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WO2006023707A2 - Utilisation de 2-aminothiophenecarboxamides comme agents chimiotherapeutiques dans le traitement du cancer - Google Patents

Utilisation de 2-aminothiophenecarboxamides comme agents chimiotherapeutiques dans le traitement du cancer Download PDF

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Publication number
WO2006023707A2
WO2006023707A2 PCT/US2005/029508 US2005029508W WO2006023707A2 WO 2006023707 A2 WO2006023707 A2 WO 2006023707A2 US 2005029508 W US2005029508 W US 2005029508W WO 2006023707 A2 WO2006023707 A2 WO 2006023707A2
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amino
alkyl
formula
methyl
compound
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WO2006023707A3 (fr
Inventor
Catherine Brennan
Harold C.E. Kluender
Philip Wickens
Istvan J. Enyedy
Zhenqiu Hong
Benjamin Jones
Ellalahewage Sathyajith Kumarasinghe
Chih-Yuan Chuang
Barton Phillips
Julie Dixon
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Bayer Pharmaceuticals Corp
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Bayer Pharmaceuticals Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to novel 2-aminothiophenecarboxamide compounds, pharmaceutical compositions containing such compounds, and the use of those compounds or compositions as cancer chemotherapeutic agents.
  • retinopathies Many disease conditions are known to be associated with deregulated angiogenesis.
  • chronic inflammatory disorders including arthritis; arteriosclerosis; atherosclerosis; macular degeneration; and neoplastic diseases such as cancer.
  • arteriosclerosis including arthritis
  • atherosclerosis including atherosclerosis
  • macular degeneration including macular degeneration
  • neoplastic diseases such as cancer.
  • much work has been carried out to find inhibitors of angiogenesis, in hopes of developing treatments for such disorders.
  • WO 2004/063330 discloses (2-carboxamido)(3-amino)thiophene compounds for the treatment of cancer.
  • Published PCT application WO 02/066470 broadly discloses heterocycles containing amido and amino substituent groups, for prophylaxis and treatment of angiogenesis-mediated diseases.
  • Published PCT application WO 2004/005279 discloses certain substituted anthranilic amide derivatives for the prophylaxis and treatment of angiogenesis-mediated diseases.
  • Published PCT application WO 2004/007458 (Amgen) relates to substituted 2-alkylamine nicotinic amide derivatives and their uses in treatment of cancer and other disorders.
  • EP-B-832 061 discloses benzamide derivatives and their use as vasopressin antagonists.
  • the present invention relates to a compound of formula (I) or formula (II)
  • R 1 represents -Ci -4 alkyl, or halogen; and the subscript a, which represents the number of substituents R 1 , is 0, 1, or 2;
  • R represents -Ci- 4 alkyl, -Ci. 4 alkoxy, or halogen; and the subscript b, which represents the number of substituents R 2 , is 0, 1, or 2;
  • R 3 represents -C(O)NR 3" 1 R 3 1 ; -NR 3 2 R 3'2 ; -NHC(O)R 3"3 ; -C(O)OR 3"4 ; -CN; -halogen; or - C I -4 alkoxy; and the subscript d, which represents the number of substituents R " , is 0, 1, or 2;
  • substituents R 3"1 each independently represent hydrogen, -Ci -4 alkyl, -C 3-6 cycloalkyl, or hydroxy-Ci. 4 -alkyl;
  • substituents R 3"2 each independently represents hydrogen or -Ci -4 alkyl, wherein -C 1-4 alkyl can optionally be substituted with a substituent selected from the group consisting of hydroxy, -Ci- 4 alkoxy, carboxy, -Ci -4 alkoxycarbonyl, morpholinyl and N- methylpiperazinyl;
  • substituent R 3"3 represents hydrogen or -Ci -4 alkyl
  • substituent R 3"4 represents hydrogen or -Ci -4 alkyl
  • R 3 represents
  • X represents N or CH
  • the present invention relates to a compound of formula (1-1) or formula (IM),
  • R 3 represents -C(O)NR 3" 1 R 3"1 ; -NR 3 2 R 3"2 ; -NHC(O)R 3"3 ; or -C(O)OR 3"4 ; and the subscript d, which represents the number of substituents R 3 , is 1, or 2;
  • substituents R 3"1 each independently represent hydrogen, -Ci -4 alkyl, -C 3-6 cycloalkyl, or hydroxy-C i -4 -alkyl ;
  • substituents R 3"2 each independently represents hydrogen or -Ci -4 alkyl, wherein -Cj -4 alkyl can optionally be substituted with a substituent selected from the group consisting of hydroxy, -Ci -4 alkoxy, carboxy, -Ci -4 alkoxycarbonyl, morpholinyl and N- methylpiperazinyl ;
  • substituent R ,3- " 3 represents hydrogen or -Ci -4 alkyl
  • R represents
  • X represents N or CH
  • the present invention relates to a compound of formula (1-2) or formula (II-2), wherein
  • R J represents -C(O)NR 3 J - " l 1 D R3 J - " l 1 .; - XNTRD W 3-2RD 3 W -2.; or -NHC(O)R ,3"-3.
  • substituents R , 3- ' 1 each independently represent hydrogen, -Ci -4 alkyl, -C 3-6 cycloalkyl, or- hydroxy-Ci. 4 -alkyl;
  • substituents R 3"2 each independently represents hydrogen or -Ci -4 alkyl, wherein -Ci -4 alkyl can optionally be substituted with a substituent selected from the group consisting of hydroxy, -Ci -4 alkoxy, carboxy, -Ci -4 alkoxycarbonyl, morpholinyl and N- methylpiperazinyl ;
  • substituent R 3"3 represents -Ci -4 alkyl
  • R represents
  • compositions which comprise a compound of formula (I) or formula (II) as defined above plus a pharmaceutically acceptable carrier.
  • the invention relates to a method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or formula (II) as defined above.
  • Pharmaceutically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzo
  • Pharmaceutically acceptable salts of the compounds (I) also include salts of customary bases, such as for example and preferably alkali metal salts (for example sodium and potassium salts, alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as illustratively and preferably ethylamine, diethylamine, triethylamine, ethyldiiso- propylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethyl aminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.
  • alkali metal salts for example sodium and potassium salts, alkaline earth metal salts (for example calcium and magnesium salts)
  • Solvates for the purposes of the invention are those forms of the compounds that coordinate with solvent molecules to form a complex in the solid or liquid state. Hydrates are a specific form of solvates, where the coordination is with water.
  • halogen and halo mean fluoro, chloro, bromo and iodo, wherein fluoro, chloro, and bromo are preferred.
  • -Ci -4 alkyl means a linear or branched saturated carbon group having from 1 to 4 carbon atoms. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • -Ci -2 alkoxy and -Ci -4 alkoxy mean a linear or branched saturated carbon group having from 1 to 2, or from 1 to 4 carbon atoms, said carbon group being attached to an oxygen atom.
  • the oxygen atom is the point of attachment of the alkoxy substituent to the rest of the molecule.
  • Such groups include but are not limited to methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • hydroxy-Ci- 4 -alkyl means an -Ci -4 alkyl in which a hydrogen atom on any carbon atom in the group is replaced by a hydroxy group.
  • groups include but are not limited to hydroxymethyl, hydroxyethyl, and the like.
  • -C ] -4 alkyl-Ci. 2 alkoxy means an -Cj -4 alkyl in which a hydrogen atom on any carbon atom in the group is replaced by a -Ci -2 alkoxy group.
  • groups include but are not limited to methoxymethyl, ethoxymethyl, 2-methoxyethyl, 4-ethoxybutyl and the like.
  • a * symbol next to a bond denotes the point of attachment in the molecule.
  • R 3 is meant to be possible to attach at any carbon atom of the pyridine or pyrimidine ring of the cyclic structure, also at the carbon atom of CH if X represents CH, substituting the hydrogen atom; likewise R 2 is meant to be possible to attach at any carbon atom of the thiophene ring of the cyclic structure.
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration. It is intended that all possible stereoisomers (including enantiomers and diastereomers) are included within the scope of the present invention.
  • Preferred compounds are those with the absolute configuration of the compound of this invention which exhibits the more desirable biological activity.
  • Separated, pure or partially purified stereoisomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the separation of said stereoisomeric mixtures can be accomplished by standard techniques known in the art.
  • the present invention relates to a compound of formula (I) or formula (H), wherein
  • R 1 represents -Ci -4 alkyl, or halogen; and the subscript a, which represents the number of substituents R 1 , is 0, 1, or 2;
  • R 2 represents -C M alkyl, -Ci -4 alkoxy, or halogen; and the subscript b, which represents the number of substituents R 2 , is 0, 1, or 2;
  • R 3 represents -C(O)NR 3 1 R 3"1 ; -NR 3'2 R 3"2 ; -CN; -halogen; or -C,. 4 alkyl; and the subscript d, which represents the number of substituents R 3 , is 0, 1, or 2;
  • substituents R 3"1 each independently represent hydrogen, -Q -4 alkyl, -C 3-6 cycloalkyl, or
  • substituents R 3"2 each independently represents hydrogen or -C ]-4 alkyl
  • the present invention relates to a compound of formula (I- 1) or formula (II- 1), wherein
  • R represents methyl; and the subscript b, which represents the number of substituents R , is 0 or 1;
  • R 3 represents -C(O)NHCH 3 ; -C(O)NHCH 2 CH 3 ; -C(O)NHC 3 H 5 ; -NHCH 3 ; -CN; or chloro; and the subscript d, which represents the number of substituents R 3 , is O or 1;
  • Suitable for use as solvents for processes of this invention are the customary organic solvents which do not change under the reaction conditions and are able to dissolve the reactants of a given reaction.
  • the preferable solvent is a protic solvent which include alcohols, such as methanol, ethanol, propanol, isopropanol, or even water.
  • the preferable solvent is an inert aprotic solvent which include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or butyl methyl ether.
  • ketones such as acetone or butanone
  • amides such as dimethylformamide or hexamethylphosphoric triamide
  • Carboxylic acids such as acetic acid or propionic acid, or dimethyl sulphoxide, acetonitrile, ethyl acetate, or halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, or pyridine, picoline or N-methylpiperidine may be used. It is also possible to use mixtures of the solvents mentioned. It is well known to one skilled in the art that many reactions, such as the process for Example 1, Step 1 require the use of anhydrous solvents while some require only solvents of ordinary purity.
  • reaction temperatures can be varied within a relatively wide range.
  • the reactions are carried out between -78°C and +200 0 C, preferably between +20 0 C and +100 0 C, in particular at the boiling point of the solvent in question.
  • the reactions can be carried out under atmospheric pressure or else under elevated or reduced pressure. In general, the reactions are carried out under atmospheric pressure.
  • Most reaction processes of this invention were conducted under an inert atmosphere of dry nitrogen or argon.
  • inert atmosphere dry nitrogen or argon.
  • Step 1 of Example 1 it is well known to those skilled in the art that some processes, such as Step 1 of Example 1 are best done using such an inert gas, while others, such as Step 2 of Example 1 probably do not require use of an inert gas, however.
  • any ratio of the substances involved in the reaction may be used.
  • the reactants are used in molar amounts.
  • Isolation and purification of the substances according to the invention can be carried out by removing the solvent by distillation under reduced pressure and recrystallizing the residue, which may be obtained in crystalline form after cooling with ice, from a suitable solvent.
  • the chromatography is conducted using silica gel and a gradient from hexane to ethyl acetate or a gradient from methylene chloride to 10 % methanol.
  • reverse phase (RP) chromatography is used with C-18 bonded packing material and a solvent gradient from, for example, 10 % to 60 % acetonitrile in water.
  • Such preparative RP chromatography is usually done with an additive such as 0.05% TFA in the solvent to sharpen peak shape.
  • other modes of chromatography such as preparative TLC, ion exchange or Fluorosil can be used for normal phase chromatography.
  • Other bonded phases, for reverse phase chromatography can also be used to purify products.
  • Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide, lithium hydroxide or potassium hydroxide.
  • Alkali metal carbonate such as sodium carbonate or potassium carbonate, or alkali metal alkoxides, such as, for example, sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide can be used.
  • Organic amines such as triethylamine, picoline or N-methylpiperidine, or amides, such as sodium amide, lithium amide, lithium isopropylamide, or organometallic compounds, such as butyl lithium or phenyl lithium can also be used.
  • R 1 -R 3 , a, b and d have the same meanings as defined hereinabove.
  • the compounds of formula (I) and (II) are generally prepared starting from the compound of formula (III), where formula (III) means either formula (Ilia) or (HIb).
  • the compound of formula (III) compound is first converted to the aminoamide of formula (IX) by reaction with an aromatic amine of formula (VIII), and the appropriate coupling agent as described above.
  • the formula (IX) compound is then converted to the formula (I) or (II) compound using either the reductive amination method direct N-alkylation as described above for preparation of (VI).
  • the third route that is described in Reaction scheme 1 starts with the protection of the amino group of formula (III) to give a compound of formula (VII) using a reagent such as (BOC) 2 .
  • the formula (IX) compound is then converted to the formula (I) or (II) compound using either the reductive amination method direct N- alkylation as described above for preparation of (VI).
  • pg protecting group, e.g., BOC
  • Y, Ig leaving group, e.g., halo, MsO, etc.
  • R' lower alkyl
  • Y leaving group, e.g., halo, MsO
  • amino compound of Formula (Ia) can be converted to the amide compound of Formula (Ib) as shown in Reaction Scheme 8, by reaction with an acid chloride.
  • chloro compound of Formula (Ic) can be converted to the substituted amino compound of Formula (Id) by reaction with an amine and a base such as pyridine in a sealed tube at elevated temperatures.
  • a base such as pyridine
  • Esters of Formula (If) and substituted amides of Formula (Ig) may be prepared from the unsubstituted amide of Formula (Ie) by the sequence illustrated in Reaction Scheme 10. Reaction of the amide (Ie) with dimethylformamide-dimethylacetal in methanol provides the ester of Formula (If); reaction of the ester with a substituted amine gives the amide of Formula (Ig).
  • Amino pyrimi dines of Formula (2- Amino Ii, Im) (6- Amino Ij, In) and unsubstituted pyrimidines of Formula (Ik) may be prepared from the 2, 6-dichloro pyrimidine of Formula (Ih) by the sequence illustrated in Reaction Scheme 11. Reaction of the 2, 6-dichloro pyrimidine of Formula (Ih) with a substituted amine ((R 3"2 ) (R 3"2 ) NH) gives a mixture of aminochloro pyrimidines of Formula (Ii and Ij) which can be reduced using palladium hydroxide and ammonium formate, to give amino pyrimidines of Formula (Im and In). The starting material of Formula (Ih) can also be reduced using palladium hydroxide and ammonium formate to give the unsubstituted pyrimidine of Formula (Ik).
  • Diamino pyrimidines of Formula (Io and Ip) can be prepared from aminochloro pyrimidines of Formula (2-Amino Ii) (6-Amino Ij) by the sequence illustrated in Reaction Scheme 12. Treatment of the aminochloro pyrimidines of Formula (2-Amino Ii) (6- Amino Ij) ) with a substituted amine ((R 3"2 ) (R 3"2 ) NH) gives the diamino pyrimidines of Formula (Io and Ip).
  • the alkoxyamino pyrimidine of Formula (Iq) can be prepared from aminochloro pyrimidines of Formula (2 -Amino Ii) by the sequence illustrated in Reaction Scheme 13. Treatment of the aminochloro pyrimidines of Formula (2-Amino Ii) with a base such as LiOH and an alcohol such as ROH gives alkoxyamino pyrimidine of Formula (Iq).
  • a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.
  • a desired salt can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • protective groups on the compound of this invention may need to be protected and deprotected during any of the above methods.
  • Protecting groups in general may be added and removed by conventional methods well known in the art (see, for example, T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)).
  • Electron impact mass spectra were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 ⁇ M coating; 30 m x 0.25 mm). The ion source is maintained at 250 0 C and spectra were scanned from 50-800 amu at 2 sec per scan.
  • Step 1 Preparation of methyl 2-[(dimethylamino)carbonyl]isonicotinate
  • 2-Diniethylcarbamoyl-isonicotinic acid methyl ester 140.00 mg, 0.67 mmol was dissolved into 1,4-dioxane (1.16 mL). MeOH (0.18 niL) and water (0.01 mL) were then added and the solution was allowed to stir 15 minutes. The solution was then cooled to 0 °C and sodium borohydride ( 31.80 mg, 0.84 mmol) was added portion-wise over the course of 1 h. The mixture was allowed to stir for 16 h. The crude reaction mixture was then added directly to a Biotage® silica samplet cartridge and dried under vacuum for 3 h.
  • Step 3 Preparation of ⁇ 2-[(dimethylamino)carbonyl]pyridin-4-yl ⁇ methyl methanesulfonate
  • Step 1 Preparation of ethyl 2-(aminocarbonyl)isonicotinate
  • Step 1 Preparation of methyl 3-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate
  • Methyl 3-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate (32 g, 124.4 mmol) (step 1) was dissolved with methanol (140 mL) and sodium hydroxide was added (IN, 190 mL). The mixture was stirred at 50 0 C for 16 h. Some starting material was remaining by TLC and so additional sodium hydroxide was added (1.7N, 275 mL) and the mixture was stirred at 50 0 C for 2 h. The mixture was cooled to rt and acidified to pH 5 with HCl (IN). Solids were filtered out and combined with the solid remaining after extraction with EtOAc, drying with Na 2 SO 4 , and evaporation. The product was used without further purification.
  • Step 3 Preparation of tert-butyl (2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5-yl) amino]carbonyl ⁇ -3-thienyl)carbamate
  • step 2 3-[(Tert-butoxycarbonyl)amino]thiophene-2-carboxylic acid (7.3 g, 30.3 mmol) (step 2) was dissolved in DCM (155 niL), triethyl amine (12 mL), DMF (31 mL) and 2,2-difluoro- l,3-benzodioxol-5-amine (5 g, 29 mmol) was added. PyBOP (16.5 g, 32 mmol) was added and the mixture was stirred at 60 0 C for 16 h. The reaction mixture was cooled and diluted with water and EtOAc. The organic layer was washed with water, dried with Na 2 SO 4 , and evaporated. The crude residue was purified using silica gel chromatography to yield the desired product (7.7 g, 67 %).
  • Step 4 Preparation of 3-amino-N-(2,2-difluoro-l,3-benzodioxol-5-yl)thiophene-2- carboxamide
  • Example 1 4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl ⁇ -3- thienyl)amino]methyl ⁇ -N-methylpyridine-2-carboxamide
  • Step 1 Preparation of methyl 3-[( ⁇ 2-[(methylamino)carbonyl]pyridin-4- yl ⁇ methyl)amino]thiophene-2-carboxylate
  • Step 2 Preparation of 3-[( ⁇ 2-[(methylamino)carbonyl]pyridin-4-yl ⁇ methyl)amino] thiophene-2-carboxylic acid
  • Methyl 3-[( ⁇ 2-[(methylamino)carbonyl]pyridin-4-yl ⁇ methyl)amino]thiophene-2- carboxylate (100 mg, O.33mmol) was added to ethanol (1.5 mL) and heated to 60°C. The mixture was stirred for 15 min until all solids had dissolved into solution. Water was added (1.5 mL) followed by the addition of LiOH (41.23 mg, 0.98 mmol). The solution was allowed to stir for 6 h at 60 0 C until all of the starting material had been consumed. The crude reaction mixture was then concentrated to an oil and taken up in EtOAc. The organic was added to a separatory funnel and water was added.
  • Step 3 Preparation of 4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl ⁇ -3- thienyl)amino]methyl ⁇ -/V-methylpyridine-2-carboxamide
  • the mixture was neutralized with a IM solution of potassium dihydrogen phosphate.
  • the mixture was extracted with dichloromethane (3x, 15 mL). The organic fractions were combined, dried with sodium sulfate, and concentrated to an oil. The oil was purified via flash chromatography (35% EtOAc in Hex) to yield 21 mg (15%) of the final product as a white solid.
  • Example 2 The following compounds (Examples 2-4) were synthesized using the same synthetic method as Example 1 but with the specific starting materials mentioned below:
  • Step 1 Intermediate F was used in place of Intermediate A.
  • Step 1 Intermediate G was used in place of Intermediate A.
  • Step 1 methyl 4-aminothiophene-3-carboxylate was used in place of methyl 4- aminothiophene-3-carboxylate.
  • Step 1 Preparation of methyl 4-[(pyridin-4-ylmethyl)amino]thiophene-3-carboxylate
  • Step 3 Preparation of N-(2,2-difluoro-l,3-benzodioxol-5-yl)-4-[(pyridin-4- ylmethyl)amino]thiophene-3-carboxamide
  • Step 1 methyl 3-aminothiophene-2-carboxylate is used in place of methyl A- aminothiophene-3-carboxylate.
  • Step 1 methyl 3-amino-5-methylthiophene-2-carboxylate is used in place of methyl A- aminothiophene-3-carboxylate.
  • Step 1 methyl 3-amino-4-methylthiophene-2-carboxylate is used in place of methyl 4- aminothiophene-3-carboxylate.
  • Example 9-16 can be synthesized using the same synthetic route as in Example 1 but with the specific starting materials mentioned below:
  • Step 1 methyl 3-amino-4-methylthiophene-2-carboxylate is used in place of methyl 3- aminothiophene-2-carboxylate.
  • Step 1 methyl 3-amino-5-methylthiophene-2-carboxylate is used in place of methyl 3- aminothiophene-2-carboxylate.
  • Example 11 4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxoI-5-yl)amino]carbonyl ⁇ -3- thienyl)amino]methyI ⁇ -N,N-dimethylpyridine-2-carboxamide
  • Step 1 Intermediate E is used in place of Intermediate A.
  • Example 12 4- ⁇ [(4- ⁇ [(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl ⁇ -3- thienyl)amino]methyl ⁇ -N-ethylpyridine-2-carboxamide
  • Step 1 methyl 4-aminothiophene-3-carboxylate is used in place of methyl 3- aminothiophene-2-carboxylate and Intermediate F is used in place of Intermediate A.
  • Step 1 methyl 4-aminothiophene-3-carboxylate is used in place of methyl 3- aminothiophene-2-carboxylate and Intermediate G is used in place of Intermediate A.
  • Example 14 3- ⁇ [(2-cyanopyridin-4-yl)methyl]amino ⁇ -N-(2,2-difluoro-l,3- benzodioxol-5-yl)thiophene-2-carboxamide
  • Step 1 Intermediate B is used in place of Intermediate A.
  • Step 1 methyl 4-aminothiophene-3-carboxylate is used in place of methyl 3- aminothiophene-2-carboxylate and Intermediate B is used in place of Intermediate A.
  • Step 1 methyl 3-amino-4-methylthiophene-2-carboxylate is used in place of methyl 3- aminothiophene-2-carboxylate and (2-chloropyridin-4-yl)methyl methanesulfonate is used in place of Intermediate A.
  • (2-chloropyridin-4-yl)methyl methanesulfonate is generated from the commercially available starting (2-chloropyridin-4-yl)methanol and mesylating the alcohol using a procedure such as that for intermediate A.
  • Step 1 Preparation of 3- ⁇ [(2-chloropyridin-4-yl)methyl]amino ⁇ -N-(2,2-difluoro- 1,3- benzodioxol-5-yl)thiophene-2-carboxamide
  • Example 16 There are three steps used in the preparation of this compound that are similar to that of Example 16.
  • the first step of the procedure is the same as that of Example 16 except in step 1 methyl 3-aminothiophene-2-carboxylate can be used instead of methyl 3-amino-4- methylthiophene-2-carboxylate.
  • 3- ⁇ [(2-chloropyridin-4-yl)methyl]amino ⁇ -N-(2,2- difluoro-l,3-benzodioxol-5-yl)thiophene-2-carboxamide is made after the first 3 steps of Example 16.
  • Step 4 Preparation of N-(2,2-difluoro-l,3-benzodioxol-5-yl)-3-( ⁇ [2- (methylamino)pyridin-4-yl]methyl ⁇ amino)thiophene-2-carboxamide
  • Example 22 methyl 4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5-yl) amino]carbonyl ⁇ -3-thienyI)amino]methyl ⁇ pyridine-2-carboxylate
  • Example 23 4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl ⁇ -3- thienyl)amino]methyl ⁇ -N-(2-hydroxyethyl)pyridine-2-carboxamide
  • Step 1 Preparation of 3- ⁇ [(2-amino-6-chloropyrimidin-4-yl)methyl]amino ⁇ -N-(2,2- difluoro- 1 ,3-benzodioxol-5-yl)thiophene-2-carboxamide
  • Step 2 Preparation of 3- ⁇ [(2-aminopyrimidin-4-yl)methyl]amino ⁇ -N-(2,2-difluoro-l,3- benzodioxol-5-yl)thiophene-2-carboxamide
  • step 1 The crude product mixture from step 1 (250 mg, 0.568 mmol), which was a mixture of the two isomers was dissolved in methanol (2 mL) and EtOAc (5mL). Palladium hydroxide (50 mg, 0.356 mmol) and ammonium formate (358 mg, 5.68 mmol) was added. The mixture was refluxed for 10 h and then evaporated. The residue was purified by HPLC using 5-45% acetonitrile in water (0.1% TFA) as eluent to separate the desired isomer (100 mg, 32%, less polar) to the undesired isomer (more polar).
  • Example 27 3- ⁇ [(6-amino-2-chloropyrimidin-4-yl)methyl]amino ⁇ -N-(2,2-difluoro- l,3-be ⁇ zodioxol-5-yl)thiophene-2-carboxamide
  • the by-product of the preparation of Example 26 step 1 was the desired product shown above and was the lower Rf spot by TLC.
  • Example 28 3-[( ⁇ 6-amino-2-[(3-hydroxypropyl)amino]pyrimidin-4- yl ⁇ methyl)amino]-N-(2,2-difluoro-l,3-benzodioxol-5-yl)thiophene-2-carboxamide
  • Example 29 methyl 4-[(4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5- yl)amino]carbonyl ⁇ -3-thienyl)amino]methyl ⁇ -6-methoxypyrimidin-2- yl)amino]butanoate
  • Step 1 Preparation of ethyl 4-[(4-chloro-6- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol- 5-yl)amino]carbonyl ⁇ -3-thienyl)amino]methyl ⁇ pyrimidin-2-yl)amino]butanoate
  • Step 2 Preparation of methyl 4-[(4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5- yl)amino]carbonyl ⁇ -3-thienyl)amino]methyl ⁇ -6-methoxypyrimidin-2-yl)amino]butanoate
  • Step 1 Preparation of 3-( ⁇ [2-chloro-6-(methylamino)pyrimidin-4-yl]methyl ⁇ amino)- N-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)thiophene-2-carboxamide
  • Step 2 Preparation of N-(2,2-difluoro-l,3-benzodioxol-5-yl)-3-( ⁇ [6-(methylamino) pyrimidin-4-yl]methyl ⁇ amino)thiophene-2-carboxamide
  • step 1 3-( ⁇ [2-Chloro-6-(methylamino)pyrimidin-4-yl]methyl ⁇ amino)-N-(2,2-difluoro- 1 ,3- benzodioxol-5-yl)thiophene-2-carboxamide (80 mg, 0.176 mmol) (step 1) was dissolved in methanol (2 mL) and EtOAc (2mL). Palladium hydroxide (50 mg, 0.356 mmol) and ammonium formate (111 mg, 1.76 mmol) was added. The mixture was refluxed for 16 h, filtered through celite, and the filtrate evaporated. The residue was purified by HPLC using 5-45% acetonitrile in water (0.1% TFA) as eluent to give the desired product (46 mg, 62%).
  • Example 31 4- ⁇ [4- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl ⁇ -3- thienyl)amino]methyl ⁇ -6-(methylamino)pyrimidin-2-yl]amino ⁇ butan ⁇ ic acid
  • Example 34 4-[(2-chloro-6- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol- S-yOaminojcarbonylJ-S-thienyOaminolniethylJpyriinidin ⁇ -y ⁇ aininolbutanoic acid
  • Step 1 Preparation of ethyl 4-[(2-chloro-6- ⁇ [(2- ⁇ [(2,2-difluoro-l,3-benzodioxol- 5-yl)amino]carbonyl ⁇ -3-thienyl)amino]methyl ⁇ pyrimidin-4-yl)amino]butanoate
  • Step 2 Preparation of 4-[(2-chloro-6- ⁇ [(2- ⁇ [(2,2-difluoro-l ,3-benzodioxol- 5-yl)amino]carbonyl ⁇ -3-thienyl)amino]methyl ⁇ pyrimidin-4-yl)amino]butanoic acid
  • Example 35 3- ⁇ [2-Chloro-6-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]- amino ⁇ -thiophene-2-carboxylic acid (2,2-difluoro-benzo[l,3]dioxol-5-yI)-amide.
  • Example 36 3-[(6-Chloro-2- ⁇ 3-[4-(3-dimethylamino-propyl)-piperazin-l-yl]- propylamino ⁇ -pyrimidin-4-ylmethyl)-amino]-thiophene-2-carboxylic acid (2,2- difluoro-benzo[l,3]dioxol-5-yl)-amide.
  • a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.
  • a desired salt can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • sensitive or reactive groups on the compound of this invention may need to be protected and deprotected during any of the above methods.
  • Protecting groups in general may be added and removed by conventional methods well known in the art (see, for example, T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999).
  • the utility of the compounds of the present invention can be illustrated, for example, by their activity in the P-AKT/PKB Cytoblot Assay described below.
  • the involvement of the P-AKT/PKB [ PI3K/AKt] pathway as a target for cancer chemotherapy has been recognized in the art.
  • P. Chang et al Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy, Leukemia, 2003, 17: p. 590-603
  • K. A. West et al Activation of the PI3K/Akt pathway and chemotherapeutic resistance
  • P. Sen et al Involvement of the Akt/PKB signaling pathway with disease processes, Molecular and Cellular Biochemistry, 2003, 253: p. 241- 246.
  • H209 small cell lung carcinoma cells in log phase were plated at 50,000 cells/well in 96- well poly-lysine coated, clear bottom/ black-sided plates (Becton-Dickinson, USA Cat # 354640) in 100 ⁇ l RPMI medium containing 0.1% (w/v) BSA, and incubated overnight at 37 0 C in 5% CO 2 incubator. The following day, compounds (10 mM stock solutions in DMSO) were added to the plates to generate final concentrations of 0.0, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0 and 10 ⁇ M for IC 5O determinations and incubated for 1 hour at 37 0 C.
  • Cells were then left untreated or stimulated with Stem Cell Factor (SCF: Biosource Cat # PHC2116) at a final concentration of 25 ng/mL for 5 minutes at 37 0 C in 5% CO 2 incubator. The media was then removed using a vacuum manifold and the cells were washed once with Tris Buffered Saline (TBS). Cells were then fixed by adding 200 ⁇ l of cold 3.7% (v/v) formaldehyde in TBS to each well for 15 minutes at 4 0 C. After removal of the formaldehyde, the cells were treated with the addition of 50 ⁇ l of methanol (at - 20 0 C) to each well for 5 minutes. After removal of the methanol, 200 ⁇ l of 1% (w/v) BSA in TBS was added to each well to block non-specific antibody binding sites and the plate was incubated at room temperature for 30 minutes.
  • SCF Stem Cell Factor
  • p-(S473) AKT rabbit polyclonal antibody (Cell Signaling, USA Cat # 9277S) was added at a dilution of 1 :250 in 0.1% (w/v) BSA in TBS, and the plate was incubated at room temperature for 1 hour. Plates were then washed 3 times with cold TBS containing 0.05% (v/v) Tween 20 (TBS-T) and 100 ⁇ l of Horseradish peroxidase (HRP)-conjugated goat-anti-rabbit antibody (Amersham, USA Cat # NA934V) at a dilution of 1:250 in TBS-T was added and the plate was incubated at room temperature for Ih.
  • HRP Horseradish peroxidase
  • Enhanced Chemiluminescence (ECL) reagent (Amersham, USA Cat# RPN2209) was added to each well and mixed on a mini-orbital shaker for 1 min. The plate was then read on a Perkin Elmer Victor 5 Multilabel Counter (#1420-0421). Compounds of examples 1-5, 19-23, 25-28, 30, 35-36, were tested in the above P- AKT/PKB Cytoblot assay, with the result that these examples exhibited IC 50 values of less than or equal to 3 ⁇ M. In one embodiment, the present invention relates to a compound which exhibits an IC 50 value of less than or equal to 3 ⁇ M in this assay.
  • ECL Enhanced Chemiluminescence
  • MDA-MB-231 cells in log phase were plated at 25,000 cells/well in 96-well opaque plates (Falcon, USA Cat # 353296) in 100 ⁇ L RPMI medium containing 10% (w/v) FBS, and incubated overnight at 37 0 C in 5% CO 2 incubator. The following day, the growth medium was removed from the plate by aspiration and replaced with RPMI medium containing 0.1 % BSA and example compounds diluted to generate final concentrations of 0.0, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1 and 3 ⁇ M. Cells were incubated with compound for 1 hour at 37 0 C in a 5% CO 2 incubator.
  • the media was then removed from the plate by aspiration and the cells were washed once with 180 ⁇ L/well cold Tris Buffered Saline (TBS). After removal of the wash buffer, the cells were fixed by adding 180 ⁇ L of cold 3.7% (v/v) formaldehyde in TBS to each well for 1 hour at 4 0 C. After removal of the formaldehyde, the cells were treated with the addition of 60 ⁇ L of -2O 0 C methanol to each well for 5 minutes at 4 0 C. The methanol was removed and the cells were washed with 180 ⁇ L/well of 5% (w/v) BSA in TBS.
  • TBS Tris Buffered Saline
  • each well was treated with 180 ⁇ L/well 5% BSA (w/v) in TBS for thirty minutes at room temperature. After removal of the blocking buffer, 50 ⁇ L of an anti-phospho-p44/42 MAP kinase (Thr202/Tyr204) rabbit polyclonal antibody (Cell Signaling, USA Cat # 9101) was added to each well at a dilution of 1: 1000 in 5% (w/v) BSA in TBS, and the plate was incubated at 4 0 C overnight. Plates were then washed three times with 300 ⁇ L/well TBS at room temperature.
  • HRP Horseradish peroxidase
  • Amersham, USA Cat. # NA934V Horseradish peroxidase
  • ECL Enhanced Chemiluminescence
  • the present invention relates to a compound which exhibits an IC 50 value of less than or equal to 3 ⁇ M.
  • the utility of the compounds of the present invention can also be illustrated, for example, by their activity in the flk-1 (murine VEGFR2) Assay described below.
  • the VEGF- VEGFR2 signaling pathway has been extensively characterized as an important regulator of angiogenesis and tumor angiogeneisis (See G. Yancopoulos et al, Vascular-specific growth factors and blood vessel formation, Nature, 2000, 407: p.. 242- 248; D. Shweiki et al, Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency inmulticell spheroids: Implications for tumor angiogenesis, Proc. Natl. Acad. Sci, 1995, 92: p. 768-772).
  • VEGFR2 receptors inhibit the growth of a wide variety of tumors (See C. Bruns et al, Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal liver metastases, Cancer, 2000, 89: p. 495-499; B. Millauer et al, Glioblastoma growth inhibited in vivo by a dominant-negative FLK-I mutant, Nature, 1994, 367: p. 576-579).
  • Neutralizing antibodies to VEGF or VEGFR2 and VEGF antisense suppress tumor growth in vivo (See K.
  • This assay was performed in 96-well opaque plates (Costar, USA Cat #3915) in the TR- FRET format. Reaction conditions were as follows: 10 ⁇ M ATP, 25 nM poly (Glu,Tyr)- biotin (CIS BIO International, USA Cat#61 GTOBLD), 2 nM Eu-labelled phospho-Tyr Ab (Perkin Elmer, USA Cat#AD0067), 10 nM Strepavidin-APC (Perkin Elmer, USA Cat#CRl 30-100), 7 nM FIk-I (kinase domain), 1% DMSO, 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 0.1 mM EDTA, 0.015% BRU, 0.1 mg/niL BSA, 0.1% mercapto-ethanol.
  • Another embodiment of the present invention thus relates to a method of using the compounds described above, including salts thereof and corresponding compositions thereof, as cancer chemotherapeutic agents .
  • This method comprises administering to a patient an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to treat the patient's cancer.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular cancer.
  • Cancers include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with known anti-hyper-proliferative, chemotherapeutic, or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), such as cisplatin.
  • anti-hyper-proliferative agents suitable for use with this invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996) such as idarubicin.
  • the active compound can act systemically and/or locally. For this purpose it can be administered in a suitable manner, such as for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, ophtalmic or otic administration or in the form of an implant or stent.
  • the active compound can be administered in forms suitable for these modes of administration.
  • Suitable forms of oral administration are those according to the prior art which function by releasing the active compound rapidly and/or in a modified or controlled manner and which contain the active compound in a crystalline and/or amorphous and/or dissolved form, such as for example tablets (which are uncoated or coated, for example with enteric coatings or coatings which dissolve after a delay in time or insoluble coatings which control the release of the active compound), tablets or films/wafers which disintegrate rapidly in the oral cavity or films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, pellets, powders, emulsions, suspensions and solutions.
  • tablets which are uncoated or coated, for example with enteric coatings or coatings which dissolve after a delay in time or insoluble coatings which control the release of the active compound
  • tablets or films/wafers which disintegrate rapidly in the oral cavity or films/lyophilisates
  • capsules e.g. hard or soft gelatin capsules
  • Parenteral administration can be carried out by avoiding an absorption step (e.g. by intravenous, intraarterial, intracardial, intraspinal or intralumbar administration) or by including absorption (e.g. by intramuscular, subcutaneous, intracutaneous or intraperitoneal administration).
  • Suitable parenteral administration forms are for example injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • Suitable forms of administration for the other modes of administration are for example inhalation devices (such as for example powder inhalers, nebulizers), nasal drops, solutions and sprays; tablets or films/wafers for lingual, sublingual or buccal administration or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions or shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milky lotions, pastes, foams, dusting powders, implants or stents.
  • inhalation devices such as for example powder inhalers, nebulizers
  • nasal drops solutions and sprays
  • tablets or films/wafers for lingual, sublingual or buccal administration or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions or shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milky lotion
  • the active compounds can be converted into the abovementioned forms of administration in a manner known to the skilled man and in accordance with the prior art using inert, non ⁇ toxic, pharmaceutically suitable auxiliaries.
  • the latter include for example excipients (e.g. microcrystalline cellulose, lactose, mannitol, etc.), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulphate, polyoxysorbitan oleate etc.), binders (e.g. polyvinyl pyrrolidone), synthetic and/or natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, such as, for example, ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) or taste- and/or odour-corrective agents.
  • excipients e.g. microcrystalline cellulose, lactose, mannito
  • the total amount of the active ingredient to be administered will generally range from about 0.01 mg/kg to about 200 mg/kg, and preferably from about 0.1 mg/kg to about 20 mg/kg body weight per day.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with known anti-hyper-proliferative, chemo therapeutic, or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), such as cisplatin.
  • anti-hyper-proliferative agents suitable for use with this invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1 , 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen,
  • the mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.
  • a single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol and the active component is added to the suspension.
  • the water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.

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Abstract

Cette invention porte sur de nouveaux composés 2-aminothiophènecarboxamides, sur des compositions pharmaceutiques contenant ces composés et sur l'utilisation de ces composés ou compositions comme agents chimiothérapeutiques dans le traitement du cancer.
PCT/US2005/029508 2004-08-20 2005-08-19 Utilisation de 2-aminothiophenecarboxamides comme agents chimiotherapeutiques dans le traitement du cancer Ceased WO2006023707A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019068572A1 (fr) 2017-10-04 2019-04-11 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2019175046A1 (fr) 2018-03-12 2019-09-19 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2019201921A1 (fr) 2018-04-20 2019-10-24 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI299664B (en) * 2003-01-06 2008-08-11 Osi Pharm Inc (2-carboxamido)(3-amino)thiophene compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019068572A1 (fr) 2017-10-04 2019-04-11 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2019175046A1 (fr) 2018-03-12 2019-09-19 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2019201921A1 (fr) 2018-04-20 2019-10-24 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides

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