WO1993018771A1

WO1993018771A1 - PLATELET AGGLUTINATION INHIBITOR CONTAINING STAUROSPORINE η-LACTAM DERIVATIVE

Info

Publication number: WO1993018771A1
Application number: PCT/JP1992/000357
Authority: WO
Inventors: Rintaro Yamada; Yasuo Sasaki; Satoshi Omura
Original assignee: Asahi Kasei Kogyo Kabushiki Kaisha; Kitasato Kenkyusho
Priority date: 1992-03-24
Filing date: 1992-03-24
Publication date: 1993-09-30

Abstract

A platelet agglutination inhibitor containing an active ingredient comprising a staurosporine η-lactam derivative having a platelet agglutination inhibitory activity and a reduced toxicity, represented by general formula (I), and a pharmacologically acceptable salt thereof, wherein R1 represents hydrogen, lower alkyl, acyl, aralkyl, aralkyloxycarbonyl or β,β,β-trichloroethoxycarbonyl; and R2 and R3 may be the same with or different from each other and each reprensents hydrogen, nitro, amino, formyl, hydroxyl, hydroxymethyl or carboxyl, provided that either R2 or R3 is hydrogen when R2 and R3 are different from each other.

Description

Akira Platelet aggregation inhibitor containing staurosporine 7-lactam conversion derivative

Technical field

The present invention relates to a platelet aggregation inhibitor comprising a staurosporine lactam conversion derivative and a pharmaceutically acceptable salt thereof as an active ingredient. Background art

Drugs that inhibit platelet aggregation are induced by platelet aggregation

It is used in the treatment and prevention of various types of thrombosis.

For example:

It is already known that staurosporine represented by has a potent vasorelaxant action and a platelet aggregation inhibitory action (Japanese Patent Publication No. 57-5

Japanese Patent Publication No. 253076 and Japanese Unexamined Patent Publication No. Hei 2-0 696 191). However, this compound is very toxic and has problems for clinical use. Was.

Ticlovidine, an antiplatelet drug, is used in postoperative thrombosis associated with vascular surgery and extracorporeal blood circulation, ischemic symptoms associated with chronic arterial occlusion, and thrombosis associated with ischemic cerebrovascular disease. I have. It is thought that ticlovidine exerts its platelet aggregation inhibitory effect by irreversibly binding to the platelet surface. However, the effect is continuous and is accompanied by side effects such as bleeding, aplastic anemia and jaundice.

Under these circumstances, it has been desired to develop a substance having a platelet aggregation inhibitory effect that is even better than conventional platelet aggregation inhibitors, and a clinically useful platelet aggregation inhibitor containing it as an active ingredient. Was.

Many factors are involved in the establishment of thrombosis, but the most important initial step is platelet adhesion and aggregation, and inhibition of platelet aggregation is considered to be the most effective antithrombotic therapy. In the present invention, a staurosporine 7-lactam conversion derivative having a high platelet aggregation inhibitory effect and a high level of platelet aggregation inhibitory effect were searched using a mouse acute pulmonary thrombus model most frequently used to examine the antithrombotic effect. This model is a pulmonary thromboembolic death model caused by injecting a coagulant directly into the vein of a mouse, similar to the pathology of acute and chronic arterial occlusion. Therefore, compounds that prevent this can be expected to be effective in preventing and treating various clinical thrombi such as peripheral arterial occlusion.

As a result, a staurosporin 7-lactam conversion derivative having a strong platelet aggregation inhibitory action and low toxicity was selected, and the present invention was completed. Disclosure of the invention

The present invention provides a compound of the general formula (I)

(Wherein, R, represents hydrogen, lower alkyl, acyl, aralkyl, aralkyloxycarbonyl, and δ, β, trifluorocarbonyl ethoxycarbonyl, and R ₂ and R ₃ represent hydrogen, nitro, amino, formyl, R ₂ and R ₃ may be the same or different, and if R ₂ and R ₃ are different, then R ₂ or R ₃ is hydrogen), which represents droxyl, hydroxymethyl and carboxyl. The present invention relates to a platelet aggregation inhibitor comprising a lactam conversion derivative (hereinafter, referred to as compound (I); the same applies to compounds having other formula numbers) and a pharmaceutically acceptable salt thereof as an active ingredient.

In the definition of R] in the general formula (I), lower alkyl means straight-chain or branched alkyl having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl. Butyl and tert-butyl and the like. In the definition of R], acyl includes benzoyl or a straight-chain or branched alkanol having 2 to 5 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl and the like. In the definition of R, aralkyl represents benzyl, phenethyl, etc. Include. In the definition of R i, aralkyloxycarbonyl includes benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and the like.

When compound (I) is a basic compound, an acid addition salt can be formed. Examples of the acid addition salts of compound (I) include hydrochloride, hydrobromide, sulfate, nitrate, formate, acetate, benzoate, maleate, fumarate, and amber. Salts, tartrate, citrate, oxalate, methanesulfonate, toluenesulfonate, aspartate, glutamate, etc.

The compounds used in the present invention are those which can be obtained usually from optically active staurosporine, but all possible stereoisomers and their mixtures are also selected in the present invention. Various methods can be considered for producing the compound represented by the general formula (I) and a salt thereof, but the compound can be easily produced by performing several steps of reaction from staurosporine.

Usually, after protecting the highly reactive nitrogen atom (for example, 1 N-position) of staurosporine, the τ-lactam ring moiety is chemically transformed by the following method 1 and deprotected to give compound (I). Can be synthesized, and then the compound (Π) can be synthesized by introducing a substituent R ₄ at the 4′-N-position according to the method 2 described below. The compound () can be produced by introducing R ₅ and R _e .

(In the formula, R ₄ represents lower alkyl, acyl, aralkyl, aralkyloxycarbonyl, and / 5, β, yS-trichloromouth ethoxycarbonyl.)

(Wherein, R ₄ has the same meaning as described above; R ₅ represents hydrogen, nitro, amino, formyl, hydroxyl, hydroxymethyl and carboxyl; R ₅ and R ₆ may be the same or different; _{When 5} and R ₆ are different, R ₅ or R ₆ is hydrogen, and R ₅ and R _s are not two hydrogens at the same time.)

It is also possible to change the order of the steps of introduction and elimination of the substituent, if necessary, and the substituents R _{4 to} R s may be introduced before the lactam ring conversion reaction. Most typical manufacturing methods are described below. The method for producing the staurosporine derivative is merely an example, and it goes without saying that the method is not limited thereto.

In the following production methods, if the defined groups change or are unsuitable for carrying out the method, methods commonly used in organic synthetic chemistry (eg, Protective Grooves It can be easily implemented by In-Organic Synthesis, by Green, see John 'Willie &' Sands' Incorporated (1981).

The methylamino group at the 4'-N-position of staurosporine is reactive Therefore, it is preferable to introduce a protecting group in order to favorably perform the conversion reaction of the y-lactam ring. As the protecting group, a carbomate-type protecting group is usually used, and a benzyloxycarbonyl group (hereinafter, Cbz

—Abbreviated as group. ) Or; 3, β, yS-trichloromouth ethoxycarbonyl group (hereinafter abbreviated as TEC- group) is preferably used.

For example, compound (V-2) can be obtained by reacting staurosporine (V-1) with N- (benzyloxycarbonyloxy) succinimide. (Cbz-OSu).

The compound (V-2) is obtained by reacting with N- (benzyloxycarbonyloxy) succinimide at 0 to 20 ° C for 6 to 24 hours in a halogenated hydrocarbon such as chloroform.

Cbz-OSi ^ il ~ l. 2 equivalents are used relative to compound (V-1).

Also, β, β, yg-trichloro mouth ethoxycarbonyl chloride (Τ

Compound (V-3) is obtained by reacting EC-Cf).

(V-1) (V-3) The compound (V-1) is reacted with TEC-Cf at 0-25 ° C in the presence of a suitable base such as triethylamine in a halogenated hydrocarbon such as chloroform. The compound (V-3) is obtained by reacting for ~ 24 hours.

The base is used in an amount of 1 to 1.5 equivalents, and TEC-Cf is used in an amount of 1 to 1.5 equivalents based on compound (V-1).

Then, after subjecting these compounds (V-2) and (V-3) to the <r-lactam ring conversion reaction of Method 1, and then deprotecting, the compound (I) in which R, in the general formula (I) is hydrogen, ) And the compound (1). The debenzyloxycarbonyl can be obtained by a commonly used reduction method, for example, a catalytic hydrogenation method or palladium (I) triethylsilane-triethylamine monochloride. The target compound is obtained by the method used.In the case of the catalytic hydrogenation method, the reaction is carried out in an inert solvent such as tetrahydrofuran (THF) or N, N-dimethylformamide (DMF) using 5% palladium Z-carbon or the like. The reaction is completed in a hydrogen atmosphere at room temperature for 1 to 24 hours using a catalyst.In the case of a method using triethylsilane, the reaction is performed in an inert solvent such as dioxane or THF in an amount of 1 to 10 equivalents of triethylsilane, 1 to 10 equivalents. Equivalent of triethylamine And 0.1 to 1 equivalent of palladium (I) chloride are heated in a nitrogen atmosphere at 60 to 130 for 1 to 4 hours. In the method of de-S, β, S-trichloromouth ethoxycarbonyl, the target compound is obtained by using a commonly used reduction method, for example, a method using zinc and an acid or a buffer near neutral. The reaction is completed in 1 to 24 hours at room temperature using zinc powder and a buffer solution such as aqueous hydrochloric acid, acetic acid or ammonium acetate in an inert solvent such as THF or methyl cellosolve.

Method 1: Conversion of <-lactam ring from imido ring to lactone ring

1-1: Imide-type compound (VII-1-1)

(VII- 1 -1)

(Wherein, R,, R ₂ and R ₃ are as defined above.)

The reaction is carried out by reacting compound (ϊ) with an alcoholic solvent such as methanol, ethanol, propanol, or butanol, an ethereal solvent such as tetrahydrofuran or dioxane, or a mixed solvent thereof, preferably tert-butyl alcohol and 1,4-dioxane. The compound is obtained by reacting an appropriate peroxide, for example, tert-butyl hydroperoxide with 2 to 20 equivalents and manganese (II) acetyl acetonate 0.1 to 1.2 equivalents in a dioxane mixed solvent. (\ ¾ [1 1 1 1) can be obtained. The reaction is usually completed in 0.5 to 30 hours. 1 -2: Lactone type compound (1-1-2)

(M- 1-1) (1-1 -2)

(Wherein, R ₂ and R ₃ are as defined above.)

Hydrogenation of compound 01-1-1-1) in an alcoholic solvent such as methanol, ethanol, propanol, butanol, water or a mixed solvent thereof, preferably a mixed solvent of 2-propanol and water in an amount of 3 to equivalent After reacting with sodium borohydride at 0 to 30 ° C for 20 to 30 hours, the compound (1-1) is reacted with 2 to 8 equivalents of acetic acid at 70 to 100 ° C for 1 to 10 hours. -2) can be obtained.

Method 2: Introduction of Substituent R ₄ Where CR, is lower alkyl, acyl, aralkyl, aralkyloxycarbonyl, or synthesis of 5, β, —trichloroethoxycarbonyl compound (1-2)]

CI-1-3) (1-2)

(Wherein, R ₂ , R ₃ and R ₄ are as defined above, and Ha is chlorine, Represents the halogen of bromine and iodine)

The reaction is carried out by subjecting compound (I-III) [compound (I-1-2) of R in which R is hydrogen] to a DMF solvent in the presence of an appropriate base, for example, 1 to 20 equivalents of triethylamine, and ice-cooling. The compound (1-2) can be obtained by reacting the compound (Cor) with 1 to 20 equivalents of the compound below. When R ₄ is acyl, an acid anhydride corresponding to the compound (cap) can be used in place of compound 01). These reactions are usually completed in 15 minutes to 24 hours.

Method 3: Introduction of substituents R ₅ and R ₆ [Synthesis of compound (I-13) modified by R ₂ and Z or R ₃ ]

3-1: Compound in which R ₂ and Z or R ₃ are two-nitro (I-3-1)

(1-2-1) (1-3-1) (wherein Ri is as defined above, and R ₂ and R ₃ are the same or different and are hydrogen or nitro, and R _2e and R ₃ cannot be hydrogen together)

The reaction is carried out by adding compound (I1-2-1) [compound (I-12) in which both R ₂ and R ₃ are hydrogen] and nitronium trifluorosulfonate prepared with trifluoroacetic acid and fuming nitric acid in dichloromethane. Compound (I3-1-1) can be obtained by reacting at 〜78 for 15 minutes to 2 hours. Nitro Niu arm triflate Ruo loss Le Honeto compound to (I one 2-1), 20 equivalents used are _c 3-2: Compound in which R ₂ and / or R ₃ is amino (I-3-2)

(1-3-1) (1-3-2)

(Wherein, R ₂ , and R _3e are as defined above, R _2b and R _3b are the same or different and are hydrogen or amino, and R _2b and R _3b are not both hydrogen.)

In the reaction, the compound (I13-2) can be obtained by reacting the compound (I13-1) with zinc powder and dilute hydrochloric acid in methyl sorb for 1 to 6 hours. Zinc and dilute hydrochloric acid are used in an amount of 10 equivalents to a large excess with respect to the compound (I-3-1).

3-3: Compound in which R ₂ and / or R ₃ is formyl (I—3—3)

(1-2-1) (1-3-3)

(Wherein Ri is as defined above, R _2c and R _3c are the same or different and are hydrogen or formyl, and both R _2c and R _3c are not hydrogen.)

The reaction is carried out by reacting compound (I-2-1) [compound (1-2) and R ₃ are both hydrogen] in dichloromethane with 2 to 30 equivalents. Compound (1-3-3) can be obtained by reacting titanium tetrachloride and 1 to 20 equivalents of dichloromethyl methyl ether at 0 to 20 ° C for 6 to 12 hours.

3-4: Compound in which R ₂ and Z or R ₃ are hydroxyl (I-3-4)

(1-3-3) (1-3-4)

(Wherein, Rj, R _2c and R _3c are as defined above, R _2d and R _3d are the same or different, is hydrogen or hydroxyl, R _2d and R _{3 d} is never both of hydrogen)

The compound (I13-4) is obtained by reacting the compound (I13-3) with dichloromethane and sodium bicarbonate in dichloromethane with light shielding at room temperature for 1 to 5 hours. Can be. The appropriate amount of methacrylo- perbenzoic acid (m-CPBA) is 1 to 10 equivalents based on the formyl group of the reaction starting material.

3-5: Compound in which R ₂ and Z or R ₃ are hydroxymethyl

(1-3-5)

(1-3-3) (1-3-5) (Wherein, R :, R _2c and R _3c are as defined above, R _2e and R _3e are the same or different and are hydrogen or hydroxymethyl, and both R _2e and R _3e are not hydrogen. )

The compound (I-3-5) can be obtained by reacting the compound (1-3-3) with sodium borohydride in THF at room temperature for 1 to 5 hours. Sodium borohydride is the starting compound

1.5 to 5 equivalents are appropriate for the formyl group of (1-3-3).

3-6: Compound where R ₂ and Z or R ₃ are carboxyl (1-3-6)

. (1-3-3) (1-3-6)

(Wherein, Ri, R _2c and R _3c are as defined above, R _2f and R _3i are the same or different and are hydrogen or carboxyl, and both R _2f and R _3f are not hydrogen: )

The compound (I-3-6) can be obtained by reacting the compound (1-3-3) with dimanganese permanganate in room temperature at room temperature for 15 minutes to 2 hours. An appropriate amount of the permanganate reactor is 1 to 50 equivalents to the formyl group of the compound (I13-3) as a reaction starting material.

The compound (I) having a desired functional group at a desired position can be obtained by appropriately combining and carrying out the above methods 1 to 3. Isolation of the product after each of the above steps. Methods such as extraction, crystallization, various types of chromatography, etc., can be appropriately combined.

The staurosporine 7-lactam conversion derivative represented by the general formula (I) used in the present invention can be used for cold pain and ulcers in the extremities associated with obstructive arteriosclerosis induced by platelet aggregation, and blood permeability in hemodialysis patients. Occlusion of the external shunt during analysis, cerebral infarction and thrombosis due to frequent transient amaurosis, cerebral vasospasm after acute cerebral aneurysm surgery, blood circulation reconstruction, sage transplantation, artificial valve replacement It is considered to be effective in improving postoperative thrombosis and embolism during surgery.

The compound represented by the general formula (I) may be orally administered in a preparation such as a tablet or a capsule together with a commonly used pharmaceutically acceptable carrier, or as a parenteral administration in a sterile solution or suspension. Prescription can improve the above symptoms.

The active ingredient used in the present invention may be administered to a patient in need of such treatment in a dose range of 0.01 to 40 mg per patient in a total daily dose of 0.1 to 200 mg per day. Can be administered. Volume can vary depending on the severity of the condition, the weight of the patient and other factors recognized by the individual (physicians).

Specific additives that can be mixed with tablets, capsules, etc. are as follows. Binders such as tragacanth, gum arabic, corn starch or gelatin; excipients such as microcrystalline cellulose; leavening agents such as corn starch, gelatinized starch, alginic acid, etc .; lubricants such as magnesium stearate; Sweetening agents such as sucrose, lactose or saccharin; flavoring agents such as peppermint, cocoa oil or cellulose are added, and if the dosage unit form is forcepsel, an oil or fat may be added to the above type of material. Such a liquid carrier as described above can be contained. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. Sterile compositions for injection dissolve the active substance in a vehicle such as water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, or synthetic fat vehicles such as ethyl ester. Alternatively, it can be formulated according to the usual formulation practice of suspending. Buffers, preservatives, antioxidants, etc. can be mixed if necessary. BEST MODE FOR CARRYING OUT THE INVENTION

Next, Table 1 shows typical examples of the compound (I) obtained by the above production method, and Table 2 shows intermediates thereof. Production examples of these compounds and intermediates thereof are shown in Reference Examples.

table 1

Reference example number Compound number Ri R ₂ R ₃

1 1 CeHsCHs-OCO H H

2 2 H H H

3 3 CH ₃ HH

4 4 n-C H H

5 5 C ₆ H ₅ C0 HH

6 6 CHaCO H H

7 7 C £ ₃ CCH ₂ 0C0 HH

8 8 • C £ ₃ CCH ₂ 0C0 N0 ₂ H

9 • 9 H NH ₂ H

10 10 C £ ₃ CCH ₂ 0C0 CHO CHO 11 11 H CHO CHO 12 12 C £ ₃ CCH ₂ 0C0 OH OH 13 13 H OH OH 14 14 C £ ₃ CCH ₂ 0C0 CH ₂ 0H CH2OH

16 16 C £ ₃ CCH ₂ 0C0 COOH COOH 17 17 H .COOH COOH Table 2

No. Ri R ₂ R ₃ R

_{_{_{18 a C 6 H 5 CH 2}}} 0C0 HHH

19 b Cf ₃ CCH ₂ 0C0 HHH

20 c C ₆ H ₅ CH ₂ 0 C0 HH 0 Reference example 1

3.0 g (4.9 mmol) of the compound c obtained in Reference Example 20 was dissolved in 2-brono, 12 Om ^ and 20 m of water, and sodium borohydride 745 mg (19.7 mmol) was dissolved. ) In addition, the mixture was stirred at room temperature for 24 hours. Next, 1 mL of acetic acid was added in, and heated at 80 for 3 hours. After completion of the reaction, the solvent was concentrated, water was added, the mixture was neutralized with a 10% aqueous sodium hydrogen carbonate solution, and extracted with chloroform. After washing with water and drying over sodium acid, the filtrate was concentrated under reduced pressure to obtain a crude product. Shi Purification by Ricagel column chromatography (ethyl benzene monoacetate) yielded 1,1.6 g (2.6 mmo1) of the compound (54% yield). Compound 1:

^! H-NMR (CDC £ ₃ ) δ; 9.30 (d, 1H, J = 8.0Hz), 7.98 (d, IH, 8.5Hz), 7.84 (d. IH, J = 8.0Hz), 7.50-7.35 (m , 8H), 7.28 (ddd, 1H, J = 8,0, 7.0, 1.2Hz), 7.15 (d, 1H, J = 8.0Hz), 6.65 (dd, IH, J = 6.0, 1.2Hz), 5.80Cs 2H). 5.10 (s, 2H), 3.78 (d, IH, J = 3.5Hz), 3.31 (dt.IH, J = 4.0, 3.5Hz), 2.83 (br.s.3H), 2.67 (ddd, IH. J = 15.0, 4.0, 1.2Hz), 2.32 IH, J = 15.0, 6.0, 3.5Hz), 2.32 (brs, 3H), 1.58 (br.s, 3H)

MS: mZz 60 1 (M ⁺ )

Reference example 2

The compound obtained in Reference Example 1, 1,1.6 g C2.6 mmol) was dissolved in dioxane 50m ^, and triethylsilane 1.9m ^, triethylamine 1.0m £, and palladium chloride (Π) 25Omg (1. 4 mm 01), and the mixture was heated under a nitrogen atmosphere at 120 for 1 hour and 45 minutes, and then 1 Om ^ of methanol was added, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, neutralized with a 10% aqueous sodium hydrogen carbonate solution, extracted, washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (black-mouthed form) to obtain the compound 2,68 Omg (1.5 mmo 1) (58%).

Compound 2:

^J H-NMR (CDCf ₃ ) δ; 9.27 (d, 1H, J = 8. OHz), 7.93 (d, 1H, 8.5 Hz), 7.80 (d, IH, J = 8.0 Hz), 7.50 (ddd, 1H) , J = 8.0, 7.0, 1.2Hz), 7.43 (ddd, IH, J = 8.5.7.0, 1.2Hz), 7.38 (ddd, IH, J = 8.0, 7.0, 1.2Hz), 7.33 mouse IH, J = 8.0, 7.0, 1.2Hz), 7.25 (d, IH, J = 8.0Hz), 6.55 (dd, IH, J = 6.0, 1.2Hz), 5.85 (s, 2H), 3.88 (d, 1H.J = 3.5Hz), 3.44 (s, 3H), 3.35 (dt, IH, J = 4.0, 3.5Hz), 2.77 (d dd, 1H, J = 15.0, 4.0, 1.2Hz), 2.40 (ddd, 1H, J = 15.0, 6.0, 3.5Hz), 2.37 (s.3H), 1.55 (s, 3H)

MS: / z 4 67 (M +)

Reference example 3

Dissolve 2,24 mg (0.05 1 mmo 1) of the compound obtained in Reference Example 2 in 0.6 m ^ of N, N-dimethylformamide, and add 0.02 m ^ of triethylamine and 0.02 m_g of methane. The mixture was stirred for 12 hours under ice cooling. After completion of the reaction, chloroform was added, and the mixture was washed with water and a 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 3,16 mg (0.033 mmo 1) of the compound (yield: 65%).

Compound 3:

'Η-Awake R (CDG £ ₃ ) δ; 9,37 (d, 1H. J = 8.0Hz), 7.98 (d. 1H, 8.5Hz), 7.74 (d, 1H, J = 8. OHz), 7.53 (dd, 1H, J = 8.0, 7.OHz), 7.40 (dd, 1H.J = 8.5, 7.0Hz), 7.36 (dd, 1H, J = 8.0, 7.0Hz), 7.31 (dd, 1H, J = 8.0, 7.0Hz), 7.21 (d, 1H, J = 8.OHz), 6.55 (dd, 1H, J = 6.0, 1.2Hz), 5.90 (s, 2H), 3.82 (d, 1H, J = 3.5Hz) ), 3.32 (dt, 1H, J-4.0.3.5Hz), 2.87 (m.1H), 2.45 (m.1H), 2.37 (s, 6H). 2.05 (s, 6H)

MS: m / z 48 1 (M ⁺ )

Reference example 4

2,24 mg (0.05 lmmo 1) of the compound obtained in Reference Example 2 was dissolved in 0.6 m ^ of N, N-dimethylformamide, and 0.02 m of triethylamine and 0.02 m of n-butyl bromide were dissolved. ^ Was added and the mixture was stirred under ice cooling for 12 hours. After completion of the reaction, chloroform was added, and the mixture was washed with water and a 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 4.1 Omg. (0.019 mmo 1) was obtained (37% yield).

Compound 4:

^ -NMR (CD1) δ; 9.18 (d, IH, J = 8.0Hz), 7.86 (d, IH, 8.5Hz), 7.66 (d, 1H, J = 8.0Hz). 7.47 (dd, IH, J = 8.0, 7.0Hz), 7.38 (dd.1H, J = 8.5.7.0Hz), 7.22 (dd, IH, J = 8.0, 7.0Hz), 7.15 (dd, IH, J = 8.0, 7.0Hz), 7.11 ( d.IH, J = 8.0Hz), 6.41 (dd, 1H, J = 6.0, 1.2Hz), 5.80 (s, 2H), .3.67 (1 IH, J = 3.5Hz), 3.25 (dt, IH, J = 4.0, 3.5Hz), 2.72 (m.IH), 2.39 (m, IH), 2.37Cs, 3H), 2.33 (s, 3H), 2.1-0.8 (m, 12H)

MS: m / z 523 (M ⁺ )

Reference example 5

Compound -2, -48 mg (0.1 Ommo 1) obtained in Reference Example 2, was dissolved in 10 m_g of chloroform, and 0.02 m ^ of pyridine was added. Benzoyl chloride (0.05 ml) was added to C under cooling, and the mixture was stirred for 10 minutes. After completion of the reaction, the mixture was washed with water and a 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (form-form methanol) to obtain 5,25 mg (0.043 mmol) of the compound. (Yield 43%).

Compound 5:

^{1 H- NMR (CDI) δ;} . 9.22 (d, IH, J = 8.0Hz), 7.92-6 88 (ra, 12H), 6.68 (m, 1H), 5.84 (s, 2H), 3.56 (m, IH), 3.33 (m, 1H), 2.86 (s, 3H), 2.72 (ra, IH), 2.36 (ra, IH), 2.46 (s, 6H)

MS: m / z 571 (M ⁺ )

Reference 6

Compound 2,5 Omg (0.1 lmmol) obtained in Reference Example 2 was dissolved in 1.5 mL of chloroform, and 0.15 m ^ of pyridine and 0.15 m of anhydrous acetic acid were added, followed by stirring at room temperature for 1 hour. did. After the reaction, After washing with water and a 5% aqueous sodium hydrogen carbonate solution, the extract was dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (form-form-methanol) to obtain 6,39 mg (0.077 mmol) of the compound (yield: 70%).

Compound 6:

^] H-NMR (CDC £ ₃ ) δ; 9.32 (d, 1H, J = 8.0 Hz), 7.88 (d, 1H, 8.5 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.51 (dd. , J = 8.0, 7.0Hz), 7.40-7.30 (m, 3H), 7.19 (d, 1H 'J = 8.0Hz), 6.62 (m, 1H), 5.83 (s, 2H), 3.82 (d, 1H, J = 3.5Hz), 3.36 (m, 1H), 2.84 (s, 3H), 2.82 (m.1H), 2.43 (m, 1H), 2.48 (s, 3H), 2.45 (s, 3H), 2.13 ( s, 3H)

MS: m / z 509 (M +)

Reference Example 7

Dissolve 2,94 Omg (2.0 lmmo 1) of the compound obtained in Reference Example 2 in 10 ml of pyridine and add 0.3 m ^ of β, β, -trichloroethyl chloroformate under cooling to 0 ° C, The mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was extracted with chloroform and washed with a 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (form: chloroform) to obtain Compound 7, 1003 mg (1.56 mmol 1) (yield: 78%).

Compound 7:

'Η— NMR (CDCf ₃ ) δ; 9.40 (d, 1H, J = 8. OHz). 7.88-7. 19 (m, 7H), 6.62 (m, 1H), 5.83 (s, 2H), 5.03 ( br. s, 2H). 4.02 (br. s, 1H), 2.84 (s, 3H), 2.83-2.42 (m, 3H), 2.60 (s, 3H), 2.41 (s, 3H)

MS: mZz 64 1 (M ⁺ )

Reference Example 8

Cool dichloromethane 2 Om ^ to 0 ° C, trifluoromethanes After adding 0.075m ^ of sulfonic acid, 0.035m ^ of fuming nitric acid was added, followed by stirring for 20 minutes. The reaction solution was cooled to 178, and 4 Om ^ of a dichloromethane solution of 7.1 g (1.55 mmo 1) of the compound obtained in Reference Example 7 was added dropwise, followed by stirring for 30 minutes. After completion of the reaction, the reaction solution was extracted with chloroform, washed with water and a 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 8,384 mg (0.560 mmol) of the compound (36% yield).

Compound 8:

! H-NMR (CDCf ₃ ) δ; 9.85 (s, 1H), 8.00-6.90 (m.6H),

6.72 (m, 1H), 5.88 (s, 2H), 5.13 (br.s.2H), 3.95 (br.s, 1H), 2.9s, 3H), 2.90-2.40 (m, 3H), 2.-70 (s, 3H), 2.41 Cs, 3H)

MS: m / z 686 ( ⁺ )

Reference Example 9

Compound 8, 35 Omg (0.5 1 mmo 1) obtained in Reference Example 8 was dissolved in 600 ml ^ of methyl sorbent, cooled to 0 ° C, and zinc powder (3.0 g) and 1N-hydrochloric acid (30 g) were dissolved. m were sequentially added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate (15 Om ^) was added, and insolubles such as zinc were removed by filtration. The solution was extracted by adding chloroform, washed with water and a 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (form-methanol in chloroform) to obtain compound 9,102 mg (0.21 lmmo 1) (yield 41%).

Compound 9:

JH-NMR (CDC £ ₃ ) δ; 8.76 (s.1H), 7.94-7.83 On, 2H),

7.40-7.00 (m, 3Η), 6.92Cm, 1Η), 6.58 (m, '1H), 5.83 (s, 2H), 3.85 (br.s, 1H), 3.39 (s.3H), 3.35-2.40 (m, 3H), 2.35 (s, 3H), 1.5 2 (s, 3H) MS: m / z 482 (M +)

Reference example 10

Dissolve 7.1 g (1.55 mmol) of the compound obtained in Reference Example 7 in 2 m_ of dichloromethane and cool the mixture to 0 ° C under cooling with titanium tetrachloride 3.2 m ^ and α, dichloromethyl methyl ether 1 3m ^ was added, and the mixture was stirred at room temperature for 10 hours. After the completion of the reaction, the resultant was washed with water and a 5% aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain 10 632 mg (0.907 mmol) of the compound (yield: 58%).

Compound 10:

'H-NMR (DMSO-de) δ 10.22 (s.1H). 9.85 (s, 1H), 9.21 (s, 1H), 8.32 (s, 1H), 8.06 (d, 1H, J = 7.8Hz ), 7.92 (d, 1H, .J = 7.8Hz), 7.71 (d, 1H, J = 7.8Hz), 7.58 (d.1H, J = 7.8Hz), 6.92 (m, 1H) .5.83 ( s, 2H), 4.89 (dr.s.2H), 4.25 (br.s, 1H), 3.10-2.10 (m, 3H), 2.91 (s, 3H), 2.70 (s, 3H), 2.41 (s, 3H)

MS: m / z 697 (M +)

Reference example 1 1

Compound 10, 35 Omg (0.5 Ommo 1) obtained in Reference Example 10 was dissolved in THF 100 m, and 2.0 g of zinc powder and 25 ml of a 1 M aqueous solution of ammonium acetate were sequentially added. Stirred for minutes. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added, and insolubles such as zinc were removed by filtration. To the solution was added a form of chloroform, extracted, washed with water and a 5% aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (form-form-methanol in methanol) to obtain compound 122 mg (0.233 mmo 1) (yield: 46%).

Compound 11: ^J H-NMR (DMSO-d ₆ ) δ; 10.12 (s, 1H), 9.91 (s.

H), 9 * 26 (s, 1H), 8.31 (s, 1H), 7.96-7.75 (m, 2H), 7.73-7.60 (m, 2H), 6.58Cm, 1H), 5.91 (s, 2H), 3.95 (br.s, 1H) .3.42Cs, 3H), 3.25-2.43 (ra, 3H), 2.32 (s.3H), 1.50 (s, 3H)

MS: mZz 523 (M +)

Reference Example 12

Compound 321 mg (0.46 mm o

I) was dissolved in 7 Om ^ of dichloromethane, 43 Omg of metabenzo-perbenzoic acid (60%) and 12 Omg of potassium hydrogencarbonate were added, and the mixture was stirred at room temperature for 3.5 hours without light. After completion of the reaction, the mixture was washed with a saturated aqueous solution of sodium sulfite, a 5% aqueous solution of sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated under reduced pressure. After dissolving the residue in 60 ml of methyl sorb, 15 mi of a 4 N aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 2 hours. Then, neutralize with 1N dilute hydrochloric acid 60m ^, extract with dichloromethane, wash with water, dry, concentrate the solvent under reduced pressure, purify the residue by silica gel column chromatography (chloroform-methanol), and obtain compound 12,228mg (0.340 mm 01) was obtained (yield 74%).

Compound 12:

'Η—NMR (DMSO-ds) δ; 8.21 (s, 1H), 7.82 (d, 1H,

J = 9.3Hz), 7.39 (d, 1H. J = 9.3Hz), 7.28 (s, 1H) .7.01 (d, 2H, J = 9.3Hz), 6-88 (br.s, 1H), 5.78 (s, 2H), 4.91 (br.s, 2H), 4.23 (br.s, 1H), 4.10-2.lOCm, 3H), 2.81 (s, 3H), 2.67 (s.3H), 2.21 (s , 3H)

MS: m / z 673 (M +)

Reference Example 13

From the compound obtained in Reference Example 12, 12,193 mg (0.286 mm o 1), the compound 13, 78 m ^ was obtained by the same reduction method as in Reference Example 11. (0.1 56 mmo 1) was obtained (55% yield).

Compound 13:

'Η-NMR (DMSO-d ₆ ) δ; 8.51 (s, IH), 8.03 (s, IH), 7.63 (d, 1H, J = 9.4Hz), 7.24 (d, IH, J = 9.4Hz), 7.01 (d, 2H, J = 9.4Hz), 6.84 (br.s, 1H), 5.81 (s, 2H), 4.03 (br.s, IH) .4.00-2.20 (m, 3H), 2.84 (s , 3H), 2.32 (s, 3H), 2.06 (s, 3H)

MS: m / z 499 (M +).

Reference example 1 4

287 mg (0.411 mmo 1) of the compound 10 obtained in Reference Example 10 was dissolved in 15 ml of THF, 88 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, 10 Om ^ of water was added, the mixture was extracted with chloroform, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-formanol) to obtain Compound 14, 125 mg (0.178 mmo 1) (yield: 4 Z%).

Compound 14:

H—NMR (DMSO-de) δ; 9.05 (s, IH), 7.88 (s, IH), 7.81 (d, 1H, J = 9.0Hz), 7.55 (d, IH, J = 9. OHz), 7.38 (d, IH, J = 9.0 Hz), 7.32 (d, IH, J = 9.0 OHz), 6.92 (m, IH), 5.84 (s, 2H), 5.18 (s, 2H), 5.12 (s , 2H). 4.94 (br.s, 2H), 4.26 (br.s, IH), 4.00-2.00 (m, 3H), 2.71 (s, 3H), 2.62 (s, 3H), 2.31 (s, 3H )

MS: m / z 701 (M ⁺ )

Reference Example 15

From the compound 14, 103 mg (0.147 mmo 1) obtained in Reference Example 14 and the same reduction method as in Reference Example 11, compound 15, 48 mg (0.01 1 mm 01) was obtained. Rate 62%).

Compound 15:

H—NMR (DMSO-d _e ) δ; 9.11 (s, IH), 8.43 (s, IH), 7.82Cd, 1H, J = 9.0Hz), 7.76 (d, 1H, J = 9.0Hz), 7.49 (d, 2H, J = 9.0Hz), 6.64 (br.s, 1H), 5.87 (s, 2H ), 4.74 (s, 4H), 4.13 (br.s, 1

H), 4.00-2.20 (m, 3H), 3.29 (s, 3H), 2.30 (s, 3H), 1.46 (s. 3H) MS: m / z 527 (M ⁺ )

Reference Example 1 6

Compound obtained in Reference Example 10, 10 274 mg (0.39 mmo

I) was dissolved in dioxane 3 Om ^, and 2.5mM permanganic acid aqueous solution of 6.5m aqueous solution was added, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, 6 Om ^ of water was added, and the mixture was adjusted to pH-3 with 5N-hydrochloric acid to precipitate crude crystals. The crude crystals were purified by silica gel column chromatography (chloroform-methanol-acetic acid) to obtain 16,147 mg (0.202 mmol 1) of Compound 16 (yield: 52%).

Compound 16:

' ^! H-NMR (DMSO-d _e ) δ; 9.91 (s, 1H), 8.82Cs, 1H), 8.16 (d, 1H, J = 8.6Hz), 8.09 (d, 1H. J = 8.6Hz), 8.01 (d, 1H, J = 8.6 Hz), 7.70 (d, IH, J = 8.6 Hz), 7.15 (br.s, 1H) .5.93 (s, 2H), 4.9 OCbr.s, 2H), 4.12 (br.s, 1H), 4.00-2.10 (m, 3H), 2.61 (s, 3H), 2.47 (s, 3H), 1.95 (s, 3H)

MS: m / z 729 (M +)

Reference Example 1 7

Compound obtained in Reference Example 16 16, 102 mg (0.14 mmo

1) was dissolved in methyl sorbate 5 Om ^, 3.0 g of zinc powder and 1.5 m of 2N-hydrochloric acid were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the zinc was removed by filtration, and the solvent was concentrated under reduced pressure to obtain a syrupy liquid. This liquid is subjected to HPLC (column: YMC—PACK S-345 0

DS, detection wavelength: 294 nm, mobile phase: aqueous solution of ammonium acetate-methanol), fractionated, and further purified by desalting to obtain compound 17, 35 mg (0.063 mmo 1). Rate 45% ) o

Compound 17:

H-band R (DMSO-d ₆ ) δ; 9.97 (s, 1H), 8.62 (s, 1H), 8.06 (d. 1H, J = 8.7Hz), 8.02 (d, 1H, J = 8.7Hz) , 8.01 (d, 1H, J = 8.7Hz), 7.72 (d, 1H, J = 8.7Hz), 6.80 (br.s, 1H), 5.85 (s, 2H), 4.1.3 (br.s, 1H), 3.40 (s, 3H), 3.30 (m, 1H), 2.5-2.2 (m, 2H), 2.32 (s, 3H), 1.35 (s, 3H)

MS: m / z 555 (M ⁺ )

Reference Example 1 8

Dissolve 498 mg (1.07 mmo 1) of staurosporine in 25 ml of the form of black mouth, add N- (benzyloxycarbonyloxy) succinimid 27 Omg (1.08 mmol), and leave for 22 hours Stirred at warm. After completion of the reaction, the reaction solution was diluted with chloroform, washed with 10% aqueous solution of sodium hydrogen oxyacid and water, dried and concentrated, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl benzene monoacetate = Purification by 2: 1) afforded 567 mg (0.945 mmo 1) of compound a (88% yield).

Compound a:

Ή-NMR (CDC £ ₃ ) δ; 9.44 (d, 1H, J = 8.0Hz), 7.90-7.200η, 12H), 6.70 (br.s, 1H), 6.66 (br.s.1H), 5.17 (s.2H), 4.96 (s, 2H), 5.10-4.50 (m, 1H), 4.04 (m, 1H), 2.80 (s, 3H), 2.50 (s, 3H), 2.70-2.50 (m, 2H), 1.78 (s.3H)

MS: m / z 600 (M ⁺ )

Reference Example 1 9

Dissolve 932 mg (2.0 mm o 1) of staurosporine in 10 m of pyridine, and add 0.3 m ^ of β, β,; β-, β-, and δ-trichloromethyl ethylformate under cooling to 0 ° C for 10 hours. Stirred. Water was added to the reaction solution, extracted with chloroform, washed with water and dried, and the solvent was concentrated under reduced pressure. 2 &.

The residue was purified by silica gel column chromatography (black-mouthed form) to obtain 1052 mg (1.63 mmol) of compound b (yield: 82%).

Compound b:

O-NMR (CDC £ ₃ ) δ; 9.40 (d. 1H, J = 8.0Hz), 8.00-7.

20 (m, 7H), 6.75-6.68 (m.IH), 6.62 (br.s, 1H), 5.00 (s, 2H), 4.77 (br.s, 2H), 4.07 (br.s, IH ), 2.-85 (s, 3H), 2.60 (s, 3H), 2.70 -2.40 (m, 3H), 2.41 (s, 3H)

MS: m / z 640 (M ⁺ )

Reference Example 20

Compound a, 505 m.g (0.842 mmo 1) obtained in Reference Example 18 was dissolved in a mixed solution of tert-butyl alcohol 5—dioxane 3 m, and manganese (BT) acetylacetonate 5 Omg and 7.0% tert. —Butyl hydroperoxide 1.011 ^ was stirred at room temperature for 30 hours at room temperature. After completion of the reaction, the solvent was concentrated under reduced pressure, and chloroform was added. The mixture was passed through celite, washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (cloform form medium). compound _c, was obtained 254mg (0. 413mmo 1) (49 % yield).

Compound. :

^{.. J H - NMR (CDC} £ 3) δ; 9.90 (. D, 1H 'J = 8 OHz) 9.24 (. D, IH J = 8.0Hz), 7.70-7.20 (ra, 12H) 6.75-6.68 (n IH), 5.20 (s.2H), 4.84 (br.s.IH), 3.98 (br.s, IH), 2.83 (s, 3H), 2.70-2.55 (m, 2H), 2.44 (s, 3H ), 1.49 (s, 3H)

MS: m / z 614 (M ⁺ )

The following examples show the effects on platelets and acute toxicity values.

mι-17 and Comparative Examples i and 2)

Effect on platelet assemblage (Mice acute lung thromboembolism death inhibitory effect) The test compound was added to a 0.5% sodium carboxymethylcellulose solution to prepare suspensions of various concentrations, and orally administered to 20 ddY mice (male, 5 weeks old) that had been fasted from the previous day, and then maintained constant. Time (Time to exhibit the maximum platelet assemblage inhibitory effect: 1 hour for selected compounds 1-17 in the present invention, 3 hours for ticlovidine) t, and platelet assemblage-inducing substance, ie, collagen solution (Note 1) or adenosine A diphosphate (ADP) solution (Note 2) was administered via the tail vein, and the number of deaths was observed within 10 minutes or less. A compound showing 50% inhibition of the death rate of the control group (Note 3) was observed. Concentration IC5. The value was determined.

Table 3 shows the test compounds and the results.

Table 3

IC ₅₀ (zM)

Compound No.Collagen ADP

1 8 1 2

2 3 1 0

3 4 1 2

4 7 1 5

5 6 1 6

6 4 1 2

7 9 1 4

8 1 1 1 7

9 4 1 1

1 0 1 2 1 8

1 1 8 1 3

1 2 1 4 1 8

1 3 5 1 1

1 4 1 6 20

1 5 5 1 3 1 6 20 22

1 7 6 1 3 Ticlovidine 1 50 200

Staurosporine (Note 4)

(Note 1) The collagen solution was dissolved in a 0.1% acetic acid aqueous solution, adjusted to pH 7.4 with a sodium hydroxide aqueous solution, and administered at 12 mg / 1 Om ^ / kg.

(Note 2) ADP solution was administered at 40 Om ^ (physiological saline) / kg.

(Note 3) The control group was orally administered with a 0.5% sodium carboxymethylcellulose solution. The concentrations and doses of the platelet aggregation-inducing substances in Note 1 and Note 2 were set so that the mortality rate in the control group was 80%.

(Note 4) Measurement was not possible due to toxicity.

(Example 18 and Comparative Examples 3 and 4)

Acute toxicity in mice

The test compound was added to a 0.5% carboxymethylcellulose sodium solution to prepare suspensions of various concentrations, and the S1c: ICR system was single-dose intraperitoneally to 5-week-old male mice. mouse mortality was determined LD ₅ 0 values from a subject the amount of compound of 50%. The results are shown in Table 4.

Compound 2 LD _s 0 value is larger as compared to Chikurobijin toxicity was markedly properly mitigated. .

Table 4

Compound LD ₅₀ value

2 40 Omg / kg or more Ticlovidine 30 Omg / kg

Sugar Rosporin 3mg / kg Table 5 Compound 2 and safety zone Chikurobijin the (LDsoZI C _5.) To indicate.

¾_5

Of compound safety margin (LD _₅₀ ZI C ₅₀₎

Collagen ADP

2.1 33 or more 40 or more Ticlovidine 2.1.5.

(Formulation example)

Taking Compound 2 as an example, tablets were produced according to the following formulation. Compound 2 '· · 1 Omg Light gay anhydride, · · 10 Omg Microcrystalline cellulose 50 mg Carboxymethylcellulose calcium · · · 25 mg

—Talc 4 mg Lactose '69 mg Magnesium stearate 2 mg The above ingredients were mixed and granulated according to a conventional method, and compression-molded to produce a tablet of 26 Omg per tablet.

Using such a method, various compounds of the present invention can be made into tablets.

(Usefulness of the present invention)

As shown in Table 3, compound (I) has higher potency and efficacy compared to existing platelet aggregation inhibitors, and as shown in Table 4, it is weaker in toxicity than ticlovidine. It has been significantly reduced compared to a certain similar structure of Susporin. In addition, as shown in Table 5, the safety margin is sufficiently large compared to existing drugs, and it can be said that the use of compound (I) (particularly compound 2) provides a very safe and platelet aggregation inhibitor. . Availability of ji

The staurosporine-y-lactam-converted derivative represented by the general formula (I) used in the present invention is characterized by: cold pain and ulcers in the extremities associated with obstructive arteriosclerosis induced by platelet aggregation, and blood in hemodialysis patients. Obstruction of the external shunt during the analysis, cerebral infarction and thrombosis due to frequent transient amaurosis, cerebral vasospasm after acute cerebral aneurysm surgery, blood circulation reconstruction, sage transplantation, artificial valve It is considered to be effective in improving postoperative thrombosis and embolism in replacement surgery.

The compound represented by the general formula (I) is orally administered in a preparation such as a tablet or a capsule together with a pharmaceutically acceptable carrier ordinarily used, or in a sterile solution or suspension for parenteral administration. Prescription can improve the above symptoms.

Claims

1. General formula (I):

Contract

3 (I)) 3

Example.

surface

(In the formula, represents hydrogen, lower alkyl, acyl, aralkyl, aralkyloxycarbonyl and / 3, β, / g-trichloroethoxycarbonyl, and R ₂ and R ₃ are hydrogen, nitro, amino, formyl, , Hydroxyl, hydroxymethyl and carboxyl; R ₂ and R ₃ may be the same or different; if R ₂ and R ₃ are different then R ₂ or R ₃ is hydrogen) A platelet aggregation inhibitor comprising, as an active ingredient, a octam conversion derivative and a pharmaceutically acceptable salt thereof.

2. Formula (I)

A platelet aggregation inhibitor comprising, as an active ingredient, a staurosporine 7-lactam conversion derivative represented by the formula: and a pharmaceutically acceptable salt thereof.

3. —General formula (ID ：

(Wherein R ₄ is lower alkyl, acyl, aralkyl, aralkyl Represents oxycarbonyl and S, β, —trichloro mouth ethoxycarbonyl. A platelet aggregation inhibitor comprising, as an active ingredient, a staurosporine lactam conversion derivative represented by the formula: and a pharmaceutically acceptable salt thereof.

4. General formula (F):

(Wherein, R ₄ are as defined above, the hydrogen and R _5, represents nitro, Amino, formyl, hydroxyl, hydroxymethyl and carboxyl, R ₅ and R ₆ may be the same or different, R ₅ And when e is different, R ₅ or R ₆ is hydrogen, and R ₅ and R ₆ are not two hydrogens at the same time.) A staurosbolin lactam-converted derivative represented by the formula and a pharmaceutically acceptable salt thereof A platelet aggregation inhibitor contained as an active ingredient.