WO2002010162A1 - Inhibiteurs n-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide de la kinase dependantes des cyclines - Google Patents

Inhibiteurs n-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide de la kinase dependantes des cyclines Download PDF

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WO2002010162A1
WO2002010162A1 PCT/US2001/015081 US0115081W WO0210162A1 WO 2002010162 A1 WO2002010162 A1 WO 2002010162A1 US 0115081 W US0115081 W US 0115081W WO 0210162 A1 WO0210162 A1 WO 0210162A1
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Prior art keywords
trifluoroacetate
hydrochloride
compound
pharmaceutically acceptable
mixture
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PCT/US2001/015081
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English (en)
Inventor
Raj N. Misra
Hai-Yun Xiao
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Bristol-Myers Squibb Company
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Priority claimed from US09/727,957 external-priority patent/US6515004B1/en
Priority claimed from US09/746,060 external-priority patent/US6414156B2/en
Priority to MXPA03000774A priority Critical patent/MXPA03000774A/es
Priority to BR0112674-1A priority patent/BR0112674A/pt
Priority to EEP200300041A priority patent/EE200300041A/xx
Priority to KR10-2003-7001141A priority patent/KR20030016429A/ko
Priority to SK1839-2002A priority patent/SK18392002A3/sk
Priority to AU2001259704A priority patent/AU2001259704A1/en
Priority to IL15359101A priority patent/IL153591A0/xx
Priority to HU0303698A priority patent/HUP0303698A2/hu
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to JP2002515891A priority patent/JP2004509857A/ja
Priority to SI200120051A priority patent/SI21099A/sl
Priority to EP01933266A priority patent/EP1303513A1/fr
Priority to CA002417254A priority patent/CA2417254A1/fr
Publication of WO2002010162A1 publication Critical patent/WO2002010162A1/fr
Priority to IL153591A priority patent/IL153591A/en
Priority to IS6696A priority patent/IS6696A/is
Priority to NO20030394A priority patent/NO20030394L/no
Priority to HR20030116A priority patent/HRP20030116A2/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is directed to compounds of formula I
  • R is alkyl
  • R 1 is hydrogen or alkyl
  • X is NR 2 or CHNR 2 R 3 ;
  • R 2 and R 3 are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; and n is O, 1, 2 or 3.
  • the compounds of formula I are particularly useful as potent, protein kinase inhibitors and are useful in the treatment of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer's disease, chemotherapy-induced alopecia, and cardiovascular disease.
  • the present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds, and for methods of using such compounds.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12, preferably 1 to 6, and more preferably 1 to 4, carbon atoms unless otherwise defined.
  • An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups can be substituted with up to four substituent groups, R 4 as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
  • Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • substituents may include, but are not limited to, one or more of the following groups: halo (such as F, CI, Br or I), haloalkyl (such as CC1 3 or CF 3 ), alkoxy, alkylthio, hydroxy, carboxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, amidinyl, or thiol.
  • Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings.
  • Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/or alkylthio.
  • alkoxy or alkylthio denote an alkyl group as described above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.
  • alkoxycarbonyl denotes an alkoxy group bonded through a carbonyl group.
  • An alkoxycarbonyl radical is represented by the formula: -C(O)OR 5 , where the R 5 group is a straight or branched C 6 alkyl group.
  • alkylcarbonyl refers to an alkyl group bonded through a carbonyl group.
  • alkylcarbonyloxy denotes an alkylcarbonyl group which is bonded through an oxygen linkage.
  • the phrase "compounds of the invention” means, collectively, compounds falling within formula I and pharmaceutically-acceptable salts, and solvates including hydrates thereof. Methods of salt formation, solvation, and hydrate formation are well known in the art.
  • the invention also encompasses mixtures of stereoisomers of compounds of the invention. Stereoisomers include, but are not limited to, enantiomers, diastereomers, and racemates where the compound has one or more chiral centers. All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
  • the definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures.
  • racemic forms and the isolated optical isomers having the specified activity.
  • the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • All configurational isomers of compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form.
  • the definition of compounds of the present invention very particularly embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cycloalkyl or heterocycloalkyl rings.
  • salts of compounds of formula I that are pharmaceutically unsuitable but useful in other respects, for example, for the isolation or purification of compounds of formula I, are also encompassed by the invention.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • phrases "pharmaceutically-acceptable salt(s)," as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds of the invention.
  • pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, dihydrochloride, sulfate, trifluoroacetate, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts and mixtures thereof.
  • salts formed with other organic and inorganic acids such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, benzoates, ascorbates, salicylates, and the like.
  • pharmaceutically acceptable salts of compounds of formula I can be formed with alkali metals, such as sodium, potassium and lithium; alkaline earth metals, such as calcium and magnesium; organic bases, such as dicyclohexylamine, tributylamine, and pyridines, and the like; and amino acids, such as arginine, lysine, and the like.
  • Salts of compounds of the invention encompass solvates, racemates, and all stereoisomeric forms thereof, including enantiomers and diastereomers (for example, D- tartrate and L-tartrate salts).
  • solvate means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of one or more solvent molecules bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • the solvent is water the solvate is termed a "hydrate”.
  • R 9 is hydrogen, alkyl, aryl, or heteroaryl
  • R 1 and R 11 are independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy, or alkoxy;
  • R 12 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, CONR I R 14 , COR 15 , or COOR 16 ;
  • R 13 , R 14 , R 15 and R 16 are independently hydrogen, alkyl, or aryl;
  • r is an integer ranging from 0 to 5;
  • s is an integer ranging from 0 to 5;
  • L is a suitable leaving group, such as halogen or sulfonate (R 6 SO 2 O ⁇ , CF 3 SO 2 O ⁇ etc., wherein R 6 is alkyl, cycloalkyl, or aryl);
  • M is hydrogen, Li, Na, K, Cs, or a quaternary ammonium ion, e.g., (R 6 ) 4 N or quaternary ammonium ions comprising cyclic alkenetetramines, such as hexamethylenetetramine;
  • Q is hydroxy, halogen or acyloxy (R 6 COO “ , R 6 OCOO “ , etc.);
  • Y is O, S, NH, N-alkyl, N-aryl or N-acyl
  • Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2 , N-alkyl, N-aryl. or N- ' acyl a d
  • P is a nitrogen-protecting group (Boc, Cbz, R 3 Si, etc.).
  • a functional group When a functional group is termed “protected,” this means that the group is in modified form to preclude undesired side reactions at the protected site.
  • Suitable protecting groups for the compounds involved in the present processes will be recognized from the specification taking into account the level of skill in the art, and with reference to standard textbooks such as Greene, T.W., Protective Groups in Organic Synthesis, 3rd edition (1999), incorporated herein by reference.
  • the processes generally involve reaction of ⁇ -halo ketones II (commercially available or readily synthesized by well-known methods) with an azide to give ⁇ -azido ketones III. Reduction of III with a reducing reagent gives ⁇ -amino ketones IV.
  • the ⁇ -amino ketones IV are prepared by reaction of ⁇ -halo ketones II with a cyclic alkylenetetramine such as hexamethylenetetramine and the like, followed by hydrolysis of the resulting, new quaternary ammonium salt III'. This reaction provides excellent yields of the desired intermediate compound IV, above 90%.
  • Step (a) involves reacting an ⁇ -substituted ketone II such as, for example, an ⁇ -halo ketone, with an azide in a suitable solvent or solvent mixtures to give an ⁇ -azido ketone III; or, more desirably, (a') reacting an ⁇ -substituted ketone II like the ⁇ -halo ketone with a cyclic alkylenetetramine such as, for example, hexamethylenetetramine in a suitable solvent or solvent mixtures to give a new quaternary ammonium salt III'.
  • an ⁇ -substituted ketone II such as, for example, an ⁇ -halo ketone
  • an azide in a suitable solvent or solvent mixtures
  • a' reacting an ⁇ -substituted ketone II like the ⁇ -halo ketone with a cyclic alkylenetetramine such as, for example, hexamethylenete
  • the ⁇ -halo ketone includes ⁇ -halo aliphatic and ⁇ -halo aromatic ketones.
  • the preferred ⁇ -halo ketones are ⁇ -halo pinacolones with ⁇ -bromo pinacolone most preferred.
  • a sulfonate for example, RSO 2 O- (where R is alkyl, aryl or heteroaryl), CF 3 SO 2 O- and the like, may be substituted for the halogen in the ⁇ -position.
  • the azides include both metal azides and quaternary ammonium azides. The metal azides are preferred with sodium azide most preferred.
  • Suitable solvent(s) include solvents such as hydrocarbons, ethers, amides, for example, dimethylformamide, ketones, etc., or mixtures thereof, with ketones such as acetone preferred for both reactions (a) and (a 1 ).
  • Step (b) comprises reacting the ⁇ -azido ketone III obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to give an ⁇ -amino ketone IV, or, more desirably, (b') reacting the quaternary ammonium salt III' obtained in step (a!) with an acid in a suitable solvent or solvent mixtures to give an ⁇ -amino ketone IV.
  • the reducing reagent in reaction (b) includes hydrogen in the presence of a transition metal catalyst such as palladium, trialkyl or triarylphosphines like triphenylphosphine. Hydrogen in the presence of a transition metal catalyst is preferred with hydrogen and palladium over activated carbon most preferred.
  • Suitable solvent(s) in reaction (b) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as methanol preferred.
  • the reduction reaction can be carried out in the presence of an acidic medium such as, for example, hydrochloric acid in ethanol to give ⁇ -amino ketone acid salt which can be isolated as the acid salt or free amine forms.
  • the acid in reaction (b') includes, but is not limited to, protic acids such as HC1,
  • Step (c) involves reacting (acylating) the ⁇ -amino ketone IV or its acid salt obtained in step (b) or (b 1 ) with an ⁇ -substituted acyl derivative V such as, for example, an ⁇ -halo acyl halide, in the presence of a base and in a suitable solvent or solvent mixtures to give an amide VI.
  • an ⁇ -substituted acyl derivative V such as, for example, an ⁇ -halo acyl halide
  • the ⁇ -halo acyl halide V includes ⁇ -alkyl or aryl substituted or unsubstituted ⁇ -halo acyl halide with the latter preferred.
  • the most preferred ⁇ -halo acyl halide is ⁇ -chloroacetyl chloride.
  • the base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines with the latter preferred. The most preferred base is triethylamine.
  • Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • reaction can be carried out using an ⁇ - substituted acid instead of the ⁇ -substituted acyl derivative and then employing a coupling reagent such as a water-soluble diimide like carbodiimide, haloformate, thionyl halide, etc.
  • a coupling reagent such as a water-soluble diimide like carbodiimide, haloformate, thionyl halide, etc.
  • a sulfonate for example, RSO 2 O- (where R is an alkyl, aryl or heteroaryl), CF 3 SO 2 O- and the like, may be substituted for the halogen in the ⁇ -position of the ⁇ -halo acyl halide or the ⁇ -halo acid reactants which are illustrated.
  • Step (d) concerns reacting the amide VI obtained in step (c) with a dehydrating reagent in a suitable solvent or solvent mixtures to give the cyclized 2-oxazolylalkyl derivative VII such as, for example, the 2-oxazolylalkyl halide.
  • the reaction is carried out using (methoxycarbonylsulfamoyl)- triethylammonium hydroxide (Burgess 1 reagent) as the dehydrating reagent.
  • Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of the Burgess' reagent in tetrahydrofuran.
  • Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acid anhydrides and the like, such as, e.g., concentrated sulfuric acid, polyphosphoric acid, etc.
  • the dehydrating reagent for instance, can be trihalophosphorus oxide such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a solvent like toluene.
  • Step (e) is directed to reacting the 2-oxazolylalkyl derivative VII obtained in step (d) with a sulfur-containing reagent VIII or VIII' in a suitable solvent or solvent mixtures to give 2-oxazolylalkyl sulfide IX, a new key intermediate compound.
  • the sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or its salt, xanthic acids or salts such as ethylxanthic acid potassium salt. Unsubstituted thiourea is preferred.
  • Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with alcohol such as methanol or ethanol preferred.
  • Step (f) concerns reacting the 2-oxazolylalkyl sulfide IX obtained in step (e) with a 5-halo-2-aminothiazole X in the presence of a base and in a suitable solvent or solvent mixtures to give 5-(2-oxazolylalkylthio)-2-aminothiazole XI.
  • the 5-halo-2-aminothiazole includes 4-N-substituted or unsubstituted 5-halo-2- aminothiazoles with 5-bromo-2-aminothiazole preferred.
  • a suitable base includes, but is not limited to, metal hydroxide, metal alkoxides, metal carbonates and aqueous amines such as ammonium hydroxide. Sodium hydroxide is preferred.
  • Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • Step (g) involves reacting the 5-(2-oxazolylalkylthio)-2-aminothiazole XI obtained in step (f) with an azacycloalkanoic acid derivative XII in the presence of a coupling reagent in a suitable solvent or solvent mixtures to give thiazolyl amide XIII. .
  • the azacycloalkanoic acid derivative includes N-protected derivatives, for example, N-protected isonipecotic acid or N-protected nipecotic acid.
  • the preferred nitrogen- protecting groups are Boc, Cbz, silicon derivatives and the like with Boc being the most preferred.
  • the coupling reagent includes, but is not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred.
  • Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures .thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • Step (h) is directed to reacting the thiazolyl amide XIII obtained in step (g) with a deprotecting reagent in a suitable solvent or solvent mixtures to give a desired 5-(2- oxazolylalkylthio)-2-azacycloalkanoylaminothiazole XIV (where R n is hydrogen).
  • the choice of the deprotecting reagent is based on the nature of the protecting group
  • the preferred deprotecting reagent is an acid such as hydrochloric acid or trifluoroacetic acid and suitable solvent(s) for such deprotecting ⁇ reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • L is a suitable leaving group, such as halogen or sulfonate (e.g., Br, CI, I, R 6 SO 2 O ⁇ , CF 3 SO 2 O ⁇ , wherein R 6 is alkyl, cycloalkyl, heteroaryl, or aryl);
  • M is hydrogen, Li, Na, K, Cs, or a quaternary ammonium ion, e.g., (R 6 ) 4 N or quaternary ammonium ions comprising cyclic alkenetetramines, such as hexamethylenetetramine;
  • Q is hydroxy, halogen or acyloxy (R 6 COO ⁇ , R 6 OCOO " , etc.); Y is O, S, NH, N-alkyl, N-aryl or N-acyl; and
  • Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2 , N-alkyl, N-aryl or N-acyl.
  • step (a) involves reacting a suitable ⁇ -substituted ketone 2, such as an ⁇ -halo ketone, with an azide in a suitable solvent or solvent mixtures to give an ⁇ -azido ketone 3; or, more desirably, (a') reacting ketone 2 with a cyclic alkyleneteframine, such as hexamethylenetetramine in a suitable solvent or solvent mixtures to give quaternary ammonium salt 3'.
  • a suitable ⁇ -substituted ketone 2 such as an ⁇ -halo ketone
  • Suitable ⁇ -halo ketones 2 include ⁇ -halo aliphatic and ⁇ -halo aromatic ketones.
  • the preferred ⁇ -halo ketones are ⁇ -halo pinacolones with ⁇ -bromo pinacolone most preferred.
  • a sulfonate, for example, R 6 SO 2 O ⁇ (where, as defined above, R 6 is alkyl, cycloalkyl, heteroaryl, or aryl), CF 3 SO 2 O " and the like, can be substituted for the halogen (as group L) in the ⁇ -position.
  • the azides include both metal azides and quaternary ammonium azides. The metal azides are preferred, with sodium azide most preferred.
  • Suitable solvent(s) include hydrocarbons, ethers, amides, such as dimethylformamide, ketones, etc., or mixtures thereof, with ketones such as acetone preferred for both reactions (a) and (a').
  • Step (b) involves reacting the ⁇ -azido ketone 3 obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to give an ⁇ -amino ketone 4, or, more desirably, (b') reacting the quaternary ammonium salt 3' obtained in step (a 1 ) with an acid in a suitable solvent or solvent mixtures to give an ⁇ -amino ketone 4.
  • the reducing reagent in reaction (b) includes hydrogen in the presence of a transition metal catalyst such as palladium, trialkyl- or triarylphosphines, such as triphenylphosphine.
  • Hydrogen in the presence of a transition-metal catalyst is preferred with hydrogen and palladium over activated carbon most preferred.
  • Suitable solvent(s) in reaction (b) include hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohols, such as methanol preferred.
  • the reduction reaction can be carried out in the presence of an acidic medium such as, hydrochloric acid in ethanol to give an ⁇ - amino ketone acid salt which can be isolated as the acid salt or free amine forms.
  • Suitable acids for use in reaction (b 1 ) include, but are not limited to, HC1, HBr, HI, H 2 SO 4 , H 3 PO 4 , etc., with HC1 preferred.
  • Suitable solvent(s) in reaction (b') include hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohols, such as ethanol preferred.
  • the ⁇ -amino ketone product can be isolated as the salt or free-base forms.
  • the ⁇ -halo acyl halide 5 includes alkyl or aryl- ⁇ -halo acyl halides (substituted or unsubstituted), with the latter preferred.
  • the most preferred ⁇ -halo acyl halide is ⁇ - chloroacetyl chloride.
  • the base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines, with the latter preferred.
  • the most preferred base is triethylamine.
  • Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • a coupling reagent such as a water-soluble diimide (e.g., carbodiimide), a haloformate, a thionyl halide, etc.
  • a sulfonate for example, R 6 SO 2 O ⁇ (where R 6 is an alkyl, cycloallkyl, aryl or heteroaryl), CF 3 SO 2 O ⁇ can be substituted for the halogen in the ⁇ -position (i.e., at group L) of compounds 5.
  • Step (d) involves reacting the amide 6 obtained in step (c) with a dehydrating reagent in a suitable solvent or solvent mixtures to give the cyclized 2-oxazolylalkyl derivative 7, for example, the 2-oxazolylalkyl halide (i.e., L is halo).
  • a dehydrating reagent in a suitable solvent or solvent mixtures to give the cyclized 2-oxazolylalkyl derivative 7, for example, the 2-oxazolylalkyl halide (i.e., L is halo).
  • the reaction is carried out using (methoxycarbonylsulfamoyl)- triethylammonium hydroxide (Burgess' reagent) as the dehydrating reagent.
  • Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of the Burgess' reagent in tetrahydrofuran.
  • Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acid anhydrides and the like, such as concentrated sulfuric acid, polyphosphoric acid, etc.
  • Step (e) comprises reacting the 2-oxazolylalkyl derivative 7 obtained in step (d) with a sulfur-containing reagent 8 or 8' in a suitable solvent or solvent mixtures to give 2- oxazolylalkyl sulfide 9.
  • the sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or its salt, xanthic acids or salts such as ethylxanthic acid potassium salt. Unsubstituted thiourea is preferred.
  • Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with alcohols such as methanol or ethanol preferred.
  • Step (f) illustrates reacting the 2-oxazolylalkyl sulfide 9 obtained in step (e) with a 2-aminothiazole 10 (preferably L is halo) in the presence of a base and in a suitable solvent or solvent mixtures to give 5-(2-oxazolylalkylthio)-2-aminothiazole 11.
  • a 2-aminothiazole 10 preferably L is halo
  • the 2-aminothiazole 10 includes 4-N-substituted or unsubstituted 5-halo-2- aminothiazoles with 5-bromo-2-aminothiazole preferred.
  • a suitable base includes, but is not limited to, metal hydroxides, metal alkoxides, metal carbonates and aqueous amines, such as ammonium hydroxide. Sodium hydroxide is preferred.
  • Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • Scheme 2 sets forth a general synthesis of compounds of formula I via reaction of amine 11 with a carboxylic acid of formula 12 in the presence of a coupling agent.
  • Suitable coupling reagents include, but are not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred, for example, the combination of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base.
  • Scheme 3 illustrates the synthesis of compounds of formula I, wherein X is NR 2 and R 2 is H.
  • an amine of formula 11 is reacted with a N-protected carboxylic acid of formula 13 in the presence of a coupling agent to form an N-protected compound of formula 14.
  • Suitable coupling reagents include, but are not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred, for example, 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base.
  • P is a nitrogen-protecting group (for example, Boc, Cbz, R 3 Si, etc.).
  • a functional group termed “protected,” this means that the group is in modified form to preclude undesired side reactions at the protected site.
  • Suitable protecting groups for the compounds involved in the present processes will be recognized from the specification taking into account the level of skill in the art, and with reference to standard textbooks such as Greene, T.W., Protective Groups in Organic Synthesis, 3rd edition (1999), incorporated herein by reference.
  • the preferred nitrogen-protecting groups are Boc, Cbz, silicon derivatives, with Boc being the most preferred.
  • Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • the choice of the deprotecting reagent is based on the nature of the protecting group (P).
  • the preferred deprotecting reagent is an acid such as hydrochloric acid or trifluoroacetic acid and suitable solvent(s) for such deprotecting reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.
  • Scheme 4 illustrates the synthesis of compounds of formula I, wherein X is NR 2 and R 2 is 2,3-dihydroxypropyl, by reacting a compound of formula I wherein X is NR 2 and R 2 is hydrogen with glyceraldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride and an alcohol such as methanol.
  • a reducing agent such as sodium triacetoxyborohydride and an alcohol such as methanol.
  • Scheme 5 illustrates the synthesis of compounds of formula I, wherein X is NR 2 and R 2 is 2-hydroxy ethyl, by reacting a compound of formula I wherein X is NR 2 and R 2 is hydrogen with a 2-(bromoethoxy)trialkylsilane of formula 15 to give intermediate 16, and deprotecting intermediate 16 with an acid such as hydrogen fluoride.
  • Preferred compounds of formula I are those wherein: R is alkyl; R 1 is hydrogen;
  • X is NR 2 or CHNR 2 R 3 ;
  • R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl or cycloalkyl; and n is 2.
  • a first group of more preferred compounds of the present invention are those of formula la:
  • R 2 is hydrogen, alkyl, substituted alkyl, or cycloalkyl.
  • a second group of more preferred compounds of this invention are those of formula lb:
  • R 2 is hydrogen, alkyl, substituted alkyl, or cycloalkyl.
  • a third group of more preferred compounds of the present invention are those of formula Ic:
  • R 2 and R 3 are each independently hydrogen, alkyl, substituted alkyl, or cycloalkyl.
  • compounds of formula I include, but are not limited, to those listed in Table 1 below and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.
  • Preferred salts of the above compounds are the hydrochloride, the hydrobromide, the dihydrochloride, the sulfate, the trifluoroacetate, the tartrate, the fumarate, the succinate, the maleate, the citrate, the methanesulfonate, the bromate, and the iodate salts or mixtures thereof.
  • the present invention also includes methods based upon the pharmacological properties of the compounds of the invention.
  • the compounds according to the invention have pharmacological properties; in particular, the compounds of formula I are inhibitors of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdkl), cdk2, cdk3, cdk4, cdk5, cdk6, cdk7 and cdk8.
  • cdks cyclin dependent kinases
  • the invention encompasses the use of compounds of the invention in the treatment, prevention, and/or management of cancer, inflammation or inflammatory disease, arthritis, Alzheimer's disease and cardiovascular disease.
  • the invention also encompasses, in a more specific embodiment, the use of compounds of the invention to treat, prevent, and/or manage proliferative diseases or symptoms thereof.
  • the invention also encompasses use of compounds of the invention in the treatment or prevention of topical and systemic fungal infections. More specifically, the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following:
  • -carcinoma including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin; -hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma, and Burkett's lymphoma;
  • -hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias and promyelocytic leukemia;
  • inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., neuro-fibro atosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock.
  • the invention also encompasses use of compounds of the invention in the treatment of Alzheimer's disease, as suggested by the recent finding that cdk5 is involved in the phosphorylation of tau protein (J. Biochem, 111, 741-749 (1995)).
  • the invention also encompasses use of compounds of the invention as inhibitors of other protein kinases, e.g., protein kinase C, her2, raf ⁇ , MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abl, VEGF, and lck, and thus be effective in the treatment of diseases associated with other protein kinases.
  • protein kinase C her2, raf ⁇
  • MEK1 MAP kinase
  • EGF receptor EGF receptor
  • PDGF receptor PDGF receptor
  • IGF receptor IGF receptor
  • PI3 kinase IGF receptor
  • PI3 kinase PI3 kinase
  • weel kinase weel kinase
  • Src Abl
  • VEGF vascular endothelial growth factor
  • lck e.g
  • the invention also encompasses use of compounds of the invention to induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases.
  • Compounds of formula I, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with abberations in apoptosis including cancer (particularly, but not limited to, follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including, but not limited to, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including, but not limited to, systemic lupus, erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, p
  • the invention encompasses a method of inhibiting cdk in a cell.
  • the invention encompasses treatment or prevention of diseases associated with cdk modulation by administering one or more compounds of the invention to a mammal in need thereof.
  • the invention encompasses treatment of mammals, particularly humans.
  • compounds of the invention can be used for treating chemotherapy- induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia or mucocitis.
  • the compounds of the invention are preferably topically applied in the form of a medicament such as a gel, solution, dispersion or paste.
  • the compounds of this invention may be used in combination (before, during, after, including cycling administration) with known anti-cancer treatments such as radiation therapy or with cytostatic and cytotoxic agents including, but not limited to, microtuble- stabilizing agents, microtuble-disruptor agents, alkylating agents, anti-metabolites, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers, growth inhibitors, hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, and the like.
  • cytostatic and cytotoxic agents including, but not limited to, microtuble- stabilizing agents, microtuble-disruptor agents, alkylating agents, anti-metabolites, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers, growth inhibitors,
  • Classes of anti-cancer agents which may be used in combination with the formula I compounds of this invention include, but are not limited to, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermohde, the pteridine family of drugs, diynenes, aromatase inhibitors, and the podophyllotoxins.
  • Particular members of those classes include, for example, paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel (disclosed in U.S.
  • Other useful anti-cancer agents which may be used in combination with the compounds of the present invention include, but are not limited to, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, interleukins, and the like.
  • the compounds o thisrinvention may be m used in combination with inhibitors of farnesyl protein transferase such as those described in U.S. 6,011,029; anti-angiogenic agents such as angiostatin and endostatin; kinase inhibitors such as her2 specific antibodies; and modulators of p53 transactivation.
  • inhibitors of farnesyl protein transferase such as those described in U.S. 6,011,029
  • anti-angiogenic agents such as angiostatin and endostatin
  • kinase inhibitors such as her2 specific antibodies
  • modulators of p53 transactivation such as those described in U.S. 6,011,029
  • Such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range.
  • Compounds of formula I may be used sequentially, in any order, with known anti-cancer or cytotoxic agents when a combination formulation is inappropriate.
  • the present invention also provides pharmaceutical compositions which comprise a compound of this invention and a pharmaceutically acceptable carrier.
  • the compounds of the invention, or compounds of formula I refer to the free base, enantiomers, diastereomers, solvates, as well as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include, but are not limited to, hydrochloride, dihydrochlori.de, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.
  • salts formed with other organic and inorganic acids such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, benzoates, ascorbates, salicylates, and the like.
  • These salts include racemic forms as well as enantiomers and diastereomers (such as, for example, D-tartrate and L-tartrate salts).
  • pharmaceutically acceptable salts of compounds of formula I may be formed with alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; organic bases such as dicyclohexylamine, tributylamine, and pyridines, and the like; and amino acids such as arginine, lysine and the like.
  • the pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable additional carriers, excipients, or diluents including, but not limited to, ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, and the like.
  • the compounds and compositions of this invention may be administered orally or parenterally including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the compounds and compositions of this invention may be administered, for example, in the form of tablets or capsules, or as solutions or suspensions.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents such as magnesium stearate are commonly added.
  • useful carriers include lactose and corn starch.
  • emulsifying and/or suspending agents are commonly added.
  • sweetening and/or flavoring agents may be added to the oral compositions.
  • sterile solutions of the active ingredient(s) are usually employed, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of the solute(s) should be controlled in order to render the preparation isotonic.
  • a fo ⁇ nula I compound of this invention is preferably administered to humans in an amount from about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day, more preferably from about 0.01 mg/kg of body weight to about 50 mg/kg of body weight per day, and most preferably from about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day.
  • cdc2/cvclin Bl Kinase Assay cdc2/cyclin Bl kinase activity was determined by monitoring the incorporation of 32 P into histone HI.
  • the reaction consisted of 50 ng baculovirus expressed GST-cdc2, 75 ng baculovirus expressed GST-cyclin Bl, 1 ⁇ g histone HI (Boehringer Mannheim), 0.2 ⁇ Ci of 32 P ⁇ -ATP and 25 ⁇ M ATP in kinase buffer (50 mM Tris, pH 8.0, 10 niM MgCl 2 , 1 mM EGTA, 0.5 mM DTT).
  • the reaction was incubated at 30 °C for 30 minutes and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15 % and incubated on ice for 20 minutes.
  • TCA cold trichloroacetic acid
  • the reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter (Marshak, D.R., Vanderberg, M.T., Bae, Y.S., Yu, I.J., J. of Cellular Biochemistry, 45, 391-400 (1991), incorporated by reference herein).
  • cdk2/cyclin E Kinase Assay cdk2/cyclin E Kinase Assay cdk2/cyclin E kinase activity was determined by monitoring the incorporation of 32 P into the retinoblastoma protein.
  • the reaction consisted of 2.5 ng baculovirus expressed GST-cdk2/cyclin E, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 ⁇ Ci 32 P ⁇ -ATP and 25 ⁇ M ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl 2 , 5 mM EGTA, 2 mM DTT).
  • the reaction was incubated at 30 °C for 30 minutes and then "stoppedby the addition of'cold ' trichloroacetic aeidTTCA) to a final concentration of 15 % and incubated on ice for 20 minutes.
  • the reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter.
  • cdk4/cyclin Dl kinase activity was determined by monitoring the incorporation of 32 P in to the retinoblastoma protein.
  • the reaction consisted of 165 ng baculovirus expressed - as-GST-cdk4, 282 ng bacterially expressed as S-tag cyclin Dl, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 ⁇ Ci 32 P ⁇ -ATP and 25 ⁇ M ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl 2 , 5 mM EGTA, 2 mM DTT).
  • the reaction was incubated at 30 °C for 1 hour and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15 % and incubated on ice for 20 minutes.
  • TCA cold trichloroacetic acid
  • the reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter (Coleman, K.G., Wautlet, B.S., Morissey, D, Mulheron, J.G., Sedman, S., Brinkley, P., Price, S., Webster, K.R. (1997) Identification of CDK4 Sequences involved in cyclin D, and pl6 binding. J. Biol. Chem. 272,30:18869-18874, incorporated by reference herein).
  • ⁇ -Bromo-pinacolone (179 g, 1 mol, 1 eq) was combined in 2 L of acetone with hexamethylenetetramine (154.21 g, 1.1 mol, 1.1 eq) and the reaction stirred under N 2 at room temperature for 26 hours. The resulting slurry was filtered, the filter cake was washed with ether (3 x 50 mL) and dried in vacuo at 50 °C overnight to provide 330 g (100%) of the title compound containing 7% hexamethylenetetramine.
  • HPLC R.T. 0.17 min (Phenomenex Inc., 5 ⁇ m C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
  • the title compound of part I (16.6 g) was dissolved in 150 mL of CH 2 C1 2 , trifluoroacetic acid (30 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours.
  • the reaction was concentrated in vacuo, diluted with water (300 mL), cooled in ice, made basic with sodium hydroxide, and the resulting solid filtered and recrystallized from ethanol, water and methanol to provide 11.2 g (83%) of the title compound as a yellow solid.
  • the white solid hydrochloride could be obtained by addition of 18 mL of IN aqueous HCI to 7 g of this material in methanol.
  • Nipecotic acid (1.3 g, 10 mmol, 1 eq) was combined with 10 mL of dioxane, 2 mL of acetonitrile, 10 mL of water, and 10 mL of IN aqueous NaOH (1 eq).
  • Di-t-butyl dicarbonate (3.3 g, 15 mmol, 1.5 eq) was added and the reaction mixture was stirred at rt overnight.
  • the reaction mixture was concentrated in vacuo to remove organic solvent and 10 %> aqueous citric acid was added
  • the mixture was extracted with ethyl acetate (3 x 100 mL). The organic extracts were dried over Na ⁇ O ⁇ filtered through silica gel, and concentrated in vacuo.
  • the crude material was recrystallized from ethyl acetate and hexanes to provide 2.2 g (96 %) of ( ⁇ )-N-t-butoxycarbonyl-nipecotic acid as a white solid.
  • Ethyl isonipecotate (3.2 g, 20 mmol, 1 eq) was combined with acetone (5.8 g, 100 mmol, 5 eq), sodium triacetoxyborohydri.de (10.5 g, 50 mmol, 2.5 eq) and 1,2- dichloroethane (200 mL). The reaction mixture was stirred at rt for 72 h. Saturated aqueous NaHCO 3 was added, and the mixture was extracted with CH 2 C1 2 .
  • Ethyl l-(l-methylethyl)-4-piperidine carboxylate (3.6 g, 18 mmol, 1 eq) was combined with barium hydroxide octahydrate (10.4 g, 33 mmol, 1.8 eq) in a mixture of 70 mL of water with 44 mL of ethanol. The mixture was heated at 60°C for 1.3 h. The reaction mixture was concentrated in vacuo and diluted with 70 mL of water. Ammonium carbonate (6.9 g, 87 mmol, 4.8 eq) was added portionwise and the reaction mixture was stirred at rt overnight. The mixture was filtered through diatomaceous earth, concentrated, and lyophilized to provide 3.1 g (100 %) of l-(l-methylethyl)-4-piperidine carboxylic acid as a white solid.
  • reaction mixture was stirred at rt for 1 h, diluted with 30 mL of water and extracted with ethyl acetate (2 x 70 mL).
  • the organic extracts were dried concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 5-10 % triethylamine in ethyl acetate.
  • the material was recrystallized from ethanol and water to provide 0.93 g (85 %) ofN-[5-[[[[5-(l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-l-(l- methylethyl)-4-piperidinecarboxamide as a yellowish solid.
  • Ethyl isonipecotate (1.57 g, 10 mmol, 1 eq) was combined with ((1- ethoxycyclopropyl)oxy)trimethyl silane (8.7 g, 50 mmol, 5 eq) in 100 mL of methanol. 5 Acetic acid (5.7 mL, 100 mmol, 10 eq) and molecular sieves were added. After 30 min at rt, sodium triacetoxyborohydride (2.5 g, 40 mmol, 4 eq) was added and the reaction mixture was heated at 65 °C overnight. The reaction mixture was cooled and Na 2 CO 3 (20 g) was added. The mixture was stirred at rt for 2 h and filtered through diatomaceous earth.
  • the diatomaceous earth was washed with methanol.
  • the filtrates were combined, concentrated ⁇ in vacuo, diluted with water, and extracted with ethyl acetate.
  • the organic extracts were dried, filtered through a silica gel pad, and concentrated in vacuo to provide 2.4 g of colorless liquid.
  • This material was combined with barium hydroxide octahydrate (5.7 g, 18 mmol, 1.8 eq) in a mixture of 38 mL of water with 24 mL of ethanol.
  • the mixture was heated at 60 °C for 1 h.
  • the reaction mixture was concentrated in vacuo and diluted with ⁇ 38 mL of water.
  • reaction mixture was stirred-at-rt-for-1 h, diluted ⁇ with water (30 mL), and extracted with ethyl acetate (2 x 70 mL).
  • the combined organic extracts were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 0-10 % triethylamine in ethyl acetate.
  • N-[5-[[[5-(l , 1 -dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (1.4 g, 3.68 mmol, 1 eq) was dissolved in 30 mL of N,N-dimethylformamide and 100 mL of tetrahydrofuran.
  • 2-(Bromoethoxy)-t- butyldimethylsilane (0.79 mL, 3.68 mmol, 1 eq), and NaHCO 3 were added and the reaction mixture was strred at 50 °C for 23 h.
  • N-[5-[[[5-(l , 1 -Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-l -(2-dimethyl-t- butylsilyloxyethyl)-4-piperidinecarboxamide (1.45 g, 2.7 mmol, 1 eq) was dissolved in 100 mL of acetonitrile and combined with aqueous HF (48 % aqueous, 2.5 mL). The reaction mixture was stirred for 4 h at rt. An additional 2.5 mL of aqueous HF was added, and the reaction mixture was stirred overnight.
  • the enantiomers were separated by chiral HPLC (Chiral Pak AD 5 x 50 cm 20 ⁇ : eluent 10 % (0.1 % triethylamine in isopropanol) in hexanes; 45 mL/min, detection at 254 nm, loading 300 mg in 5 mL of isopropanol) to give each of the two optically pure isomers: 1.65 g of the R isomer and 1.65 g of the S isomer.
  • the (R) isomer of Part A (1.65 g, 3.43 mmol, 1 eq) was dissolved in 10 mL of CH 2 C1 2 . Trifluoroacetic acid (6 mL) was added, and the mixture was stirred at rt for several hours. The reaction mixture was concentrated in vacuo and neutralized with saturated aqueous NaHCO 3 . The resulting mixture was stirred with ethyl acetate for 1 h. The organic extracts were dried over Na ⁇ O,, and concentrated in vacuo to provide a yellowish solid. The solid was dissolved in methanol and 1 eq of IN aqueous HCI was added.
  • Example 9 Preparation of c s-4-Amino-N-[5-[[[5-(l,l-dimethylethyl)-2-oxazolyl]- methyl]thio]-2-thiazolyl]cycIohexylcarboxamide hydrochloride and tr ⁇ ns-4-Amino-N-[5-[[[5-(l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2- thiazolyll-cyclohexylcarboxamide hydrochloride
  • the combined organic extracts were dried (sodium sulfate) to give a crude cis/trans product.
  • the crude material was purified by flash chromatography (Merck silica, 25x3 cm, 1:9 isopropylamine/ethyl acetate then 1:2:7 methanol/isopropylamine/ethyl acetate) to afford 0.74 g of the cis isomer as a yellow solid and 0.50 g of the trans isomer as a brown solid.
  • the cis isomer was dissolved in methanol then 0.34 mL of 5N aqueous HCI was added.

Abstract

Cette invention a trait à des composés correspondant à la formule (I), à leurs énantiomères, leurs diastéromères, leurs solvates et leurs sels acceptables du point de vue pharmaceutique. Les composés selon cette formule, qui sont des inhibiteurs de la protéine kinase, se révèlent des plus utiles dans le traitement de maladies prolifératives, notamment du cancer, des maladies inflammatoires et de l'arthrite. Ils sont également des plus utiles pour traiter la maladie d'Alzheimer, l'alopécie provoquée par une chimiothérapie et les maladies cardio-vasculaires.
PCT/US2001/015081 2000-07-26 2001-05-09 Inhibiteurs n-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide de la kinase dependantes des cyclines WO2002010162A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
EP01933266A EP1303513A1 (fr) 2000-07-26 2001-05-09 Inhibiteurs n- 5- 5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide de la kinase dependantes des cyclines
CA002417254A CA2417254A1 (fr) 2000-07-26 2001-05-09 Inhibiteurs n-¢5-¢¢¢5-alkyl-2-oxazolyl!methyl!thio!-2-thiazolyl! carboxamide de la kinase dependantes des cyclines
JP2002515891A JP2004509857A (ja) 2000-07-26 2001-05-09 サイクリン依存性キナーゼのｎ−［５−［［［５−アルキル−２−オキサゾリル］メチル］チオ］−２−チアゾリル］カルボキサミドインヒビター
EEP200300041A EE200300041A (et) 2000-07-26 2001-05-09 Tsükliin-sõltuvate kinaaside N-[5-[[[5-alküül-2-oksasolüül]metüül]tio]-2-tiasolüül]karboksamiidinhibiitorid
KR10-2003-7001141A KR20030016429A (ko) 2000-07-26 2001-05-09 시클린 의존성 키나제의ｎ-[5-[[[5-알킬-2-옥사졸릴]메틸]티오]-2-티아졸릴]카르복스아미드 저해제
SK1839-2002A SK18392002A3 (sk) 2000-07-26 2001-05-09 N-(5-{[(5-alkyl-2-oxazolyl)metyl]tio]-2-tiazolyl}karboxamidy ako inhibítory cyklín-dependentných kináz
AU2001259704A AU2001259704A1 (en) 2000-07-26 2001-05-09 N-(5-(((5-alkyl-2-oxazolyl)methyl)thio)-2-thiazolyl) carboxamide inhibitors of cyclin dependent kinases
IL15359101A IL153591A0 (en) 2000-07-26 2001-05-09 N-[5-(((5-alkyl-2-oxazolyl) methyl) thio)-2-thiazolyl] carboxamide and pharmaceutical compositions containing the same
HU0303698A HUP0303698A2 (hu) 2000-07-26 2001-05-09 Ciklin dependens kináz inhibitor N-[5-{[(5-alkil-2-oxazolil)-metil]-tio}-2-tiazolil]-karboxamid származékok, alkalmazásuk és ezeket tartalmazó gyógyszerkészítmények
MXPA03000774A MXPA03000774A (es) 2000-07-26 2001-05-09 Inhibidores de n-[5-[[[5-alquil-2-oxazolil]metil]ito]-2-tiazolil]carboxamida de cinasas dependientes de la ciclina.
BR0112674-1A BR0112674A (pt) 2000-07-26 2001-05-09 Inibidores n-[5-[[[5-alquil-2-oxazolil]metil] tio]-2tiazolil]carboxamida de quinases dependentes de ciclina
SI200120051A SI21099A (sl) 2000-07-26 2001-05-09 N-(5-(((5-alkil-2-oksazolil)metil)tio)-2-tiazolil) karboksamidni inhibitorji ciklin odvisnih kinaz
IL153591A IL153591A (en) 2000-07-26 2002-12-23 History of N–] 5 -))) 5– Alkyl– 2 – Oxazolil (Thio (–2 – thiazolil [carboxamide and pharmaceutical preparations containing them)
IS6696A IS6696A (is) 2000-07-26 2003-01-23 N-[5-[[[5-alkýl-2-oxazólýl]metýl]þíó]-2-þíazólýl]karboxamíð tálmar sýklínháðra kínasa
NO20030394A NO20030394L (no) 2000-07-26 2003-01-24 N-[5-[[[5-alkyl-2-oksazolyl]metyl]tio]-2-tiazolyl]karboksamid-inhibitorer for cyklin-avhengige kinaser
HR20030116A HRP20030116A2 (en) 2000-07-26 2003-02-19 N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]carboxamide inhibitors of cyclin dependent kinases

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US61662700A 2000-07-26 2000-07-26
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US09/727,957 US6515004B1 (en) 1999-12-15 2000-12-01 N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
US09/727,957 2000-12-01
US09/746,060 2000-12-22
US09/746,060 US6414156B2 (en) 1998-10-21 2000-12-22 Process for preparing azacycloalkanoylaminothiazoles

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WO2004022062A1 (fr) 2002-09-04 2004-03-18 Schering Corporation Pyrazolopyrimidines utiles en tant qu'inhibiteurs de kinases dependantes des cyclines
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US6897321B2 (en) 1999-12-15 2005-05-24 Briston Myers Squibb Company Process for preparing azacycloalkanoylaminothiazoles (LD 137e)
US6919341B2 (en) 2002-09-23 2005-07-19 Schering Corporation Imidazopyrazines as cyclin dependent kinase inhibitors
EP1555264A1 (fr) * 2004-01-15 2005-07-20 Sireen AG Hétérocycles à cinq chaínons comme inhibiteurs de la famille des SRC proteines kinases
WO2006087230A1 (fr) * 2005-02-17 2006-08-24 Schering Aktiengesellschaft Utilisation d'inhibiteurs de cdk ii a des fins de contraception
WO2007022258A1 (fr) * 2005-08-17 2007-02-22 Schering Corporation Ligands de kinase thiophene et furane a haute affinite
US7186740B2 (en) 2002-09-23 2007-03-06 Schering Corporation Imidazopyrazines as cyclin dependent kinase inhibitors
WO2007041712A1 (fr) 2005-10-06 2007-04-12 Schering Corporation Pyrazolopyrimidines en tant qu’inhibiteurs de protéines kinases
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US7700773B2 (en) 2005-09-09 2010-04-20 Schering Corporation 4-cyano, 4-amino, and 4-aminomethyl derivatives of pyrazolo[1,5-a]pyridines, pyrazolo[1,5-c]pyrimidines and 2H-indazole compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyrazines as cyclin dependent kinase inhibitors
EP2194058A1 (fr) 2002-09-04 2010-06-09 Schering Corporation Pyrazolopyrimidines utiisables pour le traitement de maladies cancereuses
WO2010088368A2 (fr) 2009-01-29 2010-08-05 Schering Corporation Imidazopyrazines en tant qu'inhibiteurs de protéines kinases
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EP2409700A1 (fr) 2007-05-08 2012-01-25 Schering Corporation Procédés pour le traitement de formulations intraveineuses comprenant du témozolomide
US8318735B2 (en) 2006-10-31 2012-11-27 Merck Sharp & Dohme Corp. 2-aminothiazole-4-carboxylic amides as protein kinase inhibitors
WO2013148775A1 (fr) 2012-03-30 2013-10-03 Merck Sharp & Dohme Corp. Biomarqueur prédictif utile pour thérapie anticancéreuse médiée par un inhibiteur de cdk
US8563741B2 (en) 2007-09-10 2013-10-22 Curis, Inc. CDK inhibitors containing a zinc binding moiety
US8580782B2 (en) 2002-09-04 2013-11-12 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
US8673924B2 (en) 2002-09-04 2014-03-18 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
US8691820B2 (en) 2008-12-23 2014-04-08 Curis, Inc. CDK inhibitors
US9206142B2 (en) 2006-10-31 2015-12-08 Merck Sharp & Dohme Corp. Anilinopiperazine derivatives and methods of use thereof

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WO2001044242A1 (fr) * 1999-12-15 2001-06-21 Bristol-Myers Squibb Co. Inhibiteurs contenant n-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]carboxamide inhibant des kinases dependantes des cyclines
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Cited By (35)

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US6897321B2 (en) 1999-12-15 2005-05-24 Briston Myers Squibb Company Process for preparing azacycloalkanoylaminothiazoles (LD 137e)
US8129541B2 (en) 2002-02-28 2012-03-06 Novartis Ag 5-phenylthiazole derivatives and use as PI3 kinase inhibitors
EP2311818A1 (fr) * 2002-02-28 2011-04-20 Novartis AG Combinaison d'un dérivé de 5-phenylthiazole utile comme inhibiteur de kinase PI3 et d'un composé antiinflammatoire, bronchodilatateur ou d'un antihistaminique.
WO2003072557A1 (fr) 2002-02-28 2003-09-04 Novartis Ag Derives du 5-phenylthiazol et leurs utilisations comme inhibiteurs de la pi3 kinase
US7687637B2 (en) 2002-02-28 2010-03-30 Novartis Ag 5-phenylthiazole derivatives and use as Pi3 kinase inhibitors
WO2004022062A1 (fr) 2002-09-04 2004-03-18 Schering Corporation Pyrazolopyrimidines utiles en tant qu'inhibiteurs de kinases dependantes des cyclines
US8673924B2 (en) 2002-09-04 2014-03-18 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
US8580782B2 (en) 2002-09-04 2013-11-12 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
EP2194058A1 (fr) 2002-09-04 2010-06-09 Schering Corporation Pyrazolopyrimidines utiisables pour le traitement de maladies cancereuses
US7186740B2 (en) 2002-09-23 2007-03-06 Schering Corporation Imidazopyrazines as cyclin dependent kinase inhibitors
US6919341B2 (en) 2002-09-23 2005-07-19 Schering Corporation Imidazopyrazines as cyclin dependent kinase inhibitors
US7432265B2 (en) 2002-09-23 2008-10-07 Schering Corporation Imidazopyrazines as cyclin dependent kinase inhibitors
US7902375B2 (en) 2003-08-28 2011-03-08 Novartis Ag 5-phenyl-4-methyl-thiazol-2-yl-amine derivatives as inhibitors of phosphatidylin ositol 3 kinase enzymes (PI13) for treatment of inflammatory diseases
WO2005021519A3 (fr) * 2003-08-28 2005-05-12 Novartis Ag Composes organiques
JP2007504109A (ja) * 2003-08-28 2007-03-01 ノバルティス アクチエンゲゼルシャフト 炎症性気道疾患の処置のための、ホスファチジルイノシトール３キナーゼ酵素（ｐｉ３）の阻害剤としての、５−フェニル−４−メチル−チアゾール−２−イル−アミン誘導体
WO2005021519A2 (fr) * 2003-08-28 2005-03-10 Novartis Ag Composes organiques
WO2005068458A2 (fr) * 2004-01-15 2005-07-28 Sirenade Pharmaceuticals Ag Composes inhibiteurs de kinases
WO2005068458A3 (fr) * 2004-01-15 2005-11-24 Sirenade Pharmaceuticals Ag Composes inhibiteurs de kinases
EP1555264A1 (fr) * 2004-01-15 2005-07-20 Sireen AG Hétérocycles à cinq chaínons comme inhibiteurs de la famille des SRC proteines kinases
WO2006087230A1 (fr) * 2005-02-17 2006-08-24 Schering Aktiengesellschaft Utilisation d'inhibiteurs de cdk ii a des fins de contraception
US7446195B2 (en) 2005-08-17 2008-11-04 Schering Corporation High affinity thiophene-based and furan-based kinase ligands
WO2007022258A1 (fr) * 2005-08-17 2007-02-22 Schering Corporation Ligands de kinase thiophene et furane a haute affinite
US7700773B2 (en) 2005-09-09 2010-04-20 Schering Corporation 4-cyano, 4-amino, and 4-aminomethyl derivatives of pyrazolo[1,5-a]pyridines, pyrazolo[1,5-c]pyrimidines and 2H-indazole compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyrazines as cyclin dependent kinase inhibitors
US7776865B2 (en) 2005-10-06 2010-08-17 Schering Corporation Substituted pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors
WO2007041712A1 (fr) 2005-10-06 2007-04-12 Schering Corporation Pyrazolopyrimidines en tant qu’inhibiteurs de protéines kinases
WO2007146039A3 (fr) * 2006-06-06 2008-07-17 Bristol Myers Squibb Co Formes cristallines du n-[5-[[[5-(1,1-diméthyléthyl)-2-oxazolyl]méthyl]thio]-2-thiazolyl]-4-pipéridinecarboxamide
WO2007146039A2 (fr) * 2006-06-06 2007-12-21 Bristol-Myers Squibb Company Formes cristallines du n-[5-[[[5-(1,1-diméthyléthyl)-2-oxazolyl]méthyl]thio]-2-thiazolyl]-4-pipéridinecarboxamide
US8318735B2 (en) 2006-10-31 2012-11-27 Merck Sharp & Dohme Corp. 2-aminothiazole-4-carboxylic amides as protein kinase inhibitors
US9206142B2 (en) 2006-10-31 2015-12-08 Merck Sharp & Dohme Corp. Anilinopiperazine derivatives and methods of use thereof
EP2409700A1 (fr) 2007-05-08 2012-01-25 Schering Corporation Procédés pour le traitement de formulations intraveineuses comprenant du témozolomide
US8563741B2 (en) 2007-09-10 2013-10-22 Curis, Inc. CDK inhibitors containing a zinc binding moiety
US8691820B2 (en) 2008-12-23 2014-04-08 Curis, Inc. CDK inhibitors
WO2010088368A2 (fr) 2009-01-29 2010-08-05 Schering Corporation Imidazopyrazines en tant qu'inhibiteurs de protéines kinases
WO2011025706A2 (fr) 2009-08-26 2011-03-03 Schering Corporation Composés d'amide hétérocyclique comme inhibiteurs de la protéine kinase
WO2013148775A1 (fr) 2012-03-30 2013-10-03 Merck Sharp & Dohme Corp. Biomarqueur prédictif utile pour thérapie anticancéreuse médiée par un inhibiteur de cdk

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CA2417254A1 (fr) 2002-02-07
YU4903A (sh) 2006-03-03
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AU2001259704A1 (en) 2002-02-13
CZ2003237A3 (cs) 2003-06-18
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PL365170A1 (en) 2004-12-27
EP1303513A1 (fr) 2003-04-23
BR0112674A (pt) 2003-12-30
BG107468A (en) 2004-01-30
SI21099A (sl) 2003-06-30
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