WO1998022103A1 - Raf kinase inhibitors - Google Patents
Raf kinase inhibitors Download PDFInfo
- Publication number
- WO1998022103A1 WO1998022103A1 PCT/GB1997/003102 GB9703102W WO9822103A1 WO 1998022103 A1 WO1998022103 A1 WO 1998022103A1 GB 9703102 W GB9703102 W GB 9703102W WO 9822103 A1 WO9822103 A1 WO 9822103A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methylphenyl
- cyclohexylpropionylamino
- alkyl
- acetoxybenzamide
- hydroxybenzamide
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
Definitions
- This invention relates to compounds that inhibit the enzyme raf kinase (raf), an enzyme which acts downstream of ras and plays a crucial role in transduction of signal towards the nucleus.
- the invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through raf kinase activity.
- Oncogenic forms of ras are found in 30% of all cancers, including colon (50%), lung (30%) and pancreas (90%). Mutated, oncogenic forms of the ras GTP-binding proteins are insensitive to activation of their intrinsic GTPase activity and therefore locked in an active form, constitutively activating downstream components of a mitogenic signalling pathway.
- ras binds directly to the product of the raf proto-oncogene, c-raf-1, thus implicating raf as an effector of ras mediated signalling (Cell (1993) 74, 308-313).
- Raf lies at the top of a kinase cascade which results in activation of MEK (Map kinase kinase) and then MAP-kinase and subsequent transcriptional activation of genes involved in cell proliferation.
- MEK Map kinase kinase
- MAP-kinase MAP-kinase and subsequent transcriptional activation of genes involved in cell proliferation.
- Ras antisense has antitumour activity in human tumour mouse xenograft models
- Specific cancers of interest include:
- -carcinoma including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;
- lymphoid lineage including acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma;
- - hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias and promyelocytic leukemia; -tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and
- tumors including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
- Raf inhibitors may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through Ras, e.g., neuro-fibromatosis.
- composition comprising an inhibitor of raf kinase of the formula I wherein:
- R 1 and R 2 which may be the same or different are selected from hydroxy, C,. 6 alkoxy, mercapto, C,. 6 alkylthio, amino, C
- 6 alkyl hydroxyC ⁇ alkyl, aminoC
- R 1 and R 2 which may take the same or different values for R 1 and R 2 , is 0-3, and when p is 2 or 3 each group may be the same or different;
- R 3 is C M alkyl; q is 0-4;
- R 4 is aryl or cycloalkyl wherein R 4 is optionally substituted with upto 3 substituents having any value defined for R 1 ; or a pharmaceutically-acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically-acceptable carrier with the proviso that N-[5-(3-cyclohexyl- propionylamino)-2-methylphenyl]-4-hydroxybenzamide, N-[5-(3- cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3- phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide,
- the first excluded compound is known as RPR 102359 and is described as upregulating LDL receptors by Brown et al in Atherosclerosis (1994) 109: 1 13-1 14.
- the other excluded compounds are also described as upregulating LDL receptors by Brown et al in J. Med. Chem. (1996), 39(17): 3343-3356.
- Aryl in the terms “aryl”, “arylC,_ 6 alkyl” and “arylC ⁇ -6 alkoxy” typically means phenyl or naphthyl, preferably phenyl.
- “Heteroaryl” in the terms “heteroaryl” and “heteroarylC ⁇ alkyl” means an aromatic mono- or bicyclic 5-10 membered ring with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur.
- Heterocyclyl in the terms “heterocyclyl” and “heterocyclylC
- Examples of 'heterocyclyl' include pyrrolidinyl, morpholinyl, piperidinyl, dihydropyridinyl and dihydropyrimidinyl.
- Cycloalkyl means a non-aromatic mono- or bicyclic 5-10 membered carbon ring. Examples of “cycloalkyl” include cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl and bicyclo[4.4.0]decyl.
- Typical values for generic groups include: C, .6 alkoxy for example methoxy, C,. 6 alkylthio for example methylthio, C,. 6 alkylamino for example methylamino, di-(C,. 6 alkyl)amino for example dime hylamino, C ⁇ -6 alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl, C, .6 aIkylcarbamoyl for example methylcarbamoyl, di- C,. 6 alkylcarbamoyl for example dimethylcarbamoyl,
- C,. 6 aIkylsulphonyl for example methylsulphonyl, arylsulphonyl for example phenylsulphonyl, C,. 6 alkyIaminosulphonyl for example methylaminosulphonyl, di-(C, . calkyl)aminosulphonyl for example dimethylaminosulphonyl, cyanoC, .6 alkyl for example cyanomethyl, hydroxyC,_ 6 alkyl for example hydroxymethyl, aminoC, .6 alkyl for example aminoethyl, C,.
- 6 alkanoylamino for example formamido and acetamido
- C,_ 6 alkoxycarbonylamino for example methoxycarbonylamino
- C,_ 6 alkanoyl for example formyl and acetyl
- C,. 6 aIkanoyloxy for example acetoxy
- C,. 6 alkyl for example methyl, ethyl, isopropyl or tert-butyl
- halo for example fluoro, chloro or bromo
- aryl for example phenyl, arylC,.
- 6 alkyl for example benzyl, aryloxy for example phenoxy and arylC,. 6 aIkoxy for example benzyloxy.
- Any ring in R 1 or R 2 may be optionally substituted, for example by upto 3 substituents.
- Suitable substituents include hydrogen, hydroxy, C ⁇ alkoxy, mercapto, C ⁇ _ 6 alkylthio, amino, C
- alkyl includes both straight-chain and branched-chain alkyl groups.
- references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
- An analogous convention applies to other generic terms.
- optically active or racemic forms by virtue of one or more asymmetric carbon atoms
- the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting raf.
- the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
- inhibitory properties against raf may be evaluated using the standard laboratory techniques referred to hereinafter.
- R 1 Particular values for R 1 include hydroxy; hydroxyC,. 6 alkyl for example hydroxymethyl and hydroxyethyl; carboxy; carbamoyl; C
- alkylamino for example methylamino, ethylamino and propylamino
- di-(C,_ 6 alkyl)amino for example di-methylamino, di-ethylamino and N-ethyl-N-methylamino
- C,. 6 alkoxycarbonyl for example methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
- R 1 are hydroxy, amino, C,. 6 alkylamino, di-(C,_ 6 alkyl)amino, C,. 6 alkoxy and C ⁇ _ 6 alkoxycarbonyl; more preferably hydroxy, methylamino, ethylamino, propylamino, di-methylamino, di-ethylamino and N-ethyl-N-methylamino.
- Preferred positions for substitution of R 1 into the phenyl ring indicated in Formula I are 3, 4 and/or 5; more preferably 3; 4; 3,4 or 3,5.
- R 1 is selected from 4-hydroxy; 4-dimethylamino; 3-methoxy; 3,5-dimethoxy; 3-methoxycarbonyl; and 4-hydroxy-3 -methoxy: of these 4-hydroxy is most preferred.
- R 2 is preferably hydrogen.
- Preferred values for p in (R') p are 1-2, especially 1.
- a preferred value for p in (R ) p is 0.
- R 3 is preferably C,. 3 alkyl, more preferably methyl or ethyl and especially methyl.
- R 4 is preferably aryl, more preferably phenyl, more preferably monosubstituted phenyl and especially monosubstituted phenyl in the meta position, preferably with an electron withdrawing substituent group.
- Typical electron withdrawing groups include amino, C
- R 1 and (CH 2 ) q -R 4 include: R 1 (CH 2 ) q -R 4
- R 2 is preferably hydrogen and R 1 is preferably methyl.
- an inhibitor of raf kinase of formula II is provided:
- R 1 and R 2 which may be the same or different are selected from hydroxy, C,. 6 alkoxy, mercapto, C,. 6 alkylthio, amino, C, .6 alkylamino, di-(C,. 6 alkyl)amino. carboxy, C,_ 6 alkoxycarbonyl, carbamoyl, C,. 6 alkylcarbamoyl, di-C ⁇ alkylcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl, C,. 6 alkylaminosulphonyl, di-(C l . 6 alkyl)aminosulphonyl, nitro, cyano, cyano C,.
- R 5 is selected from hydroxy, C,. 6 alkoxy, mercapto, C,. 6 alkylthio, amino, C,. 6 alkylamino, di-(C,. 6 alkyl)amino, carboxy, C,. 5 alkoxycarbonyl, carbamoyl, C,_ 6 alkylcarbamoyl, di-C,. 6 alkylcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl, C,. 6 alkylaminosulphonyl, di-(C,. 6 alkyl)aminosulphonyl, nitro, cyano, cyanoC,. 6 alkyl, hydroxyC,.
- a preferred individual compound of the invention is N- ⁇ 5-
- R 5 is preferably an electron withdrawing group.
- Typical electron withdrawing groups include amino, C,. 6 alkylamino, di-(C l . 6 alkyl)amino, carboxy, C,. 6 alkylsulphonyl, arylsulphonyl, nitro, cyano, halo, and trifluoromethyl; of these amino, C,. 6 alkylamino, di-(C,. 6 alkyl)amino, nitro, cyano and halo are preferred; more preferably di-(C,.
- prodrugs are known in the art.
- prodrug derivatives see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
- In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include methoxymethyl and for hydroxy include acetyl.
- pro-drugs include in vivo hydrolysable esters of a compound of the Formula I.
- An in vivo hydrolysable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid.
- Suitable pharmaceutically-acceptable esters for carboxy include C ⁇ _ 6 alkoxymethyl esters for example methoxymethyl, C,_ 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 _ 8 cycloalkoxycarbonyloxyC,.
- alkyl esters for example 1-cyclohexylcarbonyloxyethyl
- 1,3- dioxolan-2-ylmethyl esters for example 5-methyl-l,3-dioxolan-2-ylmefhyl
- ⁇ alkoxycarbonyloxy ethyl esters for example 1 -methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
- a suitable pharmaceutically-acceptable salt of the invention when the compound contains an acidic moiety is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
- a compound of the Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
- compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
- oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
- compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
- compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
- Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
- inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
- granulating and disintegrating agents such as corn starch or algenic acid
- binding agents such as starch
- lubricating agents
- Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil such as peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
- the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
- the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
- Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening, flavouring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol. aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
- compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
- a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
- Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable excipients include, for example, cocoa butter and polyethylene glycols.
- Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedures well known in the art.
- compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ m or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
- the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
- Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
- Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
- the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
- a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
- Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
- the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
- compounds of the Formula I are useful in treating diseases or medical conditions which are due alone or in part to the effects of raf kinase activity.
- a daily dose in the range for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses.
- lower doses will be administered when a parenteral route is employed.
- a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
- a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
- Oral administration is however preferred, particularly in tablet form.
- unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
- Compounds of this invention may be useful in combination with known anti-cancer and cytotoxic agents. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate. Therefore in a further aspect, the present invention provides a compound of the
- Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of the human or animal body.
- the present invention provides a compound of the Formula I or N-[5- (3 -cyclohexy lpropiony lamino)-2-methy lpheny 1] -4-hydroxybenzamide, N- [5 -(3 - cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3- phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(4- cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2- cyclohexylacety lamino)-2-methylpheny 1] -4-acetoxybenzamide, N- [5 -(3 - cyclohexylpropionylamino)-2-methylphenyl]-4-aminobenzamide, N-[5-(3- cyclohexylpropiony
- the present invention provides a method of treating a disease or medical condition mediated by raf kinase which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I or excluded compound or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
- the present invention also provides the use of a compound of the Formula I or excluded compound or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in the preparation of a medicament for use in a disease condition mediated by raf kinase.
- the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of raf kinase. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
- the compounds of Formula I are especially useful in treatment of tumours having a high incidence of ras mutation, such as colon, lung, and pancreatic tumours. By the administration of a composition having one (or a combination) of the compounds of this invention, development of tumours in a mammalian host is reduced.
- the present invention provides a compound of the Formula I or excluded compound or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in the preparation of a medicament for treating cancer.
- the present invention provides a process for preparing a compound of the Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises: reacting a compound of the Formula III:
- variable groups are as hereinbefore defined wherein any functional group is protected, if necessary, and: i. removing any protecting groups; ii. optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
- a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature, for example in the region -10 to 40°, typically ambient temperature of about 20°C.
- an organic solvent preferably an anhydrous polar aprotic organic solvent
- Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
- Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
- protecting groups are given below for the sake of convenience, in which "lower” as in, for example, lower alkyl signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
- a carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester- forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
- carboxy protecting groups include straight or branched chain C].
- alkyl groups for example isopropyl, t-butyl; lower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example 1 -methoxycarbonyloxyethyl, 1 -ethoxycarbonyloxy ethyl); aryl lower alkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)sily
- carboxy protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.
- hydroxy protecting groups include lower alkyl groups
- lower alkenyl groups for example allyl
- lower alkanoyl groups for example acetyl
- lower alkoxycarbonyl groups for example t-butoxycarbonyl
- lower alkenyloxycarbonyl groups for example allyloxycarbonyl
- aryl lower alkoxycarbonyl groups for example benzoyloxycarbonyl, rj-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl
- tri lower alkylsilyl for example trimethylsilyl, t-butyldimethylsilyl
- aryl lower alkyl for example benzyl
- amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl. and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkanoyl (for example acetyl); lower alkoxycarbonyl (for example t-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, r methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl and t-butyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted benzylidene groups.
- Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as o-nitrobenzyloxycarbonyl.
- groups such as p-nitrobenzyloxycarbonyl
- hydrogenation for groups such as benzyl
- photolytically for groups such as o-nitrobenzyloxycarbonyl.
- the reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents.
- the reader is referred to Protective Groups in Organic Synthesis. 2nd Edition, by Green et al, published by John Wiley & Sons for general guidance on protecting groups.
- the compound of Formula III may be prepared by reduction of the corresponding nitro compound of Formula V.
- Typical reaction conditions include the use of ammonium formate in the presence of a catalyst (for example palladium on carbon) in the presence of an organic solvent (preferably a polar protic solvent), preferably with heating, for example to about 60°. Any functional groups are protected and deprotected as necessary.
- a catalyst for example palladium on carbon
- an organic solvent preferably a polar protic solvent
- Formula Typical conditions include activating the carboxyl group of the compound of Formula VI for example by treatment with a halo reagent (for example oxalyl chloride) to form an acyl halide in an organic solvent at ambient temperature, then reacting the activated compound with the compound of Formula VII. Any functional groups are protected and deprotected as necessary.
- a halo reagent for example oxalyl chloride
- GST-MEK Tris- HC1 pH7.4, O.lmM Ethylene Glycol bis ( ⁇ -Aminoethylether)NNNN-Tetra-acetic Acid (EGTA), lmg/ml Bovine Serum Albumin (BSA), ImM sodium vanadate, 0.03% Brij-35, 0.1% ⁇ -mercaptoethanol.
- EGTA Ethylene Glycol bis ( ⁇ -Aminoethylether)NNNN-Tetra-acetic Acid
- BSA Bovine Serum Albumin
- ImM sodium vanadate 0.03% Brij-35
- 0.1% ⁇ -mercaptoethanol 0.1% ⁇ -mercaptoethanol.
- Add lO ⁇ l of Mg Adenosine Triphosphate (ATP) mix 50mM Mg Acetate, 50 ⁇ M ATP,l ⁇ Ci ⁇ 33 P ATP.
- ATP Mg Adeno
- Mg ATP mix 50mM Mg acetate, 150uM ATP,l ⁇ Ci ⁇ 3 P ATP. Incubate at room temperature for 90 minutes. Stop the reaction by adding 50 ⁇ l 20% phosphoric acid. Capture onto P81 phosphocellulose paper (Whatman), wash in 0.5% phosphoric acid three times, dry and count by liquid scintillation.
- the starting material was prepared as follows: A) Oxalyl chloride (0.5 ml) was added slowly to a stirred suspension of 4-acetoxybenzoic acid (1.09 g), dry dichloromethane (30 ml) and DMF (one drop). The mixture is stirred for two hours at ambient temperature. A solution of 2-methyl-5-nitroaniline (760 mg) and pyridine (2.0 ml) in dry dichloromethane was added over 15 minutes. The reaction mixture was stirred for a further 2 hours, washed with 5% aqueous acetic acid (2 x 25 ml), water (20 ml) and 5% aqueous sodium hydrogen carbonate solution. The organic extract was dried over magnesium sulphate, filtered and evaporated to dryness.
- Example 2 The method of Example 1 was repeated using 3,4-dichlorophenylacetic acid (0.5 mmoles). The reaction mixture was evaporated and the residue taken up in ethyl acetate (4 ml), washed with 1M hydrochloric acid (3.0 ml) and water (3.0 ml). The ethyl acetate extract was evaporated to give the desired product, 132mg (68%), shown to be 92% pure by HPLC.
- N-(5-Amino-2-methylphenyl)-4-hydroxybenzamide (85 mg) was added to a stirred solution of 3-dimethylaminobenzoic acid (89 mg) in dry DMF (0.5 ml) followed by a solution of 1 -(3 -dimethy laminopropyl)-3-ethylcarbodiimide hydrochloride (103 mg) in dry dichloromethane (3 ml) and 4-dimefhylaminopyridine (131 mg).
- the reaction was stirred at ambient temperature under argon for 18 hours.
- the reaction mixture was purified by MPLC on silica eluting in turn with 50%, 60% and 70% ethyl acetate in isohexane to give 17 mg (1 1%) of the title product.
- Compound X the active ingredient being termed "Compound X"
- Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v
- the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
- the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
- the aerosol formulations (h)-(k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU49562/97A AU4956297A (en) | 1996-11-16 | 1997-11-12 | Raf kinase inhibitors |
CA002267782A CA2267782A1 (en) | 1996-11-16 | 1997-11-12 | Raf kinase inhibitors |
JP52331698A JP2001504478A (en) | 1996-11-16 | 1997-11-12 | RAF kinase inhibitor |
EP97912325A EP0941084A1 (en) | 1996-11-16 | 1997-11-12 | Raf kinase inhibitors |
NO992336A NO992336L (en) | 1996-11-16 | 1999-05-14 | Raf kinase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9623833.2A GB9623833D0 (en) | 1996-11-16 | 1996-11-16 | Chemical compound |
GB9623833.2 | 1996-11-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998022103A1 true WO1998022103A1 (en) | 1998-05-28 |
Family
ID=10803023
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1997/003102 WO1998022103A1 (en) | 1996-11-16 | 1997-11-12 | Raf kinase inhibitors |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0941084A1 (en) |
JP (1) | JP2001504478A (en) |
AU (1) | AU4956297A (en) |
CA (1) | CA2267782A1 (en) |
GB (1) | GB9623833D0 (en) |
NO (1) | NO992336L (en) |
WO (1) | WO1998022103A1 (en) |
ZA (1) | ZA9710314B (en) |
Cited By (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999059959A1 (en) * | 1998-05-15 | 1999-11-25 | Astrazeneca Ab | Benzamide derivatives for the treatment of diseases mediated by cytokines |
WO1999059960A1 (en) * | 1998-05-15 | 1999-11-25 | Astrazeneca Ab | Benzamide derivatives for the treatment of diseases mediated by cytokines |
WO2000021539A1 (en) * | 1998-10-09 | 2000-04-20 | Anadys Pharmaceuticals, Inc. | Aryldiamine derivatives useful as antibacterial agents |
WO2000055120A1 (en) * | 1999-03-17 | 2000-09-21 | Astrazeneca Ab | Amide derivatives |
EP1047418A1 (en) * | 1997-12-22 | 2000-11-02 | Bayer Corporation | Inhibition of raf kinase using substituted heterocyclic ureas |
EP1056725A1 (en) * | 1997-12-22 | 2000-12-06 | Bayer Corporation | Inhibition of raf kinase using aryl and heteroaryl substituted heterocyclic ureas |
US6432949B1 (en) | 1998-08-04 | 2002-08-13 | Astrazeneca Ab | Amide derivatives useful as inhibitors of the production of cytokines |
US6455520B1 (en) | 1998-09-25 | 2002-09-24 | Astra Zeneca Ab | Benzamide derivatives and their use as cytokine inhibitors |
EP1017378B1 (en) * | 1997-09-23 | 2002-12-11 | AstraZeneca AB | Amide derivatives for the treatment of diseases mediated by cytokines |
WO2003056036A2 (en) * | 2001-12-21 | 2003-07-10 | The Wellcome Trust | Genes |
US6593333B1 (en) | 1998-10-01 | 2003-07-15 | Astrazeneca Ab | Substituted anilino-quinazoline (or quinoline) compounds and use thereof |
WO2004064733A2 (en) * | 2003-01-15 | 2004-08-05 | Board Of Regents, University Of Texas System | The use of c-raf inhibitors for the treatment of neurodegenerative diseases |
US6784174B1 (en) | 1999-03-23 | 2004-08-31 | Astrazeneca Ab | Pyridine and pyrimidine derivatives and their use as inhibitors of cytokine mediated disease |
US6821965B1 (en) | 1998-08-04 | 2004-11-23 | Asterzeneca Ab | Amidobenzamide derivatives which are useful as cytokine inhibitors |
WO2005004863A1 (en) * | 2003-07-11 | 2005-01-20 | Merck Patent Gmbh | Benzimidazole carboxamides as raf kinase inhibitors |
US6846827B1 (en) | 1999-10-13 | 2005-01-25 | Astrazeneca Ab | Pyrimidine derivatives |
WO2006007520A1 (en) * | 2004-07-01 | 2006-01-19 | Wisconsin Alumni Research Foundation | Hydroxybenazamide compounds for treatment of cancer |
US7008945B1 (en) | 1999-03-17 | 2006-03-07 | Astrazeneca Ab | Amide derivatives |
WO2006024836A1 (en) * | 2004-09-01 | 2006-03-09 | Astrazeneca Ab | Quinazolinone derivatives and their use as b-raf inhibitors |
WO2006067445A2 (en) * | 2004-12-22 | 2006-06-29 | Astrazeneca Ab | Csf-1r kinase inhibitors |
WO2006076706A1 (en) * | 2005-01-14 | 2006-07-20 | Millennium Pharmaceuticals, Inc. | Cinnamide and hydrocinnamide derivatives with raf-kinase inhibitory activity |
US7144911B2 (en) | 2002-12-31 | 2006-12-05 | Deciphera Pharmaceuticals Llc | Anti-inflammatory medicaments |
US7202257B2 (en) | 2003-12-24 | 2007-04-10 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
WO2007059157A1 (en) * | 2005-11-14 | 2007-05-24 | Genentech, Inc. | Bisamide inhibitors of hedgehog signaling |
US7279576B2 (en) | 2002-12-31 | 2007-10-09 | Deciphera Pharmaceuticals, Llc | Anti-cancer medicaments |
US7750154B2 (en) | 2003-10-24 | 2010-07-06 | Astrazeneca Ab | Amide derivatives |
US7772432B2 (en) | 1991-09-19 | 2010-08-10 | Astrazeneca Ab | Amidobenzamide derivatives which are useful as cytokine inhibitors |
US7838541B2 (en) | 2002-02-11 | 2010-11-23 | Bayer Healthcare, Llc | Aryl ureas with angiogenesis inhibiting activity |
US7897623B2 (en) | 1999-01-13 | 2011-03-01 | Bayer Healthcare Llc | ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors |
WO2011154846A3 (en) * | 2010-05-11 | 2012-02-16 | Mahesh Kandula | 4, 6 -dibenzoylamino- 2 -methyl- pyrimidine derivatives and their use for the treatment of cancer |
US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
US8143293B2 (en) | 2007-04-20 | 2012-03-27 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases |
WO2013149194A1 (en) | 2012-03-29 | 2013-10-03 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US8637553B2 (en) | 2003-07-23 | 2014-01-28 | Bayer Healthcare Llc | Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
US8796250B2 (en) | 2003-05-20 | 2014-08-05 | Bayer Healthcare Llc | Diaryl ureas for diseases mediated by PDGFR |
US8852730B2 (en) | 2011-08-29 | 2014-10-07 | Ticona Llc | Melt-extruded substrate for use in thermoformed articles |
US8906258B2 (en) | 2011-08-29 | 2014-12-09 | Ticona Llc | Heat-resistant liquid crystalline polymer composition having a low melting temperature |
US8940756B2 (en) | 2012-06-07 | 2015-01-27 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
WO2015041533A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | Rock in combination with mapk-pathway |
WO2015041534A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | P90rsk in combination with raf/erk/mek |
US9005475B2 (en) | 2011-08-29 | 2015-04-14 | Ticona Llc | Aromatic amide compound |
US9045685B2 (en) | 2011-08-29 | 2015-06-02 | Ticona Llc | Cast molded parts formed from a liquid crystalline polymer |
US9051514B2 (en) | 2011-08-29 | 2015-06-09 | Ticona Llc | High flow liquid crystalline polymer composition |
US9057016B2 (en) | 2011-08-29 | 2015-06-16 | Ticona Llc | Melt polymerization of low melt viscosity liquid crystalline polymers |
US9074133B2 (en) | 2011-08-29 | 2015-07-07 | Ticona Llc | Thermotropic liquid crystalline polymer with improved low shear viscosity |
US9096794B2 (en) | 2011-08-29 | 2015-08-04 | Ticona Llc | High flow liquid crystalline polymer composition |
US9102792B2 (en) | 2013-02-22 | 2015-08-11 | Ticona Llc | High performance polymer composition with improved flow properties |
WO2015156674A2 (en) | 2014-04-10 | 2015-10-15 | Stichting Het Nederlands Kanker Instituut | Method for treating cancer |
US9181188B2 (en) | 2002-02-11 | 2015-11-10 | Bayer Healthcare Llc | Aryl ureas as kinase inhibitors |
WO2015178770A1 (en) | 2014-05-19 | 2015-11-26 | Stichting Het Nederlands Kanker Instituut | Compositions for cancer treatment |
US9198911B2 (en) | 2010-11-02 | 2015-12-01 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US10966966B2 (en) | 2019-08-12 | 2021-04-06 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11185535B2 (en) | 2019-12-30 | 2021-11-30 | Deciphera Pharmaceuticals, Llc | Amorphous kinase inhibitor formulations and methods of use thereof |
US11266635B2 (en) | 2019-08-12 | 2022-03-08 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11395818B2 (en) | 2019-12-30 | 2022-07-26 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea |
US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11986463B2 (en) | 2018-01-31 | 2024-05-21 | Deciphera Pharmaceuticals, Llc | Combination therapy for the treatment of gastrointestinal stromal tumor |
US12102620B2 (en) | 2020-07-30 | 2024-10-01 | Deciphera Pharmaceuticals, Llc | Combination therapy for the treatment of mastocytosis |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993004170A1 (en) * | 1991-08-23 | 1993-03-04 | The United States Of America Represented By The Secretary, Department Of Health And Human Services | Raf protein kinase therapeutics |
-
1996
- 1996-11-16 GB GBGB9623833.2A patent/GB9623833D0/en active Pending
-
1997
- 1997-11-12 JP JP52331698A patent/JP2001504478A/en active Pending
- 1997-11-12 EP EP97912325A patent/EP0941084A1/en not_active Withdrawn
- 1997-11-12 AU AU49562/97A patent/AU4956297A/en not_active Abandoned
- 1997-11-12 WO PCT/GB1997/003102 patent/WO1998022103A1/en not_active Application Discontinuation
- 1997-11-12 CA CA002267782A patent/CA2267782A1/en not_active Abandoned
- 1997-11-14 ZA ZA9710314A patent/ZA9710314B/en unknown
-
1999
- 1999-05-14 NO NO992336A patent/NO992336L/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993004170A1 (en) * | 1991-08-23 | 1993-03-04 | The United States Of America Represented By The Secretary, Department Of Health And Human Services | Raf protein kinase therapeutics |
Non-Patent Citations (1)
Title |
---|
ASHTON ET AL.: "New Low-Density Lipoprotein Receptor Upregulators Acting via a Novel Mechanism", J. MED. CHEM., vol. 39, 1996, pages 3343 - 3356, XP002054111 * |
Cited By (126)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7772432B2 (en) | 1991-09-19 | 2010-08-10 | Astrazeneca Ab | Amidobenzamide derivatives which are useful as cytokine inhibitors |
EP1017378B1 (en) * | 1997-09-23 | 2002-12-11 | AstraZeneca AB | Amide derivatives for the treatment of diseases mediated by cytokines |
US6686467B2 (en) | 1997-09-23 | 2004-02-03 | Zeneca Limited | Amide derivatives for the treatment of diseases mediated by cytokines |
US6498274B1 (en) | 1997-09-23 | 2002-12-24 | Zeneca Limited | Amide derivatives for the treatment of diseases mediated by cytokines |
EP1047418A1 (en) * | 1997-12-22 | 2000-11-02 | Bayer Corporation | Inhibition of raf kinase using substituted heterocyclic ureas |
EP1056725A1 (en) * | 1997-12-22 | 2000-12-06 | Bayer Corporation | Inhibition of raf kinase using aryl and heteroaryl substituted heterocyclic ureas |
EP1056725A4 (en) * | 1997-12-22 | 2001-02-07 | Bayer Ag | Inhibition of raf kinase using aryl and heteroaryl substituted heterocyclic ureas |
EP1047418A4 (en) * | 1997-12-22 | 2001-02-07 | Bayer Ag | Inhibition of raf kinase using substituted heterocyclic ureas |
WO1999059959A1 (en) * | 1998-05-15 | 1999-11-25 | Astrazeneca Ab | Benzamide derivatives for the treatment of diseases mediated by cytokines |
US6579872B1 (en) | 1998-05-15 | 2003-06-17 | Astrazeneca Ab | Bezamide derivatives for the treatment of diseases mediated by cytokines |
WO1999059960A1 (en) * | 1998-05-15 | 1999-11-25 | Astrazeneca Ab | Benzamide derivatives for the treatment of diseases mediated by cytokines |
US6465455B1 (en) | 1998-05-15 | 2002-10-15 | Astrazeneca Ab | Benzamide derivatives for the treatment of diseases mediated by cytokines |
US6956037B2 (en) | 1998-05-15 | 2005-10-18 | Astrazeneca Ab | Benzamide derivatives for the treatment of diseases mediated by cytokines |
US7060700B2 (en) | 1998-08-04 | 2006-06-13 | Astrazeneca Ab | Amide derivatives useful as inhibitors of the production of cytokines |
US6432949B1 (en) | 1998-08-04 | 2002-08-13 | Astrazeneca Ab | Amide derivatives useful as inhibitors of the production of cytokines |
US6821965B1 (en) | 1998-08-04 | 2004-11-23 | Asterzeneca Ab | Amidobenzamide derivatives which are useful as cytokine inhibitors |
US6455520B1 (en) | 1998-09-25 | 2002-09-24 | Astra Zeneca Ab | Benzamide derivatives and their use as cytokine inhibitors |
US6593333B1 (en) | 1998-10-01 | 2003-07-15 | Astrazeneca Ab | Substituted anilino-quinazoline (or quinoline) compounds and use thereof |
US6716847B2 (en) | 1998-10-01 | 2004-04-06 | Astrazeneca Ab | Substituted anilino-quinoline compounds and use thereof |
US6194399B1 (en) | 1998-10-09 | 2001-02-27 | Scriptgen Pharmaceuticals, Inc. | Aryldiamine derivatives useful as antibacterial agents |
WO2000021539A1 (en) * | 1998-10-09 | 2000-04-20 | Anadys Pharmaceuticals, Inc. | Aryldiamine derivatives useful as antibacterial agents |
US7897623B2 (en) | 1999-01-13 | 2011-03-01 | Bayer Healthcare Llc | ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors |
US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
US8841330B2 (en) | 1999-01-13 | 2014-09-23 | Bayer Healthcare Llc | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
US7442704B2 (en) | 1999-03-17 | 2008-10-28 | Astrazeneca Ab | Amide derivatives |
US6794380B2 (en) | 1999-03-17 | 2004-09-21 | Astrazeneca Ab | Amide derivatives |
US6548514B1 (en) | 1999-03-17 | 2003-04-15 | Astrazeneca Ab | Amide derivatives |
CN100352804C (en) * | 1999-03-17 | 2007-12-05 | 阿斯特拉曾尼卡有限公司 | Amide derivatives |
WO2000055120A1 (en) * | 1999-03-17 | 2000-09-21 | Astrazeneca Ab | Amide derivatives |
JP2002539187A (en) * | 1999-03-17 | 2002-11-19 | アストラゼネカ アクチボラグ | Amide derivatives |
US7332483B2 (en) | 1999-03-17 | 2008-02-19 | Astrazeneca Ab | Amide derivatives |
US7008945B1 (en) | 1999-03-17 | 2006-03-07 | Astrazeneca Ab | Amide derivatives |
US6784174B1 (en) | 1999-03-23 | 2004-08-31 | Astrazeneca Ab | Pyridine and pyrimidine derivatives and their use as inhibitors of cytokine mediated disease |
US6846827B1 (en) | 1999-10-13 | 2005-01-25 | Astrazeneca Ab | Pyrimidine derivatives |
US7947819B2 (en) | 2001-12-21 | 2011-05-24 | The Wellcome Trust | B-raf polynucleotides |
US8580497B2 (en) | 2001-12-21 | 2013-11-12 | The Wellcome Trust | Methods for detection of the oncogenic T1796A B-Raf mutation |
WO2003056036A3 (en) * | 2001-12-21 | 2003-12-31 | Wellcome Trust | Genes |
WO2003056036A2 (en) * | 2001-12-21 | 2003-07-10 | The Wellcome Trust | Genes |
US9181188B2 (en) | 2002-02-11 | 2015-11-10 | Bayer Healthcare Llc | Aryl ureas as kinase inhibitors |
US7838541B2 (en) | 2002-02-11 | 2010-11-23 | Bayer Healthcare, Llc | Aryl ureas with angiogenesis inhibiting activity |
US8242147B2 (en) | 2002-02-11 | 2012-08-14 | Bayer Healthcare Llc | Aryl ureas with angiogenisis inhibiting activity |
US8618141B2 (en) | 2002-02-11 | 2013-12-31 | Bayer Healthcare Llc | Aryl ureas with angiogenesis inhibiting activity |
US7279576B2 (en) | 2002-12-31 | 2007-10-09 | Deciphera Pharmaceuticals, Llc | Anti-cancer medicaments |
US7342037B2 (en) | 2002-12-31 | 2008-03-11 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
US7144911B2 (en) | 2002-12-31 | 2006-12-05 | Deciphera Pharmaceuticals Llc | Anti-inflammatory medicaments |
US7666895B2 (en) | 2002-12-31 | 2010-02-23 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
WO2004064733A3 (en) * | 2003-01-15 | 2004-12-29 | Univ Texas | The use of c-raf inhibitors for the treatment of neurodegenerative diseases |
WO2004064733A2 (en) * | 2003-01-15 | 2004-08-05 | Board Of Regents, University Of Texas System | The use of c-raf inhibitors for the treatment of neurodegenerative diseases |
US8796250B2 (en) | 2003-05-20 | 2014-08-05 | Bayer Healthcare Llc | Diaryl ureas for diseases mediated by PDGFR |
US7691870B2 (en) | 2003-07-11 | 2010-04-06 | Merck Patent Gmbh | Benzimidazole carboxamides as raf kinase inhibitors |
WO2005004863A1 (en) * | 2003-07-11 | 2005-01-20 | Merck Patent Gmbh | Benzimidazole carboxamides as raf kinase inhibitors |
US8637553B2 (en) | 2003-07-23 | 2014-01-28 | Bayer Healthcare Llc | Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
US7750154B2 (en) | 2003-10-24 | 2010-07-06 | Astrazeneca Ab | Amide derivatives |
US7202257B2 (en) | 2003-12-24 | 2007-04-10 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
WO2006007520A1 (en) * | 2004-07-01 | 2006-01-19 | Wisconsin Alumni Research Foundation | Hydroxybenazamide compounds for treatment of cancer |
WO2006024836A1 (en) * | 2004-09-01 | 2006-03-09 | Astrazeneca Ab | Quinazolinone derivatives and their use as b-raf inhibitors |
WO2006067445A3 (en) * | 2004-12-22 | 2006-09-14 | Astrazeneca Ab | Csf-1r kinase inhibitors |
WO2006067445A2 (en) * | 2004-12-22 | 2006-06-29 | Astrazeneca Ab | Csf-1r kinase inhibitors |
US7652041B2 (en) | 2005-01-14 | 2010-01-26 | Millennium Pharmaceuticals, Inc. | Cinnamide and hydrocinnamide derivatives with kinase inhibitory activity |
WO2006076706A1 (en) * | 2005-01-14 | 2006-07-20 | Millennium Pharmaceuticals, Inc. | Cinnamide and hydrocinnamide derivatives with raf-kinase inhibitory activity |
US8101610B2 (en) | 2005-11-14 | 2012-01-24 | Genentech, Inc. | Bisamide inhibitors of hedgehog signaling |
AU2006315467B2 (en) * | 2005-11-14 | 2013-02-07 | Curis, Inc. | Bisamide inhibitors of hedgehog signaling |
WO2007059157A1 (en) * | 2005-11-14 | 2007-05-24 | Genentech, Inc. | Bisamide inhibitors of hedgehog signaling |
US8143293B2 (en) | 2007-04-20 | 2012-03-27 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases |
WO2011154846A3 (en) * | 2010-05-11 | 2012-02-16 | Mahesh Kandula | 4, 6 -dibenzoylamino- 2 -methyl- pyrimidine derivatives and their use for the treatment of cancer |
CN102933560A (en) * | 2010-05-11 | 2013-02-13 | 科瑞塞尼生物科技有限公司 | 4,6-dibenzamido-2-methyl-pyridine derivatives and applications to cancer treatment |
US11298570B2 (en) | 2010-11-02 | 2022-04-12 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US10994157B2 (en) | 2010-11-02 | 2021-05-04 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US11806555B2 (en) | 2010-11-02 | 2023-11-07 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US9895301B2 (en) | 2010-11-02 | 2018-02-20 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US9763866B2 (en) | 2010-11-02 | 2017-09-19 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US9737469B2 (en) | 2010-11-02 | 2017-08-22 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US9730877B2 (en) | 2010-11-02 | 2017-08-15 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US9198911B2 (en) | 2010-11-02 | 2015-12-01 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US10265258B2 (en) | 2010-11-02 | 2019-04-23 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
US9074133B2 (en) | 2011-08-29 | 2015-07-07 | Ticona Llc | Thermotropic liquid crystalline polymer with improved low shear viscosity |
US9096794B2 (en) | 2011-08-29 | 2015-08-04 | Ticona Llc | High flow liquid crystalline polymer composition |
US8906258B2 (en) | 2011-08-29 | 2014-12-09 | Ticona Llc | Heat-resistant liquid crystalline polymer composition having a low melting temperature |
US9057016B2 (en) | 2011-08-29 | 2015-06-16 | Ticona Llc | Melt polymerization of low melt viscosity liquid crystalline polymers |
US9051514B2 (en) | 2011-08-29 | 2015-06-09 | Ticona Llc | High flow liquid crystalline polymer composition |
US9045685B2 (en) | 2011-08-29 | 2015-06-02 | Ticona Llc | Cast molded parts formed from a liquid crystalline polymer |
US9005475B2 (en) | 2011-08-29 | 2015-04-14 | Ticona Llc | Aromatic amide compound |
US8852730B2 (en) | 2011-08-29 | 2014-10-07 | Ticona Llc | Melt-extruded substrate for use in thermoformed articles |
WO2013149194A1 (en) | 2012-03-29 | 2013-10-03 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
EP3459565A1 (en) | 2012-03-29 | 2019-03-27 | The Trustees of Columbia University in the City of New York | Methods for treating hair loss disorders |
USRE48731E1 (en) | 2012-06-07 | 2021-09-14 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
US8940756B2 (en) | 2012-06-07 | 2015-01-27 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
US9102792B2 (en) | 2013-02-22 | 2015-08-11 | Ticona Llc | High performance polymer composition with improved flow properties |
WO2015041533A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | Rock in combination with mapk-pathway |
WO2015041534A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | P90rsk in combination with raf/erk/mek |
WO2015156674A2 (en) | 2014-04-10 | 2015-10-15 | Stichting Het Nederlands Kanker Instituut | Method for treating cancer |
WO2015178770A1 (en) | 2014-05-19 | 2015-11-26 | Stichting Het Nederlands Kanker Instituut | Compositions for cancer treatment |
US11986463B2 (en) | 2018-01-31 | 2024-05-21 | Deciphera Pharmaceuticals, Llc | Combination therapy for the treatment of gastrointestinal stromal tumor |
US11426390B2 (en) | 2019-08-12 | 2022-08-30 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11969414B2 (en) | 2019-08-12 | 2024-04-30 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US12059410B2 (en) | 2019-08-12 | 2024-08-13 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11266635B2 (en) | 2019-08-12 | 2022-03-08 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11433056B1 (en) | 2019-08-12 | 2022-09-06 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11529336B2 (en) | 2019-08-12 | 2022-12-20 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11534432B2 (en) | 2019-08-12 | 2022-12-27 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US12059411B2 (en) | 2019-08-12 | 2024-08-13 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11576904B2 (en) | 2019-08-12 | 2023-02-14 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11344536B1 (en) | 2019-08-12 | 2022-05-31 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US12023326B2 (en) | 2019-08-12 | 2024-07-02 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US12023325B2 (en) | 2019-08-12 | 2024-07-02 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US12023327B2 (en) | 2019-08-12 | 2024-07-02 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US10966966B2 (en) | 2019-08-12 | 2021-04-06 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11813251B2 (en) | 2019-08-12 | 2023-11-14 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
US11612591B2 (en) | 2019-12-30 | 2023-03-28 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea |
US11185535B2 (en) | 2019-12-30 | 2021-11-30 | Deciphera Pharmaceuticals, Llc | Amorphous kinase inhibitor formulations and methods of use thereof |
US11850240B1 (en) | 2019-12-30 | 2023-12-26 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11896585B2 (en) | 2019-12-30 | 2024-02-13 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea |
US11903933B2 (en) | 2019-12-30 | 2024-02-20 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11911370B1 (en) | 2019-12-30 | 2024-02-27 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11918564B1 (en) | 2019-12-30 | 2024-03-05 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11969415B1 (en) | 2019-12-30 | 2024-04-30 | Deciphera Pharmaceuticals, Llc | (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11844788B1 (en) | 2019-12-30 | 2023-12-19 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11850241B1 (en) | 2019-12-30 | 2023-12-26 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11801237B2 (en) | 2019-12-30 | 2023-10-31 | Deciphera Pharmaceuticals, Llc | Amorphous kinase inhibitor formulations and methods of use thereof |
US11793795B2 (en) | 2019-12-30 | 2023-10-24 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea |
US12023328B2 (en) | 2019-12-30 | 2024-07-02 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US12064422B2 (en) | 2019-12-30 | 2024-08-20 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea |
US11576903B2 (en) | 2019-12-30 | 2023-02-14 | Deciphera Pharmaceuticals, Llc | Amorphous kinase inhibitor formulations and methods of use thereof |
US11395818B2 (en) | 2019-12-30 | 2022-07-26 | Deciphera Pharmaceuticals, Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea |
US12102620B2 (en) | 2020-07-30 | 2024-10-01 | Deciphera Pharmaceuticals, Llc | Combination therapy for the treatment of mastocytosis |
US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
Also Published As
Publication number | Publication date |
---|---|
GB9623833D0 (en) | 1997-01-08 |
NO992336D0 (en) | 1999-05-14 |
CA2267782A1 (en) | 1998-05-28 |
AU4956297A (en) | 1998-06-10 |
EP0941084A1 (en) | 1999-09-15 |
ZA9710314B (en) | 1998-05-18 |
JP2001504478A (en) | 2001-04-03 |
NO992336L (en) | 1999-05-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1998022103A1 (en) | Raf kinase inhibitors | |
DE69810134T2 (en) | AMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES BROUGHT BY CYTOKINS | |
DE69325262T2 (en) | VINYLENE AZAINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF | |
US10414726B2 (en) | Therapeutic agents | |
DE69921804T2 (en) | BENZAMIDE DERIVATIVES FOR THE TREATMENT OF CYTOKIN-MEDIATED DISEASES | |
JP5010917B2 (en) | c-Kit Regulator and Method of Use | |
DE69902277T2 (en) | AMID DERIVATIVES USED AS INHIBITORS OF CYTOKININS | |
JP4191825B2 (en) | 5-aminoisoxazole derivatives | |
CN115989223B (en) | Methods and compositions for targeting Tregs using CCR8 inhibitors | |
TWI407962B (en) | Quinazoline derivatives | |
PH12015502737B1 (en) | Novel fused pyrimidine compound or salt thereof | |
KR20180105700A (en) | 3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (CHK1) inhibitors, and their preparation and application | |
JP2009504626A (en) | Amide derivatives | |
DE69905143T2 (en) | ANTI-TUMOR AGENTS | |
US11696917B2 (en) | Agent enhancing antitumor effect using pyrazolo[3,4-d]pyrimidine compound | |
JP3742593B2 (en) | Farnesyltransferase inhibitors | |
DE69019217T2 (en) | Perylenquinone (UCN-1028D) derivatives. | |
DE69905142T2 (en) | ANTI-TUMOR AGENTS | |
JPH0560469B2 (en) | ||
WO2019119486A1 (en) | Class of pyrimidine derivative kinase inhibitors | |
US20240124515A1 (en) | Orally active leukemia inhibitory factor (lif) antagonists for the treatment of cancer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1997912325 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 334813 Country of ref document: NZ |
|
ENP | Entry into the national phase |
Ref document number: 2267782 Country of ref document: CA Ref country code: CA Ref document number: 2267782 Kind code of ref document: A Format of ref document f/p: F |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1998 523316 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09308173 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1997912325 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1997912325 Country of ref document: EP |