EP1173420A2 - Composes heterocycliques ayant une activite antitumorale - Google Patents

Composes heterocycliques ayant une activite antitumorale

Info

Publication number
EP1173420A2
EP1173420A2 EP00920458A EP00920458A EP1173420A2 EP 1173420 A2 EP1173420 A2 EP 1173420A2 EP 00920458 A EP00920458 A EP 00920458A EP 00920458 A EP00920458 A EP 00920458A EP 1173420 A2 EP1173420 A2 EP 1173420A2
Authority
EP
European Patent Office
Prior art keywords
oxo
dihydrofuran
compounds
formula
phenyl
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.)
Withdrawn
Application number
EP00920458A
Other languages
German (de)
English (en)
Inventor
Ernesto Menta
Marco Conti
Nicoletta Pescalli
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.)
Novuspharma SpA
Original Assignee
Novuspharma SpA
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 Novuspharma SpA filed Critical Novuspharma SpA
Publication of EP1173420A2 publication Critical patent/EP1173420A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/66—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to heterocyclic compounds having antitumor activity, in particular against solids tumors, specifically colon tumors.
  • carcinoma of the colon and rectum is a very common tumor in Western countries, in that it has an incidence of about 421,000 new cases each year in the world and is second only to lung and breast tumors as cause of death.
  • the percentage of patients which can be treated surgically is about 45-50%, the remaining patients being treated with combined chemotherapy, to obtain a complete remission percentage not above 5%.
  • Tumors of the colon and rectum are usually refractory or poorly sensitive to chemotherapy available at present and the only effective agent to some extent against this type of cancer is 5-fluorouracil .
  • EP-A- 997115391.1 discloses a novel class of compounds with antitumor activity particularly against colon tumors.
  • Said compounds are 4-ureido and thioureido derivatives of 2 (5H) -furanone or 2 (5H) -thiophenone .
  • the present invention relates to novel heterocyclic compounds having antitumor activity in particular against colon tumors, having the following general formula (I) in which:
  • R is C ⁇ _- ] _oalkyl, C3 _7cycloalkyl , C 7 _ 14 arylalkyl , naphthyl, phenyl optionally mono- or poly- substituted, 5 or 6 membered aromatic or non aromatic heterocyclic ring, optionally benzocondensed;
  • aryl group is a phenyl optionally substituted with one or two methoxy groups.
  • R is a heterocyclic ring
  • this is preferably selected from the group consisting of pyridine, pyrrole, thiazole, thiophene, furan, imidazole, pyrazine, pyrimidine, quinoline, isoquinoline, indole, 3 , 4-methylenedioxyphenyl , piperazine, piperidine, morpholine and pyrrolidine.
  • R is a mono- or poly- substituted phenyl
  • preferred substituents are C ⁇ __ 4 alkyl, in particular ethyl, C__3polyhaloalkyl , in particular, trifluoromethyl , and halogen, in particular chlorine.
  • a preferred group of compounds of formula (I) is the one in which n is 0, Y is NH, R ⁇ _ and R 2 are hydrogen, R is a substituted phenyl and the dotted line means a bond.
  • Another group of preferred compounds of formula (I) is the one in which n is 0, Y is oxygen, X is -NH-CO-NH-, R is phenyl substituted with one or more groups selected from
  • R ⁇ _ is -CH 2 -NR a R ]3 , wherein R a and R j -- are as defined above and the dotted line is a bond.
  • the present invention further relates to pharmaceutical formulations containing a pharmaceutically effective amount of one or more compounds of formula (I) in mixture with pharmaceutically acceptable excipients .
  • Another object of the invention is to provide processes for the preparation of the compounds of formula (I) .
  • the compounds of formula (I) in which the dotted line means a bond and which have an -NH- group at the 4- position of formula (I) can be prepared by reacting a compound of formula (II)
  • n, Y, R ⁇ _ and R 2 are as defined for compounds o formula (I) , with a compound of formula (III)
  • the reaction is generally carried out in solution, operating in a solvent such as an alcohol (methanol, ethanol, propanol or butanol) or an aromatic hydrocarbon (benzene, toluene, xylene) under reflux or at 50-150°C, preferably 80- 120°C.
  • a solvent such as an alcohol (methanol, ethanol, propanol or butanol) or an aromatic hydrocarbon (benzene, toluene, xylene) under reflux or at 50-150°C, preferably 80- 120°C.
  • the reaction can also be carried out either without solvent or with a small amount of a high boiling solvent, such as toluene, xylene, dioxane, dimethylformamide, nitromethane or n-butanol, if necessary to obtain a clear molten mass.
  • a small amount of a Lewis acid such as p-toluenesulfonic acid, can be optionally used.
  • the compounds of formula (I) in which the dotted line means a bond and X is -NH-CO-NH-CO- or -NH-CO-NH-S0 2 - are preferably obtained by reacting a compound of formula (II 1 )
  • the reaction is generally carried out in an inert solvent, such as tetrahydrofuran, dimethoxyethane, dioxane, toluene, xylene, at temperatures ranging from 0°C to the reflux temperature of the solvent, preferably 20-50°C.
  • an inert solvent such as tetrahydrofuran, dimethoxyethane, dioxane, toluene, xylene
  • the reaction is generally carried out in an inert solvent such as tetrahydrofuran, 1 , 2-dimethoxyethane, dioxane, toluene, xylene, dichloromethane , at a temperature ranging from -20°C to the reflux temperature of the solvent, preferably at 0-40°C, in the presence of at least one molar equivalent of an inorganic or organic base, such as, for example, alkaline or alkaline-earth metal carbonates or bicarbonates , or tertiary amines such as triethylamine or pyridine and the like.
  • an inert solvent such as tetrahydrofuran, 1 , 2-dimethoxyethane, dioxane, toluene, xylene, dichloromethane
  • an inorganic or organic base such as, for example, alkaline or alkaline-earth metal carbonates or bicarbonates , or tertiary amines such as
  • Hal is halogen and R3 is C ⁇ __3al yl, by heating them in a solvent .
  • n, Y, R ] _ and R 2 are as defined for compounds of formula (I) , with a compound of formula (VI)
  • the compounds of formula (I) in which the dotted line means no bond can be obtained starting from the corresponding unsaturated compounds of formula (I) by chemical or catalytic reduction.
  • the compounds of formula (I) in which R_ is a group of formula [CH 2 ) p -A, wherein p is different from 1 and A is different from OH or NR a R b , are prepared by reacting dicarbonyl compound of formula (II) in which R]_ is H with a compound of formula T-(CH 2 ) p -A, in which T is a leaving group, for example halogen, followed by reaction with a compound of formula W-NH 2 (III), according to the following scheme.
  • the compounds according to the invention were pharmacologically tested against human tumor cell lines: HT 29 (colon carcinoma) , PC 3 (prostate carcinoma) , H 460M (lung carcinoma) , MCF-7 (breast carcinoma) .
  • Cells were incubated for 144 hour with the tested compound, then cytotoxicity was determined using the MTT test (Mosman, T. "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay”; J. Immunolog. Methods, (1983), 65, 66; Green, L.M., “Rapid Colorimetric Assay for Cell Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines” , J. Immunol. Methods, (1984) , 70, 257-268) .
  • the obtained data showed that the compounds of the present invention have a marked activity against solid tumors, in particular colon tumors.
  • the compounds of the invention can be administered in doses ranging from 0.01 mg to 0.4 g/Kg body weight daily.
  • a preferred administration procedure is that using a dosage from about 1 mg to about 50 mg/Kg body weight daily, using such unitary doses as to administer in 24 hours from about 70 mg to about 3.5 g of the active substance to a patient of about 70 Kg.
  • Such administration procedure can be adjusted to obtain a better therapeutical effect.
  • doses can be adjusted according to the therapeutical conditions of the patient.
  • the active compounds of the invention can be administered through the oral, intravenous, intramuscular or subcutaneous routes .
  • compositions of the invention contain therapeutically effective amounts of at least one compound of the invention in mixture with excipients compatible with the pharmaceutical use.
  • compositions for the oral route generally comprise an inert diluent or an edible carrier and can be in the form of gelatin capsules or tablets.
  • Other possible oral administration forms are capsules, pills, elixirs, suspensions or syrups .
  • Tablets, pills, capsules and similar compositions can contain the following ingredients (in addition to the active compound) : a ligand, such as microcrystalline cellulose, tragacanth or gelatin; a carrier such as starch or lactose, a disintegrant such as alginic acid, primogel, maize starch and the like; a lubrificant such as magnesium stearate; a fluidifying agent such as colloidal silicon dioxide; a sweetener such as saccharose or saccharin or a flavoring agent such as mint flavor, methyl salicylate or orange flavor.
  • a liquid carrier such as a fat oil.
  • Other compositions can contain various materials, for example coating agents (for tablets and pills) such as sugar or shellac. The material used in the preparation of the compositions should be pharmaceutically pure and non toxic at the used dosages.
  • the active ingredient can be included in solutions or suspensions, which can further contain the following components: a sterile diluent such as water for injections, saline solution, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterials such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetates, citrates or phosphates and tonicity agents, such as sodium chloride or dextrose.
  • a sterile diluent such as water for injections, saline solution, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents
  • antibacterials such as benzyl alcohol
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • buffering agents such as acetates, cit
  • aqueous solution is adjusted to pH 9 with 20% NaOH and extracted with ethyl acetate (2 x 50 ml) .
  • the combined organic phases are dried and concentrated to dryness, to give a residue which is purified by column chromatography (silica; eluent ethyl acetate) to give 4- (3 -chloro-4 -ethylphenyl) semicarbazide (277 mg) which is used without further purification.
  • Preparation 2 4-chlorophenylacetamide A suspension of 4-chlophenylacetic acid (1.7 g) in thionyl chloride (5 ml) is stirred at room temperature for 3 hours. The thionyl chloride excess is distilled off under vacuum, keeping the temperature below 30°C. The residue is taken up into toluene and the solvent is distilled off under vacuum. This operation is repeated three times. After completion, the residue is dissolved in THF (50 mL) and ammonia is bubbled through the solution, keeping the temperature at about 10 °C. The resulting suspension is diluted with water to give a clear solution which is concentrated to small volume. The precipitate is recovered by filtration and washed on the filter with water/THF 7/3, to give
  • Example 13 4- (5-oxo-2 , 5-dihydrofuran-3-yl) -1-phenylsemicarbazide

Abstract

L'invention concerne des composés de formule générale (I), dans laquelle Y est O, S ou NH; n est 0 ou 1; X est choisi dans le groupe formé de NH-CO-NH, -NH-CO-, NH-SO2-, -NH-, -CO-NH-, -CO-NH-NH-, -NH-NH-CO-, -NH-NH-SO2-, -NH-CO-CO-, -NH-CO-CH2-, -NH-NH-, -NH-NH-CO-NH-, -NH-CO-NH-NH-, -NH-CO-NH-NH-, -CO-, -NH-SO2-NH-, -CO-NH-CO-NH-, -NH-CO-NH-CO-, -NH-CO-NH-SO2-, -NH-C(=NH)-NH-NH-, -NH-NH-C(=NH)-NH-, -CH=CH-, -CO-CH=CH-, -CH=CH-CO-, cyclopropane-1,2-di-yle, -NH-CH(COORC)-; R1 est choisi dans le groupe formé de H, alkyle, -(CH2)p-A, dans lequel p = 0-4 et A =OH, -NRaRb, -COORc, -CONRaRb, -CONH(CH2)q-NRaRb, -CONH(CH2)q-COORc, où q = 1-4, Ra et Rb sont H, alkyle, ou Ra et Rb ainsi que l'atome d'azote sont liés pour former un noyau hétérocyclique à 4-7 éléments; Rc est H, alkyle ou alcali ou un métal alcalino-terreux; R est alkyle, cycloalkyle, arylalkyle, naphtyle, phényle facultativement substitué, un noyau hétérocyclique aromatique ou non aromatique à 5 ou 6 éléments facultativement benzocondensé; R2 est H ou alkyle et le pointillé représente une liaison facultative, que l'on peut utiliser comme médicaments, en particulier comme agents antitumoraux.
EP00920458A 1999-03-05 2000-03-01 Composes heterocycliques ayant une activite antitumorale Withdrawn EP1173420A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI990456 1999-03-05
IT1999MI000456A IT1309593B1 (it) 1999-03-05 1999-03-05 Composti eterociclici ad attivita' antitumorale.
PCT/EP2000/001721 WO2000053581A2 (fr) 1999-03-05 2000-03-01 Composes heterocycliques ayant une activite antitumorale

Publications (1)

Publication Number Publication Date
EP1173420A2 true EP1173420A2 (fr) 2002-01-23

Family

ID=11382169

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00920458A Withdrawn EP1173420A2 (fr) 1999-03-05 2000-03-01 Composes heterocycliques ayant une activite antitumorale

Country Status (5)

Country Link
EP (1) EP1173420A2 (fr)
JP (1) JP2002539114A (fr)
AU (1) AU4103300A (fr)
IT (1) IT1309593B1 (fr)
WO (1) WO2000053581A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0612117A2 (pt) 2005-06-28 2012-09-04 Merck & Co Inc composto ou um sal farmaceuticamente aceitável ou solvato do mesmo, composição farmacêutica, e, uso de um composto
EP3350173B1 (fr) 2015-09-18 2020-02-12 Boehringer Ingelheim International GmbH Procédé stéréosélectif
CN109651310B (zh) * 2018-12-26 2022-07-22 华南师范大学 一种n-呋喃酮基芳基磺酰肼类衍生物及其制备方法和应用
CN113980004B (zh) * 2021-10-18 2023-07-04 成都大学 一种具有呋喃-2(5h)-酮骨架的化合物及其制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3496187A (en) * 1967-03-20 1970-02-17 American Home Prod N-(heterocyclyl)aconamides
US3472878A (en) * 1969-01-27 1969-10-14 American Home Prod N-(hydroxyaryl)aconamides
DE2108926C3 (de) * 1971-02-25 1980-06-04 Basf Ag, 6700 Ludwigshafen Verfahren zur Herstellung von 3-Acyl-4-hydroxy-buten-(2)-saurelactonen
JP3124373B2 (ja) * 1992-03-13 2001-01-15 塩野義製薬株式会社 免疫抑制物質
US5773459A (en) * 1995-06-07 1998-06-30 Sugen, Inc. Urea- and thiourea-type compounds
KR19990022058A (ko) * 1996-03-27 1999-03-25 마에다 가쯔노스께 케톤유도체 및 그 의약용도
CO4970714A1 (es) * 1997-09-05 2000-11-07 Boehringer Mannheim Gmbh Derivados ureido y tioureido de 4-amino-2(5h)-furanonas y 4-amino-2(5h) tiofenonas como agentes antitumorales

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0053581A2 *

Also Published As

Publication number Publication date
ITMI990456A1 (it) 2000-09-05
WO2000053581A3 (fr) 2000-12-21
JP2002539114A (ja) 2002-11-19
AU4103300A (en) 2000-09-28
WO2000053581A2 (fr) 2000-09-14
IT1309593B1 (it) 2002-01-24

Similar Documents

Publication Publication Date Title
EP0674624B1 (fr) Pyrazoles presentant une activite d'antagonistes du facteur de liberation de la cortitrophine
EP0613894B1 (fr) Dérivés de N-heteroaryl-N-phénylurée, leur préparation et utilisation
US6441018B2 (en) Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
EP0261442B1 (fr) Dérivés de l'acide malonique
WO1994013676A1 (fr) Pyrrolopyrimidines en tant qu'antagonistes du facteur liberateur de corticotrophine (crf)
CA2206201A1 (fr) Derives du pyrazole et leur emploi en pharmacie
JPH0623193B2 (ja) 新規なジスタマイシンａ同族体、その製造方法およびそれを含有する医薬組成物
CA2140440A1 (fr) 2-thioindoles (selenoindoles) et disulfides appparentes (selenides) qui inhibent les proteine-tyrosine-kinases et qui ont des proprietes antitumorales
EP2094706B1 (fr) Derives de 2,5-dfflydro-3h-pyrazolo[4,3-c]pyridazin-3-one substitues, leur preparation et leur utilisation comme ligands des recepteurs cb1 des cannabinoides
KR960002852B1 (ko) 헤테로아릴 3-옥소-프로판니트릴 유도체, 이의 제조방법 및 이를 함유하는 약제학적 조성물
BE898278A (fr) Benzoxazines antipsychotiques.
CA1184910A (fr) Derives tricycliques de la cytosine utilises contre les troubles circulatoires
US4330472A (en) Meta-sulfonamido-benzamide derivatives
US5721240A (en) 9-substituted-8-unsubstituted-9-deazaguanines
EP1899298B1 (fr) Derives de 4,5-diarylpyrrole, leur preparation et leur application en therapeutique
EP1966167B1 (fr) Derives diaryltriazolmethylamine, leur preparation et leur application en therapeutique.
US20020058694A1 (en) Ureido and thioureido derivatives of 4-amino-2(5H)-furanones and 4-amino-2(5H)-thiophenones as antitumor agents
WO1993013739A2 (fr) Analogues retroverses d'agents anticancereux a oligopeptides de pyrrole-amidino, leur procede de preparation, et compositions pharmaceutiques contenant ces analogues
WO2000053581A2 (fr) Composes heterocycliques ayant une activite antitumorale
JP3215850B2 (ja) ハロアルコキシ基を含有するピロロ［３，２―ｃ］キノリン誘導体及び薬学的に許容されるその塩
JPH09291076A (ja) 置換グアニジン誘導体およびその製法
US4293713A (en) Novel 1,1,3,5-substituted biuret compound and a pharmaceutical composition containing the same
US6448265B1 (en) Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity
FR2911136A1 (fr) Derives de n-(4-cyano-1h-pyrazol-3-yl)methylamine substitues leur preparation et leur application en therapeutique.
JPH04244083A (ja) 三環状ピリドン誘導体

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010822

AK Designated contracting states

Kind code of ref document: A2

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

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20031006

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040417