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EP0377031A1 - Analogues de 5-deaza-5,7-aminopterine bisubstituee - Google Patents

Analogues de 5-deaza-5,7-aminopterine bisubstituee

Info

Publication number
EP0377031A1
EP0377031A1 EP19890907612 EP89907612A EP0377031A1 EP 0377031 A1 EP0377031 A1 EP 0377031A1 EP 19890907612 EP19890907612 EP 19890907612 EP 89907612 A EP89907612 A EP 89907612A EP 0377031 A1 EP0377031 A1 EP 0377031A1
Authority
EP
European Patent Office
Prior art keywords
methyl
cyano
diamino
methoxymethoxy
ethoxycarbonyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19890907612
Other languages
German (de)
English (en)
Inventor
Kyoichi A. Watanabe
Tsann-Long Su
Jai-Tung Huang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Memorial Sloan Kettering Cancer Center
Original Assignee
Memorial Sloan Kettering Cancer Center
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 Memorial Sloan Kettering Cancer Center filed Critical Memorial Sloan Kettering Cancer Center
Publication of EP0377031A1 publication Critical patent/EP0377031A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Definitions

  • the antitumor agents methotrexate and aminopterin, inhibit dihydrofolate reductase to exert their antitumor activity (J.S. Erickson, et al., J. Biol. Chem., vol. 247, p. 5661, 1972).
  • Aminopterin is prepared from 2, 4, 5, 6 - tetramino pyrimidine sulfate, 2, 3-dibromopropionablehyde and paminobenzoylglutamic acid (Seeger, et al., J. Am. Chem. Soc, vol. 69, p. 2567, 1947) or from 6-(bromomethyl)2,4-diaminopteridine HBr (Piper, Montgomery, J. Heterocycl. Chem., vol. 11, p. 279, 1974). Methotrexate preparation is described in Seeger, et al., J. Am. Chem. Soc, vol. 71, p. 1753, 1949.
  • the present invention provides a method for syntheis of 5-deaza-7-substituted and 5- deaza-5, 7-disubstituted analogues of methotrexate and aminopterin.
  • the analogues of the present invention can not be metabolized to their corresponding 7-oxo derivatives since the 7 position of these molecules is already substituted.
  • These analogues are also found not to inhibit dihydrofolate reductase, yet some of them exhibit potent antitumor activity.
  • the present application describes derivatives of methotrexate and aminopterin which are useful as antitumor agents, methods of synthesizing such derivatives and the biological application derivatives.
  • the derivatives of the present invention are particularly useful for treating tumors resistant to methotrexate or aminopterin because of large production of dihydrofolate reductase.
  • R 5 is a hydrogen atom, lower alkyl group of 1 - 4 carbon atoms or a phenyl group
  • R 7 is a lower alkyl group of 1 - 4 carbon atoms or a phenyl group
  • R 10 is a hydrogen atom, a methyl group or a ethyl group.
  • the invention also concerns methods of synthesizing the compounds, and precursors and intermediates useful in the manufacture of the compounds.
  • the invention further provides pharmaceutical compositions, methods of killing tumor cells, and methods of treating a subject having a tumor which comprises the use of the compounds described hereinabove.
  • the present invention concerns 7-monosubstituted and 5, 7-disubstituted-5-deazaaminopterin and 5-deazamethotrexate derivatives of the formula I.
  • Compound of general formula I may be obtained by the synthetic route which begins with condensation of cyanothioacetamide with 4-substituted alkyl 2- alkoxymethylene-3-oxopropanoates of formula II or 3- carbalkoxypropane-1, 3-diones of formula III to give the substitued 2-thiopyxidine derivatives of general IV or V, respectively:
  • R 5 and R 7 are the same or different and are lower alkyl groups of 1 -4 carbon atoms or phenyl groups (Ph) and R is a methyl (Me) or ethyl
  • the reaction is carried out in alcohol such as methanol, ethanol or propanol, in the presence of corresponding alkoxide of alkali metal, such as lithium, sodium or potassium, or organic base such as N, N-dimethylaminoethanol, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1,5- diazabicyclo[4,3,0]non-5-ene (DBN) or piperidine, at temperature range of from 25 oC to 97 oC (boiling poin of propanol) for aperiod of from 10 minutes to 2 days.
  • alkali metal such as lithium, sodium or potassium
  • organic base such as N, N-dimethylaminoethanol, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1,5- diazabicyclo[4,3,0]non-5-ene (DBN) or pipe
  • an oxidizing agent such as sodium hypochlorate, hydrogen peroxide or m-chloroperbenzoic acid, preferably mchloroperbenzoic acid
  • an inert solvent such as a chlorinated hydrocarbon or alcohol, perferably ethanol
  • the condensation reaction can be done either by treatment of the sulfones of formulae XII and XIII with free guanidine in refluxing alcohols, such as methanol, ethanol or propanol and the like, or by heating a mixture of the sulfone and guanidine carbonate in a high boiling inert solvent, such as diglyme or diphenyl ether, at a tempterature from 160 oC to 210 oC for a period of 2 to 8 hours.
  • a high boiling inert solvent such as diglyme or diphenyl ether
  • Deprotection of compounds of formulae XIV and XV to the corresponding 6-hydroxymethylpyrido[2,3-d]pyrimidines XVI and XVII can be achieved by treatment of XIV and XV with concentrated hydrochloric acid in alcohol at reflux temperature for a period of from 2 to 6 hours, or with a Lewis acid, such as boron trichloride, in an inert solvent such as chlorinated hydrocarbon, preferably methlene chloride, at a temperature range of from -78 oC to 25 oC for a period of from 2 to 24 hours.
  • a Lewis acid such as boron trichloride
  • 6-hydroxymethyl derivatives of formulae XVI and XVII are converted into the corresponding 6-bromomethyl derivatives of general formulae XVIII and XIX by treatment with a brominating agent, preferably hydrogen bromide in dioxan.
  • a brominating agent preferably hydrogen bromide in dioxan.
  • a mixture of cyanothioacetamide (54 g, 0.54 mol), 3-ethoxycarbonyl-1-phenylpropane-1,3-dione (189 g, 0.81 mol) and piperidine (37 mL) in anhydrous ethanol (600 mL) is stirred at room temperature for 1 day, and then heated under reflux for another day.
  • the mixture is concentrated in vacuo, and the residue is dissolved in chloroform, washed with water, dried over sodium sulfate, concentrated in vacuo, and chromatographed on a silica gel column (10 x 50 cm) using chloroformhexane (4:1 v/v) as the eluent.
  • diethyl (p-aminobenzoyl)-L-glutamate (3.22 g, 10 mmol)
  • diethyl (p-aminobenzoyl)-L-glutamate 3.22 g, 10 mmol
  • the residue is triturated thoroughly with warm chloroform to remove unreacted diethyl (paminobenzoyl)-L-glutamate.
  • N-p(p-[[(2,4-diamino-5,7- dimethylpyrido[2.3-d]pyrimidin-6-y1)methyl]amino]- benzoyl]-L-glutamic acid precipitates as microcrystals is collected by filtration, washed with cold water, acetone and diethyl ether, and dried in vacuo over phosphorus pentoxide, (588 mg, 42%), mp 226-227oC.
  • HL-60 cells (1.5 x 10 /mL) are grown in RPMI 1640 medi containing 10% fetal calf serum, 100 ⁇ g/mL streptomycin 100U/mL penicillin, in humidified 5% CO 2 at 37oC. Five concentrations of each compound are added for up to 72 hours exposure. Viable cells are counted with trypan blue exclusion method.
  • ED 50 values are calculated by the median-effect equation and plot using microcomputer software. Five concentrations of each compound are used for each ED 50 determination.
  • the ID 50 values of representative 5-deaza-5,7-disubstituted aminopterin analogues for cell growth inhibition in vitro are listed in Table 1. It is interesting to note that the 7-methyl and 5,7-dimethyl analogues exhibited cell growth inhibition which approached that of methotrexate during 72 hours of exposure, though they cannot be metabolized to their corresponding 7-oxo derivatives, are extremely weak inhibitors of dihydrofolate reductase, and are 1, 200-fold less potent than methotrexate in inhibiting [6- 3 H]dUrd incorporation into DNA (Table 2). These compounds show little dose-effct relationship in which a large increase in inhibitor concentration produces only a small increase in cell growth inhibition (Table 2), but they show time-dependent cytotoxicity in inhibiting leukemic cell growth.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Composé doté de la structure (I), où R5 est un atome d'hydrogène, un groupe alkyle inférieur de 1 à 4 carbones ou un groupe phényle, R7 est un groupe alkyle inférieur de 1 à 4 carbones ou un groupe phényle, et R10 est un atome d'hydrogène, un groupe méthyle ou un groupe éthyle. La présente invention porte également sur des méthodes et des intermédiaires pour synthétiser ledit composé, sur une composition pharmaceutique dudit coomposé et sur son utilisation pour tuer des cellules tumorales et pour soigner des patients.
EP19890907612 1988-07-01 1989-06-22 Analogues de 5-deaza-5,7-aminopterine bisubstituee Withdrawn EP0377031A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21451088A 1988-07-01 1988-07-01
US214510 1988-07-01

Publications (1)

Publication Number Publication Date
EP0377031A1 true EP0377031A1 (fr) 1990-07-11

Family

ID=22799353

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19890907612 Withdrawn EP0377031A1 (fr) 1988-07-01 1989-06-22 Analogues de 5-deaza-5,7-aminopterine bisubstituee

Country Status (4)

Country Link
EP (1) EP0377031A1 (fr)
JP (1) JPH03500176A (fr)
AU (1) AU3843189A (fr)
WO (1) WO1990000172A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5286726A (en) * 1990-04-12 1994-02-15 The Regents Of The University Of Michigan Difluoroglutamic acid conjugates with folates and anti-folates for the treatment of neoplastic diseases
WO1993022312A1 (fr) * 1992-04-29 1993-11-11 Sri International Desazaaminopterines pour le traitement des inflammations
WO2010016846A1 (fr) * 2008-08-08 2010-02-11 Kalypsys, Inc. Modulateurs hétérocycliques de tgr5 pour le traitement d'une maladie

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061642A (en) * 1972-06-22 1977-12-06 Cassella Farbwerke Mainkur Ag 2,4,6-Trisubstituted-3-pyridine carboxamides
US4431805A (en) * 1981-09-25 1984-02-14 Southern Research Institute Pyrido[2,3-d]-pyrimidines
US4628089A (en) * 1982-01-11 1986-12-09 Southern Research Institute Pyrido(2,3-D)pyrimidines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9000172A1 *

Also Published As

Publication number Publication date
AU3843189A (en) 1990-01-23
JPH03500176A (ja) 1991-01-17
WO1990000172A1 (fr) 1990-01-11

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