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Withdrawn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Withdrawn legal-status Critical Current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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (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
DE19900545A DE19900545A1 (de) 1999-01-11 1999-01-11 Verwendung von Pyrimidinderivaten zur Prophylaxe und Therapie der zerebralen Ischämie
DE19900545 1999-01-11
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)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19900673A1 (de) 1999-01-11 2000-07-13 Basf Ag Verwendung von Bindungspartnern für 5-HT5-Rezeptoren zur Behandlung neurodegenerativer und neuropsychiatrischer Störungen
US6988199B2 (en) * 2000-07-07 2006-01-17 Message Secure Secure and reliable document delivery
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
DE10031390A1 (de) * 2000-07-03 2002-01-17 Knoll Ag Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie
DE10031389A1 (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
EP2471791B1 (fr) * 2009-08-26 2014-11-12 Takeda Pharmaceutical Company Limited Dérivé d'hétérocycle condensé et son utilisation
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
JP2023533724A (ja) 2020-07-02 2023-08-04 インサイト・コーポレイション Ｊａｋ２ ｖ６１７ｆ阻害剤としての三環式尿素化合物
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
WO2022046989A1 (fr) 2020-08-27 2022-03-03 Incyte Corporation Composés d'urée tricycliques en tant qu'inhibiteurs de v617f de jak2
WO2022140231A1 (fr) 2020-12-21 2022-06-30 Incyte Corporation Composés de déazaguanine utilisés en tant qu'inhibiteurs de v617f de jak2
US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors
WO2023178285A1 (fr) 2022-03-17 2023-09-21 Incyte Corporation Composés d'urée tricycliques en tant qu'inhibiteurs de jak2 v617f

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4670560A (en) * 1986-04-28 1987-06-02 Ortho Pharmaceutical Corporation Thienopyrimidine-2,4-dione derivatives and intermediates thereof
DE19636769A1 (de) 1996-09-10 1998-03-12 Basf Ag 3-Substituierte Pyrido [4',3':4,5]thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung
DE19724980A1 (de) * 1997-06-13 1998-12-17 Basf Ag 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung
DE19724979A1 (de) 1997-06-13 1998-12-17 Basf Ag 3-substituierte Pyrido [3,4,5]thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0041695A1 *

Also Published As

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

Similar Documents

Publication Publication Date Title
EP0927184B1 (fr) Derives pyrido 4',3':4,5]thieno 2,3-d]pyrimidine substitues en position 3, leur preparation et leur utilisation
EP0988306B1 (fr) Derives de 3,4-dihydro-thieno 2,3-d]pyrimidine 3-substitues, leur preparation et leur utilisation
WO2000041695A1 (fr) Utilisation de derives de pyrimidine pour assurer la prophylaxie et la therapie de l'ischemie cerebrale
EP2176266A2 (fr) Imidazo[1,2b]pyridazines substituees constituant des inhibiteurs de kinases, leur production et leur utilisation comme medicaments
WO2002002568A1 (fr) Derives de la pyrimidine et leur utilisation pour la prophylaxie et le traitement de l'ischemie cerebrale
EP0584487A2 (fr) 4,5-Dihydro-4-oxopyrrolo (1,2-a) quinoxalines et aza analogues et procédé pour leur préparation
EP1003752A1 (fr) Derives de 3,4,5,7-tetrahydro-pyrrolo 3',4':4,5]thieno 2,3-d]pyrimidine 3-substitues, leur preparation et leur utilisation comme antagonistes de 5ht
DE4325900A1 (de) Trisubstituierte Pyrimido [5,4-d] pyrimidine zur Modulation der Multidrugresistenz, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE1934172A1 (de) Neue Pyrimidinderivate und Verfahren zu ihrer Herstellung
DE2526983A1 (de) Pyrido/1,2-a/pyrimidinon-derivate und verfahren zu deren herstellung
EP1023296B1 (fr) Derives de pyrido 3',4':4,5]thieno 2,3-d]pyrimidine 3-substitues, leur preparation et leur utilisation
CA1073905A (fr) Derives de l'acide pyrazolo (1,5-a) pyrido (3,2-e) pyrimidine-7-carboxylique
EP1140099A1 (fr) Utilisation de derives de 1,2-benzisothiazol 2-substitues et de derives de tetrahydropyridopyrimidinone 3-substitues pour assurer la prophylaxie et le traitement de l'ischemie cerebrale
Chaykovsky et al. 2, 4-Diaminothieno [2, 3-d] pyrimidines as antifolates and antimalarials. 2. Synthesis of 2, 4-diaminopyrido [4', 3': 4, 5] thieno [2, 3-d] pyrimidines and 2, 4-diamino-8H-thiopyrano [4', 3': 4, 5] thieno [2, 3-d] pyrimidines
WO2024220633A1 (fr) Dérivés de pyrrolopyridine en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
DE1908497A1 (de) Neue Pyrimidinderivate und Verfahren zu deren Herstellung
CH500226A (de) Verfahren zur Herstellung neuer Pyrimidinderivate
CH508649A (de) Verfahren zur Herstellung von 5,6,7,8-Tetrahydro(1)benzothieno(2,3-d)pyrimidinen

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: 20010619

AK Designated contracting states

Kind code of ref document: A1

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 PAYMENT 20010619;SI PAYMENT 20010619

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

RTI1 Title (correction)

Free format text: PYRIMIDINE DERIVATIVES FOR PREVENTING AND TREATING CEREBRAL ISCHAEMIA

RTI1 Title (correction)

Free format text: PYRIMIDINE DERIVATIVES FOR PREVENTING AND TREATING CEREBRAL ISCHAEMIA

17Q First examination report despatched

Effective date: 20020215

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

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: 20030702