WO2000009131A1 - Diaminopyrimidines et polytherapies pour traiter efficacement les cancers positifs pour la glycoproteine p - Google Patents

Diaminopyrimidines et polytherapies pour traiter efficacement les cancers positifs pour la glycoproteine p Download PDF

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WO2000009131A1
WO2000009131A1 PCT/US1999/013669 US9913669W WO0009131A1 WO 2000009131 A1 WO2000009131 A1 WO 2000009131A1 US 9913669 W US9913669 W US 9913669W WO 0009131 A1 WO0009131 A1 WO 0009131A1
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methyl
γçö
diamino
piperazinyl
phenyl
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PCT/US1999/013669
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English (en)
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David Allen Berry
Ellen Myra Dobrusin
Judith Lynne Johnson Philipsen
Wayne Daniel Klohs
Dennis Joseph Mc Namara
Leslie Morton Werbel
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Warner-Lambert Company
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Priority to AU46909/99A priority Critical patent/AU4690999A/en
Publication of WO2000009131A1 publication Critical patent/WO2000009131A1/fr

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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • MDR multidrug resistance
  • the present invention provides combination therapies including diaminopyrimidines that overcome P-glycoprotein-induced multidrug resistance in P-glycoprotein positive tumors both in vitro and in vivo. Also provided are pharmaceutical compositions and a method of treating cancer.
  • Trimetrexate which is a lipophilic antifolate, does not use the reduced folate transport system for uptake and is not polyglutamylated. It has been demonstrated that in contrast to LV/FU/MTX, the three drug combination of LV/FU/TMQ demonstrated a high level of synergistic activity against a human lymphocytic leukemia cell line in vitro. Based on these observations, several clinical trials have been initiated in colon cancer with LV/FU/TMQ. In fact, it has been recently reported that the addition of TMQ to LV/FU resulted in a 20% response rate in colon cancer patients previously treated with FU. It was also recently reported that the combination of TMQ, FU and LV resulted in a 50% response rate in metastatic colorectal cancer patients.
  • LV potentiates FU cytotoxicity in vitro by increasing intracellular levels of N5,N ⁇ . me thylenetetrahydro folate and its polyglutamates and thereby stimulating and prolonging fluorodeoxyuridine monophosphate
  • TMQ or MTX inhibit dihydrofolate reductase which blocks purine biosynthesis and in turn, results in increased levels of phosphoribosyl pyrophosphate (PRPP).
  • PRPP phosphoribosyl pyrophosphate
  • TMQ or MTX inhibition of dihydrofolate reductase leads to the partial depletion of existing N5,Nl0-methylenetetrahydro folate pools, resulting in increased levels of dihydrofolate polyglutamates, which in turn are also able to form potent complexes with TS and FdUMP.
  • the addition of TMQ to LV/FU chemotherapy regime to treat colorectal cancer suffers from one major drawback: almost 85% of all colorectal cancers overexpress P-glycoprotein, a transport protein found on the cell surface of many cancers that rapidly transports many anticancer agents including TMQ out of the cancer cell before it can exert any cytotoxic effect.
  • TMQ's effect with LV/FU is likely limited to those few colon cancers that do not express P-glycoprotein. New methods of treating cancer are desired.
  • the compounds are disclosed to have antibacterial and antitumor activity.
  • the present invention provides a method of treating cancer, the method comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
  • Rj is hydrogen or alkyl of from one to six carbon atoms
  • R2 and R3 are independently hydrogen or methyl
  • R4 and R5 are independently: hydrogen; halogen; nitro; cyano; trifluoromethyl; hydroxyl; alkyl of from one to six carbon atoms; alkoxyl of from one to six carbon atoms; alkanoyl of from one to six carbon atoms; -NR5R7, where R5 and R7 are independently hydrogen, alkyl of from one to six carbon atoms, alkanoyl of from one to six carbon atoms; -COORg where Rg is hydrogen, a pharmaceutically acceptable metal cation, a pharmaceutically acceptable amine cation, alkyl of from one to six carbon atoms; -CONR9R10 where R9 and RJ Q are independently hydrogen, alkyl of from one to six carbon atoms, alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups, alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups and one -OH, -SH, or -
  • R ⁇ ⁇ is hydrogen, or alkyl of from one to six carbon
  • R12 is hydroxyl, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or -NR ⁇ 3R14 where R ⁇ 3 and R14 are independently hydrogen or alkyl of from one to six carbon atoms; and the pharmaceutically acceptable salts thereof.
  • the present invention also provides a method of treating cancer, the method comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
  • Rj is hydrogen or alkyl of from one to six carbon atoms
  • R2 and R3 are independently hydrogen or methyl
  • R4 and R5 are independently: hydrogen, halogen, nitro, cyano, trifluoromethyl, hydroxyl, alkyl of from one to six carbon atoms, alkoxyl of from one to six carbon atoms, alkanoyl of from one to six carbon atoms;
  • Rg and R7 are independently hydrogen, alkyl of from one to six carbon atoms, alkanoyl of from one to six carbon atoms; -COORg where Rg is hydrogen, a pharmaceutically acceptable metal cation, a pharmaceutically acceptable amine cation, alkyl of from one to six carbon atoms; -CONR9R10 where R9 and RJ Q are independently hydrogen, alkyl of from one to six carbon atoms, alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups, alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups and one -OH, -SH, or -NH2 group, alkyl of from one to six carbon atoms, substituted with one or two carboalkoxy groups of from one to six carbon atoms, alkyl of from one to six carbon atoms, substituted with one or two carboalkoxy groups of from one to six carbon atoms and one
  • R j j is hydrogen, or alkyl of from one to six carbon
  • R12 is hydroxyl, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or
  • R13 and R14 are independently hydrogen or alkyl of from one to six carbon atoms; and the pharmaceutically acceptable salts thereof.
  • the cancer is colorectal cancer.
  • the thymidylate synthase inhibitor is 2-( ⁇ 5-[Methyl-(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)- amino]-thiophene-2-carbonyl ⁇ -amino)-pentanedioic acid.
  • the thymidylate synthase inhibitor is:
  • the cancer is a P-glycoprotein positive cancer. Also provided are compounds having Formula II
  • n is independently 0 to 6; R a and R D are independently hydrogen or C1-C5 alkyl;
  • R 1 is Cj -C ⁇ alkyl or ;
  • R2 and R- are independently hydrogen, -Cj-C6 alkyl, -CH2OH, or -OH;
  • R4 is hydrogen
  • R 5 is (CH 2 )— OH, (CH 2 ) n NH 2 ,
  • R a and R D are independently hydrogen or methyl.
  • Rl is methyl.
  • R ⁇ and R are hydrogen.
  • R a and R D are independently hydrogen or methyl
  • R2 and R ⁇ are hydrogen; and R4 is hydrogen.
  • the present invention provides the compounds:
  • Benzaldehyde 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-l-piperazinyl]-, [2-[(2-hydroxyethyl)amino]ethyl]hydrazone, methanesulfonate; Ethanone, 1 -[4-(2,4-diamino-6-methyl-5-pyrimidinyl)- l-piperazinyl]phenyl]-, oxime, monohydrochloride; l - ⁇ 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-l-yl]-phenyl ⁇ - ethanone O-(2-amino-ethyl)-oxime, hydrochloride; 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-l-yl]-benzaldehyde
  • a compound of Formula II 3) a compound of Formula II. Also provided is a method of treating cancer, the method comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
  • the cancer is colorectal cancer.
  • the thymidylate synthase inhibitor is 2-( ⁇ 5-[Methyl-(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)- amino]-thiophene-2-carbonyl ⁇ -amino)-pentanedioic acid.
  • the thymidylate synthase inhibitor is:
  • the cancer is a P-glycoprotein positive cancer.
  • composition that comprises a compound of Formula II.
  • each R a and R D are independently hydrogen, ⁇ -C alkyl or CRl, or C ⁇ -C cycloalkyl; each n is independently 0 to 5;
  • R 1 is hydrogen, C1-C6 alkyl, or -NR R b ;
  • R2 and R ⁇ are independently hydrogen, Ci -C5 alkyl, -CH2OH, or -OH;
  • R 4 is hydrogen, halogen, Cj-C ⁇ alkyl, -NO , -CN. CF , -OH, -OC ⁇ -C 6 alkyl,
  • R 5 is hydrogen, CO 2 R a , — SR a , — CH ,
  • a method of treating cancer comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
  • each R a and R b are independently hydrogen, C1-C alkyl, CRl , or Cj-Cg cycloalkyl; each n is independently 0 to 5;
  • R 1 is hydrogen Ci-Cg alkyl, or -NR R b ;
  • R2 and R ⁇ are independently hydrogen, Cj-Cg alkyl, -CH2OH, or -OH;
  • R 4 is hydrogen, halogen, C1-C6 alkyl, -NO 2 , -CN, CF 3 , -OH, -OC!-C 6 alkyl, ⁇
  • R is hydrogen, -CO 2 R a H
  • the cancer is colorectal cancer.
  • the thymidylate synthase inhibitor is 2-( ⁇ 5-[Methyl-(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-amino]- thiophene-2-carbonyl ⁇ -amino)-pentanedioic acid.
  • the thymidylate synthase inhibitor is:
  • the cancer is a P-glycoprotein positive cancer.
  • alkyl means a straight or branched hydrocarbon having from
  • 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • the alkyl group can also be substituted with one or more of the substituents listed below for aryl.
  • cycloalkyl means a saturated hydrocarbon ring which contains from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • aryl means an aromatic ring which is a phenyl, 5-fluorenyl,
  • 1-naphthyl, or 2-naphthyl group unsubstituted or substituted by 1 to 3 substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, F, -CN, Cl, Br, I, CF 3 , NO ,
  • heteroaryl means an aromatic ring containing one or more heteroatoms.
  • heteroaryl radicals include thienyl, furanyl, pyrrolyl, pyridyl, imidazoyl, or indolyl group, substituted or unsubstituted by 1 or
  • heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.
  • patient means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
  • a “therapeutically effective amount” is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of cancer.
  • a therapeutically effective amount of a compound of the present invention can be easily determined by one skilled in the art by administering a quantity of a compound to a patient and observing the result. In addition, those skilled in the art are familiar with identifying patients having cancer.
  • cancer includes, but is not limited to, the following cancers: breast; ovary; cervix; pro state; testis; esophagus; glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma; bone; colon, adenocarcinoma, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkins disease, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum, large intestine, rectum; brain and central nervous system; and leukemia.
  • Preferred cancers that can be treated by the present invention include colorectal, breast, colon, rectal, gastric, pancreatic, and liver cancer.
  • a more preferred cancer to be treated is colorectal cancer.
  • the cancer is a P-glycoprotein positive cancer.
  • P-glycoprotein positive cancer means cancers that overexpress the drug resistance protein, P-glycoprotein.
  • P-glycoprotein positive cancers show the property of multidrug resistance.
  • One skilled in the art can determine if a cancer is P-glycoprotein positive by standard immunohistochemistry techniques using commercially available antibodies to P-glycoprotein.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See, for example, Berge S.M. et al., "Pharmaceutical Salts," J Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
  • Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include Ci -Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C]-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Ci -C6 alkyl amines and secondary Ci -Cg dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 -C3 alkyl primary amines and
  • C1-C2 dialkyl secondary amines are preferred.
  • Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
  • the compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art.
  • the compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
  • humectants as for example, glycerol;
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • solution retarders as for example paraffin;
  • absorption accelerators as for example, quaternary ammonium compounds;
  • wetting agents such as sodium citrate or dicalcium phosphate
  • lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the combination therapies of the present invention can be administered to a patient in a number of ways.
  • the different therapeutic agents can be given in a single dosage form such as together in a tablet, or in separate dosage forms, such as each agent in a separate tablet.
  • a therapeutic agent may be given a certain time prior to the other agents.
  • the thymidylate synthase inhibitor may be given before a compound of Formula I or Formula II.
  • the administration of the therapeutic agent should be optimized so that the combination of agents is delivered to the cancer cells so that a synergistic cytotoxic effect is accomplished.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day.
  • dosage levels in the range of about 0.1 to about 2,000 mg per day.
  • a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable.
  • the specific dosage used can vary.
  • the dosage can depended on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
  • the compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the mixture turned from a yellow solid suspension into a white solid suspension. After 20 minutes of reflux, the mixture thickened and was allowed to cool to room temperature. The mixture was further cooled in the refrigerator then filtered, washing with small portions of anhydrous ethanol, to obtain a white sticky solid. The solid was transferred to a vial and placed in an oven under vacuum overnight. To the resulting solid was added 10 mL water and 10 mL dichloromethane, and the pH of the aqueous layer was adjusted to pH 8 using 0.1 M NaOH. The aqueous layer was separated, and the cloudy organic portion was washed with brine.
  • the compounds of the present invention comprise a series of diaminopyrimidines that, like TMQ, inhibit dihydrofolate reductase (see Table 1 for selected examples) and that overcome P-glycoprotein-induced MDR in a variety of P-glycoprotein positive tumors both in vitro and in vivo (see Table 2 for selected examples).
  • TMQ dihydrofolate reductase
  • these compounds are as active in vitro against P-glycoprotein positive P388/ADR leukemia cells as they are in the parent P388S cells that do not express P-glycoprotein.
  • A-E represent the following compounds:
  • P388S and P388/ADR cells were cultured in RPMI-1640 media supplemented with 10%> horse serum and 10 ⁇ M 2-mercaptoethanol.
  • HT29 cells were cultured in Dulbecco's MEM (DMEM) media supplemented with 10% dialyzed fetal calf serum.
  • C26 cells were cultured in DMEM/F12 media supplemented with 10% dialyzed fetal calf serum.
  • DMEM Dulbecco's MEM
  • C26 cells were cultured in DMEM/F12 media supplemented with 10% dialyzed fetal calf serum.
  • LV was added for the final 4.5 hours, and FU was added for the final 4 hours of the 24-hour incubation period. Cells were then washed three times in drug-free media and incubated for 2 to 4 days in drug free media.
  • the effect of antifolates ⁇ LV and FU was determined by sulphorhodamine B method as previously described (Skehan PL, Storeng R., Scudiero D., et al., Evaluation of colorimetric protein and biomass stains for assaying in vitro drug effects upon human tumor cell lines. Proc. Am. Assoc. Cancer Res., 1989;30:612). The results are shown in Table 3.
  • P388/ADR were passed weekly in DBA/2 mice as i.p. implants of 10 ⁇ and
  • C26/clone 10 was passed every 2 weeks into Balb/c mice as tumor fragments (approximately 30 mg) which were obtained from tumors 1 g in mass. The results are shown in Table 2.
  • Colon 26/clone 10 (C26/10) life span studies were conducted in CD2Fj mice. C26/C10 cells were implanted i.p. on Day 0. Animals were treated i.p. with test agents in the vehicles described above on Days 3-7 and 10-14.
  • Adriamycin was dosed i.p. in saline on Days 5, 9, and 13. Calculations of the median day of death and %T/C were as described previously with animals surviving more than 60 days excluded from the calculations (Schabel et al., Quantitative evaluation of anti-cancer agent activity in experimental animals. Pharmacol. Ther., 1977;1 :411-435; Leopold et al., Anthrapyrazoles, a new class of intercalating agents with high-level broad spectrum activity against murine tumors. Cancer Res., 1985;45:5532-5539; Elliot et al.. Sequence and schedule dependent synergy of trimetrexate in combination with 5 fiuorouracil in vitro and in mice. Cancer Res., 1984;49:5586-5640). Percent T/C values in excess of 130 are indicative of an antitumor effect in this model. The results are shown in
  • Anticancer agents such as TMQ or Adriamycin, which are substrates for P-glycoprotein, were inactive against P388/ADR tumors in vivo.
  • TMQ murine Colon 26
  • C26 murine Colon 26
  • C26 expresses P-glycoprotein, but not to nearly the extent as P388/ADR cells, and in this regard may be more clinically relevant to the levels of P-glycoprotein expressed in human colon cancer.
  • diaminopyrimidines demonstrated significant activity against in vivo C26 colon tumors (Table 2).
  • Example 1 was actually curative against this P-glycoprotein positive colon tumor.
  • TMQ was without activity against C26 (T/C x 100> 130 represents in vivo antitumor activity). The results are shown in Table 2.
  • Example 12 90 100 97 20 16
  • Example 1 1 90 77 80 48 16
  • LV 10 ⁇ M
  • 5 ⁇ M FU was added for the final 4 hours of the 24-hour incubation.
  • TMQ concentration 10 nM.
  • Other antifolate concentration was 1 nM.

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Abstract

La présente invention concerne des composés de formule (II). L'invention concerne également un procédé pour traiter le cancer à l'aide d'une combinaison de 5-fluorouracil, de leucovorine, et d'un composé de formule (I) ou (II), ou d'une combinaison d'un inhibiteur de thymidylate synthase comme composé de formule (I) ou (II).
PCT/US1999/013669 1998-08-13 1999-06-18 Diaminopyrimidines et polytherapies pour traiter efficacement les cancers positifs pour la glycoproteine p WO2000009131A1 (fr)

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DE102012200333A1 (de) 2012-01-11 2013-07-11 Henkel Ag & Co. Kgaa Acylhydrazone als bleichverstärkende Wirkstoffe
US8501242B2 (en) 2009-05-29 2013-08-06 University Of Florida Research Foundation Methods and compositions for treating neoplasia
WO2017136556A1 (fr) * 2016-02-05 2017-08-10 Turing Pharmaceuticals Llc Compositions et méthodes de traitement d'infections bactériennes
WO2019032458A1 (fr) * 2017-08-07 2019-02-14 Vyera Pharmaceuticals, LLC Inhibiteurs de dhfr, compositions et procédés associés

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US8501242B2 (en) 2009-05-29 2013-08-06 University Of Florida Research Foundation Methods and compositions for treating neoplasia
DE102012200333A1 (de) 2012-01-11 2013-07-11 Henkel Ag & Co. Kgaa Acylhydrazone als bleichverstärkende Wirkstoffe
WO2013104631A1 (fr) 2012-01-11 2013-07-18 Henkel Ag & Co. Kgaa Acylhydrazones utilisées comme renforçateurs de blanchiment
WO2017136556A1 (fr) * 2016-02-05 2017-08-10 Turing Pharmaceuticals Llc Compositions et méthodes de traitement d'infections bactériennes
CN109071486A (zh) * 2016-02-05 2018-12-21 维耶拉制药有限责任公司 用于治疗感染的组合物和方法
US20190077794A1 (en) * 2016-02-05 2019-03-14 Vyera Pharmaceuticals, LLC Compositions and methods for treating infections
US10774073B2 (en) 2016-02-05 2020-09-15 Vyera Pharmaceuticals, LLC Compositions and methods for treating infections
AU2017213824B2 (en) * 2016-02-05 2021-11-18 Vyera Pharmaceuticals, LLC Compositions and methods for treating infections
AU2017213824B9 (en) * 2016-02-05 2021-11-25 Vyera Pharmaceuticals, LLC Compositions and methods for treating infections
US11530198B2 (en) 2016-02-05 2022-12-20 Vyera Pharmaceuticals, LLC Compositions and methods for treating infections
WO2019032458A1 (fr) * 2017-08-07 2019-02-14 Vyera Pharmaceuticals, LLC Inhibiteurs de dhfr, compositions et procédés associés

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