 7.05
~7.74 (bait, m, aromatic pton) 7.92 (IH
, d, J=3HZ, C, H) MSm/e: 282 (M+
) Example 11 2-(5,6-dihydro-6-oxobenzo[b]pyrido[3,21f]oxepiso-8-yl)propionamide: 2-[4'-(Q-cyanoethyl)phenoxy]
-3-Pyridylacetic acid 147 phosphorus was added with polyphosphoric acid 30% and heated at about 1300C for 3 hours. After the mixture was left to stand, ice water was added to decompose the excess polyphosphoric acid, the mixture was made alkaline with sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown solidified product of 32c. It was subjected to column chromatography using silica gel and eluted with chloroform, and further purified using a thin layer chromatography plate to obtain 9 of 15 colorless crystals with a melting point of 200 to 22,020 (decomposition point). Ta. IR benefit 9 branch skin-1:3
440, 3180 (N ratio), 1680 (C=〇) NMR
((CD3)2SO) 6:1.30 (thin, d, Ji7H
Z, one CH3) 3.66 (IH, q, J=7HZ, iC
H) 4.10 (2 days, s, COCH2) 6.80 (I
H, s, N ratio) 7.30-8.40 (7 days, m, aromatic protons and N ratio protons) MSm/e: 282 (M 10) Example 12 2-(10,11-dihydrodibenzo b・f] Oxepin-2-yl)-propionamide: 2-(10・1
1-dihydrodibenzo[b・f]oxepin-2-yl)-bropionic acid 132 of 9 was dissolved in benzene 2,
0.6% of thionyl chloride and 3 drops of pyridine were added, and the mixture was heated under reflux for 1 hour at room temperature and then for another 1 hour under vacuum. The solvent was removed, the solution was dissolved in chloroform, added to 28% aqueous ammonia, and stirred at room temperature for 3 hours. The reaction solution was acidified with hydrochloric acid, extracted with ethyl acetate, washed with IN aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed to obtain a yellow-brown oil, which was subjected to column chromatography using silica gel, eluted with chloroform:methanol = 200:1, and further recrystallized from benzene-n-hexane to give a product with a melting point of 122.
．． Pale yellow crystals of 2-(10·11-dihydrodibenzo[b·f]oxepin-2-yl)-propionamide 115o (yield: 87%) were obtained at 5 to 130°C. IR winding arc - 1:3320, 3160 (N ratio), 1660 (
C=〇) NMR (CDCl3) 6:1.48 (fine, d,
J = 7 days 2, = CHCH3 ) 3.12 (Misaki, s, -C
Ratio CH2-) 3.52 (IH, q, J=7HZ, -CHC) 5-1
0, 5-90 (2 days, b-S, 1 C〇N! character) 6.9
0-7.60 (7 days, m, aromatic protons) MSm/e
:267(M+) Example 13 2-(5,6-dihydro-6-oxobenzo[b]pyrido[3.21f]oxepin-8-yl)-bropionic acid: 2-(5,6-dihydro-6-oxobenzo[b] b]
Pyrido[3.21f]xepin-8-yl)-propionamide 100 parts 9, potassium hydroxide 400 parts o, water 1 part
．． A mixture of 25 ml of ethanol and 3.75 ml of ethanol was heated under reflux for 6 hours under a dark frame. After wrapping, water was added and washed with ethyl acetate, and the aqueous layer was made acidic with acetic acid and extracted with ethyl acetate. After washing with saturated brine, it was dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was treated with silica gel,
It was purified by column chromatography and eluted with chloroform to give 2-(5,6-dihydro-6-oxobenzo[b]pyrido[3,21f]oxepin-8-yl). A pale yellow oil of pionic acid 52 (yield 52%) was obtained. Every bag of IR is skin-1:1710, 1685 (C=
○) NMR (CDCl3) 6:1.50 (scarlet, d, J=
8th 2, CHCH3) 3.74 (IH, q, J=8H
Z, CHC ratio) 4.03 (but, s, -CH2CO-) 7
．． 20-8.30 (fine, m, aromatic boutons) MSm/
e: ■283 (M+) Example 14 2-(5,6-dihydrobenzo[b]pyrido[3,2-
f] Oxepin-8-yl)-propionic acid: 2-(5
・6-dihydro 6-oxobenzo[b]pyrido[3.
2-f] Oxepin-8-yl)-propionamide 3
The solution was dissolved in 30 parts of ethanol, 5 parts of hydrazine hydrate was added dropwise, and the mixture was heated under reflux for 1 hour. After the reaction, the solvent was removed, and 30% of diethylene glycol and 700% of sodium hydroxide were added to the solid obtained, and the mixture was heated at 130:00 for 3 hours under a nitrogen stream.
After cooling, water was added and the mixture was washed with ethyl acetate. The aqueous layer was made acidic with acetic acid, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography using 90% silica gel, and n-hexane/acetone (5/1-2
No. 1) was eluted, and 2-(5,6-dihydrobenzo[b
An oily product of pyrido[3.2-f]oxepin-8-yl)-propionic acid was obtained. Further, this was recrystallized from ethyl acetate to give a melting point of 182.5-1. Colorless needle crystals 17 o (yield 5.4%) were obtained. IR pot bag skin-1
:1710 (C'0) NMR (CDC13) 6:1.50 (Group, d, Jco8H
Z, CHCH3 ) 3.40 (4 days, s, one CH2CH
2-3.65 (IH, q, J=8HZ, =CHC) 6.90-8.10 (mottle, m, aromatic proton) MS
mnoe: 269 (M+) Example, 15 2-(5,6-dihydrobenzo[b]pyrido[3,2''
f]Oxepin-8-yl)-propionamide: 2-(5,6-dihydrobenzo[b]pyrido[3,2-f]
Oxepin-8-yl)-propionic acid (50 parts) and dicyclohexylcarbodiimide (50 parts) were dissolved in 10 parts of methylene chloride, and 5 parts of methylene chloride saturated with ammonia was added thereto, and the mixture was incubated under ice cooling for 2 hours.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is a hydroxy group or an amino group, Y is CH
or N and X represents an oxygen atom or two hydrogen atoms). 2. The benzoxepine derivative according to claim 1, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R and Y are the same as above). 3. The benzoxepine derivative according to claim 1, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R and Y are the same as above). 4. The benzoxepine derivative according to claim 2, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R is the same as above). 5. The benzoxepine derivative according to claim 2, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R is the same as above). 6. The benzoxepine derivative according to claim 2, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R is the same as above). 7. The benzoxepine derivative according to claim 2, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R is the same as above). 8. The benzoxepine derivative according to claim 3, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R is the same as above). 9. The benzoxepine derivative according to claim 3, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R is the same as above). 10. The benzoxepine derivative according to claim 3, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R is the same as above). 11. The benzoxepine derivative according to claim 3, which is a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R is the same as above). 12. The benzoxepine derivative according to any one of claims 1 to 11, wherein R is a hydroxy group. 13. The benzoxepine derivative according to any one of claims 1 to 11, wherein R is an amino group. 14 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y represents CH or N) A general formula characterized by subjecting a compound represented by the following to a heating reaction in the presence of a condensing agent ▲ Numerical formula, chemical formula, There are tables, etc. ▼ Method for producing dihydroxobenzoxepinate amide derivatives represented by (wherein, Y is the same as above). 15 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y represents CH or N) A general formula characterized by hydrolyzing a dihydroxobenzoxepine propionic acid amide derivative ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y is the same as above) A method for producing dihydroxobenzoxepine propionic acid derivatives. 16 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y represents CH or N) By reacting hydrazine with the dihydroxobenzoxoxepine propionic acid amide derivative, the general formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y is the same as above) A general formula characterized by the hydrazone represented by and then reacting with an alkali agent ▲ There are mathematical formulas, chemical formulas, tables, etc. A method for producing a dihydrobenzoxepine propionic acid derivative represented by ▼ (wherein Y is the same as above). 17 General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ (In the formula, Y represents CH or N) A dihydroxobenzoxoxepine propionic acid amide derivative represented by the following is reacted with a mineral acid in alcohol to form the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 represents an ester residue, and Y is the same as above) A dihydroxobenzoxoxepine propionate derivative is prepared, and then this is subjected to Clemensen reduction. It is characterized by forming a dihydrobenzoxepine propionate ester derivative represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, Y and R_1 are the same as above), and further hydrolyzing this. A method for producing dihydrobenzoxepine propionic acid derivatives represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y is the same as above).