WO2004076444A2 - Novel hydroxycoumaranone derivatives as antitumor and antimetastatic - Google Patents

Novel hydroxycoumaranone derivatives as antitumor and antimetastatic Download PDF

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Publication number
WO2004076444A2
WO2004076444A2 PCT/EP2004/001798 EP2004001798W WO2004076444A2 WO 2004076444 A2 WO2004076444 A2 WO 2004076444A2 EP 2004001798 W EP2004001798 W EP 2004001798W WO 2004076444 A2 WO2004076444 A2 WO 2004076444A2
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Prior art keywords
benzofuran
piperidin
oxo
benzamide
yloxy
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PCT/EP2004/001798
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French (fr)
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WO2004076444A3 (en
Inventor
Sabine Bauer
Richard Endele
Georg Fertig
Walter-Gunar Friebe
Matthias Koerner
Hans-Willi Krell
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F. Hoffmann-La Roche Ag
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Publication of WO2004076444A2 publication Critical patent/WO2004076444A2/en
Publication of WO2004076444A3 publication Critical patent/WO2004076444A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel hydroxycoumaranone derivatives as antitumor and antimetastafic agents with improved biological activity in cellular assays and improved stability
  • the present invention relates to novel derivatives of 2-alkylidene hydroxycoumaranones wherein the hydroxy group is substituted by a nitrogen- containing residue. These compounds have been found to possess uPA-uPAR antagonist activity and can be employed as antitumor and/or antimetastatic agents.
  • uPA urokinase-type plasminogen activator catalyzes the activation of plasminogen to plasmin which is involved in a variety of physiological and pathological processes.
  • uPA is a multi-domain protein having a catalytic "B" chain (amino acids 144-411) and an amino-terminal fragment ("ATF", aa 1-143) comprised of a growth factor-like domain (aa 4-43) and a kringle domain (aa 47-135).
  • ATF amino-terminal fragment
  • uPA is a multifunctional protein involved in tissue proteolysis, cellular migration, cellular proliferation and growth factor activation.
  • uPA is released from cells as a virtually inactive pro-enzyme, pro-uPA.
  • the activation of the single-chain pro-uPA by plasmin is regulated by tight control mechanisms which are not completely understood yet.
  • Most of the uPA activities are confined to the cell surface and the pericellular environment. This is accomplished by binding to a specific, high- affinity receptor on the cell surface (uPAR). Both forms of uPA bind to uPAR with similar affinity. The binding interaction is mediated by the growth factor-like domain (Rabbani, S.A., et al., J. Biol. Chem. 267 (1992) 14151-14156).
  • the uPA receptor is a three-domain glycoprotein where each triplicate motif comprises a cysteine rich consensus sequence of approximately 90 amino acids (Ploug, M., et al.,
  • uPAR is anchored to the cell membrane by a glycosyl-phosphatidylinositol moiety (GPI anchor).
  • GPI anchor glycosyl-phosphatidylinositol moiety
  • uPAR binds uPA with K D values between 10 "10 and 10 "9 M, depending on the experimental system.
  • the major determinants for uPA binding are located in the N-terminal domain 1.
  • uPAR can be cleaved by uPA and plasmin, liberating a water-soluble domain 1 and by the action of phospholipase C, three domains uPAR (1+2+3) can be released from the cell surface. This latter form of uPAR is also water-soluble because the GPI-anchor is missing.
  • the inhibition of uPA dependent phenomena can principally be approached in two ways, either by direct inhibition of the proteolytic activity or by inhibition of uPA receptor binding. The latter strategy has the potential of achieving greater specificity since inhibition might be
  • uPA/uPAR system has been shown to be implicated in a variety of invasive biological processes such as tumor metastasis, trophoblast implantation, inflammation and angiogenesis. Therefore, uPAR antagonists should be able to block tumor invasiveness, metastasis and angiogenesis.
  • Formulations containing uPAR antagonists represent novel therapeutic treatments for a number of highly invasive and metastasising cancers where uPA and uPAR have been found to be consistently present at the invasive foci of the tumor (Dano et al., Proteolysis and Protein Turnover, eds.
  • Inhibitors of plasmin generation by receptor bound uPA therefore have mechanism-based tumoristatic, anti-invasive, anti-metastatic, anti- angiogenic, anti- arthritic, anti-inflammatory, anti-osteoporotic, anti-retinopathic and contraceptive activities.
  • uPA urokinase-type plasminogen activator
  • uPAR uPA receptor
  • Receptor- bound uPA plays a crucial role in extracellular matrix degradation thereby contributing to tumor invasiveness, metastasis and angiogenesis.
  • Receptor-mediated activation of plasminogen to plasmin is, by several orders of magnitude, more efficient than non- receptor mediated activation.
  • uPA/uPAR interaction In syngeneic and xenograft murine tumor models, in which metastasis is driven by the uPA/uPAR interaction, inhibition of primary tumor growth, metastasis and angiogenesis has been achieved with several proteins acting as uPAR antagonists.
  • This therapeutic principle represents a novel approach since inhibitors of receptor binding of uPA are expected to provide higher therapeutic specificity than uPA enzyme inhibitors.
  • Low molecular weight uPAR antagonists should be able to inhibit the dissemination of cancer cells without the need for targeted drug and vector delivery.
  • the present invention relates to new compounds of the general formula (I) or (II)
  • R 1 , R 2 are independently hydrogen; alkyl; cycloalkyl; -NH(C ⁇ -C 4 -alk l); -N(CrC 4 -alkyl) 2 ;
  • R 1 and R 2 together with the carbon-atom to which they are attached form a cycloalkyl group
  • A is alkylene
  • B is a heterocyclic group
  • M is -NH-C(O)-
  • R 3 , R 4 are independently hydrogen; halogen;
  • n 1, 2, 3 or 4;
  • Objects of the present invention are the compounds of formula I or II, their pharmaceutically acceptable salts as well as their enantiomeric forms, diastereoisomers and racemates; the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds as uPA receptor antagonists and therefore in the control or prevention of illnesses and disorders as mentioned above, or in the manufacture of corresponding medicaments.
  • halogen denotes fluorine, chlorine, bromine or iodine.
  • alkyl means a linear or branched, saturated hydrocarbon containing from 1 to 12, preferably from 1 to 6 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, 1 -butyl, iso-butyl, sec-butyl, t-butyl or n-pentyl and n-hexyl as well as their isomers. Said alkyl group may optionally be substituted once or several times with deuterium or halogen, preferably with fluorine. Such groups are for example trideuteriomethyl or mono-, di- or trihalogenomethyl; preferably mono-, di- or trifluormetihyl.
  • - - alkyl means a linear, saturated hydrocarbon containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl or butyl.
  • alkylene as used herein means a bivalent radical of a linear or branched, saturated hydrocarbon containing from 1 to 10, preferably from 4 to 6 carbon atoms. Said alkylene group may optionally be once or several times substituted with halogen or deuterium. Preferred alkylene groups are for example:
  • -(CH 2 ) represents -CH(CH 3 )-(CH 2 ) n -; -CH(CH 3 )-(CH 2 ) n -CH(CH 3 )-; -C(CH 3 ) 2 -(CH 2 ) n -; -C(CH 3 ) 2 -(CH 2 ) n -C(CH 3 ) 2 -; -CX 2 -(CH 2 ) n -CX 2 -; -(CH 2 ) ⁇ -CX 2 -CX 2 -; wherein n is an integer from 1 to 4 and X is a halogen as definded herein before or a deuterium.
  • cycloalkyl means a saturated, monocyclic hydrocarbon containing 3 to 8, preferably from 3 to 6 carbon atoms, such as for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • heterocyclic group as used herein means a 5- to 10-membered, preferably 6- to 8- membered, mono- or bicyclic, saturated hydrocarbon, wherein 1 to 3, prefreably 1 carbon atom is replaced by nitrogen. Said heterocyclic group may optionally be once or several times substituted with an alkyl group as defined herein before, preferably with a methyl- or trifluormethyl group.
  • Preferred heterocyclic groups are bivalent radicals of piperidine; 2,6-dimethyl-piperidine; 2,6-bistrifluoromethyl-piperidine; 2,2,6,6- tetramethyl-piperidine or 8-aza-bicyclo[3.2.1]octane.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) or (II) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p- toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • Sample base-addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide.
  • a drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel, H., et. al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995, at pp. 196 and 1456-1457.
  • An embodiment of the invention are the compounds of formula I, wherein R 1 , R 2 , R 3 , R 4 , A, B and M have the significance given above.
  • Another embodiment of the invention are the compounds of formula II, wherein R 1 , R 2 , R 3 , R 4 , A, B and M have the significance given above.
  • R , R are independently hydrogen
  • R* and R 2 together with the carbon-atom to which they are attached form a cyclopentyl
  • R >3 , R are independently hydrogen; halogen; or -SO 2 -NH 2 ;
  • A, B and M have the significance given above.
  • R , R 2 are both -CH 3 ; -CD 3 ; -S-CH 3 ; -CH 2 -O-CH 3 or cyclopropyl; or R and R 2 together with the carbon-atom to which they are attached, form a cyclopentyl;
  • R , R are independently hydrogen; halogen; or
  • A has the significance given above.
  • Such compounds are for example:
  • Yet another embodiment is a compound of formula I or I-A, wherein
  • R 1 , R 2 are independently but not both at the same time hydrogen; methyl; cyclopropyl; or -N(CH 3 ) 2 ;
  • R , R and A have the significance given for formula I-A.
  • Such compounds are for example:
  • R ⁇ R" are both -CH 3 ; -CD 3 ; -S-CH 3 ; -CH 2 -O-CH 3 or cyclopropyl;
  • R , R are independently hydrogen; halogen; or
  • A has the significance given above.
  • Such a compound is for example:
  • R ⁇ R 2 are both alkyl
  • R , R are independently hydrogen; or halogen
  • Yet another embodiment of the invention are the compounds of formula I, wherein B is 8-aza-bicyclo[3.2.1]oct-3,8-diyl and M is -NH-C(O)-, of formula I-D
  • R ⁇ R 2 are both alkyl
  • R , R are independently hydrogen; or halogen
  • A has the significance given above.
  • Such compounds are for example:
  • Yet another embodiment of the invention are the compounds of formula II, wherein B is piperidin-l,4-diyl and M is -NH-C(O)-, of formula II-A
  • R , R 2 are both alkyl
  • R 1 and R 2 together with the carbon-atom to which they are attached form a cycloalkyl group
  • R j3 , ⁇ R.4 are independently hydrogen; or halogen
  • A is alkylene
  • Such compounds are for example:
  • Yet another embodiment of the invention is the process for the manufacture of compounds of the general formula (I) or (II), which comprises reacting a compound of either formula (Ilia) or (Illb)
  • LI and L2 are the same or different leaving groups such as chlorine, bromine, iodine, mesyl, tosyl or trifluoromethanesulfonyl;
  • the compounds according to the invention can in general be prepared according to the two-step process described in the patent applications EP 0 088 986, WO 99/06387 and EP 1 026 165, which are incorporated by reference.
  • the intermediate product of the first synthesis step is preferentially isolated before submitting it to the second reaction.
  • the oxygen-alkylation is performed under strongly basic conditions, preferably by means of an alkoxide of alkaline metal such as sodium ethoxide or isopropoxide or potassium carbonate in a suitable solvent, preferably a (Ci-C )alkyl alcohol or dimethylformamide, and at temperatures ranging from 20°C to the boiling temperature of the solvent.
  • the nitrogen- alkylation is instead performed at milder conditions, in the presence of a base such as an organic base, preferably a trialkylamine, or an inorganic base, preferably a carbonate of an alkaline or alkaline- earth metal, at temperatures ranging from room temperature to 50°C.
  • a base such as an organic base, preferably a trialkylamine, or an inorganic base, preferably a carbonate of an alkaline or alkaline- earth metal, at temperatures ranging from room temperature to 50°C.
  • R ⁇ CO-R 2 by reaction with an aldehyde or ketone of formula R ⁇ CO-R 2 , in which R 1 and R 2 are as above defined, in the presence of a base, preferably a hydroxide of an alkaline metal or ammonia, in an alcohol and at temperatures up to the boiling point of the solvent.
  • a base preferably a hydroxide of an alkaline metal or ammonia
  • the compounds of formula (IV) are commercial products or can easily be prepared starting from commercial products according to usual reactions such as halogenation of alcohols or their conversion into mesyl and tosyl derivatives, which are known reactions for someone skilled in the art.
  • the compounds of formula (V) can be prepared starting from a suitably mono- protected diamine of formula P-B-H, in which P is for example a benzyl or tert- butoxycarbonyl group, by acylation with a compound of formula (VII):
  • reaction is performed by using a base and an inert solvent at temperatures ranging from 0°C to 50°C.
  • the mono-protected diamines of formula P-B-H and the compounds of formula (VII) are known and mostly commercial products or can be prepared therefrom according to methods which are known to someone skilled in the art.
  • Racemates of the general formula (I) or (II) can contain one or several chiral centres and can then be present in a racemic or in an optically active form.
  • the racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • the racemic compounds can be separated into their enantiomers by chromatography on an analytical, semipreparative or preparative scale using suitable optically active stationary phases with suitable eluents.
  • Suitable optically active stationary phases include, but are not limited to, silica (e.g. ChiraSper,Merck; Chiralpak OT/OP, Baker), cellulose esters or carbamates (e.g. Chiracel OB/OY, Baker) or others (e.g. Crownpak, Daicel or Chiracel OJ-R, Baker).
  • silica e.g. ChiraSper,Merck; Chiralpak OT/OP, Baker
  • cellulose esters or carbamates e.g. Chiracel OB/OY, Baker
  • others e.g. Crownpak, Daicel or Chiracel OJ-R, Baker.
  • the compounds of formula (I) and (II) as well as their pharmaceutically usable addition salts possess valuable pharmacological properties. They were found to act as uPA receptor antagonists and may therefore block tumor invasiveness, metastasis and angiogenesis as oulined above.
  • the cellular binding assay was established for H460-M2 (2.5 x 10 4 cells/well) in a 96-well- plate format. After removing endogenous huPA by an acidic washing step, compounds to be tested and recombinant huPA are added consecutively. Finally, after a washing step, plasminogen and a colorimetric substrate is added and substrate turnover is analyzed.
  • RPMI- 1640 w/o phenolred Life Technologies, Cat.# 32404 2.
  • Binding buffer 0,1% RSA Fraction V, 5 mM Hepes, 2 mM L-Glutamin, RPMI-
  • Acidic buffer 10 % FCS 50ml/l, 2 mM L-Glutamin, RPMI-Medium, pH 3.0
  • Neutralisation buffer NaCl 0.1 mol/1, Hepes 0.5 mol/1, aqua bidest, pH 7.5
  • ATF aminoterminal fragment of urokinase
  • Substrate mix 9.3 ml RPMI-1640, 1.5 ml plasminogen and 1.2 ml Chromozyme PL
  • Neutralizating solution 7.5 ml neutralization buffer and 15 ml binding buffer
  • MTP Microtiter plates, 96-well plates collagen coated, BD Biocoat Cat.#354407
  • an embodiment of the invention is the use of a compound of formula (I) or (II) according to the present invention for the treatment of cancer.
  • compositions containing a pharmacologically effective amount of one or more compounds of formula (I) or (II) in admixture with pharmaceutically acceptable excipients and/or diluents.
  • a further embodiment of the invention is a medicament containing one or more compounds of formula (I) or (II) according to the present invention and pharmaceutically acceptable excipients.
  • Such medicaments may be in a form of a pharmaceutical composition, suitable for oral administration for example as tablets, coated tablets, dragees, capsules, solutions emulsions or suspensions; for parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream or for rectal administration as a suppository.
  • These pharmaceutical preparations can be obtained by processing the compounds according to this invention with pharmaceutically inert, inorganic or organic carriers.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can moreover contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • a preferred pharmaceutical composition can be obtained by using the following procedure for a tablet formulation:
  • Step 4 Pass the granulation from Step 3 through a suitable milling equipment.
  • the compounds according to the present invention will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg , and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • Preferably a daily dose in the range of 1-100 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • a further embodiment of the invention is a medicament containing one or more compounds according to the invention for the inhibition of tumor growth .
  • Still another embodiment of the invention is the use of a compound of formula (I) or (II) according to the present invention for the manufacture of corresponding medicaments for the inhibition of tumor growth.
  • NMR magnetic resonance
  • the title compound is obtained from the reaction of 2-( , ,l',3',3',3'-hexadeuteroisopropylidene)-4-hydroxybenzofuran-3-one (166 mg, 0.85 mmol), 1,4-dibromopentane (0.39 ml, 1.7 mmol) and potassium carbonate (130 mg, 0.94 mmol) in DMF (3.5 ml) in 76 % yield (225 mg).
  • MS (APCI): m/z 345
  • the title compound is obtained from 4-(4-bromo- pentoxy)-2-( , , ,3',3',3'-hexadeuteroisopropylidene)-benzofuran-3-one (225 mg,
  • the title compound is obtained from 4-(4-bromo- pentoxy)-2-isopropylidene-benzofuran-3-one (130 mg, 0.38 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (104 mg, 0.38 mmol) and potassium carbonate (58 mg, 0.42 mmol) in DMF (2 ml) in 10 % yield (19 mg).
  • MS (APCI): m/z 531 (M+H) +
  • the title compound is obtained from 4-(4-bromo-l- methyl-pentoxy)-2-isopropylidene-benzofuran-3-one (99 mg, 0.28 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (76.5 mg, 0.28 mmol) and potassium carbonate (43 mg, 0.31 mmol) in DMF (1.5 ml) after stirring at 50 °C for 48 hours in 4 % yield (6 mg) via preparative HPLC purification.
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (141 mg, 0.4 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (109.3 mg, 0.4 mmol) and triethyl amine (0.5 ml, 3.6 mmol) in DMF (2.0 ml) after stirring at 50 °C for 24 hours in 84 % yield (184 mg) via preparative HPLC purification.
  • MS (APCI): m/z 543 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (50 mg, 0.14 mmol), 4- chloro-N-piperidin-4-yl-3-sulfamoyl-benzamide (45 mg, 0.14 mmol) and triethyl amine (0.06 ml, 0.43 mmol) in DMF (2.0 ml) after stirring at 50 °C for 24 hours in 84
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (30 mg, 0.08 mmol), 3- chloro-N-piperidin-4-yl-benzamide (20 mg, 0.08 mmol) and N,N-diisopropyl-N- ethyl amine (44 ⁇ l, 0.25 mmol) in DMF (1.0 ml) after stirring at 50 °C for 4 hours and at room temperature over night in 98 % yield (43 mg) via preparative HPLC purification.
  • MS (APCI): m/z 509 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (30 mg, 0.08 mmol), 4- chloro-N- ⁇ iperidin-4-yl-benzamide (20 mg, 0.08 mmol) and N,N-diisopropyl-N-ethyl amine (44 ⁇ l, 0.25 mmol) in DMF (1.0 ml) after stirring at 50 °C for 4 hours and at room temperature over night in 89 % yield (39 mg) via preparative HPLC purification.
  • MS (APCI): m/z 509 (M+H) +
  • the title compound is obtained from 4-(4-bromo-l- methyl-pentyloxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (107 mg, 0.28 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide (77 mg, 0.28 mmol) and potassium carbonate (43 mg, 0.31 mmol) in DMF (2.0 ml) after stirring at 50 °C for 120 hours in 13 % yield (21 mg) via preparative HPLC purification.
  • MS (APCI): m/z 571 (M+H) +
  • the title compound is obtained from the reaction of 4-hydroxybenzofuran-3-one (1.0 g, 6.67 mmol), dicyclopropyl ketone (3.0 ml, 26.6 mmol) and gaseous ammonia in 1-butanol (30.0 ml) at 70-100 °C and stirring for 20 hours in 24 % yield (390 mg).
  • MS (APCI): m/z 243 (M+H) +
  • the title compound is obtained from the reaction of 2-dicyclopropylmethylene-4-hydroxy-benzofuran-3-one (180 mg, 0.74 mmol), 1,4- dibromobutane (0.44 ml, 3.7 mmol) and cesium carbonate (267 mg, 0.82 mmol) in DMF (10.0 ml) in 60 % yield (170 mg).
  • MS (APCI): m/z 377 (M+H) +
  • the title compound is obtained from 4 ⁇ (4-bromo- butoxy)-2-dicyclopropylmethylene-benzofuran-3-one (20 mg, 0.05 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (16 mg, 0.06 mmol) and sodium hydrogen carbonate (8 mg, 0.09 mmol) in DMF (2.0 ml) after stirring at 60 °C for 16 hours in 87 % yield (25 mg) via preparative HPLC purification.
  • MS (APCI): m/z 569 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-dicyclopropylmethylene-benzofuran-3-one (20 mg, 0.05 mmol), 4-chloro-
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-dicyclopropylmethylene-benzofuran-3-one (20 mg, 0.05 mmol), 4-chloro- N-piperidin-4-yl-benzamide (14 mg, 0.06 mmol) and sodium hydrogen carbonate (7 mg, 0.08 mmol) in DMF (2.0 ml) after stirring at 60 °C for 16 hours in 84 % yield (24 mg) via preparative HPLC purification.
  • MS (APCI): m/z 535 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-cyclopentylidene-benzofuran-3-one (190 mg, 0.54 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (170 mg, 0.62 mmol) and sodium hydrogen carbonate (75 mg, 0.89 mmol) in DMF (5.0 ml) after stirring at 60 °C for 4 hours in 27 % yield (80 mg) via preparative HPLC purification.
  • MS (APCI): m/z 543 (M+H) +
  • Preparation 13 2-Di ⁇ nethylammomethylene-4-hydroxy-benzofi ⁇ ran-3-one
  • the title compound is obtained from the reaction of 2-dimethylaminomethylene-4-hydroxy-benzofuran-3-one (620 mg, 3.0 mmol), 1,4- dibromobutane (0.7l ml, 6.0 mmol) and potassium carbonate (456 mg, 3.3 mmol) in
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-dimethylaminomethylene-benzofuran-3-one (100 mg, 0.30 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (164 mg, 0.6 mmol) and sodium hydrogen carbonate (42 mg, 0.5 mmol) in DMF (10.0 ml) after stirring at 60 °C for 4 hours in 56 % yield (89 mg) via preparative HPLC purification.
  • MS (APCI): m/z 532 (M+H) +
  • the title compound is obtained from the reaction of 4-hydroxybenzofuran-3-one (0.5 g, 3.4 mmol), l,3-dimethoxy-propan-2-one (1.94 g, 16.5 mmol) and gaseous ammonia in ethanol (10.0 ml) at 0 °C for 2 hours and subsequent stirring at 78 °C for 3 hours in 66 % yield (560 mg).
  • MS (APCI): m/z 251
  • the title compound is obtained from the reaction of 4-hydroxy-2-(2-me1no- ⁇ -l-methoxyme yl-e1i ⁇ ylidene)-benzofuran-3-one (750 mg, 3.0 mmol), 1,4-dibromobutane (0.71 ml, 6.0 mmol) and potassium carbonate (456 mg,
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-(2-methoxy-l-methoxymethyl-ethylidene)-benzofuran-3-one (770 mg, 2.0 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide (628 mg, 2.3 mmol) and sodium hydrogen carbonate (280 mg, 3.33 mmol) in DMF (25.0 ml) after stirring at 60 °C for 4 hours in 17 % yield (200 mg) via preparative HPLC purification.
  • MS (APCI): m/z 577 (M+H) +
  • the title compound is obtained from 2-(bis- methylsulfanyl-methylene)-4-(4-bromo-butoxy)-benzofuran-3-one (390 mg, 1.0 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide (315 mg, 1.15 mmol) and sodium hydrogen carbonate (190 mg, 1.65 mmol) in DMF (15.0 ml) after stirring at 60 °C for 4 hours in 37 % yield (220 mg) via preparative HPLC purification.
  • MS (APCI): m/z
  • the title compound is obtained from 4-(4-bromo- butoxy)-2,2-dimethyl-benzofuran-3-one (147 mg, 0.47 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (128 mg, 0.47 mmol) and triethyl amine (0.1 ml, 0.72 mmol) in DMF (2.0 ml) after stirring at 50 °C for 16 hours in 64 % yield (152 mg) via preparative HPLC purification.
  • MS (APCI): m/z 505 (M+H) +
  • the title compound is obtained from 4-(4-bromo- pentyloxy)-2,2-dimethyl-benzofuran-3-one (85 mg, 0.26 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (71 mg, 0.26 mmol) and triethyl amine (0.05 ml, 0.36 mmol) in DMF (1.5 ml) after stirring at 60 °C for 24 hours in 30 % yield (40 mg) via preparative HPLC purification.
  • MS (APCI): m/z 519 (M+H) +
  • the title compound is obtained from 4-(4-bromo-l- methyl-pentyloxy)-2,2-dimethyl-benzofuran-3-one (172 mg, 0.5 mmol), 3,4-dichloro- N-piperidin-4-yl-benzamide (137 mg, 0.5 mmol), potassium iodide (83 mg, 0.5 mmol) and potassium carbonate (77 mg, 0.56 mmol) in DMF (2.0 ml) after stirring at 50 °C for 120 hours in 26 % yield (94 mg) via preparative HPLC purification.
  • MS (APCI): m/z 533 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-cyclopropylidene-benzofuran-3-one (50 mg, 0.16 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (44 mg, 0.16 mmol) and triethyl amine (0.025 ml, 0.18 mmol) in DMF (1.0 ml) after stirring at 50 °C for 16 hours in 47 % yield (38 mg) via preparative HPLC purification.
  • MS (APCI): m/z 503 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (56 mg, 0.17 mmol), N-(8-aza- bicyclo[3.2.1]oct-3-yl)-3,4-dichloro-benzamide (52 mg, 0.17 mmol) and triethyl amine (0.073 ml, 0.52 mmol) in DMF (1.0 ml) after stirring at 50 °C for 16 hours in 73 % yield (68 mg) via preparative HPLC purification.
  • MS (APCI): m/z 543 (M+H) +
  • the title compound is obtained from 8-benzyl-8- aza-bicyclo[3.2.1]oct-3-ylamine (650 mg, 3.0 mmol), 3-chlorobenzoyl chloride (644 mg, 4.0 mmol) and triethyl amine (1.25 ml, 9.0 mmol) in tetrahydrofuran (5 ml) in 40 % yield (425 mg) via flash chromatography.
  • MS (APCI): m/z 355 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (30 mg, 0.09 mmol), N-(8-aza- bicyclo[3.2.1]oct-3-yl)-3-chloro-benzamide (24 mg, 0.09 mmol) and triethyl amine (0.039 ml, 0.28 mmol) in DMF (1.0 ml) after stirring at 50 °C for 24 hours in 55 % yield (26 mg) via preparative HPLC purification.
  • MS (APCI): m/z 509 (M+H) +
  • the title compound is obtained from 8-benzyl-8- aza-bicyclo[3.2.1]oct-3-ylamine (650 mg, 4.0 mmol), 4-chlorobenzoyl chloride (650 mg, 4.0 mmol) and triethyl amine (1.25 ml, 9.0 mmol) in tetrahydrofuran (5.0 ml) in 54 % yield (575 mg) via flash chromatography.
  • MS (APCI): m/z 355 (M+H) +
  • the title compound is obtained from N-(8-benzyl- 8-aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-benzamide (355 mg, 1.0 mmol), ethyl chloroformate (0.38 ml, 4.0 mmol), an aqueous solution of hydrogen bromide (4.0 ml, 47 %) and toluene (4 ml) in 38 % yield (100 mg) via flash chromatography.
  • MS (APCI): m/z 265 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (30 mg, 0.09 mmol), N-(8-aza- bicyclo[3.2.1]oct-3-yl)-4-chloro-benzamide (24 mg, 0.09 mmol) and triethyl amine (0.039 ml, 0.28 mmol) in DMF (1.0 ml) after stirring at 50 °C for 24 hours in 42 % yield (20 mg) via preparative HPLC purification.
  • MS (APCI): m/z 509 (M+H) +
  • the title compound is obtained from l-benzyl-2,6- dimethyl-piperidin-4-ylamine (500 mg, 2.3 mmol), 3,4-dichlorobenzoyl chloride (576 mg, 2.75 mmol) and triethyl amine (0.96 ml, 6.9 mmol) in tetrahydrofuran (10.0 ml) in 78 % yield (705 mg) via flash chromatography.
  • MS (APCI): m/z 391 (M+H) +
  • the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (20 mg, 0.07 mmol), 3,4-dichloro-N- (2,6-dimethyl-piperidin-4-yl)-benzamide (21 mg, 0.06 mmol) and triethyl amine (0.025 ml, 0.18 mmol) in DMF (1.5 ml) after stirring at 50 °C for 24 hours in 27 % yield (10 mg) via preparative HPLC purification.
  • MS (APCI): m/z 545 (M+H) +
  • the title compound is obtained from l-[4-(2- isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-ylo- ⁇ )-butyryl]-piperidin-4-one (400 mg, 1.1 mmol), 4-chlorobenzylamine (160 mg, 1.1 mmol), sodium triacetoxyborohydride (240 mg, 1.1 mmol) and methanol (10.0 ml) in 76 % yield (406 mg).
  • MS (APCI): m/z 484 (M+H) +
  • the title compound is obtained from l-[4-(2- isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy) -butyryl] -piperidin-4-one (400 mg, 1.1 mmol), 3,4-dichlorobenzylamine (194 mg, 1.1 mmol), sodium triacetoxyborohydride (240 mg, 1.1 mmol) and methanol (10.0 ml) in 82 % yield (467 mg).
  • MS (APCI): m/z 517 (M+H) +

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Abstract

The present invention relates to new compounds of the general formula (I) or (II), their pharmaceutically acceptable salts as well as their enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above mentioned compounds as uPA receptor antagonists and therefore in the control or prevention of corresponding illnesses and disorders as outlined herein; or in the manufacture of corresponding medicaments.

Description

Novel hydroxycoumaranone derivatives as antitumor and antimetastafic agents with improved biological activity in cellular assays and improved stability
The present invention relates to novel derivatives of 2-alkylidene hydroxycoumaranones wherein the hydroxy group is substituted by a nitrogen- containing residue. These compounds have been found to possess uPA-uPAR antagonist activity and can be employed as antitumor and/or antimetastatic agents.
The serine protease uPA (urokinase-type plasminogen activator) catalyzes the activation of plasminogen to plasmin which is involved in a variety of physiological and pathological processes. uPA is a multi-domain protein having a catalytic "B" chain (amino acids 144-411) and an amino-terminal fragment ("ATF", aa 1-143) comprised of a growth factor-like domain (aa 4-43) and a kringle domain (aa 47-135). uPA is a multifunctional protein involved in tissue proteolysis, cellular migration, cellular proliferation and growth factor activation. uPA is released from cells as a virtually inactive pro-enzyme, pro-uPA. The activation of the single-chain pro-uPA by plasmin (leading to the active two-chain form) is regulated by tight control mechanisms which are not completely understood yet. Most of the uPA activities are confined to the cell surface and the pericellular environment. This is accomplished by binding to a specific, high- affinity receptor on the cell surface (uPAR). Both forms of uPA bind to uPAR with similar affinity. The binding interaction is mediated by the growth factor-like domain (Rabbani, S.A., et al., J. Biol. Chem. 267 (1992) 14151-14156).
The uPA receptor is a three-domain glycoprotein where each triplicate motif comprises a cysteine rich consensus sequence of approximately 90 amino acids (Ploug, M., et al.,
J. Biol. Chem. 268 (1993) 17539-17546). uPAR is anchored to the cell membrane by a glycosyl-phosphatidylinositol moiety (GPI anchor). uPAR binds uPA with KD values between 10"10 and 10"9 M, depending on the experimental system. The major determinants for uPA binding are located in the N-terminal domain 1. uPAR can be cleaved by uPA and plasmin, liberating a water-soluble domain 1 and by the action of phospholipase C, three domains uPAR (1+2+3) can be released from the cell surface. This latter form of uPAR is also water-soluble because the GPI-anchor is missing. The inhibition of uPA dependent phenomena can principally be approached in two ways, either by direct inhibition of the proteolytic activity or by inhibition of uPA receptor binding. The latter strategy has the potential of achieving greater specificity since inhibition might be localized to the pericellular environment.
A bacteriophage display technique and protein engineering have recently been used to discover peptidic and species-specific uPAR antagonists (Goodson, R.J., et al., Proc. Natl. Acad. Sci. USA 91 (1994) 7129-7133; Stratton-Thomas, J.R., et al., Protein Eng. 8 (1995) 463-470, respectively).
The uPA/uPAR system has been shown to be implicated in a variety of invasive biological processes such as tumor metastasis, trophoblast implantation, inflammation and angiogenesis. Therefore, uPAR antagonists should be able to block tumor invasiveness, metastasis and angiogenesis. Formulations containing uPAR antagonists represent novel therapeutic treatments for a number of highly invasive and metastasising cancers where uPA and uPAR have been found to be consistently present at the invasive foci of the tumor (Dano et al., Proteolysis and Protein Turnover, eds.
Barret + Bond, Portlan Press, 1994, London) (e.g. breast, lung, colon, ovarian cancers).
In patients with breast cancer and non-small cell lung cancer increased levels of uPAR in plasma have been detected. Therefore, the amount of soluble uPAR appears to reflect the degree of proteolysis in the tumor and this might be closely related to patient prognosis. Both uPA and uPAR levels in tumor tissue are prognostic factors in many types of cancers.
In addition to cancer, other diseases mediated by cell-surface activity of uPA are addressed by uPAR antagonists. Inhibitors of plasmin generation by receptor bound uPA therefore have mechanism-based tumoristatic, anti-invasive, anti-metastatic, anti- angiogenic, anti- arthritic, anti-inflammatory, anti-osteoporotic, anti-retinopathic and contraceptive activities.
Some 6- and 4-piperidinoalkyloxy-2-alkylidenecumaranones are already described in EP 0 088 986 as antihystaminic agents and as inhibitors of the anafilactic shock. Derivatives of 2-alkylidene hydroxycoumaranones wherein the hydroxy group is substituted by a nitrogen-containing residue were discovered to have a significant activity of inhibition of the uPA/uPAR system functions by antagonizing the uPA receptor. These compounds possess antitumor and antimetastatic activity which has already been described in WO 99/06387 and EP 1 026 165. We now discovered novel hydroxycoumaranone derivatives which show improved biological activity on a cellular binding assay and improved metabolic stability in vitro.
Increased expression of uPA (urokinase-type plasminogen activator) and uPAR (uPA receptor) is associated with a poor prognosis in many types of cancers. Receptor- bound uPA plays a crucial role in extracellular matrix degradation thereby contributing to tumor invasiveness, metastasis and angiogenesis. Receptor-mediated activation of plasminogen to plasmin is, by several orders of magnitude, more efficient than non- receptor mediated activation. In syngeneic and xenograft murine tumor models, in which metastasis is driven by the uPA/uPAR interaction, inhibition of primary tumor growth, metastasis and angiogenesis has been achieved with several proteins acting as uPAR antagonists. This therapeutic principle represents a novel approach since inhibitors of receptor binding of uPA are expected to provide higher therapeutic specificity than uPA enzyme inhibitors. Low molecular weight uPAR antagonists should be able to inhibit the dissemination of cancer cells without the need for targeted drug and vector delivery.
The present invention relates to new compounds of the general formula (I) or (II)
Figure imgf000004_0001
formula (I) or formula (II),
wherein R1, R2 are independently hydrogen; alkyl; cycloalkyl; -NH(Cι-C4-alk l); -N(CrC4-alkyl)2;
-S-(C1-C4-alkyl); -(CH2)n-O-(C1-C4-alkyl); or
R1 and R2 together with the carbon-atom to which they are attached form a cycloalkyl group,
A is alkylene;
-(CH2)n-C(O)-; or
-(CH2)n-C(O)-NH-; B is a heterocyclic group;
M is -NH-C(O)-; or
-NH-CH2-;
R3, R4 are independently hydrogen; halogen;
-CN;
-OH;
-O-(Cι-C4-alkyl);
-NH2; -SO2-(Cι-C4-alkyl);
-SO2-NH2;
-SO2-NH(C1-C4-alkyl);
-SO2-N(Cι-C4-alkyl)2;
-C(O)-NH2; -C(O)-NH-(Cι-C4-alkyl);
-NH(Cι-C4-alkyl);
-N(C C4-alkyl)2; or alkyl; n is 1, 2, 3 or 4;
and pharmaceutically acceptable salts thereof.
Objects of the present invention are the compounds of formula I or II, their pharmaceutically acceptable salts as well as their enantiomeric forms, diastereoisomers and racemates; the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds as uPA receptor antagonists and therefore in the control or prevention of illnesses and disorders as mentioned above, or in the manufacture of corresponding medicaments.
As used herein the term "halogen" denotes fluorine, chlorine, bromine or iodine.
As used herein, the term "alkyl" means a linear or branched, saturated hydrocarbon containing from 1 to 12, preferably from 1 to 6 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, 1 -butyl, iso-butyl, sec-butyl, t-butyl or n-pentyl and n-hexyl as well as their isomers. Said alkyl group may optionally be substituted once or several times with deuterium or halogen, preferably with fluorine. Such groups are for example trideuteriomethyl or mono-, di- or trihalogenomethyl; preferably mono-, di- or trifluormetihyl.
As used herein the term " - - alkyl" means a linear, saturated hydrocarbon containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl or butyl.
The term "alkylene" as used herein means a bivalent radical of a linear or branched, saturated hydrocarbon containing from 1 to 10, preferably from 4 to 6 carbon atoms. Said alkylene group may optionally be once or several times substituted with halogen or deuterium. Preferred alkylene groups are for example:
-(CH2)„s -CH(CH3)-(CH2)n-; -CH(CH3)-(CH2)n-CH(CH3)-; -C(CH3)2-(CH2)n-; -C(CH3)2-(CH2)n-C(CH3)2-; -CX2-(CH2)n-CX2-; -(CH2)π-CX2-CX2-; wherein n is an integer from 1 to 4 and X is a halogen as definded herein before or a deuterium.
The term "cycloalkyl" means a saturated, monocyclic hydrocarbon containing 3 to 8, preferably from 3 to 6 carbon atoms, such as for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
A "heterocyclic group" as used herein means a 5- to 10-membered, preferably 6- to 8- membered, mono- or bicyclic, saturated hydrocarbon, wherein 1 to 3, prefreably 1 carbon atom is replaced by nitrogen. Said heterocyclic group may optionally be once or several times substituted with an alkyl group as defined herein before, preferably with a methyl- or trifluormethyl group. Preferred heterocyclic groups are bivalent radicals of piperidine; 2,6-dimethyl-piperidine; 2,6-bistrifluoromethyl-piperidine; 2,2,6,6- tetramethyl-piperidine or 8-aza-bicyclo[3.2.1]octane.
The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) or (II) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p- toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e. a drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel, H., et. al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995, at pp. 196 and 1456-1457. An embodiment of the invention are the compounds of formula I, wherein R1, R2, R3, R4, A, B and M have the significance given above.
Another embodiment of the invention are the compounds of formula II, wherein R1, R2, R3, R4, A, B and M have the significance given above.
Another embodiment of the invention are the compounds of formula I, wherein
R , R are independently hydrogen;
CH3 or CD3; cyclopropyl;
-N(CH3)2;
-S-CH3;
-(CH2)n-O-CH3; or
R* and R2 together with the carbon-atom to which they are attached form a cyclopentyl,
R >3 , R are independently hydrogen; halogen; or -SO2-NH2; and
A, B and M have the significance given above.
Yet another embodiment of the invention are the commpounds of formula I, wherein B is piperidin-l,4-diyl and M is -NH-C(O)-, of formula I-A
Figure imgf000009_0001
formula I-A,
wherein
R , R2 are both -CH3; -CD3; -S-CH3; -CH2-O-CH3 or cyclopropyl; or R and R2 together with the carbon-atom to which they are attached, form a cyclopentyl;
R , R are independently hydrogen; halogen; or
-SO2-NH2; provided that R3, R4 are not both -SO2-NH2; and
A has the significance given above.
Such compounds are for example:
3,4-Dichloro-N-{ 1- [4-( r, , ,3',3',3'-hexadeutero-2-isopropylidene-3-oxo-2,3- dihydro-benzofuran-4-yloxy)-butyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-l- methyl-butyl] -piperidin-4-yl} -benzamide; 3,4-Dichloro-N-{l-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyryl] -piperidin-4-yl} -benzamide; 3,4-Dichloro-N-{l-[4-(7-chloro-2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-butyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[3-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- propionylamino]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-l- methyl-pentyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(r, ,r,3',3',3'-hexadeutero-2-isopropylidene-3-oxo-2,3- dihydro-benzofuran-4-yloxy)-l-methyl-butyl]-piperidin-4-yl}-benzamide; 3,4-DicUoro-N-(l-{4-[2-(2-methox -l-methoxymethyl-ethylidene)-3-oxo-2,3- dihydro-benzofuran-4-yloxy] -butyl} -piperidin-4-yl) -benzamide;
N-(l-{4-[2-(Bis-methylsulfanyl-melhylene)-3-oxo-2,3-dihydro-benzofuran-4-yloxy]- butyl} -piperidin-4-yl) -3 ,4-dichloro-benzamide; 3,4-Dichloro-N-{l-[4-(2-cyclopentylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyl] -piperidin-4-yl} -benzamide; 3,4-Dichloro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro-benzofuran-4- yloxy) -butyl] -piperidin-4-yl}-benzamide; 4-Chloro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro-benzofuran-4- yloxy) -butyl] -piperidin-4-yl}-benzamide; or 4-Chloro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro-benzofuran-4- yloxy) -butyl] -piperidin-4-yl}-3-sulfamoyl-benzamide.
Yet another embodiment is a compound of formula I or I-A, wherein
R1, R2 are independently but not both at the same time hydrogen; methyl; cyclopropyl; or -N(CH3)2; and
R , R and A have the significance given for formula I-A. Such compounds are for example:
3,4-DicMoro-N-(l-{4-[2-(l-cyclopropyl-e1hylidene)-3-oxo-2,3-dihydro-benzofuran-
4-yloxy]-butyl}-piperidin-4-yl)-benzamide; 3,4-Dichloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro-benzofuran- 4-yloxy] - l-methyl-pentyl}-piperidin-4-yl)-benzamide;
3,4-Dichloro-N-{ 1- [4- (2-dimethylaminomethylene-3-oxo-2,3-dihydro-benzofuran-4- yloxy) -butyl] -piperidin-4-yl} -benzamide; E-3,4-Dichloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy]-butyl}-piperidin-4-yl)-benzamide; Z-3,4-Dichloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy] -butyl} -piperidin-4-yl) -benzamide; Z-4-Chloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro-benzofuran-4- yloxy] -butyl} -piperidin-4-yl) -benzamide; Z-3-Chloro-N-( l-{4- [2-( l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro-benzofuran-4- yloxy] -butyl}-piperidin-4-yl)-benzamide;
Z-4-Chloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro-benzofuran-4- yloxy] -butyl}-piperidin-4-yl)-3-sulfamoyl-benzamide; or 4-Chloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro-benzofuran-4- yloxy]-butyl}-piperidin-4-yl)-3-sulfamoyl-benzamide.
Yet another embodiment of the invention are the commpounds of formula I, wherein B is 2,6-dimethyl-piperidin-l,4-diyl and M is -NH-C(O)-, of formula I-B
Figure imgf000011_0001
formula I-B,
wherein R\ R" are both -CH3; -CD3; -S-CH3; -CH2-O-CH3 or cyclopropyl;
R , R are independently hydrogen; halogen; or
-SO2-NH2; provided that R3, R4 are not both -SO2-NH2; and
A has the significance given above.
Such a compound is for example:
3,4-Dichloro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-butyl] -2,6-dimethyl-piperidin-4-yl}-benzamide.
Yet another embodiment of the invention are the commpounds of formula I, wherein B is piperidin-l,4-diyl and M is -NH-CH2-, of formula I-C
Figure imgf000012_0001
formula I-C,
wherein
R\ R2 are both alkyl;
R , R are independently hydrogen; or halogen; and
has the significance given above. Such compounds are for example:
4-{4- [4-(Benzylamino)-piperidin- 1-yl] -4-oxo-butoxy}-2-isopropylidene-benzofuran-
3-one; 4-{4-[4-(3,4-Dichloro-benzylamino)-piperidin-l-yl]-4-oxo-butoxy}-2-isopropylidene- benzofuran-3-one; or
4-{4-[4-(4-Chloro-benzylamino)-piperidin-l-yl]-4-oxo-butoxy}-2-isopropylidene- benzofuran-3-one.
Yet another embodiment of the invention are the compounds of formula I, wherein B is 8-aza-bicyclo[3.2.1]oct-3,8-diyl and M is -NH-C(O)-, of formula I-D
Figure imgf000013_0001
formula I-D,
wherein
R^ R2 are both alkyl;
R , R are independently hydrogen; or halogen; and
A has the significance given above.
Such compounds are for example:
3,4-Dichloro-N-{8-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyl] -8-aza-bicyclo [3.2.1] oct-3-yl}-benzamide; 4-Chloro-N-{8-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-butyl]-
8-aza-bicyclo[3.2.1]oct-3-yl}-benzamide; or 3-CMoro-N-{8-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-butyl]-
8-aza-bicyclo[3.2.1]oct-3-yl}-benzamide.
Yet another embodiment of the invention are the compounds of formula II, wherein B is piperidin-l,4-diyl and M is -NH-C(O)-, of formula II-A
Figure imgf000014_0001
formula II-A,
wherein
R , R2 are both alkyl; or
R1 and R2 together with the carbon-atom to which they are attached form a cycloalkyl group;
R j3 , τ R.4 are independently hydrogen; or halogen; and
A is alkylene.
Such compounds are for example:
3,4-Dichloro-N-{l-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-l- methyl-butyl] -piperidin-4-yl} -benzamide; 3,4-Dichloro-N-{l-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-l- methyl-pentyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(2-cyclopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyl] -piperidin-4-yl} -benzamide; or 3,4-Dichloro-N-{ 1- [4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-butyl] - piperidin-4-yl} -benzamide.
Yet another embodiment of the invention is the process for the manufacture of compounds of the general formula (I) or (II), which comprises reacting a compound of either formula (Ilia) or (Illb)
Figure imgf000015_0001
(Ilia) or (Illb),
wherein R1 and R2 have the above meanings, with a compound of formula (IV)
L1-A-L2 (IV),
wherein A has the above meanings and LI and L2 are the same or different leaving groups such as chlorine, bromine, iodine, mesyl, tosyl or trifluoromethanesulfonyl;
and a compound of formula (V):
Figure imgf000015_0002
wherein B, M, R and R have the above meanings; and said reactions are processed either
by reaction of a compound of formula (Ilia) or (Illb) with a compound of formula
(IV), followed by reaction of the so obtained product with a compound of formula (V); or alternatively by reaction of a compound of formula (V) with a compound of formula (IV), followed by reaction of the so obtained product with a compound of formula
(Ilia) or (Illb).
The compounds according to the invention can in general be prepared according to the two-step process described in the patent applications EP 0 088 986, WO 99/06387 and EP 1 026 165, which are incorporated by reference.
In both cases, the intermediate product of the first synthesis step is preferentially isolated before submitting it to the second reaction. In such a process in general the oxygen-alkylation is performed under strongly basic conditions, preferably by means of an alkoxide of alkaline metal such as sodium ethoxide or isopropoxide or potassium carbonate in a suitable solvent, preferably a (Ci-C )alkyl alcohol or dimethylformamide, and at temperatures ranging from 20°C to the boiling temperature of the solvent.
The nitrogen- alkylation is instead performed at milder conditions, in the presence of a base such as an organic base, preferably a trialkylamine, or an inorganic base, preferably a carbonate of an alkaline or alkaline- earth metal, at temperatures ranging from room temperature to 50°C.
The compounds of formula (Ilia) are obtained from the compounds of formula (VI):
Figure imgf000016_0001
by reaction with an aldehyde or ketone of formula R^CO-R2, in which R1 and R2 are as above defined, in the presence of a base, preferably a hydroxide of an alkaline metal or ammonia, in an alcohol and at temperatures up to the boiling point of the solvent.
The compound of formula (VI) is known and described in J. Am. Chem. Soc. 61 (1939) 2328 which is incorporated herein by reference.
The compounds of formula (IV) are commercial products or can easily be prepared starting from commercial products according to usual reactions such as halogenation of alcohols or their conversion into mesyl and tosyl derivatives, which are known reactions for someone skilled in the art.
The compounds of formula (V) can be prepared starting from a suitably mono- protected diamine of formula P-B-H, in which P is for example a benzyl or tert- butoxycarbonyl group, by acylation with a compound of formula (VII):
Figure imgf000017_0001
in which L has the above meaning mentioned for LI, L2 and M, R3 and R4 have the significance given hereinbefore. In general, the reaction is performed by using a base and an inert solvent at temperatures ranging from 0°C to 50°C.
The mono-protected diamines of formula P-B-H and the compounds of formula (VII) are known and mostly commercial products or can be prepared therefrom according to methods which are known to someone skilled in the art.
Compounds of the general formula (I) or (II) can contain one or several chiral centres and can then be present in a racemic or in an optically active form. The racemates can be separated according to known methods into the enantiomers. Preferably diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid. Furthermore, the racemic compounds can be separated into their enantiomers by chromatography on an analytical, semipreparative or preparative scale using suitable optically active stationary phases with suitable eluents. Suitable optically active stationary phases include, but are not limited to, silica (e.g. ChiraSper,Merck; Chiralpak OT/OP, Baker), cellulose esters or carbamates (e.g. Chiracel OB/OY, Baker) or others (e.g. Crownpak, Daicel or Chiracel OJ-R, Baker).
The compounds of formula (I) and (II) as well as their pharmaceutically usable addition salts possess valuable pharmacological properties. They were found to act as uPA receptor antagonists and may therefore block tumor invasiveness, metastasis and angiogenesis as oulined above. In order to demonstrate the biological activity of the compounds according to the present invention as uPA receptor antagonists, the cellular binding assay was established for H460-M2 (2.5 x 104 cells/well) in a 96-well- plate format. After removing endogenous huPA by an acidic washing step, compounds to be tested and recombinant huPA are added consecutively. Finally, after a washing step, plasminogen and a colorimetric substrate is added and substrate turnover is analyzed.
The following materials, reagents and solutions were used:
1. RPMI- 1640 w/o phenolred: Life Technologies, Cat.# 32404 2. Binding buffer: 0,1% RSA Fraction V, 5 mM Hepes, 2 mM L-Glutamin, RPMI-
Medium pH7.5
3. Acidic buffer: 10 % FCS 50ml/l, 2 mM L-Glutamin, RPMI-Medium, pH 3.0
4. Neutralisation buffer: NaCl 0.1 mol/1, Hepes 0.5 mol/1, aqua bidest, pH 7.5
5. Urokinase: In-house manufactured, c=l mg/ml, 1:1000 diluted in binding buffer 6. ATF (aminoterminal fragment of urokinase):
American Diagnostics, c=500 μg/ml, Dilution 1:1000 in binding buffer 7. Plasminogen:
Roche Diagnostics Cat.# 1026577, lyophilisate reconstituted in aqua bidest (c=7 U/ml) 8. Chromozym PL:
Roche Diagnostics Cat.# 0378470, powder reconstituted in aqua bidest (c=9.5 mg/ml)
9. H460-M2 ceUs: 2.5xl0e4 cells/weU
10. Compound dilution in binding buffer containing 0.5% DMSO
11. Substrate mix: 9.3 ml RPMI-1640, 1.5 ml plasminogen and 1.2 ml Chromozyme PL
12. Neutralizating solution: 7.5 ml neutralization buffer and 15 ml binding buffer
13. MTP: Microtiter plates, 96-well plates collagen coated, BD Biocoat Cat.#354407
Procedure:
1 Remove culture medium
2 Put MTP onto ice (step 3-11)
3 Add acidic buffer (50 μl/well for 3 min)
4, Add neutralization solution (150 μl/well)
5 Remove solution carefully and add 200 μl/well binding buffer
6 Add compounds/positive control (75μl/well, 30 min)
7 Remove solution and add 200 μl/well binding buffer
8 Repeat step 7
9 Add urokinase (50 μl/well, 45 min)
10 Add RPMI-1640 (200μl/weU)
11 Remove and wash 2x with RPMI-1640 (200 μl/well)
Figure imgf000019_0001
13 Remove Medium and add substrate mix (100 μl/well)
14. Incubate at 37°C in a humid chamber (cell culture incubator) for 45-60 min
15 Analyze substrate turnover on a MTP-reader at 405 nm (reference 690 nm)
16 Calculate IC50 values by using a non-linear fitting software (Excel Fit) Table 1
Figure imgf000020_0001
Consequently an embodiment of the invention is the use of a compound of formula (I) or (II) according to the present invention for the treatment of cancer.
Another object of the present invention are pharmaceutical compositions containing a pharmacologically effective amount of one or more compounds of formula (I) or (II) in admixture with pharmaceutically acceptable excipients and/or diluents.
A further embodiment of the invention is a medicament containing one or more compounds of formula (I) or (II) according to the present invention and pharmaceutically acceptable excipients. Such medicaments may be in a form of a pharmaceutical composition, suitable for oral administration for example as tablets, coated tablets, dragees, capsules, solutions emulsions or suspensions; for parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream or for rectal administration as a suppository. These pharmaceutical preparations can be obtained by processing the compounds according to this invention with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical compositions can moreover contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
A preferred pharmaceutical composition can be obtained by using the following procedure for a tablet formulation:
Item Ingredients Mg Tablet
1 Compound of formula ( I ) or 25 100 ( II )
2 Anhydrous Lactose 73 35
3 Croscarmellose 6 8 Sodium
4 Povidone K30 5 6
5 Magnesium Stearate 1 1 Total Weight 140 150
Procedure:
1. Mix Items 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Granulate the powder mix from Step 1 with 20% Povidone K30 Solution (Item
4).
3. Dry the granulation from Step 2 at 50° C.
4. Pass the granulation from Step 3 through a suitable milling equipment.
5. Add the Item 5 to the milled granulation Step 4 and mix for 3 minutes. 6. Compress the granulation from Step 5 on a suitable press. The compounds according to the present invention will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg , and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-100 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
Therefore a further embodiment of the invention is a medicament containing one or more compounds according to the invention for the inhibition of tumor growth .
Still another embodiment of the invention is the use of a compound of formula (I) or (II) according to the present invention for the manufacture of corresponding medicaments for the inhibition of tumor growth.
The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims. It is understood that modifications can be made in the procedures set forth without departing from the spirit of the invention.
Unless otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;
(ii) operations were carried out at ambient temperature, that is in the range 18- 25°C and under an atmosphere of an inert gas such as argon or nitrogen;
(iii) column chromatography (by the flash procedure) and high pressure liquid chromatography (HPLC) were performed on Merck Kieselgel silica or Merck Lichroprep RP-18 reversed-phase silica obtained from E. Merck, Darmstadt, Germany; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) melting points were determined using a Mettier SP62 automatic melting point apparatus, an oil-bath apparatus or a Kofler hot plate apparatus; ( vi) the structures of the end-products of formula I or II were confirmed by nuclear
(generally proton) magnetic resonance (NMR) and mass spectral techniques
(Micromass Platform II machine using APCI or Micromass Platform ZMD using electrospray); (vii) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography;
(viii) the following abbreviations have been used:
DMF N,N-dimethylformamide;
DMSO dimethylsulphoxide;
THF tetrahydrofuran;
MeOH methanol;
HC1 hydrochloric acid;
NaH sodium hydride
CH2C12 dichloromethane
H2SO4 sulphuric acid sat. saturated sol. solution rt room temperature eq equivalent decomp. Decomposition
Examples
Preparation 1: 2-(l',l ,lt,3<,3',3<-Hexadeuteroisopropylidene)-4-hydroxybenzofuran- 3-one
A mixture of 4-hydroxycoumarane-3-one (0.6 g, 4 mmol) and potassium hydroxide (0.8 g, 14 mmol) in acetone-d6 (10 ml) is heated at 50 °C for 2 hours. The cooled reaction mixture is acidified, concentrated and extracted with dichloromethane. After flash chromatography on silica using dichloromethane as eluant 0.56 g (71 %) of the product is isolated. MS (APCI): m/z = 197 (M+H)+
Preparation 2: 4-(4-Bromo-butoxy)-2-(l',l',l',3',3<,3£-hexadeuteroisopropylidene)- benzofuran-3-one
A mixture of 2-(l',l', ,3',3',3'-hexadeuteroisopropylidene)-4-hydroxybenzofuran-3- one (196 mg, 1 mmol), 1,4-dibromobutane (0.24 ml, 2 mmol) and potassium carbonate (154 mg, 1.1 mmol) in DMF (4 ml) is stirred at 50 °C for 3 hours. The reaction mixture is concentrated, extracted with dichloromethane and purified by flash chromatography on silica using a heptane/ethyl acetate eluant to isolate 162 mg (49 %) of the desired product. MS (APCI): m/z = 331 (M+H)+
Example 1
3,4-Dichloro-N-{l-[4-(2-[r,l,,l',3',3',3'-hexadeuteroisopropylidene]-3-oxo-2,3- di ydro-benzofiιran-4-yloxy)-buryl]-piperidin-4-yl}-benzaxnide
A mixture of 4-(4-bromo-butoxy)-2-( , , ,3',3',3'-hexadeuteroisopropylidene)- benzofuran-3-one (162 mg, 0.49 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide
(134 mg, 0.49 mmol) and sodium hydrogen carbonate (57 mg, 0.68 mmol) in DMF (2 ml) is stirred for 20 hours at 60 °C. After evaporation of the solvent the crude product is purified by flash chromatography on silica using a ethyl acetate/methanol eluant to yield 69 mg (27 %) of the final product. MS (APCI): m/z = 523 (M+H)+
Preparation 3: 4-(4-Bromo-pentoxy)-2-(l<, ,l',3',3<,3'-hexadeuteroisopropylidene)- benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of 2-( , ,l',3',3',3'-hexadeuteroisopropylidene)-4-hydroxybenzofuran-3-one (166 mg, 0.85 mmol), 1,4-dibromopentane (0.39 ml, 1.7 mmol) and potassium carbonate (130 mg, 0.94 mmol) in DMF (3.5 ml) in 76 % yield (225 mg). MS (APCI): m/z = 345
(M+H)+ Example 2
3,4-Dichloro-N-{l-[4-(2-[l',l',l',3',3',3'-hexadeuteroisopropylidene]-3-oxo-2,3- d ydro-benzoftu-an-4-yloxy)-l-methyl-butyl]-piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- pentoxy)-2-( , , ,3',3',3'-hexadeuteroisopropylidene)-benzofuran-3-one (225 mg,
0.65 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide (177 mg, 0.65 mmol) and triethylamine (1.0 ml, 13.6 mmol) in DMF (3 ml) after stirring at 50 °C for 3 hours and at room temperature for another 20 hours in 31 % yield (106 mg). MS (APCI): m/z = 537 (M+H)+
Preparation 4: 4-(4-Bromo-pentyloxy)-2-isopropylidene-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of 2-isopropylidene-4-hydroxycoumarane-3-one (380 mg, 2.0 mmol), 1,4- dibromopentane (0.56 ml, 4.0 mmol) and potassium carbonate (307 mg, 2.2 mmol) in DMF (8 ml) in 75 % yield (510 mg). MS (APCI): m/z = 339 (M+H)+
Example 3
3,4-DicMoro-N-{l-[4-(2-isopropyUdene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-l- methyl-butyl]-piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- pentoxy)-2-isopropylidene-benzofuran-3-one (130 mg, 0.38 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (104 mg, 0.38 mmol) and potassium carbonate (58 mg, 0.42 mmol) in DMF (2 ml) in 10 % yield (19 mg). MS (APCI): m/z = 531 (M+H)+
Preparation 5: 4-(4-Bromo-l-methyl-pentylo- ^)-2-isopropyUdene-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of
2-isopropylidene-4-hydroxycoumarane-3-one (190 mg, 1.0 mmol), 2,5- dibromohexane (488 g, 2.0 mmol) and potassium carbonate (153 mg, 1.1 mmol) in DMF (3 ml) after a reaction time of 6 hours in 56 % yield (197 mg). MS (APCI): m/z = 353 (M+H)+
Example 4
3,4-Dichloro-N-{l-[4-(2-isopropyUdene-3-oxo-2,3-dil ydro-benzofuran-4-yloxy)-l- methyl-pentyl] -piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo-l- methyl-pentoxy)-2-isopropylidene-benzofuran-3-one (99 mg, 0.28 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (76.5 mg, 0.28 mmol) and potassium carbonate (43 mg, 0.31 mmol) in DMF (1.5 ml) after stirring at 50 °C for 48 hours in 4 % yield (6 mg) via preparative HPLC purification. MS (APCI) : m/z = 545 (M+H)+
Preparation 6: 2-(l-Cyclopropyl-ethylidene)-4-hydroxybenzofuran-3-one
A mixture of 4-hydroxycoumarane-3-one (1.0 g, 6.7 mmol) and cyclopropyl methyl ketone (2.3 g, 23.3 mmol) in ethanol (15 ml) is heated to 78 °C and gaseous ammonia is bubbled through for 4 hours. The crude product precipitates from the cooled reaction mixture and is washed with ice-cold isopropanol. If appropriate, the product is further purified by flash chromatography on silica using a toluene-methanol mixture as eluant to afford 1.05 g (73 %) of the desired compound. MS (APCI): m/z = 217 (M+H)+
Preparation 7: 4-(4-Bromo-butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of
2-(l-cyclopropyl-ethylidene)-4-hydroxybenzofuran-3-one (324 mg, 1.5 mmol), 1,4- dibromobutane (0.35 ml, 3.0 mmol) and potassium carbonate (250 mg, 1.8 mmol) in DMF (6.0 ml) in 75 % yield (393 mg). MS (APCI): m/z = 351 (M+H)+ Example 5
3,4-DicMoro-N-(l-{4-[2-(l-cyclopropyl-e1-hyHdene)-3-oxo-2,3-d-hyd^o-benzofuran-
4-yloxy]-butyl}-piperidin-4-yl)-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (141 mg, 0.4 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (109.3 mg, 0.4 mmol) and triethyl amine (0.5 ml, 3.6 mmol) in DMF (2.0 ml) after stirring at 50 °C for 24 hours in 84 % yield (184 mg) via preparative HPLC purification. MS (APCI): m/z = 543 (M+H)+
Example 6 4-CUoro-N-(l-{4-[2-(l-cyclopropyl-ethyHdene)-3-oxo-2,3-dihydro-benzofuran-4- yloxy]-butyl}-piperidin-4-yl)-3-sulfamoyl-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (50 mg, 0.14 mmol), 4- chloro-N-piperidin-4-yl-3-sulfamoyl-benzamide (45 mg, 0.14 mmol) and triethyl amine (0.06 ml, 0.43 mmol) in DMF (2.0 ml) after stirring at 50 °C for 24 hours in 84
% yield (184 mg) via preparative HPLC purification. MS (APCI): m/z = 588 (M+H)+
Example 7
3-Chloro-N- ( l-{4- [2- ( l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro-benzofuran-4- yloxy]-butyl}-piperidin-4-yl)-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (30 mg, 0.08 mmol), 3- chloro-N-piperidin-4-yl-benzamide (20 mg, 0.08 mmol) and N,N-diisopropyl-N- ethyl amine (44 μl, 0.25 mmol) in DMF (1.0 ml) after stirring at 50 °C for 4 hours and at room temperature over night in 98 % yield (43 mg) via preparative HPLC purification. MS (APCI): m/z = 509 (M+H)+ Example 8
4-CMoro-N-(l-{4-[2-(l-cyclopropyl-ethyHdene)-3-oxo-2,3-di-hydro-berιzofuran-4- yloxy]-butyl}-piperidin-4-yl)-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (30 mg, 0.08 mmol), 4- chloro-N-ρiperidin-4-yl-benzamide (20 mg, 0.08 mmol) and N,N-diisopropyl-N-ethyl amine (44 μl, 0.25 mmol) in DMF (1.0 ml) after stirring at 50 °C for 4 hours and at room temperature over night in 89 % yield (39 mg) via preparative HPLC purification. MS (APCI): m/z = 509 (M+H)+
Preparation 8: -(4-Bromo-l-methyl-pentyloxy)-2-(l-cyclopropyl-ethylidene)- benzofuran-3-one
Accordingly to preparation 2, the title compound is obtained from the reaction of 2-(l- cyclopropyl-ethylidene)-4-hydroxybenzofuran-3-one (93 mg, 0.43 mmol), 2,5- dibromohexane (210 mg, 0.86 mmol) and potassium carbonate (66 mg, 0.48 mmol) in DMF (2.0 ml) after stirring for 6 hours in 65 % yield (107 mg). MS (APCI): m/z = 379
(M+H)+
Example 9
3,4-DicMoro-N-(l-{4-[2-(l-cyclopropyl-etlιyUdene)-3-oxo-23-d-hydro-benzofuran- 4-yloxy] - l-methyl-pentyl}-piperidin-4-yl)-ben--amide
In accordance with example 1, the title compound is obtained from 4-(4-bromo-l- methyl-pentyloxy)-2-(l-cyclopropyl-ethylidene)-benzofuran-3-one (107 mg, 0.28 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide (77 mg, 0.28 mmol) and potassium carbonate (43 mg, 0.31 mmol) in DMF (2.0 ml) after stirring at 50 °C for 120 hours in 13 % yield (21 mg) via preparative HPLC purification. MS (APCI): m/z = 571 (M+H)+
Preparation 9: 2-Dicyclopropylmethylene-4-hydroxy-benzofuran-3-one
In accordance with preparation 6, the title compound is obtained from the reaction of 4-hydroxybenzofuran-3-one (1.0 g, 6.67 mmol), dicyclopropyl ketone (3.0 ml, 26.6 mmol) and gaseous ammonia in 1-butanol (30.0 ml) at 70-100 °C and stirring for 20 hours in 24 % yield (390 mg). MS (APCI): m/z = 243 (M+H)+
Preparation 10: 4-(4-Bromo-butoxy)-2-dicyclopropy]-methylene-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of 2-dicyclopropylmethylene-4-hydroxy-benzofuran-3-one (180 mg, 0.74 mmol), 1,4- dibromobutane (0.44 ml, 3.7 mmol) and cesium carbonate (267 mg, 0.82 mmol) in DMF (10.0 ml) in 60 % yield (170 mg). MS (APCI): m/z = 377 (M+H)+
Example 10
3,4-DicMoro-N-{l-[4-(2-dicycloρropylj-nethylene-3-oxo-2,3-dmydro-benzofuran-4- yloxy)-butyl] -piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4~(4-bromo- butoxy)-2-dicyclopropylmethylene-benzofuran-3-one (20 mg, 0.05 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (16 mg, 0.06 mmol) and sodium hydrogen carbonate (8 mg, 0.09 mmol) in DMF (2.0 ml) after stirring at 60 °C for 16 hours in 87 % yield (25 mg) via preparative HPLC purification. MS (APCI): m/z = 569 (M+H)+
Example 11
4-CUoro-N-{l-[4-(2-d^cyclopropylrnethylene-3-oxo-2,3-dihydro-benzofuran-4- ylosy)-butyl]-piperidin-4-yl}-3-sulfamoyl-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-dicyclopropylmethylene-benzofuran-3-one (20 mg, 0.05 mmol), 4-chloro-
N-piperidin-4-yl-3-sulfamoyl-benzamide (19 mg, 0.06 mmol) and sodium hydrogen carbonate (7 mg, 0.08 mmol) in DMF (2.0 ml) after stirring at 60 °C for 24 hours in 19 % yield (6 mg) via preparative HPLC purification. MS (APCI): m/z = 614 (M+H)+ Example 12
4-CMoro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dmydro-benzoftιran-4- yloxy)-butyl]-piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-dicyclopropylmethylene-benzofuran-3-one (20 mg, 0.05 mmol), 4-chloro- N-piperidin-4-yl-benzamide (14 mg, 0.06 mmol) and sodium hydrogen carbonate (7 mg, 0.08 mmol) in DMF (2.0 ml) after stirring at 60 °C for 16 hours in 84 % yield (24 mg) via preparative HPLC purification. MS (APCI): m/z = 535 (M+H)+
Preparation 11: 2-Cyclopentylidene-4-hydroxy-benzofuran-3- ■one
In accordance with preparation 6, the title compound is obtained from the reaction of
4-hydroxybenzofuran-3-one (1.48 g, 10.0 mmol), cyclopentanone (2.94 g, 35.0 mmol) and gaseous ammonia in ethanol (30.0 ml) at 0 °G and subsequent stirring at 78 °C for 3 hours in 45 % yield (980 mg). MS (APCI): m/z = 217 (M+H)+
Preparation 12: 4-(4-Bromo-butoxy)-2-cyclopentylidene-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of
2-cyclopentylidene-4-hydroxy-benzofuran-3-one (865 mg, 4.0 mmol), 1,4- dibromobutane (1.73 g, 8.0 mmol) and potassium carbonate (608 mg, 4.4 mmol) in DMF (20.0 ml) in 14 % yield (200 mg). MS (APCI): m/z = 351 (M+H)+
Example 13 3,4-DicUoro-N-{l-[4-(2-cyclopentyUdene-3-oxo-2,3-dihydro-benzofiιran-4-yloxy)- butyl] -piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-cyclopentylidene-benzofuran-3-one (190 mg, 0.54 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (170 mg, 0.62 mmol) and sodium hydrogen carbonate (75 mg, 0.89 mmol) in DMF (5.0 ml) after stirring at 60 °C for 4 hours in 27 % yield (80 mg) via preparative HPLC purification. MS (APCI): m/z = 543 (M+H)+ Preparation 13: 2-Diιnethylammomethylene-4-hydroxy-benzofiιran-3-one
A mixture of 4-hydroxycoumarane-3-one (0.5 g, 3.33 mmol) and N,N- dimethylformamide dimethyl acetal (0.5 g, 5.0 mmol) in N,N-dimethylformamide (10 ml) is heated to 120 °C for 4 hours. After removing of the solvent the final product is isolated after recrystallisation from isohexane in 95 % (650 mg), MS (APCI): m/z = 206
(M+H)+
Preparation 14: 4- (4-Bromo-butoxy)-2-dimethylammometh.ylene-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of 2-dimethylaminomethylene-4-hydroxy-benzofuran-3-one (620 mg, 3.0 mmol), 1,4- dibromobutane (0.7l ml, 6.0 mmol) and potassium carbonate (456 mg, 3.3 mmol) in
DMF (20.0 ml) in 40 % yield (412 mg). MS (APCI): m/z = 340 (M+H)+
Example 14
3,4-DicUoro-N-{l-[4-(2-dimetnylammomethylene-3-oxo-2,3-dmydro-benzofuran-4- yloxy)-butyl]-piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-dimethylaminomethylene-benzofuran-3-one (100 mg, 0.30 mmol), 3,4- dichloro-N-piperidin-4-yl-benzamide (164 mg, 0.6 mmol) and sodium hydrogen carbonate (42 mg, 0.5 mmol) in DMF (10.0 ml) after stirring at 60 °C for 4 hours in 56 % yield (89 mg) via preparative HPLC purification. MS (APCI): m/z = 532 (M+H)+
Preparation 15: 4-Hyάro- r-2-(2-metlιoxy-l-metho- πnet y
3-one
In accordance with preparation 6, the title compound is obtained from the reaction of 4-hydroxybenzofuran-3-one (0.5 g, 3.4 mmol), l,3-dimethoxy-propan-2-one (1.94 g, 16.5 mmol) and gaseous ammonia in ethanol (10.0 ml) at 0 °C for 2 hours and subsequent stirring at 78 °C for 3 hours in 66 % yield (560 mg). MS (APCI): m/z = 251
(M+H)+ Preparation 16: 4-(4-Bromo-butoxy)-2-(2-me1-hoxy-l-metho- rmethyl-ethylidene)- benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of 4-hydroxy-2-(2-me1no-^-l-methoxyme yl-e1iιylidene)-benzofuran-3-one (750 mg, 3.0 mmol), 1,4-dibromobutane (0.71 ml, 6.0 mmol) and potassium carbonate (456 mg,
3.3 mmol) in DMF (20.0 ml) in 67 % yield (780 mg). MS (APCI): m/z = 385 (M+H)+
Example 15
3,4-Dichloro-N- ( 1- {4- [2- (2-methoxy-l -methoxymethyl-ethylidene)-3-oxo-2,3- dihydro-benzofuran-4-yloxy]-butyl}-piperidin-4-yl)-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-(2-methoxy-l-methoxymethyl-ethylidene)-benzofuran-3-one (770 mg, 2.0 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide (628 mg, 2.3 mmol) and sodium hydrogen carbonate (280 mg, 3.33 mmol) in DMF (25.0 ml) after stirring at 60 °C for 4 hours in 17 % yield (200 mg) via preparative HPLC purification. MS (APCI): m/z = 577 (M+H)+
Preparation 17: 2- (Bis-methylsulfanyl-methylene)-4-hydroxy-benzofuran-3-one
Accordingly to a literature procedure (Monatsh. Chem. 128 (1997) 371-380), the title compound is obtained from the reaction of 4-hydroxybenzofiiran-3-one (0.9 g, 6.0 mmol), carbon disulfide (0.36 ml, 6.0 mmol), potassium tert.-butoxide (1.35 g, 12.0 mmol) and methyl iodide (0.75 ml, 12.0 mmol) in tetrahydrofuran (60.0 ml) in 62 % yield (950 mg). MS (APCI): m/z = 255 (M+H)+
Preparation 18: 2- (Bis-methylsulfanyl-methylene)-4- (4-bromo-butoxy)-benzofuran- 3-one
Accordingly to preparation 2, the title compound is obtained from the reaction of 2- (bis-methylsulfanyl-methylene)-4-hydroxy-benzofuran-3-one (2.0 g, 8.0 mmol), 1,4- dibromobutane (1.89 ml, 16.0 mmol) and potassium carbonate (1.24 g, 9.0 mmol) in DMF (35.0 ml) in 16 % yield (500 mg). MS (APCI): m/z = 389 (M+H)+
Example 16
N- ( l-{4- [2- (Bis-methylsidfanyl-methylene)-3-oxo-2,3-dmydro-benzonjran-4-yloxy] - butyl}-piperidin-4-yl)-3,4-dichloro-benzamide
In accordance with example 1, the title compound is obtained from 2-(bis- methylsulfanyl-methylene)-4-(4-bromo-butoxy)-benzofuran-3-one (390 mg, 1.0 mmol), 3,4-dichloro-N-piperidin-4-yl-benzamide (315 mg, 1.15 mmol) and sodium hydrogen carbonate (190 mg, 1.65 mmol) in DMF (15.0 ml) after stirring at 60 °C for 4 hours in 37 % yield (220 mg) via preparative HPLC purification. MS (APCI): m/z =
582 (M+H)+
Example 17
3,4-Dichloro-N-{ 1- [4- (7-chloro-2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-butyl]-piperidin-4-yl}-benzamide
To 3,4-dichloro-N-{ 1- [4-(2-isopropyUdene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyl]-piperidin-4-yl} -benzamide (103 mg, 0.2 mmol) in glacial acetic acid (5.0 ml) is added disulfur dichloride (0.017 ml, 0.21 mmol) at 10 °C. The reaction mixture is stirred at the same temperature for 10 minutes and refluxed for additional 2 hours. The final product is obtained after purification by flash chromatography on silica using an ethyl acetate/methanol eluant in 27 % yield (30 mg). MS (APCI): m/z = 552 (M+H)+, mp = 118-120 °C
Preparation 19: 4-(4-Bromo-butoxy)-2,2-draet yl-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of 4-hydroxy-2,2-dimethyl-benzofuran-3-one (89 mg, 0.5 mmol, prepared according to J. Am. Chem. Soc. 1982, 104, 2659-2661), 1,4-dibromobutane (0.12 ml, 1.0 mmol) and potassium carbonate (77 mg, 0.56 mmol) in DMF (1.5 ml) in 94 % yield (147 mg). MS (APCI): m/z = 313 (M+H)+ Example 18
3,4-DicUoro-N-{l-[4-(2,2-dimetJιyl-3-oxo-2,3-di-hydro-benzofuran-4-yloxy)-butyl]- piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2,2-dimethyl-benzofuran-3-one (147 mg, 0.47 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (128 mg, 0.47 mmol) and triethyl amine (0.1 ml, 0.72 mmol) in DMF (2.0 ml) after stirring at 50 °C for 16 hours in 64 % yield (152 mg) via preparative HPLC purification. MS (APCI): m/z = 505 (M+H)+
Preparation 20: 4-(4-Bromo-pentyloxy)-2,2-m^etlιyl-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of
4-hydroxy-2,2-dimethyl-benzofuran-3-one (96 mg, 0.54 mmol), 1,4-dibromopentane (0.14 ml, 1.0 mmol) and potassium carbonate (77 mg, 0.56 mmol) in DMF (2.0 ml) in 96 % yield (169 mg). MS (APCI): m/z = 327 (M+H)+
Example 19 3,4-DicUoro-N-{l-[4-(2,2-dimetnyl-3-oxo-2,3-άΕιyd^o-benzofuran-4-yloxy)-l- methyl-butyl]-piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- pentyloxy)-2,2-dimethyl-benzofuran-3-one (85 mg, 0.26 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (71 mg, 0.26 mmol) and triethyl amine (0.05 ml, 0.36 mmol) in DMF (1.5 ml) after stirring at 60 °C for 24 hours in 30 % yield (40 mg) via preparative HPLC purification. MS (APCI): m/z = 519 (M+H)+
Preparation 21: 4-(4-Bromo-l-methyl-pent lox )-2,2-dimethyl-benzofuran-3-one
In accordance with preparation 2, the title compound is obtained from the reaction of
4-hydroxy-2,2-dimethyl-benzofuran-3-one (178 mg, 1.0 mmol), 2,5-dibromohexane (488 mg, 2.0 mmol) and potassium carbonate (154 mg, 1.1 mmol) in DMF (4.0 ml) after stirring at 50 °C for 7 hours in 70 % yield (240 mg). MS (APCI): m/z = 341 (M+H)+
Example 20
3,4-DicWoro-N-{l-[4-(2,2-dimetiιyl-3-oxo-2,3-dihycho-benzofuran-4-yloxy)-l- methyl-pentyl] -piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo-l- methyl-pentyloxy)-2,2-dimethyl-benzofuran-3-one (172 mg, 0.5 mmol), 3,4-dichloro- N-piperidin-4-yl-benzamide (137 mg, 0.5 mmol), potassium iodide (83 mg, 0.5 mmol) and potassium carbonate (77 mg, 0.56 mmol) in DMF (2.0 ml) after stirring at 50 °C for 120 hours in 26 % yield (94 mg) via preparative HPLC purification. MS (APCI): m/z = 533 (M+H)+
Preparation 22: Cyclopropyl-(2,6-d'imethoxy-phenyl)-methanone
To a solution of 1,3-dimethoxybenzene (69 g, 0.5 mol) in diethyl ether (400 ml) is added a solution of n-butyl lithium (2.5 M in hexane, 100 ml, 0.25 mol) at room temperature. After refluxing for 4 hours the mixture is cooled down to -78 °C and treated with a solution of cyclopropanecarbonyl chloride (25.1 g, 0.24 mol) in 100 ml of diethyl ether. The reaction mixture is allowed to warm up to room temperature overnight, quenched with ice water and extracted with ethyl acetate. All volatile components are removed in vacuum, the resulting crude product is purified by vacuum distillation to yield 23.4 g (45 %) of the title compound (oil). MS (APCI): m/z
= 207 (M+H)+
Preparation 23: 2,4-Dibromo-l-(2,6-dimethoxy-phenyl)-butan-l-one
To a solution of cyclopropyl-(2,6-dimethoxy-phenyl)-methanone (12.2 g, 59.0 mmol) in dichloromethane (220 ml) is slowly added a solution of bromine (3.2 ml, 63.0 mmol) in dichloromethane (150 ml) at 0 °C. The resulting mixture is extracted with a sodium metabisulphite solution and brine. After evaporation of the solvent the crude product is recrystallised from light petrol/ethyl acetate to yield 15.5 g (72 %) of the desired product (mp = 99-100 °C). MS (APCI): m/z = 367 (M+H)+
Preparation 24: 2-(2-Bromo-etlιyl)-4-metho-^-benzofuran-3-one
To a cooled solution of 2,4-dibromo-l-(2,6-dimethoxy-phenyl)-butan-l-one (15.0 g, 41.0 mmol) in dichloromethane (200 ml) is slowly added boron tribromide (2.0 M solution in dichloromethane, 41.0 ml) at -70 °C. After warming up to room temperature the reaction mixture is extracted with water. The water layer is extracted with ethyl acetate. The dichloromethane is removed from the combined organic layers and the resulting solution is stirred with potassium carbonate for 16 hours. The crude product is purified after normal work-up by flash chromatography using a light petrol/ethyl acetate eluant and by a recrystallisation from the same solvent mixture to isolate 6.6 g (59 %) of the desired product (mp = 87-88 °C). MS (APCI): m/z = 271 (M+H)+
Preparation 25: 4-(4-Bromo-butoxy)-2-cyclopropyUdene-benzofuran-3-one
To a cooled solution of 2-(2-bromo-ethyl)-4-methoxy-benzofuran-3-one (542 mg, 2.0 mmol) in dichloromethane (15 ml) is slowly added boron tribromide (2.0 M solution in dichloromethane, 1.0 ml) at -70 °C. After warming up to room temperature the reaction mixture is quenched with water and extracted with dichloromethane. The solvent is removed and the resulting intermediate is dissolved in ethyl acetate (10 ml), treated with 1,4-dibromobutane (2.16 g, 10 mmol), potassium carbonate (552 mg, 4 mmol) and stirred for 16 hours at room temperature. The final product (oil) is obtained in 10 % yield (60 mg) after normal work-up and purification by flash chromatography using a light petrol/ethyl acetate eluant. MS (APCI): m/z = 311 (M+H)+
Example 21
3,4-DicUoro-N-{l-[4-(2-cyclopropyUdene-3-oxo-2,3-d^ydro-ber-zolτ-ιran-4-yloxy)- butyl] -piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-cyclopropylidene-benzofuran-3-one (50 mg, 0.16 mmol), 3,4-dichloro-N- piperidin-4-yl-benzamide (44 mg, 0.16 mmol) and triethyl amine (0.025 ml, 0.18 mmol) in DMF (1.0 ml) after stirring at 50 °C for 16 hours in 47 % yield (38 mg) via preparative HPLC purification. MS (APCI): m/z = 503 (M+H)+
Preparation 26: N-(8-Benzyl-8-aza-bicyclo [3.2.1 ] oct-3-yl)-3,4-dichloro-benzamide
To a solution of 8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylamine (840 mg, 3.9 mmol, prepared according to known literature procedures) and triethyl amine (1.6 ml, 11.5 mmol) in tetrahydrofuran (6 ml) is slowly added 3,4-dichlorobenzoyl chloride (980 mg, 4.7 mmol) in tetrahydrofuran (6 ml) at 0 °C. Stirring is continued for 16 hours at room temperature. The desired compound is obtained in 78 % yield (1190 mg) after purification by flash chromatography using a chloroform/methanol/ammonia eluant.
MS (APCI): m/z = 389 (M+H)+
Preparation 27: N- (8-Aza-bicyclo [3.2.1 ] oct-3-yl)-3,4-dichloro-benzamide
A solution of N-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3,4-dichloro-benzamide (300 mg, 0.77 mmol) in toluene (3 ml) is treated with ethyl chloroformate (0.3 ml, 3.1 mmol) and refluxed for 4 hours. After cooling down to room temperature an aqueous solution of hydrogen bromide (3.0 ml, 47 %) is added and the resulting mixture is stirred at 100 °C for 12 hours. The cooled reaction mixture is treated with a sodium hydroxide solution (10 M, 3.0 ml) and the product is purified by flash chromatography using an isopropanol/ chloroform/ ammonia eluant to yield 44 % (100 mg) of the free amine. MS (APCI): m/z = 299 (M+H)+ Example 22
3,4-DicMoro-N-{8-[4-(2-isopropy ene-3-oxo-2,3-d ydro-benzofuran-4-yloxy)- butyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (56 mg, 0.17 mmol), N-(8-aza- bicyclo[3.2.1]oct-3-yl)-3,4-dichloro-benzamide (52 mg, 0.17 mmol) and triethyl amine (0.073 ml, 0.52 mmol) in DMF (1.0 ml) after stirring at 50 °C for 16 hours in 73 % yield (68 mg) via preparative HPLC purification. MS (APCI): m/z = 543 (M+H)+
Preparation 28: N- (8-Benzyl-8-aza-bicyclo [3.2.1 ] oct-3-yl)-3-chloro-benzamide
In accordance with preparation 26, the title compound is obtained from 8-benzyl-8- aza-bicyclo[3.2.1]oct-3-ylamine (650 mg, 3.0 mmol), 3-chlorobenzoyl chloride (644 mg, 4.0 mmol) and triethyl amine (1.25 ml, 9.0 mmol) in tetrahydrofuran (5 ml) in 40 % yield (425 mg) via flash chromatography. MS (APCI): m/z = 355 (M+H)+
Preparation 29: N- (8-Aza-bicyclo [3.2.1 ] oct-3-yl)-3-chloro-benzamide
In accordance with preparation 27, the title compound is obtained from N-(8-benzyl-
8-aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-benzamide (355 mg, 1.0 mmol), ethyl chloroformate (0.38 ml, 4.0 mmol), an aqueous solution of hydrogen bromide (4.0 ml, 47 %) and toluene (4 ml) in 56 % yield (150 mg) via flash chromatography. MS (APCI): m/z = 265 (M+H)+
Example 23
3-CWoro-N-{8-[4-(2-isopropyHdene-3-oxo-2,3-dmydro-benzofuran-4-yloxy)-butyl]- 8-aza-bicyclo [3.2.1 ] oct-3-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (30 mg, 0.09 mmol), N-(8-aza- bicyclo[3.2.1]oct-3-yl)-3-chloro-benzamide (24 mg, 0.09 mmol) and triethyl amine (0.039 ml, 0.28 mmol) in DMF (1.0 ml) after stirring at 50 °C for 24 hours in 55 % yield (26 mg) via preparative HPLC purification. MS (APCI): m/z = 509 (M+H)+
Preparation 30: N-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-4-chloro-benzamide
In accordance with preparation 26, the title compound is obtained from 8-benzyl-8- aza-bicyclo[3.2.1]oct-3-ylamine (650 mg, 4.0 mmol), 4-chlorobenzoyl chloride (650 mg, 4.0 mmol) and triethyl amine (1.25 ml, 9.0 mmol) in tetrahydrofuran (5.0 ml) in 54 % yield (575 mg) via flash chromatography. MS (APCI): m/z = 355 (M+H)+
Preparation 31 : N- (8-Aza-bicyclo [3.2.1 ] oct-3-yl)-4-chloro-benzamide
In accordance with preparation 27, the title compound is obtained from N-(8-benzyl- 8-aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-benzamide (355 mg, 1.0 mmol), ethyl chloroformate (0.38 ml, 4.0 mmol), an aqueous solution of hydrogen bromide (4.0 ml, 47 %) and toluene (4 ml) in 38 % yield (100 mg) via flash chromatography. MS (APCI): m/z = 265 (M+H)+
Example 24 4-Chloro-N-{8-[4-(2-isopropyUdene-3-oxo-2,3-dinydro-benzofuran-4-yloxy)-butyl]-
8-aza-bicyclo [3.2.1] oct-3-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (30 mg, 0.09 mmol), N-(8-aza- bicyclo[3.2.1]oct-3-yl)-4-chloro-benzamide (24 mg, 0.09 mmol) and triethyl amine (0.039 ml, 0.28 mmol) in DMF (1.0 ml) after stirring at 50 °C for 24 hours in 42 % yield (20 mg) via preparative HPLC purification. MS (APCI): m/z = 509 (M+H)+
Preparation 32: N-( l-Benzyl-2,6-dimethyl-piperidin-4-yl)-3,4-dichloro-benzamide
In accordance with preparation 26, the title compound is obtained from l-benzyl-2,6- dimethyl-piperidin-4-ylamine (500 mg, 2.3 mmol), 3,4-dichlorobenzoyl chloride (576 mg, 2.75 mmol) and triethyl amine (0.96 ml, 6.9 mmol) in tetrahydrofuran (10.0 ml) in 78 % yield (705 mg) via flash chromatography. MS (APCI): m/z = 391 (M+H)+
Preparation 33: 3,4-Dichloro-N- (2,6-dimethyl-piperidin-4-yl)-benzamide
In accordance with preparation 27, the title compound is obtained from N-(l-benzyl- 2,6-dimethyl-piperidin-4-yl)-3,4-dichloro-benzamide (130 mg, 0.33 mmol), 1- chloroethyl chloroformate (0.073 ml, 0.66 mmol) in toluene (10 ml) after subsequent hydrolysis in refluxing methanol in 10 % yield (10 mg) via flash chromatography. MS (APCI): m/z = 301 (M+H)+
Example 25 3,4-Dichloro-N-{l- [4-(2-isopropylidene -3-oxo-2,3-dilιydro-benzofiιran-4-yloxy)- butyl]-2,6-dimethyl-piperidin-4-yl}-benzamide
In accordance with example 1, the title compound is obtained from 4-(4-bromo- butoxy)-2-isopropylidene-benzofuran-3-one (20 mg, 0.07 mmol), 3,4-dichloro-N- (2,6-dimethyl-piperidin-4-yl)-benzamide (21 mg, 0.06 mmol) and triethyl amine (0.025 ml, 0.18 mmol) in DMF (1.5 ml) after stirring at 50 °C for 24 hours in 27 % yield (10 mg) via preparative HPLC purification. MS (APCI): m/z = 545 (M+H)+
Preparation 34: 4-(2-IsopropyHdene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-butyric acid
To a solution of 4-hydroxy-2-isopropylidene-benzofuran-3-one (1.87 g, 10 mmol) and potassium carbonate (1.42 g, 12.5 mmol) in N,N-dimethylformamide (30 ml) is added ethyl 4-bromobutyrate (2.15 ml, 15 mmol). The mixture is stirred at 70 °C for 5 hours. After evaporation of the solvent and aqueous work-up, the organic layers are combined and evaporated to yield ethyl 4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-butyrate. This intermediate is used without further purification, dissolved in ethanol (35 ml) and water (10 ml) and treated with lithium hydroxide (540 mg, 22 mmol) for 48 hours at room temperature. The ethanol is removed and the aqueous solution is acidified and extracted with ethyl acetate. The crude product is purified by flash chromatography using an ethyl acetate/methanol eluant to yield 1.95 g (70 %) of the desired product. MS (APCI): m/z = 277 (M+H)+
Preparation 35: 1- [4-(2-IsopropyHdene-3-oxo-2,3-(-ihydro-benzofuran-4-yloxy)- butyryl] -piperidin-4-one
To a solution of 4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-butyric acid (718 mg, 2.6 mmol) in dichloromefhan (20 ml) and N,N-dimethylformamide (0.22 ml) is added oxalyl chloride (0.5 ml, 5.7 mmol) at 0 °C. After stirring for 40 minutes at the same temperature, this solution is added to a suspension of 4- piperidone monohydrate monohydrochloride (1.84 g, 12.0 mmol) and triethylamine (4.4 ml, 31.5 mmol) in tetrahydrofuran (20 ml) and water (3.0 ml) at room temperature. Stirring is continued for 3 hours. The final product is isolated after aqueous work-up and flash chromatography purification using an ethyl acetate/methanol eluant in 12 % yield (112 mg). MS (APCI): m/z = 358 (M+H)+
Example 26 4-{4-[4-(Benzylamino)-piperidin-l-yl]-4-oxo-butoxy}-2-isopropylidene-benzofuran-
3-one
To a solution of l-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyryl]-piperidin-4-one (500 mg, 1.4 mmol) in methanol (10.0 ml) is added successively benzylamine (0.34 ml, 3.2 mmol), sodium triacetoxyborohydride (0.6 g, 2.8 mmol) and powdered potassium hydroxide (20 mg, 0.36 mmol). Stirring is continued for 24 hours and the final product is isolated via flash chromatography using an ethyl acetate/methanol eluant in 59 % yield (0.37 g). MS (APCI): m/z = 450 (M+H)+
Example 27 4-{4-[4-(4-Chloro-benzylamino)-piperidin-l-yl]-4-oxo-butoxy}-2-isopropylidene- benzofuran-3-one
In accordance with example 26, the title compound is obtained from l-[4-(2- isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-ylo-^)-butyryl]-piperidin-4-one (400 mg, 1.1 mmol), 4-chlorobenzylamine (160 mg, 1.1 mmol), sodium triacetoxyborohydride (240 mg, 1.1 mmol) and methanol (10.0 ml) in 76 % yield (406 mg). MS (APCI): m/z = 484 (M+H)+
Example 28 4-{4-[4-(3,4-Dichloro-benzylamino)-piperidin-l-yl]-4-oxo-butoxy}-2-isopropylidene- benzofuran-3-one
In accordance with example 26, the title compound is obtained from l-[4-(2- isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy) -butyryl] -piperidin-4-one (400 mg, 1.1 mmol), 3,4-dichlorobenzylamine (194 mg, 1.1 mmol), sodium triacetoxyborohydride (240 mg, 1.1 mmol) and methanol (10.0 ml) in 82 % yield (467 mg). MS (APCI): m/z = 517 (M+H)+
Example 29
3,4-DicUoro-N-{l-[4-(2-isopropyHdene-3-oxo-2,3-dihydxo-benzofuran-4-yloxy)- butyryl] -piperidin-4-yl}-benzamide
A solution of 4-(2-isopropylidene-3-oxo-2,3-dmydro-benzofuran-4-yloxy)-butyric acid (100 mg, 0.36 mmol) in dichloromethan (10 ml) is added 3,4-dichloro-N- piperidin-4-yl-benzamide (99 mg, 0.36 mmol) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (76 mg, 0.4 mmol) is stirred at room temperature for 20 hours. After aqueous work-up the final product is isolated via flash chromatography using an ethyl acetate/methanol eluant in 36 % yield (70 mg). MS
(APCI): m/z = 531 (M+H)+
Preparation 36: 3-(2-Isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- propionic acid
To a refluxing solution of 4-hydroxy-2-isopropylidene-benzofuran-3-one (1.87 g, 10 mmol) and sodium hydroxide (0.4 g, 10 mmol) in water (50 ml) is slowly added a solution of 3-bromopropionic acid (1.53 g, 10 mmol) and sodium hydroxide (0.4 g, 10 mmol) in water (20 ml). Refluxing is continued for 2 hours and the solution is acidified and extracted with ethyl acetate after cooling down to room temperature. Treatment of the crude product with sodium hydrogen carbonate, extraction of byproducts with ethyl acetate and repeated acidification affords the desired product in 16 % yield (427 mg). MS (APCI): m/z = 263 (M+H)+
Preparation 37: N-(l-Amino-piperidin-4-yl)-3,4-dichloro-benzamide
To a solution of 3,4-dichloro-N-piperidin-4-yl-benzamide (2.0 g, 7.32 mmol) in glacial acetic acid (45 ml) is added a solution of sodium nitrite (2.5 g, 36 mmol) in water (7 ml) at room temperature. Stirring is continued for 3 hours. The reaction mixture is quenched with water and the thereby formed precipitate is washed with water and diethyl ether. To the crude intermediate (3,4-Dichloro-N-(l-nitroso-piperidin-4-yl)- benzamide; 2.0 g) used without any further purification and dissolved in 40 ml of hydrochloric acid (20 vol.%) is added in small portions zinc dust (5.0 g, 76 mmol) at 0 °C. Stirring at that temperature is continued for further 2 hours. The crude reaction mixture is filtrated, the filtrate is adjusted with cone, ammonia to an alkaline pH-value and extracted with ethyl acetate. The product can be purified by flash chromatography using acetone as eluant in 77 % yield ( 1.48 g) . MS (APCI) : m/z = 288 (M+H) +
Example 30
3,4-DicUoro-N-{l-[3-(2-isopropyhdene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- propionylamino]-piperidin-4-yl}-benzamide
To a solution of 3-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- propionic acid (250 mg, 0.95 mmol) in dichloromethan (25 ml) are added N-(l- amino-piperidin-4-yl)-3,4-dichloro-benzamide (275 mg, 0.95 mmol) and l-ethyl-3- (3'-dimethylaminopropyl)-carbodiimide hydrochloride (200 mg, 1.05 mmol) at room temperature and stirring is continued at the same temperature for further 3 hours. The reaction mixture is washed twice with water and hydrochloric acid (2N) and the combined organic layers are evaporated. The crude product is purified by flash chromatography using an ethyl acetate/methanol- eluant (10:1) to yield 26 % (134 mg) of the final product (mp = 183-185 °C, decomp.). MS (APCI): m/z = 532 (M+H)+ List of References
Ansel, H., et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995, at pp. 196 and 1456-1457 Dano et al., Proteolysis and Protein Turnover, eds. Barret + Bond, Portian Press, 1994,
London EP 0 088 986 EP 1 026 165
Goodson, R.J., et al., Proc. Natl. Acad. Sci. USA 91 (1994) 7129-7133 J. Am. Chem. Soc. 61 (1939) 2328
Monatsh. Chem. 128 (1997) 371-380 Ploug, M., et al., J. Biol. Chem. 268 (1993) 17539-17546 Rabbani, S.A., et al., J. Biol. Chem.267 (1992) 14151-14156 Stratton-Thomas, J.R., et al., Protein Eng. 8 (1995) 463-470 WO 99/06387

Claims

Patent Claims
1. The compounds of formula (I) or (II)
Figure imgf000045_0001
formula (I) or formula (II),
wherein
R ) 1 , R τ.2 are independently hydrogen; alkyl; cycloalkyl;
-NH(Cι-C4-alkyl);
-N(C C4-alkyl)2;
-S-(C1-C4-alkyl);
-(CH2)n-O-(C1-C4-alkyl); or
R1 and R2 together with the carbon-atom to which they are attached form a cycloalkyl group,
A is alkylene;
-(CH2)n-C(O)-; or
-(CH2)n-C(O)-NH-; B is a heterocyclic group; M is -NH-C(O)-; or
-NH-CH2-;
R3, R4 are independently hydrogen; halogen;
-CN; -OH;
-O-(Cι-C4-alkyl); -NH2;
-SO2-(CrC4-alkyl);
-SO2-NH2;
-SO2-NH(Ci-C4-alkyl);
-SO2-N(C1-C4-alkyl)2; -C(O)-NH2;
-C(O)-NH-(Cι-C4-a-lcyl);
-NH(C C4-alkyl);
-N(C C4-alkyl)2; or alkyl;
n is 1, 2, 3 or 4;
and pharmaceutically acceptable salts thereof.
2. The compounds of formula I acording to claim 1, wherein R1, R2, R3, R4, A, B and M have the significance given in claim 1.
3. The compounds of formula II according to claim 1., wherein R1, R2, R3, R4, A, B and M have the significance given in claim 1.
4. The compounds of formula I according to claim 1 or 2, wherein R1, R2 are independently hydrogen; CH3 or CD3; cyclopropyl;
-N(CH3)2;
-S-CH3;
-(CH2)n-O-CH3; or R and R2 together with the carbon-atom to which they are attached form a cyclopentyl;, R3, R4 are independently hydrogen; halogen; or -SO2-NH2; and
A, B and M have the significance given in claim 1.
5. The compounds according to claim 1 or 2, wherein B is piperidin-l,4-diyl and M is -NH-C(O)-, of formula I-A
Figure imgf000047_0001
formula I-A,
wherein R\ R2 are both -CH3; -CD3; -S-CH3; -CH2-O-CH3 or cyclopropyl; or R* and R2 together with the carbon-atom to which they are attached, form a cyclopentyl;
R , R are independently hydrogen; halogen; or
-SO2-NH2; provided that R .3% R* are not both -SO2-NH2; and
A has the significance given in claim 1. The compounds according to claim 5
3,4-Dichloro-N-{l-[4-(r,lM'>3',3',3'-hexadeutero-2-isopropylidene-3-oxo-2,3- dihydro-benzofuran-4-yloxy)-butyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-l-methyl-butyl]-piperidin-4-yl}-benzamide;
3,4-Dichloro-N-{l-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-butyryl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(7-chloro-2-isopropylidene-3-oxo-2,3-dihydro- benzofuran-4-yloxy)-butyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[3-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy) -propionylamino] -piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-l-methyl-pentyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-( , , ,3',3',3'-hexadeutero-2-isopropylidene-3-oxo-2,3- dihydro-benzofuran-4-yloxy) - 1 -methyl-butyl] -piperidin-4-yl}- benzamide; 3,4-Dichloro-N-( l-{4- [2-(2-methoxy- l-methoxymethyl-ethylidene)-3-oxo-2,3- dihydro-benzofuran-4-yloxy] -butyl} -piperidin-4-yl) -benzamide; N-(l-{4-[2-(Bis-methylsulfanyl-methylene)-3-oxo-2,3-dihydro-benzofuran-4- yloxy] -butyl}-piperidin-4-yl)-3,4-dichloro-benzamide;
3,4-Dichloro-N-{l-[4-(2-cyclopentylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy) -butyl] -piperidin-4-yl} -benzamide; 3,4-Dichloro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro- benzofiuran-4-yloxy)-butyl]-piperidin-4-yl}-benzamide; 4-Chloro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-butyl] -piperidin-4-yl}-benzamide; or 4-CUoro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro-benzofu.ran-4- yloxy)-butyl]-piperidin-4-yl}-3-sulfamoyl-benzamide.
7. The compounds of formula I-A according to claim 5, wherein
R1, R2 are independently but not both at the same time hydrogen; methyl; cyclopropyl; or
-N(CH3)2.
8. The compounds according to claim 7
3,4-Dichloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy] -butyl} -piperidin-4-yl) -benzamide;
3,4-Dichloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy] - 1 -methyl-pentyl} -piperidin-4-yl) -benzamide; 3,4-Dichloro-N-{l-[4-(2-dimethylaminomethylene-3-oxo-2,3-dihydro- benzofuran-4-yloxy)-butyl]-piperidin-4-yl}-benzamide; E-3,4-Dichloro-N-(l-{4-[2-(l-cyclopropyl-efhylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy] -butyl} -piperidin-4-yl) -benzamide; Z-3,4-Dichloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy] -butyl} -piperidin-4-yl) -benzamide; Z-4-Chloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy] -butyl} -piperidin-4-yl) -benzamide;
Z-3-Chloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy]-butyl}-piperidin-4-yl)-benzamide; Z-4-Chloro-N-(l-{4-[2-(l-cyclopropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy]-butyl}-piperidin-4-yl)-3-sulfamoyl-benzamide; or 4-Chloro-N-(l-{4-[2-(l-cycloρropyl-ethylidene)-3-oxo-2,3-dihydro- benzofuran-4-yloxy]-butyl}-piperidin-4-yl)-3-sulfamoyl-benzamide.
The compounds according to claim 1 or 2, wherein B is 2,6-dimethyl-piperidin- 1,4-diyl and M is -NH-C(O)-, of formula I-B
Figure imgf000050_0001
formula I-B,
wherein R , R2 are both -CH3; -CD3; -S-CH3; -CH2-O-CH3 or cyclopropyl;
R >3 , R are independently hydrogen; halogen; or -SO2-NH2; provided that R .3 , R are not both -SO2-NH2; and
A has the significance given in claim 1.
10. The compound according to claim 9,
3,4-Dichloro-N-{l-[4-(2-dicyclopropylmethylene-3-oxo-2,3-dihydro- benzofuran-4-yloxy)-butyl]-2,6-dimethyl-piperidin-4-yl}-benzamide.
11. The compounds according to claim 1 or 2, wherein B is piperidin- 1, 4- diyl and M is -NH-CH2-, of formula I-C
Figure imgf000051_0001
formula I-C,
wherein R\ R2 are both alkyl;
R .3 , R are independently hydrogen; or halogen; and
A has the significance given in claim 1.
12. The compounds according to claim 11,
4- {4- [4- (Benzylamino) -piperidin- 1 -yl] -4-oxo-butoxy} -2-isopropylidene- benzofuran-3-one; 4-{4-[4-(3,4-Dichloro-benzylamino)-piperidin-l-yl]-4-oxo-butoxy}-2- isopropylidene-benzofuran-3-one; or 4-{4- [4-(4-Chloro-benzylamino)-piperidin-l-yl] -4-oxo-butoxy}-2- isopropylidene-benzofuran-3-one.
13. The compounds according to claim 1 or 2, wherein B is 8-aza-bicyclo [3.2. l]oct- 3,8-diyl and M is -NH-C(O)-, of formula I-D
Figure imgf000052_0001
formula I-D,
wherein R , R2 are both alkyl;
R >3, R are independently hydrogen; or halogen; and
A has the significance given in claim 1.
14. The compounds according to claim 13,
3,4-Dichloro-N-{8-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy)-butyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamide;
4-Chloro-N-{8- [4- (2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy) - butyl] -8-aza-bicyclo [3.2.1 ] oct-3-yl} -benzamide; or
3-Chloro-N-{8-[4-(2-isopropylidene-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamide.
15. The compounds according to claim 1 or 3, wherein B is piperidin- 1,4- diyl and M is -NH-C(O)-, of formula II-A
Figure imgf000053_0001
formula II-A,
wherein R\ R2 are both alkyl; or R* and R2 together with the carbon-atom to which they are attached form a cycloalkyl group;
R .3 , R are independently hydrogen; or halogen; and
A is alkylene.
16. The compounds according to claim 15,
3,4-Dichloro-N-{l-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-l- methyl-butyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-4-yloxy)-l- methyl-pentyl]-piperidin-4-yl}-benzamide; 3,4-Dichloro-N-{l-[4-(2-cyclopropylidene-3-oxo-2,3-dihydro-benzofuran-4- yloxy) -butyl] -piperidin-4-yl}-benzamide; or 3,4-Dichloro-N-{l-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-4-yloxy)- butyl]-piperidin-4-yl}-benzamide.
7. A process for the manufacture of compounds according to claim 1, which comprises reacting a compound of either formula (Ilia) or (Illb)
Figure imgf000054_0001
(Ilia) or (Illb),
wherein
R1 and R2 have the significance given in claim 1, with a compound of formula
(IV)
L1-A-L2 (IV),
wherein
A has the significance given in claim 1 and Ll and L2 are the same or different leaving groups such as chlorine, bromine, iodine, mesyl, tosyl or trifluoromethanesulfonyl;
and a compound of formula (V):
Figure imgf000054_0002
wherein
B, M, R .3 a _nd i R π4 have the significance given in claim 1; and
said reactions are processed either by reaction of a compound of formula (Ilia) or (Illb) with a compound of formula (IV), followed by reaction of the so obtained product with a compound of formula (V);
or alternatively
by reaction of a compound of formula (V) with a compound of formula (IV), followed by reaction of the so obtained product with a compound of formula (Ilia) or (Illb).
18. A medicament containing one or more compounds as claimed in any one of claims 1 to 16 and pharmaceutically acceptable excipients.
19. A medicament according to claim 18 for the inhibition of tumor growth.
20. The use of a compound in any one of claims 1 to 16 for the treatment of cancer.
21. The use of a compound in any one of claims 1 to 16 for the manufacture of corresponding medicaments for the inhibition of tumor growth.
PCT/EP2004/001798 2003-02-25 2004-02-24 Novel hydroxycoumaranone derivatives as antitumor and antimetastatic WO2004076444A2 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0088986A2 (en) * 1982-03-13 1983-09-21 Roche Diagnostics GmbH Bicyclic phenol ethers, process for their preparation and medicines containing these compounds
WO1999006387A2 (en) * 1997-07-31 1999-02-11 F. Hoffmann-La Roche Ag O-substituted hydroxycumaranone derivatives as antitumor and antimetastatic agents
EP1026165A1 (en) * 1999-01-30 2000-08-09 Roche Diagnostics GmbH O-substituted Hydroxycoumaranone derivatives as antitumor and antimetastatic agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0088986A2 (en) * 1982-03-13 1983-09-21 Roche Diagnostics GmbH Bicyclic phenol ethers, process for their preparation and medicines containing these compounds
WO1999006387A2 (en) * 1997-07-31 1999-02-11 F. Hoffmann-La Roche Ag O-substituted hydroxycumaranone derivatives as antitumor and antimetastatic agents
EP1026165A1 (en) * 1999-01-30 2000-08-09 Roche Diagnostics GmbH O-substituted Hydroxycoumaranone derivatives as antitumor and antimetastatic agents

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