WO1996004293A1 - Indolopyrrolocarbazoles antitumoraux - Google Patents

Indolopyrrolocarbazoles antitumoraux Download PDF

Info

Publication number
WO1996004293A1
WO1996004293A1 PCT/JP1995/001490 JP9501490W WO9604293A1 WO 1996004293 A1 WO1996004293 A1 WO 1996004293A1 JP 9501490 W JP9501490 W JP 9501490W WO 9604293 A1 WO9604293 A1 WO 9604293A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
amino
compound
lower alkyl
hydroxy
Prior art date
Application number
PCT/JP1995/001490
Other languages
English (en)
Japanese (ja)
Inventor
Katsuhisa Kojiri
Haruki Shimokawa
Mitsuru Ohkubo
Kenji Kawamura
Hisao Kondo
Hiroharu Arakawa
Hiroyuki Suda
Original Assignee
Banyu Pharmaceutical 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 Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to AU30864/95A priority Critical patent/AU3086495A/en
Publication of WO1996004293A1 publication Critical patent/WO1996004293A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates

Definitions

  • the present invention is useful in the field of medicine, and more specifically, a novel group of compounds having an antitumor effect by inhibiting the growth of tumor cells, a method for producing the same, a use thereof, and a microorganism used for producing the compound. It is about.
  • the present inventors have conducted research on antitumor substances and found that a novel antitumor substance, BE-13793C (12,13-dihydro-1,11-dihydroxy-15H-indolo, 2,3-a] pyro-mouth [3,4-c] potassium-5,7 (6H) dione) and disclosed in the earlier patent application (Japanese Patent Application Laid-Open No. 3-20277) "The Journal J. Antibiotics, Vol. 4, pp. 73-72
  • BE-13793C was chemically modified to create a compound with even better antitumor activity.
  • the indolopyrrolocarbazole-based compounds disclosed in “The Journal of Antibiotics, Vol. 45, pp. 1797-1798 (1992)” have a monosaccharide group.
  • the present invention provides a disaccharide-based indopyrrololocarbazole derivative having a disaccharide group and exhibiting excellent antitumor properties.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a novel compound obtained by introducing a disaccharide group into an indolopyrrolocarbazole compound exhibits excellent antitumor activity. completed. That is, the present invention relates to the general formula [1]
  • X ′ and X 2 each independently represent a hydrogen atom, a halogen atom, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a hydroxy group, a lower alkoxy group, an aralkoxy group, a carboxyl group, a lower alkoxycarbo.
  • R 1 represents a hydrogen atom, an amino group, a formylamino group, a lower alkyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group or a lower alkyl group which may be substituted with one or two hydroquine groups.
  • Alkanoylamino group mono-lower alkylamino group, di-lower alkylamino group, hydroquine group, lower alkoxy group, aralkoxy group, aralkyl group, lower alkylcarbonyl group, arylcarbonyl group or lower alkyl group (the lower alkanoyl group)
  • Lamino group, mono-lower alkylamino group, di-lower alkylamino , Lower alkoxy, aralkyloxy, aralkyl, lower alkylcarbonyl, arylcarbonyl and lower alkyl are carboxyl, carbamoyl, sulfo, amino, cyano, mono-lower alkylamino , May be substituted by a lower alkylamino group, a hydroxy group, 1 to 3 hydroxy groups or 1 to 3 hydroxy groups! ⁇ , May have a lower alkyl group, t may be a heterocyclic ring
  • R 2 represents a dis
  • lower means that the group or compound to which this term is attached has 6 or less, preferably 4 or less carbon atoms.
  • a lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, tert-butyl group, pentyl group, Examples include an isopentyl group, a neopentyl group, and a hexyl group.
  • the mono-lower alkylamino group is an amino group having one linear or branched alkyl group having 1 to 6 carbon atoms.
  • the di-lower alkylamino group is an amino group having two linear or branched alkyl groups having 1 to 6 carbon atoms.
  • the lower alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec. —Butyloxy group, tert-butyloxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, hexyloxy group and the like.
  • aralkoxy group examples include a benzyloxy group, a phenethyloxy group, a phenylpropoxy group, a / S-naphthylmethoxy group, a naphthylethoxy group, and a tetrahydronaphthylmethoxy group.
  • a lower alkoxy group is a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxy.
  • a lower alkoxy group is a straight-chain or branched chain having 1 to 6 carbon atoms. It is a lucanyloxy group.
  • a pentylcarbonyloxy group an isopentylcarbonyloxy group, a neopentylcarboxyloxy group, a hexylcarboxyloxy group, and the like.
  • the lower alkanoylamino group is a linear or branched alkanoylamino group having 1 to 6 carbon atoms.
  • Examples include a mino group, a pentylcarbonylamino group, an isopentylcarbonylamino group, a neobentylcarbonylamino group, and a hexylcarbonylamino group.
  • aralkyl group examples include a benzyl group, a phenethyl group, a phenylpropyl group, a / 3-naphthylmethyl group, a naphthylethyl group, and a tetrahydronaphthylmethyl group.
  • the lower alkylcarbonyl group is a carbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms.
  • benzylcarbonyl group examples include a benzoinole group and a ⁇ -10-phenylcarbonyl group.
  • a heterocyclic group refers to a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a sulfur atom, a nitrogen atom and an oxygen atom, and includes, for example, a furanyl group, a pyrrolinyl group, an oxazolinyl group, and an imidazolinyl group. Group, chenyl group, thiazolinyl group and the like.
  • Halogen atom means fluorine atom, chlorine atom, bromine atom and iodine atom.
  • the disaccharide group means a substituent in which two pentoses or hexoses are bonded by a glycosyl bond, and the hydroxyl group of these monosaccharide groups is a hydrogen atom, a lower alkyl group, a lower alkylcarbonyloxy group, a lower alkoxy group.
  • these constituent sugars include ribose, arabinose, xylose, 2 -Deoxyribose and sugars derived from these pentoses, such as sugars derived from arose, altrose, glucose, mannose, growth, idose, galactose, talose and hexoses thereof, and glucose is preferred.
  • the disaccharide group is maltosyl group, Xylobilanosyl ribofura Sill group, glucopyranosylthio Ruri Bofuranoshiru group, easy Tobiranoshiru group, can a child illustrate cellobiose O Vila mannosyl group, maltosyl group is particularly preferred.
  • the compound of the present invention can be prepared by using a microorganism
  • R 3 represents a hydrogen atom, a lower alkyl group, a benzyloxymethyl group or an aralkyl group, and X 1 and X 2 have the above-mentioned meanings.
  • the compound represented by the general formula [1] can be produced by deriving a compound other than a hydrogen atom among the compounds represented by the general formula [1], if necessary, by the following production method.
  • the microorganism that can be used in the present invention may be any microorganism to which a disaccharide group can be added.Examples include Saccharothrixaerocol on igenes ATCC 39243 strain and the like. Can be used.
  • the medium When converting compound [2] to compound [1] -a, the medium is inoculated into a nutrient-containing medium and grown aerobically.
  • a nutrient source a known nutrient source for actinomycetes can be used.
  • a carbon source commercially available glucose, maltose, starch, sucrose, molasses, dextrin, or the like is used alone or as a mixture.
  • Nitrogen sources include commercially available soy flour, corn steep liquor, meat extract, yeast extract, dried yeast, cottonseed flour, peptone, wheat germ, fish meal, meat meal, defatted rice flour, defatted meat-and-bone meal, and inorganic ammonia.
  • Salts or sodium nitrate are used alone or as a mixture.
  • the inorganic salt commercially available calcium carbonate, sodium chloride, potassium chloride, magnesium sulfate, sodium bromide, sodium borate, various phosphates and the like can be used.
  • a trace amount of a heavy metal salt such as iron, manganese, zinc, cono-chelate, and molybdic acid can be added.
  • a defoaming agent such as vegetable oils such as soybean oil or linseed oil, higher alcohols such as octadecanol, and various silicon compounds may be appropriately added.
  • any of those which are useful for the growth by utilizing the producing bacteria for example, 3- (N-morpholino) propanesulfonic acid or sodium borate can be used.
  • the culturing method may be the same as the method for producing general microbial metabolites, and may be either solid culture or liquid culture.
  • any of stationary culture, stirring culture, shaking culture or aeration culture may be performed, but shake culture or deep aeration stirring culture is particularly desirable.
  • the culture temperature is suitably from 20 to 37 ° C, preferably from 25 to 30 ° C.
  • the preferred pH of the medium is in the range of 4 to 8, and the culture period is 2 to 20 days, preferably 4 to 15 days.
  • Culture In order to collect the desired compound represented by the general formula [1] a from the nutrient, a separation means usually used for collecting from metabolites produced by microorganisms is appropriately used.
  • the compound represented by the general formula [1] -a is present in the culture killed liquid and in the cells, a usual separation method from the cultured liquid or the cells, for example, the solvent extraction method, the ion exchange resin method or the adsorption is used.
  • the protein can be purified by a single method or a combination of a method of distribution chromatography and a gel method, and the like.
  • Preferred examples of separation and purification include the following methods. First, the culture solution is filtered to obtain bacterial cells. The obtained cells are extracted with an organic solvent such as methanol or acetone. The compound represented by the general formula [1] 1a can be obtained by subjecting the obtained crude extract to silica gel chromatography or the like.
  • the mutant strain of the microorganism having the ability to add a disaccharide group according to the present invention may be, for example, irradiated with X-ray or ultraviolet light, for example, nitrodine mustard, azaserine, nitrite, 2-aminobulin or N-aminobulin.
  • —Methyl-N ′ nitro—N-2-nitrosoguanidine (NTG) or other disaccharide groups can be obtained by commonly used bacterial species conversion methods such as treatment with a mutagen, phage contact, morphology, transformation transduction, or conjugation.
  • R 1 has the meaning described above]
  • the compound is produced by removing a protecting group as necessary.
  • the compound is converted to a compound [3] or a functional group-protected derivative thereof. Reacting hydrazine to produce a compound represented by the general formula [1] according to claim 1, wherein R 1 is an amino group;
  • It can be produced by aralkylating or alkylating the moiety represented by N-OH and, if necessary, removing a protecting group.
  • a compound in which A is an oxygen atom can be obtained by treating a compound in which A is -NR 3 -with a base, for example, by the method shown in (1) of Example 2.
  • Compound [4] can be a commercially available product, or can be produced by a known method.
  • the reaction between the compound represented by the general formula [3] or the functional group-protected derivative thereof and the compound represented by the general formula [4] is performed by using an imide or an acid anhydride widely known in the field of chemistry. Reaction with hydrazine derivatives, hydroxyylamines, alkoxyamines or lower alkylamines. This reaction is a compound
  • the compound [4] may be reacted directly with the compound [4] without solvent, but a solvent that does not adversely influence the reaction, for example, tetrahydrofuran or the like may be used as a reaction solvent.
  • a solvent that does not adversely influence the reaction for example, tetrahydrofuran or the like
  • the amount of compound [4] to be used in the reaction can be generally used in a small excess to a large excess with respect to compound [3] or a functional group-protected derivative thereof. In such a case, it is preferable to use an excess of 10 to 20 equivalents.
  • the reaction temperature is usually in the range of about 150 to about 50 ° C, and a higher or lower temperature can be selected as necessary.
  • the reaction time is usually in the range of 30 minutes to about 2 days, but a longer or shorter time can be selected as necessary.
  • the formylation of the formula N—NH 2 in the compound represented by the general formula [1] thus obtained can be carried out by a method usually used in formylation of an amino group, for example, formic acid, formamide
  • the reaction can be carried out by heating with dimethylformamide, dimethylformamide or the like, or by reacting a mixture of formic acid and an acid anhydride in a solvent that does not adversely affect the reaction or without a solvent.
  • the reaction temperature is usually about 1% when formylating with a mixture of formic acid and acid anhydride.
  • the reaction is carried out within the range of 5 C to room temperature, but may be carried out in a range of more or less as necessary.
  • the reaction time is usually from 10 minutes to about 5 hours, but if necessary. More or less time may be selected.
  • the lower alkanoylation can be carried out by a method of reacting a corresponding carboxylic acid halide or acid anhydride without a solvent or in a suitable solvent.
  • the reaction temperature is usually in the range of about ⁇ 5 ° C. to the boiling point of the solvent, but may be higher or lower as necessary.
  • the acid halide or acid anhydride is generally represented by the general formula wherein R 1 is an amino group
  • reaction time is usually about 30 minutes to about 2 days.
  • the alkylation reaction of the compound of the general formula [1] in which R ′ is an amino group can be carried out by a known method, for example, a reaction with an alkyl halide, an alkyl mesylate or an alkyl tosylate, or condensation with an aldehyde compound or a ketone compound. It can be performed by a reduction reaction or the like.
  • the aralkylation reaction of the compound of the general formula [1] in which R ′ is an amino group is as follows: It can be carried out in the same manner as in the alkylation reaction.
  • a of the compound represented by the general formula [3], wherein A is —NH— can be aralkylated, alkanoylated, arylcarbonylated or alkylated by a similar method.
  • the compound of the formula [1], wherein R 1 is an aralkyl group, a lower alkanol group, an arylcarbonyl group or a lower alkyl group, can be produced.
  • the product of the above reaction can be purified by a known method in the field of organic chemistry, for example, a precipitation method, a solvent extraction method, a recrystallization, a chromatography method, or the like.
  • a disaccharide group can be introduced into indole rubazole also by applying a method of chemically introducing various monosaccharide groups into indole rubazole. That is, the compound represented by the general formula [2] of the present invention or the compound B- [2] in which the functional group is protected is represented by the general formula [5]
  • Z represents a leaving group and R 2 has the above-mentioned meaning] or a compound B- [5] in which the functional group is protected, and if necessary, is formed. This is achieved by removing protecting groups in the product.
  • a suitable base for example, a solvent such as methanol, ethanol, propanol, acetone, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide or a mixture of these solvents can be used.
  • Suitable bases for use in the reaction include, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc. Examples include alkali metal hydroxides such as lithium metal carbonate, sodium hydroxide and potassium hydroxide, and alkali metal hydrides such as sodium hydride and lithium hydride.
  • compound [2] or compound B- [2] is usually reacted with compound [ 1 to 3 mol of 5] or B— [5] is used, but the amount of the compound [5] or B— [5] can be less than or more than that if necessary.
  • the amount of the base used in the reaction may be an equimolar amount or an excess amount with respect to the starting compound, but usually 1 to 4 mol.
  • the reaction temperature ranges from 0 ° C to the boiling point of the solvent.
  • the reaction time is not particularly limited, but is usually 30 minutes to 24 hours.
  • nitrogen gas, argon gas, etc. if necessary
  • the introduction and elimination of the protecting group may be carried out by a method commonly used in the field of chemistry [Green, Protective Group Sin Organic Chemistry, John See Weiley and Sons (1991) (see TW Greene, Plective Lr roupsin Organic Synthesis, John Wiley & Sons, 1981).
  • the production method using microorganisms is more industrially advantageous because a disaccharide group can be efficiently introduced into an indololulbazole compound without the steps of protection and deprotection required by a chemical method.
  • the antitumor activity test against mouse leukemia cell P388 was performed by dissolving the sample in dimethylsulfoxide, serially diluting it with dimethylsulfoxide, and placing it in RPMI 1640 medium containing 10% fetal calf serum (containing 2 OmM 2-mercaptoethanol). In addition, a test solution was prepared.
  • X 1 0 3 cells culture medium containing tumor cells fetal bovine serum 1 0% content P RM I 1 640 medium, containing the 2 Omm 2-mercapto Bok ethanol
  • test sample was dissolved in dimethyl sulfoxide, then serially diluted with dimethyl sulfoxide, and added to RPM11640 medium containing 10% fetal calf serum to prepare a test solution.
  • RPM11640 medium containing 10% fetal calf serum
  • the antitumor activity of the compound of the present invention on human cancer cells was tested in vitro.
  • the cells used were human lung cancer cells PC-13 and human gastric cancer cells MKN-45, and the cell culture medium used was RPMI 1640 medium containing 10% fetal calf serum for all cancer cells. It was measured using the same method as the antitumor test for co1on26.
  • the compound of the present invention exhibited a strong growth inhibitory activity against mouse and human cancer cells, and the 50% growth inhibitory concentration (IC 5 ) was as shown in Table 1.
  • IC 5 50% growth inhibitory concentration
  • Table 1 Antitumor activity of the compound of the present invention (50% growth inhibitory concentration (M)) fens QRR * olnn PC-I MKN-45 Compound of Example 1 0.037 0.22
  • the compound of the present invention is commonly used as an indicator of anti-cancer effects
  • the compound exhibited an effect on P388 cancer cells more than that of the control compound having a monosaccharide group.
  • the compound of the present invention is a novel compound showing an excellent effect as an anticancer agent.
  • R 4 is a maltosyl group
  • Solubility Easily soluble in dimethylsulfoxide and tetrahydrofuran, slightly soluble in methanol and acetone, slightly soluble in chloroform and hexane. Distinguishing between acidic, neutral and basic substances: acidic
  • R 4 represents a maltosyl group
  • Example 1 129 mg of the compound obtained in Example 1 was dissolved in 4.5 ml of a 2N aqueous solution of potassium hydroxide, and the mixture was stirred at room temperature for 1.5 hours. The mixture was partitioned by adding 50 ml of 2N hydrochloric acid saturated with 50 ml of non-salt and sodium chloride. The aqueous layer was extracted with 2-butanone, and the combined organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained yellow-brown solid was suspended in methanol, and getyl ether and n-hexane were added. The insoluble material was removed to give 213.6 mg of the title compound.
  • R 4 represents a maltosyl group
  • Example 2 1 mg of the compound obtained in Example 1 was dissolved in hydrazine monohydrate 401 and stirred at room temperature for 1 hour. After adding 1 ml of water and adjusting the pH to 7 with concentrated hydrochloric acid, a precipitate was formed. The precipitate was washed with water and dried.
  • R 5 represents one D-xylobyranosyl-D-ribofuranosyl group.
  • R 6 is a compound of D-xylobyranosyl- ⁇ — D-ribofuranosyl group (1) 2,10-dibenzyloxy 12— [5-0— (2,3,4-tri—0—benzylyl ⁇ —D—xylobilanone) 1,2,3—0—isopropylidene—D—ribofuranosyl ] 1-Methylindolo [2,3-a] Pyro-mouth [3,4-c] Caproluvazole-5,7-dione
  • R 7 is ⁇ -D-glucoviranosyl- ⁇ -D-ribofuranosyl group
  • R 1P represents one D-glucoviranosyl group; one compound having an 8-D-ribofuranosyl group
  • R 11 is a compound of 1 meaning -D-lactoviranosyl group
  • Carbazole-5,7-dione 100 mg, silver oxide 84 Omg and molecular sieve 2 OOmg are suspended in 8 ml of toluene, and the mixture is heated under reflux for 0.5 hour, and then refluxed with 1-chloro-2,3. , 6, 2 ', 3', 4 ', 6' —Hepter 0—Vivaloylue D—Lactobyranoside 1.25 g 2 ml of a toluene solution of was added dropwise. After stirring for 2 hours, the reaction solution was filtered through celite and concentrated.
  • R is a compound of 1 meaning / 3-D-lactoviranosyl group
  • R 8 is / g—D—a maltoviranosyl group
  • Example 11 The compound of Example 11 was produced in the same manner as described in Example 10 using 3 ', 4', 6'-hepter 0-benzyl-5-D-maltoviranose.
  • Example 11 The compound of Example 11 was produced in the same manner as described in Example 10 using 3 ', 4', 6'-hepter 0-benzyl-5-D-maltoviranose.
  • R 8 represents / 3— D—maltoviranosyl group
  • Example 12 One hepter 0-benzyl-1-3-D-cellobiobilanose was used to produce the compound of Example 12 in the same manner as described in Example 10.
  • Example 12
  • R 9 represents -D-cellobiopyranosyl group
  • Rf value 0.05
  • B oc represents a t er t-butoxycarbonyl group; the same shall apply hereinafter).
  • Equation (4)
  • Equation (4) Production of the compound represented by
  • the compounds of the present invention show a remarkable growth inhibitory effect on mouse and human cancer cells. Therefore, the compounds of the present invention are useful as antitumor agents in mammals including humans.

Abstract

L'invention se rapporte à un composé représenté par la formule générale [1], ou à un sel pharmaceutiquement acceptable de celui-ci, et ayant un excellent effet antitumoral, et par conséquent pouvant être utilisé comme agent antitumoral. Dans cette formule, X1 et X2 représentent chacun, indépendamment, hydrogène, halogène, amino, mono(alkyle inférieur)amino, di(alkyle inférieur)amino, hydroxy, alcoxy inférieur, aralcoxy, carboxy, alcoxycarbonyle inférieur, alcanoyloxy inférieur ou alkyle inférieur qui peut être substitué par un ou deux groupes hydroxy; R1 représente hydrogène, amino, formylamino, alcanoylamino inférieur, mono(alkyle inférieur)amino, di(alkyle inférieur)amino, hydroxy, alcoxy inférieur, aralcoxy, aralkyle, alkylcarbonyle inférieur, arylcarbonyle ou alkyle inférieur (où alcanoylamino inférieur, mono(alkyle inférieur)amino, di(alkyle inférieur)amino, alcoxy inférieur, aralcoxy, aralkyle, alkylcarbonyle, arylcarbonyle et alkyle inférieur peuvent être substitués par un à cinq groupes sélectionnés parmi carboxy, carbamoyle, sulfo, amino, cyano, mono(alkyle inférieur)amino, di(alkyle inférieur)amino, hydroxy, un hétérocycle qui peut être substitué par un à trois groupes hydroxy ou par alkyle inférieur qui peut être substitué par un à trois groupes hydroxy, et des atomes d'halogène); et R2 représente un groupe disaccharide.
PCT/JP1995/001490 1994-08-02 1995-07-26 Indolopyrrolocarbazoles antitumoraux WO1996004293A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU30864/95A AU3086495A (en) 1994-08-02 1995-07-26 Antitumor indolopyrrolocarbazoles

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP20011094 1994-08-02
JP6/200110 1994-08-02

Publications (1)

Publication Number Publication Date
WO1996004293A1 true WO1996004293A1 (fr) 1996-02-15

Family

ID=16419001

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001490 WO1996004293A1 (fr) 1994-08-02 1995-07-26 Indolopyrrolocarbazoles antitumoraux

Country Status (2)

Country Link
AU (1) AU3086495A (fr)
WO (1) WO1996004293A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2337702A (en) * 1998-05-29 1999-12-01 Merck Sharp & Dohme The use of staurosporine analogues for enhancing neurotrophin activity
EP0971717A1 (fr) * 1996-08-22 2000-01-19 Bristol-Myers Squibb Company Aminosucre cytotoxique et derives de sucre associes d'indolopyrrolocarbazoles
US6271370B1 (en) * 1999-05-11 2001-08-07 Pfizer Inc Process for the synthesis of nucleoside analogs
WO2001062769A1 (fr) * 2000-02-24 2001-08-30 Banyu Pharmaceutical Co., Ltd. Procede de preparation de derives d'indolopyrrolocarbazole, leurs intermediaires, et procede de preparation des intermediaires
EP0760375A4 (fr) * 1994-05-09 2002-03-27 Banyu Pharma Co Ltd Derive d'indolopyrolocarbazole antitumoral
US6605596B2 (en) 2000-10-31 2003-08-12 Advanced Life Sciences, Inc. Indolocarbazole anticancer agents and methods of using them
US6610727B2 (en) 2000-10-06 2003-08-26 Bristol-Myers Squibb Company Anhydro sugar derivatives of indolocarbazoles
US6653290B2 (en) 2000-10-06 2003-11-25 Bristol-Myers Squibb Company Tumor proliferation inhibitors
US6677450B2 (en) 2000-10-06 2004-01-13 Bristol-Myers Squibb Company Topoisomerase inhibitors
US6703373B1 (en) 1999-09-10 2004-03-09 Banyu Pharmaceutical Co., Ltd. Indolopyrrolocarbazole derivatives and antitumor agents
US6855698B2 (en) 2001-03-22 2005-02-15 Bristol-Myers Squibb Company Topoisomerase I selective cytotoxic sugar derivatives of indolopyrrolocarbazoles
WO2005026185A1 (fr) * 2003-09-16 2005-03-24 Banyu Pharmaceutical Co., Ltd. Nouveau derive d'indolopyrrolocarbazole a active anti-tumeur
US7122526B2 (en) 2000-10-31 2006-10-17 Nanosphere, Inc. Indolocarbazole anticancer agents and methods of using same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06128283A (ja) * 1991-11-29 1994-05-10 Banyu Pharmaceut Co Ltd 抗腫瘍性インドロピロロカルバゾール誘導体
JPH06296494A (ja) * 1992-12-14 1994-10-25 Banyu Pharmaceut Co Ltd インドロピロロカルバゾール誘導体の製造法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06128283A (ja) * 1991-11-29 1994-05-10 Banyu Pharmaceut Co Ltd 抗腫瘍性インドロピロロカルバゾール誘導体
JPH06296494A (ja) * 1992-12-14 1994-10-25 Banyu Pharmaceut Co Ltd インドロピロロカルバゾール誘導体の製造法

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0760375A4 (fr) * 1994-05-09 2002-03-27 Banyu Pharma Co Ltd Derive d'indolopyrolocarbazole antitumoral
EP0971717A1 (fr) * 1996-08-22 2000-01-19 Bristol-Myers Squibb Company Aminosucre cytotoxique et derives de sucre associes d'indolopyrrolocarbazoles
EP0971717A4 (fr) * 1996-08-22 2000-04-12 Bristol Myers Squibb Co Aminosucre cytotoxique et derives de sucre associes d'indolopyrrolocarbazoles
GB2337702A (en) * 1998-05-29 1999-12-01 Merck Sharp & Dohme The use of staurosporine analogues for enhancing neurotrophin activity
US6271370B1 (en) * 1999-05-11 2001-08-07 Pfizer Inc Process for the synthesis of nucleoside analogs
US6703373B1 (en) 1999-09-10 2004-03-09 Banyu Pharmaceutical Co., Ltd. Indolopyrrolocarbazole derivatives and antitumor agents
US6790836B2 (en) 2000-02-24 2004-09-14 Banyu Pharmaceutical Co., Ltd. Process for preparing indolopyrrolocarbazole derivatives, intermediates therefor, and preparation process of the intermediates
WO2001062769A1 (fr) * 2000-02-24 2001-08-30 Banyu Pharmaceutical Co., Ltd. Procede de preparation de derives d'indolopyrrolocarbazole, leurs intermediaires, et procede de preparation des intermediaires
US6610727B2 (en) 2000-10-06 2003-08-26 Bristol-Myers Squibb Company Anhydro sugar derivatives of indolocarbazoles
US6653290B2 (en) 2000-10-06 2003-11-25 Bristol-Myers Squibb Company Tumor proliferation inhibitors
US6677450B2 (en) 2000-10-06 2004-01-13 Bristol-Myers Squibb Company Topoisomerase inhibitors
US6686385B2 (en) 2000-10-06 2004-02-03 Bristol-Myers Squibb Company Anhydro sugar derivatives of indolocarbazoles
US7138377B2 (en) 2000-10-06 2006-11-21 Bristol-Myers Squibb Company Topoisomerase inhibitors
US6605596B2 (en) 2000-10-31 2003-08-12 Advanced Life Sciences, Inc. Indolocarbazole anticancer agents and methods of using them
US7122526B2 (en) 2000-10-31 2006-10-17 Nanosphere, Inc. Indolocarbazole anticancer agents and methods of using same
US6855698B2 (en) 2001-03-22 2005-02-15 Bristol-Myers Squibb Company Topoisomerase I selective cytotoxic sugar derivatives of indolopyrrolocarbazoles
WO2005026185A1 (fr) * 2003-09-16 2005-03-24 Banyu Pharmaceutical Co., Ltd. Nouveau derive d'indolopyrrolocarbazole a active anti-tumeur

Also Published As

Publication number Publication date
AU3086495A (en) 1996-03-04

Similar Documents

Publication Publication Date Title
CA2083534C (fr) Derives indolopyrrolocarbazole
He et al. Creation of 3, 4-bis-triazolocoumarin–sugar conjugates via flourogenic dual click chemistry and their quenching specificity with silver (I) in aqueous media
WO1996004293A1 (fr) Indolopyrrolocarbazoles antitumoraux
CA1315775C (fr) 4-demethoxy-4-aminoanthracyclines
EP0602597B1 (fr) Procédé de préparation de dérivés d'indolopyrrolocarbazole
CA1220149A (fr) Rebeccamycine et procede de preparation
US5589365A (en) Process for producing glycosylated indolopyrrolocarbazole derivatives by culturing certain microorganisms
Marminon et al. Syntheses and antiproliferative activities of rebeccamycin analogues bearing two 7-azaindole moieties
EP0528030B1 (fr) Derive antitumoral de be-13793c
US5437996A (en) Microtetraspora strain for preparation of indolopyrrolocarbazole derivatives
Messaoudi et al. Synthesis of bridged aza-rebeccamycin analogues
Maeba et al. C-nucleosides. 7. Preparation and utility of 6-hydroxy-6-(2, 3, 5-tri-O-benzoyl-. beta.-D-ribofuranosyl)-2H-pyran-3 (6H)-one as a key intermediate of C-nucleoside synthesis
Sabat et al. Synthesis, antiviral and antitumor activities investigations of a series of Ribavirin C-nucleoside analogue prodrugs
CN109912672B (zh) 一种以邻炔基苯酚醚作为离去基的碱基糖苷化的方法
RU2548045C1 (ru) N-ГЛИКОЗИДЫ ИНДОЛО[2,3-a]ПИРРОЛО[3,4-c]КАРБАЗОЛОВ, ОБЛАДАЮЩИЕ ПРОТИВООПУХОЛЕВОЙ АКТИВНОСТЬЮ
RU2427585C1 (ru) СПОСОБ ПОЛУЧЕНИЯ N-ГЛИКОЗИДОВ ИНДОЛО[2,3-а]ПИРРОЛО[3,4-с]КАРБАЗОЛ-5,7-ДИОНОВ, ОБЛАДАЮЩИХ ЦИТОТОКСИЧЕСКОЙ И ПРОТИВООПУХОЛЕВОЙ АКТИВНОСТЬЮ
KR101194908B1 (ko) 카프라젠, 그 유도체 및 이를 포함하는 제약학적 조성물
CA1296326C (fr) Derives de l'anthracycline presentant une activite cytostatique
Hénon et al. Synthesis of dipyrrolo [3, 4-a: 3, 4-c] carbazole-1, 3, 4, 6-tetraones bearing a sugar moiety
CN102125578B (zh) 具有抗癌活性的蝴蝶霉素类似物及合成方法
Koizumi et al. Synthesis and antimicrobial activity of 2′-deoxypuromycin
JP2004518633A (ja) 腫瘍増殖インヒビター
JP3038921B2 (ja) 抗腫瘍性インドロピロロカルバゾール誘導体
Baker et al. An evaluation of certain chain-extended analogs of 9-. beta.-D-arabinofuranosyladenine for antiviral and cardiovascular activity
JP2004524275A (ja) インドロカルバゾール化合物の無水糖誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES 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
NENP Non-entry into the national phase

Ref country code: CA