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WO2004080979A1 - Nouveaux derives de 3-(2-amino-4-pyrimidinyl)-4-hydroxyphenyl cetone - Google Patents

Nouveaux derives de 3-(2-amino-4-pyrimidinyl)-4-hydroxyphenyl cetone Download PDF

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Publication number
WO2004080979A1
WO2004080979A1 PCT/KR2004/000301 KR2004000301W WO2004080979A1 WO 2004080979 A1 WO2004080979 A1 WO 2004080979A1 KR 2004000301 W KR2004000301 W KR 2004000301W WO 2004080979 A1 WO2004080979 A1 WO 2004080979A1
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Prior art keywords
amino
hydroxyphenyl
pyrimidinyl
methanone
formula
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PCT/KR2004/000301
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English (en)
Inventor
Jinho Lee
Hak Joong Kim
Seihyun Choi
Hwan Geun Choi
Seunghyun Yoon
Jong-Hyun Kim
Kiwon Jo
Semi Kim
Sun-Young Koo
Min-Hyeung Kim
Jung In Kim
Sang-Yong Hong
Mi Sun Kim
Shinbyoung Ahn
Hae-Seong Yoon
Heung-Soo Cho
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LG Chem Ltd
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LG Life Sciences Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • the present invention relates to novel compounds having a 3-(2-amino-4 ⁇ pyrimidinyl)-4-hydroxyphenyl ketone structure, and more specifically, to novel compounds for inhibition of angiogenesis receptor tyrosine kinases, in particular, VEGF-Receptor-2-kinase (hereinafter, referred to as "VEGFR2 kinase” or "KDR”) activity, as will be illustrated in Formula 1 later herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, and prodrug thereof.
  • VEGFR2 kinase VEGF-Receptor-2-kinase
  • KDR VEGF-Receptor-2-kinase
  • Formula 1 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 necessary for cell survival and eliminating waste materials therefrom, allows only 0.01% of blood vessel cells to proliferate under normal conditions, 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 over which nutrients or oxygen can reach cells by diffusion (the so-called diffusion limit) (Carmeliet et al, 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), FGFR1, PDGFR- ⁇ and the like, have drawn 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 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).
  • 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
  • RI is an aromatic or heteroaromatic ring, or optionally substituted aromatic or heteroaromatic ring
  • B) R2 is one selected from the group consisting of
  • V halogen or perhaloalkyl
  • X ⁇ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl, and heteroaryl
  • X 2 is selected from the group consisting of hydrogen, lower alkoxy, pyrrolidine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carboxylic acid, sulfide, hydroxy, optionally substituted lower alkyl, and optionally substituted aryl or heteroaryl
  • ni is 0 or 1 ;
  • X 3 is selected from the group consisting of hydrogen, and optionally substituted lower alkyl, aryl and heteroaryl;
  • E is oxygen or sulfur; j is selected from the group consisting of lower alkylene, oxygen, and nitrogen;
  • Xi , X 2 and ⁇ are as defined above, respectively;
  • XI a substituent of the formula where R6 is selected from the group consisting of a) hydrogen; b) optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl; c) optionally substituted aryl; d) optionally substituted heterocycle; e) a substituent of the formula -(X 1 )n 1 -O-X 2 , where Xi, X 2 and n are as defined above, respectively; f) a substituent of the formula -NX 3 -(X 1 )n 1 -X 2 , where
  • Xi , X 2 , X 4 , m and E are as defined above, respectively; h) a substituent of the formula -S-(X 1 )n 1 -X , where Xi , X 2 and m are as defined above, respectively; and R3 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 cycloalkyl, 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, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,
  • 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, 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
  • 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.
  • the term "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 term “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.
  • prodrug without limitation, 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 metabohcally hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug might be a short peptide (polyaminoacid) bonded to an active group, where the peptide is metabolized to reveal the active moiety.
  • aromatic means an aromatic 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.
  • heteromatic means an aromatic 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.
  • perhaloalkyl refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.
  • the compound of Formula 1 above is a compound as defined below.
  • A) RI is selected from the group consisting of
  • aromatic or heteroaromatic ring substituted with one or more substituents selected from the group consisting of halogen, amide, carboxylic acid, carbamate, ester, lower alkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulphonyl, sulfoxy, sulfonamide, amidine, amidoxime, and trifluoromethyl;
  • R2 is selected from the group consisting of I) hydrogen, halogen, lower alkoxy, pyrrolidine, piperidine, piperazine, morpholine, aziridinyl, lower alkylamine, carboxylic acid, or sulfide;
  • aromatics or heteroaromatic ring substituted with one or more substituents selected from the group consisting of halogen, amide, carboxylic acid, carbamate, ester, lower alkyl, lower alkoxy, amino, lower alkylamino, cyano, hydroxy, sulphonyl, sulfoxy, sulfonamide, amidine, amidoxime, and trifluoromethyl;
  • R6 is selected from the group consisting of a) lower alkyl; b) lower alkyl substituted with one or more substituents selected from the group consisting of carboxylic acid, lower alkylamine, hydroxy, sulphonyl, sulfoxy, sulfonamide, phenyl, benzyl, furyl, imidazole, pyridine, pyrrole, and thiophene; c) carbamate;
  • R4 is each independently selected from the group consisting of aa) lower alkoxy, pyrrolidine, piperidine, piperazine, morpholine, aziridinyl, lower alkylamine, carboxylic acid, and sulfide; bb) aromatic or heteroaromatic ring substituted with one or more substituents selected form the group consisting of halogen, amide, carboxylic acid, carbamate, ester, lower alkyl, lower alkoxy, amino, lower alkylamino, cyano, hydroxy, sulphonyl, sulfoxy, sulfonamide, amidine, amidoxime, and trifluoromethyl; and cc) a substituent of the formula
  • R6 is as defined above; b) R5 is lower alkyl, carboxyl acid, or lower alkyl substituted with lower alkylamine; and c) n is 0 or 1 to 4;
  • R3 is lower alkyl, carboxyl acid, or lower alkyl substituted with lower alkylamine.
  • 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.
  • R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heteroalicyclic group.
  • the process (Step (i) - Step (ii)) for performing the conversion of the carboxyl group after the introduction of the pyrimidine substituent comprises, (a) a step of reacting the compound of Formula 2 with acetyl chloride and aluminum chloride to produce the compound of Formula 3 below; where R is the same as in Formula 2,
  • PG means a protecting group and includes, for example, but is not limited to t-butyl, alkyl ether, substituted or non-substituted benzyl group, and the like,
  • Step (ii) - Step (i)) for performing the introduction of the pyrimidine substituent after the conversion of carboxyl group comprises,
  • Bn is benzyl group as a protecting group and MOM is methoxymethyl group as a protecting group.
  • Steps (cl) and (dl) in the above preparation process can be conducted, for example, by various routes as below.
  • Steps (cl) and (dl) may be replaced with Steps (cl'), (dl') and (el 5 ) in below, (cl') a step of substituting the protecting group (PG) in the compound of Formula 8 with a carboxyl group to produce the compound of Formula 10 below;
  • 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.
  • diseases include, for example, but are not limited to cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic cardiovascular disease, atherosclerosis, Kaposi's sarcoma, etc. Therefore, the present invention provides a method for the treatment and prevention of diseases resulted from an unregulated or undesired KDR activity comprising using the compound of Formula 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of the present invention, and (b) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • 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.
  • 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 carboxymethylcellulose, 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.
  • 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.
  • other delivery systems for 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 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 LDs 0 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).
  • 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.
  • PREPARATION 5 Preparation of methyl 4-(methoxymethoxy)benzoate 9.23 g (60.7 mmol) of 4-hydroxy methyl benzoate was dissolved in 150 ml of dimethylformamide, and 16.8 g (91.1 mmol) of potassium carbonate and 6.00 ml (78.9 mmol) of chloromethylmethylether were added, followed by stirring at room temperature. After 3 hours, the solvent was removed in vacuo, the residue was dissolved in 400 ml of ethyl acetate and washed with 200 ml of water and 200 ml of saturated aqueous NaCl, then dried over anhydrous MgSO .
  • the reaction mixture was washed with 50 ml of water, 50 ml of IN aqueous hydrochloric acid and 50 ml of saturated aqueous NaCl, then dried over anhydrous MgSO .
  • PREPARATION 12 Preparation of l-bromo-2-chloro-4-methoxy benzene 356 mg (1.76 mmol) of 4-bromo-3-chlorophenol was dissolved in 20 ml of dimethylformamide, and 365 mg (2.64 mmol) of potassium carbonate and 0.13 ml (2.11 mmol) of iodomethane were added thereto, followed by stirring at room temperature. After 2 hours, the solvent was removed in vacuo, the residue was dissolved in 100 ml of ethyl acetate and washed with 50 ml of water and 50 ml of saturated aqueous NaCl, then dried over anhydrous MgSO .
  • PREPARTION 15 Preparation of 3-bromo-iV,iV-diethyl-4-methyl aniline The title compound was prepared from 4-amino-3-bromotoluene and diethylamine following the method of PREPARATION 13.
  • PREPARATION 17 Preparation of [3-(2-amino-4-pyrimidinyl)-4- (benzyloxy)phenyl][3-( ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ methyl)phenyl]methanone
  • PREPARATION 19 Preparation of l-[2-(benzyloxy)-5 ⁇ (2-fluoro-4- methylbenzoyl)phenyl]-3,3-bis(methylsulfanyl)-2-propen-l-one
  • PREPARATION 20 Preparation of [3-[2-amino-6-(methylsulfanyl)-4- pyrimidinyl]-4-(benzyloxy)phenyl](2-fluoro-4-methylphenyl)methanone
  • PREPARATION 21 Preparation of [3-[2-amino-6-(4-morpholinyl)-4- pyrimidinyl]-4-(ben yloxy)phenyl](2-fluoro-4-methylphenyl)methanone
  • PREPARATION 23 Preparation of [3-[2-amino- ⁇ -(methylsulfonyl)-4- pyrimidinyl]-4-(ben_gyloxy)phenyl](2-fluoro-4-methylphenyl)methanone
  • PREPARATION 24 Preparation of [3-(2-amino-6- ⁇ [3-(4- morpholinyl)propyl]amino ⁇ -4-pyrimidinyl)-4-(benzyloxy)phenyl](2-fluoro-4- methylphenyl)methanone 30 mg (0.061 mmol) of the compound as obtained in PREPARATION 20 was dissolved in 2 ml of acetonitrile, and 0.18 ml of 4-(3-aminopropyl)morpholine was added thereto, followed by heating with stirring for 8 hours. When the reaction was completed, a product was extracted with ethyl acetate and washed with water. The organic layer was concentrated and then purified by column chromatography to give 26 mg of the title compound at 76% yield.
  • PREPARATION 25 Preparation of 2-amino-6-[2-(benEyloxy)-5-(2-fl «oro-4- methylbenzoyl)phenyl] ⁇ 4(3I_r)-pyrimidmone
  • PRERATION 27 Preparation of [3-(2-amino-6- ⁇ [3-(2-methyl-l-piperidinyl)- propyl] amino ⁇ -4-pyrimidinyl)-4-(benzyloxy)phenyl] (2-fluoro-4- methylphenyl)methanone
  • PREPARATION 28 Preparation of 3-acetyl-4-(benzyIoxyI)-iV-methoxy-JV- methylben amide
  • PREPARATION 29 Preparation of 4-(benzyloxy)-N-methoxy-iV-methyl-3-[2- (methylamino)-4-pyrimidinyl] benzamide
  • PREPARATION 30 Preparation of 2-( ⁇ 4-[2-(benzyloxy)-5-(2-fluoro-4- methylbenzoyl)phenyl]-2-pyrimidinyl ⁇ amino)acetic acid
  • EXAMPLE 44 Preparation of (4-ehloro-2-fluorophenyl) ⁇ 4-l ⁇ ydroxy-3-[2- (methylamino)-4-pyrimidinyl]phenyl ⁇ methanone 62 mg of the title compound was prepared from the compound (140 mg, 0.37 mmol) as obtained in PREPARATION 29 and l-bromo-4-chloro-2-fluorobenzene, following the method of EXAMPLE 1, at 47% yield.
  • PREPARATION 31 Preparation of (Z)-l-[2-(benzoyloxy)-5-(2-fluoro-4- methylbenzoyl)phenyl]-3-hydroxy-3-(l-methyl-4-piperidinyI)-2-propen-l-one
  • PREPARATION 32 Preparation of (Z)-l-[2-(benzyIoxy)-5-(2-fluoro-4- met ⁇ ylbensoyl)phenyl]-7-bromo-3-hydrosy-2-hepten-l-one
  • PREPARATION 33 Preparation of [3-[2-amino-6-(4-hydroxybutyl)-4- pyrimidinyl]-4-(benzyloxy)phenyl](2-fluoro-4-methylphenyl)methanone 30 mg (0.062 mmol) of the title compound was prepared from the compound (0.33 g, 0.63 mmol) as obtained in PREPARATION 32 following the method of EXAMPLE 46, at 10% yield.
  • PREPARATION 33-1 Preparation of [3-[2-amino-6-(2-hydroxyethoxy)-4- pyrimidinyl] -4-(benzyloxy)phenyl] (2-fluoro-4-methylphenyl)methanone
  • PREPARATION 34 Preparation of ⁇ 3-[2-amino-6-(2-chIoroethoxy)-4- pyrimidinyl]-4-hydroxyphenyl ⁇ (2-fluoro-4-methylphenyl)methanone
  • EXAMPLE 53 Preparation of (3- ⁇ 2-amino-6-[2-(4-hydroxy-l- piperidinyl)ethoxy]-4-pyrimidinyl ⁇ -4-hydroxyphenyI)(2-fluoro-4- methylphenyl)methanone 27 mg of the title compound was prepared at 67% yield by using 4- hydroxypiperidine instead of 1-methylpiperazine in the method of EXAMPLE 49.
  • PREPARATION 35 Preparation of ⁇ 3-[2-amino-6-(3-chIoropropoxy)-4- pyrimidinyl]-4-hydroxyphenyl ⁇ (2-fluoro-4-methylphenyl)methanone 0.50 g (1.2 mmol) of the title compound was prepared from the compound
  • PREPARATION 36 Preparation of (£)-l-[2-(benzyloxy)-5-(2-fluoro-4- methylbenzoyl)phenyl]-3-(4-pyridinyl)-2-propen-l-one
  • PREPARATION 37 Preparation of [3-[2-amino-6-(4-pyridinyI) ⁇ 4-pyrimidinyl]- 4-(benzyloxy)phenyl](2-fluoro-4-methylphenyl)methanone
  • EXPERIMENT 1 Test of the inhibitory effect of the compounds according to the present invention on the activity of various RTKs (Receptor Tyrosine Kinases) To ascertain the inhibitory effect of the compounds according to the present invention on the activity of tyrosine kinases, in vitro experiments were carried out using five kinds of RTKs, as follows. First, only kinase domains of KDR, FLT-3, EGFR, FGFRl and PDGFR- ⁇ in the form of GST fusion or His-tag proteins were expressed in insect cells (SF21) and purified. For the KDR assay, a reaction using 20 mM Tris-HCl (pH 7.5), 10 mM MgCl 2 ,
  • GST:KDR protein was performed under the following conditions. The reaction was
  • EXPERIMENT 2 Test of the inhibitory effect of the compounds according to the present invention on VEGF- or bFGF-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 M199 media (Gibco
  • IC 50 the concentration of compounds inhibiting 50% of the cell growth induced by VEGF or bFGF, was determined using mean values from three experiments using Linear regression analysis.
  • EXPERIMENT 3 Test of the inhibitory effect of the compounds according to the present invention on PDGF-BB dependent PASMC (Pulmonary Artery Smooth Muscle Cell) growth
  • PASMC cells (5X10 3 cells/well: Clonetics) were seeded into 96-well plates and cultured in DMEM medium (Gibco BRL; supplemented with 10% FBS, 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 DMEM starvation medium supplemented with 0.1% FBS for 24 hours, after which time the starvation medium was replaced with a working medium containing compounds diluted at graded concentrations. After 2 hours, the cells were treated with 20 ng/ml of PDGF-BB (Upstate).
  • HUVEC Human umbilical vein endothelial cells having been used within passage 5 were cultured at 37°C in a 5% CO incubator to 70 ⁇ 80% confluence in a 100 mm culture dish, treated with trypsin, neutralized in Ml 99 medium supplemented with 0.2% BSA (Sigma), then seeded at a concentration of 4X10 4 cells/well into the media containing compounds diluted at graded concentrations in a 24-well plate coated with 10 mg/ml of Matrigel (R&D systems), followed by the addition of 5% FBS.
  • R&D systems Matrigel
  • HCT116 cells 3X10 3 cells/well:KCLB
  • RPMI1640 medium supplied with 5% FBS, IX
  • 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.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés possédant une structure de 3-(2-amino-4-pyrimidinyl)-4-hydroxyphényl cétone, représentée par la formule 1, permettant d'inhiber des kinases de tyrosine du récepteur d'angiogenèse, notamment l'activité de la kinase 2 (« KDR ») du récepteur VEGF, ou un sel, un hydrate, un solvant, un isomère, et un promédicament de ces composés pharmaceutiquement acceptable. Ces composés sont utiles dans le traitement et la prévention de maladies liées à l'angiogenèse, résultant notamment de l'activité de KDR non régulée ou indésirable, tel que le cancer, le psoriasis, l'arthrite rhumatoïde, la rétinopathie diabétique, etc.
PCT/KR2004/000301 2003-03-14 2004-02-13 Nouveaux derives de 3-(2-amino-4-pyrimidinyl)-4-hydroxyphenyl cetone Ceased WO2004080979A1 (fr)

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WO2005079800A1 (fr) * 2004-02-12 2005-09-01 Vernalis (R & D) Ltd. Composes de pyrimidine utilises comme antagoniste des recepteurs de la purine
WO2005100341A1 (fr) * 2004-04-15 2005-10-27 Astellas Pharma Inc. Dérivé de 2-aminopyridine
WO2006084017A3 (fr) * 2005-02-04 2006-12-14 Bristol Myers Squibb Co Composes pyrimidine a substitution phenyle utilises en tant qu'inhibiteurs de kinases
US7625931B2 (en) 2005-01-14 2009-12-01 Cgi Pharmaceuticals, Inc. Certain substituted diphenyl ureas, as modulators of kinase activity
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
KR20150087271A (ko) * 2012-11-27 2015-07-29 토마스 헬데이스 스티프텔스 퓌어 메디신스크 포르스닝 암 치료를 위한 피리미딘-2,4-다이아민 유도체
CN106632000A (zh) * 2016-12-19 2017-05-10 湖北工业大学 二芳基甲酮化合物在制备抗肿瘤药物中的应用
WO2017180813A1 (fr) 2016-04-15 2017-10-19 Macrogenics, Inc. Nouvelles molécules de liaison à b7-h3, leurs conjugués anticorps-médicaments et leurs procédés d'utilisation
US10064869B2 (en) 2014-06-04 2018-09-04 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of inflammatory and autoimmune conditions
US10179790B2 (en) 2014-06-04 2019-01-15 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of cancer
CN111821980A (zh) * 2020-08-12 2020-10-27 四川鸿鹏新材料有限公司 一种吗啉生产用催化剂及其制备方法

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WO2003030909A1 (fr) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- et 4-aminopyrimidines n-substituees par un noyau bicyclique utilisees comme inhibiteurs de kinases dans le traitement du cancer

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EP0130735A1 (fr) * 1983-06-30 1985-01-09 American Home Products Corporation Dérivés de l'aminopyrimidine
US4554276A (en) * 1983-10-03 1985-11-19 Pfizer Inc. 2-Amino-5-hydroxy-4-methylpyrimidine derivatives
US4617393A (en) * 1985-07-19 1986-10-14 American Home Products Corporation 5-substituted-6-aminopyrimidines, composition and uses as cardiotonic agents for increasing cardiac contractility
WO1997044325A1 (fr) * 1996-05-22 1997-11-27 Basf Aktiengesellschaft Derives d'acide de 2-(o-[pyrimidin-4-yl]methylenoxy)phenylacetique et leur utilisation pour lutter contre les champignons nuisibles et les parasites animaux
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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005079800A1 (fr) * 2004-02-12 2005-09-01 Vernalis (R & D) Ltd. Composes de pyrimidine utilises comme antagoniste des recepteurs de la purine
WO2005079801A1 (fr) * 2004-02-12 2005-09-01 Vernalis (R & D) Ltd Composes de pyrimidine utilises comme antagoniste des recepteurs de la purine
US7875600B2 (en) 2004-02-12 2011-01-25 Vernalis (R&D) Limited Pyrimidine compounds as purine receptor antagonist
WO2005100341A1 (fr) * 2004-04-15 2005-10-27 Astellas Pharma Inc. Dérivé de 2-aminopyridine
US7625931B2 (en) 2005-01-14 2009-12-01 Cgi Pharmaceuticals, Inc. Certain substituted diphenyl ureas, as modulators of kinase activity
WO2006084017A3 (fr) * 2005-02-04 2006-12-14 Bristol Myers Squibb Co Composes pyrimidine a substitution phenyle utilises en tant qu'inhibiteurs de kinases
JP2008530012A (ja) * 2005-02-04 2008-08-07 ブリストル−マイヤーズ スクイブ カンパニー キナーゼインヒビターとして有用な、フェニル置換ピリミジン化合物
US7923556B2 (en) 2005-02-04 2011-04-12 Bristol-Myers Squibb Company Phenyl-substituted pyrimidine compounds useful as kinase inhibitors
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
EP2925744A4 (fr) * 2012-11-27 2016-08-24 Thomas Helledays Stiftelse För Medicinsk Forskning Dérivés de pyrimidine-2,4-diamine utilisables en vue du traitement du cancer
US10174029B2 (en) 2012-11-27 2019-01-08 Thomas Helledays Stiftelse For Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
JP2016504289A (ja) * 2012-11-27 2016-02-12 トーマス・ヘレデイズ・スティフテルス・フォー・メディシンスク・フォルスクニング がん治療用のピリミジン−２，４−ジアミン誘導体
KR20150087271A (ko) * 2012-11-27 2015-07-29 토마스 헬데이스 스티프텔스 퓌어 메디신스크 포르스닝 암 치료를 위한 피리미딘-2,4-다이아민 유도체
US9604937B2 (en) 2012-11-27 2017-03-28 Thomas Helledays Stiftelse For Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
KR102194646B1 (ko) 2012-11-27 2020-12-23 토마스 헬데이스 스티프텔스 퓌어 메디신스크 포르스닝 암 치료를 위한 피리미딘-2,4-다이아민 유도체
CN105143206A (zh) * 2012-11-27 2015-12-09 托马斯·黑勒戴药物研究基金会 用于治疗癌症的嘧啶-2,4-二胺衍生物
US9944640B2 (en) 2012-11-27 2018-04-17 Thomas Helledays Stiftelse For Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
CN105143206B (zh) * 2012-11-27 2019-01-15 托马斯·黑勒戴药物研究基金会 用于治疗癌症的嘧啶-2,4-二胺衍生物
US10632125B2 (en) 2014-06-04 2020-04-28 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of inflammatory and autoimmune conditions
US10179790B2 (en) 2014-06-04 2019-01-15 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of cancer
US10064869B2 (en) 2014-06-04 2018-09-04 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of inflammatory and autoimmune conditions
WO2017180813A1 (fr) 2016-04-15 2017-10-19 Macrogenics, Inc. Nouvelles molécules de liaison à b7-h3, leurs conjugués anticorps-médicaments et leurs procédés d'utilisation
US10961311B2 (en) 2016-04-15 2021-03-30 Macrogenics, Inc. B7-H3 binding molecules, antibody drug conjugates thereof and methods of use thereof
US11591400B2 (en) 2016-04-15 2023-02-28 Macrogenics, Inc. B7-H3 directed antibody drug conjugates
CN106632000B (zh) * 2016-12-19 2019-04-26 湖北工业大学 二芳基甲酮化合物在制备抗肿瘤药物中的应用
CN106632000A (zh) * 2016-12-19 2017-05-10 湖北工业大学 二芳基甲酮化合物在制备抗肿瘤药物中的应用
CN111821980A (zh) * 2020-08-12 2020-10-27 四川鸿鹏新材料有限公司 一种吗啉生产用催化剂及其制备方法

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