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WO1993020075A1 - N5-desazapterines substituees en position 8, utilisees comme antifolates - Google Patents

N5-desazapterines substituees en position 8, utilisees comme antifolates Download PDF

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Publication number
WO1993020075A1
WO1993020075A1 PCT/AU1993/000138 AU9300138W WO9320075A1 WO 1993020075 A1 WO1993020075 A1 WO 1993020075A1 AU 9300138 W AU9300138 W AU 9300138W WO 9320075 A1 WO9320075 A1 WO 9320075A1
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Prior art keywords
compound
compounds
bind
binding
dhfr
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English (en)
Inventor
Jill E. Gready
Peter L. Cummings
Mark J. Koen
Michael T. G. Ivery
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University of Sydney
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University of Sydney
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    • 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

Definitions

  • This invention relates to a method of designing compounds which bind to the enzyme dihydrofolate reductase (DHFR), novel N5-deazapterin compounds which are useful for inhibiting DHFR and methods of selecting and preparing such compounds using theoretical calculations.
  • DHFR dihydrofolate reductase
  • DHFR dihydrofolate reductase
  • NADPH nicotinamide adenine dinucleotide phosphate
  • Analogues of folic acid, particularly inhibitors of DHFR constitute a class of cytotoxic drugs, the antifolates, which are important anticancer, antimalarial, and antibacterial agents.
  • inhibitors such as methotrexate and trimethoprim
  • Antifolates have been made and tested since 1947 when aminopterin was first made as an analogue of folate and found to be an effective anti-leukemic agent.
  • substrate-like compounds containing a pterin-type ring (2-amino-4-oxo- pteridine or deazapteridine), or "inhibitor-like” compounds based on aminopterin/ methotrexate with a 2,4-diamino-pteridine, 2,4-diamino-pyrimidine or related heterocyclic ring.
  • DHFR has been a test case for the rational design of new drugs and to that end has been subjected to intensive biochemical characterisation by both experimental and theoretical methods with the aim of understanding substrate and inhibitor binding and species selectivity at the molecular level as the basis of new predictions.
  • X-ray structures have been obtained for several dozen DHFRs from different species (including human) in many different binary complexes or ternary complexes with substrate or inhibitors by various research groups. Reported efforts in developing new antifolates using "structure-based" design approach have been of limited success and importantly, X-ray structures have not provided a convincing explanation of the established species-selectivity of binding of the major antibacterial drug trimethoprim.
  • DHFR tetrahydrofolate:NADP + oxidoreductase, EC 1.5.1.3
  • DHFR tetrahydrofolate:NADP + oxidoreductase
  • DHFR catalyses two reactions:
  • Folic acid has the following structure:
  • novel compounds we have prepared, when protonated, mimic the enzymically-active protonated form of the pterin ring of folate, ie these compounds are based on the enzymic mechanism.
  • Folate in solution protonates at N1.
  • the novel compounds of the present invention are substituted at the 8-position and in this context, the 8- substitution is believed to freeze the N5-deazapterin into the less stable N8(H)-type tautomeric form, which is calculated to be 12 kcal/mol less stable as shown in
  • the present invention provides a method of designing a compound which binds to DHFR, which comprises substituting the position 6 or 8 of a compound having the following structure
  • the substitution is alkylation.
  • 8- or 6-alkylation freezes these deazapterins into the less stable N8 (H) - or N6 (H) - type tautomeric forms.
  • This "activation" by alkylation produces compounds of "quinonoid-type" molecular structure which are necessarily more basic than the normal tautomers, protonating to form cations of the desired structure with effective pK a increase of several units.
  • the present invention provides novel compounds of formula (I), pharmaceutically acceptable salts or esters thereof
  • R 1 is hydrogen or alkyl optionally substituted by hydroxy, thio or halogen
  • R 2 is H, -CHO, -COOH, alkyl, CH(Oalk) 2 , alkyl substituted by hydroxy, thio, halogen, PABA, PABA-Glu; alkenyl, alkynyl;
  • R 3 is H, alkyl
  • R 4 is alkyl optionally substituted by hydroxy, thio, halogen; alkenyl, alkynyl;
  • Glu glutamic acid
  • alkyl is methyl, ethyl, propyl or isopropyl; alkenyl is allyl; alkynyl is propargyl; and halogen is fluoro.
  • X is preferably chloride or bromide.
  • Alkyl includes branched or straight chain alkyl.
  • the present invention provides a process of preparing compounds of formula (I), which comprises condensation of an appropriate aminopyrimidme
  • R 1 , R 2 , R 3 and R 4 are as hereinbefore defined.
  • the present invention provides a method of preparing substituted-N5-deazapterins which comprises condensation of an ⁇ , ⁇ -unsaturated carbonyl compound (IV) with the appropriate aminopyrimidine (II) according to reaction scheme 2:
  • R 1 , R 2 , R 3 and R 4 are as hereinbefore defined provided that R 1 , R 2 and R 3 are not all hydrogen.
  • the present invention provides a method of selecting a compound having binding affinity to DHFR which method comprises: fa) theoretically determining the relative binding free energy ( ⁇ F bind ) of compounds having potential for binding to DHFR of the following structure and varying substitution patterns:
  • X, Y and R are as hereinbefore defined and R is independently selected and one or more R may not be present; by using the free-energy perturbation/molecular dynamics (FEP/MD) method;
  • the present invention provides a method of preparing a compound having binding affinity to DHFR which method comprises:
  • X, Y and R are as hereinbefore defined and R is independently selected and one or more R may not be present; by using the free-energy perturbation/molecular dynamics (FEP/MD) method;
  • the malonaldehyde compound (III) can either be protected (as shown) or unprotected. Even though the unsubstituted form (at C2-position) of the malonaldehyde is shown giving compounds where R 2 is H, the substituted malonaldehydes can also be used in which case R 2 will correspond to the substituent at the C2 -position of the malonaldehyde.
  • the general reaction conditions involve placing the pyrimidine in neat carbonyl compound with the carbonyl compound in a molar excess of between 20 and 75. The mixture is heated at about 60oC for a period of several hours. The solution is then acidified with 0.1M HCl and heated further for periods of up to 48 hours. The final product is obtained by the removal of solvent followed by recrystallisation of the residue from ethanol .
  • reaction Scheme 2 Initial attempts to prepare some compounds of formula (I) using reaction scheme 1 without bisulfite (ie reaction Scheme 2) proved unsuccessful.
  • the preparation of the novel compounds in the presence of bisulfite is generally carried out by treating the appropriate pyrimidine in water with a solution of a molar equivalent of the bis (dialkylacetal) compound or two equivalents of the substituted ⁇ , ⁇ -unsaturated carbonyl compound in the presence of NaHSO 3 in water.
  • the pH of the reaction mixture is preferably adjusted to about pH 2-3 and the mixture is stirred for approximately 8 hours under gentle heat ( ⁇ 50°C).
  • reaction mixture Examination of the reaction mixture at this stage would indicate whether the pyrimidine had completely reacted with carbonyl and the first stage of the reaction was complete.
  • the solution is then acidified to pH 0-1 and heating continued for a further 16 hours approximately, resulting in a final spectrum consistent with deaza-pterin.
  • Purification is generally carried out using a column of Amberlite CG-50 weak cation exchange resin.
  • the reaction mixture is preferably adjusted to pH 4 and then applied to the column.
  • the sample is then eluted with water resulting in a blue-fluorescent band slowly moving down the column to about half column position. At this point a band showing pale-purple fluorescence begins to elute. This band is preferably completely eluted from the column leaving the blue-fluorescent band completely retained.
  • 8-R-substitution is a necessary condition for the proposed activation mechanism
  • a variety of ring- substituent patterns are also possible, at least in principle, by the addition of methyl or other groups at the 5, 6 and 7 positions of the heterocyclic ring in the case of 8-R-N5-deazapterin (8d) and the 6 and 7 positions of 8-R-pterin (8p).
  • the primary 8-methyl compounds (8d and 8p) and their various methyl derivatives are listed in Table I.
  • Ligands and abbreviations in the calculations the ligands are protonated at N3.
  • the primary "lead” member of the class the simplest derivative 8-methyl-N5-deazapterin, possesses an "intrinsic" capacity to bind to the enzyme DHFR.
  • This capacity can be increased or decreased by substitution in the 5-and/or 6- and/or 7- positions, as well as by modification of the 8- substituent itself.
  • the FEP/MD method allows the calculation of the effects on the binding constant of varying the. substituents in these positions. The binding constant for a series of compounds can then be ranked from best to worst.
  • the free energy change ( ⁇ F bind ) is the sum of the solvation ( ⁇ F solv ) and binding ( ⁇ F bind ) components.
  • this desolvation component is non-additive for different numbers and patterns of methyl groups, ie two methyl groups in different combinations of positions will show different desolvation energies resulting from different hydration spheres for the methyl groups or shielding of the 4 -oxygen by a 5- methyl group;
  • this binding component [in (3) above] is non- additive for different numbers and patterns of methyl groups.
  • the method of selecting a compound having binding affinity to DHFR comprises:
  • X, Y and R are as hereinbefore defined and R is independently selected and one or more R may not be present; by using the free-energy perturbation/molecular dynamics (FEP/MD) method;
  • the method of preparing a compound having binding affinity to DHFR comprises:
  • X, Y and R are as hereinbefore defined and R is independently selected and one or more R may not be present; by using the free-energy perturbation/molecular dynamics (FEP/MD) method;
  • the free energy differences are obtained by transforming or "mutating" the potential energy parameters of a ligand A to those of a second ligand B during a molecular dynamics (MD) simulation.
  • the relative thermodynamic stabilities of A and B are given by the free energy difference:
  • the MD potential energy function, V has the form
  • V V bad + V ele + V vdw + V hb (2)
  • V bad represents the intramolecular part of the energy, which includes all bond, angle and dihedral terms
  • V ele is the electrostatic term arising from nonbonded interactions between atomic charges
  • V vdw is the nonbonded van der Waals (vdW) interaction term
  • V hb is a hydrogen- bond interaction term.
  • the standard AMBER all-atom and united-atom protein force-field parameters were adopted for the DHFR molecule.
  • the all-atom model was used for residues within 8A of the ligand centre of mass (cm.), while the united-atom model (in which hydrogens attached to carbon are not represented explicitly) was used for the remainder of the protein.
  • ⁇ F bind of A and B can be calculated from the cycle in Scheme 2 using Equation 4.
  • the relationship between calculated and experimental values of ⁇ F bind is shown in Scheme 2 and Equation (4).
  • the ligands were solvated with boxes of Monte Carlo water using the EDIT module of AMBER. Only those water molecules within 12 ⁇ (in the x, y and z directions) of any solute atom were retained to form a rectangular simulation box.
  • the simulations were carried out for the closed, isothermal, isobaric (NTP) ensemble under periodic boundary conditions using a cutoff radius of 8 ⁇ for all nonbonded interactions. As shown in Figure 2, the calculations were divided into four stages. Energy minimization (BORN module of AMBER) was followed by MD equilibration for 7 ps before the mutations were started
  • the mutation A ⁇ B was carried out in two stages via an intermediate state A'.
  • the intermediate state A' takes on the electrostatic force field of the final state B, but has the same Sampling
  • Double-wide sampling can be employed since the Hamiltonian for the perturbation is given in general by V( ⁇ i ) - V( ⁇ i ⁇ ⁇ ). For a given mutation, double-wide sampling yields two values for the free energy change by forming the ensemble averages for both + ⁇ and - ⁇ at ⁇ i , which may be used to test for hysteresis in the calculation. While there are 66 [n(n-1)/2; n compounds] distinct mutations which directly connect any pair of the 12 compounds listed in Table I, not all are independent since the free energy is a path-independent quantity. In theory, the minimum number of FEP simulations that are required to obtain all free energy differences is therefore only 11(n-1).
  • free energy changes between two ligands can be estimated by following various pathways that each involve a differing sequence of mutations. For example, to obtain the free energy difference between 678d and 8d one would normally perform the mutation 678d ⁇ 8d directly, however, the desired free energy can also be obtained by performing the sequence of mutations 678d ⁇ 68d ⁇ 8d, where the total free energy is the sum of free energies for the two mutations.
  • NADPH.ligand complexes were neutralized by adding counterions and the region within a radius of 16 A of the ligand centre was solvated using EDIT.
  • the system was divided into "non-dynamic" atoms whose positions are frozen at the initial X-ray coordinate values and the "dynamic" atoms which are the only ones allowed to move during the various stages of the calculations.
  • the dynamic atoms were defined by including all protein residues, counter ions and water within a radius of 16 A from the ligand mass centre. Using these truncation conditions, typically 50 to 60 water molecules were involved in the dynamics. Water molecules and counter ions were restrained from leaving the dynamics region by applying a small harmonic (0.6 kcal/mol/ ⁇ 2 ) radial restoring force.
  • the mean structures obtained from these simulations were then energy minimized for the purposes of graphical (using the MidasPlus program) and least-squares superposition analysis.
  • ⁇ F bind listed in Table IV have been obtained by calculating the mean free energies over the different pathways in Table III. The resulting estimates of ⁇ F bind relative to 8-methyl-N5-deazapterin (8d) calculated using equation 1 are also listed in Table IV.
  • the compounds of formula (I) and the pharmaceutically acceptable salts and esters thereof are useful agents in inhibiting the enzyme DHFR and therefore may be useful in the treatment or prophylaxis of neoplastic or microbial diseases in mammals, including humans when administered in therapeutically effective amounts.
  • the present invention provides a method of treatment or prophylaxis of neoplastic or microbial diseases in a host which comprises administering to said host a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.
  • a pharmaceutical formulation of the present invention comprises the active compound together with one or more pharmaceutically acceptable carriers and optionally any other therapeutic ingredient.
  • the formulation may conveniently be prepared in unit dosage form and may be prepared according to conventional pharmaceutical techniques. Additionally, the formulations may include one or more accessory ingredients, such as diluents, buffers, flavouring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives and the like.
  • Perkin-Elmer LS-50 and Shimadzu spectrometers were used for fluorimetric and UV/vis spectral studies respectively. Buffers used were those of Ellis and
  • NADPH was from Boehringer.
  • K d determinations Thermodynamic dissociation constants (K d ) were determined by following the quenching of the enzyme fluorescence
  • K i value of 0.8 ⁇ M for 6,8-dimethyl-N5-deaza-pterin was determined at pH 6.6.
  • K i values were also determined for 6,8-dimethyl-N5-deaza-pterin and 7,8-dimethyl-N5-deaza-pterin by another method of measuring the initial rates at a fixed substrate concentration (50 ⁇ M dihydrofolate or 100 ⁇ M 6,8-dimethylpterin with 100 ⁇ M NADPH) but varying inhibitor concentration (12 -120 ⁇ M).
  • the second (incomplete) set of data for dihydrofolate as substrate indicates weaker but still substantial inhibition, as the K m for the 8-methylpterin is much lower (by 2 orders of magnitude) than for the 6,8-dimethylpterin.
  • UV/vis and 1 H nmr spectra were recorded using Cary 3 and Bruker AS200 spectrometers. All 1 H nmr spectra were recorded in D 2 O with the spectrum referenced to water at 54.76 or in D 6 -DMSO referenced to ⁇ 2.50. Mass spectra were recorded on an A.E.I MS9 spectrometer at 70eV with DS30 data handling system for high-resolution spectra. Microanalyses were performed by Australian Microanalytical Service, National Analytical Labs, Melbourne, and Australian National University, Canberra.
  • HPLC analysis was performed using an LKB system with LKB UV detector (260 nm), Waters fluorescence detector, Waters analysis software (Maxima) and an Activon Exsil SCX 10 ⁇ m analytical column with a flow rate of 2 mL/min.
  • the buffer system used was 100 inM NH 4 HCOO/CH 3 CN (80/20) with pH adjusted to 3.3 with formic acid.
  • Reverse phase column chromatography Reverse phase (rp) silica column packing material was prepared by the method of Kuhler and Lindsten [J.Am.Chem.Soc. 48 (1983) 3589]. This technique was used for final purification of freeze dried solid. The column used was 25 cm long and 1cm thick and was packed with approximately 2 g of silica. Approximately 40 mg of sample was applied in one experiment and eluted with 0.01M HCl. Under these conditions impurities are retained and deaza pterins are rapidly eluted.
  • the pH of the reaction mixture was then adjusted to pH 3 - 4 and a portion of the solution applied to a column of Amberlite CG-50 weak cation exchange resin.
  • the sample was eluted with water until a band exhibiting pale purple fluorescence had been completely eluted from the column.
  • the sample was then eluted with 0.01M HCl and a colourless band exhibiting strong blue fluorescence collected.
  • the UV/vis spectrum of this solution indicated it to be a deaza-pterin. This solution was freeze dried to give 30 mg of white solid 11.
  • the pH of the reaction mixture was adjusted to pH 3 - 4 and the solution applied to a column of Amberlite CG-50 weak cation exchange resin.
  • the sample was eluted with water until a band exhibiting pale purple fluorescence had been completely eluted from the column.
  • the sample was then eluted with 4% formic acid and a colourless band exhibiting strong blue fluorescence collected.
  • the UV/vis spectrum of this solution indicated it to be deaza-pterin. This solution was freeze dried to give (30mg) of 13.
  • the pH of the reaction mixture was adjusted to pH 3 - 4 and the solution applied to a column of Amberlite CG-50 weak cation exchange resin.
  • the sample was eluted with a weak bisulfite solution until a band exhibiting pale purple fluorescence had been completely eluted from the column.
  • the sample was then eluted with 0.01M HCl and a colourless band exhibiting strong blue fluorescence collected.
  • the UV/vis spectrum of this solution indicated it to be deaza-pterin. This solution was freeze dried to give (100mg) of 14. uv: pH 2 ⁇ max 358 , 278 , 214.
  • reaction mixture was passed through a wcx column eluting with water then 0.01M HCl.
  • a clear colourless blue-fluorescent fraction was collected ( ⁇ 200 mL) and freeze dried to give 60 mg of pale yellow solid (30% yield).
  • This solid was dissolved in water and passed through an rp silica column eluting with water.
  • a clear colourless blue-fluorescent fraction was collected which was acidified and freeze dried to give 50 mg of white solid.

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Abstract

Procédé permettant de développer des composés qui se lient à l'enzyme de dihydrofolate réductase (DHFR), composés de N5-désazaptérine de la formule (I) utilisés pour inhiber la DHFR et procédés de sélection et de préparation de tels composés à l'aide de calculs théoriques. Composés de la formule (I), leurs sels ou esters pharmaceutiquement acceptables, formule dans laquelle R1 représente hydrogène ou alkyle éventuellement substitué par hydroxy, thio ou halogène; R2 représente H, -CHO, -COOH, alkyle, CH(Oalk)¿2?, alkyle substitué par hydroxy, thio, halogène, PABA, PABA-Glu, alcényle, alcynyle; R?3¿ représente H, alkyle; R4 représente alkyle éventuellement substitué par hydroxy, thio, halogène, alcényle, alcynyle; X- représente halogène.
PCT/AU1993/000138 1992-04-01 1993-03-31 N5-desazapterines substituees en position 8, utilisees comme antifolates Ceased WO1993020075A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6622094B2 (en) * 1996-02-15 2003-09-16 The Trustees Of Columbia University In The City Of New York Method for determining relative energies of two or more different molecules

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4237289A (en) * 1977-07-20 1980-12-02 Burroughs Wellcome Co. 2,7-Diamino-8-methyl-5-substituted pyrido{2,3-d}pyrimidin-6-ones
AU5510886A (en) * 1985-03-08 1986-09-24 Trustees Of Princeton University, The Pyrido (2,3-d) pyrimidin derivatives
AU7426287A (en) * 1986-06-30 1988-01-07 Trustees Of Princeton University, The 4(3h)-oxo-5,6,7,8-tetrahydropyrido-(2,3-d)pyrimidine derivatives
AU7417591A (en) * 1990-04-12 1991-10-17 Health Research Inc. Difluoroglutamic acid conjugates with folates and anti- folates for the treatment of neoplastic diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4237289A (en) * 1977-07-20 1980-12-02 Burroughs Wellcome Co. 2,7-Diamino-8-methyl-5-substituted pyrido{2,3-d}pyrimidin-6-ones
AU5510886A (en) * 1985-03-08 1986-09-24 Trustees Of Princeton University, The Pyrido (2,3-d) pyrimidin derivatives
AU7426287A (en) * 1986-06-30 1988-01-07 Trustees Of Princeton University, The 4(3h)-oxo-5,6,7,8-tetrahydropyrido-(2,3-d)pyrimidine derivatives
AU7417591A (en) * 1990-04-12 1991-10-17 Health Research Inc. Difluoroglutamic acid conjugates with folates and anti- folates for the treatment of neoplastic diseases

Non-Patent Citations (2)

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Title
THE JOURNAL OF ORGANIC CHEMISTRY, Vol. 47, No. 5, issued 26 February 1982 (Birmingham, Alabama), C. TEMPLE, R. ELLIOT AND J. MONTGOMERY, "Pyrido (2,3-d) Pyrimidines. Synthesis of the 5-Deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N10-Methylfolic Acid", pages 761-764. *
THE JOURNAL OF ORGANIC CHEMISTRY, Volume 53, No. 17, issued 19 august 1988 (Spain), J. ANGUIANO et al., "AM1 Study of the Protonation of Pteridine-Related Tetraazan Aphthalenes", pages 3900-3903. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6622094B2 (en) * 1996-02-15 2003-09-16 The Trustees Of Columbia University In The City Of New York Method for determining relative energies of two or more different molecules

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