EP1467994A1 - Derives de pteridine, procede de production de ces derives et leur utilisation - Google Patents

Derives de pteridine, procede de production de ces derives et leur utilisation

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Publication number
EP1467994A1
EP1467994A1 EP03706378A EP03706378A EP1467994A1 EP 1467994 A1 EP1467994 A1 EP 1467994A1 EP 03706378 A EP03706378 A EP 03706378A EP 03706378 A EP03706378 A EP 03706378A EP 1467994 A1 EP1467994 A1 EP 1467994A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
substituent
radical
cycloalkyl
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Withdrawn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
EP03706378A
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German (de)
English (en)
Inventor
Gerhard Eisenbrand
Karl-Heinz Merz
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.)
Faustus Forschungs Cie Translational Cancer Research GmbH
Original Assignee
Faustus Forschungs Cie Translational Cancer Research GmbH
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 Faustus Forschungs Cie Translational Cancer Research GmbH filed Critical Faustus Forschungs Cie Translational Cancer Research GmbH
Publication of EP1467994A1 publication Critical patent/EP1467994A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

  • the present invention relates to new pteridine derivatives and processes for their preparation. Furthermore, the present invention relates to the use of these pteridine derivatives, inter alia, for the inhibition of cAMP-specific phosphodiesterases, for the inhibition of tumor growth, for the prophylaxis of thrombo-embolic diseases, and for the treatment of inflammatory, neurodegenerative diseases and of asthma.
  • DE-A-3540952 describes 2-piperazino-pteridines which are substituted in the 6-position with a halogen atom selected from a fluorine, chlorine or bromine atom. These compounds have been shown to inhibit the PDE activity of tumor cells and human platelets in vitro.
  • DE-A-3323932 likewise discloses 2-piperazino-pteridines and their inhibitory action on the phosphodiesterase of tumor cells and human thrombocytes in vitro.
  • the pteridines described therein have a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group in the 4-position.
  • DE-A-3445298 describes pteridines with a large number of different substituents in the 2-, 4-, 6- and 7-position, compounds with a 2-piperazino group on the pteridine structure being suitable as inhibitors for tumor growth and have antithrombotic and anti-metastatic properties.
  • US Pat. No. 2,940,972 discloses tri- and tetrasubstituted pteridine derivatives, with general statements being made that these pteridines have valuable pharmacological properties, namely coronary-expanding, sedative, antipyretic and analgesic effects.
  • R 1 is a piperazino, p-phenylenediamino, a 2,5-diazabicyclo-
  • R 2 , R 4 which are in each case identical, represent a pyrrolidino, thiazolidino, oxazolidino or imidazolidino radical which can in each case be substituted by at least one substituent,
  • R 3 represents a halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical, which can in each case be substituted by at least one substituent, or a radical -XR 7 , where XO, S or NR 8 and R 7 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical which can in each case be substituted by at least one substituent,
  • R 8 is hydrogen, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical, which can each be substituted with at least one substituent
  • R 1 is a piperazino, p-phenylenediamino, a 2,5-diazabicyclo- [2.2.1] heptane or a 2,5-diazabicyclo- [2.2.2] octane residue, each of which is substituted by at least one substituent can be, R 2 , R 4 , which are in each case identical, represent a pyrrolidino, thiazolidino, oxazolidino or imidazolidino radical which can in each case be substituted by at least one substituent,
  • R 3 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical, which can in each case be substituted by at least one substituent, or a radical -XR 7 , where X is O, S or NR 8 , and R 7 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical, which can in each case be substituted by at least one substituent
  • R 8 is hydrogen, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical, which can in each case be substituted by at least one substituent
  • R 2 and R 4 which are in each case the same, represent a pyrrolidino, thiazolidino, oxazolidino or imidazolidino radical, which can each be substituted by at least one substituent, and R 9 and rio are halogen,
  • R 2 and R 4 which are in each case identical, represent a thiazolidino, oxazolidino or imidazolidino radical, which can each be substituted by at least one substituent, and
  • R 9 and R 10 are halogen.
  • the radical R 1 is preferably a piperazine radical.
  • the radicals R 2 or R 4 are preferably pyrrolidino, thiazolidino, oxazolidino or imidazolidino residues, in particular pyrrolidino or thiazolidino residues.
  • the radical R 3 is preferably a CC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl or C 6 -C ⁇ 0 aryl radical. Furthermore, R 3 is preferably a C ⁇ -C6 alkyl, -C 6 alkoxy, C ⁇ -C 6 alkylmercapto or an C ⁇ .C 6 alkylamino. R 3 is particularly preferably a C 1 -C 3 alkylamino, CC 3 alkoxy or CC 3 alkyl mercapto radical.
  • R 3 is a CC 3 alkoxy or CrC 3 alkyl mercapto residue, ie methoxy, ethoxy, propoxy, methyl mercapto, ethyl mercapto or propyl mercapto residue, in particular a methoxy or methyl mercapto residue.
  • R 3 is halogen, fluorine, chlorine, bromine or iodine and especially chlorine or bromine are preferred.
  • R 1 to R 4 can be substituted independently of one another with at least one, preferably one to three, substituents.
  • R 7 and R 8 are, independently of one another, preferably a CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl - or C 6 -C ⁇ 0 - aryl radical, in particular a C ⁇ -C 3 alkyl.
  • R 8 is hydrogen or CC 6 alkyl.
  • R 9 and R 10 are preferably chlorine or bromine independently of one another.
  • substituents include halogen, in particular Cl, F or Br, hydroxy, amino, nitro, CN, CF 3 , CC 4 alkyl, in particular CC 3 alkyl, CC alkoxy, in particular CC 3 alkoxy, CrC 4 alkylthio, C 3 -C 7 cycloalkyl, in particular C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, NR 5 R 6 , COOR 5 , CONR 5 R 6 , NR 5 COR 6 , NR 5 COOR 6 , S (O) R 5 , SO 2 R 5 , SO 2 NR 5 R 6 , SO 3 H,
  • CC 4 alkyl CC 4 alkoxy, d-oralkylthio, C 3 -C 7 cycloalkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, aryl or provided with one or more substituents from this group heteroaryl,
  • the acid addition salts are usually pharmaceutically acceptable acid addition salts.
  • these include organic and inorganic acid addition salts, such as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, glycollate, methanesulfonate, format, malonate 2, naphthalene -sulfonate, salicylate and acetate.
  • the present invention further relates to a process for the preparation of the abovementioned compounds, comprising the steps:
  • R 7 denotes an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical, which can in each case be substituted with at least one substituent
  • XO, S or NR 8 means M is Na or Li
  • R 8 is hydrogen, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl radical, which can in each case be substituted by at least one substituent.
  • the compounds of the formula (I) or (II) according to the invention can be prepared in various ways and under customary reaction conditions.
  • the starting materials used for the process according to the invention are either commercially available or can be prepared from commercially available compounds by known processes.
  • the object of the present invention is achieved by a pharmaceutical composition which contains this compound and a pharmaceutically acceptable carrier.
  • composition according to the invention which is also referred to below as a pharmaceutical, is explained in more detail below.
  • the medicament according to the invention is used primarily intravenously, but also in other types of administration, such as administered intramuscularly, intraarterially, intraperitoneally, intrathecally, subcutaneously, orally, orally or topically. Administration by intravenous injection or intravenous infusion is preferred.
  • the medicament is produced by methods known per se, the compound according to the invention being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the medicament according to the invention contains pharmaceutical carriers in addition to the active substance, the active substance content of this mixture is 0.1 to 99.5, preferably 0.5 to 95% by weight of the total mixture.
  • the medicament according to the invention can be in any suitable formulation. be used on the condition that the formation or maintenance of sufficient drug levels is guaranteed. This can be achieved, for example, by oral or parenteral administration in suitable doses.
  • the pharmaceutical preparation of the active ingredient is advantageously in the form of unit doses which are tailored to the desired administration.
  • a unit dose can be, for example, a tablet, a coated tablet, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.
  • unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier and whose active ingredient content corresponds to a fraction or a multiple of a single therapeutic dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score line.
  • the pharmaceuticals according to the invention if they are in unit doses and for applications e.g. intended for humans, contain about 0.1 to 500 mg, preferably 10 to 300 mg and in particular 50 to 350 mg of active ingredient.
  • the active ingredient (s) are administered in a daily dose of 0.1 to 5, preferably 1 to 3 mg / kg of body weight, optionally in the form of several, preferably 1 to 3, single doses to achieve the desired results.
  • a single dose contains the active ingredient (s) in amounts of 0.1 to 10, preferably 1 to 5 mg / kg body weight. Similar doses can be used in oral treatment.
  • the therapeutic administration of the medicament according to the invention can take place 1 to 4 times a day at fixed or varying times, for example before meals and / or in the evening.
  • the doses mentioned may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individuals to be treated, the type and severity of the disease, the type of preparation and administration of the medicinal products, and the period or Interval within which the administration takes place. In some cases, it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. It may also be useful to administer the medication only once or several days apart.
  • the determination of the required optimal dosage and type of application of the active ingredients can be done by any specialist on the basis of his specialist knowledge.
  • the medicaments according to the invention generally consist of the compounds according to the invention and non-toxic, pharmaceutically acceptable medicament carriers which are used as admixtures or diluents, for example in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet coating, a sachet or of another container for the therapeutically active ingredient.
  • a carrier can e.g. serve as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener, as a taste corrector, as a colorant or as a preservative.
  • Tablets for oral use, e.g. Tablets, coated tablets, capsules, e.g. come from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
  • Tablets can contain inert fillers, for example starches and derivatives, lactose, microcrystalline cellulose (MCC), cellulose and derivatives, calcium carbonate or sodium chloride; Binders, for example starches, macrogols (PEGe), polyvidone (PVP), gelatin, alginates or gum arabic; Lubricants, e.g. magnesium stearate, stea rinic acid, talc or silicone oil; Flow agent, for example highly disperse silicon dioxide (Aerosil); Disintegrants, for example starches and derivatives or crospovidone (qPVP); Solubilizing agents; Moisturizing substances; Flavors or colorants included. They can also be provided with a coating or a jacket, which can also be designed in such a way that it causes a delayed dissolution and absorption of the pharmaceutical preparation in the gastrointestinal tract, so that, for example, better tolerance, protracting or retardation is achieved.
  • Binders for example starches, macrogols (PEGe), polyvid
  • Gelatin capsules can mix the drug with a solid, e.g. Lactose or mannitol, or an oily e.g. Olive, peanut, or soybean oil, diluent among other carriers.
  • a solid e.g. Lactose or mannitol
  • an oily e.g. Olive, peanut, or soybean oil, diluent among other carriers.
  • Aqueous suspensions can include suspending agents, e.g. Cellulose derivatives, sodium alginate, polyvidone, tragacanth or gum arabic; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethyleneoxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoate; Flavoring agents; Sweeteners, e.g. Sucrose, sodium cyclamate, dextrose or invert sugar syrup.
  • suspending agents e.g. Cellulose derivatives, sodium alginate, polyvidone, tragacanth or gum arabic
  • Dispersing and wetting agents e.g. Polyoxyethylene stearate, heptadecaethyleneoxycatanol, polyoxyethylene sorbitol monooleate or lecithin
  • Preservatives e.g. Methyl or prop
  • oily suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickeners such as e.g. Beeswax, hard paraffin or cetyl alcohol; and further auxiliaries such as e.g. emulsifiers; Sweeteners, flavoring agents; Preservatives and antioxidants included.
  • Water-dispersible powders and granules the compound of the invention can e.g. mixed with dispersing, wetting and suspending agents, e.g. the above, as well as with sweeteners, flavorings and colorants.
  • Emulsions can contain, for example, olive, peanut or paraffin oil in addition to emulsifiers, such as gum arabic, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, as well as sweeteners, flavoring agents and preservatives.
  • emulsifiers such as gum arabic, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, as well as sweeteners, flavoring agents and preservatives.
  • Aqueous solutions can contain preservatives, for example methyl or propyl hydroxybenzoate; Thickener; Flavoring agents; Contain sweeteners, such as sucrose, sodium cyclamate, dextrose, invert sugar syrup, and colorants.
  • Sterile injectable or infusible aqueous solutions, isotonic saline solutions or other solutions are used for parenteral use of the drugs.
  • sterile emulsions, suspensions or implants are used, which can also be such that a delayed dissolution and absorption of the pharmaceutical preparation is brought about, so that e.g. better tolerance, protracting or retardation is achieved.
  • the compound of the formula (I) according to the invention can be used, inter alia, for inhibiting cAMP-specific phosphodiesterases, for inhibiting tumor growth, for the prophylaxis of thrombo-embolic diseases and for the treatment of inflammatory, neurodegenerative and asthmatic diseases.
  • Figure 1 Representation of the IC 50 values of the growth inhibition using the compounds E288, E289 and E499 on the human tumor cell lines COLO 205 and NCI-H460.
  • 2,6-dichloro-4,7-dithiazolidino-pteridine (644 mg; 1.72 mmol) and piperazine (166 mg; 1.93 mmol) are suspended in 25 mL dioxane.
  • Triethylamine (195 mg; 1.93 mmol) is added and the mixture is heated to reflux for 5 h. The solvent is then removed in vacuo, the residue is washed thoroughly with water and dried. Flash chromatography gives a bright yellow solid: yield 80%.
  • 6-Chloro-2-piperazino-4,7-dipyrrolidino-pteridine 500 mg; 1.29 mmol
  • sodium methanethiolate 133 mg; 1, 9 mmol
  • the cooled reaction mixture is mixed with 50 mL water, the precipitate is filtered off and washed with water.
  • the filtrate is extracted 3 times with 75 mL chloroform.
  • the chloroform phases are combined, dried with magnesium sulfate, evaporated to dryness and combined with the precipitate filtered off.
  • the growth inhibition of tumor cells by the compounds according to the invention was determined on the human cell line LXFL529L.
  • the antitumor spectrum of the new active substances is broad, because in addition to the large-cell lung carcinoma LXFL529 as well as the colon carcinoma COLO 205 and bronchial carcinoma NCI-H460 (Fig. 1/1), other tumor cells also proved to be sensitive in the XTT assay (Scudiero et al., Cancer Res. 48, (1988), 4827-4833) with IC 50 values in the lower micromolar range.
  • human cell lines A431 fibroblasts
  • OVCAR-3 ovarian cancer
  • BT-549 and MCF-7 breast cancer
  • SK-MEL-28 and SK-MEL-5 melanoma
  • SW 620 and HCT-15 Colon
  • A549 lung carcinoma
  • glioblastoma cell line C6 of the rat include the human cell lines A431 (fibroblasts), OVCAR-3 (ovarian cancer), BT-549 and MCF-7 (breast cancer), SK-MEL-28 and SK-MEL-5 (melanoma), SW 620 and HCT-15 ( Colon), A549 (lung carcinoma) and the glioblastoma cell line C6 of the rat.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule générale (I) et les sels d'addition d'acide de ces composés. Dans ladite formule, R1 représente un groupe pipérazino, p-phénylènediamino, 2,5-diazabicyclo-2.2.1-heptane, 2,5-diazabicyclo-2.2.2-octane ou 3,8-diazabicyclo-3.2.1-octane, chacun de ces groupes pouvant être substitué par au moins un substituant, R2 et R4 sont identiques et représentent un groupe pyrrolidino, thiazolidino, oxazolidino ou imidazolidino, chacun de ces groupes pouvant être substitué par au moins un substituant, et R3 représente un groupe alkyle, alcoxy, alkylmercapto ou alkylamino, chacun de ces groupes pouvant être substitué par au moins un substituant. Ces dérivés de ptéridine sont adaptés en tant qu'inhibiteurs de phosphodiestérases et peuvent de ce fait être utilisés pour prévenir et/ou traiter des maladies neurodégénératives thrombo-emboliques, des maladies inflammatoires, des maladies asthmatiques et des maladies hémato-oncologiques.
EP03706378A 2002-01-23 2003-01-23 Derives de pteridine, procede de production de ces derives et leur utilisation Withdrawn EP1467994A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10202468 2002-01-23
DE10202468A DE10202468A1 (de) 2002-01-23 2002-01-23 Pteridinderivate, Verfahren zu deren Herstellung und ihre Verwendung
PCT/EP2003/000676 WO2003062240A1 (fr) 2002-01-23 2003-01-23 Derives de pteridine, procede de production de ces derives et leur utilisation

Publications (1)

Publication Number Publication Date
EP1467994A1 true EP1467994A1 (fr) 2004-10-20

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EP03706378A Withdrawn EP1467994A1 (fr) 2002-01-23 2003-01-23 Derives de pteridine, procede de production de ces derives et leur utilisation

Country Status (6)

Country Link
US (1) US20050054653A1 (fr)
EP (1) EP1467994A1 (fr)
JP (1) JP2005519912A (fr)
CA (1) CA2511238A1 (fr)
DE (1) DE10202468A1 (fr)
WO (1) WO2003062240A1 (fr)

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EP3507276B1 (fr) 2016-09-02 2021-11-03 Gilead Sciences, Inc. Composés modulateurs du recepteur de type toll
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TWI751517B (zh) 2019-04-17 2022-01-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202115056A (zh) 2019-06-28 2021-04-16 美商基利科學股份有限公司 類鐸受體調節劑化合物的製備方法

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US20050054653A1 (en) 2005-03-10
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DE10202468A1 (de) 2004-09-30
WO2003062240A1 (fr) 2003-07-31

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