JPS59116253A - Alkylbenzylidene derivative, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel and therapeutically useful alkylbenzylidene derivatives, processes for their preparation, and pharmaceutical compositions containing them.

The alkylbenzylidene derivative according to the present invention has the general formula (
I): [wherein n is an integer of 1 to 12 (preferably 1 to 4), k
l is a linear or branched alkyl or alkenyl group having 2 to 6 carbon atoms; metal, an alkaline earth metal such as calcium or magnesium), Xl, X2 and X3
each independently represents a hydrogen atom, a 7% rogen atom, a methoxy group, or a linear or molecular chain alkyl group having 1 to 4 carbon atoms.

Preferred compounds in the present invention are compounds represented by the general formula (■) = (in the formula, various symbols have the same meanings as defined above), in particular, where Xl is a chlorine atom or a methyl group, and X2fii is a chlorine atom. Alternatively, a group of compounds in which a methyl group or X3 is a hydrogen atom are preferred. More preferred among these are compounds in which n is 3 and R1 is ethyl, n-propyl, n-butyl, or in-hexyl group. A particularly important compound is 4-1: (5-chloro-2
-Hydroxy-3-〇-propylphenyl) (4-10
lofuenyl) methylenetuaminobutyric acid, and 4-1m
(5-chloro-2-hydroxy-3-ethylphenyl)
(4-chlorophenyl) methylene diaminobutyric acid, alkali metal and alkaline earth metal salts thereof, and amide compounds thereof.

The present invention also provides a method for producing an alkylbenzylidene derivative represented by the general formula (2), which is a benzophenone derivative represented by the general formula (■):1 (wherein, various symbols have the same meanings as defined above). , general formula (IV): H2
A compound represented by N-(CH2)n-GOR2(IV) (wherein n and 2 have the same meanings as defined above), or optionally an acid addition salt thereof such as hydrochloric acid, and methanol, ethanol or A process is provided which is characterized in that the reaction is carried out in an organic solvent such as a methanol/toluene mixture in the presence of a base, such as sodium methoxide or ethane.

Alternatively, an alkylbenzylidene derivative of the general formula (R2) in which R2 is an amine group can also be produced by reacting a corresponding compound of the general formula (R2) in which R2 is a hydroxyl group with carbonyldiimidazole and ammonia.

Compounds of the general formula (R2) in which R2 is a 10M group (M follows the definition described above) can be prepared by a method known per se, i.e., from alkali metal or alkaline earth carboxylic acids, from corresponding compounds in which R2 is a hydroxyl group. Metal salts can be produced by conventionally used methods or methods described in chemical literature.

The starting benzophenone derivatives of the general formula (II',) are novel and can be prepared, for example, according to the following reaction scheme: ).

Next, according to Examples, examples of manufacturing the alkylbenzylidene derivatives of the present invention using the above steps will be described in detail. The structure of the product was confirmed by elemental analysis and IR1NMR spectrum.

Example 14-[I(5-chloro-2-hydroxy-3-
n-7'-pylphenyl) (4-10-pylphenyl)
methylenetoaminobutanamide CX1=5”l,
X2=4-C7: , X3===I-1, n=
3, k1=n-C3R7, R2=NH2],
1. 21g (0,123 mol) of a phenolic compound represented by (5-chloro-2-hydroxy-3-n-propylphenyl)(4-10lophenyl)-meta,non
17.15 m/(o, i 23 mol) of triethylamine are added to a stirred solution of 1.31 mol of triethylamine in 1.31 ml of methylene chloride and the mixture is heated to reflux temperature.

The heating is stopped, and a solution of 21.54 g (0.123 mol) of an acid chloride represented by the formula O 2 in 100-methylene chloride is gradually added to the mixture to maintain reflux. After heating the reaction mixture under reflux for a further 8 hours, the products are left in contact with each other overnight. Then add 50 ml of cold water to this solution.
Add 0+++/, decant the organic layer, and add 250 rn! of saturated sodium bicarbonate solution! , and once with 250 d of water.

After drying the organic layer with anhydrous magnesium sulfate and filtering,
Evaporate the P solution to dryness. The oil obtained is crystallized by rubbing in petroleum ether 120d.

The crystals were washed several times to remove the solvent, redissolved in boiling petroleum ether, added with 2 g of vegetable activated carbon, stirred for 15 minutes, filtered while hot, and concentrated the P solution to about 150%. The crystals of the ester product precipitated during cooling are separated, the solvent is removed, and the crystals are dried in a desiccator. mP=49-50°C.

29.7 g (0,096 mol) of previously obtained 4-chloro-2-propylphenyl 4-chlorobenzoate were heated to 100° C. with stirring in a well-ventilated fume hood, and 29.7 fj (0,000 mol) of aluminum chloride was added. 223 mol) was added little by little over 10 minutes. The reaction medium was then heated to 160 °C in an oil bath with stirring and after being kept at this temperature for 15 minutes,
Leave to cool to 50°C.

After cooling with solid carbonic acid for 1 hour, the resulting solid is crushed and further finely ground in a mortar. This powdered complex was mixed with 11 ml of vigorously stirred water, 500 g of ice and 300 rn of concentrated hydrochloric acid! , slowly into the mixture to hydrolyze. Extract with 31 parts of methylene chloride in total, and add 5 parts of the organic layer to water.
After washing with 00-, it is decanted, dried over anhydrous magnesium sulfate, filtered, and the P solution is concentrated to about 100 rnl. This crude product is purified by passing it through a silica gel column (7001) and eluting with 31 methylene chloride. Both fractions containing the product are collected, dried over anhydrous magnesium sulfate, filtered, and the P solution is evaporated to dryness. The residual oil is crystallized from Petroleum King Telka, filtered through a frit and, after removal of the solvent, dried in a desiccator.

mP=55-56°C 2,4-C(5-chloro-2-hydroxy-3-n-
]o hirphenyl) (4-”lorophenylmethylene)
-aminobutanamide Ketone compound 6.2y (0,020 mol), 4
-Aminobutanamide hydrochloride 3.05 g<, 0.0
22 mol) and 1.25 g (0
A mixture of 22 moles) in 600 methanol
Evaporate to dryness at 00°C (bath temperature 100'C). Place 60ml of ethanol in the round bottom flask and evaporate the mixture to dryness under the same conditions. Again, ethanol 600m/! is added, evaporated, and finally distilled under reduced pressure. The residue was dissolved in methylene chloride. Dissolve in water 100m/! After washing with water, the organic layer is separated by decantation, dried over anhydrous magnesium sulfate and filtered, and the P solution is evaporated to dryness under reduced pressure. The remaining solid is dissolved in 15 rnl of hot ethyl acetate and diethyl ether is added until it becomes slightly cloudy (approximately 100 d).

Amide product precipitated on cooling (titled amide compound)
The crystals are taken out with a frit, washed with 200 ml of diethyl ether, the washing liquid is removed, and the crystals are dried in a desiccator heated to 60°C. m p =130-131°C Example 24-((5-chloro-2-hydroxy-3-ethylphenyl)(4-10lophenyl)methyleneioaminobutyric acid and its sodium salt CX1 = 5-cz,
X2=4-c! 1. X3=H, na, R1=C2
H5, R2 = OH and ON a] ■, (5-chloro-2-hydroxy-3-ethylphenyl) (4-chlorophenyl)-methanone 4-chloro-2-n-7' instead of pyruphenol 4- Working according to the steps of Example 1.1 using chloro-2-ethylphenol, the 4-
Chloro-2-ethylbenzyl 4-chlorobenzoate is obtained and this compound is reacted with aluminum chloride under the same conditions to obtain a benzophenone derivative. mP=47-49°C 2.4-[(5-chloro-2-hydroxy-3-ethylphenyl)(4-10lophenyl)-methyleno]-aminobutyric acid and its sodium salt previously obtained benzophenone'1 (3X10 ”mol), methanol 350r
nl, gabamide.

That is, γ-aminobutyric acid, abbreviated as cAnA)3.23f(3
, lX10-2 mol) and sodium methoxide 1.
72 g (3xlO-2 moles) are placed in a 11 round bottom flask. After heating the mixture under reflux for 4 hours, GABAI
, 6P (1,5×10 −2 mol) and 0.85 g (1,5×10 −2 mol) of sodium methoxide are added.

The reaction mixture is heated under reflux for a further 4 hours, then evaporated to dryness and the residue is taken up in 2.5 ml of water and adjusted to 4 μm with citric acid. Extract with methylene chloride 35orn! x2) The organic layers were combined and washed with 400 ml of water, dried over sodium sulfate and filtered, and the P solution was evaporated to dryness.

The residue is filtered through a frit with petroleum ether, the solvent removed and dried in a vacuum dessicator.

The acid produced is recrystallized into diisopropyl ether. 45 g of acid compound at mp = 131-132° and 100 rn of methanol! 15. Add 0.748N sodium methoxide solution to the solution in the solution.
7. Add d. Evaporate the methanol at 80° C. and add 100 ml of diethyl ether. is added and evaporated again, the sodium salt obtained is filtered through a frit with diethyl ether, the solvent is removed and then dried in a vacuum desiccator. Melting point of sodium salt>250°C Example 34-((5-chloro-2-hydroxy-3-L
ert,-butylphenyl)(4-chlorophenyl)methyleneioaminobutyric acid and its sodium salt [Xl = 5-Cl, X2 = 4-Cj!
%X3 = H, Rho3, R1 = t-C411g,
R2=OH and ONa]1, (5-chloro-2-hydroxy-3-terL.

-butylphenyl)(4-10lophenyl)-methanone 1.1. 4-chloro-2-LerL, -butylphenol 57f (0,309 mol), triethylamine 32
．． 3 g (0.32 mol) and 3.79 (0.03 mol) of 4-dimethylaminopyridine in diethyl ether 8
00d, 56 g (0.32 mol) of P-chlorobenzoyl chloride was added to the solution in diethyl ether 200-
Add the solution in the solution dropwise. After stirring for 6 hours at ambient temperature - overnight, 500 g of water are added to the mixture. The organic layer is washed with sodium carbonate solution and then water, dried over anhydrous magnesium sulfate and evaporated, and the residue is recrystallized from petroleum ether. The product compound has the formula: %Formula%Cl,2. Previously obtained ester compound 4.59 (0,01
39 mol) to NH benzene 200rn1. A photochemical reactor equipped with a 100 watt mercury lamp
1 month of "Novia" and irradiated for 32 hours under a nitrogen atmosphere while stirring with a magnetic stirrer. The benzene was removed by evaporation, and the residue was placed in a column chromatograph to isolate the product (column Nimerk). 40 silica gel, eluent: petroleum ether/methylene chloride, 9/1 mixture).

Both parts containing the pure substance are distilled in a sphere tube (5-chloro-2
-hydroxy-3-Lert, -butylphenyl) (4
-10 Lofenyl)-methanone is obtained.

mP = 86.5-87°C 2,4-((5-chloro-2-hydroxy-3-ter
t,-]f ruphenyl) (4-10 lophenyl) methyleneioaminobutyric acid and its sodium salt 0.128 g (1,24 mmol) of 4-aminobutyric acid and (5-chloro-2-hydroxy-3-Lert.

-butylphenyl)(4-chlorophenyl)-methanone (0.49 (1.24 mmol)) and sodium 1.
Sodium ethoxide solution containing 3 mmol 25-
Add to.

After distilling alcohol 15+y+/ fairly slowly,
Add 10 rnl of absolute ethanol and add 15 rnl of alcohol again.
− is distilled out. The residue obtained by evaporation to dryness was mixed with 20% water.
Dissolve in rnl and adjust to μI4 with citric acid.

After extraction with methylene chloride and washing the extract with water, anhydrous sodium sulfate and evaporation, the resulting residue is recrystallized from heptane, and the crystals are washed with pentane. m
p = 118-119 °C, and 125-126 °C 723 rn of a 0.332 mol/l ethanol solution of sodium ethoxide is added to a solution of 1 g (2,45 mmol) of the acid compound obtained above in 10 rnl of absolute ethanol. ! ,
(2.4 mlJ mol) is added, evaporated to dryness and the remaining oil is dissolved in cold cyclohexane 10-.

The sodium salt crystals that gradually precipitate are washed with pentane several times, and then vacuum dried at 100° C. for 8 hours. InP
=245°C (decomposition) Table 1 lists the compounds of the present invention produced in the same manner as in the above examples.

Note that Table 1 lists benzophenone compounds as starting materials.

Table ■ Nigawara-"Niyu 2" Glue L) The compound of the present invention showed central nervous system activity in pharmacological tests.

The acute toxicity of the compound of the present invention was investigated by intraperitoneal administration to mice. L I)so value (50% lethal dose, i.e., the dose that causes death in 50 animals) is 250~>10100O/(
Weight Kg) Tea Tsuta.

Next, the antidepressant activity was examined by antagonizing the head twitching induced by L-5-hydroxytryptophan (L-5-H"11'l) in mice.

Mice (male, C:I) I strain, Charles River France, body weight 18-22 g) were administered increasing amounts of the test compound or vehicle (control) at the same time as L-5-
11T P 250 UIg/KI7 is injected subcutaneously.

45 minutes after L-5-IITP injection, the number of head contractions of each mouse is observed for 1 minute, and the average number of head contractions and the displacement (%) relative to the control are calculated for each test example.

Using an effect-dose curve, Miller et al.
Ta1nter, Proc, Soc, Exp, Bio
The AD5o (50% effective dose, ie, the amount that reduces the average number of head contractions by 50%) is calculated according to the graphical method of 10Med, (1944) 57-261].

As a result, the AI]5o of the compound of the present invention was 49 to 60 .mu./(body weight 1'u!2) when administered intraperitoneally.

Next, the antispasmodic (antispasmodic) effect of the compound of the present invention was investigated by its antagonistic effect on the lethal effect of bicuculline in mice.

Bicuculline is a relatively selective antagonist of postsynaptic GABAergic receptors. The crippling and lethal effects of this compound are antagonized by compounds that increase GABA levels in the brain or by substances that have GABA-mimetic effects.

Therefore, the 50% effective dose of the compound of the present invention [AD5o, that is, the amount of the compound sufficient to protect 50% of animals (mice) from the above-mentioned effects of bicuculline] was determined.

As a result, the ADso of the compound of the present invention was 10 to 100 μ/(9% body weight) when administered intraperitoneally.

Furthermore, the anti-ulcer effects of the compounds of the present invention were investigated by their activity against stress ulcers and phenylbutacin-induced ulcers.

These two studies on stress ulcers and phenylbutacin-induced ulcers were performed using fasted body weights ranging from 180 to 2
The test was conducted using 10 g female Wistar rats. 3 immediately before stress or oral administration of phenylbutacin
After 0 minutes, a suspension of the test compound in a 1% 1'ween 80 aqueous solution was orally administered to the animal. In both cases, the stomach was examined 2 hours after the onset of the ulceration process.

As a result, the compound of the present invention was effective against stress ulcers by 3%.
It was found that a dose of 0"If/(7 points to body weight) or more and a dose of 100 n'f/(9 points to body weight) or more had a significant effect on phenylbutacin-induced ulcers.

Furthermore, the inhibitory effect of the compounds of the present invention on gastric juice secretion was investigated in a test using pylorus-ligated rats in an awake state. The pylorus of a female Wistar rat weighing 200-220 g that had been fasted for 48 hours was ligated into an ether anesthetic tube, and the test compound was immediately administered at 1, 5.25 and 50"y/(body weight Kp).
) Administer intraperitoneally. Four hours after the ligation procedure, the animals were sacrificed and the amount of gastric secretion was measured, and the free acidity and total acidity were measured by the demarcation method and compared with the control.

As a result, the compounds of the present invention each had a gastric fluid sensitivity of 45 to 45.
55%, 50-65% and 70-85%, free acidity 60-70%, 65-75% and 85-95%,
Total acidity 55-65%, 60-70 and 85-9
It was found that the ratio was reduced by 5.

From the results of the above pharmacological tests, the compound of the present invention is considered to exhibit antidepressant, ulcer suppressant, and gastric juice secretion suppressing activity, and is also effective as an anxiolytic, analgesic, and anti-inflammatory agent. Therefore, the compounds of the invention are intended for the treatment of various central system diseases such as depression and psychosis, and certain nervous system diseases such as epilepsy, sitting symptoms and movement disorders, as well as various stress ulcers and gastric ulcers. It can be used in fields that involve humans or veterinary medicine.

Therefore, the present invention is particularly useful for oral administration (tablets, tablets, etc.).
Coated tablets, gelatin capsules, regular capsules, cachets
or internal solution or suspension) or valve diameter 1
'' includes all pharmaceutical compositions comprising as an active ingredient an alkylbenzylidene conductor of the general formula (2) together with any excipients suitable for administration.

The dosage of the compound of the present invention can be 100-3000''/day.

Patent applicant Synthelabo representative Patent attorney Aobai Ao and 1 other person France 94
240 Rayu S. Rose Rue deux Margarité No. 2@R Ming. Michelle Mangan France 92320 Châtillon Saint-Bagneux-Abnue Marcel Cachin No. 44

Claims (1)

[Claims] ■, General formula (I): λ3 [In the formula, 1 is an integer of 1 to 12, R1 is a straight or branched alkyl or alkenyl group having 2 to 6 carbon atoms, R24
amino group, hydroxyl group or -OM group (M represents an alkali metal or alkaline earth metal), Xl, N and
3 each independently represents a hydrogen atom, a halogen atom, a methoxy group, or a straight or branched alkyl group having 1 to 4 carbon atoms; 1) benzylidene derivatives; 2. The benzylidene derivative according to item 1, represented by the general formula (■): [In the formula, various symbols have the same meanings as defined in item 1.] 3. The benzylidene derivative according to item 1 or 2, wherein n is an integer of 1 to 4. 4, Xl or chlorine atom or methyl group, X! The first term in which jJ< is a chlorine atom or a methyl group and the atom is a hydrogen atom,
Benzylidene derivative according to item 2 or 3. 5, n or 3, R1 or ethyl, n-propyl, +1
- The benzylidene derivative according to item 4, which is a butyl or n-hexyl group. 6.4-C(5-chloro-2-hydroxy-3-lopropylphenyl)(4-''lorophenyl)methyleneioaminobutyric acid, its alkali metal and alkaline earth metal salts, and amides. 7.4-( (5-chloro-2-hydroxy-3-ethylphenyl)(4-chlorophenyl)methyleneioaminobutyric acid, its alkali metal and alkaline earth metal salts, and amides 8, the general formula (I) described in item 1 A method for producing a benzylidene derivative represented by the general formula (nI): (wherein, various symbols have the same meanings as defined in item 1).
-(CH2)n -COR2(IV) (wherein n and square have the same meanings as defined in Section 1) or optionally an acid addition salt thereof, and a temperature range of 20 to 120'C. A method characterized in that the reaction is carried out in an organic solvent in the presence of a base. 9. A method for producing a benzylidene derivative represented by the general formula (R27) according to item 1, wherein the square is an amine group,
5. A method characterized by reacting a compound of the general formula (R) which is a hydroxyl group with carbonyldiimidazole and ammonia. 10. R2 is a 10M group (M has the same meaning as the definition in Section 1) 1. A method for producing a benzylidene derivative represented by the general formula (1) described in Item 1, wherein a compound of the general formula (R2/' A method characterized by converting the metal into a salt. 11. A pharmaceutical composition containing the benzylidene derivative represented by the general formula (1) described in item 1 as an active ingredient, particularly as an antidepressant, an antispasmodic drug, A drug used as an ulcer suppressant 9J, a gastric juice secretion suppressant, and an anxiolytic, analgesic and anti-inflammatory agent.