US20010006976A1 - Process for preparing azacycloalkanoylaminothiazoles - Google Patents
Process for preparing azacycloalkanoylaminothiazoles Download PDFInfo
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- US20010006976A1 US20010006976A1 US09/746,060 US74606000A US2001006976A1 US 20010006976 A1 US20010006976 A1 US 20010006976A1 US 74606000 A US74606000 A US 74606000A US 2001006976 A1 US2001006976 A1 US 2001006976A1
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- 0 *C1=C(C)N=C(C(C)(C)SC2=C(C)N=C(N(C)C(=O)C3CCN(C)C3)S2)O1.CC.CC Chemical compound *C1=C(C)N=C(C(C)(C)SC2=C(C)N=C(N(C)C(=O)C3CCN(C)C3)S2)O1.CC.CC 0.000 description 15
- DJKHLSSMJRYOLA-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(C(=O)NC2=NC=C(SCC3=NC=C(C(C)(C)C)O3)S2)CC1 Chemical compound CC(C)(C)OC(=O)N1CCC(C(=O)NC2=NC=C(SCC3=NC=C(C(C)(C)C)O3)S2)CC1 DJKHLSSMJRYOLA-UHFFFAOYSA-N 0.000 description 2
- VLNUTKMHYLQCQB-UHFFFAOYSA-N CCC(=O)C(C)(C)C Chemical compound CCC(=O)C(C)(C)C VLNUTKMHYLQCQB-UHFFFAOYSA-N 0.000 description 2
- CXEKPSNTAJVJNI-UHFFFAOYSA-N CC(C)(C)C(=O)CN=[N+]=[N-] Chemical compound CC(C)(C)C(=O)CN=[N+]=[N-] CXEKPSNTAJVJNI-UHFFFAOYSA-N 0.000 description 1
- WWHZELYGAZRGKC-UHFFFAOYSA-N CC(C)(C)C(=O)CNC(=O)CCl Chemical compound CC(C)(C)C(=O)CNC(=O)CCl WWHZELYGAZRGKC-UHFFFAOYSA-N 0.000 description 1
- CKHWLJOWEUKHDL-UHFFFAOYSA-N CC(C)(C)C(=O)C[N+]12CN3CN(CN(C3)C1)C2.[Br-] Chemical compound CC(C)(C)C(=O)C[N+]12CN3CN(CN(C3)C1)C2.[Br-] CKHWLJOWEUKHDL-UHFFFAOYSA-N 0.000 description 1
- LUGZUJZYTRPEDY-UHFFFAOYSA-N CC(C)(C)C1=CN=C(CCl)O1 Chemical compound CC(C)(C)C1=CN=C(CCl)O1 LUGZUJZYTRPEDY-UHFFFAOYSA-N 0.000 description 1
- RHSQSEDOPLDGMY-UHFFFAOYSA-N CC(C)(C)C1=CN=C(CSC(=N)N)O1 Chemical compound CC(C)(C)C1=CN=C(CSC(=N)N)O1 RHSQSEDOPLDGMY-UHFFFAOYSA-N 0.000 description 1
- UNUCZJRZFFSFFA-UHFFFAOYSA-N CC(C)(C)C1=CN=C(CSC2=CN=C(N)S2)O1 Chemical compound CC(C)(C)C1=CN=C(CSC2=CN=C(N)S2)O1 UNUCZJRZFFSFFA-UHFFFAOYSA-N 0.000 description 1
- IYLMWEFXWOERFM-UHFFFAOYSA-N CC(C)(C)C1=CN=C(CSC2=CN=C(NC(=O)C3CCCCC3)S2)O1 Chemical compound CC(C)(C)C1=CN=C(CSC2=CN=C(NC(=O)C3CCCCC3)S2)O1 IYLMWEFXWOERFM-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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 concerns new processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
- R is alkyl, aryl or heteroaryl
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, alkyl, aryl or heteroaryl;
- R 6 and R 7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
- R 8 is hydrogen, alkyl, aryl, heteroaryl, CONR 9 R 10 , COR 11 or COOR 12 ;
- R 9 , R 10 , R 11 and R 12 are each independently hydrogen, alkyl or aryl;
- n 0 to 5
- cdks cyclin dependent kinases
- proliferative diseases for example, cancer, inflammation, autoimmune diseases such as arthritis, viral diseases, fungal diseases, chemotherapy-induced alopecia, neurodegenerative disorders such as Alzheimer's disease and cardiovascular disease.
- the compounds of formula I are useful in the treatment of a variety of cancers such as bladder, breast, colon, kidney, liver and lung cancers.
- WO 9924416 and corresponding U.S. Pat. No. 6,040,321 describe the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I, by reacting 5-acetylthio-2-acetylaminothiazole with a base followed by trapping the thiolate with a 2-oxazolylalkyl halide.
- This invention concerns new efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles.
- the processes involve new strategies for the preparation of 2-oxazolylalkyl halides and 5-(2-oxazolylalkylthio)-2-aminothiazoles which include the method of making new key intermediate quaternary ammonium salts and 2-oxazolylalkyl sulfide derivatives.
- This invention further relates to processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
- the present invention relates to new, more efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles with application to the synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
- the process generally involves reaction of ⁇ -halo ketones II with an azide to give ⁇ -azido ketones III. Reduction of III with a reducing reagent gives ⁇ -amino ketones IV. From a practical standpoint, safety concerns make this reaction through the azide economically unfeasible.
- 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%, yet in a safer manner.
- R is alkyl, aryl or heteroaryl
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, alkyl, aryl or heteroaryl;
- R 6 and R 7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
- R 8 is hydrogen, alkyl, aryl, heteroaryl, CONR 9 R 10 , COR 11 or COOR 12 ;
- R 9 , R 10 , R 11 and R 12 are each independently hydrogen, alkyl or aryl;
- L is halogen or sulfonate (RSO 2 O—, CF 3 SO 2 O—, etc.);
- M is hydrogen, Li, Na, K, Cs or quaternary ammonium (R 4 N);
- X is hydroxy, halogen or acyloxy (RCOO—, ROCOO—, 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;
- P is a nitrogen-protecting group (Boc, Cbz, R 3 Si, etc.);
- m 0 to 5
- n 0 to 5.
- alkyl or “alk” (i.e., derivative forms of alkyl) refers to optionally substituted straight chain, branched or cyclic monovalent alkane (saturated hydrocarbon) derived radicals containing from 1 to 12 carbon atoms. When substituted, alkyl groups may be substituted with up to four substituent groups at any available point of attachment.
- alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
- the alkyl can be optionally substituted with one or more halogens or alkyl groups such as, for example, trifluoromethyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, etc.
- aryl refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like, containing from 6 to 30 carbon atoms.
- An aryl group can thus contain at least one ring having 6 atoms, with up to five such rings being present, containing up to 22 or 30 atoms therein, depending upon optionally alternating (resonating) double bonds between carbon atoms or suitable heteroatoms.
- aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, biphenyl and the like.
- acyl refers to the radical RCO—, taken alone or in combination, for example, with oxygen, nitrogen, sulfur, etc.
- halogen or “halo” refers to chlorine, bromine, fluorine or iodine, with bromine being the preferred halogen.
- heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein.
- heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl, etc.
- 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 T. W. Greene et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).
- salts of the biologically active compounds which do not significantly or adversely affect the pharmaceutical properties of the compounds such as, for example, toxicity, efficacy, etc. and include those salts which are conventionally employed in the pharmaceutical industry. Suitable examples of salts include, but are not limited to, those formed with inorganic or organic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc. Also included, particularly for the intermediate compounds of the invention, are salts which are unsuitable for pharmaceutical utility but which can be employed otherwise, for example, for isolation or purification of free active compounds or their pharmaceutically acceptable salts.
- 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 employed in the processes of the invention embraces all possible stereoisomers and their mixtures.
- the definition further embraces the 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.
- solvates e.g., hydrates
- Methods of salvation are generally known in the art. Therefore, the compounds useful in the processes of this invention may be in the free or hydrate form.
- 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′).
- step (b) 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 HCl, HBr, H[, H 2 SO 4 , H 3 PO 4 , etc., with HCl preferred.
- Suitable solvent(s) in reaction (b′) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as ethanol preferred.
- the ⁇ -amino ketone product may be isolated as the salt or free base forms.
- step (c) reacting (acylating) the ⁇ -amino ketone IV or its acid salt obtained in step (b) or (b′) 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) 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' 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) 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) 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) 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) 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 I (where R 7 is hydrogen).
- 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.
- the present invention further includes two novel key intermediate compounds of formulae III′ and IX which have been produced from the new processes to synthesize 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I.
- HPLC R.T. 0.17 min (Phenomenex Inc., 5 ⁇ m C18 column 4.6 ⁇ 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
- ⁇ -Azido-pinacolone (128.5 g, 0.911 mol) was combined in 4.2 L of methanol with 77.1 mL of concentrated HCl and 15.42 g of 10% Pd/C. The reaction mixture was stirred under hydrogen for 1.5 hours. The catalyst was removed by filtration. The solvent was distilled to give a wet solid. The residual water was azeotropically removed with isopropanol (2 ⁇ 500 mL). Tert-butyl methyl ether (300 mL) was added and the resulting slurry was stirred, filtered, washed with t-butyl methyl ether (3 ⁇ 100 mL) and dried to give 131.0 g (95.5%) of the title compound.
- Example 4 The title compound of Example 4 (130.96 g, 0.8637 mol, 1 eq) was dissolved in 3.025 L of CH 2 Cl 2 under N 2 at ⁇ 5° C. Triethylamine (301 mL, 2.16 mol, 2.5 eq) was added, followed by chloroacetyl chloride (75.7 mL, 0.450 mol, 1.1 eq) in 175 mL of CH 2 Cl 2 . The resulting slurry was stirred at ⁇ 5 to ⁇ 10° C. for 2 hours. Water (1.575 L) was added, followed by 175 mL of concentrated HCl.
- Example 5 the title compound of Example 5 (10.0 g, 52.17 mmol, 1 eq.) in 50 mL of tetrahydrofuran (THF) was combined with (methoxycarbonylsulfamyl)-triethylammonium hydroxide (Burgess' reagent, 105.70 mmol, 2.03 eq., generated in situ from 9.2 mL of chlorosulfonyl isocyanate, 4.4 mL of methanol and 14.8 mL of triethylamine in 100 mL THF). The reaction was heated to 45° C. for 1.5 hours. After cooling to room temperature, the reaction was quenched with water (50 mL).
- THF tetrahydrofuran
- Example 7 The title compound of Example 7 (1.25 g, 5 mmol, 1 eq) was added to a mixture of NaOH (3.0 g, 75 mmol, 15 eq), water (10 mL), toluene (10 mL) and tetrabutylammonium sulfate (50 mg, 0.086 mmol, 0.017 eq).
- 5-Bromo-2-aminothiazole hydrobromide (1.70 g, 5 mmol, 1 eq) was added and the reaction was stirred at room temperature for 14.5 hours.
- Example 8 The title compound of Example 8 (9.6 g, 35.6 mmol) was dissolved in N,N-dimethylformamide (36 mL) and CH 2 Cl 2 (100 mL), to which was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 g, 72 mmol, 2 eq), N-t-butoxycarbonyl-azacycloalkanoic acid (12.6 g, 55 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (2 g, 16 mmol, 0.45 eq). The clear reaction mixture became cloudy as it was stirred at room temperature for 3.5 hours.
- Example 9 The title compound of Example 9 (16.6 g) was dissolved in 150 mL of CH 2 Cl 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 1N aqueous HCl to 7 g of this material in methanol.
Abstract
The present invention relates to new, efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole compounds of formula I
or a pharmaceutically acceptable salt thereof, wherein:
R is alkyl, aryl or heteroaryl;
R1, R2, R3, R4 and R5 are each independently hydrogen, alkyl, aryl or heteroaryl;
R6 and R7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
R8 is hydrogen, alkyl, aryl, heteroaryl, CONR9R10, COR11 or COOR12;
R9, R10, R11 and R12 are each independently hydrogen, alkyl or aryl;
m equals 0 to 5; and
n equals 0 to 5,
which are novel, potent inhibitors of cyclin dependent kinases (cdks). The present invention further concerns new key intermediate compounds, a quaternary ammonium salt of formula III′ and a 2-oxazolylalkyl derivative of formula IX.
Description
- This application is a continuation-in-part of (1) patent application Ser. No. 09/616,627, filed on Jul. 26, 2000 and (2) patent application Ser. No. 09/616,629, filed on Jul. 26, 2000, which are continuation-in-part applications of patent application Ser. No. 09/464,511, filed Dec. 15, 1999.
- Not Applicable
- Not Applicable
- 1. Field of the Invention
- The present invention concerns new processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
- 2. Description of the Related Art
-
- or a pharmaceutically acceptable salt thereof, wherein:
- R is alkyl, aryl or heteroaryl;
- R1, R2, R3, R4 and R5 are each independently hydrogen, alkyl, aryl or heteroaryl;
- R6 and R7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
- R8 is hydrogen, alkyl, aryl, heteroaryl, CONR9R10, COR11 or COOR12;
- R9, R10, R11 and R12 are each independently hydrogen, alkyl or aryl;
- m equals 0 to 5; and
- n equals 0 to 5,
- are novel, potent inhibitors of cyclin dependent kinases (cdks). They are useful in the therapy of proliferative diseases, for example, cancer, inflammation, autoimmune diseases such as arthritis, viral diseases, fungal diseases, chemotherapy-induced alopecia, neurodegenerative disorders such as Alzheimer's disease and cardiovascular disease. More specifically, the compounds of formula I are useful in the treatment of a variety of cancers such as bladder, breast, colon, kidney, liver and lung cancers.
- WO 9924416 and corresponding U.S. Pat. No. 6,040,321 describe the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I, by reacting 5-acetylthio-2-acetylaminothiazole with a base followed by trapping the thiolate with a 2-oxazolylalkyl halide. Hydrolysis of the resulting 5-(2-oxazolylalkylthio)-2-acetylaminothiazole compounds afforded the 5-(2-oxazolylalkylthio)-2-aminothiazole key intermediates. The requisite 2-oxazolylalkyl halides were prepared by (i) reaction of β-hydroxy amines with α-chloroacyl chlorides followed by oxidation of the resulting β-hydroxy-α -chloroamides and subsequent oxazole ring formation (K. S. Kim et al., WO 9924416, May 20, 1999) or (ii) reaction of α-diazo ketones with α-chloronitriles (K. S. Kim et al, WO 9924416, May 20, 1999; T. Ibata et al.,Bull. Chem. Soc. Japan 1979, 52, 3597). Although a variety of 5-(2-oxazolylalkylthio)-2-aminothiazoles can be prepared by this method, this process is not amenable to large scale synthesis due to the commercial availability of the starting 5-acetylthio-2-acetylaminothiazole, the use of hazardous α-diazo ketones and expensive chromatographic separation of products.
- Reaction of α-halo ketones with azide to give α-azido ketones has been previously reported in the literature (A. Hassner et al.,Angew Chem. Int. Ed. Engl. 1986, 25, 478; M. G. Nair et al., J. Med. Chem. 1980, 23, 899; H.-J. Ha et al., Synth. Commun. 1994, 24, 2557). Reaction of α-sulfonyloxy ketones with azide to give α-azido ketones has also been previously reported (T. Patonay et al., J. Org. Chem. 1994, 59, 2902; G. A. Revelli et al, Synth. Commun. 1993, 23, 1111).
- Reduction of α-azido ketones to α-amino ketones has been described in the literature (H.-J. Ha et al.,Synth. Commun. 1994, 24, 2557; J. P. Sanchez et al., J. Heterocycl. Chem. 1988, 25, 469; S. K. Boyer et al., J. Org. Chem. 1985, 50, 3408). Reaction of α-amino ketones with α-halo acyl halides to give the corresponding amides has further been described (G. T. Newbold et al., J. Chem. Soc. 1948, 1855; G. T. Newbold et al., J. Chem. Soc. 1950, 909).
- Reaction of alkylthiouronium salts with alkyl halides to give sulfides has been previously reported (H. Chen et al.,Synth. Commun. 1990, 20, 3313). Reaction of alkylthiols with 5-bromo-2-aminothiazole to give 5-alkylthio-2-aminothiazoles has been reported (J. B. Dickey et al., J. Org. Chem. 1959, 24, 187).
- This invention concerns new efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles. The processes involve new strategies for the preparation of 2-oxazolylalkyl halides and 5-(2-oxazolylalkylthio)-2-aminothiazoles which include the method of making new key intermediate quaternary ammonium salts and 2-oxazolylalkyl sulfide derivatives. This invention further relates to processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
- Not Applicable
- The present invention relates to new, more efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles with application to the synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases. The process generally involves reaction of α-halo ketones II with an azide to give α-azido ketones III. Reduction of III with a reducing reagent gives α-amino ketones IV. From a practical standpoint, safety concerns make this reaction through the azide economically unfeasible.
- Alternatively and more advantageously, the α-amino ketones IV are prepared by reaction of α-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%, yet in a safer manner.
- Thereafter, reacting the α-amino ketones IV with an α-halo acyl halide V in the presence of a base or, alternatively, coupling the α-amino ketones IV with an α-halo acid, produces the corresponding amides VI. Then, ring closure of VI with a dehydrating reagent affords 2-oxazolylalkyl halides VII. When a conventional dehydrating reagent such as trihalophosphorus oxide like POCl3 is used, product isolation is difficult due to the formation of large amounts of hydrochloric and phosphoric acids. Thus, the process of the present invention preferably utilizes the Burgess' reagent which produces excellent yields and permits easy, safe product isolation from water.
- Subsequent treatment of 2-oxazolylalkyl halides VII with sulfur-containing reagent VIII or VIII′ affords new key intermediate compounds, 2-oxazolylalkyl sulfides IX. Coupling of IX with 5-halo-2-aminothiazole X gives 5-(2-oxazolylalkylthio)-2 -aminothiazoles XI. Coupling of XI with an azacycloalkanoic acid derivative XII affords thiazolyl amides XIII, which may be deprotected (in the case where P is a protecting group, e.g., Boc) to give 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles I, where R7 is hydrogen, inhibitors of cyclin dependent kinases.
-
- In formulas I-XIII of Scheme 1, the following terms apply:
- R is alkyl, aryl or heteroaryl;
- R1, R2, R3, R4 and R5 are each independently hydrogen, alkyl, aryl or heteroaryl;
- R6 and R7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
- R8 is hydrogen, alkyl, aryl, heteroaryl, CONR9R10, COR11 or COOR12;
- R9, R10, R11 and R12 are each independently hydrogen, alkyl or aryl;
- L is halogen or sulfonate (RSO2O—, CF3SO2O—, etc.);
- M is hydrogen, Li, Na, K, Cs or quaternary ammonium (R4N);
- X is hydroxy, halogen or acyloxy (RCOO—, ROCOO—, 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, NH2, N-alkyl, N-aryl or N-acyl;
- P is a nitrogen-protecting group (Boc, Cbz, R3Si, etc.);
- m equals 0 to 5; and
- n equals 0 to 5.
- Listed below are definitions of various terms used to describe the compounds involved in the processes of the present invention. These definitions apply to the terms as they are used throughout the specification (unless specifically indicated otherwise) either individually or as part of a larger group. It should be noted that any heteroatom with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences.
- The term “alkyl” or “alk” (i.e., derivative forms of alkyl) refers to optionally substituted straight chain, branched or cyclic monovalent alkane (saturated hydrocarbon) derived radicals containing from 1 to 12 carbon atoms. When substituted, alkyl groups may be substituted with up to four substituent groups at any available point of attachment. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The alkyl can be optionally substituted with one or more halogens or alkyl groups such as, for example, trifluoromethyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, etc.
- The term “aryl” or derivative forms thereof refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like, containing from 6 to 30 carbon atoms. An aryl group can thus contain at least one ring having 6 atoms, with up to five such rings being present, containing up to 22 or 30 atoms therein, depending upon optionally alternating (resonating) double bonds between carbon atoms or suitable heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, biphenyl and the like.
- The term “acyl” refers to the radical RCO—, taken alone or in combination, for example, with oxygen, nitrogen, sulfur, etc. The term “halogen” or “halo” refers to chlorine, bromine, fluorine or iodine, with bromine being the preferred halogen.
- The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Exemplary heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl, etc. The heteroaryl groups can be optionally substituted by one or more groups which include, but are not limited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS(O)m (where m=0, 1 or 2), thiol and the like.
- 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 T. W. Greene et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).
- The term “pharmaceutically acceptable salt” refers to those salts of the biologically active compounds which do not significantly or adversely affect the pharmaceutical properties of the compounds such as, for example, toxicity, efficacy, etc. and include those salts which are conventionally employed in the pharmaceutical industry. Suitable examples of salts include, but are not limited to, those formed with inorganic or organic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc. Also included, particularly for the intermediate compounds of the invention, are salts which are unsuitable for pharmaceutical utility but which can be employed otherwise, for example, for isolation or purification of free active compounds or their pharmaceutically acceptable salts.
- 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 employed in the processes of the invention embraces all possible stereoisomers and their mixtures. The definition further embraces the 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.
- It should be understood that solvates (e.g., hydrates) of the compounds of formula I and the intermediate compounds are also within the scope of the present invention. Methods of salvation are generally known in the art. Therefore, the compounds useful in the processes of this invention may be in the free or hydrate form.
- As set forth in Scheme 1, the processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs involve the following transformations:
- (a) reacting an α-substituted ketone II such as, for example, an α-halo ketone, with an azide in a suitable solvent or solvent mixtures to give an α-azido ketone III; or, more desirably, (a′) reacting an α-substituted ketone II like the α-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′.
- The α-halo ketone includes α-halo aliphatic and α-halo aromatic ketones. The preferred α-halo ketones are α-halo pinacolones with α-bromo pinacolone most preferred. A sulfonate, for example, RSO2O— (where R is alkyl, aryl or heteroaryl), CF3SO2O— and the like, may be substituted for the halogen in the α-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′).
- b) reacting the α-azido ketone III obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to give an α-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 α-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. Alternatively, the reduction reaction can be carried out in the presence of an acidic medium such as, for example, hydrochloric acid in ethanol to give α-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 HCl, HBr, H[, H2SO4, H3PO4, etc., with HCl preferred. Suitable solvent(s) in reaction (b′) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as ethanol preferred. The α-amino ketone product may be isolated as the salt or free base forms.
- (c) reacting (acylating) the α-amino ketone IV or its acid salt obtained in step (b) or (b′) with an α-substituted acyl derivative V such as, for example, an α-halo acyl halide, in the presence of a base and in a suitable solvent or solvent mixtures to give an amide VI.
- The α-halo acyl halide V includes α-alkyl or aryl substituted or unsubstituted α-halo acyl halide with the latter preferred. The most preferred α-halo acyl halide is α-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. Alternatively, the reaction can be carried out using an α-substituted acid instead of the α-substituted acyl derivative and then employing a coupling reagent such as a water-soluble diimide like carbodiimide, haloformate, thionyl halide, etc. In either reaction, a sulfonate, for example, RSO2O— (where R is an alkyl, aryl or heteroaryl), CF3SO2O— and the like, may be substituted for the halogen in the α-position of the α-halo acyl halide or the α-halo acid reactants which are illustrated.
- (d) 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.
- Advantageously, 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, e.g., concentrated sulfuric acid, polyphosphoric acid, etc. Although less conveniently, the dehydrating reagent, for instance, can be trihalophosphorus oxide such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a solvent like toluene.
- (e) 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.
- (f) 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.
- (g) 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.
- (h) 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 I (where R7 is hydrogen).
- The choice of the deprotecting reagent is based on the nature of the protecting group (P). For the Boc 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.
- The starting compounds of Scheme 1 are commercially available or may be prepared by methods known to one of ordinary skill in the art.
- To further illustrate Scheme 1, a process to make 5-(5-t-butyl-2-oxazolylmethylthio)-2-azacycloalkanoylaminothiazoles and analogs thereof, for example, starts with reaction of α-bromo pinacolone II (R=Bu-t, R1=H, L=Br) with sodium azide to give an α-azido pinacolone III (R=Bu-t, R1=H). Reduction of α-azido pinacolone III (R=Bu-t, R1=H) with a reducing reagent gives α-amino pinacolone IV (R=Bu-t, R1=H). Alternatively and more desirably, the α-amino pinacolone IV (R= Bu-t, R1=H) is prepared by reaction of α-bromo pinacolone II (R=Bu-t, R1=H, L=Br) with hexamethylenetetramine followed by hydrolysis of the resulting quaternary ammonium salt III′ (R=Bu-t, R1=H, L=Br). Coupling of α-amino pinacolone IV (R= Bu-t, R1=H) with an α-chloroacetyl chloride V (R2=R3=H, L=X=Cl) produces amide VI (R=Bu-t, R1=R2=R3=H, L=Cl). Ring closure of VI with a dehydrating reagent affords 5-t-butyl-2-oxazolylmethyl chloride VII (R=Bu-t, R1=R2=R3=H, L= Cl). Treatment of VII with sulfur-containing reagent VIII or VIII′ such as thiourea affords 5-t-butyl-2-oxazolylalkyl sulfide IX (R=Bu-t, R1=R2=R3=H, Y=NH, Z= NH2). Coupling of IX with 5-bromo-2-aminothiazole X (R4=R5=H, L=Br) gives 5-(5-t-butyl-2-oxazolylmethylthio)-2-aminothiazole XI (R=Bu-t, R=R2=R=R=R5=H). Coupling of XI with N-Boc azacycloalkanoic acid XII (X=OH, R6=R7=H, m=0, n= 2, P=Boc), affords thiazolyl amide XIII (R=Bu-t, R1=R2=R3=R4=R5=R6=R7= H, m=0, n=2, P=Boc), which after deprotection, gives rise to the desired 5-(5-t-butyl-2-oxazolylmethylthio)-2-azacycloalkanoylaminothiazole I (R=Bu-t, R1=R2=R3=R4= R5=R6=R7=R8=H, m=0, n=2), or an analog thereof.
- The present invention further includes two novel key intermediate compounds of formulae III′ and IX which have been produced from the new processes to synthesize 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I.
- The following examples demonstrate certain aspects of the present invention. However, it is to be understood that these examples are for illustration only and do not purport to be wholly definitive as to conditions and scope of this invention. It should be appreciated that when typical reaction conditions (e.g., temperature, reaction times, etc.) have been given, the conditions both above and below the specified ranges can also be used, though generally less conveniently. The examples are conducted at room temperature (about 23° C. to about 28° C.) and at atmospheric pressure. All parts and percents referred to herein are on a weight basis and all temperatures are expressed in degrees centigrade unless otherwise specified.
- A further understanding of the invention may be obtained from the non-limiting examples which follow below.
-
- α-Bromo-pinacolone (199.07 g, 1.1115 mol, 1 eq) was combined in 1.785 L of acetone with sodium azide (93.9 g, 1.4444 mol, 1.3 eq). The reaction was stirred at room temperature for 27.5 hours. The resulting slurry was filtered and washed with acetone (3× 150 mL). The filtrate was concentrated in vacuo to provide 154.3 g (98.4%) of the title compound. HPLC 83.85% at 2.57 minutes (Phenomenex Inc., Torrance, Calif., 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
-
- α-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 N2 at room temperature for 26 hours. The resulting slurry was filtered, the filter cake was washed with ether (3×50 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 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
-
- α-Azido-pinacolone (128.5 g, 0.911 mol) was combined in 4.2 L of methanol with 77.1 mL of concentrated HCl and 15.42 g of 10% Pd/C. The reaction mixture was stirred under hydrogen for 1.5 hours. The catalyst was removed by filtration. The solvent was distilled to give a wet solid. The residual water was azeotropically removed with isopropanol (2×500 mL). Tert-butyl methyl ether (300 mL) was added and the resulting slurry was stirred, filtered, washed with t-butyl methyl ether (3×100 mL) and dried to give 131.0 g (95.5%) of the title compound.
-
- α-Hexamethylenetetramino-pinacolone bromide (400 g, 1.254 mol, 1 eq) was combined in 2 L of ethanol with 12 N aqueous HCl (439 mL, 5.26 mol, 4.2 eq). The reaction was stirred at 75° C. for 1 hour and then allowed to cool to room temperature, the resulting slurry filtered, the filtrate concentrated in vacuo and isopropyl alcohol was added. The solution was filtered again. Addition of 1.2 L of ether caused the desired material to precipitate from solution. The material was filtered, washed with ether (2× 300 mL), and dried in vacuo at 50° C. overnight to provide 184.1 g (97%) of the title compound.
-
- The title compound of Example 4 (130.96 g, 0.8637 mol, 1 eq) was dissolved in 3.025 L of CH2Cl2 under N2 at −5° C. Triethylamine (301 mL, 2.16 mol, 2.5 eq) was added, followed by chloroacetyl chloride (75.7 mL, 0.450 mol, 1.1 eq) in 175 mL of CH2Cl2. The resulting slurry was stirred at −5 to −10° C. for 2 hours. Water (1.575 L) was added, followed by 175 mL of concentrated HCl. The organic phase was washed a second time with 1.75 L of 10% aqueous HCl, and then with 500 mL of water. The organic phase was dried over Na2SO4 and concentrated in vacuo to provide 155.26 g (93.8%) of the title compound. HPLC R.T.=2.27 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
-
- The title compound of Example 5 (180.13 g, 0.9398 mol, 1 eq) was combined with phosphorus oxychloride (262 mL, 2.8109 mol, 3 eq) under N2. The reaction was heated at 105° C. for 1 hour, the mixture was cooled to room temperature, and quenched with 1.3 kg of ice. The aqueous phase was extracted with ethyl acetate (1 L, then 2×500 mL). The organic extracts were washed with saturated aqueous NaHCO3 (4×1 L) which was back-extracted several times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaHCO3 (500 mL) followed by saturated aqueous NaCl (300 mL), dried over MgSO4, and concentrated in vacuo to give a brown oil. The crude material was distilled under high vacuum at 100° C. to provide 155.92 g (96%) of the title compound. HPLC R.T.=3.62 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
- Alternatively, the title compound of Example 5 (10.0 g, 52.17 mmol, 1 eq.) in 50 mL of tetrahydrofuran (THF) was combined with (methoxycarbonylsulfamyl)-triethylammonium hydroxide (Burgess' reagent, 105.70 mmol, 2.03 eq., generated in situ from 9.2 mL of chlorosulfonyl isocyanate, 4.4 mL of methanol and 14.8 mL of triethylamine in 100 mL THF). The reaction was heated to 45° C. for 1.5 hours. After cooling to room temperature, the reaction was quenched with water (50 mL). The organic layer was separated and washed with saturated NaHCO3 (2×50 mL) and water (50 mL), dried over MgSO4 and passed through a small silica gel plug. The solvent was removed to give an oil which was taken up in a mixture of 15 mL heptane and 90 mL of t-butyl methyl ether, and then washed with 0.2 N HCl (2×25 mL), saturated brine (25 mL) and dried (MgSO4). Filtration and removal of solvent gave 10.9 g of the title compound.
-
- The title compound of Example 6 (1.77 g, 10.2 mmol, 1.02 eq) was combined with thiourea (0.76 g, 9.98 mmol, 1 eq) under N2 in 10 mL of absolute ethanol. The reaction was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated in vacuo. Trituration of the resulting crude material with t-butyl methyl ether provided 2.32 g (93%) of the title compound. HPLC R.T.=2.05 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 mn); 1H NMR (d6-DMSO): δ 9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H), 1.24 (s, 9H).
-
- The title compound of Example 7 (1.25 g, 5 mmol, 1 eq) was added to a mixture of NaOH (3.0 g, 75 mmol, 15 eq), water (10 mL), toluene (10 mL) and tetrabutylammonium sulfate (50 mg, 0.086 mmol, 0.017 eq). 5-Bromo-2-aminothiazole hydrobromide (1.70 g, 5 mmol, 1 eq) was added and the reaction was stirred at room temperature for 14.5 hours. The mixture was diluted with water and extracted twice with ethyl acetate, the organic extracts washed with water (4×10 mL), dried over MgSO4 and concentrated in vacuo to provide 1.1 g (82%) of the title compound. HPLC 86.3% at 2.75 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); 1H NMR (CDCl3): δ6.97 (s, 1H), 6.59 (s, 1H), 5.40 (br s, 2H), 3.89 (s, 2H), 1.27 (s, 9H).
-
- The title compound of Example 8 (9.6 g, 35.6 mmol) was dissolved in N,N-dimethylformamide (36 mL) and CH2Cl2 (100 mL), to which was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 g, 72 mmol, 2 eq), N-t-butoxycarbonyl-azacycloalkanoic acid (12.6 g, 55 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (2 g, 16 mmol, 0.45 eq). The clear reaction mixture became cloudy as it was stirred at room temperature for 3.5 hours. Water (300 mL) and ethyl acetate (200 mL) were added and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the organic extracts dried over MgSO4 and concentrated in vacuo to provide a yellow solid which was combined with the precipitate obtained by filtration. The solid was boiled in a mixture of ethanol, acetone and water for 20 minutes, filtered, washed with an ethanol/water mixture and dried to give 16.6 g (97%) of the title compound.
-
- The title compound of Example 9 (16.6 g) was dissolved in 150 mL of CH2Cl2, 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 1N aqueous HCl to 7 g of this material in methanol. MS: 381 [M+H]+; HPLC: 100% at 3.12 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
- In the foregoing, there has been provided a detailed description of particular embodiments of the present invention for the purpose of illustration and not limitation. It is to be understood that all other modifications, ramifications and equivalents obvious to those having skill in the art based on this disclosure are intended to be included within the scope of the invention as claimed.
Claims (51)
or a pharmaceutically acceptable salt thereof, wherein:
R is alkyl, aryl or heteroaryl;
R1, R2, R3, R4 and R5 are each independently hydrogen, alkyl, aryl or heteroaryl;
R6 and R7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
R8 is hydrogen, alkyl, aryl, heteroaryl, CONR9R10, COR11 or COOR12;
R9, R10, R11 and R12 are each independently hydrogen, alkyl or aryl;
m equals 0 to 5; and
n equals 0 to 5;
R and R1 are as described hereinabove; and
L is halogen or sulfonate;
with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form a quaternary ammonium salt;
(b) reacting the quaternary ammonium salt with an acid in a suitable solvent or solvent mixture to form an α-amino ketone;
wherein:
R2, R3 and L are as described hereinabove; and
X is hydroxy, halogen or acyloxy;
in the presence of a base in a suitable solvent or solvent mixture to form an amide; or, alternatively, reacting the α-amino ketone with an α-substituted acid in the presence of a coupling reagent to form the corresponding amide;
(d) reacting the amide with a dehydrating reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl derivative;
(e) reacting the 2-oxazolylalkyl derivative with a sulfur-containing reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl sulfide compound;
(f) reacting the 2-oxazolylalkyl sulfide with a 5-halo-2-aminothiazole compound in the presence of a base in a suitable solvent or solvent mixture to give a 5-(2-oxazolylmethylthio)-2-aminothiazole compound;
(g) reacting the 5-(2-oxazolylmethylthio)-2-aminothiazole with an azacycloalkanoic acid derivative having the formula XII
wherein:
R6, R7 and X are as described hereinabove;
P is a nitrogen-protecting group;
m equals 0 to 5; and
n equals O to 5;
in the presence of a coupling reagent in a suitable solvent or solvent mixture to form a thiazolyl amide; and
(h) reacting the thiazolyl amide with a deprotecting reagent in a suitable solvent or solvent mixture to form the compound of formula I.
2. The process as recited in , wherein the α-substituted ketone in step (a) is an α-halo ketone.
claim 1
3. The process as recited in , wherein the α-halo ketone is an α-halo aliphatic ketone or an α-halo aromatic ketone.
claim 2
4. The process as recited in , wherein the α-halo ketone is an α-halo pinacolone.
claim 3
5. The process as recited in , wherein the α-halo pinacolone is α-bromo pinacolone.
claim 4
6. The process as recited in , wherein the solvent in step (a) is a hydrocarbon, an ether, an amide, a ketone or a mixture thereof.
claim 1
7. The process as recited in , wherein the solvent is the ketone and the ketone is acetone.
claim 6
8. The process as recited in , wherein the cyclic alkylenetetramine in step (a) is hexamethylenetetramine.
claim 1
9. The process as recited in , wherein the acid in step (b) is HCl, HBr, HI, H2SO4 or H3PO4.
claim 1
10. The process as recited in , wherein the acid is HCl.
claim 9
11. The process as recited in , wherein the solvent in step (b) is a hydrocarbon, an ether, an alcohol or a mixture thereof.
claim 1
12. The process as recited in , wherein the solvent is the alcohol and the alcohol is ethanol.
claim 11
13. The process as recited in , further comprising isolating the α-amino ketone product as the salt or free base form before performing step (c).
claim 1
14. The process as recited in , wherein the α-substituted acyl derivative in step (c) is an α-halo acyl halide.
claim 1
15. The process as recited in , wherein the α-halo acyl halide is α-chloroacetyl chloride.
claim 14
16. The process as recited in , wherein the base in step (c) is an aromatic organic amine or an aliphatic organic amine.
claim 1
17. The process as recited in , wherein the base is the aliphatic organic amine and the aliphatic organic amine is triethylamine.
claim 16
18. The process as recited in , wherein the α-substituted acid in step (c) is an α-halo acid halide and the coupling reagent is water-soluble.
claim 1
19. The process as recited in , wherein the coupling reagent is a carbodiimide, a haloformate or a thionyl halide.
claim 18
20. The process as recited in , wherein the dehydrating reagent in step (d) is an acid, an acid anhydride or a base.
claim 1
21. The process as recited in , wherein the dehydrating reagent in step (d) is concentrated sulfuric acid, polyphosphoric acid, trichlorophosphorus oxide, tribromophosphorus oxide or (methoxycarbonylsulfamoyl)triethylammonium hydroxide.
claim 1
22. The process as recited in , wherein the dehydrating reagent is (methoxycarbonylsulfamoyl)triethylammonium hydroxide.
claim 21
23. The process as recited in , wherein the solvent in step (d) is tetrahydrofuran.
claim 1
24. The process as recited in , wherein the dehydrating reagent in step (d) is (methoxycarbonylsulfamoyl)triethylammonium hydroxide and the solvent is tetrahydrofuran.
claim 1
25. The process as recited in , wherein the sulfur-containing reagent in step (e) is an N-substituted thiourea, an unsubstituted thiourea, a thio acid or a salt thereof, or a xanthic acid or a salt thereof.
claim 1
26. The process as recited in , wherein the sulfur-containing reagent is thiourea, thioacetic acid or the salt thereof, or ethylxanthic acid potassium salt.
claim 25
27. The process as recited in , wherein the 5-halo-2-aminothiazole compound in step (f) is 5-bromo-2-aminothiazole.
claim 1
28. The process as recited in , wherein the base in step (f) is a metal hydroxide, a metal alkoxide, a metal carbonate or an aqueous amine.
claim 1
29. The process as recited in , wherein the base is the metal hydroxide and the metal hydroxide is sodium hydroxide.
claim 28
30. The process as recited in , wherein the solvent in step (f) is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, an alcohol or a mixture thereof.
claim 1
31. The process as recited in , wherein the solvent is the halogenated hydrocarbon and the halogenated hydrocarbon is dichloromethane.
claim 30
32. The process as recited in , wherein the nitrogen-protecting group in step (g) is Boc or Cbz.
claim 1
33. The process as recited in , wherein the coupling reagent in step (g) is a carbodiimide, a haloformate or a thionyl halide.
claim 1
34. The process as recited in , wherein the coupling reagent is the carbodiimide and the carbodiimide is an alkylcarbodiimide.
claim 33
or a salt thereof, wherein:
R is alkyl;
R1 is hydrogen, alkyl, aryl or heteroaryl; and
L is halogen or a sulfonate;
wherein:
R, R1 and L are as described hereinabove;
with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form the compound of formula III′.
36. The process as recited in , wherein R is t-butyl.
claim 35
37. The process as recited in , wherein the cyclic alkylenetetramine is hexanethylenetetramine.
claim 35
or a salt thereof, wherein:
R is alkyl, aryl or heteroaryl;
R1, R2 and R3 are each independently hydrogen, alkyl, aryl or heteroaryl;
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, NH2, N-alkyl, N-aryl or N-acyl;
wherein:
R, R1, R2 and R3 are as described hereinabove; and
L is halogen or sulfonate;
with a sulfur-containing reagent in a suitable solvent or a solvent mixture to form the compound of formula IX.
39. The process as recited in , wherein the sulfur-containing reagent is an N-substituted thiourea, an unsubstituted thiourea, a thio acid or a salt thereof, or a xanthic acid or a salt thereof.
claim 38
40. The process as recited in , wherein the sulfur-containing reagent is thiourea, thioacetic acid or the salt thereof, or ethylxanthic acid potassium salt.
claim 39
41. The process as recited in , wherein the solvent is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, an alcohol or a mixture thereof.
claim 38
42. The process as recited in , wherein the solvent is the alcohol and the alcohol is methanol or ethanol.
claim 41
44. The compound as recited in , wherein R is t-butyl.
claim 43
45. The compound as recited in , wherein R1 is hydrogen.
claim 44
46. The compound as recited in , wherein L is halogen.
claim 45
47. The compound as recited in , α-hexamethylenetetramino-pinacolone bromide.
claim 46
or a salt thereof, wherein:
R is alkyl, aryl or heteroaryl;
R1, R2 and R3 are each independently hydrogen, alkyl, aryl or heteroaryl;
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, NH2, N-alkyl, N-aryl or N-acyl.
49. The compound as recited in , wherein R is t-butyl; Y is NH, N-alkyl, N-aryl or N-acyl and Z is NH2, N-alkyl, N-aryl or N-acyl.
claim 48
50. The compound as recited in , wherein the salt is hydrochloride.
claim 49
51. The compound as recited in , 5-(t-butyl)-2-oxazolylmethyl thiouronium hydrochloride.
claim 50
Priority Applications (63)
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US09/746,060 US6414156B2 (en) | 1998-10-21 | 2000-12-22 | Process for preparing azacycloalkanoylaminothiazoles |
US09/842,595 US6534531B2 (en) | 2000-04-27 | 2001-04-26 | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
BR0110396-2A BR0110396A (en) | 2000-04-27 | 2001-04-27 | Methods to prevent and treat chemotherapy or radiotherapy-induced alopecia |
AU2001255766A AU2001255766B2 (en) | 2000-04-27 | 2001-04-27 | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
PCT/US2001/013818 WO2001080813A2 (en) | 2000-04-27 | 2001-04-27 | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
EP01928966A EP1282419A2 (en) | 2000-04-27 | 2001-04-27 | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
CN01808658A CN1440284A (en) | 2000-04-27 | 2001-04-27 | Method for preventing and treating alopecia induced by chemotherapy or radiotherapy |
CA002407507A CA2407507A1 (en) | 2000-04-27 | 2001-04-27 | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
AU5576601A AU5576601A (en) | 2000-04-27 | 2001-04-27 | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
JP2001577914A JP2003531158A (en) | 2000-04-27 | 2001-04-27 | Methods for preventing and treating alopecia induced by chemotherapy or radiation therapy |
CNB018131786A CN1227250C (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoyl aminothiazoles |
CA002417260A CA2417260A1 (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles |
PT01932879T PT1303514E (en) | 2000-07-26 | 2001-05-02 | PROCESS FOR THE PREPARATION OF AZACICLOALCANOYLAMINOTIAZOLES |
HU0301649A HUP0301649A3 (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles |
CZ2003239A CZ2003239A3 (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoyl aminothiazoles |
EP01932879A EP1303514B9 (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles |
AT01932879T ATE299878T1 (en) | 2000-07-26 | 2001-05-02 | METHOD FOR PRODUCING AZACYCLOALKANOYLAMINOTHIAZOLES |
AU2001259369A AU2001259369B2 (en) | 1999-12-15 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles |
AU5936901A AU5936901A (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles |
PL01365464A PL365464A1 (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles |
PCT/US2001/014155 WO2002010163A1 (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles |
ES01932879T ES2245984T3 (en) | 2000-07-26 | 2001-05-02 | PROCEDURE TO PREPARE AZACICLOALCANOILAMINOTIAZOLES. |
DK01932879T DK1303514T3 (en) | 2000-07-26 | 2001-05-02 | Process for the preparation of azacycloalkanoylaminothiazoles |
BR0112748-9A BR0112748A (en) | 2000-07-26 | 2001-05-02 | Process for the preparation of azacycloalkanoyl aminothiazoles |
JP2002515892A JP2004505080A (en) | 2000-07-26 | 2001-05-02 | Method for producing azacycloalkanoylaminothiazole |
KR1020037001143A KR100764949B1 (en) | 2000-07-26 | 2001-05-02 | Process for Preparing Azacycloalkanoylaminothiazoles |
DE60112091T DE60112091T2 (en) | 2000-07-26 | 2001-05-02 | PROCESS FOR THE PREPARATION OF AZACYCLOALKANOYLAMINOTHIAZOLENE |
MXPA03000685A MXPA03000685A (en) | 2000-07-26 | 2001-05-02 | Process for preparing azacycloalkanoylaminothiazoles. |
IL15374801A IL153748A0 (en) | 2000-07-26 | 2001-05-02 | Processes for preparing azacycloalkanoylaminothiazole derivatives |
EEP200300041A EE200300041A (en) | 2000-07-26 | 2001-05-09 | N- [5 - [[[5-alkyl-2-oxazolyl] methyl] thio] -2-thiazolyl] carboxamide inhibitors of cyclin-dependent kinases |
YU4903A YU4903A (en) | 2000-07-26 | 2001-05-09 | N-/5-///5-alkyl-2-oxazolyl-methyl-thio/-2-thiazolyl/ carboxamide inhibitors of cyclin dependent kinases |
MXPA03000774A MXPA03000774A (en) | 2000-07-26 | 2001-05-09 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases. |
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 |
EP01933266A EP1303513A1 (en) | 2000-07-26 | 2001-05-09 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases |
KR10-2003-7001141A KR20030016429A (en) | 2000-07-26 | 2001-05-09 | N-[5-[[[5-Alkyl-2-Oxazolyl]Methyl]Thio]-2-Thiazolyl]Carboxamide Inhibitors of Cyclin Dependent Kinases |
GE5063A GEP20043367B (en) | 2000-07-26 | 2001-05-09 | N-[5-[[[5-Alkyl-2-Oxazolyl]Methyl]Thio]-2-Thiazolyl Carboxamide Inhibitors of Cyclin Dependent Kinases |
PL01365170A PL365170A1 (en) | 2000-07-26 | 2001-05-09 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases |
CNB018133673A CN100457753C (en) | 2000-07-26 | 2001-05-09 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases |
SI200120051A SI21099A (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 |
CA002417254A CA2417254A1 (en) | 2000-07-26 | 2001-05-09 | N-¢5-¢¢¢5-alkyl-2-oxazolyl!methyl!thio!-2-thiazolyl! carboxamide inhibitors of cyclin dependent kinases |
HU0303698A HUP0303698A2 (en) | 2000-07-26 | 2001-05-09 | N-[5-{[(5-alkyl-2-oxazolyl)-methyl]-thio}-2-thiazolyl]-carboxamide derivatives inhibitor of cyclin dependent kinase, their use and pharmaceutical compositions containing them |
CZ2003237A CZ2003237A3 (en) | 2000-07-26 | 2001-05-09 | N-(5-{[(5-Alkyl-2-oxazolyl)methyl]thio}-2-thiazolyl) carboxamides functioning as cyclin-dependent kinase inhibitors |
BR0112674-1A BR0112674A (en) | 2000-07-26 | 2001-05-09 | Cyclin-dependent kinases n- [5 - [[[5-alkyl-2-oxazolyl] methyl] thio] -2-thiazolyl] carboxamide inhibitors |
PCT/US2001/015081 WO2002010162A1 (en) | 2000-07-26 | 2001-05-09 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases |
SK1839-2002A SK18392002A3 (en) | 2000-07-26 | 2001-05-09 | N-(5-{[(5-alkyl-2-oxazolyl)methyl]thio]-2-thiazolyl} carboxamide inhibitors of cyclin dependent kinases |
JP2002515891A JP2004509857A (en) | 2000-07-26 | 2001-05-09 | N- [5-[[[5-alkyl-2-oxazolyl] methyl] thio] -2-thiazolyl] carboxamide inhibitors of cyclin-dependent kinases |
TW090111741A TWI302533B (en) | 2000-07-26 | 2001-05-16 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] caroboxamide inhibitors of cyclin dependent kinases |
MYPI20012414A MY129635A (en) | 2000-07-26 | 2001-05-22 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
EG20010550A EG24409A (en) | 2000-07-26 | 2001-05-23 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]carboxamide inhibitors of cyclin dependent kinases |
ARP010102516A AR030563A1 (en) | 2000-07-26 | 2001-05-24 | N- [5 - [[[5-ALQUIL-2-OXAZOLIL] METHYL] UNCLE] -2-TIAZOLIL] CARBOXAMIDS INHIBITING CYCLINE DEPENDENT KINASES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
PE2001000756A PE20030038A1 (en) | 2000-12-01 | 2001-07-26 | N- [5 - [[[5-ALKYL-2-OXAZOLYL] METHYL] THIO] -2-THIAZOLIL] CARBOXAMIDES INHIBITING CYCLINE-DEPENDENT KINASES |
US10/100,129 US6639074B2 (en) | 1999-12-15 | 2002-03-18 | Process for preparing azacycloalkanoylaminothiazoles |
IL153591A IL153591A (en) | 2000-07-26 | 2002-12-23 | N-[5-(((5-alkyl-2-oxazolyl) methyl)thio)-2-thiazolyl] carboxamide and pharmaceutical compositions containing the same |
IL153748A IL153748A (en) | 2000-07-26 | 2002-12-30 | Processes for preparing azacycloalkanoylaminothiazole derivatives |
LT2003001A LT5106B (en) | 2000-07-26 | 2003-01-07 | Nuo ciklinu priklausomu kinaziu n-[5-[[[5-alkil-2-oxazolil]metil]tio]-2-tiazolil]karboksamido inhibitoriai |
BG107468A BG65132B1 (en) | 2000-07-26 | 2003-01-16 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]carboxamide derivatives, pharmaceutical composition and use thereof as inhibitors of cyclin dependent kinases |
NO20030394A NO20030394L (en) | 2000-07-26 | 2003-01-24 | N- [5 - [[[5-alkyl-2-oxazolyl] methyl] thio] -2-thiazolyl] carboxamide inhibitors for cyclin-dependent kinases |
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LVP-03-24A LV13037B (en) | 2000-07-26 | 2003-02-26 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases |
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US10/639,272 US6897321B2 (en) | 1999-12-15 | 2003-08-12 | Process for preparing azacycloalkanoylaminothiazoles (LD 137e) |
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US09/176,239 US6040321A (en) | 1997-11-12 | 1998-10-21 | Aminothiazole inhibitors of cyclin dependent kinases |
US09/464,511 US6262096B1 (en) | 1997-11-12 | 1999-12-15 | Aminothiazole inhibitors of cyclin dependent kinases |
US61662700A | 2000-07-26 | 2000-07-26 | |
US09/616,629 US6214852B1 (en) | 1998-10-21 | 2000-07-26 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
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US09/727,957 Continuation-In-Part US6515004B1 (en) | 1999-12-15 | 2000-12-01 | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
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US10/100,129 Expired - Lifetime US6639074B2 (en) | 1999-12-15 | 2002-03-18 | Process for preparing azacycloalkanoylaminothiazoles |
US10/639,272 Expired - Lifetime US6897321B2 (en) | 1999-12-15 | 2003-08-12 | Process for preparing azacycloalkanoylaminothiazoles (LD 137e) |
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US (3) | US6414156B2 (en) |
EP (1) | EP1303514B9 (en) |
JP (1) | JP2004505080A (en) |
KR (1) | KR100764949B1 (en) |
CN (1) | CN1227250C (en) |
AT (1) | ATE299878T1 (en) |
AU (1) | AU5936901A (en) |
BR (1) | BR0112748A (en) |
CA (1) | CA2417260A1 (en) |
CY (1) | CY1105666T1 (en) |
CZ (1) | CZ2003239A3 (en) |
DE (1) | DE60112091T2 (en) |
DK (1) | DK1303514T3 (en) |
ES (1) | ES2245984T3 (en) |
HK (1) | HK1052928A1 (en) |
HU (1) | HUP0301649A3 (en) |
IL (2) | IL153748A0 (en) |
LT (1) | LT5106B (en) |
MX (1) | MXPA03000685A (en) |
PL (1) | PL365464A1 (en) |
PT (1) | PT1303514E (en) |
WO (1) | WO2002010163A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2002010162A1 (en) * | 2000-07-26 | 2002-02-07 | Bristol-Myers Squibb Company | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases |
US6392053B2 (en) | 1999-12-15 | 2002-05-21 | Bristol-Myers Squibb Company | Process for preparing arylacetylaminothiazoles |
US6414156B2 (en) | 1998-10-21 | 2002-07-02 | Bristol-Myers Squibb Company | Process for preparing azacycloalkanoylaminothiazoles |
US6521759B2 (en) | 1999-12-15 | 2003-02-18 | Bristol-Myers Squibb Company | Aminothiazole inhibitors of cyclin dependent kinases |
US20040192952A1 (en) * | 2003-01-07 | 2004-09-30 | Wolfgang Ebenbeck | Process for preparing arylalkynes |
US20090093507A1 (en) * | 2007-09-10 | 2009-04-09 | Changgeng Qian | Cdk inhibitors containing a zinc binding moiety |
US8691820B2 (en) | 2008-12-23 | 2014-04-08 | Curis, Inc. | CDK inhibitors |
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US6534531B2 (en) * | 2000-04-27 | 2003-03-18 | Bristol-Myers Squibb Company | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
SG156650A1 (en) * | 2004-07-16 | 2009-11-26 | Sunesis Pharmaceuticals Inc | Thienopyrimidines useful as aurora kinase inhibitors |
EP2044066A2 (en) * | 2006-06-06 | 2009-04-08 | Bristol-Myers Squibb Company | Crystalline forms of n-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl] thio]-2-thiazolyl]-4-piperidinecarboxamide |
EP3384897A1 (en) * | 2017-04-03 | 2018-10-10 | Covestro Deutschland AG | Cosmetic compositions for hair with special carbodiimides |
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CA1201431A (en) | 1981-12-17 | 1986-03-04 | Daiei Tunemoto | .beta.-LACTAM COMPOUNDS, PROCESS FOR THE PREPARATION THEREOF AND INTERMEDIATE PRODUCTS FOR THE PREPARATION THEREOF |
NO831160L (en) | 1982-04-08 | 1983-10-10 | Erba Farmitalia | PREPARATION OF SUBSTITUTED PENEM DERIVATIVES |
JPS6339868A (en) | 1986-08-04 | 1988-02-20 | Otsuka Pharmaceut Factory Inc | Di (lower alkyl) phenol derivative |
TW205041B (en) | 1989-08-07 | 1993-05-01 | Fujisawa Pharmaceutical Co | |
DE4119756A1 (en) | 1991-06-15 | 1992-12-17 | Basf Ag | AMINOALKYL-SUBSTITUTED 5-MERCAPTOTHIAZOLE, THEIR PRODUCTION AND USE |
US5491157A (en) | 1993-05-10 | 1996-02-13 | Eastman Kodak Company | Method and composition for the prevention, control and amelioration of soilborne fungi and disease caused thereby |
IL112721A0 (en) | 1994-03-10 | 1995-05-26 | Zeneca Ltd | Azole derivatives |
JPH0859669A (en) | 1994-06-13 | 1996-03-05 | Takeda Chem Ind Ltd | Cephem compound, its production and antimicrobial agent |
JPH10510258A (en) | 1994-12-09 | 1998-10-06 | 藤沢薬品工業株式会社 | Cephem compounds and their pharmaceutical uses |
IL117620A0 (en) | 1995-03-27 | 1996-07-23 | Fujisawa Pharmaceutical Co | Heterocyclic compounds processes for the preparation thereof and pharmaceutical compositions containing the same |
AUPN801196A0 (en) | 1996-02-12 | 1996-03-07 | Fujisawa Pharmaceutical Co., Ltd. | New cephem compounds and pharmaceutical use thereof |
ES2267873T3 (en) | 1997-10-27 | 2007-03-16 | Agouron Pharmaceuticals, Inc. | DERIVATIVES OF 4-AMINOTIAZOL, ITS PREPARATION AND USE AS INHIBITORS OF CYCLINE DEPENDENT KINASES. |
US6262096B1 (en) | 1997-11-12 | 2001-07-17 | Bristol-Myers Squibb Company | Aminothiazole inhibitors of cyclin dependent kinases |
US6040321A (en) | 1997-11-12 | 2000-03-21 | Bristol-Myers Squibb Company | Aminothiazole inhibitors of cyclin dependent kinases |
US6214852B1 (en) | 1998-10-21 | 2001-04-10 | Bristol-Myers Squibb Company | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
US6414156B2 (en) | 1998-10-21 | 2002-07-02 | Bristol-Myers Squibb Company | Process for preparing azacycloalkanoylaminothiazoles |
GB9823871D0 (en) | 1998-10-30 | 1998-12-23 | Pharmacia & Upjohn Spa | 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents |
MY125768A (en) | 1999-12-15 | 2006-08-30 | Bristol Myers Squibb Co | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
US6534531B2 (en) | 2000-04-27 | 2003-03-18 | Bristol-Myers Squibb Company | Methods for preventing and treating alopecia induced by chemotherapy or radiotherapy |
MXPA03000774A (en) | 2000-07-26 | 2003-09-10 | Bristol Myers Squibb Co | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases. |
-
2000
- 2000-12-22 US US09/746,060 patent/US6414156B2/en not_active Expired - Lifetime
-
2001
- 2001-05-02 AT AT01932879T patent/ATE299878T1/en not_active IP Right Cessation
- 2001-05-02 CA CA002417260A patent/CA2417260A1/en not_active Abandoned
- 2001-05-02 BR BR0112748-9A patent/BR0112748A/en not_active Application Discontinuation
- 2001-05-02 EP EP01932879A patent/EP1303514B9/en not_active Expired - Lifetime
- 2001-05-02 ES ES01932879T patent/ES2245984T3/en not_active Expired - Lifetime
- 2001-05-02 DK DK01932879T patent/DK1303514T3/en active
- 2001-05-02 JP JP2002515892A patent/JP2004505080A/en not_active Withdrawn
- 2001-05-02 KR KR1020037001143A patent/KR100764949B1/en not_active IP Right Cessation
- 2001-05-02 IL IL15374801A patent/IL153748A0/en unknown
- 2001-05-02 CZ CZ2003239A patent/CZ2003239A3/en unknown
- 2001-05-02 AU AU5936901A patent/AU5936901A/en active Pending
- 2001-05-02 DE DE60112091T patent/DE60112091T2/en not_active Expired - Fee Related
- 2001-05-02 WO PCT/US2001/014155 patent/WO2002010163A1/en active IP Right Grant
- 2001-05-02 CN CNB018131786A patent/CN1227250C/en not_active Expired - Fee Related
- 2001-05-02 HU HU0301649A patent/HUP0301649A3/en unknown
- 2001-05-02 PL PL01365464A patent/PL365464A1/en not_active Application Discontinuation
- 2001-05-02 MX MXPA03000685A patent/MXPA03000685A/en active IP Right Grant
- 2001-05-02 PT PT01932879T patent/PT1303514E/en unknown
-
2002
- 2002-03-18 US US10/100,129 patent/US6639074B2/en not_active Expired - Lifetime
- 2002-12-30 IL IL153748A patent/IL153748A/en not_active IP Right Cessation
-
2003
- 2003-01-07 LT LT2003001A patent/LT5106B/en not_active IP Right Cessation
- 2003-05-13 HK HK03103394A patent/HK1052928A1/en not_active IP Right Cessation
- 2003-08-12 US US10/639,272 patent/US6897321B2/en not_active Expired - Lifetime
-
2005
- 2005-09-02 CY CY20051101065T patent/CY1105666T1/en unknown
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6414156B2 (en) | 1998-10-21 | 2002-07-02 | Bristol-Myers Squibb Company | Process for preparing azacycloalkanoylaminothiazoles |
US6392053B2 (en) | 1999-12-15 | 2002-05-21 | Bristol-Myers Squibb Company | Process for preparing arylacetylaminothiazoles |
US6521759B2 (en) | 1999-12-15 | 2003-02-18 | Bristol-Myers Squibb Company | Aminothiazole inhibitors of cyclin dependent kinases |
US6613911B2 (en) | 1999-12-15 | 2003-09-02 | Bristol-Myers Squibb Company | Process for preparing arylacetylaminothiazoles |
US6639074B2 (en) | 1999-12-15 | 2003-10-28 | Bristol Myers Squibb Company | Process for preparing azacycloalkanoylaminothiazoles |
WO2002010162A1 (en) * | 2000-07-26 | 2002-02-07 | Bristol-Myers Squibb Company | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases |
US20040192952A1 (en) * | 2003-01-07 | 2004-09-30 | Wolfgang Ebenbeck | Process for preparing arylalkynes |
US7312350B2 (en) | 2003-01-07 | 2007-12-25 | Lanxess Deutschland Gmbh | Process for preparing arylalkynes |
US20090093507A1 (en) * | 2007-09-10 | 2009-04-09 | Changgeng Qian | Cdk inhibitors containing a zinc binding moiety |
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 |
Also Published As
Publication number | Publication date |
---|---|
US6414156B2 (en) | 2002-07-02 |
US6639074B2 (en) | 2003-10-28 |
ES2245984T3 (en) | 2006-02-01 |
HUP0301649A3 (en) | 2008-04-28 |
HK1052928A1 (en) | 2003-10-03 |
IL153748A (en) | 2009-07-20 |
HUP0301649A2 (en) | 2003-12-29 |
CZ2003239A3 (en) | 2003-08-13 |
DE60112091T2 (en) | 2006-04-20 |
CN1227250C (en) | 2005-11-16 |
EP1303514B9 (en) | 2006-11-08 |
ATE299878T1 (en) | 2005-08-15 |
MXPA03000685A (en) | 2003-09-10 |
US20040063767A1 (en) | 2004-04-01 |
AU5936901A (en) | 2002-02-13 |
US6897321B2 (en) | 2005-05-24 |
JP2004505080A (en) | 2004-02-19 |
LT2003001A (en) | 2003-11-25 |
WO2002010163A1 (en) | 2002-02-07 |
EP1303514A1 (en) | 2003-04-23 |
BR0112748A (en) | 2003-09-09 |
PL365464A1 (en) | 2005-01-10 |
CA2417260A1 (en) | 2002-02-07 |
EP1303514B1 (en) | 2005-07-20 |
KR20030064736A (en) | 2003-08-02 |
CY1105666T1 (en) | 2010-12-22 |
DE60112091D1 (en) | 2005-08-25 |
DK1303514T3 (en) | 2005-10-10 |
PT1303514E (en) | 2005-11-30 |
CN1449395A (en) | 2003-10-15 |
IL153748A0 (en) | 2003-07-06 |
US20020099217A1 (en) | 2002-07-25 |
KR100764949B1 (en) | 2007-10-08 |
LT5106B (en) | 2004-02-25 |
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