WO2003055489A1 - Composes derives de 2,4-diamino-pyrimidine utilises comme inhibiteurs de la prolylpeptidase comme inducteurs de l'apoptose et comme agents de traitement du cancer - Google Patents

Composes derives de 2,4-diamino-pyrimidine utilises comme inhibiteurs de la prolylpeptidase comme inducteurs de l'apoptose et comme agents de traitement du cancer Download PDF

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WO2003055489A1
WO2003055489A1 PCT/US2002/041146 US0241146W WO03055489A1 WO 2003055489 A1 WO2003055489 A1 WO 2003055489A1 US 0241146 W US0241146 W US 0241146W WO 03055489 A1 WO03055489 A1 WO 03055489A1
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halogen
optionally substituted
group
acid
effective amount
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PCT/US2002/041146
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Jacques Dumas
Julie Dixon
Robert Sibley
Jill Wood
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Bayer Pharmaceuticals Corporation
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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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to:
  • compositions comprising one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient;
  • the compounds described as being part of the invention are 2,4-diamino-pyrimidine derivative compounds which have the structural formula (I) or (II) defined below:
  • R 3 is hydrogen
  • R 4 is selected from the group consisting of:
  • (13) a four to eight membered saturated or fully unsaturated heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, (C 1 -C 5 ) alkoxy-, -( -Cs) alkylamino and ( -Cs) linear or branched alkyl optionally substituted by halogen; and
  • a fused bicyclo ring wherein one ring is a saturated or fully unsaturated four to eight membered heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or fully unsaturated three to eight membered carbocycle, or
  • R 3 and R 4 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with up to three substituents selected from the group consisting of: (1) amino, (2) cyano,
  • A is either:
  • R 5 is -OH, -OR 6 or -NR 8 R 9 ;
  • R 6 is:
  • R 7 is: (e) hydrogen
  • R 8 and R 9 are independently selected from the group consisting of: (h) hydrogen,
  • n and m are independently an integer from 0 - 1,
  • the preferred compounds of the invention are 2,4-diamino-pyrimidine derivative compounds which have the structural formula (I) or (II):
  • R 3 is hydrogen
  • R 4 is selected from the group consisting of:
  • R form, together with the nitrogen to which they are attached, a saturated five to eight membered heterocyclic ring, which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optic inally substituted with up to two substituents selected from the group consisting of:
  • A is either:
  • R 5 is -OH, -OR 6 or -NR 8 R 9 ;
  • R 6 is: .
  • R is:
  • R 8 and R are independently selected from the group consisting of:
  • n and m are independently an integer from 0 - 1, or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
  • the more preferred compounds of the invention are 2,4-diamino-pyrimidine derivative compounds which have the structural formula (I) or (II):
  • Ri and R 2 are independently selected from the group consisting of hydrogen and halogen
  • R 3 is hydrogen
  • R 4 is selected from the group consisting of:
  • R 3 and R 4 form, together with the nitrogen to which they are attached, a saturated five to six membered heterocyclic ring, which optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with up to two substituents selected from the group consisting of:
  • A is either:
  • R 5 is -OH, -OR 6 or -NR 8 R 9 ;
  • R 6 is: (a) -(C 1 -C 5 ) linear or branched alkyl optionally substituted by halogen, or
  • R is -(C ⁇ -C 5 ) linear or branched alkyl, optionally substituted with halogen;
  • R 8 and R 9 are independently selected from the group consisting of: (h) hydrogen, (i) -(C ⁇ -C 5 ) linear or branched alkyl, and
  • n and m are independently an integer from 0 - 1 ,
  • Salts are especially the pharmaceutically acceptable salts of compounds of fo ⁇ nulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae (I) or (II).
  • Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid.
  • Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, ⁇ -aminobutyric acid (GAB A), gluconic acid, glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, fumaric acid, oxalic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids (such as glutamic acid, aspartic acid, N-methylglycine,
  • pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N- dicyclohexylamine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DB ⁇ ) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of formula (I) or (II) in vivo. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).
  • prodrugs of the disclosed compounds of formula (I) and (II) are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
  • Major drug biotransformation reactions include ⁇ - dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, ⁇ -oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ. by McGraw-Hill, pages 12-18, (2001), which is hereby incorporated by reference).
  • halogen refers to fluorine, chlorine, bromine, and iodine substituents for the purposes of this invention.
  • the alkyl may be fully substituted, up to perhalo.
  • fused bicyclo ring refers to a substituent which is a two ring structure which share two carbon atoms.
  • the bonding between the fused bicyclo ring and the compound and/or atom to which it is attached can be through either of the two rings.
  • the invention also includes pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds of formula (I) or (II) or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient.
  • compositions are prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
  • Dermal administration includes topical application or transdermal administration.
  • Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques.
  • One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition.
  • These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition), Managing Editor, John E. Hoover, Mack Publishing Co., (1970) or Pharmaceutical Dosage Form and Drug Delivery Systems (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, (1995), each of which is hereby incorporated by reference.
  • Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); al alinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CC1 2 F 2 , F 2 C1C- CC1F 2 and CC1F 3 ) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparab
  • caramel and ferric oxide red examples include but are not limited to bentonite; emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerin, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil
  • compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures.
  • compositions of the invention can also have an additional apoptosis inducers as an active ingredient.
  • apoptosis inducers see e.g. Calbiochem's 2001 Signal Transduction Catalog, pages 702-704, the contents of which are incorporated by reference
  • apoptosis inducers include but are not limited to A23187, N-Acetyl-L-cysteine, actinomycin D, tyrphostin A9, tyrphostin A25, AG 490, AG 1714, anandamide, anisomycin, aphidicolin, bafilomycin Al, berberine hemisulfate, betulinic acid, bleomycin sulfate, CAFdA, calphostin C, camptothecin, CAPE, chelerythrine chloride, 2-chloro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine 5'-triphosphate, colcemid, cochi
  • Optional cancer treatment agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovori , lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, ral
  • cancer treatment agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al, publ.
  • cancer treatment agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of formulae (la) or (Ila) or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
  • the term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.
  • Thin-layer chromatography was performed on Whatman ® pre-coated glass-backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science ® silica gel.
  • Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected.
  • Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or residual protonated solvent (CHC1 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
  • Carbon ( 13 C) ⁇ MR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; d 3 -MeOD; ⁇ 49.0; d 6 -DMSO ⁇ 39.5) as standard.
  • HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonirile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
  • Step 1 Methyl 4-(aminomethyl)benzoate (2.24 g, 11.1 mmol, 1 eq) and sodium carbonate (2.35 g, 22.2 mmol, 2 eq) were added to a solution of 2,4 dichloro-5-methyl pyrimidine (1.81 g, 11.1 mmol, 1 eq) in ethanol were magnetically stirred at rt over a period of 16 h. Next EtOAc (50 mL) was added and this solution was washed (3 x 50 mL) with brine, dried over magnesium sulfate and then filtered.
  • Step 3 Aqueous sodium hydroxide (IN, 20 mL) was added to a solution of methyl 4-[( ⁇ 5- methyl-2-[(2-thienylmethyl)amino]-4-pyrimidinyl ⁇ amino)methyl]benzoate (0.18 g, 0.49 mmol) in methanol (10 mL). The mixture was stirred rt for 24 h. The mixture was adjusted to pH 5 with aqueous hydrochloric acid (IN) and the methanol was concentrated under reduced pressure.
  • aqueous hydrochloric acid aqueous hydrochloric acid
  • Examples 4 - 29 in Table 1 were synthesized according to the above methods or by using other synthetic methods known in the art such as those described in the monograph series "The Chemistry of Heterocyclic Compounds", edited by Weissberger, The Pyrimidines, edited by D.J. Brown, publ. by Interscience Publishers, (1962) or the monograph series "The Chemistry of Heterocyclic Compounds", edited by Weissberger and Taylor, The Pyrimidines - Supplement I, edited by D.J. Brown, publ. by Interscience Publishers, (1970), and Nol. 52, The Pyrimidines, edited by D.J.Brown, Interscience Publishers, (1994), each of which is incorporated in its entirety by reference.
  • Apoptosis (programmed cell death) is an essential process in the development and maintenance of homeostasis in an organism (1).
  • the growth fraction of a tumor is governed by the rate of cellular division as well as the rate of cell death: if the rate of division exceeds that of cell death, then net tumor expansion occurs.
  • net growth rates of tumors do not generally correlate directly with the rate of cell division within the tumor, as assessed by the abundance of mitotic figures.
  • aberrant apoptotic rate plays an important role in tumor growth and expansion (2, 3).
  • Proteases are attractive cancer drug targets since they are known to regulate apoptotic signal transduction (8, 9).
  • work on apoptosis initiated by specific inhibitors of the proteasome complex has been reported in the literature, where lactacystin and other proteasome inhibitors are shown to cause apoptosis in a number of cell lines (10, 11).
  • prolylpeptidase As an intracellular protease involved in the repression of apoptosis and, as such, prolylpeptidase is thought to be an anti- apoptotic factor (12, 13).
  • Prolylpeptidase is a serine protease that is irreversibly inactivated by diispropyl-fluorophosphate (DFP) through covalent modification of Serl54 (12) and unpublished data. It is the only known human serine protease that is fully active without additional post-translational removal of inhibitory peptide. In addition, the enzyme is localized to novel non-lysosomal cytosolic vesicles (14).
  • prolylpeptidase as well as prolylpeptidase purified from natural sources are active as dimeric proteins (106 kDa), based on size exclusion chromatography, although the gene encodes a putative enzyme with a predicted mass of 58 kDa (15).
  • prolylpeptidase has been identified in a number of solid tumor cell lines of different histological types including those from colon (HCT116 and DLD1), prostate (PC3), and breast (MDA-MB-435).
  • expression data for prolylpeptidase mRNA shows a very limited distribution across adult human tissues, with highest levels observed in the testis, and moderate levels in prostate, skeletal muscle and brain.
  • Increased expression of prolylpeptidase mRNA in human tumor specimens and the published biological data on the enzyme suggest that prolylpeptidase plays an important role in tumor cell growth or survival. In summary, these data suggest that selective inhibition of prolylpeptidase activity in tumor cells could lead to increased apoptotic rates and growth inhibition.
  • Test compounds were diluted serially 1:5 in 5% DMSO/95% water and 5 ⁇ L was added to give 100 ⁇ L as a final volume to a well containing prolylpeptidase enzyme in buffer. Drug had a final concentration ranging from 10 ⁇ M to 0.12 ⁇ M.
  • the Ala-Pro-AFC dipeptide substrate (AFC is 7-amino-4-trifluoro-methylcoumarin) in MTEN buffer was used at a final concentration of 200 ⁇ L and the reaction was initiated with 10 nM final concentration of recombinant prolylpeptidase. The reaction was allowed to proceed for 20 min at room temperature and quenched with 20 ⁇ L of 1 M Glycine-HCl pH 2.5.
  • Ala-Pro-AFC is a dipeptide substrate with a conjugated AFC fluorophore at the C-terminus. Hydrolysis of the dipeptide substrate releases free AFC which is excited at 400 nm and emission of 505 nm in a spectrofluorometer.
  • Assay buffer is 50 mM MTEN Buffer pH 4.5 (50 mM MES, 25 mM Tris, 25 mM ethanolamine, 100 mM NaCl).
  • Enzyme storage buffer was 50 mM Tris pH 7.0, 50% glycerol and was stored at -80 °C. It was diluted in assay buffer just prior to initiation of the assay.
  • the induction of apoptosis by prolylpeptidase inhibitors was measured in whole cells using the multiparameter apoptosis assay (MPA).
  • MPA multiparameter apoptosis assay
  • the assay uses the ArrayScan II (Cellomics Inc.
  • Test compounds were dissolved in 100% DMSO and diluted serially 1 :2 in
  • DMEM fetal calf serum
  • DMSO concentration 0.25% 10% fetal calf serum
  • %Control (((Experimental Units)-Blank Units)/Units from untreated Control- Blank Units)*100.
  • Y A+((B-A)/(1+(((B-E)(X/C) A D)/(E-A))).
  • the average of the IC 50 values for nuclear fragmentation, actin content and mitochondria index is used as the MPA IC 5 o.
  • Example 1 was tested in the above apoptosis assay and was found to induce apoptosis at or below a concentration of 25 ⁇ M.

Abstract

Cette invention se rapporte à des composants qui sont des dérivés de 2,4-diamino-pyrimidine représentés par la formule (I) ou (II), où A, R1, R2, R3 et R4 ont la notation mentionnée dans les pièces descriptives de la demande. Ces composés servent à inhiber la prolylpeptidase, à induire l'apoptose et à traiter le cancer.
PCT/US2002/041146 2001-12-21 2002-12-20 Composes derives de 2,4-diamino-pyrimidine utilises comme inhibiteurs de la prolylpeptidase comme inducteurs de l'apoptose et comme agents de traitement du cancer WO2003055489A1 (fr)

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WO2005016893A3 (fr) * 2003-07-30 2005-06-09 Rigel Pharmaceuticals Inc Methodes de traitement ou de prevention de maladies auto-immunes a l'aide de composes de 2,4-pyrimidinediamine
WO2005063722A1 (fr) * 2003-12-19 2005-07-14 Rigel Pharmaceuticals, Inc. Stereoisomeres et melanges stereoisomeriques d'intermediaires synthetiques de 1-(2,4-pyrimidinediamino)-2-cyclopentanecarboxamide
JP2007501793A (ja) * 2003-08-07 2007-02-01 リゲル ファーマシューティカルズ，インコーポレイティド 抗増殖剤としての２，４−ピリミジンジアミン化合物および使用
WO2007124221A1 (fr) 2006-04-18 2007-11-01 Rigel Pharmaceuticals, Inc. Méthodes de traitement des troubles cellulaires prolifératifs dans lesquelles on utilise des composés de pyrimidinediamine
CN100387602C (zh) * 2005-07-08 2008-05-14 张晴龙 一种白屈菜红碱复合物及其制备方法
US7655797B2 (en) 2002-02-01 2010-02-02 Rigel Pharmaceuticals, Inc. Intermediates for making 2,4-pyrimidinediamine compounds
US7754714B2 (en) 2004-05-18 2010-07-13 Rigel Pharmaceuticals, Inc. Cycloalkyl substituted pyrimidinediamine compounds and their uses
US7812029B1 (en) 2002-07-29 2010-10-12 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7851480B2 (en) 2004-11-24 2010-12-14 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
US7863286B2 (en) 2004-11-15 2011-01-04 Rigel Pharmaceuticals, Inc. Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses
US8148391B2 (en) 2006-10-23 2012-04-03 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors
WO2012149546A3 (fr) * 2011-04-29 2013-01-03 The Penn State Research Foundation Induction du gène trail par petite molécule par des cellules normales et tumorales en tant que thérapie anticancéreuse
US8354420B2 (en) 2010-06-04 2013-01-15 Genentech, Inc. Aminopyrimidine derivatives as LRRK2 inhibitors
CN103408501A (zh) * 2013-08-14 2013-11-27 合肥医工医药有限公司 苄基嘧啶衍生物、其制备方法及其医药用途
US8815882B2 (en) 2010-11-10 2014-08-26 Genentech, Inc. Pyrazole aminopyrimidine derivatives as LRRK2 modulators
US20150025095A1 (en) * 2012-02-17 2015-01-22 Abbvie Inc. Diaminopyrimidines And Uses Thereof
US9266912B2 (en) 2005-01-19 2016-02-23 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
CN106362696A (zh) * 2016-10-17 2017-02-01 江苏理工学院 一种表面改性纳米氧化铝的制备方法及其应用
CN111122523A (zh) * 2019-12-06 2020-05-08 山西大学 一种快速识别Ag+和Cys的三相输出功能的分子逻辑门及其构建方法
CN111620852A (zh) * 2020-01-19 2020-09-04 南京迪维奥医药科技有限公司 一种5-氯-嘧啶-2,4-二胺类化合物及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002341A1 (fr) * 1977-11-28 1979-06-13 Barry Boettcher Complexes de cuivre bivalent, procédé pour leur préparation et compositions les contenant
WO1997019065A1 (fr) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utiles en tant qu'inhibiteurs de proteine kinase
EP0945443A1 (fr) * 1998-03-27 1999-09-29 Janssen Pharmaceutica N.V. Dérivés de pyrimidine inhibiteurs de VIH
WO2001016301A1 (fr) * 1999-09-01 2001-03-08 Tufts University Dipeptidyl peptidase de cellule quiescente: une nouvelle serine protease cytoplasmique
WO2001064655A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2, 4-di(hetero-)arylamino (-oxy) pyrimidines substitues en 5, utilises comme agents antineoplasiques
WO2001064656A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2,4,di-(hetero-) arylamino (-oxy)-5 pyrimidines substitutees utilisees comme agents antineoplasiques
WO2002096888A1 (fr) * 2001-05-29 2002-12-05 Schering Aktiengesellschaft Pyrimidine inhibitrice de la cdk, sa production et son utilisation comme medicament

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002341A1 (fr) * 1977-11-28 1979-06-13 Barry Boettcher Complexes de cuivre bivalent, procédé pour leur préparation et compositions les contenant
WO1997019065A1 (fr) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utiles en tant qu'inhibiteurs de proteine kinase
EP0945443A1 (fr) * 1998-03-27 1999-09-29 Janssen Pharmaceutica N.V. Dérivés de pyrimidine inhibiteurs de VIH
WO2001016301A1 (fr) * 1999-09-01 2001-03-08 Tufts University Dipeptidyl peptidase de cellule quiescente: une nouvelle serine protease cytoplasmique
WO2001064655A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2, 4-di(hetero-)arylamino (-oxy) pyrimidines substitues en 5, utilises comme agents antineoplasiques
WO2001064656A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2,4,di-(hetero-) arylamino (-oxy)-5 pyrimidines substitutees utilisees comme agents antineoplasiques
WO2002096888A1 (fr) * 2001-05-29 2002-12-05 Schering Aktiengesellschaft Pyrimidine inhibitrice de la cdk, sa production et son utilisation comme medicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HURT C A R ET AL: "THE SYNTHESIS OF PYRIMIDOQUINAZOLONES", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, no. 1, SUPPL 7, 1966, pages 227 - 231, XP001029239, ISSN: 0040-4020 *

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