JPH0753707B2 - Substituted benzophenone oxime ether derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel substituted benzophenone oxime ether derivative having an excellent action as a medicine. More specifically, the general formula [Wherein R ¹ and R ² represent the same or different hydrogen atom, lower alkoxy group or halogen atom, and X represents (Wherein R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups) (Wherein ring A may contain nitrogen and oxygen),
Or, it means a cyano group. n means an integer of 1 to 3. However, R ¹ and R ² are both hydrogen atoms and n = 2
Except for. ] It is related with the substituted benzophenone oxime ether derivative shown by these or its pharmaceutically acceptable acid addition salt; and its manufacturing method; and the antiplatelet and antithrombotic agent which makes it an active ingredient.

In the definition of the compound (I) of the present invention, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1 -Methylpropyl, tert-butyl, n-
It means an alkyl group such as pentyl, (-ethylpropyl, isoamyl, n-hexyl, etc.) and a lower alkoxy group means a group based on these.

Examples of ring A include morpholino group, imidazoyl group,
Examples thereof include piperazyl group, pyrrolidyl group and piperidyl group.

The compound (I) of the present invention can be easily converted to an acid addition salt by reacting with a pharmaceutically acceptable inorganic acid or organic acid. Thus, inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the like, and organic acids include maleic acid, fumaric acid, succinic acid, acetic acid, malonic acid, citric acid, benzoic acid, oxalic acid. , Methanesulfonic acid, etc. can be exemplified.

The substituted benzophenone oxime ether compound provided by the present invention has an excellent inhibitory effect on platelet aggregation,
It is useful as a therapeutic agent based on this action, that is, an antiplatelet agent and an antithrombotic agent. Specifically, TIA (transient cerebral ischemic attack), cerebral infarction (thrombosis, embolism), cerebrovascular disease such as cerebral arteriosclerosis, postoperative thrombosis and embolism and blood flow associated with vascular surgery and extracorporeal blood circulation. Treatment of chronic ischemic heart disease such as disorders, Buerger's disease, arteriosclerosis obliterans, peripheral arteriosclerosis, SLE, white fistula, angina pectoris, myocardial infarction, etc.
It is useful for prevention, prevention of recurrence of these diseases, and improvement of prognosis.

The compound (I) of the present invention can be produced by various methods, and an example of the method usually used therein is as follows.

Manufacturing Method 1 The following is a schematic representation.

(Wherein R ¹ , R ² , X and n have the above-mentioned meanings and Hal means a halogen atom) That is, a benzophenone compound represented by the formula (II) is reacted with hydroxylamine to form a compound represented by the formula (III Benzophenone oxime represented by the formula (1) is obtained (step 1), and then a halide represented by the formula (IV) is subjected to a condensation reaction to obtain a target substance (V) (step 2). If necessary, this is converted to an acid addition salt by a conventional method.

In step 1, the reaction temperature is usually about 0 to 200 ° C., preferably room temperature to 100 ° C., and the solvent can be, for example, methanol, ethanol, propanol, benzene, toluene, water or the like.

In step 2, the reaction temperature is usually about 0 to 100 ° C., and as the solvent, for example, dimethylformamide (DMF), dimethylsulfoxide (DMSO), methanol, ethanol, propanol, benzene, toluene and the like can be used. At this time, preferable results can be obtained by carrying out the reaction in the presence of a base such as sodium hydride (NaH), triethylamine, dimethylaniline, potassium hydroxide, sodium methoxy (NaOMe), sodium ethoxy (NaOEt), and potassium tert-butoxide. give.

Next, representative compounds of the present invention will be enumerated, but the purpose thereof is to facilitate understanding of the present invention, and it goes without saying that the scope of the present invention is not limited thereby. Nor. In addition, all the following descriptions are in free form.

4,4'-dichlorobenzophenone, O- [2- (dimethylamino) ethyl] oxime 4,4'-dichlorobenzophenone, O- [2- (dimethylamino) ethyl] oxime 4,4'-dichlorobenzophenone , O- [2- (N-morpholino) ethyl] oxime 4,4'-dichlorobenzophenone, O- [2- (N-pyrrolidino) ethyl] oxime 4,4'-dichlorobenzophenone, O- [2- (N-piperidino) ethyl] oxime 4,4'-dichlorobenzophenone, O- [2- (N-piperazino) ethyl] oxime 4,4'-dichlorobenzophenone, O- [2- (N'-methyl- N-piperazino) ethyl] oxime 4,4'-dichlorobenzophenone, O- [2- (N'-ethyl-N-piperazino) ethyl] oxime 4,4'-dichlorobenzophenone, O -[3- (Dimethylamino) propyl] oxime 4,4'-dichlorobenzophenone, O- [3- (diethylamino) propyl] 4,4'-dichlorobenzophenone, O- [3- (N-morpholino) propyl ] 4,4'-Dichlorobenzophenone, O- [3- (N-pyrrolidino) propyl] 4,4'-dichlorobenzophenone, O- [3- (N-piperidino) propyl] 4,4'-dichloro Benzophenone, O- [3- (N-piperazino) propyl] 4,4'-dichlorobenzophenone, O- [3- (N'-Methyl-N-piperazino) propyl] 4,4'-dichlorobenzophenone, O -[3- (N'-ethyl-N-piperazino) propyl] 4,4'-diethoxybenzophenone, O- [2- (dimethylamino) ethyl] oxime 4,4'-diethoxybenzopheno , O- [2- (diethylamino) ethyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N-morpholino) ethyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N -Pyrrolidino) ethyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N-piperidino) ethyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N-piperazino) ethyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N'-methyl-N-piperazino) ethyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N'-ethyl-N-piperazino] ) Ethyl] oxime 4,4'-diethoxybenzophenone, O- [2- (dimethylamino) propyl] oxime 4,4'-diethoxybenzophenone, O- [2- Diethylamino) propyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N-morpholino) propyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N-pyrrolidino) propyl] oxime 4 , 4'-Diethoxybenzophenone, O- [2- (N-piperidino) propyl] oxime 4,4'-diethoxybenzophenone, O- [2- (N-piperazino) propyl] oxime 4,4'-diethoxy Benzophenone, O- [2- (N'-methyl-N-piperazino) propyl] oxime 4,4'-Diethoxybenzophenone, O- [2- (N'-ethyl-N-piperazino) propyl] oxime 4,4 ′ -Dimethoxybenzophenone, O- [2- (dimethylamino) ethyl] oxime 4,4′-dimethoxybenzophenone, O- [2- ( Ethylamino) ethyl] oxime 4,4'-dimethoxybenzophenone, O- [2- (N-morpholino) ethyl] oxime 4,4'-dimethoxybenzophenone, O- [2- (N-pyrrolidino) ethyl] oxime 4, 4'-dimethoxybenzophenone, O- [2- (N-piperidino) ethyl] oxime 4,4'-dimethoxybenzophenone, O- [2- (N-piperazino) ethyl] oxime 4,4'-dimethoxybenzophenone, O- [2- (N'-methyl-N-piperazino) ethyl] oxime 4,4'-dimethoxybenzophenone, O- [2- (N'-ethyl-N-piperazino) ethyl] oxime 4,4'-dimethoxybenzophenone, O- [3- (dimethylamino) propyl] oxime 4,4'-dimethoxybenzophenone, O- [3- (diethylamino) Propyl] oxime 4,4'-dimethoxybenzophenone, O- [3- (N-morpholino) propyl] oxime 4,4'-dimethoxybenzophenone, O- [3- (N-pyrrolidino) propyl] oxime 4,4'- Dimethoxybenzophenone, O- [3- (N-piperidino) propyl] oxime 4,4'-dimethoxybenzophenone, O- [3- (N-piperazino) propyl] oxime 4,4'-dimethoxybenzophenone, O- [3- (N'-Methyl-N-piperazino) propyl] oxime 4,4'-dimethoxybenzophenone, O- [3- (N'-ethyl-N-piperazino) propyl] oxime 4-methoxy-4'-ethoxybenzophenone, O -[2- (Dimethylamino) ethyl] oxime 4-methoxybenzophenone, O- [2- (dimethyla Mino) ethyl] oxime 4,4'-difluorobenzophenone, O- [2- (dimethylamino) ethyl] oxime 4,4'-difluorobenzophenone, O- [2- (diethylamino) ethyl] oxime 4,4'-difluoro Benzophenone, O- [2- (N-morpholino) ethyl] oxime 4,4'-difluorobenzophenone, O- [2- (N-pyrrolidino) ethyl] oxime 4,4'-difluorobenzophenone, O- [2- ( N-piperidino) ethyl] oxime 4,4'-difluorobenzophenone, O- [2- (N-piperazino) ethyl] oxime 4,4'-difluorobenzophenone, O- [2- (N'-methyl-N-piperazino) ) Ethyl] oxime 4,4'-difluorobenzophenone, O- [2- (N'-ethyl-N-piperazino) ethyl] o Sim 4,4'-difluorobenzophenone, O- [2- (dimethylamino) propyl] oxime 4,4'-difluorobenzophenone, O- [2- (diethylamino) propyl] oxime 4,4'-difluorobenzophenone, O- [2- (N-morpholino) propyl] oxime 4,4'-difluorobenzophenone, O- [2- (N-pyrrolidino) propyl] oxime 4,4'-difluorobenzophenone, O- [2- (N-piperidino)] Propyl] oxime 4,4'-difluorobenzophenone, O- [2- (N-piperazino) propyl] oxime 4,4'-difluorobenzophenone, O- [2- (N'-methyl-N-piperazino) propyl] oxime 4,4'-difluorobenzophenone, O- [2- (N'-ethyl-N-piperazino) propyl] o Shim 4-chloro-4'-methoxybenzophenone, O- [2- (N-piperidino) propyl] oxime 4,4'-dimethoxybenzophenone, O- (cyanomethyl) oxime 4,4'-diethoxybenzophenone, O- ( Cyanomethyl) oxime 4,4'-dichloroberezophenone, O- (cyanomethyl) oxime 4,4'-difluorobenzophenone, O- (cyanomethyl) oxime 4,4'-dimethoxybenzophenone, O-[(N-imidazoyl) ethyl ] Oxime 4,4'-diethoxybenzophenone, O-[(N-imidazoyl) propyl] oxime 4,4'-dichlorobenzophenone, O-[(N-imidazoyl) ethyl] oxime 4,4'-dichlorobenzophenone , O-[(N-imidazoyl) propyl] oxime 4,4'-difluorobenzophene , O-[(N-imidazoyl) ethyl] oxime 4,4'-difluorobenzophenone, O-[(N-imidazoyl) propyl] oxime Next, in order to explain the effect of the compound of the present invention in detail, pharmacological experimental examples To raise.

Experimental Example 1. Platelet aggregation inhibitory effect (in vitro) Blood was collected from human cubital vein so as to contain 1/10 volume of 3.8% sodium citrate solution, and the method of Packham et al. [Packham, M.
A. et al, J. Exp. Med. 126 , 171-189 (1967)] was used to prepare platelet floating plasma (PRP ... Platelet Rich Plasma). To 0.2 ml of this human PRP, 25 μl of a solution of the compound of the present invention (compounds A to G) of various concentrations was added, and the mixture was incubated at 37 ° C. for 3 minutes to obtain arachidonic acid, collagen, ADP and PA.
F caused platelet aggregation. Platelet aggregation is performed by Schenko or Nikko Bioscience Aggregom
Using etor, the method of Mustard et al. [Mustard, JF, et al, JL
ab Clin. Med. 64 , 548-559 (1964)].

The results are shown in Table 1.

Compound A is the compound of Example 6 below, compound B is the compound of Example 5 above, compound C is the compound of Example 4 below, compound D is the compound of Example 3 above, compound E is the compound of Example 2 below. The compound and the compound F mean the compound of Example 1, respectively.

2. Platelet aggregation inhibitory activity (ex vivo) In guinea pigs, compounds that are representative compounds of the compound of the present invention
B, compound D, compound E and compound F were orally administered, and 2 hours later, blood was collected from the abdominal aorta under ether anesthesia, collagen (3 μg / ml), arachidonic acid (50 μM), ADP (1 μm
The inhibitory effect on platelet aggregation by M) was examined. Solvent dose rate calculated 50% effective dose (20% effective dose for ADP aggregation)
Is shown in Table 2.

3. Acute toxicity Regarding representative compounds (compounds A to G) of the compound of the present invention,
When an acute toxicity test was carried out using rats (Wistar system weight: 300 to 400 g), the LD ₅₀ was 500 ml / μg or more in all cases.

When the compound of the present invention is used as an antiplatelet agent or an antithrombotic agent, oral administration or parenteral administration (intramuscular, subcutaneous,
It is administered intravenously). The dose depends on the disease
It varies depending on the degree of symptoms, age, etc., but is not particularly limited, but in the case of an adult, it is usually about 1 mg to 1,000 mg, preferably about 10 mg to 500 mg, more preferably about 20 to 100 mg per day.

In order to formulate the compound of the present invention, tablets, granules, powders, capsules, injections, suppositories and the like are formed into a dosage form by a conventional method in the technical field of preparation.

That is, when preparing a solid preparation for oral administration, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then tablets or coatings are prepared by a conventional method. Tablets, granules, powders, capsules, etc.

Examples of excipients include lactose, corn starch, sucrose,
Glucose, sorbit, crystalline cellulose, etc., and as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc. Examples thereof include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin and the like, and examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardening. Vegetable oils and the like are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, mentha brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder, etc. It is needed. Of course, these tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating if necessary.

When preparing an injection, a pH adjusting agent, a buffering agent, a stabilizer, a preservative, etc. are added to the main drug as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.

Next, examples of the present invention will be listed, but it goes without saying that the present invention is not limited to these.

Example 1 4,4′-dimethoxybenzophenone oxime dimethylaminoethyl ether / hydrochloride {(4,4′-dimethoxybenzophenone, 0- [2- (dimethylamino) ethyl] oxime} (1) 4,4′-dimethoxy Synthesis of benzophenone oxime 242 g (1 mol) of 4,4'-dimethoxybenzophenone was added to 2,0
Suspend in 00 ml of ethanol, and add 210 g (3 mol) of hydroxylamine hydrochloride and 300 ml (3 mol) of 10N-NaOH aqueous solution.
And heat to reflux. After 2-3 hours, ethanol is distilled off under reduced pressure, then saline is added and the mixture is extracted with chloroform. The chloroform layer is washed with water, dried over magnesium sulfate, the chloroform is distilled off, and the residue is recrystallized from ethanol to obtain 240 g of the title compound as colorless needle crystals.

Melting point (° C): 131-132 NMR (CDCl ₃ ) δ: 9.60 (bs, 1H), 7.50 (m, 8H), 3.83
(S, 3H), 3.80 (s, 3H) (2) Synthesis of 4,4'-dimethoxybenzophenone oxime dimethylaminoethyl ether 308g (1.2 mol) of 4,4'-dimethoxybenzophenone oxime obtained in (1) Dissolve it in 1,500 ml of anhydrous dimethylformamide and add 58g (1.32mol) of 55 under ice cooling.
% Sodium hydride is added in small portions.

After the generation of hydrogen is completed, 155 g (1.44 mol) of dimethylaminoethyl chloride is added, and the mixture is stirred at room temperature. After 4 to 5 hours, the reaction solution is poured into ice and extracted with ethyl acetate. The ethyl acetate layer is washed with brine and then evaporated.
The residue is dissolved in 10% hydrochloric acid, washed with n-hexane-ethyl acetate (1: 1), made basic with aqueous NaOH solution, and extracted with ethyl acetate. The ethyl acetate layer is washed with brine, dried over magnesium sulfate, and then distilled off to obtain 340 g of the objective substance 4,4'-dimethoxybenzophenone oxime dimethylaminoethyl.

Dissolve 4,4'-dimethoxybenzophenone oxime dimethylaminoethyl ether obtained by the above method in 2,000 ml of ethyl acetate, add 1.2 to 1.3 equivalents of ethyl acetate solution of hydrochloric acid gas under ice cooling, and stir for 30 minutes. . After distilling off ethyl acetate under reduced pressure and recrystallizing from ethanol, 330 g of colorless needle crystals of 4,4'-dimethoxybenzophenone oxime dimethylaminoethyl ether hydrochloride are obtained.

Melting point (° C.): 181-183 Examples 2-6 By the same method as in Example 1, the following compounds of Examples 2-6 were synthesized.

Example 2 4,4'-dimethoxybenzophenone, 0- [2- (N-morpholino) ethyl] oxime / hydrochloride Melting point (° C): 119-122 Example 3 4,4'-dimethoxybenzophenone, 0- [3 -(Dimethylamino) propyl] oxime / hydrochloride melting point (° C): 134 to 136 Example 4 4,4'-difluorobenzophenone, 0- [2- (dimethylamino) ethyl] oxime / hydrochloride melting point (° C): 160 to 163 Example 5 4,4'-dimethoxybenzophenone, 0- [2- (dimethylamino) ethyl] oxime / hydrochloride Melting point (° C): 126 to 127 Example 6 4,4'-dimethoxybenzophenone, 0- (Cyanomethyl) oxime Melting point (° C): 126-127

 ─────────────────────────────────────────────────── ─── Continuation of the front page Examiner Rinko Tanaka

Claims (7)

[Claims] 1. A general formula [Wherein R ¹ and R ² represent the same or different hydrogen atom, lower alkoxy group, or halogen atom, and X represents the formula (Wherein R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups) (In the formula, ring A may contain nitrogen and oxygen) or a cyano group. n means an integer of 1 to 3. However, R ¹ and R ² are both hydrogen atoms and n
= Except when 2], a substituted benzophenone oxime ether derivative represented by: or a pharmaceutically acceptable acid addition salt thereof. 2. A substituted benzophenone oxime ether derivative or a pharmaceutically acceptable acid addition salt thereof according to claim ¹ , wherein both R ¹ and R ² are lower alkoxy groups. 3. The substituted benzophenone oxime ether derivative or the pharmaceutically acceptable acid addition salt thereof according to claim ¹ , wherein both R ¹ and R ² are methoxy groups. 4. A substituted benzophenone oxime ether derivative or a pharmaceutically acceptable acid addition salt thereof according to claim ¹ , wherein both R ¹ and R ² are halogen. 5. X is an expression The substituted benzophenone oxime ether derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1, which is a group represented by the formula (wherein R ¹ and R ² have the above meanings). 6. A general formula (Wherein R ¹ and R ² represent the same or different hydrogen atom, lower alkoxy group, or halogen atom), and the compound represented by the general formula Hal- (CH ₂ ) nX (Wherein R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups) (Wherein ring A may contain nitrogen or oxygen) or a cyano group, and n means an integer of 1 to 3.
Hal means a halogen atom. ] The halogenated compound represented by (In the formula, R ¹ , R ² , X and n have the above-mentioned meanings.
Except when both R ¹ and R ² are hydrogen atoms and n = 2. ] The substituted benzophenone oxime ether derivative represented by the formula (1) and the optionally substituted substituted benzophenone oxime ether derivative are subjected to a salt forming reaction, or a pharmaceutically acceptable acid addition salt thereof. Manufacturing method. 7. General formula [Wherein R ¹ and R ² represent the same or different hydrogen atom, lower alkoxy group, or halogen atom, and X represents the formula (Wherein R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups) (In the formula, ring A may contain nitrogen or oxygen) or a cyano group. n means an integer of 1 to 3. However, R ¹ and R ² are both hydrogen atoms and n
Excluding when = 2. ] An antiplatelet / antithrombotic agent comprising a substituted benzophenone oxime ether derivative represented by or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.