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WO2009085040A1 - Inhibiteurs des protéines kinases - Google Patents

Inhibiteurs des protéines kinases Download PDF

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Publication number
WO2009085040A1
WO2009085040A1 PCT/US2007/088922 US2007088922W WO2009085040A1 WO 2009085040 A1 WO2009085040 A1 WO 2009085040A1 US 2007088922 W US2007088922 W US 2007088922W WO 2009085040 A1 WO2009085040 A1 WO 2009085040A1
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compound
alkyl
selenophene
heterocycloalkyl
methyl
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Inventor
Pao-Chiung Hong
Li-Jung Chen
Yann-Yu Lu
Tzu-Yun Lai
Huei-Yu Yang
Yi-Feng Kao
Kuei-Tai Lai
Young-Sun Lin
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DCB USA LLC
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DCB USA LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings

Definitions

  • protein kinases e.g., check-point kinase 1 (Chkl)
  • Chkl check-point kinase 1
  • protein kinases involved in cell-cycle regulation are potential therapeutic targets for treating hyperproliferative diseases.
  • This invention is based on the discovery that certain selenophene compounds inhibit Chkl kinase, and thus are effective in treating cancer.
  • this invention relates to selenophene compounds of formula (I):
  • each of X and Y is N or CR', in which R' is H, halo, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, OH, alkoxyl, aryloxyl, -C(O)R a , -NR b R c , -C(0)NR b R c , -(CH 2 ) n C(O)R a , -(CH 2 ) n NR b R c , or -(CH 2 ) n C(0)NR b R c , in which R a is H, OH, alkoxyl, or aryloxyl, each of R b and R c , independently, is H, alkyl, cycloalkyl, aryl, or heteroaryl, or R b and R c together with the N atom to which they
  • R 1 0 are attached are heterocycloalkyl, and n is 1, 2, 3, or 4; each of R and R , independently, is H, halo, alkyl, OH, alkoxyl, aryl, heteroaryl, CN, -NR al R bl , - NR al C(O)R bl , -C(O)R cl ,
  • R al and R bl independently, is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R and R bl together with the N atom or the N and C atoms or the N and S atoms to which they are attached are heterocycloalkyl
  • R cl is H, OH, alkoxyl, or aryloxyl
  • R dl is alkyl, aryl, or heteroaryl
  • each of R 3 , R 4 , and R 5 independently, is H, halo, alkyl, OH 7 alkoxyl, aryloxyl, -C(O)R a2 , or -C(O)NR b2 R c2 , in which R a2 is OH, alkoxy
  • selenophene compounds include those in which both of X and Y are CH.
  • R 1 is H and R 2 is phenyl optionally substituted with OH, alkoxyl, aryloxyl, or alkyl; or one of R 1 and R 2 is halo (e.g., fluoro) and the other is H.
  • Another subset of the selenophene compounds includes those in which at least one of X and Y is N.
  • R is H and R is phenyl optionally substituted with OH, alkoxyl, aryloxyl, or alkyl; or one of R 1 and R 2 is halo (e.g., fluoro) and the other is H.
  • both of X and Y can be CH;
  • R 1 can be H and R 2 can be phenyl optionally substituted with OH, alkoxyl, aryloxyl, or alkyl; one of R 1 and R 2 can be halo (e.g., fluoro) and the other can be H;
  • R 2 can be 4-hydroxyphenyl optionally substituted with OCH 3 or 4-methoxyphenyl optionally substituted with OCH 3 ;
  • each of R 3 , R 4 , and R 5 independently, can be H, CH 3 , alkyl optionally substituted with OH or OCH 3 , -COOH, -CH 2 OCH 2 C(O)R 33 , -C(O)NH(CH 2 ) m NR b3 R c3 , or
  • R a3 can be H, OH, alkyl, alkoxyl, aryloxyl, or heterocycloalkyl
  • each of R b3 and R c3 independently, can be H, alkyl, cycloalkyl, aryl, or heteroaryl, or R b2 and R c2 together with the N atom to which they are attached can be heterocycloalkyl or heteroaryl
  • at least one of R 3 , R 4 , and R 5 can be H and at least one of the others can be -COOH or -
  • R 3 , R 4 , and R 5 can be H and at least one of the other of R 3 , R 4 , and R 5 can be -C(O)NR b2 R c2 in which R b2 and R c2 together with the N atom to which they are attached can be heterocycloalkyl.
  • alkyl herein refers to a straight or branched hydrocarbon containing 1-20 carbon atoms (e.g., Ci-Ci 0 ). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, and t-butyl.
  • alkoxyl refers to an -O-alkyl.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbon moiety containing 3-30 carbon atoms (e.g., C 3 -C 20 ), such as cyclohexyl or cyclohexen-3-yl.
  • heterocycloalkyl refers to a non-aromatic cyclic moiety having at least one ring heteroatom (e.g., N, O, or S) containing 1-30 carbon atoms (e.g., C 1 -C 2O ), such as 4-tetrahydropyranyl.
  • aryl refers to a hydrocarbon moiety having one or more aromatic rings. Examples of aryl moieties include phenyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl.
  • aryloxyl refers to an -O-aryl.
  • heteroaryl refers to a moiety having one or more aromatic rings that contain at least one heteroatom (e.g., N, O, or S).
  • heteroaryl moieties include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and indolyl.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • Alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, aryloxyl and heteroaryl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise.
  • Possible substituents on cycloalkyl, heterocycloalkyl, aryl, and heteroaryl include, but are not limited to, Ci-Ci 0 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 3 -C 20 cycloalkyl, Ci-C 20 heterocycloalkyl, Ci-C 10 alkoxyl, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, Ci-Ci 0 alkylamino, Ci-C 20 dialkylamino, arylamino, diarylamino, Ci-Ci 0 alkylsulfonamino, arylsulfonamino, Ci-Ci 0 al
  • this invention features a method for treating cancer, e.g., lung cancer, melanoma, hepatoma, leukemia, gastrointestinal stromal tumors, breast cancers, prostate cancers, renal cell carcinoma.
  • the method includes administering to a subject in need thereof an effective amount of one or more selenophene compounds of formula (I) shown above.
  • treating refers to administering one or more selenophene compounds to a subject, who has cancer, a symptom of such cancer, or a predisposition toward such cancer, with the purpose to confer a therapeutic effect, e.g., to cure, relieve, alter, affect, ameliorate, or prevent the above-described cancer, the symptom of it, or the predisposition toward it.
  • An effective amount refers to the amount of one or more active selenophene compounds which is required to confer a therapeutic effect on a treated subject.
  • this invention encompasses a pharmaceutical composition that contains an effective amount of at least one of the above-mentioned selenophene compounds and a pharmaceutically acceptable carrier.
  • the selenophene compounds described above include the compounds themselves, as well as their salts, prodrugs, and solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a selenophene compound.
  • Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a selenophene compound.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • the selenophene compounds also include those salts containing quaternary nitrogen atoms.
  • prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active selenophene compounds.
  • a solvate refers to a complex formed between an active selenophene compound and a pharmaceutically acceptable solvent.
  • pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
  • a pharmaceutical composition containing one or more of the above-described selenophene compounds for use in treating cancer, as well as this therapeutic use and use of the compounds for the manufacture of a medicament for treating cancer.
  • the selenophene compounds described above can be prepared by methods well known in the art, including the synthetic routes described below.
  • Scheme 1 shown below depicts an exemplary route for synthesizing selenophene compounds of this invention.
  • selenophene compound 3 is synthesized by coupling compound 1 (i.e., arylindolin-2-one) and compound 2 (i.e., selenophene-2-carbaldehyde) under basic conditions (e.g., piperidine/EtOH).
  • Scheme 2 shown below depicts an exemplary route for synthesizing compound 7 (i.e., arylindolin-2-ones) of this invention.
  • compound 7 i.e., arylindolin-2-ones
  • 2,5- dibromonitrobenzene 4 undergoes regioselective substitution with dimethyl malonate under basic conditions.
  • the resulting malonate 5 is coupled with a boronic acid derivative to form the nitroaromatic compound 6, which is then transformed into the arylindolin-2-one 7.
  • Scheme 3 shown below depicts two closely related routes for synthesizing compound 2 (selenophene-2-carbaldehydes).
  • a 2-substituted selenophene 8 is first reacted with dimethylformamide (DMF) in the presence of butylithium (BuLi) to form the selenophene-2-carbaldehyde 9.
  • DMF dimethylformamide
  • BuLi butylithium
  • Compound 9 is then converted into the selenophene-2-carbaldehyde 10, following a regioselective bromination, protection of the aldehyde, lithium-bromine exchange, and quenching with an electrophile (E + ).
  • E + electrophile
  • Compound 10 is further elaborated into required selenophene-2-carbaldehyde 11.
  • the selenophene 12 without substitution at the 2 position is first reacted with dimethylformamide (DMF) in the presence of butylithium (BuLi) to form the selenophene-2-carbaldehyde 13.
  • DMF dimethylformamide
  • BuLi butylithium
  • Compound 13 is then converted into the selenophene-2-carbaldehyde 14, following protection of the aldehyde, regioselective lithiation, and quenching with an electrophile (E + ).
  • E + electrophile
  • Compound 14 is further elaborated into required selenophene-2- carbaldehyde 15.
  • Examples 1-57 below provide detailed descriptions of the preparation of Compounds 1-57.
  • a selenophene compound synthesized above can be purified by a suitable method such as column chromatography, high-pressure liquid chromatography, or recrystallization.
  • selenophene compounds can be prepared using other suitable starting materials through the above synthetic routes and others known in the art.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the selenophene compounds.
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing applicable selenophene compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M.
  • the selenophene compounds mentioned herein may contain one or more asymmetric centers and a non-aromatic double bond. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- isomeric forms. All such isomeric forms are contemplated.
  • a pharmaceutical composition containing an effective amount of at least one of the selenophene compounds described above and a pharmaceutical acceptable carrier.
  • a pharmaceutical acceptable carrier is a carrier compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated.
  • One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active selenophene compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
  • this invention covers a method of administering an effective amount of one or more of the selenophene compounds to a patient having cancer.
  • An effective amount refers to the amount of an active selenophene compound that is required to confer a therapeutic effect on the treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • a composition having one or more selenophene compounds can be administered parenterally, orally, nasally, rectally, topically, or buccally.
  • parenteral refers to subcutaneous, intracutaneous, intravenous, intrmuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.
  • a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
  • fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, carboxymethyl cellulose, or similar dispersing agents.
  • Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
  • commonly used carriers include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • a nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation.
  • such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a composition having one or more active selenophene compounds can also be administered in the form of suppositories for rectal administration.
  • the selenophene compounds described above can be preliminarily screened for their efficacy in inhibiting Chkl kinase, VEGFR2, or PDGFR-Beta by an in vitro assay (See Example 58 below).
  • the anti-cancer efficacy of those kinase inhibitors can then be confirmed by animal experiments and clinic trials. Other methods will also be apparent to those of ordinary skill in the art.
  • aqueous phase was adjusted to pH 2 with 30 % HCl aqueous solution and then extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO 4 , filtered, and concentrated to provide 5-formylselenophene-
  • the reaction mixture was treated with excess solid carbon monoxide.
  • the solution was allowed to reach room temperature. After 1 h, the mixture was partitioned between 2N NaOH aqueous solution and diethyl ether.
  • the aqueous phase was adjusted to pH 2 with 30 % HCl aqueous solution and then extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over
  • Compound 5 was prepared in a manner similar to that described in Example 15.
  • Compound 7 was prepared in a manner similar to that described in Example 2.
  • Example 8 Preparation of Compound 8: (Z)-5-fluoro-3-((4-(4-(pyridin-2- yl)piperazine-l-carbonyl)selenophen-2-yl)methylene)indolin-2-one
  • Example 11 Preparation of Compound 11: (Z)-2-((5-((5-iluoro-2-oxoindolin-3- ylidene)methyl)selenophen-2-yl)methoxy)acetic acid
  • Compound 12 was prepared in a manner similar to that described in Example 2.
  • Example 14 Preparation of Compound 14: (Z)-2-((5-((5-fluoro-2-oxoindolin-3 ⁇ ylidene)methyl)selenophen-3-yl)methoxy)acetic acid
  • N-butyllithium (8.6 ml, 1.6 M in hexane) was added dropwise to a stirred solution of 2-(dimethoxymethyl)selenophene (2 g) in dry THF at -78 0 C under nitrogen. The mixture was cooled with ice-water and stirred for 1 h. After cooling at -78 0 C, the reaction mixture was treated with excessive DMF. The solution was allowed to reach room temperature. After 1 h, ethyl acetate was added, and the organic solution was washed with saturated aqueous ammonium chloride and brine, dried over MgSO 4 , and evaporated. The residue was purified by flash column chromatography to provide the 5-(dimethoxymethyl)selenophene-2-carbaldehyde (2 g, 90 %).
  • Compound 16 was prepared in a manner similar to that described in Example 14.
  • Example 17 Preparation of Compound 17: (Z)-N-(3-(lH-imidazol-l-yl)propyl)-5-((5- fluoro-2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxamide
  • Example 18 Preparation of Compound 18: (Z)-5-fluoro-3-((5-methylselenophen-2- yl)methylene)indolin-2-one A stirred solution of selenophene (7 mL) in 100 mL dry THF was cooled at
  • Compound 20 was prepared in a manner similar to that described in Example 2.
  • Example 21 Preparation of Compound 21: (Z)-5-((5-fluoro-2-oxoindolin-3- ylidene)methyl)-N-(2-hydroxyethyl)selenophene-3-carboxamide Compound 21 was prepared in a manner similar to that described in Example
  • Example 23 Preparation of Compound 23: (Z)-5-((5-fluoro-2-oxoindolin-3- ylidene)methyl)-2-methyl-N-(2-morpholinoethyl)selenophene-3-carboxamide Compound 23 was prepared in a manner similar to that described in Example
  • Example 25 Preparation of Compound 25: (Z)-6-bromo-3-(selenophen-2- ylmethylene)indolin-2-one Compound 25 was prepared in a manner similar to that described in Example
  • Example 26 Preparation of Compound 26: (Z)-5-((5-fluoro-2-oxoindolin-3- ylidene)methyl)-2-methyl-N-(2-(pyrrolidin-l-yl)ethyl)selenophene-3-carboxamide Compound 26 was prepared in a manner similar to that described in Example
  • Example 27 Preparation of Compound 27: (Z)-5-((6-fluoro-2-oxoindolin-3- ylidene)methyl)-2-methyl-N-(2-(pyrrolidin-l-yl)ethyl)selenophene-3-carboxamide Compound 27 was prepared in a manner similar to that described in Example
  • Example 28 Preparation of Compound 28: (Z)-5-((6-fluoro-2-oxoindolin-3- ylidene)methyl)-2-methylselenophene-3-carboxylic acid
  • Example 29 Preparation of Compound 29: (Z)-5-((6-(4-methoxyphenyl)-2- oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxylic acid Sodium hydride (60 %, 2.13 g) was added to a dry 100 mL flask under nitrogen. Anhydrous DMF (20 mL) was added, followed by dimethyl malonate (12 ml, 105 mmol). The reaction was heated briefly to 100 0 C with stirring, and then cooled to room temperature. 2,5-dibromonitrobenzene (5.04 g, 17.9 mmol) was added and the reaction was heated at 100 0 C for 3 hrs.
  • Pd(dppf) 2 Cl 2 -CH 2 Cl 2 (0.25 g) was added to a mixture of 4- methoxyphenylboronic acid ( 1.5 g ), dimethyl 2-(4-bromo-2-nitrophenyl)malonate (2 g) and 4 mL of 2M sodium carbonate solution in 8 mL of toluene and 8 mL of ethanol.
  • the mixture was refluxed for 24 h, concentrated, and the residue extracted with ethyl acetate.
  • the ethyl acetate layer was washed with water and brine, dried, and concentrated.
  • the residue was purified by flash column chromatography to give dimethyl 2-(4'-methoxy-3-nitrobiphenyl-4-yl)malonate (1.8 g) .
  • 6-(4-methoxyphenyl)indolin-2-one was then reacted with 5-formyl-2- methylselenophene-3-carboxylic acid as outlined in Scheme 1 to produce a mixture of Compound 29 and its olefin isomer, which was separated by column chromatography.
  • Compound 30 was prepared in a manner similar to that described in Example 29.
  • Compound 31 was prepared in a manner similar to that described in Example 29.
  • Example 32 Preparation of Compound 32: (Z)-5-((6-(2,4-dimethoxyphenyl)-2- oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxylic acid
  • Example 33 Preparation of Compound 33: (Z)-N-(2-(diethylamino)ethyl)-5-((6-(2,4- dimethoxyphenyl)-2-oxomdolin-3-ylidene)methyl)-2-methylselenophene-3- carboxamide
  • Compound 33 was prepared in a manner similar to that described in Example 29.
  • Example 34 Preparation of Compound 34: (Z)-N-(2-(diethylamino)ethyl)-5-((6-(4- hydroxyphenyl)-2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3- carboxamide BBr 3 (2 g) was added to the solution of dimethyl 2-(4'-methoxy-3- nitrobiphenyl-4-yl)malonate (1.64 g) in anhydrous dichloromethane (10 mL). The mixture was stirred for 3 h at room temperature. Water was added, and the organic solution was washed with brine, dried over MgSO 4 , and evaporated. The residue was purified by flash column chromatography to give dimethyl 2-(4'-hydroxy-3- nitrobiphenyl-4-yl)malonate as a pale yellow solid ( 1.5 g, 95 % ).
  • 6-(4-hydroxyphenyl)indolin-2-one was then reacted with 5-formyl-2- methylselenophene-3-carboxylic acid as outlined in Scheme 1 to produce a mixture of (Z)-5-((6-(4-Hydroxyphenyl)-2-oxoindolin-3-ylidene)methyl)-2-methylselenophene- 3-carboxylic acid and its olefin isomer, which was separated by column chromatography.
  • Triethylamine 28 mg
  • 2-(diethylamino)ethylamine 27 mg
  • hydroxybenzotriazole 42 mg
  • l-(3-dimethylaminopropyl)-3-ethylcarbodiimided hydrochloride 53 mg
  • (Z)-5-((6-(4-Hydroxyphenyl)-2- oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxylic acid 100 mg
  • the mixture was stirred for 18 h at room temperature.
  • Example 36 Preparation of Compound 36: (Z)-5-((6-(4-hydroxy-3-methoxyphenyi)- 2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxylic acid
  • Compound 36 was prepared in a manner similar to that described in Example 35.
  • Compound 37 was prepared in a manner similar to that described in Example 35.
  • Example 39 Preparation of Compound 39: (Z)-N-(2-(diethylamino)ethyl)-5-((6- fluoro-2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxamide.
  • Example 40 Preparation of Compound 40: l(Z)-5-((6-(4-hydroxy-3-methoxyphenyl)-
  • Example 41 Preparation of Compound 41: (Z)-5-((6-bromo-2-oxoindolin-3- y lidene)methyl)-2-methylselenophene-3 -carboxylic acid
  • Compound 41 was prepared in a manner similar to that described in Example 2.
  • Example 42 Preparation of Compound 42: (Z)-5-((6-(4-hydroxyphenyl)-2- oxoindolin-3-ylidene)methyl)-2-methyl-N-(2-(pyrrolidin-l-yl)ethyl)selenophene-3- carboxamide
  • Compound 42 was prepared in a manner similar to that described in Example 34.
  • Example 43 Preparation of Compound 43: (Z)-2-methyl-5-((2-oxo-6-(4- (trifluoromethyl)phenyl)indolin-3 -ylidene)methyl)selenophene -3 -carboxylic acid Compound 43 was prepared in a manner similar to that described in Example
  • Example 44 Preparation of Compound 44: (Z)-N-(2-(diethylamino)ethyl)-5-((6-(4- hydroxy-2-methoxyphenyl)-2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3- carboxamide
  • Compound 44 was prepared in a manner similar to that described in Example 35.
  • Compound 46 was prepared in a manner similar to that described in Example 35.
  • Example 47 Preparation of Compound 47: (Z)-6-(4-hydroxyphenyl)-3-(selenophen- 2-ylmethylene)indolin-2-one A reaction mixture of 5-formylselenophene (110 mg), 6-(4- hydroxyphenyl)indolin-2-one (150 mg), and piperidine (20 mg) in 5 inL of ethanol was heated at 90 0 C for 18 h and cooled to room temperature. Acetic acid (2 mL) was slowly added.
  • Example 48 Preparation of Compound 48: (Z)-5-((5-iodo-2-oxoindolin-3- ylidene)methyl)-2-methylselenophene-3 -carboxylic acid
  • Example 49 Preparation of Compound 49: (Z)-5-((5-chloro-2-oxoindolin-3- ylidene)methyl)-2-methylselenophene-3 -carboxylic acid
  • Example 50 Preparation of Compound 50: (Z)-2-methyl-5-((2-oxoindolin-3- ylidene)methyl)selenophene-3-carboxylic acid Compound 50 was prepared in a manner similar to that described in Example
  • Example 51 Preparation of Compound 51: (Z)-N-(3-(lH-imidazol-l-yl)propyl)-2- methyl-5-((2-oxoindolin-3-ylidene)methyl)selenophene-3-carboxamide
  • Example 52 Preparation of Compound 52: (Z)-N-(3-(lH-imidazol-l-yl)propyl)-5-((5- chloro-2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxamide
  • Example 53 Preparation of Compound 53: (Z)-N-(3-(lH-imidazol-l-yl)propyl)-5-((5- iodo-2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxamide
  • Compound 53 was prepared in a manner similar to that described in Example 2.
  • Example 54 Preparation of Compound 54: (Z)-5-((5-chloro-2-oxoindolin-3- ylidene)methyl)-N-(2-(diethylamino)ethyl)-2-methylselenophene-3-carboxamide
  • Example 56 Preparation of Compound 56: (Z)-5-((6-(4-hydroxyphenyl)-2- oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxylic acid Compound 56 was prepared in a manner similar to that described in Example
  • Example 57 Preparation of Compound 57: (Z)-5-((6-(4-hydroxy-2-methoxyphenyl)- 2-oxoindolin-3-ylidene)methyl)-2-methylselenophene-3-carboxylic acid
  • Example 58 Assay for kinase activities
  • kinase activities of Chkl, vascular endothelial growth factor receptor 2 (VEGFR2), and Platelet-derived growth factor receptor-Beta were determined as follows. In the presence or absence of a test compound, 10 ng of a purified catalytic subunit of Chkl, VEGFR2, or PDGFR-Beta were incubated with 5 ng of a phosphorylate substrate CHKtide KKKVSRS-GLYRSPSMPENLNRPR or poly(Glu:Tyr) (4:1) (Sigma), and radiolabeled ATP-P 33 (50 - 100 ⁇ M) in a reaction buffer (pH 7.0) containing 8 mM 3-(N-morpholino)propanesulfonic acid (MOPS) and 0.2 mM ethylenediaminetetraacetic acid (EDTA) at 30 0 C for 30 minutes.
  • a reaction buffer pH 7.0
  • MOPS 3-(N-morpholino)propanesulfonic acid
  • EDTA
  • Phorphoric acid (3%) was added to quench the reaction and the reaction mixture was poured through a Unifilter-96 GF/B filter plate (PerkinElmer). After extensive wash with distilled water, the filter plate was air dried and then placed in Scintillation Ready Safe Cocktail (Beckman). The radioactivity of the plate, indicating the level of kinase activity, was determined by a TopCount (PerkinElmer) microplate reader.
  • test compounds covered by formula (I) showed good inhibition activity against various kinases, e.g., Ca 2+ /Calmodulin-dependent kinase, Minibrain kinase/dual-specificity tyrosine phosphorylation-regulated kinase (Mnb/Dyrkla), MAP/microtubule affinity-regulating kinase 1(MARKl), 3-phosphoinositide-dependent protein kinase 1 (PDKl), PIMl, Protein Kinase D2 (PKD2), testis-specific serine kinase 2 (TSSK2), vascular endothelial growth factor receptor 1 (VEGFR-I), FMS-like tyrosine kinase-3 (FLT3), anaplastic lymphoma kinase (ALK), RET, and Nima-related kinase 2 (NEK2).
  • kinases e.g., Ca 2+ /Calmodulin-dependent kinas

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à des composés de sélénophène de formule (I) ci-dessous : les variables de la formule (I) sont définies dans les spécifications. Ces composés peuvent être utilisés pour traiter les cancers.
PCT/US2007/088922 2007-12-27 2007-12-27 Inhibiteurs des protéines kinases Ceased WO2009085040A1 (fr)

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WO2012066578A2 (fr) 2010-11-18 2012-05-24 Kasina Laila Innova Pharmaceuticals Private Limited Composés 4-(sélénophèn-2(ou 3)-ylamino)pyrimidines substitués et leurs procédés d'utilisation

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US6462063B1 (en) * 2000-02-04 2002-10-08 Fibrogen, Inc. C-proteinase inhibitors
US20030191309A1 (en) * 1999-02-25 2003-10-09 Wen-Bin Ho N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of C-proteinase and for treating or preventing disorders related to unregulated collagen production
US20040127491A1 (en) * 2002-11-11 2004-07-01 Dan Peters Novel diazabicyclic biaryl derivatives
US20050043541A1 (en) * 2002-01-22 2005-02-24 Francis Walter Metal complexes useful in metathesis and other reactions
US20050203077A1 (en) * 1996-06-03 2005-09-15 Ching-Jer Chang Selenophene anti-tumor agents
US20060040909A1 (en) * 2004-08-23 2006-02-23 Development Center For Biotechnology Selenophene compounds

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US20050203077A1 (en) * 1996-06-03 2005-09-15 Ching-Jer Chang Selenophene anti-tumor agents
US20030191309A1 (en) * 1999-02-25 2003-10-09 Wen-Bin Ho N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of C-proteinase and for treating or preventing disorders related to unregulated collagen production
US6462063B1 (en) * 2000-02-04 2002-10-08 Fibrogen, Inc. C-proteinase inhibitors
US20050043541A1 (en) * 2002-01-22 2005-02-24 Francis Walter Metal complexes useful in metathesis and other reactions
US20040127491A1 (en) * 2002-11-11 2004-07-01 Dan Peters Novel diazabicyclic biaryl derivatives
US20060040909A1 (en) * 2004-08-23 2006-02-23 Development Center For Biotechnology Selenophene compounds

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012066578A2 (fr) 2010-11-18 2012-05-24 Kasina Laila Innova Pharmaceuticals Private Limited Composés 4-(sélénophèn-2(ou 3)-ylamino)pyrimidines substitués et leurs procédés d'utilisation
CN103221048A (zh) * 2010-11-18 2013-07-24 卡斯纳莱拉创新药物私人有限公司 取代的4-(硒吩-2(或3)-基氨基)嘧啶化合物及其使用方法
JP2013542982A (ja) * 2010-11-18 2013-11-28 カシナ ライラ イノバ ファーマシューティカルズ プライベート リミテッド 置換４−（セレノフェン−２（または３）−イルアミノ）ピリミジン化合物およびその使用方法
EP2640392A4 (fr) * 2010-11-18 2014-03-12 Kasina Laila Innova Pharmaceuticals Private Ltd Composés 4-(sélénophèn-2(ou 3)-ylamino)pyrimidines substitués et leurs procédés d'utilisation
KR101817221B1 (ko) 2010-11-18 2018-01-10 카시나 라일라 이노바 파마슈티칼스 프라이빗 리미티드 치환된 4-(셀레노펜-2(또는 3)-일아미노)피리미딘 화합물 및 이의 사용방법

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