JPH07103082B2 - Substituted benzophenone oxime ether derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a substituted benzophenone oxime ether derivative having excellent action as a medicine, a pharmacologically acceptable salt thereof, a method for producing the same, and a medicine containing the same.

2. Description of the Related Art At present, as one of the diseases that cause a serious health risk for humankind, acute vascular diseases such as myocardial infarction, stroke, cerebral thrombosis, cerebral infarction, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion. and so on.

In recent years, as one of the therapeutic agents for these diseases, antiplatelet agents have received clinical attention and are being widely used. However, the history of antiplatelet agents is relatively new, and it is expected that more excellent agents will be developed in the future. .

OBJECT OF THE INVENTION An object of the present invention is to provide a substituted benzophenone oxime ether derivative and a pharmacologically acceptable salt thereof, which have excellent effects as pharmaceuticals. It is an object of the present invention to provide a method for producing an acceptable salt, and further to provide a medicine containing the substituted benzophenone oxime ether derivative and a pharmacologically acceptable salt thereof as an active ingredient.

Structure and Effect of the Invention The object compound of the present invention is a substituted benzophenone oxime ether derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[In the formula, R ¹ and R ² represent the same or different hydrogen atoms or lower alkoxy groups.

X is the formula (In the formula, R ³ represents a hydrogen atom or a lower alkyl group)
Groups and expressions (In the formula, R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁴
Means a lower alkyl group) or a formula (Wherein R ⁶ represents a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 3). ]
A substituted benzophenone oxime ether derivative represented by.

In the above definition, the lower alkyl group represented by R ³ , R ⁴ , R ⁵ and R ⁶ is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n -Butyl, isopropyl, isobutyl, 1-methylpropyl, ter
t-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like, and the lower alkoxy group found in R ¹ and R ² means all lower alkoxy groups derived from the above lower alkyl groups. Means Among these, the most preferable ones are methyl group and ethyl group in the lower alkyl group, and methoxy group in the lower alkoxy group.

The pharmacologically acceptable salt is, for example, a metal salt such as Na, K, Ca or Mg when R ³ , R ⁵ and 1 or R ^{6 in} the structural formula (I) of the target substance is hydrogen. You can

Further, depending on the target substance, it can be easily converted into an acid addition salt by reacting with a pharmacologically acceptable inorganic acid or organic acid. Such inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc., and organic acids include maleic acid, fumaric acid, succinic acid, acetic acid, malonic acid, citric acid, benzoic acid, oxalic acid, Examples thereof include methanesulfonic acid.

Production Method There are various possible methods for producing the compound (I) of the present invention. Typical methods among these are as follows.

(In the formula, R ¹ , R ² and X 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 obtain a benzophenone oxime represented by the formula (III) (step 1), and then a halide compound represented by the formula (IV) is subjected to a condensation reaction. Then, the target substance (V) is obtained (step 2). Further, if necessary, this is converted into a pharmacologically acceptable 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) potassium tert-butoxide. .

Production Method 2 When R ³ , R ⁵ and R ^{6 in} the definition of X in the general formula (I) are hydrogen atoms (In the formula, X ′ means a case where R ³ , R ⁵ and R ⁶ are hydrogen in the definition of the formula (I), that is, a lower alkyl group). The target substance can be obtained by a conventional method by hydrolysis with an alkali such as caustic soda.

Production method 3 In the general formula (I), X is a formula (Wherein R ⁴ represents a lower alkyl group and R ⁵ represents a hydrogen atom or a lower alkyl group) (In the formula, R ¹ , R ² , R ⁴ and R ⁵ have the above-mentioned meanings.) That is, the compound (VI) is subjected to a condensation reaction with an amine represented by (VII) by a conventional method to obtain one of the target substances. The compound (VIII) is This reaction is about -20 to 200 ℃
Is preferable, and as the solvent, methanol, ethanol, propanol, benzene, toluene, water or the like can be used.

Next, representative compounds of the present invention will be enumerated, but the purpose thereof is to facilitate the understanding of the present invention, and the scope of the present invention is not limited thereby. Needless to say. In addition, all the following descriptions are in free form.

4,4'-dimethoxybenzophenone, O- (3-methoxycarbonyl-2-oxopropyl) oxime 4,4'-dimethoxybenzophenone, O- (3-ethoxycarbonyl-2-oxopropyl) oxime 4,4'-dimethoxy Benzophenone, O- (3-methoxycarbonyl-2-methoxyiminopropyl) oxime 4,4'-dimethoxybenzophenone, O- (3-ethoxycarbonyl-2-methoxyiminopropyl) oxime 4,4'-dimethoxybenzophenone, O- (3-Carboxy-2-methoxyiminopropyl) oxime 4,4'-dimethoxybenzophenone, O- (1-cyano-3-methoxycarbonylpropyl) oxime 4,4'-dimethoxybenzophenone, O- (1-cyano-3 -Ethoxycarbonylpropyl) oxime 4,4'-dimethoxybenzophenone, O- 1-cyano-3-carboxypropyl) oxime 4,4'-dimethoxybenzophenone, O- (1-cyano-4-methoxycarbonylbutyl) oxime 4,4'-dimethoxybenzophenone, O- (1-cyano-4-carboxy Butyl) oxime 4,4'-diethoxybenzophenone, O- (3-ethoxycarbonyl-2-oxopropyl) oxime 4,4'-diethoxybenzophenone, O- (3-ethoxycarbonyl-2-methoxyiminopropyl) oxime 4,4'-Diethoxybenzophenone, O- (3-carboxy-2-methoxyiminopropyl) oxime 4,4'-Diethoxybenzophenone, O- (1-cyano-3-ethoxycarbonylpropyl) oxime 4,4 ' -Diethoxybenzophenone, O- (1-cyano-3-carboxypropyl) oxime 4-methoxyben Phenone, O-(3- ethoxycarbonyl-2-oxopropyl) oxime 4-methoxybenzophenone, O-(3- ethoxycarbonyl-2-methoxy fleas Roh propyl) oxime 4-methoxybenzophenone, O-(3- carboxy -
2-Methoxyiminopropyl) oxime 4-methoxybenzophenone, O- (1-cyano-3-
Ethoxycarbonylpropyl) oxime 4-methoxybenzophenone, O- (1-cyano-3-
Carboxypropyl) oxime The substituted benzophenone oxime ether derivative provided by the present invention has an excellent platelet aggregation inhibitory action,
It is useful as a therapeutic agent based on this action, that is, an antiplatelet agent and an antithrombotic agent. Specifically, cerebrovascular disorders such as TIA (transient cerebral ischemic attack), cerebral infarction (thrombus, embolus), cerebral arteriosclerosis, postoperative thrombosis and embolism associated with vascular surgery and extracorporeal blood circulation, and blood Treatment of chronic arterial occlusion such as flow disorder, Buerger disease, arteriosclerosis obliterans, peripheral arteriosclerosis, SLE, and white fistula, angina pectoris, ischemic heart disease such as myocardial infarction, etc.
It is useful for prevention, prevention of recurrence of these diseases, and improvement of prognosis.

Next, in order to explain the effect of the compound of the present invention in detail, pharmacological experimental examples are given.

Experimental example 1. Inhibition of platelet aggregation (in vitro) Blood was collected from human cubital vein containing 1/10 volume of 3.8% sodium citrate solution and the method of Packham et al. [Packham, MA
et al, J. Exp. Med. 126, 171-189 (1967)], and platelet floating plasma (PRP ... Platelet Rich Plasma) was prepared. To 0.2 ml of this human PRP, various concentrations of the compounds of the present invention (compounds A to G) and 25 μl of solution were added and incubated at 37 ° C. for 3 minutes to obtain arachidonic acid, collagen, ADP and PAF.
Platelet aggregation was induced by. Platelets are Aggregometor manufactured by Schenko or Nikko Bioscience
Using the method of Mustard et al. [Mustard, JF, et al, J.Lab C
lin.Med.64,548-559 (1964)].

The results are shown in Table 1.

2. Platelet aggregation inhibitory effect (ex vivo) Compound A, which is a representative compound of the compounds of the present invention, is applied to guinea pigs.
G was orally administered, and 2 hours later, blood was collected from the abdominal aorta under ether anesthesia, and the inhibitory effect of collagen (3 μg / ml) and arachidonic acid (50 μM) on platelet aggregation was examined.
The solvent administration rate was determined and the 50% effective dose is shown in Table 2.

3. Acute toxicity Regarding the representative compounds (compounds A to E) of the compound of the present invention,
When an acute toxicity test was carried out using rats (body weight 300-400 g Wistar system ♂), the LD ₅₀ was 500 mg / 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 depends on the degree of symptoms and age, but is not particularly limited, but in the case of an adult, it is usually about 0.1 to 300 mg per day, preferably
0.1-60 mg, more preferably 0.3-30 mg, even more preferably 0.
6 to 10 mg.

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.

Add pH adjusters, buffers, stabilizers, preservatives, etc. to make subcutaneous, intramuscular, and intravenous injections according to the usual method.

Example 1 4,4′-Dimethoxybenzophenone, O- (3-ethoxycarbonyl-2-oxopropyl) oxime (1) Synthesis of 4,4′-dimethoxybenzophenone oxime 242 g (1 mol) 4,4′-dimethoxybenzophenone 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.

Tactile 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, O- (3-ethoxycarbonyl-2-oxopropyl) oxime 4,4'obtained in (1) -Dissolve in 2.57 g (0.01 mol) dimethylformamide of dimethoxybenzophenone oxime, add 1.2 g of potassium-tert-butoxide under ice cooling, and stir for 10 minutes. In this, 1.8 g of ethyl-
Add 4-chloroacetate and stir at room temperature. After 2 hours, pour the reaction solution into dilute hydrochloric acid and extract with ethyl alcohol. Purification of the crude product by silica gel column chromatography gives 3.1 g of the title compound.

NMR (CDCl ₃ ) δ: 6.7-7.4 (8H), 4.6 (2H) 3.9-4.2 (2H) 3.8 (6H) 3.5 (2H), 1.2 (3H) Example 2 4,4′-dimethoxybenzophenone, O- (3-Ethoxycarbonyl-2-methoxyiminopropyl) oxime 4,4′-dimethoxybenzophenone obtained in Example 1,
O- (3-ethoxycarbonyl-2-oxopropyl)
Dissolve 3.85 g of oxime in 5 ml of pyridine and add 1 g
Add the methoxylamine hydrochloride of and stir at room temperature. Two
After the lapse of time, the reaction solution was poured into ethyl acetate, washed with diluted hydrochloric acid and saturated saline, and then purified by silica gel chromatography to obtain 4 g of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ: 6.7-7.4 (8H), 5.0, 4.7 (2H), 3.8-4.2 (2H) 3.8 (9H)
3.3,3.4 (2H) 1.0-1.2 (3H) Example 3 4,4'-dimethoxybenzophenone, O- (3-carboxy-2-methoxyiminopropyl) oxime 4,4'-dimethoxy obtained in Example 2 Benzophenone,
Dissolve 4.14 g of O- (3-ethoxycarbonyl-2-methoxyiminopropyl) oxime in 20 ml of methanol, add 3 ml of 5N caustic soda aqueous solution, and stir at room temperature for 5 hours. After completion of the reaction, the reaction solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate to obtain 3.8 g of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ: 9.50 (1H), 6.8-7.5 (8H), 5.0, 6.8
(2H), 3.8-3.9 (9H), 3.5,3.3 (2H) Example 4 4,4'-dimethoxybenzophenone, O- (1-cyano-
3-Ethoxycarbonylpropyl) oxime Ethyl-4-chloroacetoacetate was replaced by 2.2 g of 4-bromo-4-cyanobutyric acid ethyl ester, and 3.6 g of the title compound having the following physical properties was obtained according to the method of Example 1. Got

NMR (CDCl ₃ ) δ: 6.8-7.5 (8H), 5.0 (1H), 4.0-4.3
(2H), 3.8 (6H), 2.2-2.6 (4H), 1.2 (3H) Example 5 4,4'-dimethoxybenzophenone, O- (1-cyano-
3-carboxypropyl) oxime 4,4′-dimethoxybenzophenone obtained in Example 4,
O- (1-cyano-3-ethoxycarbonylpropyl)
Oxime 3.96 was dissolved in 20 ml of dioxane, and
l of 5N caustic soda solution was added and reacted at 60 ° C. for 5 hours.

After completion of the reaction, the reaction solution is acidified and then extracted with ethyl acetate to obtain 3.6 g of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ: 6.7-7.5 (8H), 5.0 (1H) 3.8 (6H) 2.1-2.7 (4H) Example 6 4,4′-dimethoxybenzophenone, O- (1-cyano-
4-Methoxycarbonylbutyl) oxime In place of ethyl-4-chloroacetoacetate, 2.2 g of 5-bromo-5-cyanopentanoic acid methyl ester was used and the reaction and treatment were carried out according to the method of Example 1 to give the following physical properties. 3.7 g of the title compound are obtained.

NMR (CDCl ₃ ) δ: 6.8-7.6 (8H), 4.9 (1H), 3.8 (6
H), 3.6 (3H), 2.4 (2H), 1.6-2.2 (4H) Example 7 4,4'-dimethoxybenzophenone, O- (1-cyano-
4-Carboxybutyl) oxime The reaction was carried out according to the method of Example 5 to obtain the title compound having the following physical properties.

NMR (CDCl ₃ ) δ: 6.7-7.5 (8H), 4.9 (1H), 3.8 (6
H), 2.4 (2H), 1.6-2.2 (4H)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI technical display location C07C 251/56 251/58 253/30 255/62 9357-4H (72) Inventor Shinya Abe Ibaraki Prefecture 1083-44 Ushiku-cho, Ushiku-cho, Inashiki-gun (72) Hironori Ikuta 2-35-12 Sakae-cho, Ushiku-cho, Inashiki-gun, Ibaraki Prefecture (72) Kenji Hayashi 3-7-1 Ninomiya, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture (72) ) Inventor Hiroyuki Yoshimura 4-19-13 Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture Eisai Shiyama Dormitory (72) Tohru Fujimori 2-9-9 Tokodai, Toyosato-cho, Tsukuba-gun, Ibaraki (72) Kokichi Harada Ibaraki-prefecture 4-19-13 Kasuga, Yatabe-cho, Tsukuba-gun Eisai Shizan Dormitory (72) Inventor Isao Yamazu 3605-669 Kashida, Ushiku-cho, Inashiki-gun, Ibaraki Prefecture Examiner Rinko Tanaka

Claims (13)

[Claims] 1. A general formula [In the formula, R ¹ and R ² represent the same or different hydrogen atoms or lower alkoxy groups. X is the formula (In the formula, R ³ represents a hydrogen atom or a lower alkyl group)
Group represented by (In the formula, R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁴
Means a lower alkyl group) or a formula (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group, and n
Means an integer of 1 to 3)]
A substituted benzophenone oxime ether derivative represented by or a pharmacologically acceptable salt thereof. 2. R ¹ and R ² are both lower alkoxy groups, and X is a formula (In the formula, R ³ represents a hydrogen atom or a lower alkyl group)
The substituted benzophenone oxime ether derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by: 3. R ¹ and R ² are both lower alkoxy groups and X is a formula (In the formula, R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁴
Represents a lower alkyl group), and the substituted benzophenone oxime ether derivative or the pharmaceutically acceptable salt thereof according to claim 1. 4. R ¹ and R ² are both lower alkoxy groups and X is a formula (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group, and n
Represents an integer of 1 to 3), and the substituted benzophenone oxime ether derivative or the pharmaceutically acceptable salt thereof according to claim 1. 5. R ¹ and R ² are both methoxy groups,
X is an expression (In the formula, R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁴
Represents a lower alkyl group), and the substituted benzophenone oxime ether derivative or the pharmaceutically acceptable salt thereof according to claim 1. 6. R ¹ and R ² are both methoxy groups,
X is an expression The substituted benzophenone oxime ether derivative according to claim 1 or a pharmacologically acceptable salt thereof. 7. R ¹ and R ² are both methoxy groups,
X is an expression (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group, and n
Represents an integer of 1 to 3), and the substituted benzophenone oxime ether derivative or the pharmaceutically acceptable salt thereof according to claim 1. 8. R ¹ and R ² are both methoxy groups,
X is an expression The substituted benzophenone oxime ether derivative according to claim 1 or a pharmacologically acceptable salt thereof. 9. R ¹ and R ² are both methoxy groups,
X is an expression The substituted benzophenone oxime ether derivative according to claim 1 or a pharmacologically acceptable salt thereof. 10. General formula (Wherein R ¹ and R ² represent the same or different hydrogen atoms or lower alkoxy groups), and a benzophenone oxime compound represented by the general formula Hal-X [wherein, Hal represents a halogen atom, X Is the expression (In the formula, R ³ represents a hydrogen atom or a lower alkyl group)
Group represented by (In the formula, R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁴
Means a lower alkyl group) or a formula (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group, and n
Means an integer of 1 to 3)]
Condensation reaction with a halogenated compound represented by the general formula A substituted benzophenone oxime ether derivative represented by the formula (wherein R ¹ , R ² and X have the above-mentioned meanings), and the substituted benzophenone oxime ether derivative thus obtained is subjected to a salt-forming reaction. A method for producing the substituted benzophenone oxime ether derivative or a pharmaceutically acceptable salt thereof. 11. General formula [In the formula, R ¹ and R ² represent the same or different hydrogen atoms or lower alkoxy groups. A is the formula (In the formula, R ³ represents a hydrogen atom or a lower alkyl group)
Group represented by (Wherein R ⁵ is a hydrogen atom or a lower alkyl group), or a formula (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group, and n
Means an integer of 1 to 3)]
By hydrolyzing the ester compound represented by [In the formula, R ¹ and R ² represent the same or different hydrogen atoms or lower alkoxy groups. B is the formula (In the formula, R ³ represents a hydrogen atom), a group represented by the formula (Wherein R ⁵ is a hydrogen atom or a lower alkyl group), or a formula (Wherein R ⁶ represents a hydrogen atom, and n represents an integer of 1 to 3) and a substituted benzophenone oxime ether derivative represented by A method for producing the above-mentioned substituted benzophenone oxime ether derivative or a pharmaceutically acceptable salt thereof, which comprises subjecting an oxime ether derivative to a salt forming reaction. 12. General formula (Wherein R ¹ and R ² represent the same or different hydrogen atom or a lower alkoxy group, and R ⁵ represents a hydrogen atom or a lower alkyl group) and reacted with an amine compound represented by the general formula (Wherein R ¹ , R ² , R ⁴ and R ⁵ have the above meanings) to obtain a substituted benzophenone oxime ether derivative,
A method for producing the above-mentioned substituted benzophenone oxime ether derivative or a pharmaceutically acceptable salt thereof, which comprises subjecting the obtained substituted benzophenone oxime ether derivative to a salt-forming reaction. 13. General formula [In the formula, R ¹ and R ² represent the same or different hydrogen atoms or lower alkoxy groups. X is the formula (In the formula, R ³ represents a hydrogen atom or a lower alkyl group)
Group represented by (In the formula, R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁴
Means a lower alkyl group) or a formula (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group, and n
Means an integer of 1 to 3)]
An antiplatelet / antithrombotic agent comprising a substituted benzophenone oxime ether derivative represented by or a pharmacologically acceptable salt thereof as an active ingredient.