WO2006071035A1 - Nouveaux derives de ([1,3]thiazolo[5,4-b]pyridin-2-yl)-2-carboxamide - Google Patents

Nouveaux derives de ([1,3]thiazolo[5,4-b]pyridin-2-yl)-2-carboxamide Download PDF

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WO2006071035A1
WO2006071035A1 PCT/KR2005/004524 KR2005004524W WO2006071035A1 WO 2006071035 A1 WO2006071035 A1 WO 2006071035A1 KR 2005004524 W KR2005004524 W KR 2005004524W WO 2006071035 A1 WO2006071035 A1 WO 2006071035A1
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pyridine
thiazolo
methyl
amino
urea
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PCT/KR2005/004524
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English (en)
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Jinho Lee
Seihyun Choi
Seunghyun Yoon
Hwan Geun Choi
Yun Sik Kim
Young Kwan Kim
Kiwon Jo
Semi Kim
Sun-Young Koo
Jung In Kim
Jieun Kim
Sang-Yong Hong
Jeong-Yong Suh
Sun Hwa Lee
Hae-Seong Yoon
Heung-Soo Cho
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Lg Life Sciences, Ltd.
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Publication of WO2006071035A1 publication Critical patent/WO2006071035A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • 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 present invention relates to novel compounds having ([l,3]thiazolo[5,4- 6]pyridine-2-yl)-2-carboxamide structure, and more specifically, to novel compounds for inhibition of VEGF-Receptor-2-kinase ("VEGFR2 kinase” or “KDR”, hereinafter, referred to as "KDR”) activity, as will be illustrated in Formula 1 later herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, and prodrug thereof.
  • VEGFR2 kinase VEGFR2 kinase
  • KDR a pharmaceutically acceptable salt, hydrate, solvate, isomer, and prodrug thereof.
  • the compounds according to the present invention are useful for the treatment and prevention of angiogenesis-related diseases, particularly resulting from the unregulated or undesired KDR activity, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • Angiogenesis referring to the physiological mechanism of generating new blood vessels for providing nutrients and oxygen required for cell survival and eliminating metabolites therefrom, allows only 0.01% of blood vessel cells to proliferate under normal conditions, thereby recovering wounded parts in blood vessels (Carmeliet et ah, 2000, Nature 407:249-257).
  • angiogenesis is further required.
  • solid tumors cannot practically grow over a certain size (e.g., about 100 - 200 ⁇ m in diameter). That is because there is a limit on the distance over which nutrients or oxygen can reach cells by diffusion (the so-called diffusion limit) (Carmeliet et ah, 2000, Nature 407:249-257).
  • cancer cells distant from blood vessels become hypoxic due to oxygen deficiency.
  • cancer cells or stromal cells secrete various pro- angiogenic factors to induce angiogenesis toward a solid tumor.
  • pro- angiogenic factors there are VEGF (Vascular Endothelial Growth Factor), bFGF (basic Fibroblast Growth factor), PDGF (Platelet-derived growth factor), and the like.
  • VEGF Vascular Endothelial Growth Factor
  • bFGF basic Fibroblast Growth factor
  • PDGF Platinum-derived growth factor
  • Rheumatoid arthritis a non-cancer angiogenesis-related disease, refers to a disease state wherein newly created capillary vessels destroy cartilaginous tissues as arthritis proceeds to chronic inflammatory disease.
  • diabetic retinopathy refers to the disease caused by invasion of capillary vessels into the vitreous body of retina. It is known that pre-angiogenic factors are secreted from ischemic retina to cause diabetic retinopathy. Since eyes are tissues with the least vascularization in body, angiogenesis results directly in the loss of eyesight. As such, the ultimate therapy can be achieved only by prevention of angiogenesis (Carmeliet P., 2000, Nature Medicine 6: 389-395, Aiello L. P., 2000, Nature Medicine 6: 379-381).
  • Angiogenesis receptor tyrosine kinases as receptors of pro-angiogenic factors, such as VEGFR2 (KDR), FGFRl, PDGFR- ⁇ and the like, have drawn attention as a target for development of anti-angiogenesis drugs.
  • Such anti- angiogenesis drugs exhibit the effect of inhibiting the activity of VEGFR2 (KDR) and simultaneously also inhibiting the activity of other angiogenesis RTK family receptors. This combined inhibition effect is known as one mechanism to significantly increase the angiogenesis inhibition effect (Adams et al., 2002, Current Opinion in Chemical Biology, 5:486-492). Therefore, much research is directed toward identifying compounds useful in the treatment and prevention of angiogenesis-related diseases such as cancers, rheumatoid arthritis, diabetic retinopathy, etc.
  • the inventors of the present invention while carrying out extensive research and many experiments, synthesized novel compounds capable of inhibiting KDR activity and, after investigating their inhibitory effect, found that they can be used in the treatment or prevention of angiogenesis-related diseases resulting from the undesired or unregulated KDR activity, for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • the present invention was accomplished on the basis of such finding. According to the present invention there is provided a compound of Formula 1
  • R 1 is one selected from the group consisting of
  • Y 1 and Y 2 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl;
  • Y 3 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl, and
  • Y 4 is selected from the group consisting of hydrogen, lower alkoxy, pyrrolidinone, pyrrolidine, piperidine, thiophene, optionally substituted piperazine, morpholine, aziridine, lower alkylamine, carboxy, sulfide, hydroxy, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl;
  • n is an integer from 0 to 3;
  • Zi is selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl, or two substituents are combined to form a cyclic saturated alkyl or a cyclic saturated alkyl interrupted by N, O or S;
  • Z 2 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl;
  • Z 3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furane, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl; and n is an integer from 0 to 3;
  • R 2 is selected from the group consisting of cyclic alkyl, aryl, heteroaryl, optionally substituted cyclic alkyl, aryl and heteroaryl;
  • R 3 is selected from the group consisting of hydrogen, optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl;
  • X is selected from the group consisting of O, S and NR', where R' is hydrogen or lower alkyl.
  • the substituent group(s) is(are) substituted with one or more group(s) individually and independently selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acetyl, isocyanato, thiocyanato, isothi
  • Typical alkyl groups may be individually or independently substituted with one or more groups selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "pharmaceutically acceptable salt” means a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • Other terms such as “hydrate”, “solvate” and “isomer” also have the same meaning as the above.
  • Pharmaceutical salts can be prepared by treating a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid or p-toluenesulfonic acid; or organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, caproic acid, isobutanic acid, oxalic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid or salicylic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid
  • sulfonic acids such as methanesulfonic acid, ethanesul
  • Pharmaceutical salts can also be prepared by reacting a compound of the invention with a base to form salts such as ammonium salts, alkali metal salts such as sodium or a potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine or tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • salts such as ammonium salts, alkali metal salts such as sodium or a potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine or tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • hydrate means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound thereto by non-covalent intermolecular forces.
  • solvate means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound thereto by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • isomer means a compound of the present invention or a salt thereof, that has the same chemical formula or molecular formula but is optically or stereochemically different therefrom.
  • prodrug means an agent that is converted into the parent drug in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transport across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an active group, where the peptide is metabolized to reveal the active moiety.
  • aryl means an aryl group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine).
  • carbocyclic aryl e.g., phenyl
  • heterocyclic aryl groups e.g., pyridine
  • the term includes monocyclic or fused- ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • heteroaryl means an aryl group which contains at least one heterocyclic ring.
  • heterocycle means a cyclic group in which one or more ring carbons are replaced with oxygen, nitrogen or sulfur and which includes, for example, but is not limited to furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, etc.
  • alkyl means an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated may be branched, straight chain, or cyclic.
  • the alkyl group may have 1 to 20 carbon atoms.
  • the alkyl group may also be a medium-sized alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds of the invention may be designated as "C 1 -C 4 alkyl" or similar designations.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acetyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfonyl* pyrrolidinone, pyrrolidine, piperidine, piperazine, thiophene, morpholine, amino including
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • R refers to a substituent selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl (bonded through a ring carbon) and optionally substituted heteroalicyclic (bonded through a ring carbon).
  • a "cyano" group refers to a -CN group.
  • An “isocyanato” group refers to a -NCO group.
  • a "thiocyanato" group refers to a -CNS group.
  • An “isothiocyanato” group refers to a -NCS group.
  • a "trihalomethanesulfonamido" group refers to a Z 3 CS( ⁇ O) 2 NR- group wherein Z and R are as defined herein, respectively.
  • perhaloalkyl refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.
  • R 1 is preferably selected from the substituents I) - IX) as follows:
  • substituents selected from the group consisting of halogen, amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidin
  • alkenyl substituted with one or more substitutents selected from the group consisting of optionally substituted lower alkyl, halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
  • Z 2 is optionally substituted lower alkylene
  • Z 3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl.
  • R 2 is preferably selected from the substituents I) - IV) as follows:
  • cyclic alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carbonyl, carbamate, carboxy, acetyl, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl ;
  • substituents selected from the group consisting of halogen, hydroxy, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
  • R 2 is preferably aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl, more preferably aryl substituted with halogen, lower alkyl or hydroxy.
  • substituents selected from the group consisting of halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulf
  • R 3 is preferably selected from the substituents I) - III) as follows:
  • substituents selected from the group consisting of halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amino, lower alkylamino, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
  • R 3 is more preferably hydrogen or lower alkyl.
  • X is preferably O or S, more preferably S.
  • Representative compounds of the present invention include, for example, but are not limited to the following compounds: 1. iV-[5-(4-chloroanilino)[l ,3]thiazolo[5,4- ⁇ ]pyridine-2-yl] cyclopentanecarboxamide
  • the present invention also provides processes for preparation of the compound of Formula 1.
  • the compound according to the present invention can be prepared by various processes.
  • the preparation processes described herein below are only exemplary ones and a variety of processes can also be anticipated based upon the general technologies and practices in the organic chemistry synthesis field. As such, the scope of the instant invention is not limited to the below processes.
  • the compound of Formula 1 can be prepared by the process comprising (i) a step of introducing a NR 2 R 3 substituent as defined in Formula 1 into 2-chloro-5-nitropyridine of Formula 2 below as a starting material, (ii) a step of preparing hetero pyridine, and (iii) a step of introducing carboxamide thereto.
  • the process for preparing the compound of Formula 1 comprises,
  • the process for preparing the compound of Formula 1 comprises,
  • R 4 is as defined above, R 5 is the same as R 4 , and Ra is -NZ 1 (Z 2 )H-Z 3 .
  • the compound according the present invention is effective for the treatment and prevention of diseases associated with angiogenesis, and particularly those diseases associated with unregulated or undesired KDR activity. Therefore, the present invention provides the use of the compound of Formula 1 for manufacture of a medicament for the treatment or prevention of diseases resulting from an unregulated or undesired KDR activity.
  • diseases include, for example, but are not limited to cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic cardiovascular disease, atherosclerosis, Kaposi's sarcoma, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • composition means a mixture of a compound of the invention with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but are not limited to oral, injection, aerosol, parenteral, and topical administrations.
  • Pharmaceutical compositions can also be obtained by reacting compounds with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • a therapeutically effective amount means that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease being treated.
  • a therapeutically effective amount refers to that amount which has the effect of (i) reversing the rate of progress of a disease, or, in case of cancer reducing the size of the tumor; (ii) inhibiting to some extent further progress of the disease, which in case of cancer may mean slowing to some extent, or preferably stopping tumor metastasis or tumor growth; and/or, (iii) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the disease.
  • carrier means a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • diot defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the ionic strength conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • the compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • the pharmaceutical composition of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the agents of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compound of the present invention to be formulated as tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension and the like, for oral ingestion by a patient.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compounds of the present invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in a conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powdered mixture of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 85% w/v of the nonpolar surfactant Polysorbate 80 ® , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:D5W) consists of VPD diluted 1 :1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself has minimal toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80 ® ; the fraction of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide may also be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.
  • compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 5O as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 5O . Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 o with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the attending physician in view of the patient's condition (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as needed.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the angiogenesis receptor tyrosine kinase inhibition effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g., the concentration necessary to achieve 50-90% inhibition of the angiogenesis receptor tyrosine kinases using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the j udgment of the prescribing physician.
  • PREPARATION 8 Preparation of ⁇ -(2-fluorophenyl)[l,3]thiazolo[5,4-6] pyridine-2,5-diamine
  • PREPARATION 11 Preparation of iV 6 -(2-fluorophenyl)[l,3]thiazolo[5,4-fr
  • PREPARATION 12 Preparation of ⁇ -(S-fluoro ⁇ -methylphenyl) [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
  • PREPARATION 13 Preparation of - ⁇ 6 -(4-chloro-2-fluorophenyl) [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
  • PREPARATION 14 Preparation of ⁇ -(2,4-difluorophenyl)[l,3]thiazolo[5,4- 6]pyridine-2,5-diamine
  • PREPARATION 18 Preparation of 2-( ⁇ [5-(4-chloro-2-fluoroanilino) [1 ,3] thiazolo [5,4-6] py ridine-2-yl] amino ⁇ carbonyl)cyclopropanecarboxylic acid
  • PREPARATION 20 Preparation of iV 6 -(4-chlorophenyl)- ⁇ ' 6 -methyl [l,3]thiazoIo[5,4-Z>]pyridine-2,5-diamine
  • PREPARATION 22 Preparation of - ⁇ 6 -(2,4-difluorophenyl)-iV 6 -methyl [l,3]thiazolo[5,4-Z>]pyridine-2,5-diamine
  • PREPARATION 23 Preparation of iV 6 -(2,6-difluorophenyl)-iV 6 -methyl [l,3]thiazolo[5,4-Z>]pyridine-2,5-diamine
  • PREPARATION 24 Preparation of iV 6 -(4-bromo-2-fluorophenyl)- ⁇ ' 6 -methyl [l,3]thiazolo[5,4-6]pyridine-2,5-diamine
  • PREPARATION 25 Preparation of ⁇ ' 6 -(2-methoxyphenyl)-iV 6 -methyl [l,3]thiazolo[5,4-6]pyridine-2,5-diamine
  • PREPARATION 26 Preparation of ⁇ - ⁇ -difluorophenyO- ⁇ -methyl [ 1 ,3] thiazolo [5,4-A] py ridine-2,5-diamine
  • PREPARATION 27 Preparation of iV 6 -methyl-iV 6 -[4-(trifluoromethyl)phenyl] [l,3]thiazolo[5,4- ⁇ ]pyridine-2,5-diamine
  • PREPARATION 28 Preparation of 7V 6 -(4-methoxypheny I)-JV 6 - methy 1 [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
  • PREPARATION 29 Preparation of 7V 6 -(4-isopropyIphenyl)-i ⁇ 6 -methyl[l,3]- thiazolo[5,4- ⁇ ]pyridine-2,5-diamine
  • PREPARATION 30 Preparation of iV 6 -(2,3-dihydro-l ⁇ -indene-5-yI)-iV 6 - methy 1 [ 1 ,3] thiazolo [5,4-Z>] py ridine-2,5-diamine
  • PREPARATION 31 Preparation of ethyl 2- ⁇ 4-[2-amino[l,3]thiazolo[5,4-6] pyridine-5-yl](methyl)amino ⁇ phenyI ⁇ acetate
  • PREPARATION 32 Preparation of ⁇ - ⁇ -chlorophenylJ-iV 6 - ethyl[l,3]thiazolo[5,4-6]pyridine-2,5-diamine
  • PREPARATION 33 Preparation of ethyl 2-[4-chIoro(5-nitro-2- py ridinyl)anilino] acetate
  • PREPARATION 35 Preparation of ethyl 2-[(2-amino[l,3]thiazolo[5,4- ⁇ ]pyridine-5-yl)-4-chloroanilino]-l-ethanol
  • PREPARATION 38 Preparation of 4-[(2-amino[l,3]thiazoIo[5,4-6]pyridine-5- yl)(methyl)amino] benzoate
  • PREPARATION 40 Preparation of tert-butyl 4-((£)-3- ⁇ [5-(4-bromo-2- fluoromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yI]amino ⁇ -3-oxo-l-(propenyl)- 1 -piperidinecarboxy late 5.96 g (11.2 mmol) of the compound obtained in PREPARATION 39 was dissolved in 100 ml of tetrahydrofuran and 3.58 g (16.8 mmol) of 4-formyl-piperidine-
  • PREPARATION 41 Preparation of (E)-N- ⁇ 5-[4- chloro(methyl)anilino][l,3]thiazolo[5,4-/>]pyridine-2-yl ⁇ -3-(4-piperidinyI)-2- propeneamide
  • PREPARATION 46 Preparation of 2-[(2-amino[l,3]thiazolo[5,4-6] ⁇ yridine-5- yI)(methyl)amino]-5-fluorophenol
  • PREPARATION 47 Preparation of 2-[ ⁇ 2-[(cyclopropylcarbonyl)amino]- [l,3]thiazolo[5,4-Z»]pyridine-5-yl ⁇ (methyl)amino]-5-fluorophenyI cyclopropanecarboxylate
  • the reaction solution was dissolved in 50 ml of water and then extracted three times with 100 ml of ethyl acetate, respectively.
  • the collected organic layer was washed with 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO 4 .
  • the crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol 9/1, v/v) to give 4.68 g (11.6 mmol) of the title compound at a yield of 64%.
  • the reaction solution was dissolved in 50 ml of water and then extracted three times with 100 ml of ethyl acetate, respectively.
  • the collected organic layer was washed with 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO 4 .
  • the crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol 9/1, v/v) to give 4.85 g (11.6 mmol) of the title compound at a yield of 64%.
  • EXAMPLE 16 Preparation of iV-[5-(4-fluoro-2-hydroxy ⁇ iethyIanilino [l,3]thiazolo[5,4-Z>]pyridine-2-yl]-cyclopropanecarboxyamide 56 mg (0.13 mmol) of the compound, obtained in PREPARATION 47, was dissolved in methanol/water (2 ml/2ml, v/v). To the solution, 17 mg (0.39 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature.
  • EXAMPLE 48 Preparation of iV- ⁇ 5-[4-chIoro(ethyl)aniline][l,3]thiazolo[5,4- 6]pyridine-2-yl ⁇ acrylamide
  • EXAMPLE 50 Preparation of 2-(4-chloro ⁇ 2-[(cyclopropyIcarbonyl)amino] [l,3]thiazolo[5,4-Z>]pyridine-5-yl ⁇ aniIino)acetic acid 5.77 g (13.4 mmol) of the compound as obtained in EXAMPLE 49 was dissolved in 100 ml of tetrahydrofuran/ethanol/water (3/1/1). To the solution, 1.12 g (26.8 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature. After 8 hours, the reaction solution was neutralized with IN aqueous hydrochloric acid solution.
  • reaction solution was extracted twice with 100 ml of ethyl acetate and then dried over anhydrous MgSO 4 . After removing the solvent by distillation under reduced pressure, 3.67 g (9.11 mmol) of the title compound was obtained at a yield of 68%, without any further purification step.
  • EXAMPLE 68 Preparation of (£)-7V- ⁇ 5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-£]pyridine-2-yl ⁇ -3-(l-ethyl-4-piperidinyl)-2-propeneamide 3.83 g (8.26 mmol) of the compound as obtained in PREPARATION 41 was introduced into 100 ml of dichloromethane, and 2.09 g (20.7 mmol) of triethylamine was dded thereto, followed by stirring at room temperature.
  • reaction solution was diluted with 200 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO 4 .
  • the crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol 9/1, v/v) to give 1.53 g (3.44 mmol) of the title compound at a yield of 19%.
  • EXAMPLE 72 Preparation of 4-[ ⁇ 2-[(cyclopropylcarbonyl)amino][l,3] thiazolo[5,4-6]pyridine-5-yl ⁇ (methyl)amino]-7V-[2-(dimethyIaino)ethyl]benzamide
  • EXAMPLE 71 was conducted by using 1.38 g (15.6 mmol) of ⁇ iV-dimethylethylenediamine instead of acetaldehyde, thereby obtaining 2.83 g (6.45 mmol) of the title compound at a yield of 62%.
  • EXAMPLE 75 Preparation of iV- ⁇ 5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4- 6]pyridine-2-yl ⁇ -l-methyl-l//-imidazole-5-carboxamide
  • EXAMPLE 79 Preparation of (£)-iV- ⁇ 5-[4-chloro(methyl)aniIino][l,3] thiazolo[5,4-6]pyridine-2-yl ⁇ -4-(l,4-dioxa-8-azaspiro[4.5]de-8-cyl)-2-buteneamide
  • the same procedure as in EXAMPLE 70 was conducted except that 7.78 g (54.3 mmol) of 4-piperidine ethylene ketal was used instead of morpholine, thereby obtaining 903 mg (1.81 mmol) of the title compound at a yield of 10%.

Abstract

La présente invention concerne de nouveaux composés ayant une structure de ([1,3]thiazolo[5,4- b]pyridin-2-yl)-2-carboxamide, illustrée par la Formule 1, destinés à l'inhibition des tyrosine-kinases de récepteurs impliqués dans l'angiogenèse, en particulier, à l'inhibition de l'activité kinase du récepteur 2 du VEGF ('KDR'). L'invention concerne également des procédés de préparation de ces composés, leur utilisation et une composition pharmaceutique comprenant une quantité thérapeutiquement efficace desdits composés. Les composés selon la présente invention sont utiles dans le traitement et la prévention de maladies liées à l'angiogenèse, particulièrement celles résultant de l'activité non contrôlée ou non souhaitée du récepteur KDR, telles que les cancers, le psoriasis, la polyarthrite rhumatoïde, la rétinopathie diabétique, etc.
PCT/KR2005/004524 2004-12-31 2005-12-26 Nouveaux derives de ([1,3]thiazolo[5,4-b]pyridin-2-yl)-2-carboxamide WO2006071035A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008043183A1 (fr) * 2006-10-13 2008-04-17 Neuromed Pharmaceuticals Ltd. Composés de cyclopropyl-pipérazine en tant qu'inhibiteurs calciques
EP2184285A1 (fr) * 2007-08-29 2010-05-12 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
WO2010064611A1 (fr) 2008-12-01 2010-06-10 武田薬品工業株式会社 Composé hétérocyclique et applications
WO2010064722A1 (fr) 2008-12-02 2010-06-10 Takeda Pharmaceutical Company Limited Dérivés de benzothiazole convenant comme agents anticancéreux
JP2011522024A (ja) * 2008-06-04 2011-07-28 アストラゼネカ アクチボラグ 抗細菌薬としてのチアゾロ［５，４−ｂ］ピリジンおよびオキサゾロ［５，４−ｂ］ピリジン誘導体
US8304557B2 (en) 2007-06-05 2012-11-06 Takeda Pharmaceutical Company Limited Fused heterocycle derivatives and use thereof
US8324395B2 (en) 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
CN114437113A (zh) * 2022-03-18 2022-05-06 西安交通大学 一种噻唑并吡啶环联三氮唑类化合物及其制备方法和应用
WO2023134708A1 (fr) * 2022-01-12 2023-07-20 Beigene , Ltd. Dérivés de thiazolopyridyl amide en tant qu'inhibiteurs d'adn polymérase thêta

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050356A1 (fr) * 1997-05-07 1998-11-12 Sugen, Inc. Derives de 2-indolinone utilises en tant que modulateurs de l'activite de la proteine kinase
WO2001057008A1 (fr) * 2000-02-07 2001-08-09 Abbott Gesellschaft Mit Beschrankter Haftung & Company Kommanditgesellschaft Derives de 2-benzothiazolyle uree et leur utilisation en tant qu'inhibiteurs de proteine kinase
WO2001062252A1 (fr) * 2000-02-25 2001-08-30 Merck & Co., Inc. Inhibiteurs de tyrosine-kinase
US20040138464A1 (en) * 2002-12-02 2004-07-15 Teresa Mujica-Fernaud 2-Oxadiazolechromone derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050356A1 (fr) * 1997-05-07 1998-11-12 Sugen, Inc. Derives de 2-indolinone utilises en tant que modulateurs de l'activite de la proteine kinase
WO2001057008A1 (fr) * 2000-02-07 2001-08-09 Abbott Gesellschaft Mit Beschrankter Haftung & Company Kommanditgesellschaft Derives de 2-benzothiazolyle uree et leur utilisation en tant qu'inhibiteurs de proteine kinase
WO2001062252A1 (fr) * 2000-02-25 2001-08-30 Merck & Co., Inc. Inhibiteurs de tyrosine-kinase
US20040138464A1 (en) * 2002-12-02 2004-07-15 Teresa Mujica-Fernaud 2-Oxadiazolechromone derivatives

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008043183A1 (fr) * 2006-10-13 2008-04-17 Neuromed Pharmaceuticals Ltd. Composés de cyclopropyl-pipérazine en tant qu'inhibiteurs calciques
US8304557B2 (en) 2007-06-05 2012-11-06 Takeda Pharmaceutical Company Limited Fused heterocycle derivatives and use thereof
US8324395B2 (en) 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
EP2184285A1 (fr) * 2007-08-29 2010-05-12 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
EP2184285A4 (fr) * 2007-08-29 2011-07-20 Takeda Pharmaceutical Composé hétérocyclique et son utilisation
US8344135B2 (en) 2007-08-29 2013-01-01 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
JP2011522024A (ja) * 2008-06-04 2011-07-28 アストラゼネカ アクチボラグ 抗細菌薬としてのチアゾロ［５，４−ｂ］ピリジンおよびオキサゾロ［５，４−ｂ］ピリジン誘導体
US8697874B2 (en) 2008-12-01 2014-04-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2010064611A1 (fr) 2008-12-01 2010-06-10 武田薬品工業株式会社 Composé hétérocyclique et applications
JP5579619B2 (ja) * 2008-12-01 2014-08-27 武田薬品工業株式会社 複素環化合物およびその用途
WO2010064722A1 (fr) 2008-12-02 2010-06-10 Takeda Pharmaceutical Company Limited Dérivés de benzothiazole convenant comme agents anticancéreux
US8497274B2 (en) 2008-12-02 2013-07-30 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8143258B2 (en) 2008-12-02 2012-03-27 Takeda Pharmaceutical Company Limited Benzothiazole compounds useful for Raf inhibition
WO2023134708A1 (fr) * 2022-01-12 2023-07-20 Beigene , Ltd. Dérivés de thiazolopyridyl amide en tant qu'inhibiteurs d'adn polymérase thêta
CN114437113A (zh) * 2022-03-18 2022-05-06 西安交通大学 一种噻唑并吡啶环联三氮唑类化合物及其制备方法和应用

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