WO1998021202A1 - Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents - Google Patents
Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents Download PDFInfo
- Publication number
- WO1998021202A1 WO1998021202A1 PCT/EP1997/005986 EP9705986W WO9821202A1 WO 1998021202 A1 WO1998021202 A1 WO 1998021202A1 EP 9705986 W EP9705986 W EP 9705986W WO 9821202 A1 WO9821202 A1 WO 9821202A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carboxamido
- methyl
- pyrrole
- propionamidine
- chloroethyl
- Prior art date
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
- C07D403/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention refers to new alkylating antitumor and antiviral agents related to the known antibiotic distamycin A:
- DE-A-1795539 describes the preparation of distamycin derivatives in which the formyl group of distamycin is replaced by hydrogen or by the acid residue of an organic
- EP-B-246,868 describes distamycin analogues in which the distamycin formyl group is substituted by aromatic, alicyclic or heterocyclic moieties bearing alkylating groups .
- the present invention relates to new distamycin derivatives of formula (I) as defined hereinunder, to a process for preparing them, to pharmaceutical compositions containing them and to their use in therapy, particularly as antitumor and antiviral agents .
- object of the present invention are distamycin derivatives of formula:
- n 2, 3 or 4 ;
- A is 0, S or NR, wherein R is hydrogen or C 1 -C 4 alkyl; B is CH or N;
- R, and R 3 are selected, each independently, from: hydrogen, C- L -C 4 alkyl optionally substituted by one or more fluorine atoms, and C 1 -C 4 alkoxy; R 4 is C- L -C J alkyl or C ! -C 3 haloalkyl; X ⁇ is a halogen atom; and ( ⁇ )
- X 2 is a halogen atom; or pharmaceutically acceptable salts thereof.
- the present invention includes within its scope also all the possible isomers covered by formula (I) both separately and in admixture, as well as the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I) .
- the alkyl and alkoxy groups may have branched or straight chains.
- a C 1 -C 4 alkyl group is preferably methyl, ethyl or propyl, a alkoxy group is preferably methoxy or ethoxy, while a C x -C 3 haloalkyl group is preferably 2- chloroethyl or 2-bromoethyl .
- a C x -C 4 alkyl group is preferably a C 1 -C 4 perfluoroalkyl group, e.g. -CF 3 .
- the halogen atoms X x and X 2 are preferably chlorine or bromine. Particularly preferred values of n are 2 and 3.
- T is an alkylating moiety of formula (II) according to item (i) above with p equal to 1, the carboxamido group and the amino group on the phenyl ring are preferably in meta or para position with respect to each other, while R 2 and R 3 can be in any of the free positions.
- Pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable, either inorganic or organic, acids.
- inorganic acids are hydrochloric, hydrobromic, sulfuric and nitric acid
- organic acids are acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
- a preferred class of distamycin derivatives according to the present invention is the one of formula (I) wherein: n is 2 or 3; A is 0, S, NH or NCH 3 ; B is CH or N; R ⁇ is hydrogen;
- T is a group of formula (II) according to item (i) , wherein X ⁇ is chlorine or bromine; R 4 is ethyl, 2-chloroethyl or 2- bromoethyl; R 2 and R 3 are, each independently, hydrogen or methyl; p is zero or 1; or
- T is a group of formula (III) according to item (ii) , wherein X 2 is bromine or chlorine.
- Further object of the present invention is a process for preparing the compounds of formula (I), and the pharmaceutically acceptable salts thereof, which comprises: (1) (a) reacting a compound of formula:
- n 2, 3 or 4 , with a compound of formula:
- A is 0, S or NR, wherein R is hydrogen or C x -C 4 alkyl; B is CH or N;
- R 2 and R 3 are selected, each independently, from: hydrogen, C- L - alkyl optionally substituted by one or more fluorine atoms, and C 1 -C 4 alkoxy; R 4 is C J. -C 4 alkyl or C 1 -C 3 haloalkyl; X x is a halogen atom; and
- n, A, B, and R are defined as above, with a compound of formula: wherein X ⁇ l R 2 , R 3 , and R 4 are defined as above, and Y ⁇ is hydroxy or a leaving group; or with a compound of formula:
- reaction of a compound of formula (IV) with a compound of formula (V) can be carried out according to known methods, for instance those described in EP-B- 246,868.
- the reaction between a compound of formula (IV) and a compound of formula (V) wherein Y is hydroxy is preferably carried out with a molar ratio (IV) : (V) of from 1:1 to 1:2, in an organic solvent, such as, e.g., dimethylsulphoxide, dimethylacetamide, dimethylformamide, ethanol, benzene, or pyridine, in the presence of an organic or inorganic base such as, e.g., triethylamine, N,N' -diisopropylethylamine, or sodium or potassium carbonate or bicarbonate, and a condensing agent such as, e.g., N-ethyl-N' - (3-dimethyl aminopropyl) carbodiimide, N,N' -dicyclohexylcarbodiimide, or 1-hydroxybenzotriazole hydrate.
- the reaction temperature may vary from about -10°C to about 100°C, and the reaction time from about 1
- the reaction between a compound of formula (IV) and a compound of formula (V) , wherein Y is a leaving group as defined above, may be carried out with a molar ratio (IV) : (V) of from about 1:1 to about 1:2, in an organic solvent, such as, e.g., dimethylformamide, dioxane, pyridine, tetrahydrofurane, or mixtures thereof with water, optionally in the presence of an organic base, e.g. N,N'- diisopropylethylamine, triethylamine, or an inorganic base, e.g. sodium or potassium bicarbonate, at a temperature of from about 0°C to about 100°C, and for a time varying from about 2 hours to about 48 hours.
- an organic solvent such as, e.g., dimethylformamide, dioxane, pyridine, tetrahydrofurane, or mixtures thereof with water
- an organic base e.g. N
- the compounds of formula (IV) are known compounds, or may be prepared by known methods from known compounds: see, for instance, Arcamone et al . Gazzetta Chim. Ital . 91_, 1097 (1967) .
- the compounds of formula (V) wherein Y is hydroxy, and T is a group of formula (II) according to item (i) with p equal to 1, or a group of formula (III) according to item (ii) , can be prepared by reacting an amino compound of formula:
- A, B and R are as defined above, with a carboxylic acid, or a derivative thereof, of formula (Vila) or (Vllb) as defined above.
- the compounds of formula (V) wherein Y is hydroxy, and T is a group of formula (II) according to item (i) with p equal to zero, can be prepared by reacting a compound of formula :
- A, B, R x , and R 5 are defined as above, with ethylene oxide and then with a halogenating agent, analogously to what described above for process (c) .
- the carboxyl group is preferably protected with a suitable protecting group according to known techniques .
- the carboxylic acids of formulas (Vila) and (Vllb) , or the derivatives thereof, are commercially available products, or may be prepared through reactions well known in organic chemistry (see e.g. Tetrahedron Letters 3_1 1299 (1990),
- the compounds of formulas (X) and (XI) are commercial products, or can be obtained by known methods (see e.g. J.Am.Chem.Soc. .80., 4621 (1958), Helv. Chim.Acta 3_1, 75 (1948), Synth . Commun . 2_1, 959 (1991), Anti-cancer Drug Design 10, 25 (1995), J.Org.Chem. 2_6, 4996-97 (1961), or Synth . Commun . 2 . 4, 3129-3134 (1994)).
- the compounds of formula (VI) can be obtained by nitro- group reduction, according to known methods, of compounds of formula:
- n, A, B and R x are as defined above.
- A, B and R are as defined above, and Y 3 is hydroxy or a leaving group.
- the compounds of formula (XIII) are known compounds, or may be obtained by known methods (see, e.g., Tetrahedron Letters 3_1, 1299 (1990), Anti-cancer Drug Design 9 , 511 (1994)), JACS 62 . , 3495 (1940), J.Org.Chem. 26., 4996-97 (1963), or Synth . Commun . 24, 3129-3134 (1994)).
- the reaction according to process (c) can be carried out analogously to what described in U.S. Patent No. 4,738,980.
- the halogenating agent may be, e.g., an elemental halide, such as chlorine or bromine, or a thionyl halide, such as thionylchloride .
- the starting compounds of formula (VIII) may be obtained according to know reactions, e.g. by mono- alkylation of the amino-compounds of formula (VI) as defined above, optionally previously condensed with the corresponding amino benzoic acid, or a derivative thereof.
- the groups Y, Y 1( Y 2 , and Y 3 are hydroxy or leaving groups selected, for instance, from chloro, 2 , 4, 5-trichlorophenoxy, 2 , 4-dinitro-phenoxy, succinimido-N-oxy, imidazolyl, and the like.
- Salification of a compound of formula (I) may be carried out by known standard methods .
- Well known procedures such as, e.g., fractional crystallization or chromatography, may also be followed for separating a mixture of isomers of formula (I) into the single isomers .
- the compounds of formula (I) may be purified by conventional techniques such as, e.g., silica gel or alumina column chromatography, and/or by recrystallization from an organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide .
- an organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide .
- the compounds of formula (I) according to the present invention are useful as antineoplastic and antiviral agents. Particularly, they show cytostatic properties towards tumor cells, so that they can be useful to inhibit growth of various tumors in mammals, including humans, such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors .
- carcinomas e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors .
- Other neoplasias in which the compounds of the present invention can find application are, for instance, sarcomas, e.g. soft tissue and bone sarcomas, and the hematological malignancies such as, e.g. leukemias.
- the in vitro antitumor activity was evaluated by cytotoxicity studies carried out on murine L 1210 leukemia cells.
- Cells were derived from in vivo tumors and established in cell culture. Cells were used until the tenth passage. Cytotoxicity was determined by counting surviving cells after 48 hours treatment.
- IC 50 values concentration inhibiting 50% of the cellular growth in respect to controls
- the compounds of the invention were tested also in vivo on L 1210 murine leukemia and on murine reticulosarcoma M 5076, showing a very good antitumoral activity, with the following procedure .
- L 1210 murine leukemia was maintained in vivo by i.v. serial transplantation.
- 10 5 cells were injected i.p. in CD2F1 female mice, obtained from Charles River Italy. Animals were 8 to 10 weeks old at the beginning of the experiments. Compounds were administered i.v. at day +1 after tumor cells injections.
- M5076 reticulosarcoma was maintained in vivo by i.m. serial transplantation.
- 5x10 cells were injected i.m. in C57B16 female mice, obtained from Charles River Italy. Animals were 8 to 10 weeks old at the beginning of the experiments. Compounds were administered i.v. at day 3, 7 and 11 after tumor injection.
- T/C x 100 median survival time untreated group
- the compounds of the invention show also a remarkable effectiveness in interfering with the reproductive activity of pathogenic viruses and protect tissue cells from viral infections.
- they show activity against DNA viruses such as, for instance, herpes, e.g. herpes simplex and herpes zoster viruses, virus vaccinia, RNA viruses such as, e.g., Rhinovirus and Adenovirus, and against retroviruses such as, for instance, sarcoma viruses, e.g., murine sarcoma virus, and leukemia viruses, e.g. Friend leukemia virus .
- DNA viruses such as, for instance, herpes, e.g. herpes simplex and herpes zoster viruses, virus vaccinia, RNA viruses such as, e.g., Rhinovirus and Adenovirus, and against retroviruses such as, for instance,
- the compounds of the invention can be administered to mammals, including humans, through the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally.
- the dosage depends on the age, weight and conditions of the patient and on the administration route.
- a suitable dosage for administration to adult humans may range from about 0.1 to about 150-200 mg pro dose 1-4 times a day.
- compositions which comprise a compound of formula (I) as an active principle, in association with one or more pharmaceutically acceptable carrier and/or diluent.
- compositions of the present invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
- solutions for intravenous injection or infusion may contain as a carrier, for example, sterile water or preferably, they may be in the form of sterile aqueous isotonic saline solutions.
- Suspensions or solutions for intramuscular injections may contain, together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride .
- the active ingredient may be mixed with conventional oleaginous or emulsifying excipients .
- the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinyl- pyrrolidone; disaggregating agents, e.g.
- diluents e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch
- lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
- binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvin
- starch alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates ; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulation.
- Said pharmaceutical preparation may be manufactered by known techniques, for example by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.
- the present invention provides a method for treating tumors and viral infections in a patient in need of it, which comprises administering to said patient a composition of the invention.
- a further object of the present invention is a combined method for treating cancer or for ameliorating the conditions of mammals, including humans, suffering from cancer, said method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional antitumor agent, close enough in time and in amounts sufficient to produce a therapeutically useful effect .
- the present invention also provides products containing a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and an additional antitumour agent as a combined preparation for simultaneous, separate or sequential use in anti- cancer therapy.
- antitumor agent is meant to comprise both a single antitumor drug and "cocktails" i.e. a mixture of such drugs, according to the clinical practice.
- antitumor agents that can be formulated with a compound of formula (I) , or alternatively, can be administered in a combined method of treatment, include doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluoro- uracil, melphalan, cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin, and mitomycin, or mixtures thereof.
- Step I The intermediate 5-N,N-bis (2- chloroethyl) aminoindole-2-carboxylic acid
- ethyl 5-aminoindole-2- carboxylate prepared as reported in J.Am.Chem.Soc . 80, 4621 (1958)
- cold ethylene oxide 2.5 ml
- DMF dry dimethylformamide
- Step J The intermediate l-methyl-5- [4-N,N-bis (2- chloroethyl) aminobenzene-1-carboxamido] indole-2- carboxylic acid
- Step J The intermediate 3- [l-methyl-4- [l-methyl-4 [1- methyl-4 [4-nitrobenzothiophene-2- carboxamido] pyrrole-2 -carboxamido] pyrrole-2 - carboxamido] pyrrole-2 -carboxamido] propionamidine dihydrochloride
- 4-nitrobenzothiophene-2- carboxylic acid prepared as reported in Synth . Commun . 21, 959 (1991)
- the derivative (220 mg) obtained from Step I was dissolved in 10 ml of DMF and reduced over Pd catalyst (10% on charcoal) under reduced pres ⁇ ure (50 p ⁇ i) in a Parr apparatu ⁇ .
- the solution obtained after filtration of the catalyst was evaporated in vacuo and the ⁇ olid re ⁇ idue di ⁇ olved in 5 ml of dry DMF, cooled to 5°C and added with 0.055 ml of N,N' -dii ⁇ opropylethylamine.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97945879A EP0937070B1 (en) | 1996-11-11 | 1997-10-23 | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
JP52210098A JP2001504109A (en) | 1996-11-11 | 1997-10-23 | Benzoheterocyclic distamycin derivatives, processes for their preparation and their use as antitumor and antiviral agents |
US09/284,958 US6153642A (en) | 1996-11-11 | 1997-10-23 | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
DE1997626593 DE69726593T2 (en) | 1996-11-11 | 1997-10-23 | BENZOHETEROCYCLIC DISTAMYCINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS ANTITUMOR AND ANTIVIRAL AGENTS |
AU51216/98A AU5121698A (en) | 1996-11-11 | 1997-10-23 | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
CA002271299A CA2271299A1 (en) | 1996-11-11 | 1997-10-23 | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9623522.1A GB9623522D0 (en) | 1996-11-11 | 1996-11-11 | Benzoheterocycle distamycin derivatives process for preparing them and their use as antitumour and antiviral agents |
GB9623522.1 | 1996-11-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998021202A1 true WO1998021202A1 (en) | 1998-05-22 |
Family
ID=10802813
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/005986 WO1998021202A1 (en) | 1996-11-11 | 1997-10-23 | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
Country Status (11)
Country | Link |
---|---|
US (1) | US6153642A (en) |
EP (1) | EP0937070B1 (en) |
JP (1) | JP2001504109A (en) |
AR (1) | AR009413A1 (en) |
AU (1) | AU5121698A (en) |
CA (1) | CA2271299A1 (en) |
DE (1) | DE69726593T2 (en) |
ES (1) | ES2212138T3 (en) |
GB (1) | GB9623522D0 (en) |
WO (1) | WO1998021202A1 (en) |
ZA (1) | ZA979997B (en) |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999050266A1 (en) * | 1998-03-27 | 1999-10-07 | Pharmacia & Upjohn S.P.A. | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents |
WO2001085144A2 (en) * | 2000-05-08 | 2001-11-15 | Pharmacia Italia S.P.A. | Use of substituted acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione |
WO2001097618A2 (en) * | 2000-06-23 | 2001-12-27 | Pharmacia Italia S.P.A. | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites |
WO2001097790A2 (en) * | 2000-06-23 | 2001-12-27 | Pharmacia Italia S.P.A. | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and alkylating agents |
WO2001097789A2 (en) * | 2000-06-23 | 2001-12-27 | Pharmacia Italia S.P.A. | Pharmaceutical compositions comprising acryloyl distamycin derivatives and topoisomerase i and ii inhibitors |
WO2002022655A1 (en) * | 2000-09-15 | 2002-03-21 | Pharmacia Italia S.P.A. | Glutathione conjugates with distamycin derivatives having antitumoral activity |
JP2002536345A (en) * | 1999-02-04 | 2002-10-29 | ジョルン ブラーディーク | Formulation for preventing and / or treating mesenchymal-derived tissue change |
WO2003004019A1 (en) * | 2001-07-02 | 2003-01-16 | Universita' Degli Studi Di Ferrara | Use of heterocyclic and benzoheterocyclic polyamides structurally related to the natural antibiotic distamycin a for the treatment of beta-thalassaemia |
US6559125B1 (en) | 2000-01-28 | 2003-05-06 | California Institute Of Technology | Polyamide-alkylator conjugates and related products and method |
WO2003059881A2 (en) * | 2001-12-24 | 2003-07-24 | University Of Strathclyde | Dna minor groove binding compounds |
US6825228B2 (en) | 2001-06-13 | 2004-11-30 | Genesoft Pharmaceuticals, Inc. | Benzothiophene compounds having antiinfective activity |
US6906199B2 (en) | 2000-11-28 | 2005-06-14 | Pharmacia Italia S.P.A. | Process for preparing distamycin derivatives |
US6951951B2 (en) | 2000-07-04 | 2005-10-04 | Pharmacia Italia S.P.A. | Process for preparing distamycin derivatives |
US6969592B2 (en) | 2001-09-26 | 2005-11-29 | Pharmacia Italia S.P.A. | Method for predicting the sensitivity to chemotherapy |
US7129214B2 (en) | 2002-12-10 | 2006-10-31 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
US7141680B2 (en) | 2002-09-20 | 2006-11-28 | Genelabs Technologies, Inc. | Aromatic compounds possessing antifungal or antibacterial activity |
US7265129B2 (en) | 2002-10-25 | 2007-09-04 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
US7348427B2 (en) | 2001-06-13 | 2008-03-25 | Genesoft Pharmaceuticals, Inc. | Antipathogenic benzamide compounds |
US7498349B2 (en) | 2002-08-02 | 2009-03-03 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
US8012967B2 (en) | 2006-09-30 | 2011-09-06 | University Of Strathclyde | Minor groove binders |
CN102807540A (en) * | 2012-09-06 | 2012-12-05 | 无锡万全医药技术有限公司 | Novel method for preparing 5-aminobenzene-2-formic acid |
WO2016165210A1 (en) | 2015-04-15 | 2016-10-20 | Nuhigh Biotechnologies Co.Ltd. | Oligonucleotide fragment, and method as well as application of selective amplifiction of variant of target nucleic acid sequence using the same |
WO2018047148A1 (en) | 2016-09-12 | 2018-03-15 | Novartis Ag | Compounds for the inhibition of mirna |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2002312371A1 (en) * | 2001-06-13 | 2002-12-23 | Roland W. Burli | Aryl-benzimidazole compounds having antiinfective activity |
EP1554271A1 (en) * | 2002-10-15 | 2005-07-20 | Rigel Pharmaceuticals, Inc. | Substituted indoles and their use as hcv inhibitors |
DE102006026764A1 (en) * | 2006-06-09 | 2007-12-13 | Comsort Gmbh | Bulk goods discharging method, involves detecting dimensions of bulk goods, which can be discharged, where bulk goods are moved to sorting table and are shifted in parallel to stream of bulk goods |
WO2020242719A2 (en) * | 2019-05-01 | 2020-12-03 | The University Of North Carolina At Chapel Hill | Inhibitors of rna-binding proteins, compositions thereof, and therapeutic uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0246868A1 (en) * | 1986-05-20 | 1987-11-25 | FARMITALIA CARLO ERBA S.r.l. | Site specific alkylating agents |
WO1993013739A2 (en) * | 1992-01-10 | 1993-07-22 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues |
WO1994020463A1 (en) * | 1993-03-01 | 1994-09-15 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Novel distamycin analogues |
WO1996005196A1 (en) * | 1994-08-08 | 1996-02-22 | Pharmacia S.P.A. | Distamycin a analogues as antitumour or antiviral agents |
WO1997003957A1 (en) * | 1995-07-21 | 1997-02-06 | Pharmacia & Upjohn S.P.A | Bis-(2-haloethyl)aminophenyl substituted distamycin derivatives as antitumor and antiviral agents |
-
1996
- 1996-11-11 GB GBGB9623522.1A patent/GB9623522D0/en active Pending
-
1997
- 1997-10-23 CA CA002271299A patent/CA2271299A1/en not_active Abandoned
- 1997-10-23 ES ES97945879T patent/ES2212138T3/en not_active Expired - Lifetime
- 1997-10-23 WO PCT/EP1997/005986 patent/WO1998021202A1/en active IP Right Grant
- 1997-10-23 JP JP52210098A patent/JP2001504109A/en not_active Ceased
- 1997-10-23 DE DE1997626593 patent/DE69726593T2/en not_active Expired - Fee Related
- 1997-10-23 AU AU51216/98A patent/AU5121698A/en not_active Abandoned
- 1997-10-23 EP EP97945879A patent/EP0937070B1/en not_active Expired - Lifetime
- 1997-10-23 US US09/284,958 patent/US6153642A/en not_active Expired - Fee Related
- 1997-11-06 ZA ZA9709997A patent/ZA979997B/en unknown
- 1997-11-10 AR ARP970105209A patent/AR009413A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0246868A1 (en) * | 1986-05-20 | 1987-11-25 | FARMITALIA CARLO ERBA S.r.l. | Site specific alkylating agents |
WO1993013739A2 (en) * | 1992-01-10 | 1993-07-22 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues |
WO1994020463A1 (en) * | 1993-03-01 | 1994-09-15 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Novel distamycin analogues |
WO1996005196A1 (en) * | 1994-08-08 | 1996-02-22 | Pharmacia S.P.A. | Distamycin a analogues as antitumour or antiviral agents |
WO1997003957A1 (en) * | 1995-07-21 | 1997-02-06 | Pharmacia & Upjohn S.P.A | Bis-(2-haloethyl)aminophenyl substituted distamycin derivatives as antitumor and antiviral agents |
Non-Patent Citations (2)
Title |
---|
ARCAMONE F.M. ET AL.: "SYNTHESIS, DNA-BINDING PROPERTIES, AND ANTITUMOR ACTIVITY OF NOVEL DISTAMYCIN DERIVATIVES", JOURNAL OF MEDICINAL CHEMISTRY, vol. 32, no. 4, 1989, pages 774 - 778, XP000608784 * |
D'ALESSIO R. ET AL.: "Structure-activity relationship of novel distamycin A derivatives: Synthesis and antitumor activity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 4, no. 12, December 1994 (1994-12-01), pages 1467 - 1472, XP000671766 * |
Cited By (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6458768B1 (en) | 1998-03-27 | 2002-10-01 | Pharmacia & Upjohn, S.P.A. | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents |
WO1999050266A1 (en) * | 1998-03-27 | 1999-10-07 | Pharmacia & Upjohn S.P.A. | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents |
JP2002536345A (en) * | 1999-02-04 | 2002-10-29 | ジョルン ブラーディーク | Formulation for preventing and / or treating mesenchymal-derived tissue change |
US6559125B1 (en) | 2000-01-28 | 2003-05-06 | California Institute Of Technology | Polyamide-alkylator conjugates and related products and method |
EA007506B1 (en) * | 2000-05-08 | 2006-10-27 | Фармация Италия С.П.А. | Use of acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione |
US7030089B2 (en) | 2000-05-08 | 2006-04-18 | Pharmacia Italia S.P.A. | Use of substituted acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione |
CZ300791B6 (en) * | 2000-05-08 | 2009-08-12 | Nerviano Medical Sciences S.R.L | Medicament for the treatment of tumors over expressing GSH/GSTs system |
WO2001085144A3 (en) * | 2000-05-08 | 2002-05-16 | Pharmacia Italia Spa | Use of substituted acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione |
WO2001085144A2 (en) * | 2000-05-08 | 2001-11-15 | Pharmacia Italia S.P.A. | Use of substituted acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione |
CN100479824C (en) * | 2000-06-23 | 2009-04-22 | 内尔维阿诺医学科学有限公司 | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites |
WO2001097790A2 (en) * | 2000-06-23 | 2001-12-27 | Pharmacia Italia S.P.A. | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and alkylating agents |
EA008502B1 (en) * | 2000-06-23 | 2007-06-29 | НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. | Combined therapy against tumors comprising submitted acryloyl distamycin derivatives and alkylating agents |
EP1889624A2 (en) | 2000-06-23 | 2008-02-20 | NERVIANO MEDICAL SCIENCES S.r.l. | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites |
WO2001097618A2 (en) * | 2000-06-23 | 2001-12-27 | Pharmacia Italia S.P.A. | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites |
US8642580B2 (en) | 2000-06-23 | 2014-02-04 | Nerviano Medical Sciences S.R.L. | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and platinum derivatives |
US7642229B2 (en) | 2000-06-23 | 2010-01-05 | Nerviano Medical Sciences S.R.L. | Pharmaceutical composition and a product which includes a substituted acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite |
CZ301053B6 (en) * | 2000-06-23 | 2009-10-21 | Nerviano Medical Sciences S.R.L | Pharmaceutical composition and pharmaceutical products |
EP1889624A3 (en) * | 2000-06-23 | 2009-02-25 | NERVIANO MEDICAL SCIENCES S.r.l. | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites |
KR100869037B1 (en) | 2000-06-23 | 2008-11-17 | 네르비아노 메디칼 사이언시스 에스.알.엘. | Antitumor composition comprising substituted acryloyl distamycin derivatives and alkylating agents |
WO2001097789A2 (en) * | 2000-06-23 | 2001-12-27 | Pharmacia Italia S.P.A. | Pharmaceutical compositions comprising acryloyl distamycin derivatives and topoisomerase i and ii inhibitors |
KR100853955B1 (en) | 2000-06-23 | 2008-08-25 | 네르비아노 메디칼 사이언시스 에스.알.엘. | Pharmaceutical compositions comprising acryloyl distamycin derivatives and topoisomerase ? and ? inhibitors |
WO2001097618A3 (en) * | 2000-06-23 | 2002-06-13 | Pharmacia & Upjohn Spa | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites |
WO2001097789A3 (en) * | 2000-06-23 | 2002-05-16 | Pharmacia Italia Spa | Pharmaceutical compositions comprising acryloyl distamycin derivatives and topoisomerase i and ii inhibitors |
WO2001097790A3 (en) * | 2000-06-23 | 2002-05-16 | Pharmacia Italia Spa | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and alkylating agents |
US6951951B2 (en) | 2000-07-04 | 2005-10-04 | Pharmacia Italia S.P.A. | Process for preparing distamycin derivatives |
WO2002022655A1 (en) * | 2000-09-15 | 2002-03-21 | Pharmacia Italia S.P.A. | Glutathione conjugates with distamycin derivatives having antitumoral activity |
US6838547B2 (en) | 2000-09-15 | 2005-01-04 | Pharmacia Italia S.P.A. | Glutathiaone conjugates with distamycin derivatives having antitumoral activity |
US6906199B2 (en) | 2000-11-28 | 2005-06-14 | Pharmacia Italia S.P.A. | Process for preparing distamycin derivatives |
US7348427B2 (en) | 2001-06-13 | 2008-03-25 | Genesoft Pharmaceuticals, Inc. | Antipathogenic benzamide compounds |
US6825228B2 (en) | 2001-06-13 | 2004-11-30 | Genesoft Pharmaceuticals, Inc. | Benzothiophene compounds having antiinfective activity |
US7329765B2 (en) | 2001-06-13 | 2008-02-12 | Genesoft Pharmaceuticals, Inc. | Benzothiophene compounds having antiinfective activity |
WO2003004019A1 (en) * | 2001-07-02 | 2003-01-16 | Universita' Degli Studi Di Ferrara | Use of heterocyclic and benzoheterocyclic polyamides structurally related to the natural antibiotic distamycin a for the treatment of beta-thalassaemia |
US7396851B2 (en) | 2001-07-02 | 2008-07-08 | Universita' Degli Studi Di Ferrara | Heterocyclic and benzoheterocyclic polyamides structurally related to the natural antibiotic distamycin A for the treatment of β-thalassaemia |
US6969592B2 (en) | 2001-09-26 | 2005-11-29 | Pharmacia Italia S.P.A. | Method for predicting the sensitivity to chemotherapy |
WO2003059881A3 (en) * | 2001-12-24 | 2003-11-27 | Univ Strathclyde | Dna minor groove binding compounds |
WO2003059881A2 (en) * | 2001-12-24 | 2003-07-24 | University Of Strathclyde | Dna minor groove binding compounds |
US7700765B2 (en) | 2001-12-24 | 2010-04-20 | University Of Strathclyde | DNA minor groove binding compounds |
US7498349B2 (en) | 2002-08-02 | 2009-03-03 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
US7141680B2 (en) | 2002-09-20 | 2006-11-28 | Genelabs Technologies, Inc. | Aromatic compounds possessing antifungal or antibacterial activity |
US7265129B2 (en) | 2002-10-25 | 2007-09-04 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
US7642245B2 (en) | 2002-12-10 | 2010-01-05 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
US7129214B2 (en) | 2002-12-10 | 2006-10-31 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
US8012967B2 (en) | 2006-09-30 | 2011-09-06 | University Of Strathclyde | Minor groove binders |
CN102807540A (en) * | 2012-09-06 | 2012-12-05 | 无锡万全医药技术有限公司 | Novel method for preparing 5-aminobenzene-2-formic acid |
WO2016165210A1 (en) | 2015-04-15 | 2016-10-20 | Nuhigh Biotechnologies Co.Ltd. | Oligonucleotide fragment, and method as well as application of selective amplifiction of variant of target nucleic acid sequence using the same |
WO2018047148A1 (en) | 2016-09-12 | 2018-03-15 | Novartis Ag | Compounds for the inhibition of mirna |
Also Published As
Publication number | Publication date |
---|---|
AR009413A1 (en) | 2000-04-12 |
EP0937070A1 (en) | 1999-08-25 |
EP0937070B1 (en) | 2003-12-03 |
ES2212138T3 (en) | 2004-07-16 |
ZA979997B (en) | 1998-05-25 |
DE69726593D1 (en) | 2004-01-15 |
AU5121698A (en) | 1998-06-03 |
DE69726593T2 (en) | 2004-11-18 |
GB9623522D0 (en) | 1997-01-08 |
JP2001504109A (en) | 2001-03-27 |
US6153642A (en) | 2000-11-28 |
CA2271299A1 (en) | 1998-05-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0937070B1 (en) | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents | |
US5017599A (en) | Site specific alkylating agents | |
AU635733B2 (en) | Acryloyl substituted pyrrole derivatives | |
EP1064281B1 (en) | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents | |
US6165980A (en) | Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents | |
EP0915845B1 (en) | Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents | |
US6177408B1 (en) | Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents | |
WO1997003957A1 (en) | Bis-(2-haloethyl)aminophenyl substituted distamycin derivatives as antitumor and antiviral agents | |
EP1100777B1 (en) | Sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents | |
MXPA97001949A (en) | Derivatives of distamycine substituted with bis- (2-haloethyl) aminophenylene as anatomy agents yantivira | |
EP1100778B1 (en) | Oxidised sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents | |
US5049579A (en) | Site specific alkylating agents | |
US5310752A (en) | Site specific alkylating agents | |
EP1084120B1 (en) | Cinnamoyl distamycin analogous derivatives, process for their preparation, and their use as antitumor agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BG BR CA CN CZ EE HU IL JP KR LT LV MX NO NZ PL SG SI TR UA US AM AZ BY KG KZ MD RU TJ TM |
|
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 | ||
WWE | Wipo information: entry into national phase |
Ref document number: 09284958 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2271299 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1998 522100 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1997945879 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1997945879 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 1997945879 Country of ref document: EP |