JPH0584299B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to new and pharmaceutically useful benzophenone derivatives and acid addition salts thereof. [Prior Art] U.S. Patent No. 3,243,461 describes a 4,4'-substituted benzophenone derivative as a raw material compound for a compound having an anti-inflammatory effect and a blood lipid-lowering effect. No pharmacological effects have been shown. Also, journal
Of Medicinal Chemistry, Volume 21, 1084
(1978) disclosed a 3,3'-substituted benzophenone derivative as a close relative of a compound known as an interferon-inducing antiviral agent, and investigated its interferon-inducing effect and toxicity to mice. ing. [Problems to be Solved by the Invention] The present inventors have conducted extensive studies in order to develop a compound that has actions such as promoting leukocyte anemia, promoting leukocyte sterilization, restoring cell production, and enhancing infection resistance. Summer. [Means for Solving the Problems] As a result, the present inventors have discovered that a novel benzophenone derivative has the above-mentioned excellent effects, and have completed the present invention. That is, the present invention is based on the general formula

The present invention relates to a benzophenone derivative represented by the following formula or an acid addition salt thereof. In the above formula, R ¹ , R ² , R ³ , and R ⁴ are the same or different and represent a hydrogen atom or lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc.), or
R ¹ , R ² and R ³ , R ⁴ are each bonded to an adjacent nitrogen atom to form a heterocyclic ring which may be the same or different [the heteroatom further includes an oxygen atom, a sulfur atom, or a lower alkyl (methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tertiary butyl, etc.) or hydroxyalkyl (hydroxymethyl, 2-hydroxyethyl, etc.), for example, 1- pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-
Piperazinyl, 4-(2-hydroxyethyl)-1
-piperazinyl, morpholino, thiomorpholino,
1-Homopepyrazinyl, etc. ], and X ¹ and X ² are the same or different and represent a hydrogen atom, halogen (chlorine, bromine, fluorine, iodine),
lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc.) or nitro, A ¹ and A ² are the same or different, -CH (CH ₃ ) CH ₂ -, -CH ₂ , CH ₂ −, −
CH ₂ , CH ₂ , CH ₂ −, −CH ₂ CH ₂ , CH ₂ , CH ₂ −,
or −CH ₂ CH ₂ OCH ₂ CH ₂ −. The compound of the present invention represented by the general formula () can be produced by the method shown below. general formula

[In the formula, Y ¹ and Y ² are the same or different and represent a hydroxyl group or a halogen (chlorine, bromine, fluorine, iodine), and the other symbols have the same meanings as above. ]

Compounds represented by and general formula

【formula】

[Action and effect of the invention]

The benzophenone derivative represented by the general formula () and its acid addition salt of the present invention have effects such as excellent leukocyte phagocytosis promoting effect, leukocyte bactericidal ability enhancing effect, splenic plaque-forming cell production recovery effect, and infection resistance enhancing effect. However, it is useful as a preventive or therapeutic agent for leukopenia caused by chemotherapy with anticancer drugs, infectious diseases caused by a decline in the body's defenses after surgery, rheumatism, cancer, asthma, etc. Experimental Example Leukocyte Phagocytosis Enhancement Effect 0.3 mg/Kg of the compound of the present invention was orally administered to male ICR mice weighing approximately 25 g, and then killed yeast was immediately administered intraperitoneally to induce peritonitis. 2 more
After a period of time, ascites was collected, and the phagocytic ability of ascites polymorphonuclear leukocytes to kill yeast was measured under a microscope. The phagocytic ability was calculated as a percentage compared to the control group (group without administration of the compound of the present invention), and the results were used in the first
It is summarized in the table. The compounds used are as follows. Compound A: 2,4'-bis(2-dimethylaminoethoxy)-3'-methylbenzophenone dimaleate Compound B: 2,4'-bis(2-dimethylaminoethoxy)-3',5 -Methylbenzophenone dioxalate compound C: 2,4'-bis(2-dimethylamino-1-methylethoxy)benzophenone dihydrochloride 1
hydrate

〔Example〕

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto. Example 1 2.7 g of 60% oily sodium hydride is suspended in 30 ml of dimethylformamide, and 9.4 g of 1-dimethylamino-2-propanol is added dropwise to this with stirring. After dropping the entire amount, stir at 40°C for 1 hour.
The reaction mixture was then cooled on ice, and 6.6 g of 2,4'-difluorobenzophenone was added thereto. After stirring at 50°C for 2 hours, pour into ice water. The resulting oil is extracted with toluene, washed with water, dried, and concentrated.
The residue is dissolved in an ethyl acetate-isopropanol mixed solvent, acidified with a hydrochloric acid-isopropanol solution, and then cooled. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of ethyl acetate and isopropanol to yield 2,4'-bis(2-dimethylamino-1-methylethoxy)benzophenone dihydrochloride 1 water with a melting point of 110-115°C. 8.5 g of hydrate are obtained as white crystals. Example 2 2 g of 50% oily sodium hydride is suspended in 30 ml of dimethylformamide, and 4.9 g of 1-dimethylamino-2-propanol is added dropwise thereto. After dropping the entire amount, stir at 40°C for 1 hour. The reaction mixture was then cooled on ice and 2,4'-difluoro-
Add 5 g of 3'-chlorobenzophenone. After stirring at 50°C for 1 hour, pour into ice water. The resulting oil is extracted with toluene, washed with water, dried, and concentrated.
The residue is dissolved in acetone, acidified with hydrochloric acid-ethanol solution, and cooled on ice. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of acetone and ethanol to yield 2,4'-bis(2-dimethylamino-1-methylethoxy)-3'-chlorobenzophenone with a melting point of 210-213°C. 5.6 g of dihydrochloride are obtained as white crystals. Example 3 1.74 g of 50% oily sodium hydride is suspended in 30 ml of dimethylformamide, and 5.3 g of 2-piperidinoethanol is added with stirring. 50℃
After stirring for 1 hour, 2,4'-difluoro-3'-
Add 4g of methylbenzophenone. 1.5 at 60℃
After stirring for an hour, pour into ice water. The resulting oil is extracted with toluene, and the toluene layer is then extracted with dilute hydrochloric acid. The dilute hydrochloric acid layer is ice-cooled and made alkaline with an aqueous sodium hydroxide solution, and the resulting oil is extracted again with toluene. After washing with water and drying, concentrate. The residue was dissolved in acetone, acidified with a hydrochloric acid-ethanol solution, and cooled on ice. When the precipitated crystals are recrystallized from an acetone-ethanol mixed solvent, 2,4'-bis(2-piperidinoethoxy)-3'-methylbenzophenone with a melting point of 218-220°C (decomposition) is obtained.
6.3 g of dihydrochloride are obtained as white crystals. Example 4 4.4g of sodium hydroxide was dissolved in 10ml of water,
Next, 8.9 g of 2-dimethylaminoethyl chloride hydrochloride, 60 ml of toluene and 3',5-dimethyl-2-hydroxy-4'-fluorobenzophenone
Add 10 g and stir under reflux for 20 hours. After cooling, separate the toluene layer, wash with water, and extract with dilute hydrochloric acid.
Cool the dilute hydrochloric acid layer on ice and make it alkaline with sodium hydroxide. The resulting oil is extracted with chloroform, and the chloroform layer is washed with water, dried, and concentrated.
7.7g of the obtained residual oil was dissolved in dimethylformamide.
Sodium 2 dissolved in 10 ml and adjusted in advance
- Add dimethylaminoethoxide to a mixed solution of 20 ml of dimethylformamide and 20 ml of toluene while stirring. After stirring at 50°C for 18 hours, pour into ice water. After adding ethyl acetate and stirring, the ethyl acetate layer is dispersed, washed with water, dried, and concentrated. The residue is dissolved in ethanol and oxalic acid is added to crystallize it. When the obtained crystals are recrystallized with methanol,
7.5 g of 2,4'-bis(2-dimethylaminoethoxy)-3',5-dimethylbenzophenone dioxalate having a melting point of 200-201 DEG C. are obtained as white crystals. Example 5 4.2g of 60% oily sodium hydride was added to 60% of toluene.
ml and suspended in 60 ml of dimethylformamide,
Add 10.7 g of 2-dimethylaminoethanol to this and stir at 40°C for 1 hour. 14 g of 2-chloro-4'-fluoro-5-nitrobenzophenone and 10 ml of dimethylformamide were added to the reaction mixture under ice-cooling and stirring.
Add the solution dropwise over 30 minutes. After dropping the entire amount, at room temperature
After stirring at 30°C for 1 hour, pour into ice water.
Add ethyl acetate to this and stir. The ethyl acetate layer is separated, washed with water, dried, and concentrated. The residue is dissolved in acetone, acidified with a hydrochloric acid-ethanol solution and crystallized. When the obtained crystals are recrystallized from an acetone-ethanol mixed solvent, the melting point is 192-195℃.
(Decomposition) 12.3 g of 2,4'-bis(2-dimethylaminoethoxy)-5-nitrobenzophenone dihydrochloride 1/2 hydrate is obtained as white crystals. The following compound is obtained in the same manner as in the above example. Example 6 2,4'-bis(3-dimethylaminopropoxy)benzophenone dihydrochloride, melting point 226-228°C Example 7 2,4'-bis(2-dimethylaminoethoxy)
-3'-Methylbenzophenone 2maleic hydrochloride, melting point 63-70°C Example 8 2,4'-bis(2-dimethylamino-1-methylethoxy)-3'-methylbenzophenone 2syu Acid acid, melting point 158-161°C Example 9 2,4'-bis(2-dimethylaminobutoxy)
Benzophenone dihydrochloride, melting point 170-171°C Example 10 2,4'-bis(2-dimethylaminoethoxy)
-3′-chlorobenzophenone dihydrochloride, melting point
120-122℃ Example 11 2,4'-bis(2-dimethylaminoethoxy)
-5-Methylbenzophenone dihydrochloride 1/2 hydrate, melting point 167-170°C Example 12 2,4'-bis(2-morpholinoethoxy)benzophenone dioxalate monohydrate , melting point 118
~124℃ (decomposition) Example 13 2,4'-bis(2-dimethylaminoethoxy)
-5-chlorobenzophenone, dioxalate, melting point 170-172°C (decomposition) Example 14 2,4'-bis(2-diethylaminoethoxy)
Benzophenone 5/2 oxalate, melting point 176-178
°C Example 15 2,4'-bis(2-dimethylaminoethoxy)
Benzophenone dioxalate, melting point 180-181℃
(Decomposition) Example 16 2,4'-bis[2-(2-diethylaminoethoxy)ethoxy]benzophenone, pale yellow oil Nuclear magnetic resonance spectrum (deuterochloroform) 1.02ppm (multiplet 12H) 2.6ppm (multiplet 12H) ) 3.35~4.3ppm (multiple line 12H) 7.8ppm (doublet 2H)

Claims (1)

[Claims] 1. A benzophenone derivative represented by the general formula [Formula] or an acid addition salt thereof. In the above formula, R ¹ , R ² , R ³ , R ⁴ are the same or different and represent a hydrogen atom or lower alkyl, or R ¹ , R ² and R ³ , R ⁴ are each bonded to an adjacent nitrogen atom. represents a group forming a heterocycle which may be the same or different, X ¹ and X ² are the same or different and represent a hydrogen atom, halogen, ^lower alkyl or ^nitro ; −CH( _CH3 ) _CH2− , _−CH2 ,
_{CH2- , -CH2} , _CH2 , _{CH2- , -CH2CH2 , CH2 , CH2-} , or _{-CH2CH2OCH2CH2-} .