WO2000078314A1 - Process for making arylthiazolidinedione derivatives - Google Patents
Process for making arylthiazolidinedione derivatives Download PDFInfo
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- WO2000078314A1 WO2000078314A1 PCT/US2000/016716 US0016716W WO0078314A1 WO 2000078314 A1 WO2000078314 A1 WO 2000078314A1 US 0016716 W US0016716 W US 0016716W WO 0078314 A1 WO0078314 A1 WO 0078314A1
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- aryl
- heteroaryl
- alkyl
- compound
- optionally substituted
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the instant invention is concerned with processes for making arylthiazolidinediones and pharmaceutically acceptable salts thereof, which are useful as therapeutic compounds, particularly for the treatment of non-insulin dependent diabetes mellitus (NTDDM) and conditions that are associated with NIDDM.
- NTDDM non-insulin dependent diabetes mellitus
- Arylthiazolidinediones having structures of Formula I below have only recently been described in U.S. Patent No. 6,008,237. These compounds have activity as PPAR gamma and/or alpha agonists and are useful in the treatment, prevention and control of non-insulin dependent diabetes and various diseases and disorders that commonly accompany diabetes, such as obesity, atherosclerosis, and various lipid disorders, such as hyperlipidemia and hypercholesterolemia. Methods of synthesizing the compounds are described in the patent. These are suitable for laboratory scale synthesis. Improvements in these syntheses have now been made which are suitable for commercial scale production of the compounds.
- the instant invention discloses improved methods for making arylthiazolidinediones having structure I and methods for making pharmaceutically acceptable salts, including a synthesis of a particularly preferred compound, crystal forms of that compound, and its sodium salt.
- the sodium salt is also new.
- the present invention provides a process for making arylthiazolidinediones having the formula I:
- Arl is (1) arylene or
- Ar2 is (1) ortho-substituted aryl or (2) ortho-substituted heteroaryl, wherein said ortho substituent is selected from R; and aryl and heteroaryl are optionally further substituted with from 1-4 groups independently selected from R a ;
- X and Y are independently O, S, or N-Rb;
- n is 0 to 3;
- R is (1) C3-10 alkyl optionally substituted with 1-4 groups selected from halo and C3.6 cycloalkyl,
- R is (1) C1-15 alkanoyl
- heteroaryl wherein said alkyl, alkenyl, alkynyl, and alkanoyl are optionally substituted with from 1-5 groups selected from Re, and said aryl and heteroaryl optionally substituted with 1 to 5 groups selected from Rd;
- Rb is (1) hydrogen
- RC is (1) halo
- C3_8cycloalkyl wherein said cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 3 groups of halo or C ⁇ . alkyl; Rd is (1) a group selected from Re,
- aryl Ci-ioalkyl or (6) heteroaryl C ⁇ _ ⁇ o alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R e ;
- Re is (1) halogen,
- Rg represents an alkyl group having 1-15 carbon atoms, where Rg can be linear or branched, and can also be substituted with an aryl group, a cycloalkyl group, a heterocyclic group, or a heteroaryl group. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, benzyl, 2-phenethyl, and the like.
- Rg may also be a silane group, preferably a trialkylsilane, such as trimethylsilane, triethylsilane, tert-butyldimethylsilane, and so forth.
- the silane groups specifically listed above are all available in large scale quantities as their chlorides.
- Intermediate C may be prepared by convergent synthesis by first attaching the tether T having two terminal leaving groups to either Arl 0 r Ar2 (i.e. A_! or A2 to yield B . or B_2).
- L and L' represent independently of each other a conventional leaving group such as halide (for example bromide), sulfonyloxy (e.g.
- the two displacement steps are catalyzed by a base, preferably an inorganic base, such as CS2CO3, KOH, NaOH, K2CO3 ; potassium tert-butoxide, sodium tert-amylate, and other carbonates, hydroxides, and alkoxides of Li, Na, Cs, and K.
- the displacement reactions take place in a solvent, preferably a polar aprotic solvent, such as DMF, NMP, HMPA, DMSO, DMAc, and the like.
- the starting materials T, Al, and A2 are either commercially available or may be prepared using known organic synthesis procedures.
- Compounds of formula A2 may be prepared according to the methods described in published PCT Applications 97/27857, 97/28115 and 97/28137.
- leaving groups L and L' on T are different both in structure and in their ease of displacement, as for example Cl and Br.
- the more easily displaced group (Br in the case of Br and Cl) will be displaced preferentially to yield the product Bl or B2 in high yield, with a minimal amount of by-product having either two Al substituents or two A substituents.
- C_selectively is to use a tether precursor T_ in which L' is halo (e.g. bromo) or one of the other kinds of leaving groups described above, and L is hydroxy, or a protected hydroxy.
- L' is halo (e.g. bromo) or one of the other kinds of leaving groups described above, and L is hydroxy, or a protected hydroxy.
- the better leaving group is displaced first in a base catalyzed substitution with Al or A2, and then the hydroxy group L (after deprotection, if needed) is coupled to the aromatic phenol group of the other of Al or A2 by the well-known Mitsonobu coupling reaction.
- Mitsonobu coupling reaction See Organic Reactions, Vol. 42, pp. 377-656, John Wiley and Sons, New York, 1992. This route could also be carried out with the Mitsonobu coupling first and the substitution reaction second.
- Another alternate route uses the reaction of an allyl halide or other compound having an allylic leaving group with Al or A2 in the presence of a base to form an intermediate with an allyl group that will become the tether group.
- the terminal olefin of the allyl group is functionalized with a terminal leaving group for the second displacement reaction .
- the second leaving group can be introduced by several routes that are known to practitioners in the art, such as hydroboration followed by oxidation, which yields a terminal alcohol.
- the terminal alcohol can then be coupled to an aromatic phenol by a Mitsonobu reaction, or it can be subjected to a displacement reaction.
- alpha-halogenation of the arylacetate ester intermediate C with a halogenating agent e.g. chlorine, bromine, N-bromosuccinimide, N- chlorosuccinimide, dimethyl-N,N-dichlorohydantoin, dimethyl-N,N- dibromohydantoin, ⁇ -bromomalonates, ⁇ -chloromalonates, ⁇ -bromo or ⁇ -chloro- Meldrum's acid, carbon tetrachloride, carbon tetrabromide, hexachloroethane, pyridinium tribromide, N-bromoacetamide, and the like) in the presence of a base produces an alpha-halo intermediate which may be ring-closed with thiourea in the presence of an aqueous acid or a base (e.g.
- a halogenating agent e.g. chlorine, bromine, N-bromosuccinimide,
- ester intermediate C is first saponified to a salt of the free carboxylic acid, which in many cases is more easily purified.
- the carboxylic acid salt form of C (e.g.
- a lithium salt is water soluble, allowing impurities that are soluble in organic solvents that are not miscible with water to be separated from an aqueous solution of the salt.
- the salt can then be neutralized with acid and isolated as the carboxylic acid, which may be pure enough or may be suitable for recrystallization.
- the carboxylic acid can then be reacted with a base (for example ammonia, alkylamine, dialkylamine, or an alkali metal hydroxide or carbonate), to yield a salt (for example an ammonium, alkylammonium, dialkylammonium, or an alkali metal salt), which can be purified in accordance with its crystallinity and solubility characteristics.
- the salt or free acid is then halogenated in the position alpha to the carboxylic acid group to yield an alpha-halo carboxylic acid as the free acid or a salt, and this is subsequently cyclized in two steps to a thiazolidinedione.
- the halogenation reaction of the free acid is carried out with two equivalents of base and two equivalents of a silylating agent, such as TMSC1, TESC1, tert-butyldimethylchlorosilane, and the like.
- a silylketene acetal which is then halogenated by treatment with a halogenating agent, such as chlorine, bromine, N-bromosuccinimide, N- chlorosuccinimide, dimethyl-N,N-dichlorohydantoin, dimethyl-N,N- dibromohydantoin, ⁇ -bromomalonates, ⁇ -chloromalonates, ⁇ -bromo or ⁇ -chloro- Meldrum's acid, pyridinium tribromide, N-bromoacetamide, and the like. Cyclization is brought about by treatment of the alpha-halo acid with thiourea.
- a halogenating agent such as chlorine, bromine, N-bromosuccinimide, N- chlorosuccinimide, dimethyl-N,N-dichlorohydantoin, dimethyl-N,N- dibromohydantoin, ⁇ -bromomalonates
- Suitable acids include strong aqueous acids, such as HC1 or H2SO4, in an alcohol solvent, such as 2- methoxyethanol, propanol, and isopropanol, as well as other organic solvents, such as THF or DMF.
- alcohol solvents such as 2- methoxyethanol, propanol, and isopropanol, as well as other organic solvents, such as THF or DMF.
- Other alcohol solvents may also be used , such as any of the alkyl or branched alcohols up through the C15 alcohol.
- the hydroxyl groups can be on primary, secondary, or tertiary positions on the alkyl portion of the alcohol.
- the compounds prepared by the above process are acidic at the 3- position of the thiazolidinedione ring, and may be isolated as salts by reacting the compounds with a base.
- Pharmaceutically acceptable salts are those that are non- toxic, and they include salts of both organic and inorganic bases.
- Preferred salts include ammonium, sodium, potassium, calcium, and magnesium salts. These are all made by reacting the acid form of the compound with a solution of an alkali or alkaline earth hydroxide (about one equivalent, preferably concentrated), an alkoxide, ammonia, or an amine that yields a non-toxic salt to make a solution of the salt in water or a non-toxic organic solvent. The salt is then crystallized by cooling the solution and/or adding a miscible non-toxic liquid that is a poor solvent for the salt.
- Arl is arylene optionally substituted with 1-4 groups selected from R a .
- Arl j s phenylene optionally substituted with 1-2 groups selected from halogen and Ci-4 alkyl. More preferably Arl i s phenylene.
- X and Y are each O or S.
- X and Y are each O.
- R is C3-4alkyl optionally substituted with one to four groups selected from halo and C3_6cycloalkyl
- R a ' is selected from R a , or 2 Ra' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from N, O and S(O)m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra.
- R a ' is selected from ORb, aryl optionally substituted with 1 to 5 groups independently selected from Rd, and Ci-15 alkyl optionally substituted with 1 to 5 groups independently selected from R c .
- R a ' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 1-2 heteroatoms selected from N, O and S(O)m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra.
- Ra' is selected from O-phenyl in which phenyl is optionally substituted with 1 to 4 groups selected from Rd, phenyl which is optionally substituted with 1 to 2 halogens, and C1-.5 alkyl which is optionally substituted with 1 to 5 groups independently selected from halogen, phenyl, and C3-8cycloalkyl.
- R a ' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring selected from isoxazole, thiophene (S-oxide and S-dioxide), furan each of which is optionally substituted with 1 to 2 groups selected from R a .
- n is 1 or 2. The process is also applicable to a preferred embodiment of formula I comprising compounds of formula la:
- R a ' is selected from Ra, or 2 Ra' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from
- Another preferred embodiment that can be made by this method comprises compounds of formula la wherein Y is S or O, and X is O.
- Another preferred embodiment that can be made by this method comprises compounds of formula la wherein R is C3-4alkyl.
- Another preferred embodiment that can be made by this method comprises compounds of formula la wherein n is 1 or 2.
- R a ' is O-aryl optionally substituted with 1 to 3 groups independently selected from Rd, aryl optionally substituted with 1-3 groups selected from Rd, or Ci-5alkyl optionally substituted with 1-5 groups selected from R c , or 2 R a ' groups on adjacent carbon atoms taken together complete a 5- or 6- membered aromatic ring containing 0-2 heteroatoms selected from N, O and S(O) m
- X is O
- Y is (1) O or
- R is C3-4 alkyl
- Ra is (1) halogen or
- R a' is (1) O-aryl optionally substituted with 1 to 3 groups independently selected from Rd,
- Ci-5alkyl optionally substituted with 1-5 groups selected from Re, or
- R a' groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from N, O and S(O)m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra.
- Example 3 A highly preferred embodiment is the compound whose synthesis is described in Example 1 (below). The synthesis of the sodium salt is illustrated in Example 3.
- Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
- alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
- alkenyl means carbon chains which contain at least one carbon- carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
- Alkynyl means carbon chains which contain at least one carbon- carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
- Cycloalkyl means mono- or bicyclic saturated carbocyclic rings, each of which has from 3 to 10 carbon atoms. The term also includes a monocyclic ring fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
- Aryl (and “arylene”) means mono- or bicyclic aromatic rings containing only carbon ring atoms. The term also includes aryl groups fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point(s) of attachment is on the aromatic portion.
- Heterocyclyl means a fully or partially saturated ring containing at least one heteroatom selected from N, S and O, each of said rings having from 3 to 10 atoms.
- aryl examples include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, and the benzene rings of 2,3- dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like.
- Heteroaryl (and heteroarylene) means a mono-, bi- or tricyclic aromatic ring containing at least one ring heteroatom selected from N, O and S (including SO and SO2), with each ring containing 5 to 6 atoms.
- heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, dibenzofuran and the like.
- Halogen includes fluorine, chlorine, bromine and iodine.
- fluorine includes fluorine, chlorine, bromine and iodine.
- ortho-substituted means the substituent is attached to a ring atom that is adjacent to the point of attachment to the backbone of the molecule.
- composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- DSC differential scanning calorimetry
- DMAc N,N-dimethylacetamide
- DMF N,N-dimethylformamide
- DMSO dimethylsulfoxide
- IPA isopropyl alcohol
- IPAc isopropyl acetate
- LHMDS lithium hexamethyldisilazane
- HMPA hexamethylphosphoramide
- NBS N-bromosuccinimide
- NCS N-chlorosuccinimide
- NMP N-methylpyrollidinone
- TESC1 triethylchlorosilane
- TGA thermogravimetric analysis
- THF - tetrahydrofuran
- the two alkylation steps are carried out sequentially without purification.
- the product of these, ester 4 is saponified to yield the lithium salt of the carboxylic acid as part of a biphasic solution at the end of the reaction.
- the biphasic mixture is diluted with approximately equal volumes of 3% NaCl solution and methyl t-butyl ether.
- the lithium salt of compound 5 is in the organic layer.
- the organic phase is combined with water, which now results in the lithium salt dissolving in the aqueous phase.
- the aqueous phase is washed with MTBE, and the combined organic layers are discarded.
- the pH of the aqueous layer is adjusted to about 3.0, which results in the separation of acid 5 as a concentrated oil.
- the solvent for the organic phase is switched to heptane by adding heptane and distilling off the residual organic solvent.
- Carboxylic acid product 5 crystallizes out of solution.
- the carboxylic acid 5 is then brominated as shown in Scheme 3 by first adding slightly more than two equivalents of TMSCI and slightly more than two equivalents of strong base (LHMDS) in THF, which is believed to yield a silyl ketene acetal, and then adding a slight excess of NBS as a brominating agent.
- the reaction is quenched with 2M HCl, and the organic phase which contains Compound 6 is then treated with about 1 equivalent of thiourea in THF to yield imine 7 in solution.
- Imine 7 is diluted with isopropanol, and excess THF is then removed by distillation.
- Imine 7 is then hydrolyzed with 1M HCl in refluxing isopropanol to yield compound 8, which is 5-[3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenyl]-2,4-thiazolidinedione.
- the isopropanol solution of Compound 8 is diluted with isopropyl acetate (IP Ac) and cooled, resulting in phase separation into two liquid layers.
- IP Ac isopropyl acetate
- the organic phase, containing IP Ac, some isopropanol, and compound 8, is washed with brine and is then concentrated to remove isopropanol, yielding a solution of Compound 8 in IP Ac. Addition of heptane to the IP Ac solution of Compound 8 yields crystalline Compound 8.
- the x-ray powder diffraction pattern of this crystal form is shown in Figure 1 and Table 1.
- Recrystallization of this material from isopropanol affords a higher melting crystal form, as characterized by DSC, with an onset temperature of 113.6°C and a peak temperature of 115.4°C (112.5 J/g).
- the x-ray powder diffraction pattern of this crystal form is shown in Figure 2 and Table 2.
- the crystal form having the higher melting point (about 114°C) is the preferred crystal form of the material for pharmaceutical uses.
- the lower melting crystal form is a useful synthetic intermediate.
- EXAMPLE 2 An alternate method of isolating Compound 8 is to cool the isopropanol solution that results from hydrolysis of the imine 7. Compound 8 crystallizes out upon cooling of the isopropanol solution. It is washed with water when it is filtered.
- the product has the NMR spectrum characteristic of Compound 8 and the x-ray powder diffraction spectrum characteristic of the crystal form described above that has a melting point of about 114°C.
- DSC analysis of this product shows an endotherm having an onset at 102.97°C and a peak at 108.47°C (86.65 J/g).
- the melting point measured in a capillary is about 105°C - 110°C.
- the product that is isolated by this route is therefore the crystal form that has a melting point of about 114°C in Example 1.
- EXAMPLE 3 Sodium salt.
- the sodium salt of Compound 8 is made by adding sufficient 50 wt% sodium hydroxide solution (about 1 equivalent) to an isopropyl alcohol solution of Compound 8 at about 60°C to neutralize it. After cooling, the sodium salt crystallizes out.
- DSC analysis of the product shows two endotherms, one having a peak at 81.53°C (22.15 J/g, onset at 77.04°C) and a second having a peak at 229.26°C (38.74 J/g, onset at 222.20°C), the second endotherm being associated with decomposition.
- the product is crystalline and has the powder x-ray diffraction pattern shown in Table 3 and Figure 3.
- the product is referred to hereinafter as "salt form I.”
- Salt form II is converted to salt form I by heating salt form II to about 75°C as a dry powder.
- salt form II can be converted to salt form I by heating a slurry of the salt in isopropyl alcohol to the reflux temperature of isopropyl alcohol.
- the DSC of salt form ⁇ has four endotherms with peaks at 80.2°C (5.22 J/g, onset at 74.5°C); 85.4°C (15.3 J/g, onset at 82.5°C); 205.1°C (1.877 J/g, onset at 190.5°C); and 230.6°C (47.54 J/g, onset at 225.6°C).
- the x-ray powder diffraction pattern of salt form II is shown in Figure 4 and Table 4.
- Salt form I is the preferred salt form for pharmaceutical uses.
- Salt form II may be a useful synthetic intermediate for making salt form I.
- K-Alpha l wavelength (A): 1.54056 K-Alpha2 wavelength (A): 1.54439 K- Alpha2/K- Alpha 1 intensity ratio: 0.50000 K-AIpha wavelength (A): 1.54056 K-Beta wavelength (A): 1.39222
- Peak search parameter set As Measured Intensities Peak positions defined by: Minimum of 2 nd derivative Minimum peak tip width (°2Theta): 0.01 Minimum peak tip width (°2Theta): 1.00 Peak base width (°2Theta): 2.00 Minimum significance: 0.60 d-spacing Relative . Angle Peak Background Tip Significance
- Peak search parameter set: As Measured Intensities
- Diffractometer system 1 Generator settings: 45 kV, 40 mA Cu alpha 1.2 wavelengths: 1.54060, 1.54439 Ang Step size, sample time: 0.015 deg.0.20 s, 0.075 deg/s Monochrornator used: Yes Divergence slit Automatic (Irradiated sample length: 13.0 mm)
- Peak angle range 2.007 -40.002 deg Range in D spacing: 2.25207-43.9723 Ang Peak position criterion: Top of smoothed data
- Cryst peak width range 0.00 -2.00 deg
- Minimum peak significance 0.75
- Peak search parameter set As Measured Intensities Peak positions defined by: Minimum of 2" derivative Minimum peak tip width (°2Theta): 0.01 Minimum peak tip width (°2Theta): 1.00 Peak base width (°2Theta): 2.00 Minimum significance: 0.60 d-spacing Relative Angle Peak Background Tip Significance Intensity Height Width
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Abstract
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AU58769/00A AU5876900A (en) | 1999-06-18 | 2000-06-16 | Process for making arylthiazolidinedione derivatives |
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US13985399P | 1999-06-18 | 1999-06-18 | |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999032465A1 (en) * | 1997-12-19 | 1999-07-01 | Merck & Co., Inc. | Arylthiazolidinedione derivatives |
WO2000078313A1 (en) * | 1999-06-18 | 2000-12-28 | Merck & Co., Inc. | Arylthiazolidinedione and aryloxazolidinedione derivatives |
WO2000078312A1 (en) * | 1999-06-18 | 2000-12-28 | Merck & Co., Inc. | Arylthiazolidinedione and aryloxazolidinedione derivatives |
-
2000
- 2000-06-16 AU AU58769/00A patent/AU5876900A/en not_active Abandoned
- 2000-06-16 WO PCT/US2000/016716 patent/WO2000078314A1/en active Search and Examination
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1999032465A1 (en) * | 1997-12-19 | 1999-07-01 | Merck & Co., Inc. | Arylthiazolidinedione derivatives |
WO2000078313A1 (en) * | 1999-06-18 | 2000-12-28 | Merck & Co., Inc. | Arylthiazolidinedione and aryloxazolidinedione derivatives |
WO2000078312A1 (en) * | 1999-06-18 | 2000-12-28 | Merck & Co., Inc. | Arylthiazolidinedione and aryloxazolidinedione derivatives |
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