WO2006068410A1 - Novel 3-(2-amino-6-pyridinyl)-4-hydroxyphenyl amine derivatives - Google Patents

Novel 3-(2-amino-6-pyridinyl)-4-hydroxyphenyl amine derivatives Download PDF

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WO2006068410A1
WO2006068410A1 PCT/KR2005/004418 KR2005004418W WO2006068410A1 WO 2006068410 A1 WO2006068410 A1 WO 2006068410A1 KR 2005004418 W KR2005004418 W KR 2005004418W WO 2006068410 A1 WO2006068410 A1 WO 2006068410A1
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Prior art keywords
amino
hydroxyphenyl
methyl
pyridinyl
chloro
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PCT/KR2005/004418
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English (en)
French (fr)
Inventor
Jinho Lee
Yun Sik Kim
Seihyun Choi
Hwan Geun Choi
Seunghyun Yoon
Young Kwan Kim
Kiwon Jo
Min-Hyeung Kim
Sun-Young Koo
Jieun Kim
Jung In Kim
Dongchul Lim
Kyoung-Hee Kim
Ji Soo Song
Hae-Seong Yoon
Heung-Soo Cho
Joonghoon Park
Jin-A Hwang
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Lg Life Sciences, Ltd.
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Publication of WO2006068410A1 publication Critical patent/WO2006068410A1/en

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    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/73Unsubstituted amino or imino radicals
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
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    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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    • A61P19/00Drugs for skeletal disorders
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to novel compounds having 3-(2-amino-6- pyridinyl)-4-hydroxyphenyl amine structure, more specifically, novel compounds for inhibition of VEGF receptor 2 kinase (hereinafter, referred to as "VEGFR2 kinase” or “KDR”) activity, as will be illustrated in Formula 1 later, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, and prodrug thereof.
  • VEGFR2 kinase ase activity
  • KDR VEGF receptor 2 kinase
  • the compounds according to the present invention is useful for the treatment and prevention of angiogenesis-related diseases, particularly resulting from the undesired KDR activity, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • Angiogenesis referring to the physiological mechanism that makes new blood vessels for providing nutrients and oxygen necessary for cell survival and eliminating waste materials therefrom, allows only 0.01% of blood vessel cells to proliferate under a normal condition, thereby recovering wounded parts in blood vessels (Carmeliet et al., 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 that nutrients or oxygen can reach cells by diffusion (so-called, diffusion limit) (Carmeliet et al., 2000, Nature 407:249-257).
  • cancer cells distant from blood vessels become under the hypoxia condition due to the deficiency of oxygen.
  • cancer cells or stromal cells secrete various pro-angiogenic factors to induce angiogenesis toward a solid cancer.
  • 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 refers to the disease that capillary vessels created newly while arthritis proceeding to chronic inflammatory disease invade articulation to destroy cartilaginous tissues.
  • 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 the diabetic retinopathy. Since eyes are tissues with most rarely blood vessels in body, angiogenesis results in directly 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, draw an attention as a target for development of anti-angiogenesis drugs.
  • anti-angiogenesis drugs exhibit the effect of inhibiting the activity of VEGFR2 (KDR) and simultaneously also inhibiting the activity of other angiogenesis RTK families.
  • This combined inhibiting effect is known as one mechanism of significantly increasing the angiogenesis inhibiting effect (Adams et al., 2002, Current Opinion in Chemical Biology, 6:486- 492). Therefore, many researches are being carried out to find 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 researches and many experiments, could synthesize novel compounds capable of inhibiting the KDR activity and, after measuring their inhibition abilities, found that they can be used in treatment or prevention of angiogenesis-related diseases, for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc., resulting from the undesired activation of KDR.
  • angiogenesis-related diseases for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • R 1 is an aryl, heteroaryl, or optionally substituted aryl or heteroaryl;
  • R 2 is one selected from the group consisting of
  • R 3 is selected from the group consisting of
  • X 1 is a direct bond, oxygen, optionally substituted amino, optionally substituted alkyl, or optionally substituted aryl;
  • X 2 is selected from the group consisting of hydrogen, pyrrolidine, piperazine, morpholine, lower alkyl amine, hydroxyl, halogen, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl, optionally substituted piperidine and optionally substituted thiazole; and
  • X 3 is selected from the group consisting of hydrogen, halogen and optionally substituted lower alkyl
  • X 4 and X 5 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted sulfone and alkyl carbamate, or X 4 and X 5 are together taken to form optionally substituted cyclic or heterocyclic group;
  • n 1 to 5;
  • R 4 is selected from the group consisting of
  • substituent group(s) may be covalently bonded to the primary molecule.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, oxo, cyano, halogen, carbonyl, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, optionally substituted sulfonyl, C-carboxy, O-carboxy, isocyanato,
  • 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. Therefore, wherever a substituent is described as being "optionally substituted” that substituent may be substituted with one of the above substituents.
  • 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, 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, ethanesulfonic acid or p-
  • Pharmaceutical salts can also be prepared by treating 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.
  • the term “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.
  • the compounds of Formula 1 in the present invention may have an asymmetric carbon center according to the kind of substituents, and in this case, they can be present in the form of optical isomers such as enantiomers or diastereomers.
  • 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.
  • Formula 1 is intended to include the compound itself, and/or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof.
  • 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, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • 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.
  • substituent is described as being "optionally substituted", that substituent may be substituted with one of the above substituents.
  • R refers to a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and 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.
  • N-sulfonamido refers to a RS( ⁇ O) 2 NH- group wherein R is as defined herein.
  • perhaloalkyl refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.
  • R 1 is preferably an aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, lower alkyl, amino and lower alkoxy.
  • R 1 is more preferably a phenyl substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, C 1 -C 5 alkyl, amino and C 1 -C 5 alkoxy.
  • R 2 is preferably hydrogen or lower alkyl, and more preferably hydrogen or C 1 -C 5 alkyl.
  • X 3 is preferably hydrogen, and n is 1 or 2, and more preferably 1.
  • R 4 is preferably hydrogen or cyclic lower alkyl containing N or O.
  • Representative compounds of the present invention include, for example, but are not limited to the following compounds:
  • 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 NRjR 2 as defined in Formula 1 into 5- bromo-2-hydroxyacetophenone of Formula 2 below as a starting material, (ii) a step of introducing a pyrimidine substituent thereto, and (iii) a step of introducing R 3 by the conversion of nitrile group.
  • the step of performing the conversion of the carboxyl group after the introduction of the pyrimidine substituent comprises,
  • PG means a protecting group and includes, for example, but is not limited to t-butyl, alkyl ether, substituted or unsubstituted benzyl group, and the like,
  • the process for introducing various substituents by the conversion of the cyano group as defined in Formula 8 comprises,
  • the process also comprise,
  • the compound of Formula 4 may be prepared from p-anisidine as defined in the compound of Formula 11 below as a starting material, as shown in Reaction Scheme 1.
  • Bn means a benzyl group as a protecting group.
  • Reaction Scheme 2 illustrates the preparation of a compound in which R 1 is 4-chloro-2-fluorobenzene, R 2 is methyl, R 3 is cyano and R 4 is hydrogen in Formula 1.
  • Bn means a benzyl group as a protecting group.
  • 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 as defined in claim 1 for manufacture of a medicament for the treatment or prevention of these diseases.
  • 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, ethanesulfonic 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.
  • 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.
  • a suitable propellant e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
  • 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.
  • 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, 8% 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. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 50 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 50 .
  • 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 50 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 judgment of the prescribing physician.
  • the solid compound was dissolved in 1500 ml of toluene, then 200 ml of ethylene glycol and catalytic amount (3 g) of p-toluenesulfonic acid were added thereto, followed by stirring under Dean-Stark reflux for 48 hours. After completion of the reaction, 300 ml of ethyl acetate was added thereto, and the reaction mixture was washed 3 times with water, then the residue was concentrated to obtain 533 g (0.999 mol) of the title compound in a yield of 94%.
  • PREPARATION 2 4-(benzyloxy)-N-(4-chlorophenyl)-N-methyl-3-(2-methyl-l,3- dioxolane-2-yl)aniline
  • PREPARATION 3 l- ⁇ 2-(benzyloxy)-5-[4-chloro(methyl)anilino]phenyl ⁇ -l- ethanone 6.59 g (16.1 mmol) of the compound obtained in PREPARATION 2 was dissolved in 100 ml of methanol, and 20 ml of aqueous 6 N hydrochloride was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was cooled and neutralized with aqueous 6 N sodium hydroxide. The methanol was removed by evaporation in vacuo, and 100 ml of water was added thereto. The precipitated solids were filtered and dried to obtain 5.78 g (15.6 mmol) of the title compound in a yield of 97%.
  • reaction mixture was allowed to stir at room temperature for 1 hour. After completion of the reaction, 20 ml of water added thereto, the reaction solution was extracted twice with 20 ml of ethyl acetate. The residue was concentrated and purified by the column chromatography to obtain 17 mg (0.040 mmol) of the title compound in a yield of 24%.
  • EXAMPLE 11 tert-butyl (2-amino-6- ⁇ 5-[4-chloro(methyl)anilino]-2- hydroxyphenyl ⁇ -3-pyridinyl)methyl carbamate 34 mg (0.096 mmol) of the compound obtained in EXAMPLE 2 was dissolved in 10 ml of dichloromethane, and 23 mg of di-t-butyl dicarbonate was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the residue was purified by the column chromatography to obtain 41 mg (0.091 mmol) of the title compound in a yield 95%.
  • EXAMPLE 13 iV-[(2-amino-6- ⁇ 5-[4-chloro(methyl)anilino]-2-hydroxyphenyI ⁇ -3- py ridinyl)methyl] acetamide
  • the title compound was obtained from the compound obtained in EXAMPLE 2 in the same manner as Process B.
  • This compound was dissolved in 700 ml of N,N-dimethylformamide, then 144 g (1.04 mol) of potassium carbonate and 106 ml (0.92 mol) of benzyl bromide were added thereto in sequence, followed by stirring at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated, and 800 ml of water added thereto, then a solid compound thus obtained were filtered and dried to obtain 17O g (0.60 mol) of a compound. This compound was dissolved in 700 ml of dichloromethane, and 170 g (0.78 mol) of di-t- butyl dicarbonate was added thereto, followed by stirring at room temperature for 4 hours.
  • reaction solution was concentrated, and 500 ml of methanol was added and dissolved thereto.
  • 500 ml of aqueous 2 N sodium chloride was added thereto followed by stirring at room temperature for 30 minutes.
  • solvent was removed by evaporation in vacuo, 700 ml of water was added thereto, then a solid compound thus obtained was filtered and dried to obtain 199 g (0.58 mol) of a compound.
  • This compound was dissolved in 1 / of N,N-dimethylformamide, and the solution was allowed to cool to 0°C.
  • PREPARATION 7 4-(benzyloxy)-iV-(4-bromophenyl)-iV-methyI-3-(2-methyl-l,3- dioxolane-2-yl)aniline
  • the title compound was obtained from the compound obtained in PERPARATION 6 and 4-iodinebromobenzene in the same manner as in PREPARATION 2.
  • EXAMPLE 36 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]- nicotinamide 47 mg (0.14 mmol) of the compound obtained in EXAMPLE 35 was dissolved in 3 ml of 6 N potassium hydroxide and 2 ml of ethanol, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was concentrated and neutralized with aqueous 2 N hydrochloric acid then exatrcted twice by 10 ml of ethyl acetate. The product was concentrated and purified by the column chromatography to obtain 23 mg (0.066 mmol) of the title compound in a yield of 47%.
  • the title compound was obtained from the compound obtained in EXAMPLE 41 in the same manner as in EXAMPLE 3 and 4 in sequence.
  • the title compound was obtained from the compound obtained in EXAMPLE 101 in the same manner as in EXAMPLE 65.
  • EXAMPLE 104 2-(6-amino-5- ⁇ [(3-hydroxypropyl)ammo]methyl ⁇ -2-pyridinyl)-4- (2-fluoro-4-dimethylanilino)phenol
  • the title compound was obtained from the compound obtained in EXAMPLE 79 in the same manner as in EXAMPLE 103.
  • EXAMPLE 110 JV-( ⁇ 2-6-amino-6-[5-(2-fluoro-4-dimethyIanilino)-2- hydroxyphenyl]-3-pyridinyl ⁇ methyl)-l-ethanesulfonamide
  • EXAMPLE 111 Ethyl l-( ⁇ 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]-3-pyridinyl ⁇ methyl)-2-aziridinecarboxyIate
  • PREPARATION 8 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-iV-methyl-iV-methoxynicotmamide
  • EXAMPLE 284 4-[( ⁇ 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hy droxyphenyl] -3-py ridinyl ⁇ methyl)amino] -4-oxobutanoic acid
  • the title compound was obtained from the compound obtained in EXAMPLE 300 in the same manner as in EXAMPLE 42.
  • EXAMPLE 339 (2S)-N-[(2-amino-6- ⁇ 5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyl ⁇ -3-pyridinyl)methyl]-2,3-dihydroxypropanamide 23 mg (0.0475 mmol) of the compound obtained in EXAMPLE 337 was dissolved in 10 ml of methanol, 1 ml of concentrated hydrochloric acid was added, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was neutralized with aqueous 2 N sodium hydroxide and concentrated in vacuo. The residue was extracted twice with 20 ml of ethyl acetate to obtain 18 mg (0.0405 mmol) of the title compound in a yield of 85%.
  • EXAMPLE 341 N-[(2-amino-6- ⁇ 5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyI ⁇ -3-pyridinyl)methyl]-4-methyl-l-piperazinecarboxyamide Using 4-methyl-l-piperazinecarbonyl chloride instead of 4- morpholinecarbonyl chloride in EXAMPLE 340, the title compound was obtained in the same manner as in EXAMPLE 294.
  • EXPERIMENT 1 Test of the inhibitory effect of the compounds according to the present invention on the activity of various RTKs (Receptor Tyrosine Kinases)
  • the reaction was carried out in a total reaction volume of 20 ⁇ l, with the respective compounds contained in 5% DMSO at varied concentrations of the compound, at 30°C for 10 minutes, then stopped by the addition of 10% phosphoric acid.
  • the resultant reaction solution was transferred onto Immobilon-PVDF membrane (Milipore) of 96-well format, washed four times with 0.5% phosphoric acid, and the amount of radiation adhered onto the membrane was quantified with Phosphorimager (Molecular Dynamics).
  • IC 50 the concentration of a compound inhibiting 50% of the total activity, was determined by the mean value calculated from more than three repetitions of the assay, using Linear regression analysis.
  • EXPERIMENT 2 Test of the inhibitory effect of the compounds according to the present invention on VEGF-dependent HUVEC (Human Umbilical Vein Endothelial Cell) growth
  • HUVEC cells separated from placenta were seeded into 0.3% Gelatin-coated 96-well plates at a density of 5X10 3 cells per well, and cultured in M 199 media (Gibco BRL; supplemented with 10% FBS, 30 ⁇ g/ml ECGS, 50 ⁇ g/ml Heparin, IX Penicillin/Streptomycin and 0.5 mM Glutamine) at 37°C in a 5% CO 2 incubator for one day. Thereafter, serum starvation was performed in M 199 starvation medium supplemented with 0.5% FBS for 24 hours, after which time the starvation medium was replaced with a working medium containing compounds diluted at graded concentrations.
  • M 199 media Gibco BRL; supplemented with 10% FBS, 30 ⁇ g/ml ECGS, 50 ⁇ g/ml Heparin, IX Penicillin/Streptomycin and 0.5 mM Glutamine
  • VEGF vascular endothelial growth factor
  • HUVEC Human umbilical vein endothelial cells having been used within passage 5 were cultured at 37°C in a 5% CO 2 incubator to 70-80% confluence in a
  • HCTl 16 cells 3X10 3 cells/well:KCLB
  • RPMIl 640 medium supplemented with 5% FBS, IX Penicillin/Streptomycin and 0.5 mM Glutamine; Gibco BRL
  • the medium was treated with compounds diluted at graded concentrations.
  • cells were fixed with 4% formaldehyde (Sigma) for 3-4 hours, washed five times with PBS, then dried in an oven set to 55°C for 10 minutes.
  • GI 50 the concentration of compounds of inhibiting 50% of the total cell growth, was determined using mean values from three experiments using Linear regression analysis.
  • EXPERIMENT 5 Test of the inhibitory effect of the compounds according to the present invention on cancer cell growth in vivo
  • B ALB/c nude mice (5 - 6 weeks age, female) purchased from Harlan (USA) were raised in a cage equipped with a clean room HEPA filter and adapted to the cage for a week.
  • Human cancer cells selected for test were cultured at each suitable condition and then subcutaneously administered to the nude mice at the amount of 5 ⁇ 10 X 10 5 cells/100 ⁇ l.
  • the compounds according to the present invention were orally administered at a predetermined amount once a day.
  • the size of tumor and the weight of mice were measured three times a day, and the clinical manifestation was investigated and recorded once or twice a day.
  • the size of tumor was recorded as a volume value by measuring the width, length and height of tumor and then calculating the volume value on the basis of (width x length x height)/6 formula. The test continued for 15 ⁇ 18 days.
  • the inhibitory effect on the tumor growth was determined by two factors, i.e., IR% (Inhibition Rate %) and %T/C.
  • IR% (1 - Average tumor size of administration group / Average tumor size of control group) X 100
  • %T/C ⁇ (Average tumor size of administration group at a certain day - Average tumor size of administration group at an administration starting day) / (Average tumor size of control group at a certain day - Average tumor size of control group at an administration starting day) ⁇ X 100
  • IC 50 values of some compounds of Formula 1 showing the ability to inhibit the cell growth of HCTl 16 cells, bFGF-dependent HUVEC and PDGF-dependent PASMC.
  • Some compounds of Formula 1 showed a significant inhibitory effect in the in vivo test regarding the inhibitory effect on the cancer cell growth using nude mice.

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008025820A1 (en) * 2006-08-30 2008-03-06 Cellzome Limited Aminopyridine derivates as kinase inhibitors
US20120129813A1 (en) * 2010-11-22 2012-05-24 Heidelbaugh Todd M Novel compounds as receptor modulators with therapeutic utility
US9120752B2 (en) 2010-07-16 2015-09-01 Purdue Pharma, L.P. Pyridine compounds as sodium channel blockers
CN106458908A (zh) * 2014-06-27 2017-02-22 阿格罗-金正株式会社 2‑氨基‑6‑甲基烟酸的制造方法
US9714252B2 (en) 2012-12-20 2017-07-25 Purdue Pharma L.P. Cyclic sulfonamides as sodium channel blockers
US9718780B2 (en) 2012-03-16 2017-08-01 Purdue Pharma L.P. Substituted pyridines as sodium channel blockers
US10730866B2 (en) 2014-04-07 2020-08-04 Purdue Pharma L.P. Indole derivatives and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002090352A2 (de) * 2001-05-08 2002-11-14 Schering Aktiengesellschaft Selektive anthranylamidpyridinamide als vegfr-2 und vegfr-3 inhibitoren
WO2004013102A1 (de) * 2002-07-31 2004-02-12 Schering Aktiengesellschaft Vegfr-2 und vegfr-3 inhibitorische anthranylamidpyrimidene
WO2004111005A1 (de) * 2003-06-13 2004-12-23 Schering Aktiengesellschaft Vegfr-2 und vegfr-3 inhibitorische anthranylamidpyridone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002090352A2 (de) * 2001-05-08 2002-11-14 Schering Aktiengesellschaft Selektive anthranylamidpyridinamide als vegfr-2 und vegfr-3 inhibitoren
WO2004013102A1 (de) * 2002-07-31 2004-02-12 Schering Aktiengesellschaft Vegfr-2 und vegfr-3 inhibitorische anthranylamidpyrimidene
WO2004111005A1 (de) * 2003-06-13 2004-12-23 Schering Aktiengesellschaft Vegfr-2 und vegfr-3 inhibitorische anthranylamidpyridone

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1900727A1 (en) * 2006-08-30 2008-03-19 Cellzome Ag Aminopyridine derivatives as kinase inhibitors
WO2008025820A1 (en) * 2006-08-30 2008-03-06 Cellzome Limited Aminopyridine derivates as kinase inhibitors
US9120752B2 (en) 2010-07-16 2015-09-01 Purdue Pharma, L.P. Pyridine compounds as sodium channel blockers
US9765029B2 (en) 2010-07-16 2017-09-19 Purdue Pharma L.P. Pyridine compounds as sodium channel blockers
CN103328492A (zh) * 2010-11-22 2013-09-25 阿勒根公司 作为受体调节剂具有疗效的新型化合物
US8703746B2 (en) 2010-11-22 2014-04-22 Allergan, Inc. Compounds as receptor modulators with therapeutic utility
US8653270B2 (en) * 2010-11-22 2014-02-18 Allergan, Inc. Compounds as receptor modulators with therapeutic utility
US20120129813A1 (en) * 2010-11-22 2012-05-24 Heidelbaugh Todd M Novel compounds as receptor modulators with therapeutic utility
US9718780B2 (en) 2012-03-16 2017-08-01 Purdue Pharma L.P. Substituted pyridines as sodium channel blockers
US9714252B2 (en) 2012-12-20 2017-07-25 Purdue Pharma L.P. Cyclic sulfonamides as sodium channel blockers
US10730866B2 (en) 2014-04-07 2020-08-04 Purdue Pharma L.P. Indole derivatives and use thereof
US11834447B2 (en) 2014-04-07 2023-12-05 Purdue Pharma L.P. Indole derivatives and use thereof
CN106458908A (zh) * 2014-06-27 2017-02-22 阿格罗-金正株式会社 2‑氨基‑6‑甲基烟酸的制造方法
CN106458908B (zh) * 2014-06-27 2018-11-06 阿格罗-金正株式会社 2-氨基-6-甲基烟酸的制造方法

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