WO2008056149A1 - Dérivés de la quinazoline et compositions pharmaceutiques les contenant - Google Patents

Dérivés de la quinazoline et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO2008056149A1
WO2008056149A1 PCT/GB2007/004264 GB2007004264W WO2008056149A1 WO 2008056149 A1 WO2008056149 A1 WO 2008056149A1 GB 2007004264 W GB2007004264 W GB 2007004264W WO 2008056149 A1 WO2008056149 A1 WO 2008056149A1
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WO
WIPO (PCT)
Prior art keywords
infection
pharmaceutically acceptable
derivative
acceptable salt
use according
Prior art date
Application number
PCT/GB2007/004264
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English (en)
Inventor
Surinder Chana
Original Assignee
Arrow Therapeutics Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Arrow Therapeutics Limited filed Critical Arrow Therapeutics Limited
Publication of WO2008056149A1 publication Critical patent/WO2008056149A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to specific quinazoline derivatives which are useful in treating or preventing a flaviviridae infection and which have enhanced permeability, absorption and bioavailability.
  • Viruses of the family flaviviridae are small, icosahedral, enveloped viruses that contain a positive-sense RNA genome.
  • the family consists of three genera, flavivirus, pestivirus and hepacivirus.
  • Many of the flaviviridae viruses are important human pathogens.
  • the hepacivirus genus includes the hepatitis C virus. Compounds active against flaviviridae infections are therefore of potential significant therapeutic benefit.
  • MDCK Mandin Darby Canine Kidney
  • WO 2005/105761 discloses lipophilic 6-heteroaryl and 6-aryl quinazolines. Many such compounds have low Papp values (e.g. Papp ⁇ 5), which can translate into poor exposure and variable pharmacokinetic profiles in animal studies. However, surprisingly, the introduction of an appropriate substituent ortho to the anilino-quinazoline nitrogen atom in specific 6-thiazolyl quinazoline compounds consistently increases the Papp value 7-fold or higher and hence the compounds are likely to be more extensively and/or more rapidly absorbed.
  • the present invention therefore provides a quinazoline derivative of formula (I), or a pharmaceutically acceptable salt thereof,
  • R represents C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • R represents a methyl, methoxy or ethoxy substituent.
  • Particularly preferred compounds of formula (I) are therefore: (2-methyl-4-morpholin-4-yl-phenyl)-(6-thiazol-2-yl-quinazolin-4-yl)-amine; (2-methoxy-4-morpholin-4-yl-phenyl)-(6-thiazol-2-yl-quinazolin-4-yl)-amine; (2-ethoxy-4-morpholin-4-yl-phenyl)-(6-thiazol-2-yl-quinzolin-4-yl)-amine; and pharmaceutically acceptable salts thereof.
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic o ⁇ p- toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines.
  • the starting materials in the above reaction schemes are known compounds, or can be prepared by analogy with known methods.
  • the compounds of the present invention are therapeutically useful.
  • the present invention therefore provides a quinazoline derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in treating the human or animal body.
  • composition comprising a quinazoline derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention.
  • Preferred pharmaceutical compositions are sterile and pyrogen free.
  • the compounds of the invention are active against a flaviviridae infection.
  • the present invention therefore provides the use of a quinazoline derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing a flaviviridae infection.
  • Also provided is a method for treating a patient suffering from or susceptible to a flaviviridae infection which method comprises administering to said patient an effective amount of a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof.
  • the flaviviridae family contains three genera. These are hepacivirus, fiavivirus and pestivirus.
  • the compounds of the invention are active in treating or preventing a hepacivirus infection, a fiavivirus infection or a pestivirus infection.
  • Typical pestivirus infections which can be treated with the compounds of the invention include bovine viral diarrhea virus, classical swine fever virus and border disease virus.
  • Typical fiavivirus infections which can be treated with the compounds of the invention include yellow fever virus, dengue fever virus, Japanese encephalitis virus and tick borne encephalitis virus.
  • Typical hepacivirus infections that can be treated with the compounds of the invention include hepatitis C virus.
  • Compounds of the present invention are especially active against hepatitis C.
  • said fiavivirus is therefore hepatitis C virus.
  • the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose,o corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.o
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the 5 active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • o Compounds of the present invention may be used in conjunction with known anti- viral agents.
  • Preferred known anti- viral agents in this regard are interferon and ribavirin, and derivatives thereof, which are known for the treatment of hepatitis C (Clinical Microbiology Reviews, 2000, 67-82).
  • the said medicament therefore typically further comprises interferon or a derivative thereof and/or ribavirin or a derivative thereof.
  • the present invention provides a pharmaceutical composition comprising:
  • interferon or a derivative thereof and/or ribavirin or a derivative thereof for separate, simultaneous or sequential use in the treatment of the human or animal body.
  • a preferred interferon derivative is PEG-interferon.
  • a preferred ribavirin derivative is viramidine.
  • a therapeutically effective amount of a compound of the invention is administered to a patient.
  • a typical dose is from about 0.01 to 100 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 0.05 to 16 mg per kg of body weight, more preferably, from 0.05 to 1.25 mg per kg of body weight.
  • Example 2 (N-(2-Methoxy-4-morpholinophenyl)-6-(thiazol-2-yl)quinazolin-4-amine Intermediate 3 (100 mg) and Intermediate 8 (89 mg) were combined in acetic acid (4 ml) and heated at 120 °C for 3h. Workup as for Example 1 gave the title compound (90 mg).
  • HCV replicon cells Huh 9B (ReBlikon), containing the firefly luciferase - ubiquitin - neomycin phosphotransferase fusion protein and EMCV-IRES driven HCV polyprotein with cell culture adaptive mutations.
  • Cells were cultured at 37 °C in a 5% CO 2 environment and split twice a week on seeding at 2 x 10E6 cells/flask on day 1 and 1 x 10E6 3 days later. Some 0.25 mg/ml G418 was added to the culture medium (125 ⁇ l per 25ml) but not to the assay medium.
  • the culture medium consisted of DMEM with 4500 g/1 glucose and glutamax (Gibco 61965-026) supplemented with 1 x non-essential amino acids, penicillin (100 IU/ml) / streptomycin (100 ⁇ g/ml), FCS (10%, 50 ml) and 1 mg/ml G418 (Invitrogen cat no 10131-027) and 10% foetal calf serum.
  • a flask of cells was trypsinised and a cell count carried out.
  • Cells were diluted to 100,000 cells/ml and 100 ⁇ l of this used to seed one opaque white 96-well plate (for the replicon assay) and one flat-bottomed clear plate (for the tox assay) for every seven compounds to be tested for IC50.
  • Wells G12 and H12 were left empty in the clear plate as the blank. Plates were then incubated at 37 0 C in a 5% CO 2 environment for 24h.
  • the cells in the white plate were harvested by washing with 200 ⁇ l/ well of warm (37 °C) PBS and lysed with 20 ⁇ l cell culture lysis buffer (Promega). After 5 min incubation at RT, luciferin solution was added to the luciferase assay buffer (LARB at 200 ⁇ l per 10 ml LARB).
  • the M injector of the microplate luminometer (Lmax, Molecular Devices) was primed with 4 x 300 ⁇ l injections. Plates were inserted into the luminometer and 100 ⁇ l luciferase assay reagent was added by the injector on the luminometer. The signal was measured using a 1 second delay followed by a 4 second measurement programme.
  • the IC50 the concentration of the drug required for reducing the replicon level by 50% in relation to the untreated cell control value, can be calculated from the plot of the percentage reduction of the luciferase activity vs. drug concentration.
  • the clear plate was stained with 100 ⁇ l 0.5% methylene blue in 50% ethanol at RT for Ih, followed by solvation of the absorbed methylene blue in 100 ⁇ l per well of 1% lauroylsarcosine. Absorbance of the plate was measured on a microplate spectrophotometer (Molecular Devices) and the absorbance for each concentration of compound expressed as a proportion of the relative DMSO control.
  • the TD50, the concentration of drug required to reduce the total cell area by 50% relative to the DMSO controls can be calculated by plotting the absorbance at 620 nm vs drug concentration.
  • the in vitro apical to basolateral permeability of the compounds was tested in a permeability assay using an MDCK cell line (ATCC Catalogue number: CCL-34, Passage number: 55, Lot number: 3563161). The integrity of the monolayers used in the assay is then checked with a Lucifer Yellow rejection assay.
  • Cells were grown in 75 cm 2 tissue culture flasks in an atmosphere of 5% (v/v) CO 2 in a 37 °C humidified incubator. Cells were passaged at 90% confluence by rinsing the flask with PBS, followed by a two-minute incubation with Versene, followed by a five to ten minute incubation with trypsin-EDTA. Detached cells were washed from the flask with growth medium. Cell number was estimated by counting using a heamocytometer slide. Cell suspensions were then diluted accordingly in growth medium.
  • cells were seeded in growth medium at 1 x 10 5 cells/cm 2 in a 24- well plate containing tissue culture treated inserts, and allowed to grow for 48h at 5% (v/v) CO 2 , 37 0 C in a humidified incubator. Growth medium was then renewed and cells allowed to grow a further 24h. On day 3, compounds were diluted to 10 ⁇ M in HBSS. Cells were washed three times with 500 ⁇ l HBSS and the inserts were transferred to the 24-well plate containing the 500 ⁇ l/well fresh HBSS.
  • Each compound dilution (500 ⁇ l) was then added in the inserts containing the cells, in duplicate, alongside a mix of control compounds (atenolol, dexamethasone and propranolol).
  • Final compound concentrations in the assay was 10 ⁇ M ; final DMSO concentration was 1% (v/v).
  • Cells were incubated for 2h at 5% (v/v) CO 2 , 37 0 C in a humidified incubator. The reaction was stopped by removing the inserts from the plate. Then, a 200 ⁇ l sample was taken from the inserts, and diluted 1 :2 with acetonitrile + 0.05% (v/v) formic acid, directly into the LC-MS analysis plate.
  • the Lucifer Yellow rejection was calculated using the following formula:
  • the % rejection is considered very good if between 98 and 100% and good if between 96 and 98%. A rejection below 96% suggests that the monolayers were likely compromised during the assay.
  • Bioavailability Rats were dosed orally at 5 mg/kg of compound as a suspension in 1% carboxymethyl cellulose (CMC) by gavage.
  • CMC carboxymethyl cellulose
  • the compounds were formulated in a mixture of DMSO and saline at 1 mg/mL with a dose volume of 1 mL/kg giving a 1 mg/kg dose.
  • Blood samples were taken over 24h; the plasma was separated by centrifugation and then extracted using protein precipitation. The compounds were measured using a highly specific LC-MS/MS analytical method and the data used to determine the area under the plasma concentration time profile, (AUCo - ⁇ ). Bioavailability was established by comparison of the dose normalised systemic exposure of the compounds following oral administration to that obtained from the intravenous route.
  • Table 2 shows the respective bioavailability figures for Example 1 and an analogue lacking the substitution ortho to the anilino-quinazoline nitrogen atom.

Abstract

La présente invention concerne des composés de formule (I) actifs dans l'inhibition de la réplication des virus flavivirus, où R représente alkyle C1-C4 ou alcoxy C1-C4.
PCT/GB2007/004264 2006-11-09 2007-11-08 Dérivés de la quinazoline et compositions pharmaceutiques les contenant WO2008056149A1 (fr)

Applications Claiming Priority (2)

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US85801906P 2006-11-09 2006-11-09
US60/858,019 2006-11-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101575319B (zh) * 2009-06-18 2011-07-27 南京医科大学 拉帕替尼合成中间体的制备工艺
US20120245351A1 (en) * 2009-09-29 2012-09-27 Natco Pharma Limited Process for the preparation of lapatinib and its pharmaceutically acceptable salts

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105761A1 (fr) * 2004-04-28 2005-11-10 Arrow Therapeutics Limited Derives de morpholinylanilinoquinazoline utilises en tant qu'agents antiviraux
WO2006079833A1 (fr) * 2005-01-31 2006-08-03 Arrow Therapeutics Limited Dérivés de quinazoline servant d'agents antiviraux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105761A1 (fr) * 2004-04-28 2005-11-10 Arrow Therapeutics Limited Derives de morpholinylanilinoquinazoline utilises en tant qu'agents antiviraux
WO2006079833A1 (fr) * 2005-01-31 2006-08-03 Arrow Therapeutics Limited Dérivés de quinazoline servant d'agents antiviraux

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101575319B (zh) * 2009-06-18 2011-07-27 南京医科大学 拉帕替尼合成中间体的制备工艺
US20120245351A1 (en) * 2009-09-29 2012-09-27 Natco Pharma Limited Process for the preparation of lapatinib and its pharmaceutically acceptable salts

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