- ANTIFOLATE-CARRYING NANOPARTICLES AND THEIR USE IN MEDICINE
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The present invention provides a nanoparticle comprising: a core comprising a metal and/or a semiconductor; and a plurality of ligands covalently linked to the core, wherein said ligands comprise: (i) at least one dilution ligand comprising a carbohydrate, glutathione or an ethylene glycol-containing moiety; and (ii) a ligand of the formula D-L1-Z-L2, wherein D comprises an antifolate drug or folic acid, L1 comprises a first linker portion comprising a C2-C12 glycol and/or C2-C12 alkyl chain, L2 comprises a second linker portion comprising a C2-C12 glycol and/or C2-C12 alkyl chain, wherein L1 and L2 may be the same or different, and wherein Z represents a carbonyl-containing group linking L1 and L2, and wherein L2 is coupled to said core, Also provided are pharmaceutical compositions comprising such nanoparticles, medical uses thereof and methods for producing the nanoparticles.
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Page/Page column 74
(2020/07/07)
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- PRODRUGS ACTIVATED BY REACTIVE OXYGEN SPECIES FOR USE IN THE TREATMENT OF INFLAMMATORY DISEASES AND CANCER
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Prodrugs activated predominantly or exclusively in inflammatory tissue, more particularly prodrugs of methotrexate and derivatives thereof, which are selectively activated by Reactive Oxygen Species (ROS) in inflammatory tissues associated with cancer and inflammatory diseases, as well as method for preparing said prodrugs.
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Page/Page column 27; 28; 32
(2018/09/25)
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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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- Tetrahydrofurfuroxy folic acid analogue synthetic method
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The invention relates to a novel method for synthesis of tetrahydrofolic acid analogues, and mainly solves the problems of uneasily controllable reaction conditions and many produced by products in a conventional synthesis method. A series of tetrahydrofolic acid analogues are prepared by employing 5-aminouracil or 2,4,5,6-tetraaminopyrimidine, 2,5,6-triamino-4-hydroxypyrimidine as an initial raw material and combining the steps of cyclization, oxidation, chlorination, ammonolysis, catalytic hydrogenation reduction, intramolecular cyclization, aziridine ring opening, nucleophilic substitution, ethoxycarbonyl hydrolysis, etc. Compared with a conventional synthesis method, the novel method provided by the invention has the characteristics of mild and stable reaction conditions, few by-products, wide application range, etc.
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Paragraph 0087; 0088
(2016/10/10)
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- DIAMINOPTERIDINE DERIVATIVES
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The present invention relates novel diaminopteridine derivatives, their compositions and method of treatment comprising the same for use as anti-infectives.
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Page/Page column 48-49
(2010/11/04)
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- USE OF THE STAUDINGER LIGATION IN IN VIVO ASSEMBLY OF A BIOLOGICALLY ACTIVE COMPOUND
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The invention provides methods and tools for the in vivo self-assembly of drugs. This makes it possible to reduce problems associated with the lack of selectivity, reduced solubility and other disadvantages of intact drugs.
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Page/Page column 23
(2008/06/13)
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- Aminopterin dosage forms and methods for inflammatory disorders
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Embodiments of the present invention provide dosage forms and methods for treating a patient with an inflammatory disorder with a therapeutically effective amount of aminopterin, or a pharmaceutically acceptable salt thereof, that achieve efficacy without concomitant toxicity. Within certain embodiments, the present invention provides a method for treating an inflammatory disorder in a patient with uninterrupted doses of aminopterin.
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Page/Page column 11
(2008/06/13)
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- Compositions and methods employing aminopterin
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The present invention relates to pharmaceutical compositions containing the antifolate aminopterin, processes for making the compositions, and methods of using them to treat disorders in adult and pediatric patients. Pharmaceutical compositions substantially free of impurities are provided comprising a therapeutically effective amount of aminopterin, or a pharmaceutically acceptable salt thereof. Relative to the teachings of the prior art, the disclosed methods and compositions provide unexpected improvements that include a greater interpatient oral bioavailability in pediatric patients, a smaller interpatient coefficient of variation of oral bioavailability, a smaller mean intrapatient coefficient of variation of oral bioavailability, a greater therapeutic index, a smaller coefficient of variation of toxicity, efficacy in combination therapy, and efficacy of certain polyglutamated metabolites.
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Page/Page column 16
(2008/06/13)
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- Methods of treating inflammatory diseases with ammonium salts of ornitihine derivatives
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The present invention relates to pharmaceutically active ornithine compounds, particularly to pharmaceutically acceptable ammonium salts of Nδ-acyl derivatives of Nα(4-amino-4-deoxypteroyl)-L-ornithine compounds; and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such ammonium salts. The ammonium salts provided by the invention exhibit superior chemical stability than corresponding acidic Nδ-acyl derivatives of Nδ-acyl derivatives of Nα(4-amino-4-deoxypteroyl)-L-ornithine compounds.
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- Pteridines. Part CXIII. Protection of Pteridines
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The low solubulity of pterins can drastically be improved by N2-acylation or formation of the N2-[(dimethylamino)methylene] derivatives. Both types of compounds can be alkylated under Mitsunobu conditions to form from N2-acylpterins (see 2 and 3) and their derivatives (see 5, 6, 8, 9, 11, 13, 15, and 17) selectively the O4-alkyl derivatives 22-31, whereas the electron-donating [(dimethylamino)methyleneamino] function in 46-51 gives, in a selective reaction, the N(3)-substitution (->52-61). N2,N2-Dimethylpterins and 18 and 19 and N2-methylpterins 20 and 21 direct alkylation also to the O4-position (->32-35, 38 and 39). Deacylation can be achieved under very mild conditions by solvolysis with MeOH (22->40, 26->41), and displacement of the O4-[2-(4-nitrophenyl)ethyl] group proceeds with ammonia at room temperature to the corresponding pteridin-2,4-diamine 42-45. Cleavage of the N2-[(dimethylamino)methylene] group works well with ammonia (->62-67). The advantage of applying the 2-(4-nitrophenyl)ethyl (npe) group as blocking group is seen in its selective removal by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under aprotic conditions without harming the other substituents.
- Yao, Qizheng,Pfleiderer, Wolfgang
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- Photohydrolysis of methotrexate produces pteridine, which induces poly-G-specific DNA damage through photoinduced electron transfer
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Methotrexate (MTX), an antineoplastic agent, demonstrates phototoxicity. The mechanism of damage to biomacromolecules induced by photoirradiated MTX was examined using 32P-labeled DNA fragments obtained from a human gene. Photoirradiated MTX ca
- Hirakawa, Kazutaka,Aoshima, Masahiro,Hiraku, Yusuke,Kawanishi, Shosuke
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p. 467 - 472
(2007/10/03)
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- Phosphinic acid pseudopeptides analogous to glutamyl-γ-glutamate: Synthesis and coupling to pteroyl azides leads to potent inhibitors of folylpoly-γ-glutamate synthetase
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Several routes to a complex phosphinate phosphapeptide analogous to the γ-glutamyl peptide Gluγ-Glu have been investigated. Formation of γ-phosphono glutamate derivatives via addition of a phosphorus-based radical to protected vinylglycine was found to be of limited value because of the elevated temperatures required. Alkylation and conjugate addition reactions of trivalent phosphorus (PIII) species were investigated. In situ generation of bis-trimethylsilyl esters of phosphinous acids proved to be an effective route to phosphinates of modest structural complexity. However, this chemistry could not be extended to the incorporation of an amino acid moiety at the N-terminal side of the desired phosphinate. A successful synthesis of the target phosphinate phosphapeptide was effected using PIII chemistry and dehydrohalogenation to yield an α,β-unsaturated phosphinic acid ester, following which conjugate addition of diethylacetamido malonate and acid-mediated hydrolysis afforded the desired phosphinate phosphapeptide. Coupling of the unprotected phosphinate phosphapeptide with two acyl azides derived from folic acid and methotrexate led to the corresponding pteroylphosphapeptides of interest as possible mimics of tetrahedral intermediates in the reaction catalyzed by folylpolyglutamate synthetase.
- Valiaeva,Bartley,Konno,Coward
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p. 5146 - 5154
(2007/10/03)
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- The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase
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This paper describes the design and synthesis of potential inhibitors of Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T. cruzi enzyme was compared with the structure of the human enzyme. The differences were used to design modifications of methotrexate to produce compounds which should be selective for the parasite enzyme. The derivatives of methotrexate were synthesised and tested against the enzyme and intact parasites.
- Zuccotto, Fabio,Brun, Reto,Gonzalez Pacanowska, Dolores,Ruiz Perez, Luis M.,Gilbert, Ian H.
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p. 1463 - 1468
(2007/10/03)
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- Synthesis of tritiated N-[4-(2,4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1,4- benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68)
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Synthesis of tritiated N-[4-(2,4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1,4-benzothiazine-7 -carbonyl]-L-homoglutamic acid, [9-3H,]MX-68 (3), is described. [9-3H1MX-68 (3) was prepared via tritiation at the carbonyl group in 2,4-bis(butanoylamino)-6-formylpteridine (7) with sodium borotritiide.
- Matsuoka, Hiroharu,Kuroki, Toshio,Yano, Keiichi,Takeda, Yasuhisa
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p. 363 - 368
(2007/10/03)
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- Pteridines, LXIX. Synthesis and Reactivity of 2,4-Diamino-6-(hydroxymethyl)pteridine
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Condensation of 2,4,5,6-tetraaminopyridine (2) with 1,3-dihydroxyacetone in the presence of gaseous oxygen, rather than air, resulted in 2,4-diamino-6-(hydroxymethyl)pteridine (3) virtually uncontaminated with 2,4-diamino-6-methylpteridine (4).Acetylation of 3 led to 6-acetoxymethyl-2,4-bis(acetylamino)pteridine (5) which turned out to be very labile forming various di- and monoacetyl derivatives (6, 7, 9, 10) on mild hydrolytic conditions.Their structures are proven by physical-chemical means.Silylation of 3 to the tris(trimethylsilyl) derivative 11 followed by treatment with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (12) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (15), respectively, in the presence of boron trifluoride,led to selective formation of the corresponding acylated 2,4-diamino-6-pteridinyl O-glycosides 13 and 15, respectively.Deacylations of these afforded the free O-glycosides 14 and 17 which have been characterized by UV- and NMR spectra as well as pKa measurements.
- Boyle, Peter H.,Pfleiderer, Wolfgang
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p. 1514 - 1523
(2007/10/02)
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- Process of preparing N[p-{[(2,4-diamino-6-pteridyl)-methyl]N10 -methylamino}-benzoyl]-glutamic acid
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A three-step process is provided for preparing the L,D and DL isomers of N[p-{[(2,4-diamino-6-pteridyl)-methyl]N10 -methylamino}-benzoyl]-glutamic acid. The first step produces: 2,4-diamino-6-hydroxymethyl pteridine by condensation in a buffered aqueous media of 2,3,4,5-tetraminopyrimidine dihydrochloride with the bisulphite addition product of 1,3-dihydroxyacetone in the presence of cysteine as catalyst and using selenium dioxide and a continuous air bubbling as oxidation agents. In the next step, 2,4-diamino-6-halomethylpteridine is obtained by halogenation of the previously obtained 2,4-diamino-6-hydroxymethylpteridine in an inert media with a halogenation agent such as thionyl chloride, in the presence of a basic catalyst such as pyridine or triethylamine. In the third step, N[p-{[(2,4-diamino-6-pteridyl)-methyl]-N10 -methylamino}-benzoyl-]-glutamic acid is produced by condensation of the 2,4-diamino-6-halomethylpteridine with N[p-(N-methylamino)-benzoyl]-glutamic acid at pH 3-4 in an aqueous buffered solution.
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