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WO1998003509A1 - Derives de dc-89 - Google Patents

Derives de dc-89 Download PDF

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Publication number
WO1998003509A1
WO1998003509A1 PCT/JP1997/002516 JP9702516W WO9803509A1 WO 1998003509 A1 WO1998003509 A1 WO 1998003509A1 JP 9702516 W JP9702516 W JP 9702516W WO 9803509 A1 WO9803509 A1 WO 9803509A1
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WO
WIPO (PCT)
Prior art keywords
compound
added
mixture
mmol
solution
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1997/002516
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English (en)
Japanese (ja)
Inventor
Nobuyoshi Amishiro
Hiromitsu Saito
Akihiko Okamoto
Katsushige Gomi
Masami Okabe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KH Neochem Co Ltd
Original Assignee
Kyowa Hakko Kogyo Co Ltd
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 Kyowa Hakko Kogyo Co Ltd filed Critical Kyowa Hakko Kogyo Co Ltd
Priority to AU34631/97A priority Critical patent/AU3463197A/en
Publication of WO1998003509A1 publication Critical patent/WO1998003509A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a DC-89 derivative or a pharmacologically acceptable salt thereof, which exhibits excellent antitumor activity and is useful as an antitumor agent.
  • DC-89A As compounds related to the DC-89 derivative of the present invention, DC-89A 1.
  • DC-89A2 DC-89B1 and DC-89B2 represented by the following structural formulas are known. In addition to showing antibacterial activity against bacteria, it also has anti-femoral activity against melanomas B-16.
  • DC-89A1 is disclosed in W087 / 06265, and DC-89A2 DC-89B1 and DC-89B2 are disclosed in JP-A-2-119787. Further, SF 2 582 A and SF 2 582 B which are the same compounds as DC-8 (JA2 and DC-89A1) are disclosed in JP-A-1-139590.
  • DC-88A having the following structural formula is disclosed in W087 / 06265, and DC113 is disclosed in JP-A-2-77890, which shows antibacterial activity against various bacteria. Shows antitumor activity against 6 mag.
  • DC-88A derivative and the DC-89 derivative are disclosed in JP-A-2-288879, JP-A-3-7287, JP-A-3-128379, JP-A-4-226988, JP-A-4-356485, and JP-A-5-51384. And JP-A-5-178858.
  • JP-A-278881 JP-A-278881
  • CC-1065 which is an anti-tumour compound having a structure similar to DC-88 and DC-89, and its derivatives are described.
  • related derivatives are disclosed in JP-A-6-116269 and ⁇ Am. Chem.So, ⁇ 7, 8917-8925 (1995).
  • JP-A-5-178858 discloses the following compounds (A), (B) and (C).
  • the present invention provides a compound of the formula (I)
  • R is a hydrogen atom or COR 1 (where R 1 is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted complex A ring group, NR 2 R 3 (wherein, R 2 and R 3 are the same or different and represent a hydrogen atom or a substituted or unsubstituted lower alkyl),
  • N-R 5 (wherein, R 5 is t represents a hydrogen atom or a lower alkyl) or, Represents Wherein, n R 2a and R 3a have the same meanings as R f , R 2 and! 3 , respectively; or 0H 6 (where ii 6 is a substituted or unsubstituted lower alkyl) Represents).
  • ⁇ where W is
  • Y 1 represents an oxygen atom
  • R ib is as defined Xiao ⁇ Symbol H f.
  • a sulfur atom or an N-lT b represents, Q 1 and Q 2 are the same or different and each represents a hydrogen atom , 01 (wherein, H 7 represents a hydrogen atom or a substituted or unsubstituted lower alkyl), N 0 2 , NR ′ b R 3b (wherein, R 2b and H 3b are the above-mentioned R z and R 3 , respectively) Synonymous with 3. ) or NHC0 2 K 6a
  • Y 2 represents an oxygen atom, a sulfur atom or NR f (wherein IT has the same meaning as described above.), And Q 3 and Q 5 have the same meaning as the above-mentioned Q ′ or Q z . ] Is represented. ⁇ It relates to a DC-89 derivative represented by the formula or a pharmacologically acceptable salt thereof.
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by the formula (I).
  • lower alkyl means straight or branched alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, isooctyl and the like.
  • aryl include phenyl, naphthyl, anthranil, bienyl and the like.
  • Heterocyclic groups include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidino, piperazinyl, homobiperazinyl, morpholino, thiomorpholino, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl Phthalazinyl, naphthyridinyl, quinoxalinyl, chenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, prinyl, viranyl, pihydridyl, tephridylyl And the like.
  • substituent of the substituted lower alkyl examples include the same or different and substituted 1 to 3 hydroxy lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, amino, mono- or di-lower alkylamino, halogen, aryl, etc. Is included.
  • substituent of the substituted aryl and the substituted heterocyclic group examples include the same or different and substituted or unsubstituted substituted or unsubstituted lower alkyl, lower alkoxy, lower alkoxycarbonyl, amino, mono- or di-lower alkylamino, halogen and the like. Include.
  • the lower alkyl portion of the lower alkoxy, the lower alkyl thio, the lower alkoxycarbonyl, the mono- or di-lower alkylamino is the same as the lower alkyl.
  • the halogen include fluorine, chlorine, bromine and iodine atoms.
  • Pharmacologically acceptable salts of compound (I) include, for example, hydrochloride, hydrobromic acid Inorganic acid addition salts such as salts, hydroiodide, sulfate, phosphate, nitrate and acetate, benzoate ⁇ , maleate, fumarate, succinate, tartrate, citrate And organic acid addition salts such as salts, oxalates, glyoxylates, aspartic acid ⁇ , and methanesulfonates.
  • hydrochloride hydrobromic acid Inorganic acid addition salts such as salts, hydroiodide, sulfate, phosphate, nitrate and acetate
  • benzoate ⁇ maleate, fumarate, succinate, tartrate, citrate
  • organic acid addition salts such as salts, oxalates, glyoxylates, aspartic acid ⁇ , and methanesulfonates.
  • the base includes sodium hydride, lithium diisopropylamide, t-butoxycar- ium, triethylamine, 4-dimethylaminopyridine, and the like. It is used in an amount of 1 to 3 equivalents based on the normal compound (A).
  • the inert solvent N, N-dimethylformamide (DMF), tetrahydrofuran (THF), toluene, dimethyl sulfoxide or the like is used alone or as a mixture.
  • Examples of the reactive derivative of carboxylic acid include acid halides such as acid chloride and acid bromide, p-difluorophenyl ester, 2,4,5-trichlorophenyl ester, penfluorofluoroester, Active esters such as N-oxysuccinic acid imido ester are included.
  • the reactive derivative is usually used in an amount of 1 to 3 equivalents based on the compound (A), and the reaction is carried out at -80 to 30 ° C and is completed in 30 minutes to 24 hours.
  • Compound (I) a can also be produced by reacting compound (I) b described below with a base in an inert solvent.
  • the base includes 1,8-diazabicyclo [5.4.0] -7-indene (DBU) and the like, and is usually used in an amount of 1 to 10 equivalents to compound (I) b.
  • DBU 1,8-diazabicyclo [5.4.0] -7-indene
  • As the inert solvent acetonitrile, pyridine and the like are used alone or in combination.
  • the reaction is usually performed at room temperature and is completed in 1 to 24 hours.
  • R is a hydrogen atom
  • compound (I) b is obtained by converting compound (I) a into an inert solvent , Hydrochloric acid or hydrobromic acid.
  • Hydrochloric acid or hydrobromic acid is usually used in an amount of 1 to 20 equivalents based on compound (I) a.
  • the inert solvent water, DMF, THF, toluene, dioxane, acetate nitrile and the like are used alone or in combination.
  • the reaction is usually performed at ⁇ 3 to 50 ° C., and is completed in 10 minutes to 1 hour.
  • Compound (I) b is prepared by reacting compound (A) with hydrochloric acid or hydrobromic acid in an inert solvent, and then reacting the corresponding carboxylic acid in an inert solvent in the presence of a condensing agent. Can also be manufactured.
  • Hydrochloric acid or hydrobromic acid is generally used in an amount of 1 to 20 equivalents based on compound (A).
  • the condensing agent include dicyclohexyl carpoimide (DCC), 1- (3-dimethylaminopropyl) 1-3-ethyl carpoimide or its hydrochloride, and usually 1 to compound (A). ⁇ 3 equivalents are used.
  • the inert solvent water, DMF, THF, toluene, dioxane, acetonitrile and the like are used alone or as a mixture. The reaction is usually performed at room temperature and is completed in 12 to 24 hours.
  • R is C0R la (where R la is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group).
  • c is a compound of DC (;, 1- (3-dimethylaminopropyl) —3-ethylcarboimide or a condensing agent such as hydrochloride thereof and compound (4-dimethylaminopyridine) in an inert solvent with compound (I) b.
  • R la CO 2 H wherein R ia has the same meaning as described above
  • R la C0 2 H a condensing agent and 4-dimethylaminopyridine are usually used in an amount of 1 to 10 equivalents to compound (I) b, respectively.
  • the inert solvent methylene chloride, chloroform, DMF, THurethane, toluene, dioxane, acetonitrile and the like are used alone or as a mixture. The reaction is usually carried out at -50 to 50 ° C, and is completed in 0 to 48 hours.
  • Compound (I) c can also be produced by reacting compound (I) b with a corresponding acid anhydride or acid halide in an inert solvent in the presence of a base.
  • R la , W and X are as defined above, and V represents chlorine, bromine or iodine.
  • the acid anhydride or acid halide is usually used in an amount of 1 to 10 equivalents based on compound (1) b.
  • a base potassium t-butoxy, triethylamine, pyridine, 4-dimethylaminopyridine, etc. is usually used in an amount of 1 to 10 equivalents to the compound (I) b, but when it also serves as a solvent, it is used in a large excess.
  • the inert solvent methylene chloride, chloroform, DMF, THF, toluene, dioxane, acetonitrile, pyridine and the like are used alone or as a mixture.
  • the reaction is usually performed at ⁇ 20 to 50 ° C., and is completed in 10 minutes to 10 hours.
  • R is C0R lb (where R lb is NR 2 R 3 (where R 2 and R 3 are as defined above) 0 ),
  • Compound (11) can be produced by reacting compound (I) b with p-nitrophenylchloroformate in an inert solvent in the presence of a base.
  • the p-nitrophenyl chloride form is usually used in an amount of 1 to 5 equivalents to the compound (I) b.
  • the base includes potassium t-butoxy, triethylamine, pyridine, 4-dimethylaminoviridine, and the like.
  • the compound (I) b is usually used for the compound (I) b,
  • the inert solvent methylene chloride, chloroform, pyridine, DMF, THF, toluene, dioxane and the like are used alone or as a mixture.
  • the reaction is usually performed at -80 to 50 t, and is completed in 10 minutes to 20 hours.
  • Compound (I) d can be produced by reacting Compound (HI) a with Compound (1) c.
  • R lc is NR 2 R 3 (wherein R 2 and R 3 are as defined above)
  • R 2 and R 3 are as defined above
  • Nf a NR 2 a R 3 a (wherein, a, R Z a and R 3 a is as defined above.) Represents, W and X Is as defined above. ]
  • the base includes triethylamine, pyridine, 4-dimethylaminopyridine and the like, and is usually used in an amount of 1 to 5 equivalents to the compound (11), but when used as a solvent, it is used in a large excess.
  • the inert solvent methylene chloride, chloroform, DMF, T111 ′′, toluene, dioxane, pyridine and the like are used alone or as a mixture.
  • the reaction is usually performed at -80 to 50 ° C, and is completed in 10 minutes to 24 hours.
  • R is C0R ld wherein K ′ d is OR 6 (wherein is as defined above).
  • C1 C0 2 R 6 can be used from 1 to 10 equivalents relative to the normal Compound (I) b.
  • Bases include t-butoxycar- ium, triethylamine, pyridine, and 4-dimethylaminopropyl.
  • Gin and the like which are usually used in an amount of about 5 to 5 equivalents to the compound (I) b, but are used in a large excess when they also serve as a solvent.
  • As the inert solvent methylene chloride, chloroform, DMF, THF, toluene, dioxane, pyridine and the like are used alone or as a mixture. The reaction is usually performed at -40 to 50 ° C, and is completed in 10 minutes to 10 hours.
  • the product in each of the above steps can be isolated and purified by a method used in ordinary organic synthesis. For example, after completion of the reaction in each step, if necessary, water, an acid, a buffer, an aqueous solution of sodium hydrogen carbonate, etc. are added to the reaction solution, and the mixture is extracted with a water-insoluble solvent such as ethyl acetate, chloroform, ether. .
  • a water-insoluble solvent such as ethyl acetate, chloroform, ether.
  • the extract is washed with water, aqueous sodium hydrogen carbonate, saline, etc., dried over anhydrous sodium sulfate, etc., and the residue obtained after evaporation of the solvent is subjected to column chromatography using silica gel, Purify by layer chromatography, high-performance liquid preparative chromatography, recrystallization, etc.
  • compound (I) when it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, the compound may be purified as it is, and when compound (I) is obtained in a free form, compound (I) may be purified using an appropriate solvent.
  • the salt may be formed by dissolving or suspending in water and adding an appropriate acid.
  • reaction intermediate can be used in the next step without isolation and purification.
  • Compound (I) or a pharmacologically acceptable salt thereof may be present in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Further, all possible isomers including the optically active form of compound (I) and mixtures thereof are also included in the present invention.
  • Table 1 shows the structures and compound numbers of typical compounds belonging to compound (I), and Table 2 shows their starting compounds.
  • Me and Boc represent methyl and t-butoxycarbonyl, respectively.
  • Test example 1 He La S 3 cell growth inhibition test
  • Test Example 2 Therapeutic effect on sarcoma 180 tumor
  • 5x10 sarcoma 180 tumors were implanted subcutaneously in the axillary region in five i-groups of male ddY mice weighing 18 to 20 g. After transplantation, 0.2 ml of physiological saline containing Compound (I) at the concentrations shown in Table 1 was administered intravenously. 7 days after transplantation, C / C [T: mean tumor volume of test group (mm 3 ), C: mean tumor volume (mm 3 ) of control group (intravenous saline 0.2 ml)] It was measured.
  • mice Each drug was administered once into the tail vein of male ddY mice (body weight 20 ⁇ lg) in the same amount as in Test Example 2, and blood was collected from the orbital venous plexus of the mice 7 days later.
  • the platelet count was measured with a microcell counter -CC-180A (Toa Medical Electronics), and the platelet count in mice without drug administration relative to the control (%)
  • Compound (I) or a pharmacologically acceptable salt thereof can be used alone or together with at least one pharmaceutically acceptable adjuvant as an antitumor composition.
  • the compound (I) or a salt thereof is dissolved in an aqueous solution of physiological saline, glucose, lactose, mannitol, or the like to prepare a pharmaceutical composition suitable for injection, or the compound (1) or a salt thereof. Is freeze-dried according to a conventional method, and sodium chloride is added thereto to prepare a powder injection.
  • the present pharmaceutical composition can contain additives known in the pharmaceutical field, for example, pharmaceutically acceptable salts and the like, if necessary.
  • the dose of this composition varies depending on the age, symptoms, etc. of the patient, but is administered as 0.001 to lmg / kg / day as compound (I) to mammals including humans. Dosing may be, for example, once a day (single dose or continuous dose) or intermittently i-! Once or twice a week, administer 1 ⁇ intravenous injection.
  • intravenous administration, intraperitoneal administration, intrathoracic administration, and the like can be performed in the same dosage and administration form.
  • oral administration is possible in the same dosage and administration form.
  • Oral dosage forms include tablets, capsules, powders, granules, ampoules and the like, which include pharmaceutical auxiliaries well known in the art of manufacture.
  • silica gel plate Silicagel 60F2i JS 0.5 mm 20 x 20 cm
  • Merck silica gel for column chromatography
  • the port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • the port-form layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • the pore-form layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 24 mg of an amino compound.
  • the chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • the obtained crude product was purified by silica gel chromatography (chloroform) to obtain 842 mg of Compound a (yield 94%).
  • the obtained crude product was purified by silica gel chromatography (hexane: ethyl acetate-10: 1) to obtain 544 mg (yield 67%) of 1-ethoxymethyl-4-methoxythiophene.
  • 10 ml of methanol and 4 ml of 4N hydrochloric acid were added to 496 mg (2.29 mmol) of 2-methoxyethoxy-4-methoxythiophene, and the mixture was stirred at room temperature for 30 minutes.
  • 0.5 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • CT0 3 of 348 mg (3.48 mmol) in pyridine 1.51ml was added and ⁇ 20 minutes at room temperature.
  • To this reaction solution was added 2 ml of methylene chloride, and a solution of 276 mg (l.16 ol) of 2-hydroxymethyl_5,6,7-trimethoxyindole in methylene chloride was added, followed by stirring at 0 ° C to room temperature for 17 hours. .
  • 0.5 N hydrochloric acid was added to the reaction mixture, followed by filtration.
  • 0.5 N hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate.
  • a DC-89 derivative or a pharmacologically acceptable salt thereof which exhibits excellent antitumor activity and is useful as an antitumor agent, is provided.

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

Abstract

Dérivés de DC-89 de formule générale (I) ou sels pharmaceutiquement acceptables desdits dérivés. Dans ladite formule, la formule (II) représente la formule (III) ou (IV) dans lesquelles X représente Cl ou Br et R représente hydrogène ou COR1 et W représente la formule (V) ou (VI). Du fait de leurs excellents effets antitumoraux, ces composés sont utiles en tant qu'agents antitumoraux.
PCT/JP1997/002516 1996-07-23 1997-07-22 Derives de dc-89 Ceased WO1998003509A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34631/97A AU3463197A (en) 1996-07-23 1997-07-22 Dc-89 derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP19263496 1996-07-23
JP8/192634 1996-07-23

Publications (1)

Publication Number Publication Date
WO1998003509A1 true WO1998003509A1 (fr) 1998-01-29

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PCT/JP1997/002516 Ceased WO1998003509A1 (fr) 1996-07-23 1997-07-22 Derives de dc-89

Country Status (2)

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AU (1) AU3463197A (fr)
WO (1) WO1998003509A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000058312A1 (fr) * 1999-03-26 2000-10-05 Japan Science And Technology Corporation Composes capables de cliver la double helice d'adn et mode d'utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03128379A (ja) * 1989-07-03 1991-05-31 Kyowa Hakko Kogyo Co Ltd Ｄｃ―８８ａ誘導体
JPH06116269A (ja) * 1992-08-21 1994-04-26 Kyorin Pharmaceut Co Ltd トリフルオロメチルピロロインドールカルボン酸エステル誘導体及びその製造方法
WO1996010405A1 (fr) * 1994-09-30 1996-04-11 Kyowa Hakko Kogyo Co., Ltd. Agent antitumoral

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03128379A (ja) * 1989-07-03 1991-05-31 Kyowa Hakko Kogyo Co Ltd Ｄｃ―８８ａ誘導体
JPH06116269A (ja) * 1992-08-21 1994-04-26 Kyorin Pharmaceut Co Ltd トリフルオロメチルピロロインドールカルボン酸エステル誘導体及びその製造方法
WO1996010405A1 (fr) * 1994-09-30 1996-04-11 Kyowa Hakko Kogyo Co., Ltd. Agent antitumoral

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000058312A1 (fr) * 1999-03-26 2000-10-05 Japan Science And Technology Corporation Composes capables de cliver la double helice d'adn et mode d'utilisation

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