[go: up one dir, main page]

WO2005016878A2 - Procedes de preparation de composes 5-fluoro-pyrrolo[2,3-d]pyrimidine - Google Patents

Procedes de preparation de composes 5-fluoro-pyrrolo[2,3-d]pyrimidine Download PDF

Info

Publication number
WO2005016878A2
WO2005016878A2 PCT/US2004/026245 US2004026245W WO2005016878A2 WO 2005016878 A2 WO2005016878 A2 WO 2005016878A2 US 2004026245 W US2004026245 W US 2004026245W WO 2005016878 A2 WO2005016878 A2 WO 2005016878A2
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolo
pyrimidine
fluoro
fluorinating reagent
electrophilic fluorinating
Prior art date
Application number
PCT/US2004/026245
Other languages
English (en)
Other versions
WO2005016878A3 (fr
Inventor
Xiaojing Wang
Punit P. Seth
Eric E. Swayze
Michael T. Migawa
Original Assignee
Isis Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Isis Pharmaceuticals, Inc. filed Critical Isis Pharmaceuticals, Inc.
Publication of WO2005016878A2 publication Critical patent/WO2005016878A2/fr
Publication of WO2005016878A3 publication Critical patent/WO2005016878A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Definitions

  • FIELD [0002] This invention relates to 5-fluoropyrrolo[2,3- ]pyrimidine compounds and methods for their preparation.
  • tubercidin and its derivatives include; in vitro cytotoxicity in mammalian cell strains, significant in vivo antitumor activity, inhibition of RNA and DNA virus replication and the inhibition of the growth of a variety of microorganisms (Anderson, J. D. et al. Nucleosides & Nucleotides, 8: 1201-1216, 1989; Cottam, H. B. et al. Journal of Medicinal Chemistry, 28: 1461-1467, 1985; Nichol, C. A.; et al. Cancer Chemother., Proc. Takeda lnt. Confi, Osaka 185-195, 1967; De Clercq, E.; et al.
  • the present invention is generally related to a method of synthesis of 5-fluoro- and 5-fluoro-pyrrolo[2,3-d]pyrimidine nucleoside compounds.
  • the method of synthesis relates to electrophilic fluorination of a 4-substituted pyrrolo[2,3- cQpyrimidine to yield 4-substituted-5-fluoro-pyrrolo[2,3-rf]pyrimidine.
  • Suitable 4-substituted pyrrolo[2,3-d]pyrimidines include 4-halo, 4-protected amino, 4-oxo and 4-alkyl where alkyl includes Cl to C6 alkyl.
  • the invention more particularly relates to electrophilic fluorination of a 4-halogenated pyrrolo[2,3-d]pyrimidine to yield 4-halo-5-fluoro-pyrrolo[2,3- ⁇ f]pyrimidine.
  • the invention more particularly relates to electrophilic fluorination of a 4-chloro-pyrrolo[2,3- rf]pyrimidine to yield 4-chlopo-5-fluoro-pyrrolo[2,3-rf]pyrimidine.
  • the present invention further relates to a method of synthesis by electrophilic fluorination of a 4-substituted pyrrolo[2,3-cT]pyrimidme including 4-halogenated pyrrolo[2,3--flpyrimidine particularly 4- chloro-pyrrolo[2,3- ]pyrimidine, cuhninating in the synthesis of 4-amino-5-fluoro-pyrrolo[2,3- ( jpyrimidine nucleoside, e.g., 5-fluorotubercidin.
  • the methods of the invention further provide compounds useful as intermediates in the systhesis of 5-fiuorotubercidin.
  • the compound 5-fluoro-pyrrolo[2,3- Jpyrimidine is provided.
  • the compound 4-chloro-5-fluoro-7H- pyrrolo[2,3-d]pyrimidine is provided.
  • the compound 4-chloro-5-fluoro- 5H-pyrrolo[2.3-d]pyrimidine is provided.
  • the compound 4-chloro-5- fluoro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidm-6-ol is provided.
  • the compound 4-chloro-5-fluoro-7-( ⁇ -D-ribofuranosyl)pyrrolo[2.3-d]pyrimidine is provided.
  • R 1 ⁇ R 2 , and R 3 are selected, independently, from hydroxyl or a hydroxyl protecting group.
  • the methods comprise the steps of providing 4-halo-pyrrolo[2,3-d]pyrimidine, and reacting the 4-halo-pyrrolo[2,3-d]pyrimidine with an electrophilic fluorinating reagent to form 4-halo-5-fluoro-pyrrolo[2,3- ]pyrimidine.
  • methods comprise the steps of providing 4-chloro-pyrrolo[2,3- ( jpyrimidine, and reacting the 4-chloro-pyrrolo[2,3-rf]pyrimidine with an electrophilic fluorinating reagent to form 4-chloro-5-fluoro-pyrrolo[2,3- ⁇ fJpyrimidine.
  • the 4-chloro-pyrrolo[2,3-d]pyrimidine is reacted with the electrophilic fluorinating reagent in the presence of acetonitrile and acetic acid.
  • the electrophilic fluorinating reagent is l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafmoroborate).
  • the reaction of the 4-chloro- pyrrolo[2,3-rf]pyrimidine with the electrophilic fluorinating reagent is effected at a temperature that is approximately 70°C.
  • methods comprise the steps of providing 4-halo- pyrrolo[2,3- ⁇ i]pyrimidine, reacting the 4-halo-pyrrolo[2,3- ⁇ i]pyrimidine with an electrophilic fluorinating reagent to form 4-halo-5-fluoro-pyrrolo[2,3- ]pyrimidine, reacting the 4-halo-5- fluoro-pyrrolo [2,3- ⁇ Jpyrimidine with a sugar derivative to form 4-halo-5-fluoro-pyrrolo[2,3- cTjpyrimidine nucleoside, and reacting the 4-halo-5-fluoro-pyrrolo[2,3-- ]pyrimidine nucleoside with ammonia to form 4-amino-5-fluoro-pyrrolo[2,3-(i]pyrimidine nucleoside.
  • the 4-halo-pyrrolo[2,3- ]pyrimidine is 4-chloropyrrolo[2,3-cT]pyrimidine.
  • the 4-chloro-pyrrolo[2,3-d]pyrimidine is reacted with the electrophilic fluorinating reagent in the presence of acetonitrile and acetic acid.
  • the electrophilic fluorinating reagent is l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
  • the reaction of the 4-chloro-pyrrolo[2,3-J]pyrimidine with the electrophilic fluorinating reagent is effected at a temperature that is approximately 70°C. h a further detailed embodiment, the reaction with the electrophilic fluorinating reagent occurs for a time period of approximately 2 to approximately 14 hours.
  • Sugar derivatives include ⁇ - , ⁇ -Z, a-D and -L forms of ribo, xylo, lyxo and arabino sugars and further include 2', 3', 4' and 5' substituted derivatives of these sugars. In a detailed embodiment such sugar derivatives include 2' and 3' halo, alkoxyl and alkyl derivatives of these sugars.
  • the sugar derivative is a D- ribofuranose derivative.
  • 5-fluorotubercidin useful as the sugar derivative is 1-O- acetyl-2,3,5,-tri-O-benzoyl- ⁇ -D-ribofuranose.
  • methods comprise the steps of providing 4-chloro- pyrrolo[2,3-rf]pyrimidine, reacting the 4-chloro-pyrrolo[2,3-d]pyrimidine with an electrophilic fluorinating reagent to form 4-chloro-5-fluoro-pyrrolo[2,3- ⁇ pyrimidine, reacting the 4-chloro-5- fluoro-pyrrolo[2,3-J]pyrimidine with an appropriate protected sugar derivative, e.g., D- ribofuranose, to form 4-chloiO-5-fluoro-pyrrolo[2,3-rf]pyrimidine nucleoside, and reacting the 4- chloro-5-fluoro-pyrrolo[2,3- ]pyrimidine nucleoside with ammonia to form 4-amino-5-fmoro- pyrrolo[2,3-cT]pyrimidine nucleoside.
  • the present invention relates to electrophilic fluorination of 4- substituted pyrrolo[2,3-d]pyrimidines particularly 4-halo-pyrrolo[2,3- ⁇ i]pyrimidines and even more particularly 4-chloro-5-fluoro-pyrrolo[2,3-d]pyrimidines.
  • These compounds are useful intermediates for the synthesis of 4-amino-5-fluoro-pyrrolo[2,3-rf]pyrimidine nucleosides, e.g., 5-fluorotubercidin.
  • 5-fluorotubercidin was prepared and evaluated in a variety of cell lines for antiproliferative activity.
  • the trans isomer of compound 3 was studied by 1 H NMR and 19 F NMR, and the 5-H tautomer (4) was also identified.
  • a modified Vorbruggen procedure using compound 2 and tetra-O- acetylribose gave 4-chloro-5-fluoro-7-(2,3,5,-tri-0-benzoyl- ⁇ -D-ribofuranosyl)pyrrolo[2,3- cTjpyrimidine (6) in a 65% yield.
  • Treatment of compound 6 with ammonia in dioxane gave 5- fluorotubercidin (7).
  • Other nucleosides are prepared in a like manner using compound 2 and an appropriate protected sugar.
  • nucleosides in addition to the above described ⁇ -D-ribo nucleoside would include ⁇ -D-ribo, ⁇ -Z,-ribo, ⁇ -J-ribo, ⁇ -D-xylo, ⁇ -D-xylo, ⁇ -Z-xylo, ⁇ -X-xylo, ⁇ -D-lyxo, ⁇ -D-lyxo, ⁇ -L-lyxo, ⁇ -J-lyxo, ⁇ -D-arabino, ⁇ -D-arabino, ⁇ -L-arabino, ⁇ -X-arabino, ⁇ -D-deoxy, ⁇ -D-deoxy, ⁇ -L-deoxy, ⁇ -X-deoxy, ⁇ -D-dideoxy, ⁇ -D-dideoxy, ⁇ -L-dideoxy, -L- dideoxy nucleoside analogs of compound 6 as well as 2', 3', 4' and 5' substituted nucle
  • 5-fluorotubercidin was prepared as described in the detailed examples below. 5- fluorotubercidin as well as 5-iodotubercidin and tubercidin were evaluated for cellular cytotoxicity using an MTT assay against Huh-7 liver cells, normal mouse spleen cells stimulated with Con A (a T-cell mitogen), and normal mouse spleen stimulated with LPS (a B-cell mitogen). No significant toxicity was observed for these compounds (IC50 > 200 ⁇ M) in these cells. However in fibroblast cells tubercidin was toxic at 12 ⁇ M whereas no toxicity was observed for 5-fluorotubercidin in concentrations of up to 200 ⁇ M.
  • 5- iodotubercidin showed activity at > 10 ⁇ M, tubercidin at 2-3 ⁇ M and 5-fluorotubercidin at 1 ⁇ M.
  • increased anti-proliferative toxicity of 5-fluoiOtubercidin (7) compared to tubercidin was observed against L-1210 tumor cells, while toxicity in fibroblast cells was reduced. While we do not wish to be bound by theory, this suggests 5-fluorotubercidin might be less cytotoxic than tubercidin and thus have a greater therapeutic index for antitumor indications as compared to tubercidin.
  • 5-fluorotubercidin was also compared to 5-iodotubercidin and tubercidin for their ability to inhibit bacterial transcription/translation as well as antibacterial activity against E. coli and S. aureus. No antibacterial activity observed at concentrations up to 100 ⁇ M.
  • 5-halogenated pyrrolo[2,3- ]pyrimidine nucleosides can be prepared by a direct halogenation of an appropriately protected tubercidin. For example, direct bromination of tubercidin with NBS in DMF gives the 5-bromotubercidin, while the use of NBS in a KO Ac- buffered medium gives 6-bromotubercidin (Bergstrom, D. E.et al.
  • 4-chloro-5-fluoro-pyrrolo[2,3- JJpyrimidine heterocycle was first prepared and coupled to an appropriately substituted ribose.
  • 4-Chloro-pyrrolo[2,3- ]pyrimidine (1) was chosen as starting material.
  • Other 4-substitutent groups might also be used including 4-halo, 4-oxo, 4-protected amino and 4-alkyl where halo includes bromo, chloro, fluoro and iodo and alkyl is Cl to C6 alkyl. While we do not wish to be bound by any particularly theory, the 4-chloro moiety is preferred to facilitate the electrophilic fluorination process.
  • electrophilic fluorination of heterocycles is carried out using the highly reactive fluorine gas or acetyl hypofluorites (Erian, A. W. Journal ofHeterocyclic Chemistry, 38: 793-808, 2001).
  • 5-fluorotubercidin i.e., 4-amino-5-fmoro-7-( ⁇ -D- riboflxranosyl)pyrrolo[2,3-rf]pyrimidine) (7) was synthesized from 4-chloro-5-fluoropyrrolo[2,3- (fjpyrimidine (2) using a modified Vorbruggen procedure to give 4-chloro-5-fluoro-7-(2,3,5-tri- O-benoyl- ⁇ -D-ribofuranosyl)pyrrolo[2,3-J]pyrimidine (6), in a 65% yield (Vorbrueggen, H., Ace.
  • test compound Compounds were tested in a black 96 well microtiter plate with an assay volume of 35 ⁇ L. Each test well contained: 5 ⁇ L test compound, 13 ⁇ L S30 premix (Promega), 4 ⁇ L 10X complete amino acid mix (1 mM each), 5 ⁇ L E. coli S30 extract and 8 ⁇ L of 0.125 ⁇ g/ ⁇ L pBest LucTM. The transcription translation reaction was incubated for 35 minutes at 37°C followed by detection of functional luciferase with the addition of 30 ⁇ L LucLiteTM (Packard). Light output was quantitated on a Packard TopCount. [0025] Minimum Inhibitory Concentrations (MICs).
  • the assays are carried out in 150 ⁇ L volume in duplicate in 96-well clear flat-bottom plates.
  • the bacterial suspension from an overnight culture growth in appropriate medium is added to a solution of test compound in 2.5% DMSO in water.
  • Final bacterial inoculum is approximately 10 2 -10 3 CFU/well.
  • the percentage growth of the bacteria in test wells relative to that observed for a control wells containing no compound is determined by measuring absorbance at 595 nm (A 5 5 ) after 20-24 h at 37°C.
  • the MIC is determined as a range of concentration where complete inhibition of growth is observed at the higher concentration and bacterial cells are viable at the lower concentration. Both ampicillin and tetracycline are used as antibiotic positive controls in each screening assay for E.
  • MTT Assays MTT proliferation assays were purchased as kits from Promega and were run according to the manufacturer's protocol.
  • Example 1 4-Chloro-5-fluoro-7H-pyrroIo[2,3- ⁇ /]pyrimidine (2).
  • 4-Chloro-7H-pyrrolo ⁇ yrimidine 1 (5 g, 32.7 mmol) and Selectfluor (17.35 g, 49 mmol) were placed in a round bottom flask, followed by the addition of dry acetonitrile (250 mL) and AcOH (50 mL). The solution was then heated at 70 °C for 14 h under N 2 .
  • Example 2 4-Chloro-5-fluoro-6,7-dihydro-5H-pyrroIo[2,3-rf]pyrimidin-6-ol (3).
  • 4-Chloro-7H-pyrrolopyrimidine 1 (10 mg, 0.065 mmol) and Selectfluor (115 mg, 0.33 mmol) were placed in a round bottom flask, followed by the addition of acetonitrile (1 mL) and two drops of water. The mixture was then stirred at room temperature for 4 hours. After evaporation, the crude product was purified by column chromatography using DCM : MeOH (98:2) to give 5 mg brown solid.
  • Example 3 4-ChIoro-5-fluoro-7-(2,3,5,-tri-0-benzoyl- ⁇ -D-ribofuranosyl)pyrroIo[2,3- .flpyrimidine (6).
  • N,O-Bis(trimethylsilyl)acetamide (BSA, 0.16 mL, 0.64 mmol) was added to a stirred suspension of 4-chloro-5-fluoro-7H-pyrrolo[2,3-- ]pyrimidine (0.1 g, 0.58 mmol) in dry acetonitrile (4 mL).
  • Example 5 5-Fluorotuberidicin (7).
  • 4-Chloro-5-fluoro-7-(2,3,5,-tri-O-benzoyl- ⁇ -D-ribofuranosyl)pyrrolo[2,3- (ijpyrimidine 6 230 mg, 0.42 mmol was dissolved in dioxane (3 mL) and liquid ammonia (8 - 10 mL). The reaction was sealed in a steel bomb and heated in an oil bath at 75°C for 14 hours. The reaction was then cooled and the solvent evaporated to provide the crude nucleoside.
  • Example 6 MTT Toxicity Assay The MTT cell proliferation assay was used to test for cell toxicity (see van de Loosdrecht, A. A.; Beelen, R. H.; Ossenkoppele, G. J.; Broekhoven, M. G.; Langenhuijsen, M. M. J. Immunol. Methods 1994, 174, 311-320).
  • An assay kit was purchased from American Type Culture Collection (Manassas, VA, USA), and treatment of cells and the specific assay protocol was carried out according to the manufacturer's recommendations.
  • the MTT cell proliferation assay measures cell viability and growth by the reduction of tetrazolium salts.
  • Cyquant cell proliferation assay was used to test compounds for cell toxicity.
  • 5-fluorotubercidin showed inhibitory active as measured by retardation of cell growth of both HeLa cell line and human lung cancer cell line H460 (wild-type-p53) at concentrations ranging from 200 nM to 2000 nM.
  • An assay kit (Molecular Probes #C-7026) was used for treatment of cells with 5- fluorotubercidin. Treatment of cells and the specific assay protocol was carried out according to the manufacturer's recommendations.
  • the Cyquant assay utilizes green fluorescent dye (CyQUANT GR) that exhibits strong fluorescence enhancement when bound to cellular nucleic acids.
  • CyQUANT GR dye After treatment, cells were frozen, thawed and lysed in a buffer containing the CyQUANT GR dye. Fluorescence was measured directly and gives a linear representation of relative cell number. [0036] Cyquant proliferation data was measured for both HeLa cells and H460 cells. In the HeLa cell proliferation assay, at the start of the assay baseline fluorescence measured 10000 RFU. At concentrations below 200 nM no cell growth retardation activity was noted. At a concentration of 200 nM at 25 minutes the baseline 10000 RFU value was maintain whereas at 50 minutes the cells begin to proliferate and fluorescence increase to 17000 RFU and at 75 minutes to 22500 RFU.
  • the present invention provides methods of making compound suitable for use in pharmaceutical compositions that comprise a therapeutically effective amount of one or more compounds described herein, their pharmaceutically acceptable salts, prodrugs or derivatives and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be used as nucleoside antimetabolites in cancer chemotherapy or treatment of benign or malignant abnormal tissue growth.
  • Such pharmaceutical compositions can be used to treat or prevent a variety of neoplastic diseases such as, solid tumors, hematological malignancy, leukemia, colorectal cancer, benign or malignant breast cancer, uterine cancer, uterine leiomyomas, ovarian cancer, endometrial cancer, polycystic ovary syndrome, endometrial polyps, prostate cancer, prostatic hypertrophy, pituitary cancer, adenomyosis, adenocarcinomas, meningioma, melanoma, bone cancer, multiple myeloma, CNS cancers, such as glioma or astroblastoma, and other benign or malignant abnormal tissue growth.
  • neoplastic diseases such as, solid tumors, hematological malignancy, leukemia, colorectal cancer, benign or malignant breast cancer, uterine cancer, uterine leiomyomas, ovarian cancer, endometrial cancer, polycystic
  • pharmaceutically acceptable salt, prodrug or derivative related to any pharmaceutically acceptable salt, ester, ether, salt of an ester, solvate, such as ethanolate, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).
  • the compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases.
  • These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo.
  • the compounds When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
  • pharmaceutically acceptable carriers for example, solvents, diluents and the like
  • Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
  • Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions for administering the pyrrolo[2,3- ⁇ f]pyrimidine compounds (see, e.g., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 18 th ed., 1990, incorporated herein by reference).
  • the pharmaceutical compositions generally comprise the pyrrolo[2,3- (fjpyrimidine compounds in a form suitable for administration to a patient.
  • the pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.
  • GMP Good Manufacturing Practice
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg.
  • Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. [0046] These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
  • Adjuvant customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • the preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
  • active compounds may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des composés 5-fluoro-pyrrolo[2,3-d]pyrimidine et des composés 5-fluoro-pyrrolo[2,3-d]pyrimidine nucléoside et des procédés permettant de les préparer.
PCT/US2004/026245 2003-08-13 2004-08-11 Procedes de preparation de composes 5-fluoro-pyrrolo[2,3-d]pyrimidine WO2005016878A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US49498803P 2003-08-13 2003-08-13
US60/494,988 2003-08-13

Publications (2)

Publication Number Publication Date
WO2005016878A2 true WO2005016878A2 (fr) 2005-02-24
WO2005016878A3 WO2005016878A3 (fr) 2005-06-02

Family

ID=34193263

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/026245 WO2005016878A2 (fr) 2003-08-13 2004-08-11 Procedes de preparation de composes 5-fluoro-pyrrolo[2,3-d]pyrimidine

Country Status (1)

Country Link
WO (1) WO2005016878A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019116302A1 (fr) 2017-12-13 2019-06-20 Lupin Limited Composés hétérocycliques bicycliques substitués utilisés en tant qu'inhibiteurs de prmt5

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7323453B2 (en) * 2002-02-13 2008-01-29 Merck & Co., Inc. Methods of inhibiting orthopoxvirus replication with nucleoside compounds
CA2492607A1 (fr) * 2002-07-25 2004-02-05 Micrologix Biotech Inc. Nucleosides d de 7-deaza antiviraux et leurs utilisations

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019116302A1 (fr) 2017-12-13 2019-06-20 Lupin Limited Composés hétérocycliques bicycliques substitués utilisés en tant qu'inhibiteurs de prmt5
US11459330B2 (en) 2017-12-13 2022-10-04 Lupin Limited Substituted bicyclic heterocyclic compounds as PRMT5 inhibitors
US11952380B2 (en) 2017-12-13 2024-04-09 Lupin Limited Substituted bicyclic heterocyclic compounds as PRMT5 inhibitors

Also Published As

Publication number Publication date
WO2005016878A3 (fr) 2005-06-02

Similar Documents

Publication Publication Date Title
Radwan et al. Synthesis, molecular docking and antimicrobial activity of new fused pyrimidine and pyridine derivatives
Chittepu et al. Nucleosides and oligonucleotides containing 1, 2, 3-triazole residues with nucleobase tethers: Synthesis via the azide-alkyne ‘click’reaction
Gorle et al. Synthesis, molecular docking study and in vitro anticancer activity of tetrazole linked benzochromene derivatives
KR102653823B1 (ko) Cd73 억제제, 그 제조 방법 및 용도
HUT70954A (en) Bicyclic-heterocyclic amines containing nitrogen heteroatoms
JPH09323995A (ja) チロシンキナーゼ阻害剤としての４−置換ピロロピリミジン化合物
Rashad et al. Synthesis of some biologically active pyrazoles and C-nucleosides
WO2008117047A1 (fr) Dérivés de pyrazolo[3,4-d]pyrimidine utilisés comme composés antibactériens
Migawa et al. Design, synthesis and antiviral activity of novel 4, 5-disubstituted 7-(β-D-ribofuranosyl) pyrrolo [2, 3-d][1, 2, 3] triazines and the novel 3-amino-5-methyl-1-(β-D-ribofuranosyl)-and 3-amino-5-methyl-1-(2-deoxy-β-D-ribofuranosyl)-1, 5-dihydro-1, 4, 5, 6, 7, 8-hexaazaacenaphthylene as analogues of triciribine
Seela et al. Palladium-catalyzed cross coupling of 7-iodo-2’-deoxytubercidin with terminal alkynes
EP4582427A1 (fr) Inhibiteur d'usp1
Seela et al. 2-Amino-7-(. beta.-D-arabinofuranosyl) pyrrolo [2, 3-d] pyrimidin-4 (3H)-one. Synthesis of ara-7-deazaguanosine via phase-transfer glycosylation
Lawson et al. Synthesis and photophysical characterisation of new fluorescent triazole adenine analogues
Mishra et al. Efficient synthesis of chirally enriched 1H-Imidazo [1, 2-b] pyrazole-and 4H-Imidazo [1, 2-b][1, 2, 4] triazole-based bioactive glycohybrids
Badawey et al. Potential antineoplastics. Synthesis and cytotoxicity of certain 4-chloro-3-(2-chloroethyl)-2-methylquinolines and related derivatives
Lauria et al. A New Tetracyclic, Ring System of Biological Interest. Indolo (3, 2-e)-(1, 2, 3) triazolo (1, 5-a) pyrimidines through Domino Reactions of 2-Azidoindole
Seela et al. Synthesis of 6-Substituted 7-Carbapurine 2′, 3′-Dideoxynucleosides: Solid-Liquid Phase-Transfer Glycosylation of 4-Chloropyrrolo [2, 3-d] pyrimidine and Deoxygenation of its 2′-Deoxyribofuranoside
Seela et al. Synthesis of certain 5‐substituted 2′‐deoxytubercidin derivatives
Minakawa et al. Nucleosides and nucleotides. 116. Convenient syntheses of 3-deazaadenosine, 3-deazaguanosine, and 3-deazainosine via ring closure of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide or-carbonitrile
WO2005016878A2 (fr) Procedes de preparation de composes 5-fluoro-pyrrolo[2,3-d]pyrimidine
Abdelall et al. Synthesis and cytotoxic activity of new pyrazolo [1, 5-a] pyrimidines and determination of pyrimidine regiospecific ring formation with 2D NMR
CN110357892B (zh) 四氢嘧啶并[1,2-a]吲哚衍生物及其合成方法与应用
Meade et al. Synthesis, antiproliferative, and antiviral activity of 4-amino-1-(. beta.-D-ribofuranosyl) pyrrolo [2, 3-d] pyridazin-7 (6H)-one and related derivatives
Seela et al. 8‐Aza‐7‐deaza‐2′, 3′‐dideoxyguanosine: Deoxygenation of its 2′ deoxy‐β‐D‐ribofuranoside
PL225349B1 (pl) Pochodne 2’,5’-dideoksy-5-fluorourydyny o działaniu cytotoksycznym, sposób ich wytwarzania i zastosowanie

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase