WO1997013760A1 - Composes condenses tricycliques et compositions pharmaceutiques les contenant - Google Patents

Composes condenses tricycliques et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1997013760A1
WO1997013760A1 PCT/EP1996/004396 EP9604396W WO9713760A1 WO 1997013760 A1 WO1997013760 A1 WO 1997013760A1 EP 9604396 W EP9604396 W EP 9604396W WO 9713760 A1 WO9713760 A1 WO 9713760A1
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Prior art keywords
alkyl
compound
group
formula
hydrogen
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PCT/EP1996/004396
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English (en)
Inventor
Stephen Carl Mckeown
Martin John Page
Sadie Vile
Ann Louise Walker
Alan Thomas Hudson
Paul Barraclough
Karl Witold Franzmann
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Glaxo Group Limited
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Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU72895/96A priority Critical patent/AU7289596A/en
Publication of WO1997013760A1 publication Critical patent/WO1997013760A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine.
  • the invention relates to tricyclic fused systems containing a pyridine or pyrimidine ring which exhibit protein tyrosine kinase inhibition.
  • Protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A.F.Wilks, Progress in Growth Factor Research, 1990 (2), 97-111 ). Protein tyrosine kinases can be broadly classified as growth factor receptor (e.g. EGF-R, PDGF-R, FGF-R and c-erbB-2) or non-receptor (e.g. c-src, bcr-abl) kinases. Inappropriate or uncontrolled activation of many of these kinases i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth.
  • growth factor receptor e.g. EGF-R, PDGF-R, FGF-R and c-erbB-2
  • non-receptor e.g. c-src,
  • Aberrant EGF-R activity has, for example, been implicated in cancers of the head and neck, and aberrant c-erbB-2 activity in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers.
  • Inhibitors of protein tyrosine kinase should therefore provide a treatment for tumours such as those outlined above.
  • thrombosis (Salari et al, FEBS; 1990, 263(1 ). 104-108) and nervous system diseases (Ohmichi et al, Biochemistry, 1992, 31, 4034- 4039).
  • Inhibitors of the specific protein tyrosine kinases involved in these diseases eg PDGF-R in restenosis and EGF-R in psoriasis, should lead to novel therapies for such disorders.
  • P56lck and zap 70 are indicated in disease conditions in which T cells are hyperactive eg rheumatoid arthritis, autoimmune disease, allergy, asthma and graft rejection.
  • R 1 and R ⁇ together form specified optionally substituted groups containing at least one heteroatom so as to form a 5 or 6 membered ring, optionally substituted by one or two specified substituents, in which a N atom is located at the 6-position of the quinazoline ring.
  • R3 includes, independently, hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C) alkoxy, di-[(1-4C)alkyl]amino, or (2-4C)alkanoylamino. There is, however, no mention of substitution of the 4- anilino ring by a further group confining an aromatic or heterocyclic moiety.
  • WO95/19970 discloses tricyclic compounds of formula (2) which are capable of inhibiting EGF-R tyrosine kinase:
  • A, B, D and E can be all C; or two of them may be N provided the remainder are
  • C, or any two contiguous positions in A-E may be a single heteroatom N, O or S provided that at least one of the remaining atoms is C; and X is O, NR or S.
  • R ⁇ includes lower alkyl, lower alkoxy, cycloalkyl and cycloalkoxy, or two R2 may together form a 5-7 membered carbocyclic ring.
  • the aromatic ring (Ar) may be substituted by a further group containing an aromatic or heterocyclic moiety.
  • the present invention envisages that other disorders mediated by protein tyrosine kinase activity may be treated effectively by preferential inhibition of the appropriate protein tyrosine kinase activity.
  • protein tyrosine kinases such as c-erbB-2, c-src, p56lck, EGF-R, PDGF-R, and zap70 protein tyrosine kinases.
  • a further object of the present invention is to provide compounds useful in the treatment of protein tyrosine kinase related diseases which minimise undesirable side-effects in the recipient.
  • the present invention relates to certain tricyclic pyridine and pyrimidine derivatives which may be used to treat disorders mediated by protein tyrosine kinases and in particular have anti-cancer properties. More particularly, the compounds of the present invention are potent inhibitors of protein tyrosine kinases such as c-erbB-2, EGF-R and p56lck thereby allowing clinical management of particular diseased tissues.
  • the present invention envisages, in particular, the treatment of human malignancies, for example breast, stomach, ovary, colon, lung and pancreatic tumours, especially those driven by c-erbB-2, using the compounds of the present invention.
  • the invention includes compounds which are highly active against the c-erbB-2 protein tyrosine kinase in preference to the EGF receptor kinase hence allowing treatment of c-erbB-2 driven tumours.
  • the present invention envisages that disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition of the appropriate protein tyrosine kinase activity in a relatively selective manner, thereby minimising potential side effects.
  • each of J, K, L and M represent carbon atoms that may be independently replaced by N, O or S; or (ii) any two contiguous positions in J, K, L and M taken together represent a single atom C, N, O or S with at least one of the remaining atoms being carbon and the other being selected from carbon, N, O or S; or (iii) any two contiguous positions in J, K , L and M taken together represent a
  • the substituents when the ring atom is carbon, are independently selected from the group comprising: amino, cyano, halogen, hydroxy, C- j _4 alkyl, C-
  • X is N or CH
  • Y is a group W(CH2), (CH2)W, or W, in which W is O, S(O) m wherein m is 0, 1 or 2, or NR a wherein R a is hydrogen or a C- ⁇ s alkyl group;
  • R1 and R2 are independently selected as appropriate to the nature of P and Q from the group comprising: not present, a lone pair of electrons, amino, hydrogen, halogen, hydroxy, nitro, carboxy, trifluoromethyl, trifluoromethoxy, carbamoyl, ureido, C ⁇
  • alkylamino di[C ⁇
  • R 3 is selected from the group comprising; hydrogen, halogen, trifluoromethyl, C- ⁇ 4 alkyl and C-
  • R 4 is a group ZR 5 wherein Z is joined to R 5 through a (CH2)p group in which p is 0, 1 or 2 and Z represents a group V(CH 2 ), V(CF 2 ), (CH 2 )V, (CF 2 )V, or V in which V is a hydrocarbyl group containing 0,1 or 2 carbon atoms, carbonyl, CH(OH), sulphonamide, amide, O, S(O) m or NR D where R D is hydrogen or R b is C-
  • R5 is an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety, or an optionally substituted C3_6 cycloalkyl provided p is not zero;
  • each R 6 is independently selected from the group comprising; hydrogen, hydroxy, halogen, C-
  • P and Q are both C atoms, and in a preferred aspect J, K, L, and M are all C atoms, and more preferably with J, K, L and M forming a further aromatic ring.
  • one of P and Q is a N, O or S atom, with the other being a bond.
  • J, K, L and M are all C atoms, more preferably with J, K , L and M forming a further aromatic ring.
  • R 1 and R2 are independently selected from the group comprising: amino, hydrogen, halogen, hydroxy, nitro, C ⁇
  • R 3 is hydrogen, C-
  • R 5 is an optionally substituted 5, 6, 7, 8, 9 or 10 membered-carbocyclic or heterocyclic moiety
  • R 6 is hydrogen, hydroxy, halogen, C-
  • Z is oxygen, S or NR D wherein R b is hydrogen, or C-
  • R ⁇ and R2 are independently selected from the group comprising: hydroxy, halogen, amino, C1. alkyl such as methyl, and C ⁇
  • R 3 is hydrogen or methyl; preferably R 3 is hydrogen.
  • R 4 is selected from the group comprising: benzyl, phenoxy and benzyloxy; and in a preferred aspect, X is N and Y is NH; or X is CH and Y is O, S(O) m wherein m and R a are as herein before defined.
  • R 4 is in the para position with respect to Y.
  • R 5 is thiophene or cyclohexane and p is 1 where Z is oxygen
  • R 6 is hydrogen, halogen or methyl, preferably R 6 is hydrogen.
  • X is N.
  • Y is NR b , NR b (CH 2 ), or (CH2)NR b , preferably Y is NR wherein R is hydrogen or methyl, preferably R is hydrogen.
  • Z is CH 2 , NR b NR (CH 2 ), (CH 2 )NR b O, O(CH 2 ), O(CF 2 ), (CH 2 )O, (CF 2 )O, S(CH 2 ), or carbonyl; preferably Z is CH 2 , NR O, O(CH2) or O(CF2), and more preferably Z is O.
  • Preferred compounds of the present invention include: 4-(4-Benzyloxyanilino)benzo[g]quinazoline hydrochloride and 4-(4-Benzyloxyanilino)benzothieno[3,2-d]pyrimidine hydrochloride.
  • the fused 5 or 6-membered ring represented by J, K, L and M may optionally bear one or two substituents in order to satisfy the valency requirements of the atoms in the fused ring.
  • substituents include: amino, cyano, halogen, hydroxy, C ⁇
  • substituents together may form an optionally substituted methylenedioxy or ethylenedioxy group.
  • Suitable substituents for a nitrogen atom in the fused ring include: C-
  • the 5, 6, 7, 8, 9 or 10- membered heterocyclic moiety is selected from the group comprising: furan, dioxolane, thiophene, pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine, morpholine, piperidine, oxazoline, oxazolidine, thiazole, thiadiazole, benzofuran, indole, isoindole, quinazoline, quinoline and isoquinoline.
  • the 5, 6, 7, 8, 9 or 10- membered carbocyclic moiety is selected from the group comprising: phenyl, benzyl, indene, napthalene, tetralin, decalin, cyclopentyl, cyclohexyl, and cycloheptyl.
  • halo is meant fluoro, chloro, bromo or iodo.
  • Alkyl groups containing three or more carbon atoms may be straight, branched or cyclised.
  • Heterocyclic groups comprise one or more rings which may be saturated, unsaturated, or aromatic and which may independently contain one or more heteroatoms in each ring.
  • Carbocyclic groups comprise one or more rings which may be independently saturated, unsaturated or aromatic and which contain only carbon and hydrogen.
  • Optional substituents include, but are not limited to, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, C-j_4 alkoxy, C ⁇
  • Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen in the compound of formula (I).
  • the therapeutic activity resides in the moiety derived from the compound of the invention as defined herein and the identity of the other component is of less importance although for therapeutic and prophylactic purposes it is, preferably, pharmaceutically acceptable to the patient.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic and methanesulphonic and arylsulphonic, for example 2-toluenesulphonic, acids.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic and methanesulphonic and arylsulphonic, for example 2-toluenesulphonic, acids.
  • the present invention provides a process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, which process comprises the reaction of a compound of the formula (II).
  • L is a leaving group and X, Y, J, K, L, M, P, Q and R 1 to R 6 are as hereinbefore defined.
  • Suitable leaving groups will be well known to those skilled in the art and include, for example, halo such as chloro and bromo; sulphonyloxy groups such as methanesulphonyloxy and toluene-p-sulphonyloxy; and alkoxy groups.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent, for example a C- ⁇ _ alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone at a non-extreme temperature, for example from 0 to 150°, suitably 10 to 100°C, preferably 50 to 100°C.
  • a suitable inert solvent for example a C- ⁇ _ alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone
  • suitable bases include an organic amine such as triethylamine, or an alkaline earth metal carbonate, hydride or hydroxide, such as sodium or potassium carbonate, hydride or hydroxide.
  • one compound of formula (I) may be converted to another compound of formula (I) by chemical transformation of the appropriate substituent or substituents using appropriate chemical methods (see for example, J.March “Advanced Organic Chemistry", Edition III, Wiley Interscience, 1985).
  • a compound containing an alkyl or aryl mercapto group may be oxidised to the corresponding sulphinyl or sulphonyl compound by use of an organic peroxide (eg benzoyl peroxide) or suitable inorganic oxidant (eg OXONE
  • a compound containing a nitro substituent may be reduced to the corresponding amino-compound, eg by use of hydrogen and an appropriate catalyst (if there are no other susceptible groups) or by use of Raney Nickel and hydrazine hydrate.
  • Amino or hydroxy substituents may be acylated by use of an acid chloride or an anhydride under appropriate conditions. Equally an acetate or amide group may be cleaved to the hydroxy or amino compound respectively by treatment with, for example, dilute aqueous base. In addition reaction of an amino substituent with triphosgene and another amine (eg aqueous ammonia, dimethylamine) gives the urea substituted product.
  • triphosgene and another amine eg aqueous ammonia, dimethylamine
  • amino substituent may also be converted to a dimethylamino substituent by reaction with formic acid and sodium cyanoborohydride.
  • the present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof (hereinafter identified as the 'active ingredients') for use in medical therapy, and particularly in the treatment of disorders mediated by aberrant protein tyrosine kinase activity such as human malignancies and the other disorders mentioned above.
  • the compounds are especially useful for the treatment of disorders caused by aberrant c-erbB-2 activity such as breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers.
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from a disorder mediated by aberrant protein tyrosine kinase activity which comprises administering to the human or animal subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in therapy.
  • a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of malignant tumours.
  • a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of atherosclerosis, resterosis or thrombosis.
  • the compounds or salts of the present invention Whilst it is possible for the compounds or salts of the present invention to be administered as the new chemical, it is preferred to present them in the form of a pharmaceutical formulation. According to a further feature of the present invention we provide pharmaceutical formulations comprising at least one compound of the formula (I), or pharmaceutically acceptable salt(s) thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain for example 0.5mg to 1g, preferably 5mg to 100mg of a compound of the formula (I) depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil liquid emulsions.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti ⁇ oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the compounds of the formula (I) and salts thereof have anticancer activity as demonstrated hereinafter by their inhibition of the protein tyrosine kinase c-erbB- 2 enzyme. It has thus been established that compounds of the present invention are of use in medicine and, in particular in the treatment of certain human malignancies, for example breast, ovarian non-small cell lung, pancreatic, gastric and colon cancers. Accordingly, the present invention provides a method for the treatment of susceptible malignancies in an animal, e.g. a human, which comprises administering to the animal a therapeutically effective amount of a compound or salt of the present invention. In the alternative, there is also provided a compound or salt of the present invention for use in medicine and, in particular, for use in the treatment of cancers.
  • the present invention also provides the use of a compound of formula (I) or a salt thereof for the manufacture of a medicament for treatment of malignant tumours.
  • the animal requiring treatment with a compound or salt of the present invention is usually a mammal, such as a human being.
  • a therapeutically effective amount of a compound or salt of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • an effective amount of a compound of the present invention for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt of the present invention may be determined as a proportion of the effective amount of the compound ger se.
  • IR spectra were recorded on a Perkin-Elmer 257 grating spectrophotometer or a
  • Petrol refers to petroleum ether, either the fraction boiling at 40-60°C, or at 60-
  • DMSO dimethylsulphoxide
  • the substrate phosphorylation assay uses a baculovirus expressed, recombinant construct of the intracellular domain of c-erbB-2 that is constitutively active.
  • the method measures the ability of the isolated enzyme to catalyse the transfer of 33 P-labelled ⁇ -phosphate from ATP onto tyrosine residues in a synthetic peptide.
  • the enzyme is incubated for 1 hour, at room temperature, with 100 ⁇ M ATP, 10mM MnCl2, 1 mg/ml PolyGluAlaTyr (6:3:1 ) and test compound (diluted from a 5mM stock in DMSO, final DMSO concentration is 2%) in 40mM HEPES buffer, pH 7.4.
  • the cell proliferation assay uses an immortalised human breast epithelial cell line (HB4a) which has been transformed by over-expression of c-erbB-2. Growth of these cells in low serum is dependent upon the c-erbB-2 tyrosine kinase activity. The specificity of the effect of the test compounds on tyrosine kinase dependent growth over general toxicity is assessed by comparison to an HB4a cell line which has been transfected with ras. Cells are plated at 3000/well in 96-well plates in 0.1 ml medium and allowed to attach ovemight. test compound is added in 0.1 ml medium, with a final concentration of 0.5% DMSO, and the plates incubated for 4 days at 37°C.
  • HB4a immortalised human breast epithelial cell line
  • the cells are then examined microscopically for evidence of morphological detransformation and cell mass is estimated by staining with methylene blue and measuring the absorbance at 620nm. The results are shown in the second and third columns of Table 1 below as the IC50 values in nM.

Abstract

Les composés hétéroaromatiques substitués, en particulier les composés condensés tricycliques substitués dans lequel un noyau terminal est une pyridine ou une pyrimidine, constituent des inhibiteurs de la tyrosine kinase. On décrit de tels composés ainsi des procédés permettant de les préparer, des compositions pharmaceutiques contenant ces composés et leur utilisation en médecine, par exemple pour traiter: psoriasis, fibrose, athérosclérose, resténose, maladies auto-immunes, allergies, asthme, rejet de greffon, inflammations, thrombose, maladies du système nerveux et cancer.
PCT/EP1996/004396 1995-10-11 1996-10-10 Composes condenses tricycliques et compositions pharmaceutiques les contenant WO1997013760A1 (fr)

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AU72895/96A AU7289596A (en) 1995-10-11 1996-10-10 Tricyclic fused compounds and pharmaceutical compositions containing them

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GBGB9520822.9A GB9520822D0 (en) 1995-10-11 1995-10-11 Therapeutically active compounds
GB9520822.9 1995-10-11

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