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WO1993018771A1 - INHIBITEUR DE L'AGGLUTINATION PLAQUETTAIRE CONTENANT UN DERIVE DE STAUROSPORINE η-LACTAME - Google Patents

INHIBITEUR DE L'AGGLUTINATION PLAQUETTAIRE CONTENANT UN DERIVE DE STAUROSPORINE η-LACTAME Download PDF

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Publication number
WO1993018771A1
WO1993018771A1 PCT/JP1992/000357 JP9200357W WO9318771A1 WO 1993018771 A1 WO1993018771 A1 WO 1993018771A1 JP 9200357 W JP9200357 W JP 9200357W WO 9318771 A1 WO9318771 A1 WO 9318771A1
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WO
WIPO (PCT)
Prior art keywords
compound
hydrogen
reference example
reaction
staurosporine
Prior art date
Application number
PCT/JP1992/000357
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English (en)
Japanese (ja)
Inventor
Rintaro Yamada
Yasuo Sasaki
Satoshi Omura
Original Assignee
Asahi Kasei Kogyo Kabushiki Kaisha
Kitasato Kenkyusho
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asahi Kasei Kogyo Kabushiki Kaisha, Kitasato Kenkyusho filed Critical Asahi Kasei Kogyo Kabushiki Kaisha
Priority to PCT/JP1992/000357 priority Critical patent/WO1993018771A1/fr
Publication of WO1993018771A1 publication Critical patent/WO1993018771A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • 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.
  • staurosporine represented by has a potent vasorelaxant action and a platelet aggregation inhibitory action (Japanese Patent Publication No. 57-5
  • Ticlovidine an antiplatelet drug
  • Ticlovidine 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.
  • ticlovidine exerts its platelet aggregation inhibitory effect by irreversibly binding to the platelet surface.
  • the effect is continuous and is accompanied by side effects such as bleeding, aplastic anemia and jaundice.
  • thrombosis 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.
  • 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.
  • the present invention provides a compound of the general formula (I)
  • R represents hydrogen, lower alkyl, acyl, aralkyl, aralkyloxycarbonyl, and ⁇ , ⁇ , trifluorocarbonyl ethoxycarbonyl
  • 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
  • R 2 or R 3 is hydrogen
  • 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.
  • 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.
  • 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.
  • aralkyl represents benzyl, phenethyl, etc. Include.
  • aralkyloxycarbonyl includes benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and the like.
  • an acid addition salt can be formed.
  • 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.
  • the ⁇ -lactam ring moiety is chemically transformed by the following method 1 and deprotected to give compound (I).
  • the compound ( ⁇ ) 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 .
  • R 4 represents lower alkyl, acyl, aralkyl, aralkyloxycarbonyl, and / 5, ⁇ , yS-trichloromouth ethoxycarbonyl.
  • 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.
  • 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.
  • a protecting group a carbomate-type protecting group is usually used, and a benzyloxycarbonyl group (hereinafter, Cbz).
  • TEC- group ⁇ , yS-trichloromouth ethoxycarbonyl group (hereinafter abbreviated as TEC- group) is preferably used.
  • 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.
  • Compound (V-3) is obtained by reacting EC-Cf).
  • 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).
  • 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.
  • 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.
  • 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.
  • the reaction is carried out by reacting compound ( ⁇ ) 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.
  • ( ⁇ 3 ⁇ 4 [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)
  • 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.
  • R 4 is acyl
  • an acid anhydride corresponding to the compound (cap) can be used in place of compound 01).
  • 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)
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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
  • 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).
  • 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.
  • 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.
  • 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 3 shows the test compounds and the results.
  • 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.
  • various compounds of the present invention can be made into tablets.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de l'agglutination plaquettaire contient un ingrédient actif comprenant un dérivé de staurosporine η-lactame qui présente une activité inhibitrice de l'agglutination plaquettaire ainsi qu'une toxicité réduite, répondant à la formule générale (I), de même qu'un sel de cet inhibiteur acceptable sur le plan pharmacologique. Dans la formule générale (I), R1 représente hydrogène, alkyle inférieur, acyle, aralkyle, aralkyloxycarbonyle ou β,β,β-trichloroéthoxycarbonyle; et R2 et R3, qui peuvent être identiques ou non, représentent chacun hydrogène, nitro, amino, formyle, hydroxyle, hydroxyméthyle ou carboxyle, à condition que R2 ou R3 représente hydrogène quand ils sont différents l'un de l'autre.
PCT/JP1992/000357 1992-03-24 1992-03-24 INHIBITEUR DE L'AGGLUTINATION PLAQUETTAIRE CONTENANT UN DERIVE DE STAUROSPORINE η-LACTAME WO1993018771A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP1992/000357 WO1993018771A1 (fr) 1992-03-24 1992-03-24 INHIBITEUR DE L'AGGLUTINATION PLAQUETTAIRE CONTENANT UN DERIVE DE STAUROSPORINE η-LACTAME

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1992/000357 WO1993018771A1 (fr) 1992-03-24 1992-03-24 INHIBITEUR DE L'AGGLUTINATION PLAQUETTAIRE CONTENANT UN DERIVE DE STAUROSPORINE η-LACTAME

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WO1993018771A1 true WO1993018771A1 (fr) 1993-09-30

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PCT/JP1992/000357 WO1993018771A1 (fr) 1992-03-24 1992-03-24 INHIBITEUR DE L'AGGLUTINATION PLAQUETTAIRE CONTENANT UN DERIVE DE STAUROSPORINE η-LACTAME

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5373501A (en) * 1976-12-11 1978-06-30 Kitasato Inst Novel antibiotics amm2282 and process for preparing same
EP0296110A2 (fr) * 1987-06-15 1988-12-21 Ciba-Geigy Ag Dérivés de staurosporine substitués à l'azote du méthylamino

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5373501A (en) * 1976-12-11 1978-06-30 Kitasato Inst Novel antibiotics amm2282 and process for preparing same
EP0296110A2 (fr) * 1987-06-15 1988-12-21 Ciba-Geigy Ag Dérivés de staurosporine substitués à l'azote du méthylamino

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