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EP1140096A1 - Utilisation de derives de pyrimidine pour assurer la prophylaxie et la therapie de l'ischemie cerebrale - Google Patents

Utilisation de derives de pyrimidine pour assurer la prophylaxie et la therapie de l'ischemie cerebrale

Info

Publication number
EP1140096A1
EP1140096A1 EP99967980A EP99967980A EP1140096A1 EP 1140096 A1 EP1140096 A1 EP 1140096A1 EP 99967980 A EP99967980 A EP 99967980A EP 99967980 A EP99967980 A EP 99967980A EP 1140096 A1 EP1140096 A1 EP 1140096A1
Authority
EP
European Patent Office
Prior art keywords
ethyl
thieno
pyrimidin
piperazin
hexahydro
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Withdrawn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
EP99967980A
Other languages
German (de)
English (en)
Inventor
Gerd Steiner
Kurt Schellhaas
Wilfried Lubisch
Uta Holzenkamp
Dorothea Starck
Monika Knopp
Laszlo Szabo
Franz Emling
Francisco Javier Garcia-Ladona
Hans-Peter Hofmann
Liliane Unger
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Publication of EP1140096A1 publication Critical patent/EP1140096A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of pyrimidine derivatives for the prophylaxis and therapy of cerebral ischemia
  • R 1 is a hydrogen atom, a Ci-C-alkyl group, an acetyl or benzoyl group, a phenylalkyl C __- C_ radical, the aromatic optionally by halogen, Ci-C 4 alkyl, trifluoromethyl, hydroxy, C ⁇ -C 4th Alkoxy, amino, cyano or mitro groups is substituted, a naphthylalkyl C ⁇ C radical, a phenylalkanone C -C 3 radical or a phenylcarbamoylalkyl C 2 radical, where the phenyl group can be substituted by halogen,
  • R 2 is optionally mono, di- or tri-substituted by halogen atoms, -CC alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C ⁇ -C alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups
  • C represents hydrogen, methyl or hydroxy
  • X represents a nitrogen atom
  • Y is CH 2 , CH 2 -CH 2 , CH 2 -CH 2 -CH 2 or CH 2 -CH,
  • Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
  • n represents the number 2, 3 or 4.
  • R 3 represents a cyano group or a C ⁇ _ 3 alkyl-carboxylic acid ester group
  • R 4 represents C ⁇ - 3 alkyl
  • C represents hydrogen, methyl or hydroxy, with a primary amine of the formula III
  • R 2 and B has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
  • reaction is conveniently carried out in an inert organic compound
  • Solvents in particular a lower alcohol, for example methanol or ethanol, or a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or without a solvent.
  • the reaction is usually carried out at from 20 to 190 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
  • R 3 represents a cyano group or a C ⁇ - 3 alkyl-carboxylic acid ester group
  • R 4 represents C ⁇ - 3 alkyl
  • C represents hydrogen, methyl or hydroxy, with a primary amine of the formula IV
  • halogenating agent e.g.
  • the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
  • the free 3-substituted pyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
  • Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
  • the aqueous phase was extracted again with methylene chloride and the combined organic phases were concentrated after drying.
  • the crude product was purified by column chromatography (silica gel, mobile phase acetone). 2.3 g (72%) of product were isolated, which was dissolved in 100 ml of ethyl acetate and converted into the hydrochloride with a melting point of 233-235 ° C. using HCl / ethyl acetate solution.
  • the aqueous phase was extracted again with methylene chloride and the combined organic phases were concentrated after drying.
  • the crude product was purified by column chromatography (silica gel, mobile phase acetone). 1.0 g (25%) of the product was isolated, which was dissolved in 100 ml of ethyl acetate and converted into the hydrochloride having a melting point of 190-192 ° C. (decomp.) Using HCl / ethyl acetate solution.
  • disorders and dysthymia This also includes anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorders and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory.
  • Q shrinkage and psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.
  • R 1 is a hydrogen atom, a C 1 -C 4 alkyl group, an acetyl group, a phenylalkyl C 1 -C 4 radical, the aromatic optionally being replaced by halogen, C 1 -C 4 alkyl, trifluoromethyl, hydroxy, C 1 -C 4 alkoxy, Amino, cyano or nitro groups are substituted or a carboxylic acid -C 3 -C 3 alkyl ester radical,
  • R 2 is optionally mono- or disubstituted by halogen atoms, C 1 -C 4 -alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups
  • Phenyl, pyridyl, pyrimidinyl or pyrazinyl group optionally with a benzene nucleus, optionally by halogen atoms, C 1 -C 4 alkyl, hydroxy, trifluoromethyl, C 1 -C 4 alkoxy, amino, Cyano or nitro groups can be mono- or disubstituted and can optionally contain 1 nitrogen atom, or can be fused with a 5- or 6-membered ring which can contain 1-2 oxygen atoms,
  • A represents NH or an oxygen atom
  • Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
  • R 3 represents a cyano group or a C ⁇ _-alkyl-carboxylic acid ester grouping and R 4 C ⁇ _ 3 alkyl, with a primary amine of formula III
  • R 2 has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
  • reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, e.g. Methanol or ethanol, or a cyclic saturated ether, especially tetrahydrofuran or dioxane.
  • a lower alcohol e.g. Methanol or ethanol
  • a cyclic saturated ether especially tetrahydrofuran or dioxane.
  • the reaction is usually carried out at from 20 to 110 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
  • R 3 represents a cyano group or a C ⁇ _ 3 -alkyl-carboxylic acid ester group and R 4 means C ⁇ _ 3 -alkyl, with a primary amino alcohol of the formula IV
  • the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
  • [3 ', 4': 4,5] thieno [2, 3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
  • Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
  • the following examples serve to illustrate the invention:
  • the cells were grown in RPMI 1640 medium (Life Technologies), which additionally contained 10% fetal calf serum (FCS), 2 mmol / 1 L-glutamine and 400 mg / 1 Geneticin G 418. The cells were kept until a closed, single-layer
  • 35-day cell layer (“monolayer") in a so-called “tub stack” in an air / 5% CO 2 incubator incubated at 37 ° C.
  • the cells were then detached from the culture vessels using a buffer of the following composition: (data per liter) trypsin 10 mg; EDTA 4 mg; EGTA 200 mg; KC1 200 mg; KH 2 P0 4
  • the compounds according to the invention have a high affinity (K; 30 30 nM) for human 5-HT, 5-HT 3 and 5-HT ID receptor types which are expressed in cloned cell lines.
  • radioligand solution [ 3 H] 5-carboxamidotryptamine (5-CT) for h5HTlB and h5HTlD receptors or [ 3 H] 8-hydroxy-di-propylaminotetralin (8-OH-DPAT) for h5HTlA receptors.
  • the final concentrations the radioligands were set to 3 nmol / 1 and 0.3 nmol / 1, respectively.
  • the assay mixture was incubated at 25 ° C. for 30 minutes and then filtered through fiberglass filters (Whatman GF / B) using a cell harvester (Skatron) and the filters were washed with 5 to 9 ml of cold buffer.
  • the filters were combined in scintillation vials with 5 ml Ultima GoldxR liquid scintillator (Packard), shaken for 1 hour and then the radioactivity was determined in a beta counter (Wallac).
  • the measurement data were determined by means of an iterative non-linear regression analysis using the "Statistical Analysis System (SAS), that described by Munson and Rodbard (Anal. Biochem: 107, 220 (1980))
  • Disorders and dysthymia This includes anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorder and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory loss as well as psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.
  • R 1 and R 2 represent a hydrogen atom or a -CC alkyl group
  • R 3 is an optionally mono- or disubstituted phenyl by halogen atoms, C 1 -C 4 -alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups -, pyridyl, pyrimidinyl or
  • Pyrazinyl group optionally with a benzene nucleus, which may optionally be mono- or disubstituted by halogen atoms, -CC alkyl, hydroxy, trif luormethyl, -C-alkoxy, amino, cyano or nitro groups and if necessary 1
  • A represents NH or an oxygen atom
  • Z represents a nitrogen atom, carbon tom or CH, where the bond between Y and Z can also be a double bond,
  • R 3 represents a cyano group or a C ⁇ _-alkyl-carboxylic acid ester group and R 4 C ⁇ _ 3 alkyl, with a primary amine of formula III
  • reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, e.g. Methanol or ethanol, or a cyclic saturated ether, especially tetrahydrofuran or dioxane.
  • a lower alcohol e.g. Methanol or ethanol
  • a cyclic saturated ether especially tetrahydrofuran or dioxane.
  • the reaction is usually carried out at from 30 ° to 110 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
  • R 1 has the meaning given above
  • R 3 represents a cyano group or a C 1 -C 8 -alkyl-carboxylic acid ester group
  • R 4 denotes C 3 -C 3 -alkyl, with a primary amino alcohol of the formula IV
  • halogenating agent e.g.
  • the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
  • the free 3-substituted pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
  • Pharmaceutically acceptable acids are for example hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
  • R 1 is a hydrogen atom, a C 1 -C 4 -alkyl group, an acetyl group, a phenylalkyl C 1 ⁇ C radical, the aromatic optionally being replaced by halogen, C 1 -C 4 -alkyl, trifluoromethyl, hydroxyl, C 1 -C 4 -alkoxy, Amino, cyano or nitro groups is substituted or represents a phenylalkanone radical, where the phenyl group can be substituted by halogen,
  • R 2 is an optionally mono- or disubstituted phenyl by halogen atoms, -C ⁇ C alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C ⁇ -C 4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups -, Pyridyl, pyrimidinyl or pyrazinyl group, optionally with a benzene nucleus, optionally by halogen atoms, -CC alkyl, hydroxy, trifluoromethyl, C ⁇ -C alkoxy, amino, cyano - or nitro groups can be mono- or disubstituted and can optionally contain 1 nitrogen atom, or can be fused with a 5- or 6-membered ring which can contain 1-2 oxygen atoms,
  • A represents NH or an oxygen fatom
  • Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
  • n represents the number 2, 3 or 4.
  • R 3 represents a cyano group or a C ⁇ _ 3 -alkyl-carboxylic acid ester group and R 4 means C ⁇ _ 3 -alkyl, with a primary amine of the formula III
  • R 2 has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
  • reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, e.g. Methanol or ethanol, or a cyclic saturated ether, especially tetrahydrofuran or dioxane.
  • a lower alcohol e.g. Methanol or ethanol
  • a cyclic saturated ether especially tetrahydrofuran or dioxane.
  • the reaction is usually carried out at from 20 to 110 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
  • R 3 represents a cyano group or a C ⁇ _ 3 alkyl-carboxylic acid ester group and R 4 means C ⁇ _ 3 alkyl, with a primary amino alcohol of the formula IV
  • halogenating agent e.g.
  • the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
  • the free 3-substituted pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
  • Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methane sulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
  • the 6-position acetyl group can be analogous to DE 19 636 769.7 with 10 percent. Hydrochloric acid are cleaved under reflux to the corresponding 30 secondary amines. The alkylations on N-6 to the 6-alkyl derivatives can also be carried out as described in DE 19 636 769.7.
  • central nervous disorders such as seasonal mood disorders and dysthymia.
  • anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorders and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory loss as well as psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.
  • A represents NH or an oxygen atom
  • C represents hydrogen, methyl or hydroxy
  • E - C - NR 3 R 4 means or
  • X represents a nitrogen atom
  • Y is CH 2 , CH 2 -CH 2 , CH 2 -CH 2 -CH 2 or CH 2 -CH,
  • Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
  • R 1 is a hydrogen atom, a C 1 -C 4 alkyl group, an acetyl or benzoyl group, a phenylalkyl C ⁇ -C 4 radical or phenylalkoxy C 2 -C 5 radical, the aromatic optionally by halogen, C] .- C -Alkyl-, trifluoromethyl, hydroxy, C ⁇ -C -alkoxy, amino, cyano or nitro groups is substituted, a naphthylalkyl C] _- C 3 radical, a phenylalkanone C -C radical or a phenyl or Pyridylcarbamoylalkyl means C 2 radical, where the phenyl or pyridyl group can be substituted by halogen, a C ⁇ -C alkyl group, a methoxy group and by a nitro or amino group,
  • R 2 is an optionally mono, di- or tri-substituted phenyl by halogen atoms, -CC alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C ⁇ C alkoxy, amino, monomethyl ino, dimethylamino, cyano or nitro groups -, pyridyl,
  • Pyrimidinyl or pyrazinyl group which optionally with a benzene nucleus, optionally mono- or disubstituted by halogen atoms, -CC 4 alkyl, hydroxy, trifluoromethyl, -C 4 alkoxy, amino, cyano or nitro groups can be and optionally contain 1 nitrogen atom, or can be fused with a 5- or 6-membered ring, which can contain 1-2 oxygen atoms, or by a phenyl-C ⁇ -C 2 alkyl or. alkoxy group may be substituted, where the phenyl radical may be substituted by halogen, a methyl, trifluoromethyl or methoxy group,
  • R 3 and R 4 independently of one another represent a hydrogen atom or a C 1 -C 4 -alkyl group
  • One use according to the invention also relates to neuroprotection.
  • the use according to the invention can take place in the usual way orally or parenterally, intravenously or intramuscularly.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active substance is between approximately 1 and 100 mg / kg body weight when administered orally and between 0.1 and 10 mg / kg body weight when administered parenterally.
  • the drugs can be used in common galenical forms of administration, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et. Al: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 1 to 99% by weight.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de dérivés de pyrimidine de la formule (I) dans laquelle les substituants ont la signification mentionnée dans la description, ainsi que leur sels physiologiquement tolérables pour préparer des médicaments pour assurer la prophylaxie et le traitement de l'ischémie cérébrale et de l'apoplexie cérébrale.
EP99967980A 1999-01-11 1999-12-24 Utilisation de derives de pyrimidine pour assurer la prophylaxie et la therapie de l'ischemie cerebrale Withdrawn EP1140096A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19900545 1999-01-11
DE19900545A DE19900545A1 (de) 1999-01-11 1999-01-11 Verwendung von Pyrimidinderivaten zur Prophylaxe und Therapie der zerebralen Ischämie
PCT/EP1999/010369 WO2000041695A1 (fr) 1999-01-11 1999-12-24 Utilisation de derives de pyrimidine pour assurer la prophylaxie et la therapie de l'ischemie cerebrale

Publications (1)

Publication Number Publication Date
EP1140096A1 true EP1140096A1 (fr) 2001-10-10

Family

ID=7893836

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99967980A Withdrawn EP1140096A1 (fr) 1999-01-11 1999-12-24 Utilisation de derives de pyrimidine pour assurer la prophylaxie et la therapie de l'ischemie cerebrale

Country Status (24)

Country Link
US (1) US6387912B1 (fr)
EP (1) EP1140096A1 (fr)
JP (1) JP2002534465A (fr)
KR (1) KR20010101442A (fr)
CN (1) CN1334732A (fr)
AU (1) AU2433800A (fr)
BG (1) BG105689A (fr)
BR (1) BR9916887A (fr)
CA (1) CA2359253A1 (fr)
CZ (2) CZ20012484A3 (fr)
DE (1) DE19900545A1 (fr)
HK (1) HK1042649A1 (fr)
HU (1) HUP0201149A3 (fr)
ID (1) ID30022A (fr)
IL (1) IL144146A0 (fr)
MX (1) MXPA01006967A (fr)
MY (1) MY133107A (fr)
NO (1) NO20013409L (fr)
NZ (1) NZ512767A (fr)
PL (1) PL348920A1 (fr)
SK (1) SK9692001A3 (fr)
TR (1) TR200102008T2 (fr)
WO (1) WO2000041695A1 (fr)
ZA (1) ZA200105475B (fr)

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JP4548882B2 (ja) * 1999-11-30 2010-09-22 興和創薬株式会社 ４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン化合物
DE10031389A1 (de) * 2000-07-03 2002-01-17 Knoll Ag Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie
DE10031390A1 (de) * 2000-07-03 2002-01-17 Knoll Ag Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie
DE10259382A1 (de) * 2002-12-18 2004-07-01 Abbott Gmbh & Co. Kg 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-4-on-Derivate, ihre Herstellung und Verwendung
WO2008138126A1 (fr) * 2007-05-09 2008-11-20 Neuromed Pharmaceuticals Ltd. Dérivés bicycliques de pyrimidine en tant que bloqueurs des canaux calciques
US8927718B2 (en) 2009-08-26 2015-01-06 Takeda Pharmaceutical Company Limited Fused heterocyclic ring derivative and use thereof
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
WO2021257863A1 (fr) 2020-06-19 2021-12-23 Incyte Corporation Composés de pyrrolotriazine utilisés en tant qu'inhibiteurs de v617f de jak2
HRP20250814T1 (hr) 2020-07-02 2025-09-12 Incyte Corporation Spojevi tricikličke uree kao jak2 v617f inhibitori
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
WO2022140231A1 (fr) 2020-12-21 2022-06-30 Incyte Corporation Composés de déazaguanine utilisés en tant qu'inhibiteurs de v617f de jak2
CA3211748A1 (fr) 2021-02-25 2022-09-01 Incyte Corporation Lactames spirocycliques utilises comme inhibiteurs du v617f de jak2
IL315647A (en) 2022-03-17 2024-11-01 Incyte Corp Tricyclic urea compounds as Jak2 and 617f inhibitors

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SK9692001A3 (en) 2002-05-09
NO20013409L (no) 2001-08-30
MXPA01006967A (es) 2002-04-10
ID30022A (id) 2001-11-01
NZ512767A (en) 2003-05-30
HUP0201149A2 (hu) 2002-07-29
CA2359253A1 (fr) 2000-07-20
CZ20012484A3 (cs) 2002-05-15
JP2002534465A (ja) 2002-10-15
ZA200105475B (en) 2002-10-03
NO20013409D0 (no) 2001-07-10
WO2000041695A1 (fr) 2000-07-20
TR200102008T2 (tr) 2001-12-21
PL348920A1 (en) 2002-06-17
MY133107A (en) 2007-10-31
BR9916887A (pt) 2001-11-20
KR20010101442A (ko) 2001-11-14
AU2433800A (en) 2000-08-01
BG105689A (en) 2002-02-28
HK1042649A1 (zh) 2002-08-23
HUP0201149A3 (en) 2003-07-28
CZ20012485A3 (cs) 2002-04-17
DE19900545A1 (de) 2000-07-13
CN1334732A (zh) 2002-02-06
IL144146A0 (en) 2002-05-23
US6387912B1 (en) 2002-05-14

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