- METHOTREXATE ANALOGS AND METHODS OF USE
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Compounds having general formula (I) or a pharmaceutically acceptable salt, N-oxide, or hydrate thereof are provided herein. Also provided are methods of making the compounds and methods of their use, including in treatment of cancer, autoimmune disorders, and viral infections.
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- Synthesis process of methotrexate
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The invention relates to a synthesis process of methotrexate, which comprises the following steps: synthesizing a methotrexate crude product, preparing the synthesized methotrexate crude product into methotrexate disodium salt, adjusting the pH value to 5-6, and refining into a methotrexate pure product, the reaction synthesis steps are less, the raw materials are easy to purchase, the cost is low, and the experimental operation is simple; the methotrexate disodium salt is recrystallized and separated out by acetone, the yield is improved, and the purity of the compound after detection reaches 99% or above.
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Paragraph 0045-0088; 0101; 0110-0115
(2021/05/29)
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- A preparation method of methotrexate (by machine translation)
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The invention provides a preparation method of methotrexate, including: A) 6 - bromomethyl pterin and to the methylamino benzoyl glutamate in the solvent in the reaction, the obtained solid product; the to the methylamino benzoyl glutamate is selected from methylamino benzoyl glutamic acid zinc salt, to the methylamino benzoyl glutamic acid calcium salt and to the methylamino benzoyl glutamic acid magnesium salt in one or several kinds of; the solvent is selected from the HBr and/or HI; B) the solid product soluble in aqueous solution, adjusting the pH value, to obtain the crude product of methotrexate; C) for purifying the crude product obtained methotrexate methotrexate. The invention will be 6 - bromomethyl pterin and to the methylamino benzoyl glutamate in the HBr and/or HI the solvent in the reaction, choose the specific reaction raw materials and specific reaction solvent, combined with a specific refining process for the preparation of the methotrexate high purity and yield and, at the same time the invention simple preparation method, raw material sources are extensive, favorable to industrial production. (by machine translation)
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Paragraph 0123; 0124; 0125; 0126-0129
(2019/04/26)
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- A sequential enzyme-activated and light-triggered pro-prodrug nanosystem for cancer detection and therapy
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DT-diaphorase is a cytosolic flavoenzyme whose level is strongly elevated in a number of tumor types. Incorporating a DT-diaphorase's substrate in the structure of anticancer drugs may facilitate cancer detection and therapy. Herein, we developed a novel pro-prodrug nanosystem for cancer detection and therapy, which features enzyme-activated fluorescence emission and subsequent light-triggered drug release. The pro-prodrug molecule comprises an anticancer drug methotrexate (MTX), an enzyme (DT-diaphorase) responsive quinone propionic acid moiety and a light-activatable coumarinyl. In the absence of DT-diaphorase, the quinone propionic acid moiety quenches the fluorescence of coumarin via photoinduced electron transfer (PET) and blocks the photocleavage pathway. DT-diaphorase can annihilate the effect of PET and restore the fluorescence of coumarin. This fluorescence serves as the reporting signal for assessing the enzyme biomarker level and discriminates tumor cells from normal cells, and subsequently photocontrollable release of the active drug, MTX, can be activated via one- or two-photon irradiation. This pro-prodrug nanosystem shows strong cytotoxicity toward cancer cells and a negligible effect on normal cells. This strategy provides a new platform for constructing nanosystems for cancer detection and subsequent on-demand selective killing of cancer cells via both internal- and external-stimuli activation.
- Chen, Zelin,Li, Bowen,Xie, Xin,Zeng, Fang,Wu, Shuizhu
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p. 2547 - 2556
(2018/05/22)
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- Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis
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A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of H2O2 proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.
- Peiró Cadahía, Jorge,Bondebjerg, Jon,Hansen, Christian A.,Previtali, Viola,Hansen, Anders E.,Andresen, Thomas L.,Clausen, Mads H.
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p. 3503 - 3515
(2018/05/01)
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- A photochemical approach for controlled drug release in targeted drug delivery
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Photochemistry provides a unique mechanism that enables the active control of drug release in cancer-targeting drug delivery. This study investigates the light-mediated release of methotrexate, an anticancer drug, using a photocleavable linker strategy based on o-nitrobenzyl protection. We evaluated two types of the o-nitrobenzyl-linked methotrexate for the drug release study and further extended the study to a fifth-generation poly(amidoamine) dendrimer carrier covalently conjugated with methotrexate via the o-nitrobenzyl linker. We performed the drug release studies by using a combination of three standard analytical methods that include UV/vis spectrometry, 1H NMR spectroscopy, and anal. HPLC. This article reports that methotrexate is released by the photochemical mechanism in an actively controlled manner. The rate of the drug release varies in response to multiple control parameters, including linker design, light wavelength, exposure time, and the pH of the medium where the drug release occurs.
- Choi, Seok Ki,Verma, Manisha,Silpe, Justin,Moody, Ryan E.,Tang, Kenny,Hanson, Jeffrey J.,Baker Jr., James R.
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experimental part
p. 1281 - 1290
(2012/04/10)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- Leukocyte internalized peptide-drug conjugates
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The invention discloses compositions and methods useful for treating and preventing autoimmune diseases. The compositions and methods utilize peptides that are cell-specific. The peptides are conjugated to drugs. The peptide-drug conjugate can be internalized by the targeted cells thereby allowing for cell-specific delivery of the drug.
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- Agents for corneal or intrastromal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing dissolution of corneal proteoglycans and organized healing of corneal stroma, softening of the cornea for non-surgical refractive correction of eyesight, removing corneal haze and opacification, inhibiting fibroblasts and preventing corneal fibrosis and scar formation, treating pterigiums and treating corneal neovascularization as well as iris neovascularization. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) antimetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate, isopropyl alcohol, ethanol, polyethylene glycol, polypropylene glycol or other compound capable of causing nonenzymatic dissolution of the corneal protoeglycans or f) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Enantioseparation using cyclosophoraoses as a novel chiral additive in capillary electrophoresis
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Cyclosophoraoses, cyclic β-(1→2)-D-glucans produced by Rhizobium meliloti 2011, were used as a novel chiral additive for the separation of terbutaline, amethopterin, thyroxine and N-acetylphenylalanine enantiomers in aqueous capillary electrophoresis (CE). Enantioseparation took place in the normal- or reversed-polarity mode when a high concentration of neutral (60 mM) or anionic (40 mM) cyclosophoraoses was added to the background electrolyte (BGE).
- Lee, Sanghoo,Jung, Seunho
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p. 1143 - 1146
(2007/10/03)
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- Agents for intravitreal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing posterior vitreous disconnection or disinsertion. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) a non-steroidal anti-inflamatory agents, d) antmetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, thymidine, thimitadine, uradine, uracil, cystine), uric acid, calcium acetal salicylate, ammonium sulfate or other compound capable of causing non-enzymatic dissolution of the hyaloid membrane or e) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Methods and compositions for treating primary and secondary tumors of the central nervous system (CNS)
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Methods and compositions for the treatment and/or prophylaxis and/or suppression of primary and/or secondary tumors of the central nervous system (brain and spinal cord, eyes) in mammalian subjects are disclosed, wherein an effective dose of a methylol transfer agent such as Taurolidine and/or Taurultam and/or a bioequivalent is administered to a mammalian subject suffering from, or at risk of growth of, tumors of the central nervous system. Furthermore, methods for local application of Taurolidine and/or Taurultam and/or a bioequivalent in solution are disclosed using microdialysis methods, irrigation methods, implantation methods and angiographic methods.
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- Lipophilic methotrexate conjugates with antitumor activity
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Lipophilic methotrexate (MTX)-lipoamino acid conjugates coupled with amide or ester linkages (1a-1r) were synthesised. The inhibitory activity of the conjugates was evaluated on bovine liver DHFR. The in vitro growth inhibitory effect against MTX-sensitive human lymphoblastoid CCRF-CEM cells and an MTX-resistant sub-line (CEM/MTX), which displays defective intracellular transport of MTX, was determined under short-term and continuous (120-h incubation) exposure conditions. The α, γ, or α,γ amide conjugates showed different activity in inhibiting the growth of parent cells. CEM/MTX cells were much less susceptible than CCRF-CEM cells to inhibition by α or α,γ-substituted lipoamino acid conjugates, whereas both cell lines were almost equally sensitive to the MTX-γ conjugates. Although less potent than MTX, they could partially circumvent the impaired transport system. These findings confirm that lipophilic MTX conjugates may be good lead compounds on the drug development for the treatment of some MTX-resistant tumors. Ester-type conjugates displayed an interesting activity against parent CCRF-CEM cells, although they were less potent against the transport-resistant sub-line. Stability studies on these molecules indicated that they are not degraded into MTX in the culture medium, thus suggesting that they are not able to over-cross cell resistance despite of their lipophilicity. Copyright (C) 2000 Elsevier Science B.V.
- Pignatello, Rosario,Spampinato, Giuseppina,Sorrenti, Valeria,Di Giacomo, Claudia,Vicari, Luisa,McGuire, John J.,Russell, Cynthia A.,Puglisi, Giovanni,Toth, Istvan
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p. 237 - 245
(2007/10/03)
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- Efficient syntheses of pyrofolic acid and pteroyl azide, reagents for the production of carboxyl-differentiated derivatives of folic acid
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Reaction of folic acid (1) with excess trifluoroacetic anhydride provides access to both the previously unknown N10-(trifluoroacetyl)pyrrofolic acid (8) and pyrofolic acid (9). Reaction of either of these materials with hydrazine selectively affords pteroyl hydrazide (13), which may be oxidized to pteroyl azide (27) on a large scale (62% overall from I without the need for chromatography). Treatment of 27 with differentially protected glutamates provides a convenient and high-yielding synthesis of differentially protected, optically pure folates.
- Luo, Jin,Smith, Michael D.,Lantrip, Douglas A.,Wang, Susan,Fuchs
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p. 10004 - 10013
(2007/10/03)
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- N-acetylcarboxymethylchitosan derivatives and process for preparation thereof
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N-acetylcarboxymethylchitosan derivatives are provided by the present invention. They are represented by the following formula (I): STR1 wherein R1 and R2 individually mean H or carboxymethyl group; P denotes a group R3 CO--, a group R4 NH-- or a group R5 O-- with assuming that R3 COOH denotes a compound having carboxyl group, R4 NH2 denotes a compound having amino group and R5 OH denotes an alcohol compound; Q stands for H or a group --OH; X represents a peptide chain containing same or different, one to ten amino acids; a1 and a2 individually represent zero or a positive integer, provided that both of a1 and a2 are not zero at the same time, and b stands for a positive integer; and having the following characteristic values (1)-(4): ______________________________________(1) carboxymethylation degree: 0.5-1.2(2) molecular weight (as measured 3,000-300,000 by gel filtration method):(3) a/(a + b): 0.01-1 [provided that a = a1 + a2 ](4) P/X ratio (molar ratio): 0.1-1______________________________________ P in the formula (I) can be the residue of a pharmaceutical compound. In this case, the substances of the formula (I) are derivatives of the pharmaceutical compound, which derivatives have been improved in the properties such as organotropism in vivo. P in the formula (I) can also be protective groups. In this case, removal of the protective groups from the substances of the formula (I) by deprotection makes it possible to provide such N-acetylcarboxymethylchitosan derivative which is useful as carrier for pharmaceutical compounds and which has the terminals of the so deprotected peptide chains capable of being linked with a pharmaceutical compound. There are further obtained such derivatives of the substances of the formula (I), in which derivatives some of the N-acetylcarboxymethylglucosamine units have been replaced by units having a high solubility in water.
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- N-(L-α-aminoacyl) derivatives of methotrexate
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Methotrexate di-t-butyl ester 3 was coupled with N-t-butyloxycarbonyl-L-leucine by the p-nitrophenyl ester and carbodiimide methods to give the di-t-butyl esters 5a - 7a of 2-, 4-, and 2,4-di(N-t-butyloxycarbonyl-L-leucyl)methotrexate. The corresponding L-alanyl analogues 5b - 7b were also synthesised by the latter method. The positions of the acyl groups uere determined from 13C-nmr and uv data. Upon deprotection with trifluoroacetic acid, the 2-acyl products 5a and 5b yielded 2-L-leucyl- and 2-L-alanylmethotrexate 4a and 4b, but the 4-acyl analogues 6a and 6b gave decomposition products. The enzymic cleavage of the 2-(L-α-aminoacyl) pro-drug derivatives 4a and 4b by porcine microsomal leucine aminopeptidase was followed by high-pressure liquid-chromatography (HPLC).
- Cheung, H.T.Andrew,Boadle, Deborah K.,Tran, Trung Q.
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p. 751 - 758
(2007/10/02)
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- Amino acid and hydroxyamino acid transporter compounds for therapeutic applications, process and use
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Amino acid and hydroxyamino acid transporter compounds are provided, in which an amino acid or hydroxyamino acid as a carrier is linked via an ester linkage to a therapeutic compound, and having one of the general formulae: in which AA represents the amino acid or hydroxyamino acid, HAA represents the hydroxyamino acid, and Z1 and Z2 represent a therapeutic compound, or a linking compound attached to COOH or OH of the hydroxyamino acid and to the therapeutic compound, as well as a process for preparing the same, and a process for administration of the same to animals, to obtain the benefit of the therapeutic effect of the therapeutic compound.
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- Method of treating nausea and vomiting with certain substituted-phenylalkylamino (and aminoacid) derivatives and other serotonin depleting agents
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A method for the treatment of emesis in a mammal, which method comprises administering to said mammal an emesis inhibiting amount of a compound which depletes serotonin in the brain of mammals; among which are compounds having the formula: STR1 wherein, R is selected from hydrogen, loweralkyl, trifluoromethyl, carboxyl, or loweralkoxycarbonyl; R1 and R2 are hydrogen or loweralkyl; Z is trifluoromethyl or halogen; the optical isomers and pharmaceutically acceptable salts thereof; two of the preferred compounds of the invention are fenfluramine and norfenfluramine.
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- Process for the preparation of pteridine derivatives
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Pteridine derivatives of general formula STR1 in which R is hydrogen or methyl, i.e. aminopterin or methotrexate, are made by the action of a silazane on a pteridine derivative of formula STR2
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- SYNTHESIS OF MULTI-13C-ENRICHED METHOTREXATE FOR NMR STUDIES OF DRUG - ENZYME INTERACTIONS
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Methotrexate N--L-glutamic acid, 13C-enriched at positions 6; 2,7,9; 4,7,8a,9; and 2,4a,6 were synthesized from the correspondingly labelled 2,4-diamino-6-methylpteridine by "benzylic" bromination followed by displacement of the bromide by di-t-butyl N-(p-methylaminobenzoyl)-L-glutamate.Acid treatment of each methotrexate di-t-butyl ester formed yielded the corresponding 13C-enriched methotrexate.
- Cheung, H.T. Andrew,Smal, Mary,Chau, Diem Dieu
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p. 507 - 514
(2007/10/02)
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- Process for the production of methotrexate
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Process for the production of methotrexate, which is N[p-([(2,4-diamino-6-pteridyl)-methyl]-N10 -methylamino)-benzoyl]-L-glutamic acid. The process includes converting 1,1-dichloroacetone with 2,4,5,6-tetraaminopyrimidine in the presence of sodium bisulfite at a constant pH between 3.5 and 5 and at a temperature between 10° and 100° C. The resultant 2,4-diamino-6-methylpteridine is converted in a reaction medium with bromide. 0.3 to 1.0 ml of bromine is used per 1.0 g of the 2,4-diamino-6-methylpteridine. The 2,4-diamino-6-bromo methyl pteridine is converted with p-(N-methyl)-aminobenzoyl-L-glutamic acid or a salt thereof in a polar reaction medium into methoxtrexate.
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- 6-(Bromomethyl)-2,4-diaminopteridine hydrobromide
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A pteridine compound having the formula of 6-(bromomethyl)-2,4-diaminopteridine hydrobromide. 2,4-diamino-6-pteridine-methanol.HBr is reacted with triphenylphosphine dibromide or phosphorus tribromide to form 6-(bromomethyl)-2,4-diaminopteridine hydrobromide. The bromine atom in the molecule can then be replaced with the functional group, N-[4-(methylamino)-benzoyl]-L-glutamic acid in the case of methotrexate and N-(4-aminobenzoyl)-L-glutamic acid in the case of aminopterin.
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- Process for preparing methotrexate or an N-substituted derivative thereof and/or a di (lower) alkyl ester thereof and precursor therefor
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There is disclosed a process for the preparation of the pyrazine precursor of methotrexate or an N-substituted derivative thereof and/or a di(lower)alkyl ester thereof having the formula: STR1 wherein R and R' may each be hydrogen or a lower alkyl group, e.g., ethyl. In a preferred embodiment, the process comprises reacting in one step the compounds aminomalononitrile, β-halopyzuvaldoxime and a di(lower)alkyl p-methylaminobenzoyl-L-glutamate to form the di(lower)alkyl ester of the pyrazine oxide precursor of methotrexate having the formula: STR2 This compound is then treated with either titanium trichloride or iodoformamidinium iodide to deoxygenate the compound. There is also disclosed a process for the preparation of a di(lower)alkyl ester of methotrexate having the formula: STR3 by treating the di(lower)alkyl ester of the pyrazine precursor of methotrexate with a guanidine salt of a weak organic acid, e.g., guanidine acetate.
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