WO2004076446A1 - Derive de benzothiophene - Google Patents

Derive de benzothiophene Download PDF

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Publication number
WO2004076446A1
WO2004076446A1 PCT/JP2004/002427 JP2004002427W WO2004076446A1 WO 2004076446 A1 WO2004076446 A1 WO 2004076446A1 JP 2004002427 W JP2004002427 W JP 2004002427W WO 2004076446 A1 WO2004076446 A1 WO 2004076446A1
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WIPO (PCT)
Prior art keywords
methyl
amino
thiophene
benzo
acid
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PCT/JP2004/002427
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English (en)
Japanese (ja)
Inventor
Miyuki Asai
Kohsuke Asoh
Ikumi Hyoudoh
Masami Kohchi
Kazunao Masubuchi
Masahiro Sakaitani
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Publication of WO2004076446A1 publication Critical patent/WO2004076446A1/fr

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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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel benzothiophene derivative, a method for producing the same, and a medicament containing the derivative.
  • the pharmacoprotein transferase is a cystine residue of the C-terminal tetrapeptide sequence CAAX (C: cysteine, A: aliphatic amino acid, X: serine, methionine, cysteine, glutamine or alanine) present in Ras protein and the like. It is an enzyme that catalyzes the transfer of a huanesyl group to
  • low molecular weight GTP-binding proteins such as cGMP phosphodiesterase, phosphorylase 8, phosphorylase 8, tyrosine phosphatase, transducin and oral dopsin kinase are known to undergo pharmacosylation, many of which are cell cycle, growth
  • cGMP phosphodiesterase phosphorylase 8
  • phosphorylase 8 phosphorylase 8
  • tyrosine phosphatase tyrosine phosphatase
  • transducin and oral dopsin kinase
  • Non-Patent Document 1 In normal cells, the molecular switch mechanism is highly regulated, and many of these low-molecular-weight GTP-binding proteins adopt an inactive GDP-binding conformation. However, in tumor cells, some of the aforementioned low molecular weight GTP-binding proteins have undergone structural activation, which contributes to abnormal cell proliferation.
  • Inhibitors of pharmacoprotein transferase are known to have tumor cell growth inhibitory activity and have antitumor activity in the clinic, and the activity of pharmacosylation is necessary for the activation of these low molecular weight GTP-binding proteins. To control (Karp, JE, et al., Current Opinion in Oncology, 2001, 13, 470-476) (Non-Patent Document 2). Therefore, it is believed that inhibitors of pharmacoprotein transferase may be useful as anticancer and antitumor agents.
  • Patent Document 1 Inhibitors of pharmacoprotein transferase having antitumor activity are described in WO97 / 21701 (Patent Document 1) and Japanese Patent Application Laid-Open No. H10-1051405 (Patent Document 2).
  • Patent Document 2 Japanese Patent Application Laid-Open No. H10-1051405
  • Patent Document 1
  • Patent Document 2
  • An object of the present invention is to provide a compound useful as an antitumor agent, a method for producing the same, and a medicament containing the compound. Disclosure of the invention
  • the present inventors have conducted intensive studies in view of the above problems, and as a result, have found that the benzothiophene derivative represented by the formula (I) exhibits the inhibitory activity of farnesyl protein transferase, thereby completing the present invention.
  • the present invention provides a compound represented by the formula (I):
  • R 2 represents a hydrogen atom, a halogen, an aryl group optionally having 1 to 3 substituents, or heterocyclyl.
  • R 3 represents a linear or branched alkyl group having 1 to 4 carbon atoms.
  • the present invention also relates to a pharmaceutical composition containing a compound represented by the formula (I), a salt, a prodrug or a solvate thereof as an active ingredient.
  • the present invention relates to the use of a compound represented by the formula (I), a salt, a prodrug or a solvate thereof for the manufacture of a medicament for treating a cell proliferative disease, and a therapeutically effective amount of the formula:
  • the present invention also relates to a method for treating a cell proliferative disease, comprising administering a compound represented by the formula (I), a salt thereof, a prodrug or a solvate to a patient in need of treatment.
  • the present invention also relates to a method for producing a compound represented by the formula:
  • the present invention also relates to a method for producing a compound represented by the formula: BEST MODE FOR CARRYING OUT THE INVENTION
  • Halogen refers to fluorine, chlorine, bromine, and iodine.
  • Alkoxy means a group represented by one O—R.
  • R represents an alkyl, and is preferably a linear or branched alkyl having 1 to 4 carbon atoms.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, ⁇ -butoxy, i-butoxy, sec-butoxy or tert-butoxy.
  • Substituted means that one or more substituents are substituted, and unless otherwise indicated, when two or more substituents are substituted, each independently selected substituent Has been replaced by
  • Substituted by means substituted by a substituent selected from the specified substituent group.
  • Salt means a commonly used acid addition salt or base addition salt, which can be produced using an organic or inorganic acid or an organic or inorganic base, and is preferably a pharmaceutically acceptable salt.
  • the acid addition salt include salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid Salts obtained from organic acids such as acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid and fumaric acid are included.
  • Base addition salts include, for example, potassium, sodium, And salts obtained from quaternary ammonium compounds such as monium or tetramethylammonium hydroxide.
  • “Pharmaceutically acceptable” means pharmacologically acceptable and substantially non-toxic when the substance is administered to a subject.
  • “Pharmaceutically effective metabolite” is a metabolite produced by metabolizing a compound of formula (I) in a living body, which is a pharmaceutically acceptable and pharmaceutically effective compound. means.
  • prodrug is meant a derivative of a compound of formula (I) that is converted under physiological conditions or by solvolysis to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound of formula (I).
  • 1 ⁇ represents a nitro group, a cyano group or a pyridin-3-yl group, and is preferably nitro, cyano or pyridine-3-inole.
  • R 2 represents a hydrogen atom, a halogen, an aryl group optionally having 1 to 3 substituents, or a heterocyclyl group.
  • the “aryl group” represented by R 2 means phenyl or naphthyl.
  • phenol is preferred.
  • substituent of the aryl group which may be substituted include halogen, cyano, linear or branched alkoxy having 1 to 4 carbon atoms (halogen, linear or branched alkoxy having 1 to 4 carbon atoms). Alkyl or mono- or di-substituted amino, hydroxy, or straight-chain or branched-chain alkoxy having 1 to 4 carbon atoms), straight-chain or 1 to 4 carbon atoms.
  • Branched-chain alkyl (halogen, which may be mono- or di-substituted with straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, diamino, hydroxy, or straight-chain or branched-chain alkyl having 1 to 4 carbon atoms)
  • halogen which may be mono- or di-substituted with straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, diamino, hydroxy, or straight-chain or branched-chain alkyl having 1 to 4 carbon atoms
  • aryl heterocyclyl
  • amino mono- or di-substituted with linear or branched alkyl having 1 to 4 carbon atoms
  • acyl Hi Proxy
  • the above-mentioned optionally substituted alkoxy includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy Tert-butoxy, trifluoromethoxy, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, hydroxymethoxy, methoxymethoxy, and the like.
  • the above-mentioned optionally substituted alkyl include, for example, methyl, ethynole, n-propynole, i-propynole, n-butynole, i-butynole, sec-butynole, tert-butyl, trifluoromethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, hydroxymethyl, methoxymethyl and the like.
  • substituent of the aryl group which may be substituted halogen, cyano, or a straight or branched alkoxy having 1 to 4 carbon atoms is preferable.
  • the number of substituents of the aryl which may be replaced is preferably from 1 to 3, and more preferably 1.
  • the optionally substituted aryl group is preferably an unsubstituted aryl group and a substituted aryl group having 1 to 3 substituents, and more preferably an unsubstituted aryl group and the number of substituents.
  • An aryl group in which is 1 is preferred.
  • heterocyclyl group represented by R 2 is an aromatic 5- to 10-membered cyclic group having one or two rings, at least one of a nitrogen atom, an oxygen atom and It means those containing a hetero atom selected from sulfur atoms. When the heterocyclyl group has two rings, it may be partially saturated.
  • the number of heteroatoms contained in the heterocyclyl group is preferably from 1 to 3.
  • heterocyclyl group examples include, for example, furyl, chenyl, pyridyl, pyrimidyl, quinolinyl, pyrazini ⁇ /, thiazolyl, oxazolyl, thioxazolyl, imidazolyl, thiaziazole, tetrazolyl, pyrrolidyl, piperidinyl, pyridinyl, benzopyranol, benzopyranol Benzo-Chenole, benzo [1,3] dioxonor-1-yl, chromanyl, isochomayl and the like, among which pyridine-3-yl or benzo [1,3] dioxole-5-yl are preferred.
  • R 2 represents a hydrogen atom; a halogen; a halogen, a cyano, and a carbon number:!
  • Phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of straight-chain or branched alkoxy of 1 to 4, pyridine-1-yl or benzo [1, 3] Dioxol-1-yl is preferred.
  • R 2 is, among others, halogen, phenol, 3-chlorophenyl, 3-full T JP2004 / 002427
  • R 3 represents a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl, ethynole, n-propyl, i-propynole, n-butynole, i-butynole, sec-butynole or tert-butyl However, among them, methyl is preferable.
  • Preferred compounds of the formula (I) are those wherein nitro is R 2, halogen, phenyl, 3-chlorophenyl, 3-chlorophenol, 4-chlorophenol, 3-methoxyphenol, 3-methoxyphenol, —Ethoxypheninole, 3-cyanophenyl, pyridine-13-yl or benzo [1,3] dioxol-5-yl, a compound that is an R 3 -force methyl.
  • Still another preferred compound of the formula (I) is that R t is pyridine-3-yl, and R 2 is halogen, feninole, 3-chlorofeninole, 3-funenol, or —Fluoropheninole, 3-methoxyphenyl, 3-ethoxyphenyl, 3-cyanophenyl, pyridine-3-yl or benzo [1,3] dioxole-1-inole, and R 3 is methyl Compound.
  • R t is pyridine-3-yl
  • R 2 is halogen, feninole, 3-chlorofeninole, 3-funenol, or —Fluoropheninole, 3-methoxyphenyl, 3-ethoxyphenyl, 3-cyanophenyl, pyridine-3-yl or benzo [1,3] dioxole-1-inole
  • R 3 is methyl Compound.
  • Still other preferred compounds of formula U) are guano, wherein R 2 halogen, feninole, 3-clofenenol, 3 ⁇ / l ⁇ l ⁇ l ⁇ n ⁇ nole, 4 ⁇ l ⁇ l ⁇ l ⁇ l ⁇ n ⁇ n ⁇ le
  • the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound represented by the formula (I), a salt, a prodrug or a solvate thereof, and a pharmaceutically acceptable carrier.
  • chemotherapeutic agents include, for example, cell division Inhibitors, alkylating agents, metabolic inhibitors, inter-acting antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, enzyme inhibitors, aromatase inhibitors, topoisomerase inhibitors, biological response modifiers ( It may be any one selected from the group consisting of biological response modifiers), anti-hormones, anti-estrogens and anti-androgens.
  • the pharmaceutical composition of the present invention can be suitably used for treatment of a cell proliferative disease, and particularly suitably for treatment of cancer.
  • the cancers to which the pharmaceutical composition of the present invention can be preferably used include lung cancer, bone cancer, victory cancer, skin cancer, head and neck cancer, melanoma, ovarian cancer, ovarian cancer in the skin or eyes.
  • HPV human immunodeficiency virus
  • the compound of the present invention represented by the formula (I) also has an action of enhancing the radiosensitivity of tumor cells. Therefore, it is also useful as a radiosensitizer in radiotherapy.
  • the compound of the present invention represented by the formula (I), a salt thereof, a prodrug and a solvate thereof may be a pharmaceutically acceptable carrier, excipient, binder, diluent, stabilizer, lubricant, or the like.
  • Flavoring agent, disintegrant, coating agent, colorant, antioxidant, buffer, aqueous solvent, oily solvent, tonicity agent, dispersant, preservative, solubilizing agent, fluidizing agent, soothing agent, p It can be orally or parenterally administered as a pharmaceutical composition containing an H-regulating agent, preservative, base and other additive components.
  • oral preparations include, for example, granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions and the like.
  • parenteral preparations include injections such as subcutaneous injections, intravenous injections, intramuscular injections, and intraperitoneal injections; transdermal administrations such as ointments, creams, and lotions; Suppositories such as suppositories and vaginal suppositories; intranasal preparations; These preparations can be produced by a known method usually used in a preparation process.
  • excipients used in the pharmaceutical composition of the present invention include sugars such as lactose, sucrose, sucrose, D-mannitol, and sorbitol; crystalline cellulose, hydroxypropyl / resenololose, and hydroxypropinolemethy.
  • Cellulose such as noresenorelose and methylcellulose and derivatives thereof; starch such as corn starch, potato starch, a-starch, dextrin, j3-cyclodextrin, sodium carboxymethyl starch, and hydroxypropyl starch; and derivatives thereof; Silicates such as aluminum silicate, magnesium aluminate, calcium silicate, magnesium silicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate; Examples include lithic acid, potassium hydrogen tartrate, and magnesium hydroxide.
  • binder examples include agar, stearyl alcohol, gelatin, tragacanth, polybutyl alcohol, polybutylpyrrolidone; crystalline cellulose, hydroxypropinoresethenololose, hydroxypropinolemethinoresenorelose, methylcellulose, etc. Cellulose and derivatives thereof; corn starch, potato starch, starch such as starch, dextrin, ⁇ -cyclodextrin, sodium carboxymethinolestarch, and hydroxypropinolestarch and derivatives thereof; lactose, sucrose, glucose, D — Sugars such as mantol and sorbitol.
  • stabilizer examples include hydrogenated oil, sesame oil, sodium chondroitin sulfate, dibutylhydroxytoluene, adipic acid, ascorbic acid, stearic acid L-asconolevate, sodium L-ascorbate, and L-aspartic acid.
  • Alcoholes such as choles; benzanolecone chloride; phenols such as phenol and cresonole; sorbic acid; sulfites such as sodium hydrogen sulfite and sodium sulfite; edetates such as sodium edetate and tetrasodium edetate; can give.
  • lubricant examples include gum arabic powder, cocoa butter, carmellose calcium, carmellose sodium, carotide, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry aluminum hydroxide gel, glycerin, Light liquid paraffin, crystalline cellulose, hardened oil, synthetic aluminum silicate, sesame oil, wheat starch, talc, macrogol, phosphoric acid; stearinic acids such as stearic acid, calcium stearate, magnesium stearate; salami beeswax, carnauparo And the like; waxes such as sodium sulfate; sodium acids such as sodium sulfate; caustic acids such as magnesium silicate and light acid anhydride; and lauryl sulfates such as sodium lauryl sulfate.
  • flavoring agent for example, ascorbic acid, L-aspartic acid, sodium L-aspartate, magnesium L-aspartate, aspartame, Amatilla, Amatilla extract, Amatilla powder, aminoethylsulfonic acid, aminoacetic acid, DL-aranin, sodium saccharin, d 1 menthol, 1 menthol; saccharides such as lactose, sucrose, pudose, and D-mannitol.
  • Disintegrators include, for example, agar, gelatin, tragacanth, adipic acid, arginic acid, sodium alginate; crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl pinoremethinoresenorelose, methinoresenorelose, etc. Loose and its derivatives; calcium carbonate, sodium hydrogen carbonate, magnesium carbonate, and other carbonates; corn starch, potato starch, ⁇ -starch, dextrin, ⁇ -cyclodextrin, carboxymethyl starch sodium, hydroxypropyl starch And their derivatives and the like.
  • coating agents include shellac, polyvinylpyrrolidone, polyethylene glycol, macrogol, methacrylic acid copolymer, liquid paraffin, eudragit; cellulose acetate, hydroxypropyl cellulose, vinegar 00 Fiber 427
  • Cellulose derivatives such as cellulose 15-phthalate and hydroxypropylmethylsenololose.
  • coloring agent examples include indigo carmine, caramel, riboflavin and the like.
  • buffer examples include aminoaminoacetic acid, L-arginine, benzoic acid, sodium benzoate, ammonium chloride, potassium chloride, sodium chloride, dried sodium sulfite, dried sodium carbonate, dilute hydrochloric acid, citric acid, calcium citrate, and pentane.
  • aqueous solvent examples include distilled water, physiological saline, Ringer's solution and the like.
  • oily solvent examples include propylene glycol; vegetable oils such as olive oil, sesame oil, cottonseed oil, and corn oil.
  • tonicity agent examples include potassium chloride, sodium chloride, glycerin, sodium bromide, D-sorbitol, nicotinic acid amide, glucose, boric acid and the like.
  • dispersing agent examples include arabia gum, pyrene glycol ester of alginate, sonorebitan sesquioleate, D-sonorebitol, tragacanth, methyl cellulose, aluminum monostearate, aminoalkyl methacrylate copolymer RS, lactose, concentrated glycerin, Propylene glycol, macrogol, sodium lauryl sulfate; zinc stearate, magnesium stearate, etc. And stearic acid and its salts.
  • preservatives examples include benzalcodium chloride, benzethonium chloride, dried sodium sulfite, dried sodium sulfate, cresol, chlorocresol, dibutyl hydroxytoluene, sorbic acid sodium, sodium dehydroacetate, phenol, formalin, and phosphorus.
  • Solubilizers include, for example, sodium benzoate, ethylenediamine, citric acid, sodium citrate, glycerin, sodium acetate, sodium salicylate, sonolebitan sesquioleate, nicotinic acid amide, glucose, penzinoleanol cornore, polyvier pyrrolidone , Acetone, ethanol, isopropanol, D-sorbitol, sodium bicarbonate, sodium carbonate, lactose, urea, sucrose, etc.
  • the fluidizing agent examples include hydrous silicon dioxide, talc, anhydrous ethanol, crystalline cellulose, synthetic aluminum silicate, calcium hydrogen phosphate; stearic acid such as calcium stearate and magnesium stearate, and salts thereof.
  • Examples of the soothing agent include benzalco-dum chloride, proforce hydrochloride, mepril hydrochloride, lidocaine hydrochloride, lidocaine and the like.
  • pH adjuster examples include hydrochloric acid, citric acid, succinic acid, acetic acid, boric acid, maleic acid, and sodium hydroxide.
  • preservatives include benzoic acid, sodium benzoate, cetylpyridinium chloride, salicylic acid, sodium salicylate, sorbic acid, potassium sorbate, thymol, methyl parahydroxybenzoate, and butyl paraoxybenzoate.
  • preservatives include benzoic acid, sodium benzoate, cetylpyridinium chloride, salicylic acid, sodium salicylate, sorbic acid, potassium sorbate, thymol, methyl parahydroxybenzoate, and butyl paraoxybenzoate.
  • Fins bentonite, isopropyl lanolin fatty acid, vaseline, polysorbates, macrogol, lauryl alcohol, sodium lauryl sulfate, ethyl linoleate, sodium hydrogen phosphate, rosin; vegetable oils such as olive oil, sesame oil, and wheat germ oil And so on.
  • the amount of the compound represented by the general formula (I) contained in the pharmaceutical composition of the present invention varies depending on the dosage form, but is preferably about 0.1 to 100% by weight based on the total amount of the pharmaceutical composition. is there.
  • the dosage of the pharmaceutical composition of the present invention may vary widely depending on the type of administration control (human or other warm-blooded animal, etc.), severity of symptoms, age, sex, administration method, diagnosis by a doctor, and the like.
  • the dose of the compound represented by the formula (I) to an adult in the case of oral or parenteral administration is about 0.1 to 200 Omg / kg / day, although it can be varied. That's good ,.
  • the above dose is a value per unit weight of the administration subject. Further, in the present invention, the above dose may be administered once in one to seven days, or may be administered in several or more doses depending on the severity of symptoms, the judgment of a doctor, and the like. Is also good.
  • LDA lithium diisopropylamide.
  • WSC I means 11- (3-dimethylaminopropyl) -hydrochloric acid-3-ethyl-carbodiimide.
  • DIEA means N-ethyldiisopropylamine.
  • HB t means N-hydroxybenzotriazole monohydrate.
  • TMA means trifluoroacetic acid.
  • DMAP means 4-dimethylaminopyridine.
  • HMT means hexamethylenetetramine.
  • P d (PP h 3 ) 4 means tetrakis (triphenylphosphine) palladium (0).
  • the compounds of the formula (I) according to the invention can be prepared starting from known compounds or starting from compounds which can be prepared from known compounds by known methods according to the methods described above. More specifically, it can be produced by appropriately changing the starting compound or the reaction reagent according to the target compound based on V in Method 1 to Method 3 below.
  • 2,6-Dibromo_4-12 trobenzaldehyde is a commercially available 1,3-dibutene 2-methinolate 5-2-2. Very high yields are obtained by bromination with N-promosuccinimide followed by oxidation with trimethylamino N-oxide in DMSO (Godfrey AG, and Ganem B., Tetrahedron Letters, 31, 4825-4826, 1990). Rate can be obtained.
  • benzo [b] thiophene was determined by a method modified by a method established by Rahman (Rahman LA and Scrowston RM, J. Chem. Soc. Perkin Trans. I., 385-390, 1984). It can be performed using 4-nitro-benzaldehyde. First, by condensing 2,6-jib mouth mo 4-12 trobenzaldehyde 2 and rhodanine 3 in the presence of triethylamine, 5- (2,6-jib mouth mo 4-12 trobenzylidene) 1 2-Thioxo-thiazolidine-1-one A can be obtained.
  • aryl aryl boronic acid or aryl port having the required substituent on the aryl group is obtained.
  • the biaryl derivative 14 is obtained by introducing an aryl group into the sulfinamide 13 which is an important intermediate by the cross-coupling reaction used. Subsequently, the desired 4-amino-3- (3-methyl-3H-imidazolone-1-inole) -1- (6-nitro-1) is obtained by deprotecting the 2-methyl-2-propanesulfer group under acidic conditions. Benzo [b] thiophene-2-yl) monomethyl] benzonitrile derivative 15 is obtained.
  • the compound wherein R 2 is heterocyclyl can be produced by using a compound wherein the aryl of the above arylboronic acid or aryl is a corresponding heterocyclyl.
  • 3- (3,5-dipromophenyl) -pyridine 18 is a commercially available palladium complex of 1,3,5-tribromobenzene 16 and pyridine-13-boronic acid 17 in catalytic amounts. It is obtained by coupling under the conditions of the Suzuki reaction in the presence of Selective formylation of the 4-position of 3-pyridine (3,5-dibutyral morphol) 1 pyridine 18 is carried out after lithiation using lithium 2,2,6,6-tetramethyl-piperidine. This is achieved by quenching with DMF to give 2,6-Jib mouth morphine 4-pyridine-13-ilubenzaldehyde 19.
  • the 2,6-dipromo-4-pyridine-13-inolebenzaldehyde 19 can be treated with mercaptoacetic acid methyl ester in the presence of sodium hydride to give 4-bromo-6-pyridine-13-ylbenzo [ b] Thiophene-I 2-force Converted to rubonic acid methyl ester 20.
  • the aryl group is introduced into the sulfinamide 2'5, which is an important intermediate, by cross-coupling reaction with arylboronic acid or arylboronate having the required substituent on the aryl group. Yields the biaryl derivative 26. Subsequently, the desired 4-amino-1- (3-methyl-methyl-2-propane) group is deprotected under acidic conditions by deprotection of the 2-methyl-2-propane sulfier group.
  • the compound wherein R 2 is heterocyclyl can be produced by using a compound wherein the aryl of the above aryloxy or aryl boronate is the corresponding heterocyclyl.
  • ammonia was removed.
  • 4-bromo-16-canolebamoyl-benzo [b] thiophen-12-methylester 31 can be obtained.
  • [B] 1-thiophene 6-carbonitrile 34 is obtained.
  • the introduction of the cyanophenyl group can usually be carried out at 180 ° C. to 110 ° C., and 100 ° C. It is preferably performed in C.
  • the compound in which R 2 is heterocyclyl can be produced by using a compound in which the aryl of aralkyl poronic acid or aryl of aralkyl poronato is the corresponding heterocyclyl.
  • the starting materials used and some of the intermediates are known compounds and can be produced by commercially available power or a method described in the literature.
  • Example 1 one i) and 1 one; in an analogous manner to that described in i), 2-methyl-one pro Nono 0 Hmm 2- Sunorefin acid [(4 one promoter 6- two Torrox base emission zone [b] Chiofen one 2- (yl)-(4-cyano-phenyl) 1- (3-methyl-3H-imidazole—4-yl) 1-methyl] amide and benzo [1,3] dioxole _5-yl-boronate was also subjected to a Suzuki force coupling reaction, followed by treatment with hydrogen chloride (4N solution in EtOAc) to give the title compound as a yellow powder.
  • 2-methyl-one pro Nono 0 Hmm 2- Sunorefin acid [(4 one promoter 6- two Torrox base emission zone [b] Chiofen one 2- (yl)-(4-cyano-phenyl) 1- (3-methyl-3H-imidazole—4-yl) 1-methyl] amide and benzo [1,3] dioxole _5-
  • N, O-dimethyl-hydroxylamine hydrochloride (1.82 g, 18.7 brittle)
  • WSCI (3.60 g, 18.7 )
  • HOBt (2.53 g, 18.7 ol)
  • N, N-diisopropylethylethylamine (6.53 ml, 37.44 mmol) were added at room temperature.
  • the mixture was stirred at room temperature under nitrogen for 4 hours. Quench the reaction mixture with water and add EtO
  • 3 subunits are expressed in pT7-7 (Comb Chera High Throughput Screen. 1999 Vol. 5 pp279-87, Application of homogeneous time-resolved fluorescence (HTRFTM) to monitor poly-ubiquitination of wild -type p53.
  • Methods Enzymol. 1995 Vol. 250 pp3-12 essentially except that Yabuki, N., Watanabe, S., Kudoh, T., Nihira, Si., and Miyamato, C.) were used.
  • Bacterial expression and purnication of human protein prenyltransf erases using epitope-tagged, translationally coupled systems.Omer, Charles A. Diehl, Ronald E.
  • the human protein and the] 3 subunit were co-expressed in E. coli, BL21 CodonPlus (DE3) RIL using pGEX4T-1 (Amersham Pharmacia Biotech). Cultured cells were sonicated in phosphate buffered saline containing 1% Triton X-100. The crude extract
  • Geranylgerale protein transferase was purified from the supernatant using Gratathione Sepharose 4FF (Amersham Pharmacia Biotech) and HiTrapQ (Amersham Pharmacia Biotech) column chromatography. Store geranylgeranyl protein transferase containing fractions and contain 20% glycerol, pH 7.5
  • the pharmacotransferase activity was measured by [3H] pharmacosylation of recombinant human K-Ras4B protein by filtration.
  • Reaction mixture 50 1 The, 5 OmM Tris-Cl (p H 7. 5), 5 mM Jichiotorei Torr, 0. 3 MZ n C l 2 , 1 OmM Mg C l 2, 6 0 nM [1-3 H] Fuaruneshirupiro phosphorylase Fuato (6 0nCi, Muromachi Yakuhin Kogyo), was contained 8 6nM K- R as, and human Tofuarune sills protein transferase 0. 4 ⁇ ⁇ .
  • the test compound was dissolved in dimethyl sulfoxide (DMS O) and added to the reaction mixture so that the final concentration of DMS O was less than 1%.
  • the reaction was started by adding [113H] bulnesyl pyrophosphate to a 96-well plate. 30. After 60 minutes incubation, the reaction was stopped by adding 50 ⁇ l of 10% TCA. The mixture was transferred to a multi-screen plate (MAFBN0B50, Millipore) to which 10 ⁇ l of ethanol had been previously added to each well. Next, the plate was filtered and washed three times with ethanol.
  • DMS O dimethyl sulfoxide
  • Liquid scintillator OptiPhase “SuperMix” (Wallac) 30 ⁇ 1 was added to each well, and the radioactivity was measured with a MicroBeta scintillation counter (Wallac). IC 5. The value was calculated as the concentration that inhibited the pharmacophorase activity by 50% compared to the control.
  • Gera - the Rugera two Rutanpaku protein transferase activity the reaction, 5 OmM Tris HC1 (p H 7. 5), 5 mM Jichiotorei Torr, 0. Z n C l 2, 1 OmM Mg C l 2, 5raM AT P, 1.2 ⁇ [13H] Geranylgeranyl pyrophosphate (3 / Ci, Muromachi Sangyo Kogyo), 86 nM K—Ras, and the same method except that 7 xg of human gel-rugeranil protein transferase was included Was measured.
  • Antiproliferative activity was performed as follows. A single suspension of tumor cells was inoculated into serially diluted 96-well microtest plates. The template was then incubated at 37 ° C. for 4 days in a 5% C 2 atmosphere (2-3 cells 10 3 cells per well). The degree of cell proliferation in the monolayer was measured using WST-8 (Dojindo Laboratories, Japan). IC 5 of the drug to the tumor cells. Values were calculated as the drug concentration that inhibited tumor cell growth by 50% OD compared to control. The results are shown in the table below.
  • the compound of the present invention causes regression or remission of a solid tumor and has a therapeutic activity.
  • composition examples illustrate representative pharmaceutical compositions in unit dosage form suitable for systemic or local administration to warm-blooded animals according to the present invention.
  • active ingredient used in the following formulation examples means a compound of the formula (I) or (II), an addition salt thereof with a pharmaceutically acceptable acid or base, or a stereoisomer thereof. .
  • the solution thus obtained was combined with the previously obtained solution, and an appropriate amount of water was added to make 20 liters, thereby obtaining a liquid preparation for oral administration containing 5 mg of the active ingredient per 1 teaspoon (5 ml).
  • the obtained liquid was filled in an appropriate container.
  • a mixture of 100 g of active ingredient, 570 g of lactose and 200 g of starch was mixed well and moistened with a solution containing 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in about 20 Oral of water.
  • the wet powder mixture was sieved, dried and sieved again.
  • 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil were added. The whole was mixed well and compressed to give 10,000 tablets, each tablet containing 1 Omg of the active ingredient.
  • the core tablets prepared above were coated with the mixture prepared here in a coating apparatus.
  • the compounds of the present invention have excellent pharmacological activities such as pharmacoprotein transferase inhibitory activity and antitumor activity, and are useful as pharmaceuticals.

Abstract

Composé utile en tant qu'agent antitumoral, méthode servant à préparer ce composé et substance médicinale contenant ce composé. Ce dernier est représenté par la formule (I), dans laquelle R1 représente nitro, R2 représente hydrogène, R3 représente alkyle C1-4 linéaire ou ramifié, sel de ce composé ou promédicament ou solvate de ce sel ou de ce composé.
PCT/JP2004/002427 2003-02-27 2004-02-27 Derive de benzothiophene WO2004076446A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006101454A1 (fr) * 2005-03-21 2006-09-28 S*Bio Pte Ltd Derives du benzothiophene: preparation et applications pharmaceutiques
JP2007536334A (ja) * 2004-05-03 2007-12-13 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ６−ブロモ−４−（３−クロロフェニル）−２−メトキシ−キノリンを用いるジアステレオ選択的合成方法
JP2007536333A (ja) * 2004-05-03 2007-12-13 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ スルフィンイミン類に対するリチオ化されたｎ−メチルイミダゾールのジアステレオ選択的付加

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Publication number Priority date Publication date Assignee Title
WO2000047574A1 (fr) * 1999-02-11 2000-08-17 Pfizer Products Inc. Derives de quinolin-2-one a substitution heteroaryle convenant comme anti-cancereux
WO2002024686A2 (fr) * 2000-09-25 2002-03-28 Janssen Pharmaceutica N.V. Derives de la quinoleine et de la quinazoline 6-heterocyclylmethyle inhibiteurs de la farnesyle transferase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000047574A1 (fr) * 1999-02-11 2000-08-17 Pfizer Products Inc. Derives de quinolin-2-one a substitution heteroaryle convenant comme anti-cancereux
WO2002024686A2 (fr) * 2000-09-25 2002-03-28 Janssen Pharmaceutica N.V. Derives de la quinoleine et de la quinazoline 6-heterocyclylmethyle inhibiteurs de la farnesyle transferase

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007536334A (ja) * 2004-05-03 2007-12-13 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ６−ブロモ−４−（３−クロロフェニル）−２−メトキシ−キノリンを用いるジアステレオ選択的合成方法
JP2007536333A (ja) * 2004-05-03 2007-12-13 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ スルフィンイミン類に対するリチオ化されたｎ−メチルイミダゾールのジアステレオ選択的付加
JP4917021B2 (ja) * 2004-05-03 2012-04-18 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ スルフィンイミン類に対するリチオ化されたｎ−メチルイミダゾールのジアステレオ選択的付加
JP4917022B2 (ja) * 2004-05-03 2012-04-18 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ６−ブロモ−４−（３−クロロフェニル）−２−メトキシ−キノリンを用いるジアステレオ選択的合成方法
WO2006101454A1 (fr) * 2005-03-21 2006-09-28 S*Bio Pte Ltd Derives du benzothiophene: preparation et applications pharmaceutiques

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