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WO1998017662A1 - Derives d'heterocyclyle bicyclique a substitution phenyle et utilisation de ces derives - Google Patents

Derives d'heterocyclyle bicyclique a substitution phenyle et utilisation de ces derives Download PDF

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Publication number
WO1998017662A1
WO1998017662A1 PCT/EP1997/005697 EP9705697W WO9817662A1 WO 1998017662 A1 WO1998017662 A1 WO 1998017662A1 EP 9705697 W EP9705697 W EP 9705697W WO 9817662 A1 WO9817662 A1 WO 9817662A1
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Prior art keywords
hydroxy
salt
chlorophenyl
methoxy
quinolone
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PCT/EP1997/005697
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English (en)
Inventor
Peter Traxler
Urs Sequin
Jennifer Mary Green
Pascal Furet
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Novartis Ag
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Priority to AU49479/97A priority Critical patent/AU4947997A/en
Publication of WO1998017662A1 publication Critical patent/WO1998017662A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones

Definitions

  • the invention relates to the use of a phenyl-substituted bicyclic heterocyclyl derivative, or a salt thereof, in the inhibition of protein kinase activity, in the treatment of a proliferative disease that depends on protein kinase activity, especially of a tumour disease and/or of psoriasis if said disease is dependent on protein kinase activity; to its use in the preparation of a pharmaceutical composition for the treatment of said disease, to a pharmaceutical composition comprising said compound or a salt thereof, especially for the treatment of said disease, to a method of treatment of said disease with said compound or a salt thereof, to the use of said compound or a salt thereof for the inhibition of a protein tyrosine kinase, as well as to a novel phenyl-substituted bicyclic heterocyclyl derivative or a salt thereof, to such a novel compound or a salt thereof for use in a method for the diagnostic or therapeutic treatment of the human or animal body, to a process
  • Tumour diseases are one of the main causes of death in the industrial countries. Very great efforts are being made to make available effective ways and means of treating tumours. In particular, because of the large number and wide variety of possible tumour diseases, there is a constant need for new pharmaceutical compounds and compositions which, by virtue of their active ingredients, are suitable either for treating as many tumours as possible or, alternatively, for treating very specific tumours.
  • R 1 is an aryl group, a heteroaryl group, a cycloalkyl group, an aralkyl group, a lower alkoxy- group, an aryloxy group or an arylsulfonyl group;
  • R 2 is hydrogen or lower alkyl; and the ring A is unsubstituted or substituted by one or more halogen atoms or hydroxy, lower alkyl or lower alkoxy groups.
  • a phenyl-substituted bicyclic heterocyclyl derivative that can be used in accordance with the invention is a compound of formula I,
  • Ri and R 2 independently of each other, represent hydrogen, hydroxy or lower alkoxy, or Ri and R 2 together form lower alkylenedioxy;
  • R 3 is halogen, lower alkyl, halogen substituted lower alkyl, hydroxy, phenyloxy, C 3 -C 7 - cycloalkyioxy or lower alkoxy; any R 4 is, independently of R 3 and independently of any other R 4 if present, selected from halogen, lower alkyl, halogen substituted lower alkyl, hydroxy, phenyloxy, C 3 -C cyclo- alkyloxy or lower alkoxy;
  • X is oxygen, imino or (halogen-substituted or unsubstituted lower alkanoyl, [lower alkyl or carboxy-, lower alkoxycarbonyl-, aminocarbonyl-, N-mono- or N,N-di-lower alkylamino- carbonyl]-lower alkyl; or C 6 -C ⁇ 2 -aryl)-substituted imino; and
  • n 0, 1 , 3 or 4;
  • the invention relates to the use of a compound of formula I, or a salt thereof, or a method of treatment of said compound or a salt thereof, for the therapeutic treatment of warm-blooded animals, especially humans, or to the use of said compound or a salt thereof in the preparation of pharmaceutical compositions for the treatment of a disease mentioned hereinbefore and hereinafter and/or, further, to a pharmaceutical composition comprising said compound or a salt thereof for use in the treatment of the diseases described hereinbefore and hereinafter.
  • the compounds of formulal may be in the form of mixtures of enantiomers or (where two or more centres of asymmetry are present) mixtures of diastereoisomers, or in the form of the pure enantiomers or diastereoisomers.
  • Lower alkoxy Ri or R 2 is especially methoxy.
  • Lower alkylenedioxy formed together by Ri and R 2 is preferably a bivalent radical selected from ethylenedioxy (-O-CH 2 -CH 2 -O-) and especially methylenedioxy (-O-CH 2 -O-).
  • Halogen R 3 is fluorine, iodine or preferably bromine or chlorine.
  • R 3 is preferably chlorine.
  • Lower alkyl R 3 is preferably methyl or ethyl.
  • Halogen substituted lower alkyl R 3 or R 4 is lower alkyl, such as methyl, that is substituted by halogen, such as fluoro or chloro, and is especially trifluoromethyl.
  • C 3 -C 7 -Cycloalkyloxy is preferably cyclohexyloxy, lower alkoxy (which, in the group consisting of phenyloxy, C 3 -C 7 -cycloalkyloxy and lower alkoxy, is preferred) is especially ethoxy or more especially methoxy.
  • Halogen R 4 is, independently, defined as halogen R 3 .
  • Lower alkyl R 4 is preferably methyl.
  • X is oxygen (-O-), imino (-NH-) or substituted imino (with H replaced by a substituent).
  • the imino substitutent is especially lower alkanoyl that is substituted by halogen or especially unsubstituted lower alkanoyl; lower alkyl, especially methyl, ethyl, n-propyl or isopropyl; or substituted lower alkyl (preferably methyl or ethyl), wherein the substituents (one or more, especially one substituent) are selected from carboxy, lower-alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, aminocarbonyl, N- mono- or N,N-di-lower al
  • the index n is preferably 0 or 1 , most preferably 0.
  • Salts of compounds of formula I are especially acid addition salts with organic or inorganic acids, especially the pharmaceutically acceptable, non-toxic salts.
  • Suitable inorganic acids are, for example, carbonic acid (preferably in the form of the carbonates or hydrogen carbonates); hydrohalic acids, such as hydrochloric acid; sulfuric acid; or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine or N-acetyl- cystine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1 -phosphoric acid, fructo
  • Compounds of formula I having at least one free carboxy group are capable of forming internal salts or metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N'- dimethyl-piperazine.
  • suitable organic amines such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N'- dimethyl-piperazine.
  • pharmaceutically unacceptable salts for example picrates or perchlorates. Salts that are pharmaceutically acceptable are used therapeutically and those salts are therefore preferred.
  • any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate and expedient, and furthermore to solvates, such as hydrates, that are formed e.g. by precipitation from water or other solvents, either of the salts and/or of the free compounds.
  • the compounds of formula I have valuable pharmacologically useful properties. In particular they exhibit specific inhibitory activities that are of pharmacological interest. They are effective especially as tyrosine protein kinase inhibitors and/or (furthermore) as inhibitors of seri- ne/threonine protein kinases; they exhibit, for example, powerful inhibition of the tyrosine kinase activity of the receptor for epidermal growth factor (EGF) and of c-erbB2 kinase. Those receptor-specific enzyme activities play a key role in signal transmission in a large number of mammalian cells, including human cells, especially epithelial cells, cells of the immune system and cells of the central and peripheral nervous system.
  • EGF epidermal growth factor
  • EGF-induced activation of receptor-associated tyrosine protein kinase is a prerequisite for cell division and hence for the proliferation of the cell population.
  • An increase in the number of EGF-receptor-specific tyrosine kinase inhibitors thus inhibits the proliferation of the cells.
  • the compounds of formula I also inhibit to varying extents other tyrosine protein kinases that are involved in signal transmission mediated by trophic factors, for example abl kinase, especially v-abl kinase, kinases from the family of the src kinases, especially c-src kinase, lck, fyn; other kinases of the EGF family, for example c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; members of the family of the PDGF-receptor tyrosine protein kinases, for example PDGF-receptor kinase, CSF-1 receptor kinase, Kit-receptor kinase, VEGF-receptor kinase (e.
  • abl kinase especially v-abl kinase
  • KDR and Flt-1 Flt-1 and FGF-receptor kinase
  • FGF-receptor kinase the receptor kinase of the insulin-like growth factor (IGF-1 kinase), and/or serine/threonine kinases, for example protein kinase C or cdc kinases, all of which play a part in growth regulation and transformation in mammalian cells, including human cells.
  • IGF-1 kinase insulin-like growth factor
  • serine/threonine kinases for example protein kinase C or cdc kinases, all of which play a part in growth regulation and transformation in mammalian cells, including human cells.
  • EGF-receptor-specific tyrosine protein kinase (EGF-R-TPK) can be demonstrated using known methods, for example using the recombinant intracellular domain of the EGF-receptor (EGF-R ICD; see, for example, E. McGlynn et ai, Europ. J. Biochem. 207, 265-275 (1992)).
  • EGF-R ICD the recombinant intracellular domain of the EGF-receptor
  • the compounds of formula I inhibit the enzyme activity by 50 % (IC 50 ), for example in a concentration of from 0.001 up to 10 ⁇ M, especially from 0.005 to 5 ⁇ M.
  • the action of the compounds of formula I on EGF-stimulated cellular tyrosine phos-phoryla- tion in the EGF-receptor can be determined in the human A431 epithelial carcinoma cell line by means of an ELISA which is described in U. Trinks er a/., J. Med. Chem. 37:7, 1015- 1027 (1994).
  • the compounds of formula I preferably exhibit an IC 5 o of approximately from 0.1 to 10 ⁇ M.
  • the compounds of formula I exhibit, for example, inhibition of the cell growth of EGF-dependent cell lines, for example the epidermoid BALB/c mouse ke- ratinocyte cell line (see Weissmann, B.A., and Aaronson, S.A., Cell 32, 599 (1983)) or the A431 cell line, which are recognised useful standard sources of EGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153, 279-282 (1985)).
  • EGF-dependent cell lines for example the epidermoid BALB/c mouse ke- ratinocyte cell line (see Weissmann, B.A., and Aaronson, S.A., Cell 32, 599 (1983)) or the A431 cell line, which are recognised useful standard sources of EGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153, 279-282 (1985)).
  • a known test method
  • the inhibitory activity of the compounds of formula I is determined, briefly, as follows: BALB/MK cells (10 000/microtitre plate well) are transferred to 96-weli microtitre plates. The test compounds (dissolved in DMSO) are added in a series of concentrations (dilution series) in such a manner that the final concentration of DMSO is not greater than 1 % (v/v). After the addition, the plates are incubated for three days during which the control cultures without test compound are able to undergo at least three cell-division cycles.
  • the growth of the MK cells is measured by means of methylene blue staining: after the incubation the cells are fixed with glutaraldehy- de, washed with water and stained with 0.05 % methylene blue. After a washing step the stain is eluted with 3 % HCI and the optical density per well of the microtitre plate is measured using a Titertek Multiskan at 665 nm. IC 50 values are determined by a computer-aided system using the formula:
  • ICso [(ODte ⁇ , - OD start )/(OD CO ntroi - OD ⁇ )] x 100.
  • the IC 50 value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50 % lower than that obtained using the control without inhibitor.
  • the compounds of formula I exhibit inhibitory activity in the micromolar range, preferably an IC 50 of approximately from 0.1 to 50 ⁇ M.
  • the compounds of formula I exhibit inhibition of the growth of tumour cells also in vivo, as shown, for example, by the following test: The test is based on inhibition of the growth of the human epidermoid carcinoma A431 (ATCC No. CRL 1555; American Type Culture Collection, Rockville, Maryland, USA; see Santon, J.B., et ai., Cancer Research 46, 4701 - 4705 (1986) and Ozawa, S., et ai., Int. J. Cancer 40, 706-710 (1987)), which is transplanted into female BALB/c nude mice (Bomholtgard, Denmark). That carcinoma exhibits a growth that correlates with the extent of the expression of the EGF-receptor.
  • tumours having a volume of approximately 1 cm 3 cultured in vivo are surgically removed from experimental animals under sterile conditions.
  • the tumours are comminuted and suspended in 10 volumes (w/v) of phosphate-buffered saline.
  • the suspension is injected s.c. (0.2 ml/mouse in phosphate-buffered saline) into the left flank of the animals.
  • 1 x 10 6 cells from an in vitro culture in 0.2 ml of phosphate-buffered saline can be injected.
  • Treatment with test compounds of formula I is started 5 or 7 days after the transplant, when the tumours have reached a diameter of 4-5 mm.
  • the test compound in question is administered (in different doses for different animal groups) once a day for 15 successive days.
  • the tumour growth is determined by measuring the tumour diameter along three axes that are perpendicular to each other.
  • the tumour volumes are calculated using the known formula p x L x D 2 /6 (see Evans, B.D., et ai., Brit. J. Cancer 45, 466-8 (1982)).
  • the compounds of formula I also inhibit other tyrosine protein kinases that are involved in signal transmission mediated by trophic factors, for example abl kinase, such as especially v-abl kinase, kinases from the family of the src kinases, such as especially c-src kinase and c-erbB2 kinase (HER-2), and serine/threonine kinases, for example protein kinase C, all of which are involved in growth regulation and transformation in mammalian cells, including human cells.
  • abl kinase such as especially v-abl kinase
  • kinases from the family of the src kinases such as especially c-src kinase and c-erbB2 kinase (HER-2)
  • serine/threonine kinases for example protein kinase C, all of which are involved in growth regulation and transformation in ma
  • c-erbB2 tyrosine kinase HER-2
  • the inhibition of c-erbB2 tyrosine kinase can be determined, for example, analogously to the method used for EGF-R-TPK (see C. House et at, Europ. J. Biochem. 140, 363-367 (1984)).
  • the c-erbB2 kinase can be isolated, and its activity determined, by means of protocols known per se, for example in accordance with T. Akiyama et ai, Science 232, 1644 (1986).
  • the compounds of formula I which inhibit the tyrosine kinase activity of the receptor for the epidermal growth factor (EGF) or of the other tyrosine protein kinases mentioned are therefore useful, for example, in the treatment of (a) proliferative disease(s), especially of benign or malignant tumour disease(s) and of epidermal hyperproliferation, such as especially psoriasis, especially if said diseases depend on the activity of a protein tyrosine kinase, especially EGF-R kinase. They are capable of effecting tumour regression and of preventing the formation of tumour metastases and the growth of micrometastases.
  • the compounds of formula I can be used also in the treatment of those disorders of the immune system in which several or, especially, individual tyrosine protein kinases and/or (furthermore) serine/ threonine protein kinases are involved; those compounds of formula I can also be used in the treatment of those disorders of the central or peripheral nervous system in which signal transmission by several or, especially, a single tyrosine protein kinase(s) and/or (furthermore) serine/threonine protein kinase(s) is/are involved.
  • the present invention relates also to the use of the compounds of formula I in the inhibition of the mentioned protein kinases, especially protein tyrosine kinases, most especially EGF-R kinase.
  • the compounds of formula I may also be used for diagnostic purposes; for example, proliferating cells, such as tumour cells, obtained from mammals, especially humans, which will also grow in cell culture may be tested in cell culture for their sensitivity to compounds of formula I, thus allowing better determination of possible methods of treatment.
  • the compounds according to the invention may be used either on their own or in combination with other pharmacologically active substances, for example together with inhibitors of the enzymes of polyamine synthesis, inhibitors of protein kinase C, inhibitors of other tyrosine kinases, cytokines, negative growth regulators, for example TGF-b or IFN-b, aromatase inhibitors, antioestrogens and/or cytostatics.
  • other pharmacologically active substances for example together with inhibitors of the enzymes of polyamine synthesis, inhibitors of protein kinase C, inhibitors of other tyrosine kinases, cytokines, negative growth regulators, for example TGF-b or IFN-b, aromatase inhibitors, antioestrogens and/or cytostatics.
  • Preferred is the use of a compound of formula I, or a salt thereof, preferably as defined below, for the inhibition of a protein tyrosine kinase, especially EGF-R tyrosine kinase, either in vivo or in vitro.
  • a compound of formula I preferably as defined below, or a salt thereof if at least one salt-forming group is present, for the treatment or in the preparation of a pharmaceutical formulation for the treatment of a disease that depends on protein kinase activity, especially protein tyrosine kinase activity; or a pharmaceutical preparation, preferably for the treatment of a disease that depends on protein kinase activity, especially protein tyrosine kinase activity, comprising a compound of formula I, preferably as defined below, or a salt thereof if at least one salt-forming group is present, together with at least one pharmaceutically acceptable carrier; or a method of treatment of a disease that depends on protein kinase activity, especially protein tyrosine kinase activity, said method comprising administering to an animal in need thereof an amount of a compound of formula I, preferably as defined below, or a salt thereof if at least one salt-forming group is present, that is effective in the inhibition of protein tyrosine
  • a compound of formula I preferably as defined below, or a salt thereof if at least one salt-forming group is present, for the treatment or in the preparation of a pharmaceutical formulation for the treatment of a tumour disease, especially a neoplasia of epithelial character or a leukaemia, and/or of psoriasis, where said disease(s) depend(s) on protein tyrosine kinase activity; or a pharmaceutical preparation, preferably for the treatment of a tumour disease, especially a neoplasia of epithelial character or a leukemia, and/or of psoriasis, where said disease(s) depend(s) on protein tyrosine kinase activity, comprising a compound of formula I, preferably as defined below, or a salt thereof if at least one salt-forming group is present, together with at least one pharmaceutically acceptable carrier; or a method of treatment of a tumour disease and/or of psori
  • R; and R 2 independently of each other, represent hydrogen; hydroxy; or lower alkoxy, especially methoxy; or together form lower alkylenedioxy, especially methylenedioxy; preferably R 2 being selected from the group comprising hydroxy; and lower alkoxy, especially methoxy; and R T being selected from the group comprising hydrogen; and, independently of R 2 , from hydroxy; or from lower alkoxy, especially methoxy;
  • R 3 is halogen, especially chlorine or bromine or hydroxy
  • R 4 is, independently of R 3 , halogen, especially chlorine, R 4 if present being fixed preferably in the 4-position of the phenyl ring in formula I;
  • X is oxygen, imino or imino substituted with lower alkanoyl, especially acetyl; lower alkyl, especially methyl, ethyl, n-propyl or isopropyl; carboxy-lower alkyl, such as carboxymethyl (-CH 2 -COOH); lower-alkoxycarbonyl-lower alkyl, such as methoxycarbonylmethyl or ethoxycarbonylmethyl (-CH 2 -COOCH 3 or -CH 2 -COOCH 2 .CH 3 ); aminocarbonyl (-CO-NH 2 ); or phenyl-lower alkyl, especially 2-phenylethyl;
  • n O or 1
  • Ri and R 2 independently of each other, represent hydrogen; hydroxy; or lower alkoxy, especially methoxy; or together form lower alkylenedioxy, especially methylenedioxy; preferably R 2 being selected from the group comprising hydroxy; and lower alkoxy, especially methoxy; and Ri being selected from the group comprising hydrogen; and, independently of R 2 , from hydroxy; or from lower alkoxy, especially methoxy; R 3 is halogen, especially chlorine or bromine or hydroxy;
  • R 4 is, independently of R 3 , halogen, especially chlorine, R 4 if present being fixed preferably in the 4-position of the phenyl ring in formula I;
  • X is oxygen
  • n O or 1
  • the invention also relates to novel compounds of the formula I, or salts thereof where salt- froming groups are present.
  • novel compounds of formula I according to the invention as such, there is preferred a compound of the formula I, wherein
  • Ri and R 2 independently of each other, represent hydrogen; hydroxy; or lower alkoxy, especially methoxy; or together form lower alkylenedioxy, especially methylenedioxy; preferably R 2 being selected from the group comprising hydroxy; and lower alkoxy, especially methoxy; and Ri being selected from the group comprising hydrogen; and, independently of R 2 , from hydroxy; or from lower alkoxy, especially methoxy;
  • R 3 is halogen, especially chlorine or bromine, or hydroxy
  • R 4 is, independently of R 3 , halogen, especially chlorine, R 4 if present being fixed preferably in the 4-position of the phenyl ring in formula I;
  • X is oxygen, imino or imino substituted with lower alkanoyl, especially acetyl; lower alkyl, especially methyl, ethyl, n-propyl or isopropyl; carboxy-lower alkyl, such as carboxymethyl (-CH 2 -COOH); lower-alkoxycarbonyl-lower alkyl, such as methoxycarbonylmethyl or ethoxycarbonylmethyl (-CH 2 -COOCH 3 or -CH 2 -COOCH 2 .CH 3 ); aminocarbonyl (-CO-NH 2 ); or phenyl-lower alkyl, especially 2-phenylethyl;
  • n O or 1
  • R-, and R 2 independently of each other, represent hydrogen; hydroxy; or lower alkoxy, especially methoxy; or together form lower alkylenedioxy, especially methylenedioxy; preferably R 2 being selected from the group comprising hydroxy; and lower alkoxy, especially methoxy; and Ri being selected from the group comprising hydrogen; and, independently of R 2 , from hydroxy; or from lower alkoxy, especially methoxy;
  • R 3 is halogen, especially chlorine or bromine, or hydroxy
  • R 4 is, independently of R 3 , halogen, especially chlorine, R 4 if present being fixed preferably in the 4-position of the phenyl ring in formula I;
  • X is imino or imino substituted with lower alkanoyl, especially acetyl; lower alkyl, especially methyl, ethyl, n-propyl or isopropyl; carboxy-lower alkyl, such as carboxymethyl (-CH 2 -COOH); lower-alkoxycarbonyl-lower alkyl, such as methoxycarbonyi methyl or ethoxycarbonylmethyl (-CH 2 -COOCH 3 or -CH 2 -COOCH 2 .CH 3 ); aminocarbonyl (-CO-NH 2 ); or phenyl-lower alkyl, especially 2-phenylethyl;
  • n 0 or 1
  • Ri and R 2 independently of each other, represent hydrogen; hydroxy; or lower alkoxy, especially methoxy; or together form lower alkylenedioxy, especially methylenedioxy; preferably R 2 being selected from the group comprising hydroxy; and lower alkoxy, especially methoxy; and Ri being selected from the group comprising hydrogen; and, independently of R 2 , from hydroxy; or from lower alkoxy, especially methoxy;
  • R 3 is halogen, especially chlorine or bromine or hydroxy
  • R 4 is, independently of R 3 , halogen, especially chlorine, R 4 if present being fixed preferably in the 4-position of the phenyl ring in formula I;
  • X is imino or imino substituted with lower alkyl, especially methyl, ethyl, n-propyl or isopropyl; lower-alkoxycarbonyl-lower alkyl, such as methoxycarbonylmethyl or ethoxycar- bonylmethyl (-CH 2 -COOCH 3 or -CH 2 -COOCH 2 .CH 3 ); or further aminocarbonyl (-CO-NH 2 ); or phenyl-lower alkyl, especially 2-phenylethyl;
  • n is 0 or 1 , especially 0;
  • the invention relates to the use thereof in the treatment of a disease that depends on protein kinase activity such as a tumour disease and/or of psoriasis, to its use in the preparation of a pharmaceutical composition for the treatment of said disease, to a pharmaceutical composition comprising said compound or a salt thereof, especially for the treatment of said disease, to a method of treatment of said disease with said compound or a salt thereof, to the use of said compound or a salt thereof for the inhibition of protein tyrosine kinase, as well as to such a novel compound or a salt thereof for use in a method for the diagnostic or therapeutic treatment of the human or animal body, to a process for its preparation, and/or to new intermediates or salts thereof.
  • the compounds of formula I can be prepared in accordance with methods that are known per se (processes based on novel intermediates and/or leading to novel compounds of formula I or salts thereof, especially the compounds mentioned to be novel in the present disclosure, being analogy processes that are novel at least by virtue of the fact that new starting materials are employed and/or that new compounds of formula I are the result), preferably by
  • Ri, R 2 , R 3 , R 4 and n have the meanings given above for compounds of formula I and wherein X' is oxygen (-O-) or imino (-NH-), any free functional groups present being protected if necessary by readily removable protecting groups,
  • the end products of formula I may contain substituents that can also be used as protecting groups in starting materials for the preparation of other end products of formula I.
  • protecting group is used in this text to denote only a readily removable group that is not a constituent of the particular desired end product of formula I.
  • Protective groups for functional groups in starting materials (especially of formula III) whose reaction is to be avoided, in particular carboxyl, amino and hydroxyl groups include, in particular, those protective groups (conventional protecting groups) which are customarily used in the synthesis of peptide compounds or else of cephalosporins and penicillins, and also nucleic acid derivatives and sugars. These protective groups can already be present in the precursors and are intended to protect the functional groups concerned against unwanted side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis, etc. In certain cases, the protective groups can, in addition to this, have the effect of making the course of reactions selective, for example stereoselective.
  • protective groups are readily removable, i.e. without undesirable side reactions, for example solvolytically, reductively, photolytically or else enzymically, for example under physiological conditions as well, and that they are not present in the end products.
  • a carboxyl group is, for example, protected as an ester group which can be selectively cleaved under mild conditions.
  • a carboxyl group which is protected in esterified form is primarily esterified with a lower alkyl group which is preferably branched in the 1 position of the lower alkyl group or is substituted by suitable substituents in the 1 or 2 position of the lower alkyl group.
  • a protected carboxyl group which is esterified with a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.
  • a protected carboxyl group which is esterified with a lower alkyl group which is branched in the 1 position of the lower alkyl group is, for example, tert-lower-alkoxycarbonyl, for example tert-butoxycarbonyl.
  • a protected carboxyl group which is esterified with a lower alkyl group which is substituted in the 1 or 2 position of the lower alkyl group by suitable substituents is, for example, 1 -aryl-lower-alkoxycarbonyl, such as aryl methoxycarbonyl, having one or two aryl radicals, in which aryl is phenyl which is unsubstituted or is substituted once, twice or three times by, for example, lower alkyl, for example tert-lower-alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxyl, halogen, for example chlorine, and/or nitro, for example benzyloxycarbonyl, benzyloxycar- bonyl which is substituted by the said substituents, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl which is substitute
  • a carboxyl group can also be protected as an organic silyloxycarbonyl group.
  • An organic silyloxycarbonyl group is, for example, a tri-lower-alkylsilyioxycarbonyl group, for example trimethylsilyloxycarbonyl.
  • the silicon atom of the silyloxycarbonyl group can also be substituted by two lower alkyl, for example methyl, groups, and an amino or carboxyl group of a second molecule of the formula I.
  • Compounds possessing such protective groups can be prepared, for example, using corresponding tri-lower-alkylhalosilanes, such as tert-butyldimethylchlorosilane, as silylating agents.
  • a carboxyl group can also be protected in the form of an internal ester with a hydroxyl group which is present in the molecule at a suitable distance, for example in the ⁇ position with regard to the carboxyl group, i.e. in the form of a lactone, preferably a ⁇ -lactone.
  • a protected carboxyl group is preferably tert-lower-alkoxycarbonyl, for example tert-butoxy- carbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl, or a protected carboxyl group in the form of a lactone, in particular a ⁇ -lactone, and most preferably lower-alkoxycarbonyl, such as methoxycarbonyl or ethoxy- carbonyl.
  • a protected amino group is protected by an amino protecting group, for example in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower-alk-1-enylamino or silylamino group, or as an azido group.
  • an amino protecting group for example in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower-alk-1-enylamino or silylamino group, or as an azido group.
  • acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, in particular of a lower-alkanecarboxylic acid which is unsubstituted or substituted, for example, by halogen or aryl, or of benzoic acid which is unsubstituted or substituted, for example, by halogen, lower alkoxy or nitro, or, preferably, of a carbonic acid semiester.
  • Such acyl groups are, preferably, lower alkanoyl, such as acetyl, propionyl or pivaloyl, halo-lower- alkanoyl, for example 2-haloacetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, benzoyl which is unsubstituted or substituted, for example, by halogen, lower alkoxy or nitro, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4- nitrobenzoyl, iower-alkoxycarbonyl, lower-alkoxycarbonyl which is preferably branched in the 1 position of the lower-alkyl radical or is suitably substituted in the 1 or 2 position, for example tert-lower-alkoxycarbonyl, such as tert-butoxycarbonyl, 1 -aryl-lower
  • aryl radicals are, in particular, phenyl radicals which are unsubstituted or substituted. Examples of such groups are benzyl-, diphenylmethyl- or, in particular, t tyl-amino.
  • the mercapto group is primarily present as substituted arylthio or aryl-lower-alkylthio in which aryl is, for example, phenyl which is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, for example 4-nitrophenylthio.
  • aryl is, for example, phenyl which is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, for example 4-nitrophenylthio.
  • acyl is, for example, the corresponding radical of a lower-alkanecarboxylic acid, of a benzoic acid which is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, or, in particular, of a carbonic acid semiester, such as a carbonic acid lower-alkyl semiester.
  • Corresponding protective groups are, primarily, 1-lower- alkanoyl-lower-alk-1-en-2-yl, for example 1 -lower-alkanoyl-prop-1-en-2-yl, such as 1-acetyl- prop-1-en-2-yl, or iower-alkoxycarbonyl-lower-alk-1-en-2-yl, for example lower-alko- xycarbonyl-prop-1-en-2-yl, such as 1-ethoxycarbonyl-prop-1 -en-2-yl.
  • 1-lower- alkanoyl-lower-alk-1-en-2-yl for example 1 -lower-alkanoyl-prop-1-en-2-yl, such as 1-acetyl- prop-1-en-2-yl
  • iower-alkoxycarbonyl-lower-alk-1-en-2-yl for example lower-alko- xycarbonyl-prop-1-en-2-y
  • a silylamino group is, for example, a tri-lower-alkylsilylamino group, for example trimethylsilylamino or tert-butyldi- methylsilylamino.
  • the silicon atom of the silylamino group can also only be substituted by two lower alkyl groups, for example methyl groups, and the amino group or carboxyl group of a second molecule of the formula I.
  • Compounds having such protective groups can be prepared, for example, using the corresponding chlorosilanes, such as tert-butyldimethyl- chlorosilane, as silating agents.
  • suitable corresponding anions are primarily those of strong inorganic acids, such as of sulfuric acid, phosphoric acid or hydrohalic acids, for example the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid.
  • Preferred amino protective groups are lower-alkoxycarbonyl, phenyl-lower-alkoxycarbonyl, fluorenyl-lower-alkoxycarbonyl, 2-lower-alkanoyl-lower-alk-1-en-2-yl or lower-alkoxycarbo- nyl-lower-alk-1 -en-2-yl, especially tert-butoxycarbonyl or benzyloxycarbonyl, or most preferably lower alkanoyl, especially acetyl.
  • a hydroxyl group can, for example, be protected by an acyl group, for example lower alkanoyl which is unsubstituted or substituted by halogen, such as chlorine, such as acetyl or 2,2-dichloroacetyl, or, in particular, by an acyl radical, which is specified for protected amino groups, of a carbonic acid semiester.
  • acyl group for example lower alkanoyl which is unsubstituted or substituted by halogen, such as chlorine, such as acetyl or 2,2-dichloroacetyl, or, in particular, by an acyl radical, which is specified for protected amino groups, of a carbonic acid semiester.
  • a hydroxyl group can also be protected by tri-lower- alkylsilyl, for example trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilyi, a readily detachable etherifying group, for example an alkyl group, such as tert-lower-alkyl, for example tert- butyl, an oxa- or a thia-aliphatic or -cycloaliphatic, in particular 2-oxa- or 2-thia-aliphatic or - cycloaliphatic, hydrocarbon radical, for example 1 -lower-alkoxy-lower-alkyl or 1 -lower-alkyl- thio-lower-alkyl, such as methoxymethyl, 1 -methoxymethyl, 1 -ethoxy methyl, methylthio- methyl, 1 -methylthioethyl or 1 -ethylthioethyl, or 2-oxa-
  • a hydroxyl group can be protected in the form of an C 6 -C 12 -aryl-lower alkyl or a lower alkyl ether, for example as lower-alkyl ether, especially as methyl ether, or as phenyl-lower alkyl ether, especially as benzyl ether.
  • Two hydroxyl groups, in particular adjacent hydroxyl groups, which are present in a molecule, or an adjacent hydroxyl group and amino group, can, for example, be protected by bivalent protective groups, such as a methylene group which is preferably substituted, for example by one or two lower alkyl radicals or oxo, for example by unsubstituted or substituted alkylidene, for example lower alkylidene, such as isopropylidene, cyclo- alkylidene, such as cyclohexylidene, a carbonyl group or benzylidene.
  • a hydroxyl group which is located adjacent to a carboxyl group can be protected by the formation of an internal ester (lactone), in particular of a ⁇ -lactone.
  • a protected hydroxyl group is protected by lower alkyl, such as methyl.
  • Detachment of the protective groups which are not components of the desired end product of the formula I, for example the carboxyl, amino and/or hydroxy protective groups is effected in a manner known per se, for example using solvoiysis, in particular hydrolysis, alcoho- lysis or acidolysis, or by means of reduction, in particular hydrogenolysis, or by means of other reducing agents, and also photolysis, as desired stepwise or simultaneously, with it also being possible to use enzymatic methods.
  • Detachment of the protective groups is described, for example, in the standard works which are mentioned above in the section on protective groups.
  • a protected carboxyl for example, for example lower-alkoxycarbonyl (which is preferably branched in the 1 position), such as tert-lower-alkoxycarbonyl, lower-alkoxycarbonyl which is substituted in the 2 position by a tri-substituted silyl group or in the 1 position by lower alkoxy or lower-alkylthio, or diphenylmethoxycarbonyl which is unsubstituted or substituted, can be converted into free carboxyl by treatment with a suitable acid, such as formic acid, acetic acid, oxalix acid, hydrochloric acid or trifluoroacetic acid, if desired while adding a nucleophilic compound, such as phenol or anisole.
  • a suitable acid such as formic acid, acetic acid, oxalix acid, hydrochloric acid or trifluoroacetic acid
  • Benzyloxycarbonyl which is unsubstituted or substituted can, for example, be set free by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst.
  • suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl
  • bonyl group into a corresponding 2-iodo-lower-alkoxycarbonyl group) or aroylmethoxycar- bonyl can also be converted into free carboxyl.
  • Aroylmethoxycarbonyl can be cleaved by treating with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenoxide or sodium iodide.
  • the carboxyl group can also be set free from 1-aryl-lower-alkoxycarbonyl, for example arylmethoxycarbonyl, such as benzyloxycarbonyl, by hydrolysing in the presence of a base such as an alkali metal hydroxide, for example sodium, lithium or potassium hydroxide.
  • 2-(Tri-substituted silyl)-lower-alkoxycarbonyl such as 2-tri-lower-alkylsilyl-lower- alkoxycarbonyl
  • a salt of hydrofluoric acid which provides the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride
  • a macrocyclic polyether such as a macrocyclic polyether ("crown ether")
  • a fluoride of an organic quaternary base such as tetra-lower-alkylammonium fluoride or tri-lower-alkylaryl-lower-alkylammonium fluoride, for example tetraethylammo- nium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylace
  • Carboxyl which is protected as organic silyloxycarbonyl, such as tri-lower-alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, can be released solvolytically in a customary manner, for example by treating with water, an alcohol or acid, or, in addition, fluoride, as described above.
  • Esterified carboxyl can also be set free enzymically, for example using esterases or suitable peptidases, for example esterified arginine or lysine, such as lysine methyl ester, using trypsin.
  • Carboxyl which is protected as lower aikylester or as an internal ester, such as a g-lactone, can be released by hydrolysis in the presence of a hydroxide-containing base, such as an alkaline earth metal hydroxide or, in particular, an alkali metal hydroxide, for example NaOH, KOH or LiOH, in particular LiOH, with the corresponding protected hydroxyl group being set free simultaneously.
  • a hydroxide-containing base such as an alkaline earth metal hydroxide or, in particular, an alkali metal hydroxide, for example NaOH, KOH or LiOH, in particular LiOH
  • a protected amino group is set free in a manner which is known per se and which differs depending on the nature of the protective groups, preferably using solvolysis or reduction.
  • Lower-alkoxycarbonylamino such as tert-butoxycarbonylamino
  • acids for example mineral acids, for example hydrohalic acid, such as hydrochloric acid or hydrobromic acid, in particular hydrobromic acid, or of sulfuric acid or phosphoric acid, preferably of hydrochloric acid, or of relatively strong organic acids, such as formic acid, oxalic acid, trichloroacetic acid or trifluoroacetic acid, in polar solvents, for example water or a carboxylic acid, such as acetic acid or formic acid, esters, such as lower alkyl lower alkanoates, e.g.
  • halohydrocarbons such as chlorinated lower-alkanes, for example dichloromethane or chloroform
  • ethers preferably cyclic ethers, such as di- oxane, or in organic carboxylic acids which are liquid at the reaction temperature, without solvent, for example in formic acid.
  • aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can, for example, be cleaved by treating with a suitable reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
  • Aroylmethoxycarbonylamino can also be cleaved by treating with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenoxide, and 4-nitrobenzyloxycarbonylamino also by treating with an alkali metal dithionite, for example sodium dithionite.
  • a nucleophilic, preferably salt-forming, reagent such as sodium thiophenoxide, and 4-nitrobenzyloxycarbonylamino also by treating with an alkali metal dithionite, for example sodium dithionite.
  • Substituted or unsubstituted diphenylmethoxycar- bonylamino, tert-lower-alkoxycarbonylamino or 2-(trisubstituted silyl)-lower-alkoxycarbonyl- amino, such as 2-tri-lower-alkylsilyl-lower-alkoxycarbonylamino, can be cleaved by treating with a suitable acid, for example formic or trifluoroacetic acid, for example in a halogenated hydrocarbon, such as methylene chloride or chloroform (in particular, if hydroxyl which is simultaneously protected with benzyl is not to be set free), 1 -aryl-lower-alkoxycarbonylamino, such as substituted or unsubstituted benzyloxycarbonylamino, can, for example, be cleaved by means of hydrogenolysis, i.e.
  • a suitable hydrogenation catalyst such as a palladium catalyst
  • a support material such as carbon
  • polar solvents such as di-lower-alkyl-lower-alkanoylami- des, for example dimethylformamide
  • ethers such as cyclic ethers, for example dioxane
  • esters such as lower-alkyl lower-alkanoates, for example ethyl acetate
  • alcohols such as methanol, ethanol or propanol, with methanol being particularly preferred, preferably, for example, at room temperature
  • An amino group which is protected by 2-haloacetyl for example 2-chloroacetyl, can be set free by treating with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of the thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution product.
  • a thiolate salt such as an alkali metal thiolate of the thiourea
  • solvolysis such as alcoholysis or hydrolysis
  • An amino group which is protected by 2-(trisubstituted si- lyl) -lower-alkoxycarbonyl such as 2-tri-lower-alkylsilyl-lower-alkoxycarbonyl, can also be converted into the free amino group by treating with a fluoride anion-providing salt of the hydrofluoric acid, as indicated above in connection with the release of a correspondingly protected carboxyl group.
  • Silyl such as trimethylsilyl or tert-butyldimethylsiiyl, which is bonded directly to a heteroatom, such as nitrogen, can likewise be detached with fluoride ions, preferably using a fluoride of an organic, quaternary nitrogen base, such as tetra-lower-alkylammonium fluoride or tri-lower-alkylaryl-lower-alkylammonium fluoride, for example te- traethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide, or, in particular, of an ether, such as tetrahydrofuran, at temperatures between 0 and 50°C, in particular, for example, at room temperature.
  • aprotic, polar solvent such as dimethyl sulfoxide or N,N-dimethylacet
  • Amino which is protected in the form of an azido group is converted into free amino, for example, by means of reduction for example by means of catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, by means of reduction with mercapto compounds, such as dithiothreitol or mercaptoethanol, or by treating with zinc in the presence of an acid, such as acetic acid.
  • a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel
  • mercapto compounds such as dithiothreitol or mercaptoethanol
  • the catalytic hydrogenation is preferably carried out in an inert solvent, such as a haloge- nated hydrocarbon, for example methylene chloride, or else in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at from approximately 20°C to 25°C, or else while cooling or heating.
  • an inert solvent such as a haloge- nated hydrocarbon, for example methylene chloride
  • an organic solvent such as an alcohol or dioxane
  • a hydroxyl group which is protected by a suitable acyl group, a tri-lower-alkylsilyl group or by substituted or unsubstituted 1-aryl(such as 1 -phenyl)-lower-alkyl is set free in an analogous manner to a correspondingly protected amino group.
  • a hydroxyl group which is protected by 2,2-dichloroacetyl is set free, for example, by basic hydrolysis, while a hydroxyl group which is protected by tert-lower-alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is set free by acidoiysis, for example by treating with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid.
  • a hydroxyl group which is protected by benzyloxy is set free, for example, by means of hydrogenolysis, i.e.
  • a suitable hydrogenation catalyst such as a palladium catalyst, for example bound to a support material, such as charcoal, preferably in polar solvents, such as di-lower-alkyl-iower-alkanoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower-alkylalkanoates, for example ethyl acetate, chlorinated hydrocarbons, such as dichloromethane, or alcohols, such as methanol, ethanol or propanol, with methanol being particularly preferred, or mixtures of two or more of these solvents, preferably, for example, at room temperature.
  • polar solvents such as di-lower-alkyl-iower-alkanoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower-alkylalkanoates, for example ethy
  • Two hydroxyl groups, or an adjacent amino group and hydroxyl group, which are together protected by means of a bivalent protective group preferably, for example, a methylene group which is substituted once or twice by lower alkyl, such as by lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be set free by acidic solvolysis, particularly in the presence of a mineral acid or a strong organic acid.
  • a th-lower-alkylsilyl group is likewise detached by means of acidolysis, for example by mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid.
  • Hydroxyl can also preferably be set free from tri-lower-alkylsilyloxy by treating with a fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, for example sodium or potassium fluoride, in the absence or presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower-alkylammonium fluoride or tri- lower-alkylaryl-lower-alkylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide.
  • a fluoride anion-providing salt of hydrofluoric acid such as an alkali metal fluoride, for example sodium or potassium fluoride
  • 2-Halo-lower-alkoxycarbonyl is removed by the above- mentioned reducing agents, for example reducing metal, such as zinc, reducing metal salts, such as chromium(ll) salts, or by sulfur compounds, for example sodium dithionite or, preferably, sodium sulfide and carbon disulfide.
  • reducing metal such as zinc
  • reducing metal salts such as chromium(ll) salts
  • sulfur compounds for example sodium dithionite or, preferably, sodium sulfide and carbon disulfide.
  • Esterified hydroxyl groups for example lower- alkanoyloxy, such as acetyloxy, can also be set free with esterases, while acylated amino can, for example, be set free using suitable peptidases.
  • Etherified hydroxy especially phenyl-lower alkoxy, such as benzyloxy, or lower alkoxy, such as methoxy
  • a boron trihalide such as boron trichloride (at low temperatures, preferably in a halogenated hydrocarbon, especially methylene chloride, preferably in the temperature range from - 80 to 15 °C ) or especially boron tribromide (in an inert solvent, such as a hydrocarbon, for example benzene, toluene of xylene, preferably in the temperature range from 20 °C to the boiling temperature of the reaction mixture), or with a phosphoryl trihalide, such as phosphoroxychloride (preferably in a N,N-di-lower alkylform- amide, such as dimethyl formamide, at elevated temperatures, preferably in the range from 60 °C to the boiling temperature of the reaction mixture, for example at about 80 °C).
  • a boron trihalide such as boron
  • the reactive formaldehyde derivative is preferably a formylation reagent of the Vilsmeyer type, especially a N,N-di-lower alkylformamide, preferably dimethylformamide, or furthermore a formylation reagent of the Gattermann-Adams type (zinc cyanide in the presence of hydrogen chloride), formamide or formanilide (in the case of the two latter reagents in the presence of an inert gas, such as nitrogen).
  • a N,N-di-lower alkylformamide especially N,N-dimethylformamide.
  • boron trifluoride etherate the complex of boron trifluoride with diethyl ether
  • a halide of a strong acid either in an excess of the reactants (especially the N,N- di-lower alkyl formamide) or in inert organic solvents or solvent mixtures.
  • the halide of a strong acid is preferably a chloride of a strong acid, phosporoxychloride, thionylchloride, phosgene, oxaloylchloride, lower alkane sulfonyl chloride, such as methane sulfonyl chloride, benzene sulfonylchloride or p-toluene sulfonylchloride being especially preferred.
  • the reaction with methane sulfonylchloride in the presence of boron trifluoride etherate is especially preferred.
  • the reaction preferably takes place with a solution of a phenylketone of formula I which is dissolved in a solvent, the solvent preferably being dry formamide, to which solution the boron trifluoride etherate, preferably in an amount of 3 to 6 equivalents when related on the amount of the phenylketone, is added.
  • a further solution which comprises the methane sulfonylchloride (preferably in an excess) in an excess of dry dimethylformamide is added, an excess of 1 equivalent of methane sulfonylchloride being added for each hydroxy group present in the phenylketone of formula III.
  • the reaction preferably takes place at temperatures in the range from 40 °C up to the reflux temperature of the reaction mixture, for example at about 100 °C.
  • the product is then obtained after addition of water to the reaction mixure or addition of the reaction mixture to water at lower temperatures, especially from about 0 °C to about 10 °C, for example by pouring the reaction mixture onto ice.
  • Process variant )ii) is especially preferred in the case where X' in the phenylketone of formula III is oxygen.
  • Preferred among the reactions leading to such conversion is any of the following reactions, or a combination of twwo or more such reactions, where appropriate: a) Conversion of hydroxy into etherified hydroxy (for example, hydroxy R 1 ( R 2 , R 3 and/or R 4 ), e.g.
  • the reaction preferably takes place between a compound of formula I with at least one hydroxy group and a lower alkyl halogenide, such as methyl iodide, a lower alkane sulfate, such as dimethyl sulfate, in the presence of an alkali- metal salt of the respective alcohol of the formula I (obtainable, e.g., by use if potassium hydroxide in water) in water or preferably by reaction of a compound of formula I with at least one hydroxy group in a lower alkanol, such as ethanol or especially methanol, with diazomethane in etherial solution (can be obtained, e.g., from N-methyl-N-nitroso-toluene- sulfonamide, N-methylnitroso urea in the presence of diethylether and a strong base, such as potassium hydroxide) at a preferred temperature in the range from -40 to 20 °C, especially around -20 °C
  • the reaction is primarily taking place between a compound of formula I, wherein at least one etherified hydroxy group, such as methoxy, is present, and a boron trihalide, especially boron tribromide, preferably in an inert solvent, such as a hydrocarbon, especially benzene, toluene or xylene, or a mixture thereof, preferably at elevated temperature, such as between 60 and about 110 °C.
  • an acid binding base such as a tertiary nitrogen base, e.g. pyridine
  • Z-Q (V) wherein Z is lower alkyl or substituted lower alkyl and Q is a nucleofugal leaving group, preferably arylsulfonyl, such as p-toluolsulfonyl, alkylsulfonyl, such as methylsulfonyl, or halogen, such as chloro, bromo or iodo, in the presence of an acid binding compound, such as a carbonate or hydrogen carbonate salt, e.g. an alkalimetal carbonate or -hydrogen carbonate, especially potassium carbonate, in an appropriate solvent, e.g.
  • an acid amide such as N,N-dimethylformamide
  • the reaction primarily takes place under customary conditions fo the hydrolysis of esters, especially in the presence of hydroxide salts, such as alkaline metal hydroxides, especially lithium hydroxide or sodium hydroxide, at temperatures ranging from 0 °C to the reflux temperature of the reaction mixture, preferably from 20 °C to about 100 °C.
  • the conversion of a salt of a compound of formula I into a different salt is carried out, for example, in solvents, especially in organic solvents, more especially in polar organic solvents, very especially in esters, for example lower alkanoyl-lower alkyl esters, such as ethyl acetate, in amides, for example N,N-di-lower alkyl-lower alkanoylamides, such as dimethylformamide, in alcohols, for example hydroxy-lower alkanes, such as methanol, ethanol, ethylene glycol or glycerol, or aryl alcohols, such as phenols, for example phenol, or in dimethyl sulfoxide, in the absence or presence of water, preferably in the presence of water, or in water itself.
  • solvents especially in organic solvents, more especially in polar organic solvents, very especially in esters, for example lower alkanoyl-lower alkyl esters, such as ethyl acetate, in
  • reaction in alcohols such as the last-mentioned hydroxy-lower alkanes, in mixtures of such alcohols and water, or in water itself.
  • the reaction is carried out, for example, in free solution, but it may also be effected over chromatographic columns, for example by gel filtration.
  • the reaction is carried out at temperatures from immediately above the freezing point to the boiling point of the solutions in question, preferably at from 0 to 50°C, especially at from 20 to 40 C C, for example at room temperature, in the presence or absence of a protecting gas, such as nitrogen or argon.
  • the compounds of formula I and the salt-forming base or acid are used in suitable molar ratios, or the salt forming base or acid is employed in excess.
  • the individual components are used in the molar ratio that corresponds to the ratio of the molarity of the base of formulal and the acid in the resulting salts.
  • the salts that are formed precipitate, for example, by themselves, in some cases only after cooling, or they are precipitated by the addition of solvents, especially of non-polar solvents, for example ethers, such as diethyl ether, or of water, and/or are obtained by partial or complete concentration by evaporation.
  • the reaction may also be effected yja the free compounds of formula I, which are prepared, for example, by converting the base or acid salt of a base of formula I, with a first base or acid, used as starting material into the free compound with the aid of an acid or base, for example a hydroxy base, such as an alkali metal hydroxide, for example NaOH or KOH, or with an OH -charged ion exchanger in aqueous solution in the presence or absence of an organic solvent, as defined above; the subsequent conversion of the free compound may be carried out, for example, as described above.
  • a hydroxy base such as an alkali metal hydroxide, for example NaOH or KOH
  • an OH -charged ion exchanger in aqueous solution in the presence or absence of an organic solvent, as defined above
  • the free compounds of formula I are preferably prepared as just described, also by chro- matography, for example by gel filtration, or over ion exchangers.
  • R 3 , R 4 and n have the meanings given above for a compound of formula I and A is halogen, especially chloro or bromo, any free functional groups present being protected if necessary by readily removable protecting groups, with a phenol deriative of the formula VII,
  • Ri and R 2 are as defined for formula I
  • Po is a hydroxy protecting group, preferably as mentioned above, especially methyl
  • X b is either oxygen or protected imino wherein the protecting group is one as described above for the protection of an amino group, especially lower alkanoyl, such as acetyl; any free functional groups present being protected if necessary by readily removable protecting groups,
  • a Friedel-Crafts-catalyst especially stannic chloride (SnCI 4 )
  • an appropriate solvent e.g. a halogenated hydrocarbon, such as 1 ,2-di- chloroethane
  • the reaction temperature preferably being in the range of from -20 to 50 °C, especially from 0 to 25 °C, and subsequent hydrolysis, especially with ice water.
  • protecting groups can be removed after the reaction in accordance with the methods mentioned above for removal of protecting group to obtain a compound of formula I.
  • R 3 , R 4 and n are as defined for a compound of formula I, any free functional groups in a starting material of the formula VII and/or VIII present being protected if necessary by readily removable protecting groups, in the presence of an appropriate catalyst, such as aluminium chloride (AICI 3 ) or preferably zinc chloride (ZnCI 2 ) and in an appropriate solvent, such as an ether, especially diethylether and subsequent hydrolysis in the presence of HCI (e.g. by pouring the reaction mixture on ice or into ice water).
  • an appropriate catalyst such as aluminium chloride (AICI 3 ) or preferably zinc chloride (ZnCI 2 )
  • an appropriate solvent such as an ether, especially diethylether and subsequent hydrolysis in the presence of HCI (e.g. by pouring the reaction mixture on ice or into ice water).
  • protecting groups can be removed after the reaction in accordance with a method mentioned above for removal of protecting group to obtain a compound of formula I.
  • the starting materials can be prepared by methods analogous to those given in the examples.
  • Free compounds of formula I having salt-forming properties that are obtainable in accordance with the process can be converted into their salts in a manner known p_er se, for example by treatment with acids or suitable derivatives thereof, or with bases, for example by the addition of the acid or base in question to the compound of formula I dissolved in a suitable solvent, for example an ether, such as a cyclic ether, especially dioxane or more especially tetrahydrofuran. Where appropriate and where a salt-forming group is present, starting materials and intermediates can also be used in the form of salts.
  • reaction steps mentioned above can be carried out under reaction conditions that are known per se, in the absence or, customarily, in the presence of solvents or diluents, preferably solvents or diluents that are inert towards the reagents used and are solvents therefor, in the absence or presence of catalysts, condensation agents (e.g.
  • phosphorus pentoxide or neutralising agents, for example bases, especially nitrogen bases, such as triethylamine hydrochloride, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from approximately - 80°C to approximately 200°C, preferably from approximately -20°C to approximately 150°C, for example at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere.
  • bases especially nitrogen bases, such as triethylamine hydrochloride, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from approximately - 80°C to approximately 200°C, preferably from approximately -20°C to approximately 150°C, for example at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere
  • Solvents and diluents are, for example, water, alcohols, for example lower alkyl hydroxides, such as methanol, ethanol, propanol or, especially, butanol, diols, such as ethylene glycol, triols, such as glycerol, or aryl alcohols, such as phenol, acid amides, for example carboxylic acid amides, such as dimethylformamide, dimethylacetamide or 1 ,3-dimethyl-3,4,5,6--- tetrahydro-2(1H)-pyrimidinone (DMPU), carboxylic acids, especially formic acid or acetic acid, amides of inorganic acids, such as hexamethylphosphoric acid triamide, ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons,
  • customary processes for example solvolysis of excess reagents; recrystallisation; chromatography, for example partition, ion or gel chromatography; partitioning between inorganic and organic solvent phases; extraction one or more times, especially after acidification or in- creasing the basicity or the salt content; drying over hygroscopic salts; digestion; filtration; washing; dissolution; concentration by evaporation (if necessary in vacuo or under a high vacuum); distillation; crystallisation, for example of resulting compounds in oil form or from the mother liquor, inoculation with a crystal of the end product also being possible; or a combination of two or more of the mentioned working-up steps, which may also be used repeatedly.
  • customary processes for example solvolysis of excess reagents; recrystallisation; chromatography, for example partition, ion or gel chromatography; partitioning between inorganic and organic solvent phases; extraction one or more times, especially after acidification or in- creasing the basicity or the salt content; drying over h
  • Starting materials and intermediates may be used in pure form, for example after working up as mentioned above, in partially purified form or, for example, directly in the form of a crude product.
  • any reference hereinbefore and hereinafter to the free compounds or their salts is be understood as meaning also the corresponding salts or free compounds, respectively, where appropriate and expedient, provided that the compounds contain salt- forming groups.
  • the compounds, including their salts may also be obtained in the form of hydrates, or as soivates; their crystals may include, for example, the solvent used for crystallisation.
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example a salt thereof.
  • compositions comprising those compounds as active ingredient
  • the present invention relates also to pharmaceutical compositions that comprise a compound of formula I, or a salt thereof, as active ingredient and that can be used especially in the treatment of the diseases mentioned at the beginning.
  • compositions for enteral such as nasal, buccal, rectal or, especially, oral, and parenteral, such as intravenous, intramuscular or subcutaneous, administration to warm-blooded animals, especially humans.
  • the compositions comprise the active ingredient on its own or, preferably, together with a pharmaceutically acceptable carrier.
  • the dose of active ingredient depends on the disease to be treated, and on the species, its age, weight and individual condition, on individual pharmacokinetic conditions, and on the mode of administration.
  • the invention relates also to pharmaceutical compositions for use in a method for the, especially therapeutic, treatment of the human or animal body, especially for the treatment of one of the diseases mentioned above, to a process for the preparation thereof (especially as compositions for the treatment of tumours and/or psoriasis), and to a method of treating a tumour disease and/or psoriasis , especially those diseases mentioned above.
  • the invention relates also to processes for, and to the use of compounds of formula I in, the preparation of pharmaceutical compositions that comprise compounds of formula I as active component (active ingredient).
  • a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human or furthermore a commercially usable mammal, suffering from a disease as described above, preferably from a disease that is responsive to inhibition of a protein kinase, especially a protein tyrosine kinase, preferably EGF-R kinase, for example psoriasis or a tumour, which composition comprises a compound of formula I, or a salt thereof where a salt-forming group is present, in an amount that is effective in the treatment o said disease, together with at least one pharmaceutically acceptable carrier.
  • compositions for the treatment of tumour diseases and/or psoriasis in a warm-blooded animal, especially a human or furthermore a commercially usable mammal, which requires such treatment, especially which is suffering from such a disease which composition comprises as active ingredient a novel compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount that is, especially, therapeutically effective against the mentioned disease.
  • the pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, dosage forms that are in single dose form preferably comprising from approximately 20% to approximately 90% active ingredient, and dosage forms that are not in single dose form preferably comprising from approximately 5% to approximately 20% active ingredient.
  • Unit dose forms are, for example, dragees, tablets, ampoules, vials, suppositories or capsules.
  • Other dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc.
  • Examples are capsules comprising from approximately 0.05g to approximately 1.0g of the active ingredient.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
  • solutions of the active ingredient, or suspensions or dispersions especially isotonic aqueous solutions, dispersions or suspensions, which, for example in the case of lyophilised compositions comprising the active ingredient on its own or together with a carrier, e.g. mannitol, may be prepared before use.
  • the pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known p_er se, for example by means of conventional dissolving or lyophilising processes.
  • Said solutions or suspensions may comprise viscosity- increasing substances, such as sodium carboxymethylcelluiose, carboxymethylcellulose, dextran, poiyvinylpyrrolidone or gelatin, and/or solubilisers, for example ®Tween 80 [poiy- oxyethylene(20) sorbitan monooleate; trade mark of ICI Americas, Inc, USA].
  • viscosity- increasing substances such as sodium carboxymethylcelluiose, carboxymethylcellulose, dextran, poiyvinylpyrrolidone or gelatin
  • solubilisers for example ®Tween 80 [poiy- oxyethylene(20) sorbitan monooleate; trade mark of ICI Americas, Inc, USA].
  • Suspensions in oil comprise as the oil component a vegetable, synthetic or semi-synthetic oils customarily used for injection purposes.
  • liquid fatty acid esters which contain as acid component a long-chain fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, thdecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, where appropriate with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of those fatty acid esters has not more than 6 carbon atoms and is a mono- or poly-valent, for example mono-, di- or tri-valent, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol and glycerol.
  • fatty acid esters ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M2375” (polyoxyethylene glycerol trioleate from Gattefosse, Paris), “Labrafil M1944 CS” (unsaturated polyglycolised glycerides prepared by alcoholysis of apricot kernel oil and composed of glycerides and polyethylene glycol esters; Gattefosse, France), “Labrasol” (saturated polyglycolised glycerides prepared by alcoholysis of TCM and composed of glycerides and polyethylene glycol esters; Gattefosse, France) and/or "Miglyol 812” (triglyceride of saturated fatty acids having a chain length of from C 8 to C ⁇ 2 from H ⁇ ls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesam
  • the preparation of the injection compositions is carried out in customary manner under sterile conditions, as are the introduction, for example, into ampoules or vials and the sealing of the containers.
  • compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, granulating a resulting mixture, where appropriate, and processing the mixture or granules, if desired, where appropriate with the addition of additional excipients, to form tablets or dragee cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example trical- cium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, or alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stea- ric acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Dragee cores can be provided with suitable, where appropriate enteric coatings, there being used inter alia concentrated sugar solutions, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • enteric coatings there being used inter alia concentrated sugar solutions, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate. Colouring
  • compositions for oral administration are also hard gelatin capsules, and soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the hard gelatin capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders and/or giidants, such as talc or magnesium stearate, and, where appropriate, stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it likewise being possible to add stabilisers and detergents, for example of the poly- oxyethylene sorbitan fatty acid ester type.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it likewise being possible to add stabilisers and detergents, for example of the poly- oxyethylene sorbitan fatty acid ester type.
  • oral dosage forms are, for example, syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of approximately from 5% to 20%, preferably approximately 10% or in a similar concentration that provides a suitable single dose when administered, for example, in a measure of 5 or 10 ml.
  • syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of approximately from 5% to 20%, preferably approximately 10% or in a similar concentration that provides a suitable single dose when administered, for example, in a measure of 5 or 10 ml.
  • powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packed in single dose quantities.
  • Suitable rectaliy administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • aqueous solutions of an active ingredient in water-soluble form for example in the form of a water-soluble salt, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilisers.
  • the active ingredient where appropriate together with one or more excipients, can also be in the form of a lyophilisate and be made into a solution prior to parenteral administration by the addition of suitable solvents.
  • Solutions used, for example, for parenteral administration can also be used as infusion solutions.
  • Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or micro- bicides, such as sorbic acid or benzoic acid.
  • Ointments are oil-in-water emulsions that comprise up to 70%, but preferably from 20 to 50%, water or aqueous phase.
  • fatty phase especially hydrocarbons, for example "Vaseline, paraffin oil or hard paraffins, which, in order to improve the water-binding capacity, preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters ("Spans), for example sorbitan oleate and/or sorbitan isostearate.
  • Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and perfumes.
  • humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and perfumes.
  • Fatty ointments are anhydrous and comprise as base especially hydrocarbons, for example paraffin, Vaseline' or paraffin oil, also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated peanut oil or castor oil, also fatty acid partial esters of glycerol, for example glycerol mono- and/or di- stearate, and also, for example, the fatty alcohols increasing water absorption, emulsifiers and/or additives mentioned in connection with the ointments.
  • hydrocarbons for example paraffin, Vaseline' or paraffin oil
  • natural or partially synthetic fats for example coconut fatty acid triglyceride
  • hardened oils for example hydrogenated peanut oil or castor oil
  • fatty acid partial esters of glycerol for example glycerol mono- and/or di- stearate
  • the fatty alcohols increasing water absorption, emulsifiers and/or additives mentioned in
  • Creams are oil-in-water emulsions that comprise more than 50% water.
  • oily base there are used especially fatty alcohols, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example ⁇ Vaseline (petrolatum) or paraffin oil.
  • Suitable emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty acid esters fTween), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol.
  • corresponding non-ionic emulsifiers for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorb
  • Additives to the aqueous phase are inter alia agents that reduce the drying out of the creams, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, also preservatives and perfumes.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, also preservatives and perfumes.
  • Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, also talc and/or aluminium silicates, the purpose of which is to bind any moisture or secretions present.
  • metal oxides for example titanium oxide or zinc oxide
  • talc and/or aluminium silicates the purpose of which is to bind any moisture or secretions present.
  • Foams are administered from pressurised containers and are liquid oil-in-water emulsions in aerosol form, there being used as propellants halogenated hydrocarbons, such as chloro- fluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, or preferably non-halogenated gaseous hydrocarbons, air, N 2 O or carbon dioxide.
  • halogenated hydrocarbons such as chloro- fluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, or preferably non-halogenated gaseous hydrocarbons, air, N 2 O or carbon dioxide.
  • oil phase there are used inter alia the oil phases used above under ointments and creams, likewise the additives mentioned therein.
  • Tinctures and solutions generally have an aqueous-ethanolic base to which there are added inter alia polyalcohols, for example glycerol, glycols and/or polyethylene glycol, as humec- tants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with low molecular weight polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances removed from the skin by the ethanoi, and, if necessary, other excipients and additives.
  • polyalcohols for example glycerol, glycols and/or polyethylene glycol
  • humec- tants for reducing evaporation for glycerol, glycols and/or polyethylene glycol
  • fat-restoring substances such as fatty acid esters with low molecular weight polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for
  • the invention relates also to a process or a method for the treatment of the pathological conditions mentioned above, especially those which are responsive to inhibition of protein kinases.
  • the compounds of formulal may be administered prophylactically or therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount that is effective against the mentioned diseases, to a warm-blooded animal, for example a human, requiring such treatment, the compounds being used especially in the form of pharmaceutical compositions.
  • a daily dose of from approximately 0.1 g to approximately 5g, preferably from approximately 0.5g to approximately 2g, of a compound of the present invention is administered.
  • the starting material is prepared in the following way: Step 1a) 2-(3-Chlorophenyl)-1 -(2,4,6-trihvdroxyphenyl)ethanone)
  • the compound is prepared from 2-(3-bromophenyl)-1 -(2,4,6-trihydroxyphenyl)ethanone (synthesis in analogy to Step 1a) starting from phloroglucine and (instead of 3-chloroben- zylcyanide) 3-bromobenzylcyanide) and boron trifluoride etherate.
  • Example 3 but starting from phloroglucine and (instead of 3-bromobenzylcyanide) 3,4- dichiorobenzylcyanide) and diazomethane).
  • Example 6 3-(3-Chlorophenyl)-5-hydroxy-7-methoxy-4-quinolone DMF (1 ml) is cooled to 10 °C and 0.74 ml (9.67 mMol) of phosphoroxychloride is added. The reaction mixture is stirred at room temperature for 30 min, developing a deep pink colour. 2.80 g (8.06 mMol) of 2-(3-chiorophenyl)-1 -(2,4-dimethoxy-6-acetamide-phenyl)- ethanone, dissolved in 2 ml of DMF, is added to the DMF-POCl3-complex, upon which the colour of the reaction mixture turns into deep red.
  • 3-methoxyphenyl-acetylchloride [can be obtained from 3-methoxphenyi-acetic acid (Fluka, Buchs, Switzerland) by reaction with thionyl chloride or phosphortrichloride under reflux] and acetamido-3,5-dimethoxybenzene with 2-(3-methoxyphenyl)-1 -(2,4-dimeth- oxy-6-acetamide-phenyl)ethanone as intermediate, which is then demethylated with the DMF-POC -compiex under removal of two methoxy groups, yielding the title compound).
  • Example 10 N-Methyl-3-(3-chlorophenyl)-5-hydroxy-7-methoxy-4-quinolone 0.123 g (0.41 mMol) of 3-(3-chlorophenyl)-5-hydroxy-7-methoxy-4-quinolone (Example 6) is dissolved in 4ml of DMF. Then methyl iodide (0.03ml, 0.48 mMol) and potassium carbonate (0.1 g, 1 mMol) are added. The reaction mixture is stirred at room temperature for 30 min, poured into water and extracted with ethyl acetate. The organic phase is dried and the solvent removed in vacuo to yield a yellow solid.
  • Example 11 N-(2-Phenylethyl)-3-(3-chlorophenyl)-5-hydroxy-7-methoxy-4-quinolone 60mg (0.198 mMol) of 3-(3-chlorophenyl)-5-hydroxy-7-methoxy-4-quinolone (Example 6) is dissolved in 5 ml of DMF. Then 0.1 ml (0.74 mMol) of 2-phenylethyl bromide (Fluka, Buchs, Switzerland) and 0.1 g (1 mMol) of potassium carbonate is added. The reaction mixture is stirred at room temperature for 17 h, poured into water and extracted with ethyl acetate.
  • Example 13 3-(3-Chlorophenyl)-1 -ethoxycarbonylmethyl-5-hvdroxy-7-methoxy-4-guinolone
  • the title compound is prepared from3-(3-chlorophenyl)-5-hydroxy-7-methoxy-4-quinolone (Example 6) and bromoacetic acid ethylester (Fluka, Buchs, Switzerland).
  • Example 14 a) 1 -(Carboxy-methyl)-3-(3-chlorphenyl)-5-hvdroxy-7-methoxy-4-quinolone-
  • Example 15 Dry-filled capsules
  • Preparation process The mentioned substances are pulverised and forced through a sieve of 0.6 mm mesh size. 0.33 g portions of the mixture are introduced into gelatin capsules using a capsule-filling machine.
  • Preparation process The active ingredient is pulverised and suspended in PEG 400 (polyethylene glycol having an M r of from approx. 380 to approx. 420, Fluka, Switzerland) and Tween ® 80 (polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland) and ground in a wet pulveriser to a particle size of approx. from 1 to 3 ⁇ m. 0.43 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
  • PEG 400 polyethylene glycol having an M r of from approx. 380 to approx. 420, Fluka, Switzerland
  • Tween ® 80 polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland
  • 0.43 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
  • Example 18 Inhibition of EGF-R protein tyrosine kinase:
  • EGF-R ICD EGF-receptor
  • Example 19 Inhibition of the growth of the epidermoid mouse keratinocyte cell line: In accordance with the test system given above (see Meyer et ai, Int. J. Cancer 43, 851 (1989)), the inhibitory activity of the compounds of formula I on the growth of the epidermoid mouse keratinocyte cell line is determined as follows, the result being given as IC 50 ( ⁇ M):

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Abstract

Cette invention concerne l'utilisation d'un composé de formule (I) dans laquelle R1 et R2 représentent indépendamment l'un de l'autre hydrogène, hydroxy ou alcoxy inférieur, ou bien R1 et R2 forment ensemble alkylènedioxy inférieur; R3 représente halogène, alkyle inférieur, alkyle inférieur à substitution halogène, hydroxy, phényloxy, cycloalkyloxy C3-C7 alcoxy inférieur; tout R4 indépendamment de R3 et indépendamment de tout autre R4 existant est sélectionné parmi halogène, alkyle inférieur, alkyle inférieur à substitution halogène, hydroxy, phényloxy, cycloalkyloxy C3-C7 alcoxy inférieur; X représente oxygène, imino ou imino à substitution (alcanoyle inférieur à substitution halogène ou non substitué, [alkyle inférieur ou carboxy-, alcoxycarbonyle inférieur, aminocarbonyle, N-mono- ou N,N,di-alkylamino inférieur-carbonyle] alkyle inférieur; ou aryle C6-C12); et n représente 0, 1, 3 ou 4. On peut utiliser ce composé ou un de ses sels s'il existe au moins un groupe formant un sel, dans le traitement de certaines maladies et pour inhiber des protéine kinases. Cette invention concerne également de nouveaux composés de formule (I) ainsi que leurs sels.
PCT/EP1997/005697 1996-10-18 1997-10-16 Derives d'heterocyclyle bicyclique a substitution phenyle et utilisation de ces derives WO1998017662A1 (fr)

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FR2797444A1 (fr) * 1999-08-13 2001-02-16 Lafon Labor Compositions pharmaceutiques comprenant des 4-quinolones
WO2001083469A1 (fr) * 2000-05-03 2001-11-08 Lg Life Sciences Ltd. Inhibiteurs de cdk avec structure 3-hydroxychromen-4-une
LT4855B (lt) 1997-10-27 2001-11-26 Agouron Pharmaceuticals,Inc. Pakeisti 4-amino-tiazol-2-il junginiai kaip nuo ciklino priklausomų kinazių inhibitoriai
FR2813791A1 (fr) * 2000-09-14 2002-03-15 Lafon Labor Utilisation de 2- et 4-quinolones pour inhiber la neo-proliferation intimale
WO2002047686A1 (fr) * 2000-12-16 2002-06-20 The University Of Nottingham 4-quinolones substituees
US6462069B2 (en) 2000-04-18 2002-10-08 Agouron Pharmaceuticals, Inc. Compounds, pharmaceutical compositions, and methods for inhibiting protein kinases
US6462060B2 (en) 2000-08-18 2002-10-08 Agouron Pharmaceuticals, Inc. Heterocyclic-hydroxyimino-fluorene nuclei compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use
US6555539B2 (en) 2000-01-18 2003-04-29 Agouron Pharmaceuticals Indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation
WO2003035635A1 (fr) * 2001-10-25 2003-05-01 Novogen Research Pty Limited 6-hydroxy isoflavones, derives et medicaments les mettant en oeuvre
US6566363B2 (en) 2000-08-09 2003-05-20 Agouron Pharmaceuticals, Inc. Pyrazole-thiazole compounds, pharmaceutical compositions containing them
KR100399364B1 (ko) * 2000-09-18 2003-09-26 주식회사 엘지생명과학 사이클린 의존 키나아제의 저해제로서 유용한3-히드록시-6-아미노-크로멘-4-온 유도체
US6635641B2 (en) 2000-01-21 2003-10-21 Agouron Pharmaceuticals, Inc. Amide compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use
WO2004030662A1 (fr) * 2002-10-02 2004-04-15 Novogen Research Pty Ltd Compositions chimiotherapeutiques combinees et procedes correspondant
WO2004092154A1 (fr) * 2003-04-03 2004-10-28 Vertex Pharmaceuticals Incorporated Compositions utiles en tant qu'inhibiteurs de proteines kinases
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