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WO1993013079A1 - Quinazolines anti-folates - Google Patents

Quinazolines anti-folates Download PDF

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Publication number
WO1993013079A1
WO1993013079A1 PCT/US1992/010730 US9210730W WO9313079A1 WO 1993013079 A1 WO1993013079 A1 WO 1993013079A1 US 9210730 W US9210730 W US 9210730W WO 9313079 A1 WO9313079 A1 WO 9313079A1
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WIPO (PCT)
Prior art keywords
compound
group
compound according
making
mmol
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Application number
PCT/US1992/010730
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English (en)
Inventor
Terence R. Jones
Michelle Caldwell
Kathleen K. Lewis
William H. Romines, Iii
Original Assignee
Agouron Pharmaceuticals, Inc.
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Publication of WO1993013079A1 publication Critical patent/WO1993013079A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to certain quinazoline compounds which are capable of inhibiting folate metabolic pathways, to pharmaceutical compositions containing these compounds, and to the use of these compounds to inhibit folate metabolic pathways, including all effects derived from the inhibition of folate metabolic pathways.
  • Effects derived from the inhibition of folate metabolic pathways include the inhibition of the growth and proliferation of the cells of higher organisms and microorganisms, such as bacteria, yeasts and fungi. Such effects may include the inhibition of the enzymes thymidylate synthase or dihydrofolate reductase, or both.
  • a process for preparing the antifolate quinazoline compounds according to the present invention is also
  • a large class of antiproliferative agents includes antimetabolite compounds.
  • a particular subclass of antiproliferative agents includes antimetabolite compounds.
  • antimetabolites known as antifolates or antifols are
  • antifolates closely resemble the structure of folic acid and incorporate the characteristic p-benzoyl glutamate moiety of folic acid. Because the glutamate moiety of folic acid takes on a double negative charge at physiological pH, this
  • MTX methotrexate
  • MTX has been used widely in the treatment of human neoplastic diseases, such as malignant diseases.
  • the cytotoxic action of MTX is ascribed generally to its inhibition of the enzyme dihydrofolate reductase
  • DHFR a key enzyme which maintains the pools of one- carbon carrying tetrahydrofolates.
  • MTX a key enzyme which maintains the pools of one- carbon carrying tetrahydrofolates.
  • DHFR DHFR
  • piritrexim and trimetrexate both of which lack the glutamate moiety
  • these two agents penetrate the cell wall by passive diffusion and, thus, can affect both normal tumor cells and those resistant because of a transport defect.
  • These compounds have been found active even against tumor cells having an MTX transport defect. Because they are more soluble than MTX in organic solvents and in lipids, they have been termed lipophilic DHFR inhibitors.
  • trimetrexate may be active against opportunistic infections which occur in patients infected with HIV (human
  • TS thymidylate synthase
  • dUMP 2'-deoxyuridylate
  • dTMP 2'-deoxythymidylate
  • the present invention relates to novel quinazoline compounds which are capable of inhibiting folate metabolic pathways, to pharmaceutical compositions containing these compounds, and to the use of these compounds to inhibit folate metabolic pathways, including all effects derived from the inhibition of folate metabolic pathways.
  • Effects derived from the inhibition of folate metabolic pathways include the inhibition of the growth and proliferation of the cells of higher organisms and of microorganisms, such as bacteria, yeasts and fungi. Such effects may include the inhibition of the enzymes thymidylate synthase or dihydrofolate reductase, or both.
  • the present invention relates to quinazoline compounds having the formula I
  • R 1 and R 2 which may be the same or different, represent electron-donating substituents;
  • R 3 represents a -S-CH 2 - group, a -CH 2 -S- group or a
  • R 5 is hydrogen or a lower alkyl
  • R 4 represents a substituted or unsubstituted aryl or heteroaryl group
  • R 4 does not represent (a) an unsubstituted phenyl; (b) an unsubstituted naphthyl; (c) a substituted phenyl selected from the group consisting of mono-, di- or tri-(lower alkyl)phenyl, mono- or di- halophenyl, hydroxyphenyl, mono-, di- or tri-(lower alkoxy)phenyl, carboxyphenyl, carb-(lower alkoxy)phenyl, nitrophenyl, aminophenyl, mono- or di-(lower alkyl) aminophenyl, and acetamidophenyl; (d) a phenyl substituted in the para-position with any of the following groups: -CO-NHR b where R b is such that NH 2 -R b is an amino acid, a poly(amino acid), a lower alkyl ester of an
  • the language “capable of inhibiting folate metabolic pathways” refers to the ability of a
  • such a compound may effectively inhibit the growth and proliferation of the cells of higher organisms and
  • quinazoline compounds according to the present invention are either capable of inhibiting the enzyme thymidylate synthase or capable of inhibiting the enzyme dihydrofolate reductase, or both.
  • thymidylate synthase refers to a compound having a TS inhibition constant K i of less than or equal to about 10 -4 M.
  • TS K i values in the range of less than about 10 -5 M, preferably less than about 10 -6 M, more preferably less tftan about 10 -9 M and most preferably less than about 10 -12 M.
  • dihydrofolate reductase refers to a compound having a DHFR inhibition constant K i of less than or equal to about 10 -6 M.
  • DHFR K i values in the range of less than about 10 -8 M, preferably less than about 10 -10 M, more preferably less than about 10 -12 M and most preferably less than about 10 -13 M.
  • substituents R 1 and R 2 of formula I above include -NH 2 , -NH-
  • lower alkyl (lower alkyl), -NHOH, -NHNH 2 , -S-(lower alkyl) and -NR 6 R 7 , wherein R 6 and R 7 represent substituted or unsubstituted lower alkyl groups.
  • the language “lower alkyl”, “lower alkoxy” and the like refers to groups having one to six carbon atoms.
  • “lower alkyl” may refer to methyl, ethyl, n-propyl, isopropyl and the like.
  • at least one of R 1 and R 2 is -NH 2 . More
  • both R 1 and R 2 are -NH 2 .
  • substituent R 3 of formula I may be a -S-CH 2 - group, a -CH 2 -S- group or a -N(R 5 )-CH 2 - group, wherein R 5 is hydrogen or a lower alkyl.
  • R 3 is a
  • R 5 is preferably a methyl or ethyl group.
  • R 4 substituent of formula I can be any one of a large number of ring compounds selected from the group consisting of substituted or unsubstituted aryl and
  • heteroaryl rings examples include phenyl, 1,2,3,4-tetrahydro-naphthyl, naphthyl, phenanthryl, anthryl and the like.
  • aryl ring groups include phenyl, 1,2,3,4-tetrahydro-naphthyl, naphthyl, phenanthryl, anthryl and the like.
  • typical heteroaryl rings include 5-membered monocyclic ring groups such as thienyl, pyrrolyl, 2H-pyrrolyl, imidazolyl,
  • R 1 and R 2 both represent -NH 2 , R 4 , does not represent (a) an unsubstituted phenyl; (b) an
  • a substituted phenyl selected from the group consisting of mono-, di- or tri-(lower alkyl)phenyl, mono- or di- halophenyl, hydroxyphenyl, mono-, di- or tri-(lower alkoxy)phenyl, carboxyphenyl, carb-(lower alkoxy)phenyl, nitrophenyl, aminophenyl, mono- or di-(lower alkyl) aminophenyl, and acetamidophenyl; (d) a phenyl substituted in the para-position with any of the following groups: -CO-NHR b where R b is such that NH 2 -R b is an amino acid, a poly(amino acid), a lower alkyl ester of an amino acid, or a lower alkyl ester of a poly(amino acid); (e) a substituted naphthyl selected from the group consisting of
  • R 1 and R 2 are -NH 2
  • R 4 is preferably a monocyclic or bicyclic aryl or heteroaryl ring. More preferably, R 4 is a phenyl, naphthyl or monocyclic or bicyclic heteroaryl ring, and most preferably, R 4 is phenyl.
  • R 4 may be unsubstituted, or R 4 may be substituted with one or more of a wide variety of electron-donating and electron-withdrawing substituents.
  • electron-withdrawing refers to groups such as -NO 2 , -CN, carboxy, halogen, SO 2 R 8 , wherein R 8 is as defined hereunder, and the like.
  • electron-donating refers to groups such as -NH 2 , -NH- (lower alkyl), -NHOH, -NHNH 2 , -S-(lower alkyl) and -NR 6 R 7 , wherein
  • R 6 and R 7 represent lower alkyl groups, and the like.
  • quinazoline compounds according to the claimed invention may demonstrate activity against serine
  • hydroxymethyltransferase glycineamineribotide transformylase and aminoimidazolecarboxamideribotide transformylase.
  • Typical substituents for R 4 include halogen, hydroxy, lower alkoxy, lower alkyl, hydroxyalkyl, fluoroalkyl, amino,
  • R 4 is substituted with at least one electron-withdrawing group such as -NO 2 , -CN, carboxy, halogen, -SO 2 R 8 , wherein R 8 is as defined hereunder, and the like. More preferably, R 4 is substituted with a -CN or -SO 2 group. Even more preferably, R 4 is substituted by a
  • R 8 represents an aryl or heteroaryl group, such as phenyl, naphthyl, indole, or morpholino.
  • R 4 is substituted in the para-position (i.e., the
  • R 8 When R 4 is a phenyl group substituted by a -SO 2 -R 8 group wherein R 8 is an aryl or heteroaryl group, R 8 may also be substituted with a variety of substituents, such as those discussed above for R 4 .
  • R 8 is phenyl substituted by hydroxy, lower alkoxy, amino, (lower alkyl)-amino, (lower alkyl)-thio, nitro, carboxy, halogen and the like.
  • R 4 Particularly preferred structures for R 4 include:
  • a preferred class of compounds according to the present invention includes those compounds according to formula I, wherein at least one of R 1 and R 2 is -NH 2 , R 3 is -N(lower alkyl)CH 2 -, preferably -N(CH 3 )CH 2 -and R 4 is phenyl
  • R 8 is an aryl or heteroaryl group as discussed above.
  • R 8 is unsubstituted phenyl or phenyl substituted by hydroxy, lower alkoxy, amino, (lower alkyl)-amino, (lower alkyl)-thio, nitro, carboxy, halogen and the like.
  • a particularly preferred class of compounds according to the present invention includes those compounds according to formula I, wherein both R 1 and R 2 are -N H2 , R 3 is -N(CH 3 )CH 2 - or -N(CH 2 CH 3 )CH 2 -, and R 4 is phenyl substituted at the para position by -SO 2 -R 8 , wherein R 4 is an aryl or heteroaryl group as discussed above. More preferably, R 8 is
  • Another preferred class of compounds according to the present invention includes those compounds according to formula I, wherein at least one of R 1 and R 2 is -NH 2 , R 3 is - S-CH 2 - or -CH 2 -S-, and R 4 is phenyl substituted at the para position by -SO 2 -R 8 , wherein R 8 is an aryl or heteroaryl group as discussed above. More preferably, R 8 is
  • R 1 and R 2 are -NH 2 ,
  • Another preferred class of compounds according to the present invention includes those compounds according to formula I, wherein at least one of R 1 and R 2 is -NH 2 , R 3 is -
  • R 4 is a cyanophenyl group. More preferably, both R 1 and R 2 are -NH 2 .
  • Particularly preferred compounds according to the present invention include:
  • Another aspect of the present invention relates to processes of making the antifolate quinazoline compounds of formula I.
  • a preferred process according to the present invention for making the antifolate quinazoline compounds of formula I, wherein R 1 -R 4 have the same meanings as described previously, comprises the steps of:
  • step (2) reacting the product of step (1) with 5-chloro-2- nitrobenzontrile to form a nitro-containing intermediate
  • step (3) (4) reacting the product of step (3) with a cyclization reagent.
  • the first step of reacting the compound L - CH 2 - R 4 with a (lower alkyl) -amine compound can be carried out under widely varying conditions, but is preferably carried out with an excess of the amine, and if not, then in the presence of a base, typically at a temperature varying from about 0°C to about 100°C, preferably from about room temperature to about
  • Step (2) may also be carried out under widely varying conditions, but is typically carried out in a solvent, preferably DMSO, and in the presence of a base, such as CaCO 3 , at a temperature varying from about room temperature to about 189°C, preferably from about 60°C to about 150°C, and most preferably from about 80°C to about 120°C.
  • a solvent preferably DMSO
  • a base such as CaCO 3
  • Step (3) the reducing step, can be performed under widely varying reduction conditions, but is preferably carried out in an organic solvent such as ethanol, methanol, ethyl acetate, tetrahydrofuran or acetic acid, in the
  • a reducing agent such as a KBH 4 ./CuCl or hydrogen gas
  • a vapor pressure of one atmosphere or higher under a vapor pressure of one atmosphere or higher, and at a temperature varying from about room temperature to about 100°C, preferably from about room temperature to about 60°C, and most preferably at about room temperature.
  • a reduction catalyst such as Raney nickel, palladium on
  • charcoal, palladium on barium sulfate and the like may also be used where appropriate.
  • step (4) cyclization of the product of step (3) may be induced by reacting the product of step (3) with a
  • cyclization reagent such as chlorformamidine hydrochloride, cyanamide together with pyridine hydrochloride, S,S- dimethyldithiocarbiminium iodide, thiourea, and the like. If thiourea is used as the cyclization reagent, compounds according to the present invention may be obtained by further reacting the product of step (4) with NaH, followed by iodomethane. Step (4) may be carried out under widely varying conditions, but is typically carried out in the presence of an acid at a temperature varying from about room temperature to about 200°C, preferably from about room temperature to about 180°C, and most preferably from about 150°C to about 165°C.
  • Another process of making the antifolate quinazoline compounds of formula I, wherein R 1 -R 4 have the same meanings as discussed previously, comprises the steps of:
  • L is a leaving group, for example, a halogen atom such as Br, Cl, F and I, the lower alkyl amino is, for example, methylamino,
  • R 4 has the same meaning as described above for formula I;
  • step (2) reacting the product of step (1) with a cyclization reagent.
  • the first step of reacting the compound L - CH 2 - R 4 with a 2-amino-5-(lower alkyl amino)benzonitrile compound can be carried out under widely varying conditions, but is typically carried out in the presence of a base at a
  • 150°C preferably from about 45°C to about 110°C, and most preferably at about 60°C.
  • step (2) the cyclization step, the reagent used to induce cyclization may be a wide variety of compounds such as chlorformamidine hydrochloride, cyanamide together with pyridine hydrochloride, S,S-dimethyldithiocarbiminium iodide, thiourea, and the like. If thiourea is used, compounds according to the present invention may be obtained by further reacting the product of step (2) with NaH, followed by iodomethane. Step (2) may be carried out under widely varying conditions, but is typically carried out in the presence of an acid at a temperature varying from about room temperature to about 200°C, preferably from about room temperature to about 180°C, and most preferably from about
  • Another process according to the present invention for making the compounds of formula I, wherein R 1 -R 4 have the same meaning as discussed previously, comprises the steps of:
  • step (2) lysing the trifluoroacetyl group of the product of step (1); and (3) reacting the product of step (2) with a cyclization reagent.
  • Step (1) can be carried out under widely varying
  • a base at a temperature varying from about 0°C to about 100°C, preferably from about room temperature to about 60°C, and most preferably at about room temperature.
  • Step (2) which is a deprotection step, can be performed under widely varying lytic conditions, but is preferably carried out with methanolic ammonia at a temperature varying from about 0°C to about 100°C, preferably from about room temperature to about 60°C, and most preferably at about room temperature.
  • lytic conditions includes, but is not limited to, hydrolytic, alcoholytic, ammonolytic and aminolytic conditions.
  • step (3) the cyclization step
  • the reagent used to induce cyclization may be a wide variety of compounds such as chlorformamidine hydrochloride, cyanamide together with pyridine hydrochloride, S,S-dimethyldithiocarbiminium iodide, thiourea, and the like. If thiourea is used, compounds according to the present invention may be obtained by further reacting the product of step (3) with NaH, followed by iodomethane.
  • Step (4) may be carried out under widely varying
  • an acid at a temperature varying from about room temperature to about 200°C, preferably from about room temperature to about 180°C, and most preferably from about 150°C to about
  • This reaction may be carried out under widely varying conditions, but is typically carried out at a temperature varying from about room temperature to about 150°C,
  • CH 2 -S, and R 4 has the same meaning as discussed previously, comprises the steps of:
  • R 3 is -S-CH 2 - or -CH 2 -S-, with a reducing agent to give a compound having the formula
  • R 3 is -S-CH 2 - or -CH 2 -S-;
  • R 3 is -S-CH 2 - or -CH 2 -S-;
  • step (3) (4) reacting the product of step (3) with a cyclization reagent.
  • concomitant hydrolysis of the nitrile group may be carried out under widely varying conditions which employ a reducing agent, but is preferably carried out (i) with stannous chloride dihydrate in ethyl acetate or in ethanol at a temperature varying from about 0°C to about 77°C, preferably from about room temperature to about 77°C, and most
  • Step (2) may also be carried out under widely varying conditions, but is typically carried out with an excess of the reagent in the presence of a base in an inert solvent at a temperature varying from about 0°C to about 100°C,
  • Step (3) which is a deprotection step, can be performed under widely varying lytic conditions, but is preferably carried out with methanolic ammonia at a temperature varying from about 0°C to about 100°C, preferably from about room temperature to about 60°C, and most preferably at about room temperature.
  • the reagent used to induce cyclization may be a wide variety of compounds such as chlorformamidine hydrochloride, cyanamide together with pyridine hydrochloride, S,S-dimethyldithiocarbiminium iodide, thiourea, and the like. If thiourea is used, compounds according to the present invention may be obtained by further reacting the product of step (4) with NaH, followed by iodomethane.
  • 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; or a 2-(trimethylsilyl)ethoxymethyl 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 trifluoroacetic acid, or with a base such as tetra-n-butylammonium fluoride ("TBAF") or lithium hydroxide
  • 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.
  • protecting group for a hydroxyl group is a group such as tbutyldiphenylsilyl (-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 CO-), which may be removed by treatment with an aqueous inorganic acid such as nitric, sulfuric or hydrochloric acid.
  • an alkylcarbonyl group such as an acetyl group (CH 3 CO-)
  • an aqueous inorganic acid such as nitric, sulfuric or hydrochloric acid.
  • 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.
  • 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.
  • Preferred protecting groups include an esterifying group, an alpha-arylalkyl group, an alkylcarboxyl group, a substituted or unsubstituted alkoxycarbonyl group, a
  • oxyether-type group such as methoxymethyl or 2- (trimethylsilyl)ethoxymethyl, or a silicon group such as a tert-butyldiphenylsilyl group.
  • antifolate quinazoline compounds of the present invention which may be employed in the pharmaceutical compositions according to the present invention, include all of those compounds described above, as well as
  • 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 maleate, fumarate, lactate, oxalate, ethanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, glucuronate citrate, sulfate, 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 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.
  • invention may also be active inhibiting the growth of bacteria.
  • antifolate compounds according to the present invention may be incorporated into convenient dosage forms such as capsules, tablets, or inje-ctable preparations.
  • Solid or liquid pharmaceutically acceptable carriers may be
  • 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.
  • the pharmaceutical preparations 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, intraocular, intraaural and rectal
  • 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), other DHFR inhibitors (e.g., methotrexate, piritrexim and trimetrexate), other TS inhibitors, antimetabolites (e.g., 5- fluorouracil and cytosine arabinoside), intercalating a mitotic inhibitors (e.g., vinblastine), alkylating agents (e.g., cis-platin, carboplatin and cyclophosphamide), other DHFR inhibitors (e.g., methotrexate, piritrexim and trimetrexate), other TS inhibitors, antimetabolites (e.g., 5- fluorouracil and cytosine arabinoside), intercalating
  • a mitotic inhibitors
  • 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,
  • DHFR 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 folate metabolic pathways, which process comprises administering to a host, such as a
  • vertebrate host for example, a mammal or bird, an amount effective to inhibit the folate metabolic pathways of a compound according to the present invention.
  • 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 antifolate 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
  • 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 antifolate compounds according to the present invention may be further 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
  • the compounds are especially useful in producing an antitumor effect in a vertebrate host harboring a tumor.
  • Proton magnetic resonance spectra were determined using a General Electric QE-300 spectrometer operating at a field strength of 300 MHz. Chemical shifts are reported in parts per million ( ⁇ ) downfield from tetramethylsilane as an internal standard and peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; dq, doublet of quartets; t, triplet; br s, broad singlet; br d, broad doublet; br m, broad multiplet; br, broad signal; m, multiplet. El mass spectra were determined using a VG 7070E- HF high resolution mass spectrometer using the direct
  • N,N-Dimethylformamide (DMF) was dried over activated (250°C) 3- ⁇ molecular sieves; N,N-dimethylacetamide (DMA, Aldrich Gold Label grade), and hexamethylphosphoramide (HMPA, Aldrich) were similarly dried.
  • Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl under nitrogen.
  • AIBN is 2,2'-azobis (2-methylpropionitrile).
  • Diglyme is bis(2-methoxyethyl) ether.
  • Ether refers to diethyl ether.
  • Petrol refers to petroleum ether of bp 36-53°C. Flash
  • TLC plates were aluminium oxide 60F 254 (Merck Art 5731), and flash column packing was basic alumina (Merck Art 1076). Extracts were dried over Na 2 SO 4 or MgSO 4 . Melting points were determined on a Mel-Temp apparatus and are corrected.
  • 2,4-Diamino-6-nitroquinazoline (3) was prepared from 2,4-diaminoquinazoline by a published method (ibid, method a) conducted on a 0.19 mol scale. Yield>90%.
  • 2,4,6-Triaminoquinazoline (4) was prepared by a slightly modified procedure of the above reference. A suspension of 2,4-diamiono-6-nitroquinazoline (25 g) in DMF (900 mL) containing 10% Pd:C (5 g) was stirred for 22 h at 25°C and atmospheric pressure. The mixture was filtered through celite, and the filtrate was evaporated under reduced
  • 2-Amino-4-hydroxy-6-nitroquinazoline (8 ) was prepared from 5-nitroisatoic anhydride (7 ) by a published method [J . B . Hynes, Y.C.S. Yang, J.G. McGill, S.J. Harmon and W.L.
  • the gum was dissolved in glacial HOAc (200 mL) to give a solution which was then brought to pH 6 with 1N NaOH.
  • the resulting crude solid was filtered off, washed with water and redissolved in boiling HOAc (800 mL).
  • the solution was charcoal treated and brought to pH 5 with 2N NaOH.
  • the resulting yellow-orange, flocculent solid was filtered off, washed with water, and dried in a desiccator (12.41 g, 51%).
  • the resulting solution was heated at 70-100°C for 2 h 15 min, cooled to room temperature, carbon treated, and filtered.
  • the liquid layer when brought to pH 9 with NH 4 OH, contained no desired product by TLC (SiO 2 /5% Et 3 N, 10% MeOH, 85% CH 2 Cl 2 ), and was thus discarded.
  • the resin was treated with a mixture of DMF (100 mL), and Et 3 N (13 mL, 88 mmol) and gently warmed to give a dark brown solution which was treated with charcoal and filtered. The charcoal was rinsed with MeOH (30 ml), and the combined filtrate was cooled. It was then poured onto ice (500 g) containing 1 N NaOH (100 mL) with stirring. The resulting crude orange-colored product was collected, washed with H 2 O (2 x 100 mL) and dried in a desiccator. It was coated onto SiO 2 (30 g) from DMF and flash chromatographed on SiO 2 (400 g) using 5% Et 3 N, 10% MeOH, 85% CH 2 Cl 2 as the eluant.
  • N-(p-toluenesulfonyl)morpholine 55, 10.00 g, 41 mmol
  • CCl 4 CCl 4
  • N- bromosuccinimide 8.85 g, 49 mmol 1.2 eq
  • the organic phase was extracted with H 2 O (400 mL), dried, and evaporated to give the crude product as a beige solid which was used without purification (14 g). It contained about 50% desired monobromide by TLC (SiO 2 -50% EtOAc in hexane).
  • chlorformamidine hydrochloride (0.08 g, 0.7 mmol, 0.5 eq) was added. At 1 h 40 min, the mixture was cooled, and the diglyme layer was decanted from the brown resin which had formed. The resin was dissolved in DMF (4.5 mL), treated with Et 3 N (0.97 mL, 7 mmol, 5 eq), poured into H 2 O (50 mL), and extracted with EtOAc (25 mL). Saturated brine (50 mL) was added to the aqueous layer and it was extracted once more with EtOAc (25 mL). The extracts were combined, dried, and evaporated to give an orange-colored oil which was
  • the resin was dissolved in EtOH (30 mL), treated with N,N-diisopropylethylamine (0.69 mL, 4 mmol, 4 eq), poured into saturated brine (175 mL), and extracted with EtOAc (2 x 30 mL). The combined extracts were dried and coated onto basic alumina (2 g). Chromatography on basic alumina (40 g) with 10% MeOH in CH 2 Cl 2 as eluant gave the product as an orange-colored solid (40 mg, 9.2%), mp 272- 274°C.
  • Method B A mixture of 2-amino-5-(N-(4-((4- fluorophenyl) sulfonyl)benzyl)methylamino)benzonitrile (1.98 g, 5 mmol), pyridine hydrochloride (3.47 g, 30 mmol, 6 eq), and cyanamide (0.84 g, 20 mmol, 4 eq), was heated at 165°C to give a brown melt which spontaneously resolidified after 5 min. The mixture was immediately cooled, and the solid was broken up and triturated with boiling EtOH (25 mL), treated give a brown melt which spontaneously resolidified after 5 min.
  • methylamino)benzonitrile (23.3 g, 54.6 mmol) and diglyme (100 mL) were stirred at about 70°C for 20 min.
  • Chlorformamidine hydrochloride (7.5 g, 65.5 mmol, 1.2 eq) was then added in portions during 15 min.
  • the resulting mixture was heated at 150°C for 1.5 h with occasional manual stirring with a glass rod.
  • the cooled mixture was triturated with Et2 ⁇ (2 x 100 mL).
  • the ether was decanted, and the remaining solid was dissolved in a warm water mixture of DMF (260 mL) and Et 3 N (26 mL). The resulting solution was treated with charcoal and filtered.
  • 4-((2-Naphthyl)sulfonyl)toluene (88) was prepared by the method of B. Graybill [J. Org. Chem. 32, 2931, (1967)]: 2- Naphthalene sulfonic acid, 70% (120 g, 0.40 mol), toluene (80 mL, 69 g, 0.75 mol, 1.3 eq.), and polyphosphoric acid (1 Kg) were placed in a flanged reaction kettle with mechanical stirring and heated at 80°C for 16 h. The mixture was removed from the heat and poured into ice-water (2 L) and stirred until it attained ambient temperature.
  • Methyl dithiocarbamate was prepared by a published method [J. von Braun, Berichte Deutschen Chemischen
  • Trifluoroacetic anhydride (0.59 mL, 4.16 mmol, 1.leq) was added dropwise during 15 min to a stirred solution of 2- amino-5-methylbenzonitrile (111, 500 mg, 3.78 mmol) and Et 3 N (0.58 mL, 4.2 mmol, 1.leq) in CH 2 Cl 2 (5 mL) in an ice bath. The resulting mixture was then stirred at 25°C for 30 min. It was treated with 1N HCl (5 mL) to give pH ⁇ 2.
  • the toluene 112 (13.11 g, 57.5 mmol) was dissolved in warm benzene (50 mL). H 2 O (25 mL) was added, and the mixture was brought to reflux. A 200 watt light was shone on it, and a solution of bromine (3.26 mL. 63.2 mmol, 1.leq) in benzene (25 mL) was added dropwise during 45 min at a rate that maintained an orange-red color. The organic layer was separated, dried, and evaporated to give a pale yellow, feathery, crystalline solid which was dried in vacuo over P 2 O 5 (13.92 g) It was used without further purification.
  • cyanamide (44 mg, 1.05 mmol. 4 eq) was homogenized with a glass rod in a 25 mL round bottom flask, which was then immersed in a 165°C oil bath for 5 min. A melt resulted which was cooled to room temperature, whereupon it became a sludge.
  • EtOH (5 mL) was added, and the mixture was heated to boiling while being worked with a glass rod.
  • Et 3 N (0.29 mL, 2.10 mmol, 8 eq) was then added, and the mixture boiled further; a yellow precipitate formed. The mixture was cooled and put on ice.
  • Each diaminoquinazoline was prepared by heating a
  • Glucuronic acid (32.8 g, 169 mmol, 5 eq) was dissolved in boiling MeOH (1 L), and to it was added 2,4-diamino-6-(N- (4-(phenylsulfonyl)benzyl)methylamino)quinazoline (22, 14.2 g, 33.8 mmol).
  • the resulting solution was immediately hot filtered to remove traces of entrained matter, and the filtrate was boiled for 10 min to reduce its volume to about 820 mL, whereupon the first trace of product, a fluffy solid, started to appear.
  • the mixture was removed from heat, cooled slowly, and kept for 10 days at 25°C to fully crystallize.
  • Glucuronate salts were prepared by dissolving glucuronic acid (5 mol eq) in boiling MeOH to give a solution to which was added the free base ( 1 mol eq). The resulting hot solution was immediately filtered to remove trace particulate matter, and the filtrate was allowed to cool to room
  • the glucuronate 130 was prepared by dissolving the glucuronic acid (5 eq) in boiling MeOH followed by
  • the glucuronate 134 was precipitated with Et 2 O (450 mL), collected, and washed with Et 2 O (250 mL).
  • the filtrate was evaporated down to a volume of 200 mL, and Et 2 O (200 mL) was added to precipitate a second crop which was collected and washed with Et 2 O (150 mL).
  • Et 2 O 200 mL
  • the second filtrate deposited a third crop which was filtered off and washed with Et 2 O (100 mL).
  • Thymidylate synthase activity was measured using a modification of the tritium release method of Lomax and
  • dUMP 2'-deoxyuridine 5'- monophosphate
  • coli TS and 60 ng for human TS).
  • Assays of human TS also contained 1-5 ⁇ g/ mL bovine serum albumin to stabilize the protein. Reactions were initiated by the addition of enzyme and were carried out for 5 minutes at 24°C, and then quenched by the addition of charcoal (15 mg in 0.1 mL H 2 O). The quenched samples were centrifuged at 10,000 rpm for 12-15 min at 40°C to remove unreacted dUMP which had bound to the charcoal, and 0.1 mL of the supernatant was counted by liquid scintillation in the presence of 5 mL ecolume to determine the release of tritium label from the 5-position of the dUMP.
  • DHFR inhibition constants were determined using purified human recombinant enzyme at 25°C. All reaction mixtures contained 50 ⁇ M Tris at pH 7.5, 60 ⁇ M NADPH (nicotinamide adenine dinucleotide, reduced form).
  • Reaction mixtures containing DHFR, were preincubated for 2 min in the presence of inhibitor before initiation by
  • DHF concentration of DHF was 50 ⁇ M(s).
  • a time course was monitored for each inhibitor concentration to determine the maximum steady state reaction rate after
  • Rate measurements for at least eight inhibitor concentrations were used in each K i determination.
  • K i slope K i , app / (1 + s/K m )
  • lymphoblastic leukemia line of T-cell origin ATCC CCL 119
  • 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% (L1210, CCRF- CEM) or 10% (GC 3 /M TK-) heat-inactivated fetal bovine serum without antibiotics.
  • IC 50 values were determined in 150 ⁇ L microcultures each containing 1500 (L1210) or 10,000 (CCRF-CEM, GCg/M TK-) cells established in 96 well plates in growth medium

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Abstract

On décrit certains composés de quinazoline pouvant inhiber les voies métaboliques des folates, des compositions pharmaceutiques les contenant, et leur utilisation dans l'inhibition des voies métaboliques des folates, notamment tous les effets dérivés de l'inhibition des voies métaboliques des folates. Les effets dérivés de l'inhibition des voies métaboliques des folates sont notamment l'inhibition de la croissance et de la prolifération des cellules des organismes supérieurs et des microorganismes, par exemple les bactéries, les levures et les champignons. Ces effets comprennent éventuellement l'inhibition des enzymes thymidylate-synthase et/ou dihydrofolate-réductase. On a également prévu un procédé de préparation de ces composés anti-folates de quinazoline.
PCT/US1992/010730 1991-12-20 1992-12-16 Quinazolines anti-folates WO1993013079A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
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EP0797980A1 (fr) * 1996-03-29 1997-10-01 Wella Aktiengesellschaft Composition de teinture d'oxydation des fibres kératiniques comprenant un 2,5-diaminobenzonitrile ainsi que dérivés de 2,5-diaminobenzonitrile
WO2000071160A1 (fr) * 1999-05-24 2000-11-30 Sankyo Company, Limited Compositions medicinales contenant un anticorps anti-fas
WO2001004087A1 (fr) * 1999-07-13 2001-01-18 Eli Lilly And Company Limited Derives benzylamine substitues de sulfonamides et leur utilisation comme medicaments
JP2007532625A (ja) * 2004-04-13 2007-11-15 セファロン インコーポレイティド チオ置換アリールメタンスルフィニル誘導体
US7829708B2 (en) 2004-09-08 2010-11-09 Chelsea Therapeutics, Inc. Metabolically inert antifolates for treating disorders of abnormal cellular proliferation and inflammation
US20110009369A1 (en) * 2008-02-05 2011-01-13 British Columbia Cancer Agency Branch Anti-influenza compounds
US7951812B2 (en) 2007-01-19 2011-05-31 Chelsea Therapeutics, Inc. Substituted pyrrolo[2,3-d]pyrimidines as antifolates
WO2011121309A1 (fr) 2010-03-31 2011-10-06 Takeda Pharmaceutical Company Limited Dérivés phénylsulfonyle et leur utilisation comme antagonistes de l'histamine h3
US8530653B2 (en) 2009-11-06 2013-09-10 Chelsea Therapeutics, Inc. Enzyme inhibiting compounds
US8658652B2 (en) 2010-12-07 2014-02-25 Chelsea Therapeutics, Inc. Antifolate combinations
WO2021078995A1 (fr) 2019-10-25 2021-04-29 Umc Utrecht Holding B.V. Composé et test de blocage de la synthèse de polypeptides sélectif

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US4857530A (en) * 1987-11-03 1989-08-15 Warner-Lambert Company Substituted quinazolinones as anticancer agents
EP0373891A2 (fr) * 1988-12-15 1990-06-20 Imperial Chemical Industries Plc Agents antitumoraux

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EP0373891A2 (fr) * 1988-12-15 1990-06-20 Imperial Chemical Industries Plc Agents antitumoraux

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CHEMICAL ABSTRACTS, vol. 110, no. 5, 30 January 1989, Columbus, Ohio, US; abstract no. 33336g, YAN 'Antitumor effects of 66 quinazolines and pyrimidines in vitro.' *
CHEMICAL ABSTRACTS, vol. 111, no. 11, 11 September 1989, Columbus, Ohio, US; abstract no. 97177j, ZHOU 'Synthesis and antimalarial and antitumor activities of 2,4-diamino-6-(ben zylmethylamino)quinazolines.' page 738 ;column 2 ; *
CHEMICAL ABSTRACTS, vol. 115, no. 5, 5 August 1991, Columbus, Ohio, US; abstract no. 50236v, MARSHAM 'Quinazoline antifolate thymidylate synthase inhibitors' page 907 ;column 2 ; *
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J.MED.CHEM. vol. 15, no. 11, 1972, pages 1138 - 46 ELSLAGER ET AL 'Folate Antagonists' Tables I and II: many compounds only excluded by provisos a)-c). *
J.MED.CHEM. vol. 15, no. 8, 1972, pages 812 - 826 DAVOLL ET AL 'Folate Antagonists' Formula Vi, examples 49-53,77 *
J.MED.CHEM. vol. 17, no. 9, 1974, pages 943 - 47 RICHTER ET AL 'Inhibition of Mammalian Dihydrofolate Reductase by selected 2,4-Diaminoquinazolines and Related Compounds.' Table I: many compounds only excluded by the provisos. *
J.MED.CHEM. vol. 20, no. 1, 1977, pages 96 - 102 HANSCH ET AL 'Quantitative Structure-Activity Relationships of Antimalarial and Dihydrofolate Reductase Inhibition by Quinazolines and 5-Substituted Benzyl-2,4,-diaminopyridines.' Table 1, i.a. examples 17,22-24,31,32 *
J.MED.CHEM. vol. 21, no. 7, 1978, pages 639 - 43 ELSLAGER ET AL 'Folate Antagonists.' Ia-Ic only excluded by provisos. *
J.MED.CHEM. vol. 22, no. 5, 1979, pages 483 - 91 CHEN ET AL 'Multivirate Analysis and Quantitative Structure-Activity Relationships.' Table I; i.a. examples 41-48 *
J.MED.CHEM. vol. 24, no. 2, 1981, pages 127 - 140 ELSLAGER ET AL 'Synthesis and Antimalarial Effects of N2-Aryl-N4-Ä(dialkylamino)alkylÜ- and N4-A ryl-N2-Ä(dialkylamino)alkyl]-2,4-quinazoli nediamines.' VIIa, example 73 *
J.MED.CHEM. vol. 31, no. 2, 1988, pages 449 - 454 HYNES ET AL 'Inhibition of Murine Thymidylate Synthase and Human Dihydrofolate Reductase by 5,8-Dideaza analagues of Folic Acid and Aminopterin.' Examples 2a-c, 3a-e,4a-e *
J.MED.CHEM. vol. 32, no. 7, 1989, pages 1559 - 1565 PATIL ET AL 'Inhibition of Mammalian Folylpolyglutamate Synthetase and Human Dihydrofolate Reductase by5,8-Dideaza Analogues of Folic Acid and Aminopterin Bearing a Terminal L-Ornithine.' 2a,3a *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0797980A1 (fr) * 1996-03-29 1997-10-01 Wella Aktiengesellschaft Composition de teinture d'oxydation des fibres kératiniques comprenant un 2,5-diaminobenzonitrile ainsi que dérivés de 2,5-diaminobenzonitrile
US5865856A (en) * 1996-03-29 1999-02-02 Wella Aktiengesellschaft 2, 5-diaminobenzonitrile compounds and oxidation hair dye compositions containing same
WO2000071160A1 (fr) * 1999-05-24 2000-11-30 Sankyo Company, Limited Compositions medicinales contenant un anticorps anti-fas
US6746673B2 (en) 1999-05-24 2004-06-08 Sankyo Company, Limited Pharmaceutical compositions containing anti-Fas antibody
WO2001004087A1 (fr) * 1999-07-13 2001-01-18 Eli Lilly And Company Limited Derives benzylamine substitues de sulfonamides et leur utilisation comme medicaments
JP2007532625A (ja) * 2004-04-13 2007-11-15 セファロン インコーポレイティド チオ置換アリールメタンスルフィニル誘導体
US7829708B2 (en) 2004-09-08 2010-11-09 Chelsea Therapeutics, Inc. Metabolically inert antifolates for treating disorders of abnormal cellular proliferation and inflammation
US7951812B2 (en) 2007-01-19 2011-05-31 Chelsea Therapeutics, Inc. Substituted pyrrolo[2,3-d]pyrimidines as antifolates
US20110009369A1 (en) * 2008-02-05 2011-01-13 British Columbia Cancer Agency Branch Anti-influenza compounds
US8673884B2 (en) * 2008-02-05 2014-03-18 Versitech Limited Anti-influenza compounds
US8530653B2 (en) 2009-11-06 2013-09-10 Chelsea Therapeutics, Inc. Enzyme inhibiting compounds
WO2011121309A1 (fr) 2010-03-31 2011-10-06 Takeda Pharmaceutical Company Limited Dérivés phénylsulfonyle et leur utilisation comme antagonistes de l'histamine h3
US8658652B2 (en) 2010-12-07 2014-02-25 Chelsea Therapeutics, Inc. Antifolate combinations
WO2021078995A1 (fr) 2019-10-25 2021-04-29 Umc Utrecht Holding B.V. Composé et test de blocage de la synthèse de polypeptides sélectif

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