WO1998025900A1 - Composes presentant une activite antitumorale - Google Patents

Composes presentant une activite antitumorale Download PDF

Info

Publication number
WO1998025900A1
WO1998025900A1 PCT/JP1997/004574 JP9704574W WO9825900A1 WO 1998025900 A1 WO1998025900 A1 WO 1998025900A1 JP 9704574 W JP9704574 W JP 9704574W WO 9825900 A1 WO9825900 A1 WO 9825900A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen atom
same
alkyloxy
optionally substituted
different
Prior art date
Application number
PCT/JP1997/004574
Other languages
English (en)
Japanese (ja)
Inventor
Mitsutaka Natsume
Iwao Utsunomiya
Hideaki Muratake
Original Assignee
Shionogi & Co., Ltd.
Research Foundation Itsuu Laboratory
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 Shionogi & Co., Ltd., Research Foundation Itsuu Laboratory filed Critical Shionogi & Co., Ltd.
Publication of WO1998025900A1 publication Critical patent/WO1998025900A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention relates to a compound having a strong cell growth inhibitory action and having excellent selectivity for tumor cells.
  • the compound of the present invention is particularly useful as a medicine. Background art
  • Compounds related to the compound of the present invention include duocarmycin SA (JP-A-2-177890), 1,2,9,9a-tetrahydrocyclopropa [c] benz [e] indole-4- On (CB I :) derivatives (Bioorganic & Medicinal Chemistry, Vol. 3, No. 11, p: 1429-1453, WO 97/12862), substituted CB I derivatives (J. Org. Chem., 1996, 61, p: 1710-1729, WO 97/32850), CBI derivatives (Japanese Patent Application Laid-Open No. 6-56667), and pyroquinone derivatives (Japanese Patent Application Laid-Open No. 8-347886, Japanese Patent Application Laid-open No. JP-A-8-347 8 9) is mentioned.
  • the inventors of the present invention have a problem with such chemotherapeutic agents, and therefore, have a compound having higher antitumor activity and excellent selectivity for cancer cells, and possessing properties of these compounds.
  • intensive research has been conducted on the creation of compounds that can be chemically bonded to drug carriers.
  • R 1 and R 4 each independently represent a hydrogen atom, lower alkyl, lower alkyloxy, nitro, or optionally substituted amino
  • R 2 and R 3 both represent a hydrogen atom
  • Z represents an oxygen atom or a sulfur atom
  • R 5 and R 6 are the same or different and represent hydrogen atom, a lower alkyl or optionally substituted
  • Y represents an oxygen atom or a sulfur atom
  • R 7, R 8, R 9, and R 1 0 are the same or different connexion water Atom
  • a lower alkyl or substituted shows the even better Arukiruokishi have
  • m represents an integer of 0 to 3
  • R 11 represents a hydrogen atom, lower alkyl, lower alkyloxy, hydroxy, nitro, cyano, or a formula:
  • R 2 1 represents a hydrogen atom or a lower alkyl
  • R 2 2 is a hydrogen atom or a lower alkyl
  • X is an oxygen atom, a sulfur atom or, - N
  • R 1 2 and R 1 3 are the same or different and each represents a hydrogen atom, lower alkyl, lower Arukiruokishi arsenide Dorokishi, a nitro or Shiano
  • W is an oxygen atom, a sulfur atom or a N
  • R 1 4, R 1 6 and R 1 7 Is the same or different and represents a hydrogen atom, lower alkyl, lower alkyloxy, or hydroxy
  • R 15 represents a hydrogen atom, lower alkyl, optionally substituted alkyloxy, optionally substituted amino, or a compound represented
  • R 2 and R 3 are the same or different and each represents hydroxy, nitro, lower alkyl, optionally substituted alkyloxy, or optionally substituted amino, or R 2 and R 3 3 represents a 5- to 7-membered ring group which may contain one or more oxygen atoms, nitrogen atoms or sulfur atoms in the ring together with adjacent carbon atoms, and R 1 , R 4 and B are The same as defined above), an optically active form thereof, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • R 1 and R 4 are the same or different and represent a hydrogen atom or lower alkyloxy, and R 2 and R 3 are the same or different and are hydroxy, nitro, substituted Represents an optionally substituted alkyloxy or an optionally substituted amino, or R 2 and R 3 may combine to form a lower alkylenedioxy, R 14 , R 16 and R 17 Is the same or different and represents a hydrogen atom or a lower alkyloxy; R 15 represents an optionally substituted alkyloxy or an optionally substituted amino; W is the same as defined above);
  • R 1 and R 4 are both hydrogen atoms, or one is a hydrogen atom, the other is a lower alkyloxy, and R 2 and R 3 are the same or different and are hydroxy, nitro, optionally substituted alkyloxy, Or an optionally substituted amino, or a methylenedioxy formed by combining R 2 and R 3 , wherein R 15 , R 16 , and R 17 are the same or different and represent a hydrogen atom or a lower alkyloxy group; W indicates one NH—
  • optically active form thereof or a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • R 1 and R 4 both represent a hydrogen atom, or one represents a hydrogen atom, the other represents a lower alkyloxy, and R 2 and R 3 are the same or different and are hydroxy or substituted
  • R 1 5, R 16 and R 1 7 are the same or different A hydrogen atom or lower alkyloxy
  • W represents —NH—
  • R 1 and R 4 are both hydrogen atoms, or one is a hydrogen atom or lower alkyloxy, the other is nitro or optionally substituted amino, and R 2 and R 3 are the same or different hydroxy
  • R 1 and R 4 are both a hydrogen atom, or one is a hydrogen atom, the other is a lower alkyloxy, and R 2 and R 3 are one lower alkyloxy, the other is hydroxy, nitro or substituted.
  • Alkyloxy or substituted R 15 , R 16 and R 17 are the same or different and each represent a hydrogen atom or a lower alkyloxy, and W represents —NH—), a compound represented by the formula: The body, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • R 2 and R 3 each represent methyloxy and the other represents substituted alkyloxy or optionally substituted amino
  • an optically active form thereof or a pharmacologically active substance thereof. Salts or hydrates thereof.
  • R 5 , R 6 , Z and B are as defined above
  • an optically active form thereof or a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • R 15 is an optionally substituted alkyloxy or an optionally substituted Represents diamino
  • R 14 , R 16 and R 17 are the same or different and represent a hydrogen atom or lower alkyloxy
  • W represents —NH—
  • R 5 , R 6 and Z have the same meanings as described above
  • R 15 , R 16 and R 17 each independently represent a hydrogen atom or lower alkyloxy, W represents —NH—, and Z represents the same meaning as described above).
  • R 7 , R 8 , R 9 , R 1 Q , Y and B have the same meanings as defined above), or an optically active form thereof, or a pharmacologically acceptable form thereof. Salts and their hydrates.
  • R 1 5 represents a good I Amino be also good Arukiruokishi or substituted optionally substituted
  • R 14, R 1 6 and R 1 7 represents a hydrogen atom or a lower Arukiruokishi same or different
  • W represents one NH—
  • Y, R 7 , R 8 , R 9 , and R 1 Q have the same meanings as defined above
  • an optically active form thereof or a pharmacologically acceptable salt thereof. , Or their hydrates.
  • R 15 , R 16 and R 17 each independently represent a hydrogen atom or a lower alkyloxy, W represents —NH—, and Y has the same meaning as described above), or a compound thereof.
  • R 1 and R 4 are hydrogen atoms, R 2 and R 3 are one lower alkyloxy, the other substituted alkyloxy or optionally substituted amino, R 15 , A compound wherein R 16 and R 17 are lower alkyloxy, W is —NH—, or an optically active form thereof, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • R 1 and R 4 are hydrogen atoms, R 2 and R 3 are both lower alkyloxy, R 15 is substituted alkyloxy or optionally substituted amino, R 1
  • R 1 and R 4 are hydrogen atoms, R 2 and R 3, one Mechiruokishi, Arukiruokishi the person other is unsubstituted Dorokishi or amino, hydroxyalkyl be alkyl properly substituted by amino optionally substituted amino, lower ⁇ Rukanoiru, -CO (CH 2) p NHC OOR 2 3 (wherein, R 23 is lower alkyl or lower alkenyl,, p is 1 integer of 5), or - CO ( CH 2 ) q Amino substituted with NH 2 (where q is an integer of 1 to 5), a compound wherein R 15 , R 16 and R 17 are methyloxy, and W is -NH_, or Optically active forms thereof, or pharmacologically acceptable salts thereof, or hydrates thereof.
  • R 1 and R 4 are hydrogen atoms, R 2 and R 3 are both methyloxy, R 15 is alkyloxy substituted with lower alkyloxy substituted with hydroxy or amino, or —CO (CH 2 ) q An amino substituted with NH 2 (wherein Q is an integer of 1 to 5), a compound in which R 16 and R 17 are a hydrogen atom, W is —NH—, or an optically active form thereof, or Their pharmacologically acceptable salts or their hydrates.
  • R 1 and R 4 are hydrogen atoms
  • R 2 and R 3 are substituted with methyloxy on one side, alkyloxy substituted on the other side by hydroxy or amino, lower alkyloxy substituted by amino or hydroxy
  • R 15 , R 16 and R 17 are methyloxy
  • W is —NH, alkyloxy substituted or amino substituted with amino or hydroxy and alkyl substituted with 1 or 2 lower alkyls.
  • R 1 and R 4 are hydrogen atoms, R 2 and R 3, one Mechiruokishi, Arukiruokishi the other is substituted with hydroxy or Amino, R 1 5, R 1 6 and R 1 7 is Methyloxy, a compound in which W is —NH—, or an optically active form thereof, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • lower alkyl refers to straight-chain or branched C 6 alkyl.
  • Methyl, ethyl, n-propyl, i-propyl are preferred.
  • lower alkanol means an alkanol in which the above “lower alkyl” is bonded to a carbonyl group.
  • Acetyl is preferred.
  • lower alkyloxy means lower alkyloxy wherein the lower alkyl moiety is the above “lower alkyl”.
  • the alkyl moiety means a Arukiruokishi a C i to C i 2 alkyl linear or branched.
  • methyloxy, ethyloxy, n-propyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy are exemplified. More preferably, methyloxy, ethyloxy, n-propyloxy, n-butyloxy and n-pentyloxy are mentioned.
  • substituted alkyloxy in the "optionally substituted alkyloxy” and the “substituted alkyloxy” refer to hydroxy, amino, phenyl, hydroxy-lower alkyloxy, amino-lower alkyloxy and the like. Means the above “alkyloxy”.
  • optionally substituted amino refers to a C i Cs linear alkyl having a nitrogen atom substituted with the above “lower alkyl”, “lower alkanol”, hydroxy or amino, —CO ( CH 2 ) pNHCOOR 23 (where R 23 is lower alkyl or lower alkenyl, p is an integer of 1 to 5), —CO (CH 2 ) q NH 2 (where q is an integer of 1 to 5) Etc. means an amino which may be substituted at one or two places.
  • the “5- to 7-membered ring group which may contain one or more oxygen atoms, nitrogen atoms, or sulfur atoms together with adjacent carbon atoms in the tube” includes 1, 3 — A dioxolane ring, a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a pyrazole ring, an isoxazole ring, a 1,4-dioxane ring, a piperidine ring, and a piperazine ring. 1,3-Dioxolane rings are preferred.
  • lower alkylenedioxy means an alkylenedioxy having 1 to 2 carbon atoms and two oxygen atoms, for example, methylenedioxy, ethylenedioxy and the like. Methylenedioxy is preferred.
  • lower alkenyl refers to C 2 -C 8 alkenyl.
  • vinyl, aryl and the like can be mentioned.
  • aryl is used.
  • the compound of the present invention can be produced by the same method as described in JP-A-9-310975 or the method described below, but is not particularly limited thereto. If it has a substituent (amino, carboxy, hydroxy, etc.) that hinders the reaction, it should be protected in advance by the method described in Protective Groups in Organic Synthesis, Theodora W. Green (oohn Wiley & Sons), etc. To remove the protecting group.
  • a substituent amino, carboxy, hydroxy, etc.
  • a compound (XIII) is synthesized.
  • 4-Methyloxypyridine (XI) is mixed with a solvent such as tetrahydrofuran, dimethyl ether, 1,2-dimethyloxetane and a solvent such as methanol and ethanol, preferably a mixed solvent of tetrahydrofuran-methanol.
  • a solvent such as tetrahydrofuran, dimethyl ether, 1,2-dimethyloxetane
  • a solvent such as methanol and ethanol, preferably a mixed solvent of tetrahydrofuran-methanol.
  • Dissolve and add methyl chloroformate at 180 ° C to room temperature, preferably -80 ° C to 120 ° C, under an atmosphere of argon or nitrogen, and add 10 minutes to 1 hour, preferably 15 minutes. Stir for ⁇ 30 minutes.
  • a silylating agent such as trifluoromethanesulfonate is added, and the mixture is stirred at ⁇ 30 ° C. to room temperature, preferably at 120 ° C. to ice, for 30 minutes to 2 hours, preferably 1 to 2 hours, Post-treatment gives a silyl phenol ether of the compound (XII).
  • a Lewis acid such as trimethylsilyltrifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, trifluoroporanyl monoterate, or the like, preferably trimethylsilyltrifluoromethanesulfonate, is added at 180 ° C. to ⁇ 20 ° C.
  • the compound (XIII) is obtained by stirring the mixture at a temperature of preferably from 75 ° C. to 144 ° C. for 15 minutes to 1 hour, preferably for 20 to 40 minutes, and performing a usual post-treatment.
  • the compound (XIV) is synthesized using a Heck reaction.
  • Compound (XIII) a palladium catalyst, preferably a mixture of palladium acetate and tri (o-tolyl) phosphine, benzyltrimethylammonium chloride or tetrabutylammonium chloride, and an organic base such as triedulamine and pyridine.
  • the acetonitrile solution is heated in a sealed tube at 100 to 150 ° C, preferably at 100 to 110, for 10 to 20 hours, preferably 12 to 16 hours. After standing to cool, ordinary post-treatment is performed to obtain compound (XIV).
  • R 1 , R 2 , R 3 , and R 4 are as defined above, and M s represents methanesulfonyl
  • compound (XV) is synthesized.
  • the double bond is Oxidation to methylene or m-chloroperbenzoic acid (MCPBA) leads to diol form.
  • MCPBA m-chloroperbenzoic acid
  • the compound (XIV) and trimethylamine oxide are dissolved in a mixed solvent of acetone and water, a catalytic amount of osmium tetroxide is added, and the mixture is cooled under ice to 50 t, preferably at room temperature. The mixture is stirred for 24 hours, preferably 3 to 4 hours, and subjected to ordinary post-treatment to obtain a diol form.
  • de-OH conversion is performed.
  • the resulting diol is dissolved in a solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and the like, and triethylsilane and trifluoroborane etherate are added, and the mixture is ice-cooled to 50 ° C, preferably room temperature.
  • the mixture is stirred for 30 minutes to 3 hours, preferably for 12 hours, and subjected to ordinary post-treatment to obtain a monoalcohol. Finally, protect the hydroxyl groups.
  • the temperature is reduced to ⁇ 30 to room temperature, preferably at ⁇ 20 ° C. to ice-cooling. And add methanesulfonyl chloride, and stir for 30 minutes to 2 hours, preferably 11.5 hours.
  • the reaction may be carried out by dissolving the monoalcohol compound in pyridin and adding methanesulfonyl chloride at room temperature under ice cooling to room temperature. Perform the usual post-treatment to obtain compound (XV).
  • R 1 , R 2 R 3 and R 4 are as defined above, Ms is methanesulfonyl, TEA is triethylamine, and Ac is acetyl.
  • compound (XVI) is synthesized.
  • the key reaction is to perform a dehydrogenation reaction by an oxygen oxidation reaction using a palladium catalyst.
  • the compound (XVI) is dissolved in a solvent such as dichloromethane, chloroform, dichloroethane and the like, and an organic base such as trieduramine and pyridine is added.
  • a silylating agent such as triethylsilyl trifluoromethanesulfonate or trimethylsilyl trifluoromethanesulfonate is added at a temperature of 120 ° C. to ice-cooling, and the mixture is added for 30 minutes to 2 hours, preferably 1 to 1.5.
  • silyl phenol ether compound After stirring for an hour, ordinary post-treatment is performed to obtain a silyl phenol ether compound. Next, the obtained silyl phenol ether is dissolved in dimethyl sulfoxide, and a catalyst such as palladium acetate is added thereto. The mixture is stirred for 10 to 50 hours, preferably for 10 to 30 hours, and subjected to ordinary post-treatment to obtain a dehydrogenated product. The obtained dehydrogenated product is dissolved in pyridine and acetic anhydride, and the mixture is stirred under ice-cooling to 50 ° C, preferably at room temperature for 1 to 5 hours, preferably for 2 to 3 hours to perform acetylation. The usual post-treatment is performed to obtain the compound (XVI).
  • the amino group (obtained by reduction of the nitro group) or the xyl group (obtained by deprotection of the protected hydroxyl group) of the substituents R 2 and R 3 of the compound (XVI) is
  • the alkylation can be carried out by a conventional alkylation reaction.
  • compound (XVII) is synthesized.
  • the compound (XVI) is dissolved in a solvent such as methanol, acetonitrile, dimethylformamide and the like, and a base such as sodium carbonate and potassium carbonate is added thereto.
  • the mixture is cooled with ice to 50 ° C, preferably at room temperature.
  • the mixture is stirred for up to 5 hours, preferably 1 to 3 hours, and subjected to ordinary post-treatment to obtain compound (XVII).
  • a compound represented by the general formula (II) is synthesized.
  • Compound (XVII) is converted to tetrahydrofuran, getyl ether, 1,2-dimethyloxo Dissolve in a mixed solvent of a solvent such as tan and a solvent such as dimethylformamide, dimethylsulfoxide, etc., add a base such as sodium hydride, potassium hydride, etc., under an atmosphere of argon or nitrogen, and The mixture is stirred at room temperature, preferably at ⁇ 20 ° C. to under ice-cooling, for 10 minutes to 1 hour, preferably for 15 minutes to 45 minutes.
  • a compound (XVIII) in which B is activated with carbonyldiimidazole or B activated by an activator usually used as a carboxylic acid activator is added, and the mixture is added at the same temperature for 30 minutes to 3 hours, preferably.
  • the compound represented by the general formula (II) can be obtained by stirring for 1 to 3 hours and performing ordinary post-treatment.
  • the compound represented by the general formula (II) can be obtained by reacting the compound (XVII) with the compound (XVIII) in a solvent such as dimethylformamide with carbon dioxide rim at room temperature for 3 to 15 hours. You.
  • the compound of the present invention can bind to the above drug carrier at R 2 , R 3 and R 15 , but is preferably bound at R 2 and R 3 to obtain a more active compound.
  • a pharmacologically acceptable salt or a hydrate thereof is also conjugated.
  • alkali metals lithium, sodium, potassium, etc.
  • alkaline earth metals magnesium, calcium, etc.
  • ammonium salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid)
  • organic acids acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p — Toluenesulfonic acid, etc.
  • These salts can be formed by a commonly used method. When forming a hydrate, it may be coordinated with any number of water molecules.
  • the optically active form refers to a compound in which both cyclopropane rings are formed by a bond in an ⁇ -configuration, and a compound in which both cyclopropane rings are formed by a bond in a 3-configuration.
  • Each of these compounds can be obtained by resolving the racemate using an appropriate optically active reagent or by separating and purifying it by chromatography using a chiral column.
  • the compound of the present invention has a strong cell growth inhibitory action and has excellent selectivity for tumor cells, it can be used as an antitumor agent.
  • a pharmaceutical formulation can be prepared by mixing an effective amount of the compound with excipients, binders, wetting agents, disintegrating agents, lubricants and other pharmaceutical additives suitable for the dosage form, if necessary. it can.
  • excipients binders, wetting agents, disintegrating agents, lubricants and other pharmaceutical additives suitable for the dosage form, if necessary. it can.
  • they should be sterilized with a suitable carrier to produce the preparation.
  • Dosages will vary depending on the disease state, route of administration, age or weight of the patient, but for oral administration to adults, they will usually be between 0.01 and 100 g / kgZ days, preferably between 0. 1 to 10 gZkgZ days.
  • Triethylsilan (0.30 ml) and then trifluoropropane etherate (0.15 ml) were added dropwise to a dichloromethane solution (5 ml) of the residue (135 mg) in dichloromethane, and the mixture was added at room temperature for 1 hour. Half agitated. A saturated aqueous sodium hydrogen carbonate solution and sodium chloride powder were added, and the mixture was extracted with 10% methanol-dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • Example 1 Compounds (8) to (15) were synthesized in the same manner as in the first to fifth steps. The results are shown in Tables 1 to 3.
  • Example 1 The same reaction as in the first to fourth steps was performed to obtain the title compound.
  • glycol aldehyde dimer 22 mg
  • acetic acid 0.1 ml
  • sodium borocyano hydride 12 mg
  • An aqueous saturated sodium hydrogen carbonate solution and sodium chloride powder were added, and the mixture was extracted with 10% methanol-dichloromethane. The organic layer was washed with brine, dried (anhydrous sodium sulfate) and evaporated.
  • Methyl iodide (1.5 ml) was added dropwise to a solution of magnesium (661 mg) in ethyl ether (40 ml), and the mixture was stirred at room temperature for 30 minutes.
  • a solution of 5-benzyloxy-2-promo 4-methyloxybenzaldehyde [J. Chem. Soc. (C), 1052 (1966)] (2.50 g) in tetrahydrofuran (30 ml). ) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with dichloromethane.
  • Example 1 The same reaction as in the first to fourth steps was performed to obtain the title compound.
  • the compounds shown in Table 1 can be synthesized in the same manner as described above or by deprotecting the compound obtained above.
  • Cells derived from mouse and human are seeded on a 96-well microplate with 5,000 to 100,000 wells.
  • the culture solution should be a MEM solution, RPMI-164 solution, etc. plus 10% serum.
  • the next day add the drug to the culture solution. Cells are kept in contact with the drug, suspension cells are cultured for 3 days, and other adherent cells are cultured for 4 days.
  • MTT attestation tetrazolium salt staining
  • a granule containing the following ingredients is produced.
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass the cone through a 120-mesh sieve. These are mixed with a V-type mixer. An aqueous solution of HP C-L (low viscosity hydroxypropyl cellulose) is added to the mixed powder, kneaded, granulated (extrusion granulated with a pore size of 0.5 to lmm), and dried. The obtained dried granules are combed through a vibrating sieve (12 to 60 mesh) to obtain granules.
  • HP C-L low viscosity hydroxypropyl cellulose
  • a tablet is prepared containing the following ingredients:

Abstract

L'invention concerne des composés présentant une puissante activité cytostatique et une excellente spécificité vis-à-vis de cellules tumorales, les composés sont représentés par la formule générale (I) dans laquelle R2 ou R3 représentent méthyloxy et l'autre représente alkyloxy substitué ou amino facultativement substitué. L'invention concerne également leurs isomères actifs optiquement, leurs sels acceptables en pharmacologie ou leurs hydrates.
PCT/JP1997/004574 1996-12-13 1997-12-12 Composes presentant une activite antitumorale WO1998025900A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/332591 1996-12-13
JP33259196 1996-12-13

Publications (1)

Publication Number Publication Date
WO1998025900A1 true WO1998025900A1 (fr) 1998-06-18

Family

ID=18256658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/004574 WO1998025900A1 (fr) 1996-12-13 1997-12-12 Composes presentant une activite antitumorale

Country Status (1)

Country Link
WO (1) WO1998025900A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7129261B2 (en) 2001-05-31 2006-10-31 Medarex, Inc. Cytotoxic agents
JP2010519310A (ja) * 2007-02-21 2010-06-03 メダレックス インコーポレイテッド 単一のアミノ酸を有する化学リンカーおよびその複合体
US20110065767A1 (en) * 2007-08-01 2011-03-17 Patrick Henry Beusker Substituted CC-1065 Analogs and Their Conjugates
US8461117B2 (en) 2006-12-28 2013-06-11 Medarex, Inc. Chemical linkers and cleavable substrates and conjugates thereof
US9421278B2 (en) 2014-01-10 2016-08-23 Synthon Biopharmaceuticals B.V. Duocarmycin ADCS showing improved in vivo antitumor activity
US9427480B2 (en) 2014-01-10 2016-08-30 Synthon Biopharmaceuticals B.V. Duocarmycin ADCs for use in treatment of endometrial cancer
JP2016533330A (ja) * 2013-09-25 2016-10-27 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ 新しい抗腫瘍剤としてのチエノ［２，３−ｅ］インドール誘導体
US9629924B2 (en) 2010-04-21 2017-04-25 Syntarga Bv Conjugates of CC-1065 analogs and bifunctional linkers
US9815784B2 (en) 2008-11-03 2017-11-14 Syntarga B.V. CC-1065 analogs and their conjugates
US9901567B2 (en) 2007-08-01 2018-02-27 Syntarga B.V. Substituted CC-1065 analogs and their conjugates
US10266606B2 (en) 2014-01-10 2019-04-23 Synthon Biopharmaceuticals B.V. Method for purifying Cys-linked antibody-drug conjugates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997032850A1 (fr) * 1996-03-08 1997-09-12 The Scripps Research Institute Analogues mcbi de cc-1065 et des duocarmycines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997032850A1 (fr) * 1996-03-08 1997-09-12 The Scripps Research Institute Analogues mcbi de cc-1065 et des duocarmycines

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
J. ORG. CHEM., 61(5), (1996), pages 1710-29. *
J. ORG. CHEM., 62(17), (1997), pages 5849-5863. *
J. ORG. CHEM., 62(25), (1997), pages 8875-8891. *
TETRAHEDRON LETT., 38(43), (1997), pages 7577-7580. *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7129261B2 (en) 2001-05-31 2006-10-31 Medarex, Inc. Cytotoxic agents
US8461117B2 (en) 2006-12-28 2013-06-11 Medarex, Inc. Chemical linkers and cleavable substrates and conjugates thereof
JP2010519310A (ja) * 2007-02-21 2010-06-03 メダレックス インコーポレイテッド 単一のアミノ酸を有する化学リンカーおよびその複合体
US8664407B2 (en) 2007-02-21 2014-03-04 Medarex, LLC Chemical linkers with single amino acids and conjugates thereof
US20110065767A1 (en) * 2007-08-01 2011-03-17 Patrick Henry Beusker Substituted CC-1065 Analogs and Their Conjugates
US8680293B2 (en) * 2007-08-01 2014-03-25 Syntarga B.V. Substituted CC-1065 analogs and their conjugates
US9901567B2 (en) 2007-08-01 2018-02-27 Syntarga B.V. Substituted CC-1065 analogs and their conjugates
US9815784B2 (en) 2008-11-03 2017-11-14 Syntarga B.V. CC-1065 analogs and their conjugates
US11052155B2 (en) 2010-04-21 2021-07-06 Syntarga Bv Conjugates of CC-1065 analogs and bifunctional linkers
US9629924B2 (en) 2010-04-21 2017-04-25 Syntarga Bv Conjugates of CC-1065 analogs and bifunctional linkers
JP2016533330A (ja) * 2013-09-25 2016-10-27 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ 新しい抗腫瘍剤としてのチエノ［２，３−ｅ］インドール誘導体
US9427480B2 (en) 2014-01-10 2016-08-30 Synthon Biopharmaceuticals B.V. Duocarmycin ADCs for use in treatment of endometrial cancer
US10092659B2 (en) 2014-01-10 2018-10-09 Synthon Biopharmaceuticals B.V. Duocarmycin ADCs for use in treatment of endometrial cancer
US10266606B2 (en) 2014-01-10 2019-04-23 Synthon Biopharmaceuticals B.V. Method for purifying Cys-linked antibody-drug conjugates
US10603387B2 (en) 2014-01-10 2020-03-31 Synthon Biopharmaceuticals B.V. Duocarmycin ADCs showing improved in vivo antitumor activity
US9421278B2 (en) 2014-01-10 2016-08-23 Synthon Biopharmaceuticals B.V. Duocarmycin ADCS showing improved in vivo antitumor activity
US11382982B2 (en) 2014-01-10 2022-07-12 Byondis B.V. Duocarmycin ADCs showing improved in vivo antitumor activity

Similar Documents

Publication Publication Date Title
RU2276140C2 (ru) Производные тетрагидропиридина и фармацевтическая композиция на их основе
EP3661921B1 (fr) Inhibiteurs sélectifs de l'inflammasome nlrp3
KR102041442B1 (ko) 중수소화된 디아미노피리미딘 화합물 및 이 화합물을 함유하는 약물 조성물
KR100591501B1 (ko) 트리시클릭 알킬히드록사메이트, 이들의 제조, 및 세포증식 억제제로서 이들의 용도
KR100628013B1 (ko) 트리시클릭 락탐 및 술탐 유도체, 및 히스톤 디아세틸라제억제제로서 이들의 용도
TW201014863A (en) Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
BRPI0706623A2 (pt) moduladores de receptor canabinóide
KR20170004968A (ko) 암 치료용의 ｅｒｂｂ 티로신 키나제 억제제로서의 벤즈이미다졸 유도체
EA005679B1 (ru) Бициклические гетероциклы, содержащие эти соединения лекарственные средства, их применение и способ их получения
JP2002069057A (ja) ピペリジン誘導体
EP3428159B1 (fr) Formes cristallines de sel de mésylate de dérivé de pyridinyl-aminopyrimidine, procédés de préparation et applications associés
WO1998025900A1 (fr) Composes presentant une activite antitumorale
CN113683598B (zh) 一种免疫调节剂
WO2023098426A1 (fr) Dérivés de 7-(naphtalén-1-yl)pyrido[4,3-d]pyrimidine, leur procédé de préparation et leur utilisation
JP5762624B2 (ja) 安定な７員環ラクトンを含むカンプトテシン化合物、それらの製造方法及び使用
WO2013107428A1 (fr) Dérivé d'hanfangichin b substitué en position 7, et procédé de préparation et utilisation de celui-ci
CN112142746B (zh) 苯二氮卓类化合物及其制备方法和在医药上的作用
JP4548884B2 (ja) ４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン誘導体
WO2013185613A1 (fr) Dérivés d'acylation de saponines paridis i, procédé de préparation associé et application associée
HU204838B (en) Process for producing nitriferous derivatives of epipodophyllotoxin glycosides and pharmaceutical compositions comprising such active ingredient
WO2022188889A1 (fr) Composé utile en tant qu'inhibiteur de parp7
JP4548882B2 (ja) ４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン化合物
JP4038245B2 (ja) 新規なフェナンスリジニウム誘導体
EP2474550A1 (fr) Dérivés d'englérine pour le traitement du cancer
WO1996032394A1 (fr) DERIVES DE PYRAZOLO[1,5-a]PYRIMIDINE

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase