JPH03181443A - Novel dibenzo(a,d)cycloheptene derivative - Google Patents

Abstract

NEW MATERIAL:The dibenzo[a,d]cycloheptene derivative of formula I [R<1> is H, halogen, alkyl or alkoxy; R<2> is OH or alkoxy; R<3> is H or alkyl; A is group of formula II [n is 1 or 2; R<4> is H or alkyl; R<5> is H, 5 or 6-membered cycloamino, -OCOR<6> (R<6> is alkyl) or -NH(CH2)n-R<7> (n is 0 or 1; R<7> is OH or hydroxycarbonyl)] or 5 or 6-membered cycloamino]. EXAMPLE:3-Methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene-2-ac etic acid. USE:A drug having anti-inflammatory, analgesic and antithrombogenic actions. PREPARATION:The compound of formula I can be produced e.g. by using the compound of formula III as a raw material and esterifying or amidating the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel dibenzo(a,d)cycloheptene derivative useful as a pharmaceutical having anti-inflammatory, analgesic and antithrombotic effects.

[Conventional technology]

10,11-dihydro-5-oxo-5H-dibenzo (
a, d) 2nd position (or 8th position) of the cycloheptene derivative
Compounds having an acetic acid residue or a propionic acid residue at position) are disclosed in JP-A-50-24260. Japanese Patent Publication No. 51-34141
It is reported in Japanese Patent Application Laid-Open No. 52-148058. Among them, compounds that use hydroxyl groups in combination are U, S, Pat
, 4172949+ Journal of Med
icinal chemistry, 1986+29
, 2347-2351. It is publicly known. However, as in the present invention, a compound having an electron-donating substituent at the 3-position adjacent to the alkanoic acid serving as a proton source at the 2-position is not known.

[Problem that the invention seeks to solve]

While non-steroidal acidic anti-inflammatory drugs generally exhibit more distinct pharmacological effects than basic anti-inflammatory drugs, they also have relatively notable side effects, and although various compounds have been developed to solve this problem, there are still no drugs available. It is hard to say that the situation is satisfactory. The same can be said, for example, of the compounds described in U.S. Pat, 4172949. Therefore, the present invention has discovered a novel drug that not only exhibits excellent anti-inflammatory and analgesic effects, but also has significantly lower side effects such as gastrointestinal disorders and toxicity than existing anti-inflammatory analgesics, and is highly safe. It is intended for this purpose.

[Means to solve the problem]

The present invention is based on the general formula [] [wherein R1 is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, R2 is a hydroxyl group or a lower alkoxy group, R3 is a hydrogen atom or lower alkyl is an integer of 2, R4 is a hydrogen atom or a lower alkyl group, R5 is a hydrogen atom, a cyclic amino group consisting of a 5- to 6-membered ring, -0COR'
(In the formula, R& means a lower alkyl group) ), -
NH(CHz)n-R' (in the formula, n is an integer of O or l, R7 means a hydroxyl group or a hydroxycarbonyl group), means a cyclic alkyl group consisting of a 5- to 6-membered ring] The present invention relates to dibenzo(a,d)cycloheptene derivatives represented by the following formula.

To explain the substituents in the above formula in more detail, RI is a hydrogen atom, a halogen atom such as fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, 1so
-propyl, n-butyl, iso-butyl, ter
It means a lower alkyl group such as t-butyl. I? Z is a hydroxyl group, methoxy, ethoxy, n-propoxy, 1so-
propoxy, n-butoxy, iso-butoxy, tar
A lower alkoxy group such as t-butoxy, and R3 is a hydrogen atom, methyl, ethyl, n-propyl, 1so-propyl, n-butyl, iso-butyl, tert-
It means a lower alkyl group such as butyl. A is a hydroxyl group, a lower alkoxy group having 1 to 6 carbon atoms, -0(Cll
z)n-R" (where n is an integer of 1 or 2, R8
means a pyrrolidino group, piperidino group, morpholino group, piperazino group) and a compound represented by -Nl ((Cllz)
n-R'' (where n is an integer of 0 or 1, R11+
means a hydroxyl group, an alkoxy group consisting of 1 to 6 carbon atoms, a hydroxycarbonyl group), 5
It means a cyclic amino group consisting of a ~6-membered ring (pyrrolidino group, piperidino group, morpholino group, piperazino group, etc.).

Next, a method for producing the compound of the present invention will be explained.

Manufacturing method 1 [In the formula, R1 and R3 are the same as above, R11, H1! represents an alkenyl group, and RI3 represents a lower alkyl group] Compound 1 (In the formula, the alkenyl group of R1 is allyl, 2-
butenyl, 2-pentenyl, 2-hexenyl, 2-hebutenyl, etc.) is an inert gas 1 in the presence or absence of (e.g. nitrogen, helium, etc.)
1-2 at 00-300℃, preferably 200-270℃
By reacting for 4 hours, preferably 1 to 12 hours, compound 2 (in the formula, the alkenyl group of R12 is allyl, l
-buten-3-yl, 1-penten-3-yl, 1-hexen-3-yl, l-hebuten-3-yl, etc. with 3 carbon atoms
~12 alkenyl groups) are obtained.

Compound 2 is heated at 0-150°C, preferably at 0-100°C, in the presence of an alkylating agent (e.g. methyl iodide, ethyl iodide, dimethyl sulfate, etc.) and an inert solvent (e.g. acetone, benzene, tetrahydrofuran, dimethylformamide, etc.).
Compound 3 is obtained by reacting at ℃ for 0.5 to 24 hours. Compound 3 is hydrolyzed and ring-closed with trifluoroacetic anhydride or polyphosphoric acid, and then treated with an oxidizing agent (e.g., potassium permanganate, potassium dichromate, sodium periodate, ozone, etc.) and an inert solvent (e.g., acetone, acetic acid, water, benzene, etc.) at -20 to 100℃.
．． Dibenzocycloheptene m4 was reacted for 5 to 20 hours.
Compound 6 can be obtained in good yield.

Production method 2 [In the formula, R1, R1, R3 are the same as above, A means an ester residue or an amino group] Compound 7 can be converted into a corresponding ester or amide by a method known to those skilled in the art.

In addition, the compound of the present invention may be used as an inorganic salt (sodium salt, potassium salt, calcium salt, alkium salt, hydrochloride, etc.) or organic salt (fumarate, maleate, succinate, phthalate, etc.) as necessary. salt, lysinate, ethanolamine salt,
addition salts (such as pyridine salts) can be formed. It is also possible to form an clathrate compound with cyclodextrin or the like for the purpose of improving stability or solubility.

The compounds of the present invention can also be in the form of pharmaceutically acceptable agents in combination with conventional excipients.

For example, oral drugs or injections in the form of tablets, granules, syrups, capsules, suppositories, ointments, gels, creams, lotions,
It can be used as a parenteral agent such as liniment or patch i.

〔Example〕

The present invention will be explained in more detail with reference to Reference Examples and Examples below, but the present invention is of course not limited to these Examples.

Reference Example 0.5 g of benzoyl peroxide was added to a mixture of 50.0 g of methyl toluic acid and 59.3 g of N-bromsuccinimide in 400 ml of carbon tetrachloride, and the mixture was refluxed for 1 hour while stirring. After the reaction was completed, insoluble matter was filtered, and the filtrate was dried under reduced pressure. 300 ml of acetonitrile and 96.0 g of triphenylphosphine were added to the residue, and the mixture was refluxed for 1 hour while stirring. Ether was added and the precipitated crystals were collected by filtration and dried to obtain 123.4 g of phosphonium salt.

Dissolve 30.0 g of phosphonium salt in acetonitrile,
13.6 g of 4-benzyloxybenzaldehyde and 1
．． 2 g of 8-diazabicyclo(5,4,0)-7-undecene (hereinafter abbreviated as DBU) io was added, and the mixture was refluxed for 1 hour with stirring. After the reaction, dry under reduced pressure and add 25% of ethyl acetate.
The solution was dissolved in 0ml, washed with 7% hydrochloric acid and then with water, dried, and then dried under reduced pressure.

The residue was dissolved in 200ml of ethanol, 2.0g of palladium on carbon was added, and the mixture was heated to 100k hydrogen pressure in an autoclave.
g/ctl, stirred at 80 °C for 18 h. After the reaction was completed, the palladium on carbon was filtered off, and the filtrate was dried under reduced pressure.

The residue was dissolved in 40 ml of diethylaniline and
The reaction was carried out at 70°C for 3 hours. After cooling, the reaction product was dissolved in 250 ml of ethyl acetate, washed successively with 10% hydrochloric acid and water, dried, and dried under reduced pressure to obtain 13.9 g of a rearranged product.

Next, 13.4 g of the rearranged product was dissolved in 150 ml of acetone, 8.5 g of dimethyl sulfate and 9.4 g of potassium carbonate were added, and the mixture was refluxed for 16 hours with stirring. After the reaction was completed, insoluble matter was filtered off, and the filtrate was dried under reduced pressure. The residue is methanol 150 ni
75 ml of an aqueous solution containing 5.7 g of potassium hydroxide dissolved in 1 liter of water was added, and the mixture was refluxed for 3 hours with stirring. The reaction solution was dried under reduced pressure, then dissolved in 200 ml of ethyl acetate, washed successively with 10% hydrochloric acid and water, dried, and then dried under reduced pressure to obtain 12.7 g of carboxylic acid.

Subsequently, 12.6 g of carboxylic acid was added to 120 a of dichloromethane.
24 ml of trifluoroacetic anhydride was added, and the mixture was reacted under reflux for 24 hours. The reaction solution was dried under reduced pressure, the residue was dissolved in 200 ml of ethyl acetate, washed successively with a 5% aqueous potassium carbonate solution and water, dried, dried under reduced pressure, adsorbed on a column packed with silica gel, and dissolved in isopropyl ether/hexane ( 1: Expanded in 2). The solvent of the effluent was distilled off to obtain 4.9 g of 2-allyl-3-methoxy-10,11-dihydro-5-oxo-5H-dibenzo(a,d)cycloheptene.

Example 1 2-allyl-3-methoxy-10.11-dihydro-5
-oxo-5H-dibenzo(a,d)cycloheptene 4
．． 9g in 100ml of acetone, 35ml of acetic acid, 11ml of water, 50ml of water
Potassium permanganate dissolved in 11.1 at 5-10℃
g was added over 1 hour, and the mixture was stirred at 20°C for 1 hour.

After decomposing unreacted potassium permanganate with sodium hydrogen sulfite, insoluble matter was filtered, and the filtrate was dried under reduced pressure.

Add 150s11 of ethyl acetate to the residue, wash successively with 10% potassium carbonate aqueous solution and water, dry and dry under reduced pressure. The resulting crystals were recrystallized with ethyl acetate to give colorless needle-like crystals of 3-methoxy-10,11. -dihydro-5-oxo~5H-dibenzo(a,d)cyclohepten-2-acetic acid 1.8
I got g.

Melting point 165-167℃ IR (KBr) 3058-2840cm-', 1709
cmMASS (n+/e) 296 (M”) Elemental analysis value Cl1lIII604 Theoretical value C near 2.96 H: 5.44 Actual value C near 2.74 H: 5.40 Example 2 2-(1'-butene- 37-yl)-3-methoxy-7
-Methyl-10,11-dihydro-5-oxo5H-dibenzo(a,d) 1.8 g of cycloheptene was mixed with 40a of acetone + 13ml of L acetic acid. Dissolve in 20ml of water, 5~
3.8 g of potassium permanganate was added over 1 hour at 10°C, and the mixture was stirred at 25°C for 1 hour. Example 1 after the reaction
Perform the same operation as 2-(3-methoxy7-methyl-1
0,11-dihydro-5-oxo-5H-dibenzo(a
, d) 0.5 g of cycloheptene)propionic acid was obtained.

Melting point 153-155℃ IR (KBr) 2982-2852cm-', 16
98cm-MASS (m/e) 324 (M”) Elemental analysis value C2°H2°04 Theoretical value C near 4.06 H: 6.21 Actual value C near 3.77 H: 6.27 Example 3 3- Methoxy-10,11-dihydro-5-oxo-5
I(-dibenzo(a,d)]cyclohepten-2
-1.0 acetic acid was dissolved in 8 ml of 47% hydrogen bromide and 8 ml of acetic acid and refluxed for 20 hours with stirring. After the reaction was completed, 100 ml of ethyl acetate was added, washed successively with a 5% aqueous potassium carbonate solution and water, dried, and dried under reduced pressure. The resulting crystals were recrystallized with ethyl acetate to give 3-hydroxy-10 as light yellow needles. ，
11-dihydro-5-oxo-5H dibenzo (a, d
) 0.4 g of cyclohebutene-2-acetic acid was obtained.

Melting point 180-182℃ IR (KBr) 3376cm-', 3076-28
52cm-', 1702cm-'MASS (m/e
) 2B2 (M"") elemental analysis value CI? H1404 Theoretical value C near 2.33 11:5.00 Actual value C near 2.41 H:5.18 Example 4 2-(3-methoxy-8-methyl-10,11-dihydro-5-oxo-5H -dibenzo(a,d)cycloheptene> 1.2 g of propionic acid was added to 1.3 g of thionyl chloride in 30 ml of benzene, and the mixture was heated under reflux for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and 1.3 g of thionyl chloride was added to 1.2 g of propionic acid in 30 ml of benzene.
The operation of adding 1 and distilling it off under reduced pressure was repeated twice. Benzene 30n+1 and 2-pyridine methanol 0.5 to the residue
Then, 7 g of DBUo was added dropwise at 10 to 15°C, and the mixture was further stirred at the same temperature for 1 hour. After completion of the reaction, 50% ethyl acetate
After adding m1 and washing with water, washing with 10% sodium bicarbonate water, the solvent was distilled off,
It was purified by silica gel column chromatography using isopropyl ether. Further, thin film distillation was performed in a glass tube oven at 240°C. 2-(3-
Methoxy-8-methyl-10,11-dihydro-5-oxo-5H-dibenzo(a,d)cycloheptene)
0.75 g of propionic acid 2-picolyl ester was obtained.

IR(neat)1742cm-111640c+a-
'MASS (n+/e)415 (M'') Elemental analysis value CzilbsNOn Theoretical value C near 5.16 H: 6.06 N: 3.
37 actual measurement value C near 4.97 H: 5.92 N:
3.69 Example 5 2-(3-methoxy-10,11-dihydro-5-oxo-5H-dibenzo(a,d)cyclohepten)propionic acid 1.2 g, 1,1-ethylidene diacetate 1.2 g, P-) 70 ml of toluene sulfonic acid was heated under reflux in 50 n+1 toluene for 45 hours. After the reaction, toluene was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using isopropyl ether.

Furthermore, when thin film distillation is performed in a glass tube oven, sublimable substances flow out first, but from the fraction at 235°C/1 mmHg, 0.12 g of 1-acetoxyethyl-2 = (3
-methoxy-10,11-dihydro-5-oxo5H-
Dibenzo(a,d)cyclohebutenyl)propionate was obtained.

IR(neat)1760cm-'+1644cm
-'MASS (w/e) 396 (M") Elemental analysis value Czsllt<Oh Theoretical value C: 69.68 H: 6.10 Actual value C:
69.96 +1:6.26 Examples 6-15 The compounds of the present invention shown in the following table were synthesized according to the methods of Examples 1-5.

* The boiling point is the distillation temperature when thin film distillation is performed in a glass tube oven. [Effects of the invention] Various pharmacological experiments have shown that the compound of the present invention has excellent anti-inflammatory, analgesic and antithrombotic effects, and has few side effects. It turned out to be safe.

Therefore, the compound of the present invention is a compound useful as a pharmaceutical having anti-inflammatory, analgesic, and antithrombotic effects.

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. An alkoxy group, R^3 is a hydrogen atom or a lower alkyl group, A is a hydroxyl group, ▲ Numerical formulas, chemical formulas, tables, etc. ▼ {In the formula, n is an integer of 1 or 2, R^4 is a hydrogen atom or A lower alkyl group, R^5 is a hydrogen atom, a cyclic amino group consisting of a 5- to 6-membered ring, -OCOR^6 (in the formula, R^6 means a lower alkyl group)}, -NH(CH_2)n -R^
7 (wherein n is an integer of 0 or 1, R^7 means a hydroxyl group or a hydroxycarbonyl group), a cyclic amino group consisting of a 5- to 6-membered ring]
a, d] Cycloheptene derivative.