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WO1994003439A1 - Composes tricycliques a activite antiproliferatrice - Google Patents

Composes tricycliques a activite antiproliferatrice Download PDF

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Publication number
WO1994003439A1
WO1994003439A1 PCT/US1993/005612 US9305612W WO9403439A1 WO 1994003439 A1 WO1994003439 A1 WO 1994003439A1 US 9305612 W US9305612 W US 9305612W WO 9403439 A1 WO9403439 A1 WO 9403439A1
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Prior art keywords
compound
group
compound according
amino
carried out
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PCT/US1993/005612
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English (en)
Inventor
Siegfried H. Reich
Dzuy T. Nguyen
Michael D Varney
Gifford P. Marzoni
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Agouron Pharmaceuticals, Inc.
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Application filed by Agouron Pharmaceuticals, Inc. filed Critical Agouron Pharmaceuticals, Inc.
Priority to AU46328/93A priority Critical patent/AU4632893A/en
Publication of WO1994003439A1 publication Critical patent/WO1994003439A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/60—Naphthoxazoles; Hydrogenated naphthoxazoles
    • 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

  • the present invention relates to tricyclic compounds which demonstrate antiproliferative activity, such as antitumor activity, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to the use of these compounds to inhibit the growth and proliferation of the cells of higher organisms and microorganisms, such as bacteria, yeasts and fungi.
  • Preferred compounds of the present invention are capable of inhibiting the enzyme thy idylate synthase. Effects derived from the inhibition of the enzyme thymidylate synthase include those discussed above.
  • a large class of antiproliferative agents includes antimetabolite compounds.
  • a particular subclass of antimetabolites known as antifolates or antifols are antagonists of the vitamin folic acid.
  • antifolates closely resemble the structure of folic acid and incorporate the characteristic p-benzoyl glutamate moiety,of folic acid.
  • the glutamate moiety of folic acid takes on a double negative charge at physiological pH. Therefore, this compound and its analogues have an active, energy-driven transport system to cross the cell membrane and exert a metabolic effect.
  • a compound without the glutamate group may passively diffuse into a cell.
  • Thymidylate synthase catalyzes the C-methylation of 2'-deoxyuridylate ("dUMP") to provide 2'-deoxythymidylate (“dTMP").
  • dUMP 2'-deoxyuridylate
  • dTMP 2'-deoxythymidylate
  • This one-carbon transfer reaction is critical to cell division.
  • folate analogues have been synthesized and studied for their ability to inhibit the enzyme thymidylate synthase.
  • a prototypic, specific, tight- binding inhibitor of thymidylate synthase, 10-propargyl-5,8- dideazafolic acid T. R.
  • the present invention relates to novel tricyclic compounds which demonstrate antiproliferative activity, such as antitumor activity. These compounds are effective in inhibiting the growth and proliferation of the cells of higher organisms and microorganisms, such as bacteria, yeasts and fungi, processes for preparing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds.
  • Preferred compounds according to the present invention are capable of inhibiting the enzyme thymidylate synthase. Effects derived from the inhibition of the enzyme thymidylate synthase include those discussed above.
  • X is nitrogen or carbon
  • Y is oxygen or nitrogen
  • Z is nitrogen
  • Y and Z together form part of a heterocyclic ring
  • a and B which may be the same or different, represent hydrogen, substituted or unsubstituted alkyl groups, or mono- or disubstituted nitrogen groups; with the proviso that, when B is not a mono- or disubstituted nitrogen group, A must be either (a) a mono- or disubstituted nitrogen group, when X is carbon, or (b) a substituted alkyl group, when X is nitrogen.
  • the compounds of the present invention are effective in inhibiting the growth and proliferation of the cells of higher organisms and microorganisms, such as bacteria, yeasts and fungi.
  • Preferred compounds are capable of inhibiting the enzyme thymidylate synthase.
  • TS K. thymidylate synthase inhibition constant
  • Thymidylate synthase is merely exemplary of the activity of the tricyclic compounds of the present invention. Indeed, certain compounds may demonstrate an antifolate activity besides, or even in addition to, thymidylate synthase inhibition. Further, certain compounds may show antiproliferative activity stemming from a completely different locus of action than the inhibition of folic metabolic pathways.
  • tricyclic compounds according to the present invention may possess one or more asymmetric carbon atoms, and therefore may exist in racemic and optically active forms.
  • the present invention thus is intended to encompass the racemic forms of the tricyclic compounds according to the present invention, as well as any optically active forms thereof, which possess antitumor activity.
  • alkyl includes both straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. Furthermore, as used herein, the language “alkyl”, “alkenyl”, “alkynyl” and the like encompasses both substituted and unsubstituted groups.
  • alkyl refers to groups having one to eight, preferably one to six carbon atoms.
  • alkyl may refer to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentyl, hexyl, isohexyl, and the like.
  • Suitable substituted alkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropy1, hydroxymethy1, 2-hydroxyethy1, 3-hydroxypropyl, and the like.
  • alkenyl refers to groups having two to eight, preferably two to six carbon atoms.
  • alkenyl may refer to prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like.
  • alkynyl which also refers to groups having two to eight, preferably ' two to six carbon atoms, includes, but is not limited to, prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like.
  • substituents Y and Z of formula I form a heterocylic ring.
  • Y and Z may a form a variety of heterocyclic rings, they preferably form a five- or six- membered heterocyclic ring. Five-membered rings such as oxazole or imidazole rings are particularly preferred.
  • Y and Z form either a
  • P is hydrogen; an alkyl group; oxygen; an oxygen atom which together with other atoms forms such groups as an oxo linkage (-0-), a hydroxy group, or the like; sulfur; a sulfur atom which together with other atoms forms such groups as a thio linkage (-S-), thioalkylene, thioamide, or the like; an amino group; or the like.
  • P is hydrogen, oxygen, sulfur, or an amino group.
  • heterocyclic rings formed by Y and Z include the following:
  • a and B may represent mono- or disubstituted nitrogen groups.
  • Preferred mono- and disubstituted nitrogen groups have the formula -NR-R 2 , wherein (i) R, and R 2 , which may be the same or different, represent hydrogen atoms or substituted or unsubstituted alkyl, -CH 2 -alkenyl, -CH 2 -alkynyl, aryl or heteroaryl groups, providing that at least one of R. and R 2 is not hydrogen, or (ii) R. and R 2 form together with the nitrogen atom an aryl or heteroaryl group.
  • preferred alkyl groups for R 1 and R 2 include methyl and ethyl; preferred -CH 2 ⁇ alkynyl groups include propargyl; preferred aryl groups include phenyl and naphthyl; and preferred heteroaryl groups include pyridyl and guinolyl.
  • R, and R 2 preferably form a 5- membered or 6-membered ring, such as a pyrrolidine group.
  • At least one of R, and R 2 is substituted by an aryl or heteroaryl group.
  • Suitable aryl and heteroaryl substituents include both monocyclic and polycyclic groups, which in turn may be either substituted or unsubstituted. Examples of useful aryl substituents include phenyl, 1,2,3,4-tetrahydro- naphthyl, naphthyl, phenanthryl, anthryl, phenanthro and the like.
  • heteroaryl substituents include 5- membered monocyclic ring groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like; 6-membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like; and polycyclic heterocyclic ring groups such as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoguinolyl, quinolyl, phthalazinyl, naphth
  • aryl and heteroaryl groups which may serve as substituents for at least one of R. and R 2 , may likewise be substituted by a variety of groups.
  • they may be substituted by an oxygen atom which forms an ether linkage to another substituted or unsubstituted aryl or heteroaryl group or which, when taken together with other atoms, forms such groups as hydroxy, alkoxy, alkyleneoxy, oxamido, oxamyl, acetoxy, phenoxy, phenylsulfa yl, phenylsulfonamido, and the like; a nitrogen atom which taken together with other atoms forms an amino group -NR3R4, wherein R-, and R.
  • aryl or heteroaryl groups represent independently of one another hydrogen atoms or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl groups; or a -S0 2 group, which may be further linked to a substituted or unsubstituted aryl or heteroaryl group such as a phenyl, naphthyl, indolyl, morpholinyl, or piperizinyl group.
  • X is nitrogen
  • A is a substituted alkyl group.
  • Preferred substituted alkyl groups for use as substituent A include, but are not limited to, alkyl groups which are substituted by one or more of the aryl or heteroaryl groups discussed in the two preceding paragraphs.
  • Particularly preferred substituted alkyl groups for substituent A include -CH 2 Ph and - CH 2 PhS0 2 PhOCH 3 .
  • Particularly preferred mono- and di-substituted amino groups for use as substituent A include, but are not limited to, the following:
  • Particularly preferred mono- and disubstituted amino groups for use as substituent B include, but are not limited to, the following:
  • X is carbon; A is hydrogen; Y and Z together form one of the following
  • X is carbon; B is hydrogen; Y and Z together form one of the following:
  • A is one of the following:
  • Particularly preferred compounds according to the present invention include the following:
  • Another aspect of the present invention relates to processes of making the antiproliferative tricyclic compounds of formula I.
  • the compounds obtained above may then be subjected to a second substitution reaction with a compound of the formula Sub 2 -L, wherein L is a leaving group and Sub 2 is the second desired substituent, to form a compound of the formula
  • Both of the selective substitution reactions described above can be carried out under widely varying conditions, but are typically carried out at a temperature of from about - 20°C to about 100°C. The preferred temperature will vary depending upon the substrate.
  • Each of the substitution reactions may be carried out under anhydrous anionic conditions in the presence of NaH, KH, and the like.
  • Each of the reactions may also be carried out in the presence of an organic solvent, a weak base which will not itself react with one of the reactants, or both.
  • an organic solvent is an aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, or tetrahydrofuran.
  • Especially preferred solvents include dimethylformamide and dimethylacetamide.
  • Useful bases include, for example, organic bases such as the substituted amines diisopropylethylamine, dimethyl-sec- butylamine, N-methyl-N-ethylaniline, N,N-dimethylaniline, or the like; and inorganic weak bases such as sodium, potassium or calcium carbonate, or the like.
  • the leaving group L can be any group which is displaceable under the reaction conditions used, and is typically a halogeno such as chloro, bromo, or iodo; a substituted sulfonyloxy such as methanesulfonyloxy, trifluoromethanesulfonyloxy, toluene-p- sulfonyloxy, or 4- bromobenzenesulfonyloxy; or the like.
  • a halogeno is a preferred leaving group, with bromo being particularly preferred.
  • substitution reaction also can be carried out in an aldehyde process under reductive alkylation conditions, such as in the presence of NaCNBH, at a pH of less than 7.
  • the compounds obtained by the selective substitution reactions described above may be subjected to functional group modification reactions to obtain other compounds according to the present invention. Furthermore, prior to carrying out the substitution reactions, it may be necessary to provide protecting groups on the starting materials. Therefore, it may be necessary in some case to subject the compounds obtained by the substitution reactions to deprotection reactions.
  • Example 5 describes the preparation of intermediate compounds (10), (15) and (16), and serves as an example of functional group modification reactions which may be used according to the present invention.
  • Examples 6 and 7 describes the preparation of preferred compounds (11), (13), (17) and (18), and thus serves as an example of deprotection reactions according to the present invention.
  • Another process for preparing particularly preferred compounds according to the present invention comprises the steps of:
  • the reaction conditions used during reducing step (1) may vary widely. However, the reduction is preferably carried out by reacting the 2,4-dinitronaphthol with NaSH, Na 2 S-NH.OH, or HC0 2 H-Et 3 N-Pd at a temperature of from about 50°C to about 80°C. According to a preferred embodiment, the 2,4-dinitronaphthol is reacted with NaSH at a temperature of about 65°C.
  • Cyclizing step (2) may be carried out under widely varying conditions, but is preferably carried out in the presence of an organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, or tetrahydrofuran, at a temperature of from about 20°C to about 40°C.
  • Step (3) which involves providing a protecting group for a thione group, may be carried out under widely varying conditions, but is preferably carried out by reacting the product of' step (2) with methylchloromethyl ether, in the presence of an organic solvent and a base.
  • Suitable solvents include dimethylformamide, dimethylacetamide, or tetrahydrofuran.
  • Useful bases include, substituted amines such as diisopropylethylamine, dimethyl-sec-butylamine, N- methyl-N-ethylaniline, N,N-dimethylaniline, or the like.
  • Protecting step (3) is preferably carried out at a temperature of from about 0°C to about 25°C, preferably from about 10°C to about 25°C.
  • the thione group of the product of step (2) is protected by reacting the product with methylchloromethyl ether in the presence of tetrahydrofuran and diisopropylethylamine at a temperature of about 25°C.
  • the methoxymethyl ether group may be removed by reacting the product with a MeOH-HCL mixture at a temperature of about 25°C.
  • the reaction conditions used during reducing step (4) may vary widely.
  • the reduction preferably involves one or more of the following: (a) treatment with Fe,(CO) 12 in methanol; (b) treatment with zinc in the presence of acetic acid; (c) treatment with SnCl 2 in the presence of hydrochloric acid; (d) treatment with hydrogen gas in the presence of a palladium-on-charcoal catalyst; (e) treatment with hydrogen gas in the presence of a platinum oxide catalyst in an organic solvent such as glacial acetic acid; or (f) treatment with a hydrazine in the presence of a reduction catalyst.
  • the reduction is preferably carried out at a temperature of from about 50°C to about 100°C.
  • reducing step (4) is carried out by treating the product of step (3) with Fe 3(C0), 2 in methanol at a temperature of about 80°C.
  • Step (5) involves substituting one or both of the hydrogen atoms of the amino group of the compound obtained from step (4) with the desired substituent or substituents.
  • Step (5) may be carried out according to the description provided previously for selective substitution reactions. Examples 3 and 4 below describe preferred methods used to prepare intermediate compounds (8), (9), (12) and (14) according to the present invention using selective substitution reactions. If desired, the compounds resulting from step (5), such as compounds (8), (9), (12) and (14), may be subjected to functional group modification or deprotection reactions to obtain other compounds according to the present invention.
  • compounds of the formula I may be prepared by a process comprising the steps of:
  • Step (1) may be carried out under widely varying conditions known for providing an hydroxyl group with an acetate protecting group and for reducing a nitro group to an amino group.
  • Step (2) involves substituting one or both of the hydrogen atoms of the amino group of the compound obtained from step (1) with the desired substituent or substituents.
  • Step (2) may be carried out according to the description provided previously for selective substitution reactions. However, due to the use of the acetate protecting groups, the selective substitution reaction or reactions may be carried out under thermal or reductive conditions.
  • the product of step (1) may be reacted with the desired Sub--L and Sub 2 -L compounds in the presence of Et 3 N, iPr 2 EtN, or K 2 ⁇ °3 '
  • the reaction is carried out in the presence of iPr 2 EtN, and L is a halogen; or the reaction is carried out in the presence of NaCHBH 3 /H , and L is a CHO group.
  • step (3) may be subjected to functional group modification or deprotection reactions to obtain other compounds according to the present invention.
  • Another process for preparing compounds of the present invention comprises substituting one or both of the hydrogen atoms of the amino group in an aminonaphthoxazole to form a compound of
  • substitution reaction above may be carried out according to the methods described previously for selective substitution reactions.
  • the reaction or reactions are carried out in the presence of iPr 2 EtN, and L is a halogen; or the reaction or reactions are carried out in the presence of NaCHBH 3 /H , and L is a CHO group.
  • the resulting compounds may be subjected to functional group modification or deprotection reactions to obtain other compounds according to the present invention.
  • Another process for preparing compounds according to the present invention comprises the steps of:
  • Cyclizing step (1) may be carried out under widely varying conditions, but is preferably carried out by reacting the starting compound with NaH or KH in the presence of THF, at a temperature of from about 0°C to about 50°C, more preferably from about 0°C to about 25°C. According to a preferred embodiment, the starting compound is reacted with EtOCOCl/NaH at a temperature of about 25°C.
  • the reaction conditions used during reducing step (2) may vary widely. However, the reduction preferably involves treating the product of step (1) with hydrazine in the presence of a reduction catalyst such as Raney Nickel.
  • step (3) may be carried out according to the methods described previously for selective substitution reactions.
  • the product of step (2) is first reacted with ethyl iodide and then with PhS0 2 PhCH 2 Br, both reactions being carried out in the presence of potassium carbonate and dimethylformamide.
  • the resulting compounds may be subjected to functional group modification or deprotection reactions to obtain other compounds according to the present invention.
  • the oxo group may be replaced with an amino group by treating the resulting compound with P0C1 3 , followed by NH OH, NH4CI and EtOH.
  • Another process according to the present invention comprises the steps of:
  • Subi Step (1) may be carried out under the conditions provided previously for selective substitution reactions.
  • Sub..-L is
  • Cyclizing step (2) may be carried out by reacting the product of step (1) with CNBr, HC(OCH 3 ) 3 , or CH 3 C(OCH 3 ) 3 , at a temperature of from about 0°C to about 80°C, preferably from about 40°C to about 80°C.
  • CNBr is used as the cyclizing agent, and the cyclizing takes place in the presence of MeOH at a temperature of about 60°C.
  • Another process for preparing compounds according to formula I comprises the steps of:
  • Cyclizing step (1) may be carried out under widely varying conditions, but is typically carried out by (i) first treating the l,2-diamino-4-nitro-naphthalene with Rh/Al 2 0 3 and H 2 , or the like, in the presence of dimethylformamide, dimethylacetamide, or the like, and NH.OH, or the like, at a temperature of about 25°C; and then (ii) reacting the resulting product with an appropriate cyclizing agent such as Imid 2 C0, phosgene, or the like, in the presence of THF, CH 2 C1 2 , or the like, at a temperature of from about 0°C to about 25°C, preferably at about 25°C.
  • an appropriate cyclizing agent such as Imid 2 C0, phosgene, or the like
  • the l,2-diamino-4-nitro-naphthalene is first treated with Rh/Al 2 0 3 and H 2 in the presence of dimethyleformamide and NH.OH, and then with Imid 2 C0 at 25°C.
  • Reducing step (2) may be carried out under widely varying conditions, but is preferably carried out by treating the product of step (1) with Pd-C, Pt-C, RaNi, or the like, in the presence of hydrazine and EtOH, or the like, at a temperature of about 25°C.
  • the product of step (1) is treated with Pd-C in the presence of hydrazine and EtOH.
  • Step (3) may be carried out according to the methods described previously for selective substitution reactions.
  • step (3) is carried out by reacting the product of step (2) with PhS0 2 PhCH 2 Br in the presence of dimethylformamide and iPr 2 EtN.
  • the resulting compounds may be subjected to functional group modifications to obtain other compounds according to the present invention.
  • the oxo group may be replaced with a chloro group by reacting the resulting compound with P0C1 3 at a temperature of about 175°C.
  • the resulting chloro group may then be replaced with an amino group by reacting the chloro containing compound with NH.C ⁇ , NH.OH, and EtOH at a temperature of about 155°C.
  • a suitable protecting group for a ring nitrogen, such as may be included in a heteroaryl group is for example, a pivaloyloxymethyl group, which may be removed by hydrolysis with a base such as sodium hydroxide; a tert-butyloxycarbonyl group, which may be removed by hydrolysis with an acid, such as hydrochloric acid or trifluoroacetic acid, or with a base such as tetra-n-butylammonium fluoride ("TBAF") or lithium hydroxide; a methoxymethyl group, which may be removed by hydrochloric acid and p-Toluenesulfonic acid; or a 2- (trimethylsilyl)ethoxy ethyl group, which may be removed by TBAF or with an acid such as hydrochloric acid.
  • a base such as sodium hydroxide
  • a tert-butyloxycarbonyl group which may be removed by hydrolysis with an acid, such as hydrochloric acid or trifluor
  • a suitable protecting group for a hydroxyl group is, for example, an esterifying group such as an acetyl or benzoyl group, which may be removed by hydrolysis with a base such as sodium hydroxide.
  • the protecting group may be, for example, an alpha- arylalkyl group such as a benzyl group, which may be removed by hydrogenation in the presence of a catalyst such as palladium on charcoal or Raney nickel.
  • An additional protecting group for a hydroxyl group is a group such as t- butyldiphenylsilyl (-Si-t-Bu-Ph 2 ), which may be removed by treatment with TBAF.
  • a suitable protecting group for a mercapto group is, for example, an esterifying group such as an acetyl group, which may be removed by hydrolysis with a base such as sodium hydroxide.
  • a suitable protecting group for an amino group may be, for example, an alkylcarbonyl group such as an acetyl group (CH 3 C0-), which may be removed by treatment with an aqueous inorganic acid such as nitric, sulfuric or hydrochloric acid.
  • Another protecting group for an amino group is an alkoxycarbonyl group such as a methoxycarbonyl or a tert- butyloxycarbonyl group. These groups may be removed by treatment with an organic acid such as trifluoroacetic acid.
  • a suitable protecting group for a primary amino group is, for example, an acetyl group, which may be removed by treatment with an aqueous inorganic acid such as nitric, sulfuric, or hydrochloric acid, or a phthaloyl group, which may be removed by treatment with an alkylamine such as dimethylaminopropylamine or with hydrazine.
  • an acetyl group which may be removed by treatment with an aqueous inorganic acid such as nitric, sulfuric, or hydrochloric acid
  • a phthaloyl group which may be removed by treatment with an alkylamine such as dimethylaminopropylamine or with hydrazine.
  • a suitable protecting group for a carboxy group may be an esterifying group, for example, a methyl or an ethyl group, which may be removed by hydrolysis with a base such as sodium hydroxide.
  • Another useful protecting group is a tert- butyl group, which may be removed by treatment with an organic acid such as trifluoro-acetic acid.
  • the antiproliferative tricyclic compounds of the present invention which may be employed in the pharmaceutical compositions of the present invention, include all of those compounds described above, as well as pharmaceutically acceptable salts of these compounds.
  • Pharmaceutically acceptable acid addition salts of the compounds of the invention containing a basic group are formed, where appropriate, with strong or moderately strong organic or inorganic acids in the presence of a basic amine by methods known in the art.
  • Exemplary of the acid addition salts which are included in this invention are: (1) organic acid salts such as maleate, fumarate, lactate, oxalate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, glucuronate, citrate, and acetate; and (2) inorganic acid salts such as hydrobromide, hydrochloride, hydrosulfate, phosphate and nitrate salts.
  • organic acid salts such as maleate, fumarate, lactate, oxalate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, glucuronate, citrate, and acetate
  • inorganic acid salts such as hydrobromide, hydrochloride, hydrosulfate, phosphate and nitrate salts.
  • Pharmaceutically acceptable base addition salts of compounds of the invention containing an acidic group are prepared by known methods from organic and inorganic bases, and include nontoxic alkali metal and alkaline earth bases, for example, calcium, sodium and potassium hydroxides; ammonium hydroxides; and nontoxic organic bases such as triethylamine, butylamine, piperazine and tri(hydroxymethyl)-methylamine.
  • nontoxic alkali metal and alkaline earth bases for example, calcium, sodium and potassium hydroxides; ammonium hydroxides; and nontoxic organic bases such as triethylamine, butylamine, piperazine and tri(hydroxymethyl)-methylamine.
  • the compounds of the invention possess antiproliferative activity, a property which may express itself in the form of antitumor activity.
  • a compound of the invention may be active per se or it may be a pro-drug that is converted in vivo to an active compound.
  • Preferred compounds of the invention are active in inhibiting the enzyme thymidylate synthase.
  • Particularly preferred compounds are active in inhibiting the growth of the L1210 cell line, a mouse leukemia cell line which can be grown in tissue culture.
  • Such compounds of the invention are also active in inhibiting the growth of bacteria such as Escherichia coli gram negative bacteria which can be grown in culture.
  • the compounds of the invention may also be active inhibiting the growth of bacteria.
  • the antiproliferative compounds according to the present invention may be incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations.
  • Solid or liquid pharmaceutically acceptable carriers may be employed.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier or diluent may include any prolonged release materiel, such as glyceryl monostearate or glyceryl distearate, alone or with wax.
  • the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • compositions are made following conventional techniques of a pharmaceutical chemist involving steps such as mixing, granulating and compressing, when necessary for tablet forms; or mixing, filling and dissolving the ingredients, as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraoccular, intraaural and rectal administration.
  • the composition of the invention may further comprise one or more other compounds which are antitumor agents, such as a.
  • mitotic inhibitors e.g., vinblastine
  • alkylating agents e.g., cis-platin, carboplatin and cyclophosphamide
  • dihydrofolate reductase inhibitors e.g., methotrexate, piritrexim and trimetrexate
  • other thymidylate synthase inhibitors e.g., antimetabolites (e.g., 5-fluorouracil and cytosine arabinoside)
  • intercalating antibiotics e.g., adriamycin and bleomycin
  • enzymes e.g., asparaginase
  • topoisomerase inhibitors e.g., etoposide
  • biological response modifiers e.g., interferon
  • composition of the invention may also comprise one or more other compounds, including antibacterial, antifungal, antiparasitic, antiviral, antipsoriatic and anticoccidial agents.
  • antibacterial agents include, for example, sulfonamide such as sulfamethoxazole, sulfadiazine, sulfameter or sulfadoxine; dihydrofolate reductase inhibitors such as trimethoprim, bromodiaprim or trimetrexate; penicillins; cephalosporins; aminoglycosides; bacteriostatic inhibitors of protein synthesis; the quinolonecarboxylic acids and their fused isothiazolo analogs.
  • Another aspect of the invention relates to a therapeutic process of inhibiting the growth and proliferation of cells of higher organisms and microorganisms, which process comprises administering to a host, such as a vertebrate host (e.g., a mammal or bird) an effective amount of a compound according to the present invention.
  • a particularly preferred therapeutic process comprises administering to a host an effective amount of a compound according to the present invention to inhibit the enzyme thymidylate synthase.
  • the compounds of the invention are particularly useful in the treatment of mammalian hosts, such as human hosts, and in the treatment of avian hosts.
  • any of the antiproliferative compounds described above, or pharmaceutically acceptable salts thereof, may be employed in the therapeutic process of the invention.
  • the compounds of the invention may be administered in the form of a pharmaceutically acceptable composition comprising a diluent or carrier, such as those described above.
  • Doses of the compounds preferably include pharmaceutical dosage units comprising an efficacious quantity of active compound.
  • an efficacious quantity is meant a quantity sufficient to inhibit the folate metabolic pathways and derive the beneficial effects therefrom through administration of one or more of the pharmaceutical dosage units.
  • An exemplary daily dosage unit for a vertebrate host comprises an amount of up to about 1 gram of active compound per kilogram of the host, preferably one half of a gram, more preferably 100 milligrams, and most preferably about 50 milligrams per kilogram of the host.
  • the selected dose may be administered to a warmblooded animal or mammal, for example a human patient, in need of treatment mediated by folate metabolic pathways inhibition by any known method of administration, including topically (e.g. as an ointment or cream), orally, rectally (e.g., as a suppository), parentally, by injection or continuously by infusion, intravaginally, intranasally, intrabronchially, intraaurally or intraocularly.
  • topically e.g. as an ointment or cream
  • rectally e.g., as a suppository
  • parentally by injection or continuously by infusion, intravaginally, intranasally, intrabronchially, intraaurally or intraocularly.
  • the compounds according to the present invention may be characterized as producing any one or more of an antiproliferative effect, an antibacterial effect, an antiparasitic effect, an antiviral effect, an antipsoriatic effect, an antiprotozoal effect, an anticoccidial effect or an antifungal effect.
  • the compounds are especially useful in producing an antitumor effect in a vertebrate host harboring a tumor.
  • 2,4-Dinitronaphthol (5.0 g, 21.4 mmol) in 100 mL MeOH was treated with NaHSxH 2 0 (4.8 g, 85.5 mmol) and heated to reflux. Additional NaSH was added (2.4 g) after 6 hours, and (1.2 g) after 7 hours, for a total of 7 equiv. (8.4 g, 150 mmol) to consume all of the starting naphthol. The reaction was filtered hot, and the crude red aminonapthol (4) (4.5 g, 103%) was used directly in the subsequent step. m.p. (sealed capillary) 246-247°C.
  • the amine (7) (205 g, 0.78 mmol) in 3 mL DMF was treated with NaH (35 mg of a 60% dispersion in mineral oil, 0.87 mmol) at -20°C, and the mixture was stirred for 2 hours at -20°C.
  • N-tertButoxycarbonyl-piperazinylsulfamoylbenzyl bromide (330 mg, 0.79 mmol) was then added directly as a solid, and the reaction was allowed to warm to 25°C and then stirred an additional 4 hours. The reaction was poured into water and extracted with EtOAc. The organic layers were washed with brine, dried (MgSO.), and concentrated to afford 696 mg of a crude brown oil.
  • the amine (8) (279 mg, 0.42 mmol) in 2 mL DMF was treated with NaH (20 mg of a 60% dispersion in mineral oil, 0.50 mmol) at -25°C. The green solution was stirred for 1 hour at -20°C, after which the color had turned to a deep red. Propargyl bromide (55 mg, 0.46 mmol) was added to the reaction, and the temperature was allowed to slowly reach 25°C. The mixture was stirred at 25°C for 3 hours, diluted with EtOAc, washed with water and brine, dried (MgS0 4 ), and concentrated.
  • Zinc (0.368 g, 5.6 mmol) was added to a solution of (30) (0.398 g, 0.94 mmol) in AcOH (10 mL) at 25°C. The reaction was then stirred for 15 minutes. The reaction was then neutralized with NaHC0 3 and extracted with EtOAc. The organic layer was then dried with Na 2 S0., and the solvent removed to afford a solid. This solid was taken up in acetonitrile and methanol (6 mL, 1:1). Cyanogen bromide (0.28 mL of 5 M in CHgCN, 1.41 mmol) was added to this solution at 25°C. The temperature of the reaction was raised to 60°C for 20 minutes.
  • reaction was cooled to 25°C, and the reaction mixture was poured into 2N HCI (150 mL) and was washed with EtOAc. The aqueous layer was then collected, neutralized with 1 N NaOH and then extracted with CH 2 C1 2 (3 X 50 mL) . The organic layers were combined and dried with Na 2 S0 4 . Removal of solvent gave 0.2 g of a solid.
  • Thymidylate synthase activity was measured using a modification of the tritium release method of Lomax and Greenberg [M.I.S. Lomax and G.R. Greenberg, J. Biol . Chem. 242 109 (1967)].
  • Inhibition constants, K., slope and K., intercept [W.W. Cleland, Biochim. Biophys. Acta 67 173 (1963)] were determined against the cofactor (6R, 6S)-5,10- methylene-tetrahydrofolate which was generated in situ by reaction of tetrahydrofolate with formaldehyde [R.G. Kallen and W.P. Jencks, J. Biol . Chem. 241 5851 (1966)].
  • the cofactor was present as the variable substrate under conditions of saturating radiolabelled 2'-deoxyuridine 5'- monophosphate (dUMP) .
  • Assays in a total volume of 0.1 mL contained 50mM Tris @ pH 7.6, lOmM DTT (dithiothreitol) , ImM EDTA (ethylenediaminetetraacetic acid), 25mM MgCl 2 , 15mM formaldehyde, ⁇ 1% DMSO (depending on the solubility of the
  • Cellular growth in the presence of the compounds in question was assessed using three cell lines: the L1210 murine leukemia (ATCC CCL 219), CCFR-CEM, a human lymphoblastic leukemia line of T-cell origin (ATCC CCL 119), and a thymidine kinase-deficient human colon adenocarcinoma, GC 3 /M TK " (supplied by Drs. P.J. and J.A. Houghton, St. Jude Childrens Research Hospital, Memphis, TN) . Cell lines were maintained in RPMI 1640 medium containing 5% (LI210, CCRF- CEM) or 10%' (GC 3 /M TK " ) heat-inactivated fetal bovine serum without antibiotics.
  • L1210 murine leukemia ATCC CCL 219
  • CCFR-CEM a human lymphoblastic leukemia line of T-cell origin
  • IC ⁇ Q values were determined in 150 ⁇ l> microcultures each containing 1500 (L1210) or 10,000 (CCRF-CEM, GC 3 /M TK " ) cells established in 96 well plates in growth medium supplemented with 50 U/mL penicillin and 50 ⁇ g/mL streptomycin. Growth was measured over 3 days (L1210) or 5 days (CCRF-CEM, GC 3 /M TK ⁇ ) of continuous exposure to varying concentrations of each test compound, added 4 hours after initial cell plating, by the MTT-tetrazolium reduction assay of T.J. Mosmann [ J. Immunol . Meth . 65 55 (1983) ] modified according to Alley et al. [ Cancer Res. 48589 (1988)]. Water insoluble derivatives were dissolved in DMSO and diluted to a final concentration of 0.5% solvent in cell cultures.

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Abstract

Composés tricycliques qui inhibent la synthase de thymidylate (TS), procédés de préparation desdits composés, compositions pharmaceutiques contenant ces composés et utilisation de ces composés pour inhiber la TS, y compris tous les effets découlant de l'inhibition de la TS. Les effets découlant de l'inhibition de la TS comprennent l'inhibition de la croissance et de la prolifération des cellules d'organismes supérieurs et de microorganismes, tels que des levures, des bactéries et des champignons. Ces effets comportent une activité antitumorale.
PCT/US1993/005612 1992-07-29 1993-06-16 Composes tricycliques a activite antiproliferatrice WO1994003439A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747499A (en) * 1994-05-05 1998-05-05 British Technology Group Limited Anti-cancer compounds
US5789417A (en) * 1992-11-06 1998-08-04 Zeneca Limited Tricyclic compounds with pharmaceutical activity
RU2178791C2 (ru) * 1995-12-12 2002-01-27 Лаборатуар Иннотера, Сосьете Аноним Использование трициклических призводных 1,4-дигидро-1,4-диоксо-1н-нафталина и новые его соединения, фармацевтическая композиция на их основе и производные замещенных нафталинов в качестве промежуточных соединений
CN107593764A (zh) * 2017-10-13 2018-01-19 中国民用航空局民用航空医学中心 一种消毒液及其用途

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EP0012983A1 (fr) * 1978-12-23 1980-07-09 Hoechst Aktiengesellschaft Diaminophénylurées, procédé pour leur préparation et leur utilisation dans la préparation d'aminobenzimidazolones-(2)
EP0034249A2 (fr) * 1980-02-08 1981-08-26 Gruppo Lepetit S.P.A. Dérivés du naphtimidazole et du naphtoxazole, leur préparation et leur utilisation dans des médicaments
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EP0012983A1 (fr) * 1978-12-23 1980-07-09 Hoechst Aktiengesellschaft Diaminophénylurées, procédé pour leur préparation et leur utilisation dans la préparation d'aminobenzimidazolones-(2)
EP0034249A2 (fr) * 1980-02-08 1981-08-26 Gruppo Lepetit S.P.A. Dérivés du naphtimidazole et du naphtoxazole, leur préparation et leur utilisation dans des médicaments
WO1992005173A1 (fr) * 1990-09-25 1992-04-02 Agouron Pharmaceuticals, Inc. Composes tricycliques substitues

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CHEMICAL ABSTRACTS, vol. 81, no. 22, 2 December 1974, Columbus, Ohio, US; abstract no. 137561a, A.M. OSMAN ET AL: "Synthesis of some arylnaphthoxazoles from nitrosonaphthols" page 71; *
INDIAN J. CHEM., vol. 12, no. 2, 1974, pages 120 - 123 *
M. KAMEL ET AL: "Novel studies on 5-amino-2-methylnaphth(1,2)-imidazole and 5-amino-2-methyl-3oxonaphth(1,2)imidazole", TETRAHEDRON ), vol. 23, 1967, OXFORD GB, pages 1863 - 1866 *
SIEGFRIED H. REICH ET AL: "Novel angular tricyclic inhibitors of thymidylate synthase", MEDICAL CHEMISTRY RESEARCH, vol. 2, no. 4, 15 July 1992 (1992-07-15), pages 195 - 207 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5789417A (en) * 1992-11-06 1998-08-04 Zeneca Limited Tricyclic compounds with pharmaceutical activity
US5747499A (en) * 1994-05-05 1998-05-05 British Technology Group Limited Anti-cancer compounds
RU2178791C2 (ru) * 1995-12-12 2002-01-27 Лаборатуар Иннотера, Сосьете Аноним Использование трициклических призводных 1,4-дигидро-1,4-диоксо-1н-нафталина и новые его соединения, фармацевтическая композиция на их основе и производные замещенных нафталинов в качестве промежуточных соединений
CN107593764A (zh) * 2017-10-13 2018-01-19 中国民用航空局民用航空医学中心 一种消毒液及其用途

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