Definitions

• the present invention relates to 2-arylbenzothiazoles of the general formula (I) or a salt or a prodrug or a stereoisomer thereof.
• the compounds of the invention are exceptionally useful for the treatment of diseases associated with abnormal and hyperproliferation of cells in a mammal, especially humans. In particular, they are useful for the treatment of all forms of cancer. Furthermore a process of preparing said 2-arylbenzothiazole derivatives is disclosed.
• Protein kinases play a central role in the regulation of cellular functions. This includes processes like cell growth and division, cell differentiation and cell death, but also many other cellular activities. Protein kinases catalyze the transfer of phosphate residues from ATP on target proteins which as a consequence of this protein kinase mediated phosphorylation change their three-dimensional structure and thereby their physiological function. Depending on the amino acid which is phosphorylated by a protein kinase these en ⁇ ymes are grouped in two families, the so-called serine/threonine protein kinases and the tyrosine protein kinases.
• oncogenes are pathologically modified genes which in their proto- oncogenic form encode for protein kinases involved in normal, physiological regulation of cell growth and division. Since protein kinases are key regulators of cell functions and since they can show dysregulated enzymatic activity in cells they are promising targets for the development of therapeutic agents. There are many ongoing drug discovery projects in the pharmaceutical industry with the goal to identify modulators of protein kinases. The major focus is currently on protein kinases involved in inflammation and cancer, but besides this protein kinases are currently discussed as promising targets in almost every area of diseases. In the field of tumors the first protein kinase inhibitors (Gleevec, Iressa) have already reached the market.
• EGF Epidermal Growth Factor
• VEGF Vascular Endothelial Growth Factor
• All these compounds have been developed with the goal to specifically inhibit one particular protein kinase, for which there is evidence that it interferes with one of the four major molecular processes of tumor progression. These four processes are (1) cell proliferation/cell cycle control, (2) regulation of programmed cell death (apoptosis) and cell survival, (3) tumor angiogenesis and (4) tumor metastasis.
• the present invention relates to 2-arylbenzothiazole derivatives which may be useful for inhibition of protein kinases involved in diseases besides cancer, but which are especially useful as anti-tumor agents.
• This includes monospecific protein kinase inhibitors, which preferentially inhibit one protein kinase which is causatively involved in tumor progression, but also so-called multi-target protein kinase inhibitors, which inhibit at least two different protein kinases which either relate to the same or to two or more different molecular mechanism of tumor progression.
• a compound could be an inhibitor of tumor angiogenesis and, in addition, also a stimulator of apoptosis.
• multi-target protein kinase inhibitors The concept of multi-target protein kinase inhibitors is a new approach although the idea of developing "multiplex protein kinase inhibitors" has already been described by J. Adams et al., Current Opinion in Chemical Biology 6, 486-492, 2002. Therein compounds are described, which, at the same time, inhibit several protein kinases, which however all are involved in one molecular mechanism of tumor progression, namely tumor angiogenesis.
• UV-filters used as skin and hair sunscreens.
• the present invention relates to compounds of the general formula (I) or a salt or a prodrug or a stereoisomer thereof,
• Y independently represents a divalent linkage selected from S, O, NR 2 , SO, SO 2 ;
• A independently represents a divalent linkage selected from a five- or six- membered aromatic carbocycle or heterocycle each of which is optionally substituted by one to four substituents selected from R and R , with the proviso that A-Y is not NR 2 attached at the 2- or 4-position of a pyrimidine ring represented by A and A-Y is not NR 2 attached to 2-halopyridine represented by A;
• R 2 independently represents H, alkyl, cycloalkyl, -COR 11 , -SOR 11 , -SO 2 R 11 , -CN, hydroxyalkyl, haloalkyl, haloalkyloxy, or alkylamino;
• R 3 independently represents H, -COR 11 , -CO 2 R 11 , -SOR 11 , -SO 2 R 11 , -SO 3 R 11 , -NO 2 , -CN, -CF 3 , -OCH 3 , -OCF 3 , alkyl, cycloalkyl, alkoxy, NH 2 , alkylamino, -NR 8 COR 11 , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, or haloalkyloxy;
• R 4 independently represents H, -COR 11 , -CO 2 R 11 , -SOR 11 , -SO 2 R 11 , -SO 3 R 11 , -NO 2 , -CN, -CF 3 , -OCH 3 , -OCF 3 , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamino, -NR 8 COR 11 , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
• R 5 independently represents H, -COR 11 , -CO 2 R 11 , -SOR 11 , -SO 2 R 11 , -SO 3 R 11 , -NO 2 , -CN, -CF 3 , -OCH 3 , -OCF 3 , alkyl, cycloalkyl, alkoxy, -NH 2 ,
• R 6 independently represents H, -COR 11 , -CO 2 R 11 , -SOR 11 , -SO 2 R 11 , -SO 3 R 11 , -NO 2 , -CN 3 -CF 3 , -OCH 3 , -OCF 3 , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamino,
• -NR 8 COR 11 halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
• R 7 independently represents H, -COR 11 , -CO 2 R 11 , -SOR 11 , -SO 2 R 11 , -SO 3 R 11 , -NO 2 ,
• R 8 independently represents H, alkyl, cycloalkyl, -COR 11 , -SOR 11 , -SO 2 R 11 , hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
• R 9 independently represents H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
• R 11 independently represents H, alkyl, cycloalkyl, -NR 8 R 9 , -NR 8 NR 8 R 9 , -ONR 8 R 9 ,
• R 1 independently represents one of the following groups: where * indicates the point of attachment
• Z independently represents O, NR 8 , or S
• R 12 independently represents H, -NHR 8 ; or one of the following groups:
• R , 12a independently represents one of the following groups:
• R » 13 independently represents H, halogen, nitro, -CN, trifluoromethyl, alkyl, aryl, heteroaryl, _ o ⁇ r - V X2 2 ⁇ R> 1 1 8*.;
• R , 13a independently represents H, nitro, -CN, trifluoromethyl, alkyl, aryl, or heteroaryl;
• R , 14 independently represents H, halogen, nitro, -CN, trifluoromethyl, alkyl, aryl, heteroaryl, -NR 8 ⁇ rR> 9 y , o _r - V X2 2 ⁇ R> 18.
• R 15 independently represents H, halogen, nitro, -CN, trifluoromethyl, alkyl, aryl, heteroaryl, -NR 8 8 rR>9 y , o _r - V X2 2 ⁇ R, 1 1 8 8 .;
• R , 16 independently represents H, halogen, nitro, -CN, trifluoromethyl, alkyl, aryl, heteroaryl, -NR 8 8 ⁇ R>9 y , o _r - V X2 2 ⁇ R> 1 1 8 8 .;
• R , 16a independently represents H, halogen, nitro, -CN, trifluoromethyl, alkyl, heteroaryl, -NR 8 8 rR> 9 y , otitle matterr - V X2 2 D R18.
• R , 17 independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR 8 R 9 , or -X 2 R 18 ;
• X r 2 independently represents a direct bond, -O-, -CH 2 -, -OCO-, CO, -S-,
• R , 1 18 8 independently represents H, alkyl, cycloalkyl, -COR 11 , -SOR 11 , -SO 2 R 11 , -OCH 3 , -OCF 3 , hydroxyalkyl, haloalkyl, haloalkyloxy, or one of the following groups:
• # indicates the point of attachment m independently represents an integer from 1-3;
• L is absent or represents a divalent linkage group selected from alkylen, cycloalkylen, heterocyclylen, arylen, or heteroarylen, wherein one or more of the (-CH 2 -) groups may be replaced by an oxygen or a NR 8 , and wherein one or more carbon atoms may be independently substituted by one or two substituents selected from halogen, hydroxy, alkoxy, haloalkyloxy, phoshonooxy, or phoshonooxyalkyl;
• X 3 independently represents -COOH, -COOalkyl, -CONR 8 R 9 , -OH,
• R , 19 independently represents H, alkyl, cycloalkyl, alkylamino, or alkoxy;
• R ⁇ independently represents H, -CO 2 R", -CONHR", -CR” O, -SO 2 NR", -NR" -CO- haloalkyl, -NO 2 , -NR"-SO 2 -haloalkyl, -NR"-SO 2 -alkyl, -SO 2 -alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heteroaryl;
• R" independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
• an alkylene group denotes a divalent linear or branched Ci-C 6 -alkylene, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2 -C 6 -alkenylene or a linear or branched C 2 -C 6 -alkynylene group, which may be substituted by one or more substituents R';
• a cycloalkylene group denotes a divalent non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be substituted by a group E, E being O, S, SO, SO 2 , N, or NR", R" being as defined above;
• a heterocyclylene group denotes a 3 to 8-membered divalent heterocyclic non-aromatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another non-aromatic ring and may be substituted by one or more substituents R ⁇ , wherein R ⁇ is as defined above;
• an arylene group denotes an aromatic divalent group having five to fifteen carbon atoms, which may be substituted by one or more substituents R ⁇ and may be fused to another aromatic ring, where R ⁇ is as defined above;
• a heteroarylene group denotes a divalent 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another aromatic ring and may be substituted by one or more substituents R ⁇ wherein R ⁇ is as defined above;
• a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being O, S, SO, SO 2 , N, or NR", R" being as defined above;
• the C 3 -C 8 -cycloalkyl residue may be selected from the group comprising -CyCIo-C 3 H 5 , -CyCIo-C 4 H 7 , -cyclo-CsHp, -cyclo-C ⁇ H ⁇ , -CyCIo-C 7 H 13 , -cyclo-CgHjs, morpholine-4-yl, piperazinyl, l-alkylpiperazine-4-yl;
• an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, /-butoxy or pentoxy group;
• an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above;
• an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R 10 ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10' ) 2 , -CH 2 - CR 10 (R 10' )R 10" , -C 3 (R 10 ) 7 , or -C 2 H 4 -C(R 1 V wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
• a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
• an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R 1 V -OCR 10 (R 10> ) 2 , -OCR 10 (R 10' )R 10" , -OC 2 (R 1 V -OCH 2 -C(R 1 V -OCH 2 -
• a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH- group, the alkyl group being as defined above;
• an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
• an arylamino group denotes an HN-aryl, or N-diaryl, or -N-aryl-alkyl group, the alkyl and aryl group being as defined above;
• a halogen group is fluorine, chlorine, bromine, or iodine
• an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R", where R' is as defined above; the aryl group is preferably a phenyl group, -0-C 6 H 4 - R ⁇ -m-C 6 H 4 - R ⁇ -p-C 6 H 4 - R ⁇ 1-naphthyl, 2-naphthyl, 1 -anthracenyl or 2-anthracenyl;
• a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S.
• This heterocyclic group can be fused to another aromatic ring.
• this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thi
• the invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), in free form, or in the form of a pharmaceutically acceptable salt, or a prodrug thereof, together with a pharmaceutically acceptable diluent or carrier therefore.
• physiologically functional derivative refers to compounds which are not pharmaceutically active themselves but which are transformed into their pharmaceutical active form in vivo, i.e. in the subject to which the compound is administered.
• physiologically functional derivatives are prodrugs such as those described below in the present application.
• prodrug refers to compounds which are not pharmaceutically active themselves but which are transformed into their pharmaceutical active form in vivo, i.e. in the subject to which the compound is administered.
• Prodrugs of the compounds of the present invention include but are not limited to: esters, which are transformed in vivo into the corresponding active alcohol, esters, which are transformed in vivo into the corresponding active acid, imines, which are transformed in vivo into the corresponding amines, imines which are metabolized in vivo into the corresponding active carbonyl derivative (e.g.
• stereoisomer refers to compound with at least one stereogenic center, which can be R- or S-configurated. It has to be understood, that in compounds with more than one stereogenic center each of which independently from each other can be R- or S-configurated.
• stereoisomer also refers to salts of the compounds herein described with optically active acids or bases.
• stereoisomer also means cis/trans or E/Z isomerism. More particularly, the possible double bond(s) present in the various substituent of the compounds of the present invention can be E or Z configuration.
• stereoisomer includes also all the isomeric forms, alone or as mixture, resulting from the presence of one or more axes and / or centers of symmetry in the molecules, and resulting in the rotation of a beam of polarized light. More particularly, it includes enatiomers and diastereomers, in pure form or as a mixture.
• the present invention provides methods for preparing the compounds of the invention such as compounds of formula (I).
• the compounds of formula (I) may be obtained via various methods.
• an activated acid derivative e.g. acid chloride
• the acid according to formula (IX) may be used instead of the acid according to formula (IX).
• Another way to synthesize compounds of the formula (VII) is the conversion of compounds of formula (XI), a disulfide, into the benzothiazole of formula (VII) by reduction of the disulfide and subsequent condensation.
• Compounds of the formula (XT) may be obtained by reaction of a disulfide according to formula (XET) with a compound of formula (IX) or alternatively an activated carboxylic acid derivative.
• R 21 H, NH 2 , Me
• a preferred embodiment of the invention are compounds of the formula (I) wherein Y is NR 2 or O.
• a preferred embodiment of the invention are compounds of the formula (II)
• R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
• the compounds of formula (II) are the compounds where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (II) wherein Y is NR 2 or O.
• a preferred embodiment of the invention are compounds of the formula (II) wherein Y is NR 2 or O and where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (IT) wherein Q is C or CH and R 3 is F, Cl, or OCH 3 .
• a preferred embodiment of the invention are compounds of the formula (II) wherein Q is C or CH and R 3 is F, Cl, or OCH 3 and where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (II) wherein Y is NR 2 or O and wherein Q is C or CH and R 3 is F, Cl, or OCH 3 .
• a preferred embodiment of the invention are compounds of the formula (II) wherein Y is NR 2 or O and wherein Q is C or CH and R 3 is F, Cl, or OCH 3 and where Y is attached at the 3- or 4-position of the cycle A.
• Q independently represents C, N, CH; Y, R 3 , R 4 , R 5 , R 6 , R 7 , R 13 , R 14 , R 15 , and R 16a are as defined above.
• the compounds of formula (III) are the compounds where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (III) wherein Y is NR 2 Or O.
• a preferred embodiment of the invention are compounds of the formula (IH) wherein Y is NR 2 or O and where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (III) wherein Q is C or CH and R 3 is F, Cl, or OCH 3 .
• a preferred embodiment of the invention are compounds of the formula (III) wherein Q is C or CH and R 3 is F, Cl, or OCH 3 and where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (III) wherein Y is NR 2 or O and wherein Q is C or CH and R 3 is F, Cl, or OCH 3 .
• a preferred embodiment of the invention are compounds of the formula (III) wherein Y is N NRR 2 oorr OO aanndd wwhheerreeiinn QQ iiss CC oorr ⁇ CH and R 3 is F, Cl, or OCH 3 and where Y is attached at the 3- or 4-position of the cycle A.
• Another preferred embodiment of the invention are compounds of the formula (IV)
• Q independently represents C, N, CH
• Y, R 3 , R 4 , R 5 , R 6 , R 7 and R 13 are as defined above.
• the compounds of formula (FV) are the compounds where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (TV) wherein Y is NR 2 or O.
• a preferred embodiment of the invention are compounds of the formula (FV) wherein Y is NR 2 or O and where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (TV) wherein Q is C or CH and R 3 is F, Cl, or OCH 3 .
• a preferred embodiment of the invention are compounds of the formula (FV) wherein Q is C or CH and R 3 is F, Cl, or OCH 3 and where Y is attached at the 3- or 4-position of the cycle A.
• a preferred embodiment of the invention are compounds of the formula (FV) wherein Y is NR 2 or O and wherein Q is C or CH and R 3 is F, Cl, or OCH 3 .
• a preferred embodiment of the invention are compounds of the formula (IV) wherein Y is NR 2 or O and wherein Q is C or CH and R 3 is F, Cl, or OCH 3 and where Y is attached at the 3- or 4-position of the cycle A.
• Exemplary compounds of formula (I) of the present invention include, but are not limited to, the following:
• the compounds of the present invention can form salts with inorganic or organic acids or bases.
• pharmaceutically acceptable salts comprise without limitation nontoxic inorganic or organic salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enantate derived from heptanoic acid, formiate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methan
• Salts of phosphonoxy- and phosphonoxyalkyl groups may be those formed with alkali metal ions e.g. sodium or potassium, or those formed with alkaline earth metal ions e. g. calcium or magnesium, or those formed with zinc ions.
• Such salts of the compounds of the present invention may be anhydrous or solvated. Such salts can be produced by methods known to someone of skill in the art and described in the prior art.
• salts like oxalate derived from oxalic acid which is not considered as pharmaceutically acceptable can be appropriate as intermediates for the production of compounds of the present invention or a pharmaceutically acceptable salt thereof or a prodrug or a stereoisomer thereof.
• the compounds according to the invention and medicaments prepared therewith are generally useful for the treatment of cell proliferation disorders, for the treatment or prophylaxis of immunological diseases and conditions (as for instance inflammatory diseases, neuroimrnuno logical diseases, autoimmune diseases or other).
• the compounds of the present invention are useful for the treatment of diseases which are caused by malignant cell proliferation, such as all forms of solid tumors, leukemias and lymphomas. Therefore the compounds according to the invention and medicaments prepared therewith are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death or to induce systemic changes in metabolism such as changes in sugar, lipid or protein metabolism.
• cell generation poiesis including blood cell growth and generation (prohematopoietic effect) after depletion or destruction of cells, as caused by, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune dysregulation, anemia and the like or to provide a therapeutic control of tissue generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.
• cancer as hematological (e.g. leukemia, myeloma), or lymphomas (e.g. Hodgkin's and non-Hodgekin's lymphoma), or solid tumors (for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, cervical, and ovarian, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squameous cell carcinoma, sarcomas as Kaposi's sarcoma and osteosarcoma).
• hematological e.g. leukemia, myeloma
• lymphomas e.g. Hodgkin's and non-Hodgekin's lymphoma
• solid tumors for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorec
• 2-arylbenzothiazole derivatives of the present invention as new pharmaceutically active agents, especially for the preparation of a pharmaceutical composition for the treatment of diseases which are cured or relieved by the inhibition of one or several kinases and/or phosphatases.
• the compounds of the present invention may be used for treating and/or preventing diseases by inhibition of one or or more kinases like: Aurora-A, Aurora-B, EGF-R, ERBB2, PDGFR, FLT3, IGFl-R, VEGF- R2, VEGF-R3, EPHB4, TIE2, FAK and SRC.
• Treatment is intended to mean complete or partial healing of a disease, prevention of a disease, or alleviation of a disease, or stop of progression of a given disease.
• the compounds of the present invention can further be used for diseases that are caused by protozoal infestations in humans and animals.
• the compounds of the present invention can further be used for viral infections or other infections caused for instance by Pneumocystis carinii.
• the invention relates to a method of treatment or prevention of diseases which comprises the administration of an effective amount of compounds of the present invention or a salt or prodrug or a stereoisomer thereof.
• the compounds of the according invention and their pharmacologically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, dogs and chickens as therapeutics per se, as mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active constituent contain an effective dose of at least one compound of the present invention or a salt thereof, in addition to customary pharmaceutically innocuous excipients and additives.
• the production of medicaments containing the compounds according to the present invention and their application can be performed according to well-known pharmaceutical methods.
• the compounds according to the present invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
• Such salts of the compounds may be anhydrous or solvated.
• the invention provides medicaments comprising compounds according to the present invention, or a salt or a prodrug or a stereoisomer thereof, together with one or more pharmaceutically acceptable carriers thereof, and, optionally, other therapeutic and/or prophylactic ingredients.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
• a medicament of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
• sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier is a finely divided solid which is in a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
• Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
• cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
• a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
• the active component is dispersed homogeneously therein, as by stirring.
• the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
• Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
• parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
• the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
• the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
• the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
• Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
• Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
• viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
• the medicament is applied topically or systemically or via a combination of the two routes.
• the medicament is prepared in form of an ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphophilic emulsion system (oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a powder.
• an ointment a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphophilic emulsion system (oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a powder.
• Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
• compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
• the compositions may be provided in single or multi-dose form, hi the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
• Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
• a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
• CFC chlorofluorocarbon
• the aerosol may conveniently also contain a surfactant such as lecithin.
• the dose of drug may be controlled by provision of a metered valve.
• the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
• a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
• PVP polyvinylpyrrolidone
• the powder carrier will form a gel in the nasal cavity
• the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
• the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
• compositions adapted to give sustained release of the active ingredient may be employed.
• the pharmaceutical preparations are preferably in unit dosage forms, hi such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
• compositions can also contain two or more compounds of the present invention or their pharmacologically acceptable salts and also other therapeutically active substances.
• the compounds of the present invention can be used in the form of one compound alone or in combination with other active compounds - for example with medicaments already known for the treatment of the aforementioned diseases, whereby in the latter case a favorable additive, amplifying effect is noticed.
• pharmaceutically inert inorganic or organic excipients can be used.
• pills tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.
• Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
• Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc.
• Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
• the dose can vary within wide limits and is to be suited to the individual conditions in each individual case.
• the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of about 1 to 100 mg/kg animal body weight preferably 1 to 50 mg/kg.
• Suitable dosage rates for larger mammals, for example humans are of the order of from about 10 mg to 3 g/day, conveniently administered once, in divided doses 2 to 4 times a day, or in sustained release form.
• the following examples are included to demonstrate preferred embodiments of the invention.
• Preparative HPLC-MS Waters 600 Multisolvent Delivery System with peparative pump heads. 2000 ⁇ l or 5000 ⁇ l Sample loop. Column, Waters X-Terra RPl 8, 7 ⁇ m, 19 x 150 mm with X-Terra RP 18 guard cartridge 7 ⁇ m, 19 x 10 mm; used at flow rate 20 ml/min or YMC ODS-A, 120 A, 40 x 150 mm with X-Terra RP 18 guard cartridge 7 ⁇ m, 19 x 10 mm; used at flow rate 50 ml/min. Make-up solvent: MeCN - H 2 O - HCO 2 H 80 : 20 : 0.05 (v:v:v).
• Eluent A H 2 O + 0.1% HCO 2 H
• eluent B MeCN.
• Step 1 To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100°C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na 2 SO 4 , the solvent was removed to yield methyl 4-ben2yloxy-3-methoxybenzoate or methyl 3- benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
• Step 2 Crude material of step 1 (40.0 mmol) was converted into methyl 4-benzyloxy-5- methoxy-2-nitrobenzoate or methyl 5-benzyloxy-4-methoxy-2-nitrobenzoate, respectively, in 91-94% yield as described in US 02/0026052 Al, page 51, reference example 15.
• Step 3 In a 1 1 Schlenk flask filled with argon, product of step 2 (36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4- hydroxy-5-methoxybenzoate or methyl 2-amino-5-hydroxy-4-methoxybenzoate, respectively, quantitatively, which, again, was used without further purification.
• Step 4 A mixture of formamide (29 mL), ammonium formate (3.41 g, 54 mmol) and crude material of step 3 (36.0 mmol) was heated to 140°C for 4 h. After cooling to r.t., water (75 mL) was added. After stirring for 1 h, the precipitated 7-hydroxy-6-methoxy-3,4- dihydroquinazolin-4-one or 6-hydroxy-7-methoxy-3 ,4-dihydroquinazolin-4-one, respectively, was filtered off, washed with water and dried (76-85%).
• Step 5 A mixture of product step 4 (30.5 mmol), acetic anhydride (21.5 mL, 229 mmol) and pyridine (4.9 mL, 61 mmol) was heated to 100°C for 4 h. After cooling to r.t., ice water (200 mL) was added and the mixture was vigorously stirred for 1 h. The precipitated 7-acetoxy-6-methoxy-3 ,4-dihydroquinazolin-4-one or 6-acetoxy-7-methoxy-3 ,4- dihydroquinazolin-4-one, respectively, was filtered off, washed with water and dried (93- 96%). Step 6.
• Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6- methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95%) by reacting them with thionylchloride (12 mL) and DMF (0.3 mL) at 85 °C for 1.5 h. Excess thionylchloride was removed by distillation. Traces of thionylchloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl 3 and PCl 5 . The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt%) in dioxane / water (100 mL / 20 mL) at 0 °C to r.t.
• 3-Morpholin-4-yl-propan-l-ol (b.p., 180°C / 1 mbar) was synthesized in analogy to 3-(4- methylpiperazin- 1 -yl)-propan- 1 -ol from 3-bromopropanol and morpholine.
• reaction mixture was partitioned between satd aq. NaHCOs/brine 1 :3 (100 mL) and CHCl 3 (100 mL, then 2x50 mL). Combined org. phases were re-extracted once against 50 mL brine and dried over MgSO 4 . If necessary, product was purified by preparative TLC (1 mm silica gel, CH 2 Cl 2 ZMeOH 90:10 or prep. HPLC on reversed phase. Product was crystallized from CHC1 3 /Et 2 ⁇ or acetone/Et 2 O.
• Step 1 (in analogy to S. L. Buchwald et ah, J. Org. Chem. 2000, 65, 1158-1174): An oven- dried G24 vial was charged subsequently with Pd(OAc) 2 (44.0 mg, 0.196 mmol), biphenyl- 2-yl-di-tert-butyl-phosphine ligand (114 mg, 0.392 mmol), 2-chloro-pyridin-4-ylamine (252 mg, 1.96 mmol), 2-(4-bromophenyl)-benzothiazole ( 683 mg, 2.35 mmol) and K 3 PO 4 (583 mg, 2.74 mmol).
• the tube was evacuated and purged with argon and DME (4.0 mL) was added.
• the vial was sealed and heated to 100°C for 21 h.
• the mixture was partitioned between half-saturated brine (50 mL, 1:1 H 2 O/brine) and CHCl 3 (2 x 35 mL).
• Combined org. phases were extracted once with half-saturated brine (50 mL, 1:1 H 2 O/brine) and black fluffy precipitate formed was filtered off and discarded.
• Combined aq. phases were extracted again with CHCl 3 (2 x 35 mL).
• Combined org. phases were dried over MgSO 4 , mounted on silica gel and purified by chromatography on using PE/EE 20:1 to 1 :2.
• Product fraction was further purified by prep. TLC (1 mm silica gel, PE/CH 2 Cl 2 /Me0H 70:70:15) and subsequent dissolving in acetone/MeOH and crushing out the product by adding H 2 O. Crude product was treated with Et 2 O and ultrasound, and the suspension was layered with petroleum ether to give two crystal fractions, 10% total yield of (4-benzothiazol-2-yl-phenyl)-(2-chloro-pyridin-4-yl)-amine.
• Step 2 A mixture of product of step 1 (19.0 mg, 0.056 mmol) and 3-amino-5- methylpyrazole (8.20 mg, 0.084 mmol) in ethylene glycol (0.5 mL) was treated with 4 M
• Step 1 A mixture of methylamine hydrochloride (149 mg, 2.20 mmol), 2-chloro-4- aminopyridine (257 mg, 2.00 mmol), DIEA (174 ⁇ L, 1.00 mmol) and NaI (300 mg, 2.00 mmol) in rcBuOH (4 niL) was stirred at 120°C for 24 h.
• Step 2 (in analogy to S. L. Buchwald et al., J. Org. Chem. 2000, 65, 1158-1174): An oven- dried G4 vial was charged subsequently with Pd 2 dba 3 (36.6 mg, 0.040 mmol), biphenyl-2- yl-di-tert-butyl-phosphine ligand (47.8 mg, 0.160 mmol), product step 1 (98.6 mg, 0.800 mmol, 2-(4-bromophenyl)-benzothiazole (155 mg, 0.880 mmol) and sodium tert-pentoxide (123 mg, 1.12 mmol).
• the tube was evacuated and purged with argon and toluene (1.6 mL) was added.
• the vial was sealed and heated to 110°C for 21 h.
• the mixture was partitioned between half-saturated brine (50 mL, 1:1 H 2 O/brine) and CHCl 3 (3 x 35 mL). Combined org. phases were dried over MgSO 4 and purified by prep HPLC.
• Two product fractions were collected (constitutional isomers), partitioned between satd aq. NaHCO 3 (20 mL) and CHCl 3 (3 x 30 mL) to remove any formic acid still present from HPLC and dried again over MgSO 4 . Both fractions were finally purified by prep.
• Step 1 A mixture of methylamine hydrochloride (544 mg, 8.05 mmol) and 4- chloropicolinic acid (296 mg, 2.30 mmol) in DMF (5 mL) was treated with EDC + HCl (661 mg, 3.45 mmol) and DIEA (2.0 mL, 11.5 mmol) at r.t. for 40 h. was continued over night (LCMS: ST179_21h).
• Reaction mixture was partitioned between aq. satd NaHCO 3 (50 mL) and CHCl 3 (3 x 35 mL). Combined org. phases were washed with aq. satd NH 4 Cl (2 x 50 mL) and dried over MgSO 4 .
• the organic phase was purified by chromatography on silica gel using petroleum ether/ethyl acetate 2:1 to pure ethyl acetate.
• Product was finally purified by prep. HPLC.
• Product fraction was again partitioned between satd aq. NaHCO 3 (20 mL) and CHCl 3 (3 x 30 mL) to remove any formic acid still present from HPLC, and dried over MgSO 4 . Resulting oil was dried only under reduced pressure, 25 mbar, as product is volatile at high vacuum.
• Step 2 A mixture of 4-benzothiazol-2-yl-phenylamine (59.7 mg, 0.264 mmol), product step 1 (40.9 mg, 0.240 mmol) and 4.0 M HCl/dioxane (45 ⁇ L, 0.180 mmol) in DMF (0.5 mL) was heated to 160°C for 7 h. Slurry was rinsed out into a frit (pore size 4) with EtOH, the filter cake was washed several times with the same solvent and finally with some Et 2 O.
• a proprietary protein kinase assay ( 33 PanQinase ® Activity Assay) was used for measuring the kinase activity. All kinase assays were performed in 96-well FlashPlatesTM in a 50 ⁇ l reaction volume. The assay for all enzymes contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCl 2 , 3 mM MnCl 2 , 3 ⁇ M Na-orthovanadate, 1.2 mM DTT, 50 ⁇ g/ml PEG 2O ooo and 1 ⁇ M [ ⁇ - 33 P]-ATP (approx. 5x10 5 cpm per well).
• reaction cocktails were incubated at 30 0 C for 80 minutes.
• the reaction was stopped with 50 ⁇ l of 2% (v/v) H 3 PO 4 , plates were aspirated and washed two times with 200 ⁇ l of 0.9% (w/v) NaCl.
• Incorporation of 33 P 1 was determined with a microplate scintillation counter. All assays were performed with a BeckmanCoulter/ Sagian robotic system.
• the effect of 2-arylbenzothiazole derivatives was tested in cellular assays by determining the inhibition of the receptor tyrosine kinases (RTKs) of the growth factor receptors EGF- R, PDGF-R, TIE2, and VEGF-R2.
• RTKs receptor tyrosine kinases
• EGF- R the growth factor receptor
• PDGF-R the growth factor receptor
• TIE2 the effect of 2-arylbenzothiazole derivatives was tested in cellular assays by determining the inhibition of the receptor tyrosine kinases (RTKs) of the growth factor receptors EGF- R, PDGF-R, TIE2, and VEGF-R2.
• RTKs receptor tyrosine kinases
• test compounds at different concentrations in 100% DMSO were added to the cell culture medium in a 1:100 dilution step resulting in a final DMSO assay concentration of 1%.
• test compounds were stimulated at room temperature for several min with receptor-specific ligands.
• Receptor stimulation was followed by cell lysis using a lysis buffer complemented with standard protease and phosphatase inhibitors.
• the phosphorylation status of the various RTKs was quantified in 96-well plates via a sandwich ELISA using receptor-specific capture antibodies and a generic biotinylated anti- phosphotyrosine detection antibody.
• HT29 colon-carcinoma cells were seeded on day 1 of the experiment at 100,000 cells per well in 6-well cell culture dishes in 3 ml of DMEM medium containing 10% FCS, 100 units/ml Pencillin, 100 mg/ml Streptomycin at 37°, 10% CO 2 .
• test compounds at different concentrations in 100% DMSO were added to the medium in a 1:1000 dilution step resulting in a final DMSO assay concentration of 0.1%.
• Cells were incubated with test compounds for 3 days.
• the cells were harvested by trypsinization, combined with corresponding supernatants, centrifuged, and resuspended in 80% methanol for. fixation and permeabilization at 4° C overnight.
• fixed cells were centrifuged, rehydrated in PBS/1% FCS for 1 h, and subsequently incubated with RNAse A and PI for 30 min at room temperature.
• Stained cells were analyzed for DNA-content by FACS as follows. For analyses of the cell cycle distribution of the cell population, 5000 single-cell-events of the differently treated cells were aquired by FACS . DNA-intercalated PI was detected by measuring fluorescence emission using a 650 nm pass filter (FL3) upon excitation at 488 nm with an argon laser. Single cell events were plotted in a histogram according to their FL3-A signal. Signal amplification for the first peak of the FL-3 amplitude (FL3-A) was set to about 200 arbitrary units (AU). Using an untreated cell population, gates were defined for each of the different cell cycle phases.
• the area containing the gaussian-curve-shaped first peak at 200 AU was defined as ,,cells in Gl -phase" containing the double set of chromosomes (2n).
• the area around the peak at 400 AU was defined as ,,cells in G2/M-phase" containing the quadruple set of chromosomes (4n).
• Events inbetween Gl and G2/M are defined as ,,cells in S-phase", those below Gl (subGl) as ,,apoptotic".
• all events beyond the G2/M-gate were defined as ,,endoreduplicated cells" (EndoR).
• EndoR Endoreduplicated cells
• HT-29 colon-carcinoma cells were seeded on day 1 and on day 2 test compounds at different concentrations were added. Cells were incubated with test compounds for 1 hour. Subsequently, Calyculin A was added for 30 min.
• DELFIA®- detection PerkinElmer
• HisH3-pS10 lysates were transferred to a microtiterplate and incubated with detecting antibody directed against HisH3-pS 10 and Europium-labelled secondary anti-IgG-antibody. Emission at 615 nm was measured upon excitation at 340 nm and the percentage of inhibition was calculated for each concentration of the test compounds ⁇ relative to controls without inhibitor. Mean values of HisH3-pS10 percentage were plotted versus compound concentration for calculation of IC 50 - values. Results
• the following examples show IC 50 values lower than 500 nM on at least one kinase selected from Aurora- A, Aurora-B, EGF-R, ERBB2, PDGFR, IGFl-R, VEGF-R2, VEGF- R3 3 EPHB4, TIE2, and SRC or display a beneficial activity profile by inhibiting at least two kinases from at least two different molecular mechanisms of tumor progression with IC 50 values lower than 500 nM: 31, 32, 39, 40, 44, 45, 48, 49, 50, 51, 52, 54, 59, 60, 70, 75, 76, 77, 78, 79, 81, 83, 85, 87, 88, 89, 90, 91, 92, 93, 94, 95.
• the following compounds show IC50 values lower than 10 ⁇ M in the Cellular Receptor Tyrosine Kinase Assay and / or the Cellular Aurora-B Kinase Assay: 45, 51, 93, 94, 95.

Landscapes

• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (1)

Applications Claiming Priority (3)

Publications (1)

Family

ID=39264354

Family Applications (1)

Country Status (3)

Families Citing this family (4)

Family Cites Families (5)

• 2006
  • 2006-05-16 CA CA002615420A patent/CA2615420A1/en not_active Abandoned
  • 2006-05-16 EP EP06753651A patent/EP1910349A1/de not_active Withdrawn
  • 2006-05-16 JP JP2008520728A patent/JP2009501164A/ja active Pending

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events