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WO2004032930A1 - Metrode de traitement du cancer - Google Patents

Metrode de traitement du cancer Download PDF

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Publication number
WO2004032930A1
WO2004032930A1 PCT/JP2003/013046 JP0313046W WO2004032930A1 WO 2004032930 A1 WO2004032930 A1 WO 2004032930A1 JP 0313046 W JP0313046 W JP 0313046W WO 2004032930 A1 WO2004032930 A1 WO 2004032930A1
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WO
WIPO (PCT)
Prior art keywords
group
alkyl group
lower alkyl
yield
synthesis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2003/013046
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English (en)
Japanese (ja)
Inventor
Chikage Mataki
Tatsuhiko Kodama
Takeshi Doi
Masahiro Tamura
Toshiaki Oda
Masao Ohkuchi
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Kowa Co Ltd
Original Assignee
Kowa Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kowa Co Ltd filed Critical Kowa Co Ltd
Priority to AU2003272972A priority Critical patent/AU2003272972A1/en
Publication of WO2004032930A1 publication Critical patent/WO2004032930A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings

Definitions

  • the present invention relates to novel cancer therapeutics and methods.
  • the present inventors have used a cultured cell system to search for a substance having an inhibitory effect on cancer cell growth, and surprisingly surprisingly found that the group of compounds represented by the general formula (1) described below is an excellent cancer
  • the present inventor has found that it has a cell growth inhibitory effect and is useful as a therapeutic agent for cancer, and has completed the present invention.
  • R 1 and R 2 each represents a hydrogen atom or a main butoxy group, an R 1 when R 2 is a hydrogen atom main butoxy group, when it is R 2 turtles butoxy group R 1 Represents a hydrogen atom;
  • a method for treating cancer which comprises administering an effective amount of the cyclic diamine compound represented by the formula (I), an acid addition salt thereof or a hydrate thereof.
  • the present invention also provides a therapeutic agent for cancer containing the cyclic diamine compound, an acid addition salt thereof or a hydrate thereof as an active ingredient.
  • the present invention further provides a pharmaceutical composition for treating cancer comprising the above cyclic diamine compound, an acid addition salt thereof or a hydrate thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above-mentioned cyclic diamine compound, an acid addition salt thereof or a hydrate thereof for producing a therapeutic agent for cancer.
  • the lower alkyl groups represented by R 3 and R 4 include: C 6 -alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, and n-hexyl group, particularly Preferred are a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like.
  • hydroxy lower alkyl group examples include a hydroxy c 2 _ c 6 -alkyl group, for example, a 2-hydroxyethyl group, a 2-hydroxy-11-methylethynole group, a 2-hydroxy_1,1-dimethylethyl group, and a 3-hydroxyethyl group.
  • examples include hydroxypropyl pill group, 3-hydroxy-2-methylpropyl pill group, 4-hydroxybutyl group, 5-hydroxypentyl group, and 6-hydroxyhexyl group, particularly 2-hydroxyethyl group and 2-hydroxyethyl group.
  • Preferred are a 1-hydroxy-11-methylethyl group, a 2-hydroxy-1,1-dimethylethyl group, a 3-hydroxypropyl group and the like.
  • Lower alkoxy lower alkyl groups include Ci-Cs-alkoxy-Ci-Ce-alkyl groups, for example, 2-methoxyethyl group, 2-methoxy-1-methylethyl group,
  • aryl group C 6 — C.
  • aryl groups such as phenyl groups.
  • Aryl C] -C 6 -alkynole group for example, phenethyl group, benzyl group and the like.
  • a hydrogen atom, a C 6 -alkyl group or a phenyl group is particularly preferred, and a hydrogen atom, a methyl group or a phenyl group is more preferred.
  • the skeleton represented by is preferably a skeleton selected from naphthalene, quinoline, quinazoline, benzimidazo mono, benzothiazono, benzoxazono, indone, benzothiophene and benzofuran.
  • n is a number of 1 to 5, more preferably 1 to 4, and particularly preferably 1 to 3.
  • the acid addition salt of the compound (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. Not included but acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; benzoate, methanesulfonate, ethanesulfonate, benzene Acid addition salts of organic acids such as sulphonate, p-toluenesulphonate, oxalate, maleate, fumarate, tartrate, citrate, acetate can be mentioned.
  • mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; benzoate, methanesulfonate, ethanesulfonate, benzene
  • Acid addition salts of organic acids such as sulphonate, p-toluenesulphonate, oxalate, maleate, fumarate, tartrate, citrate, acetate
  • the compound (1) may exist in the form of a solvate represented by a hydrate, and the solvate is also included in the present invention.
  • the compound (1) can be produced according to the following Method A or Method B.
  • X represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, and RRA, B, m and n are the same as above]
  • the compound (1) is obtained by condensing the compound (2) with the cyclic diamine (3).
  • the halogen atom represented by X is preferably a chlorine atom or a bromine atom.
  • the alkylsulfonyloxy group is preferably a methanesulfonyloxy group, and the arylsulfonyloxy group is preferably a p-toluenesulfonyloxy group.
  • the condensation reaction between the compound (2) and the cyclic diamine (3) is carried out in a solvent such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile in the presence of a base such as carbon dioxide.
  • the stirring is carried out at a temperature of from 100 ° C to 100 ° C, preferably at room temperature for 1 hour to several days, more preferably for 5 hours.
  • the compound (2) used here can be produced, for example, according to the following reaction formula.
  • R 5 represents a hydrogen atom or a lower alkyl group
  • RR 2 , A, B, n and X are the same as above
  • the carboxylic acid or its ester (4) or aldehyde (5) is reduced with a reducing agent such as lithium aluminum hydride to obtain an alcohol (6), which is then halogenated with a salt, such as dihythionyl.
  • Compound (2) can be obtained by reacting an agent or a sulfonylating agent such as methanesulfoerck-opening or p-toluenesulfonyl chloride.
  • the alcohol form (6) reacts the terminal olefin with a side-opening volatilization reaction. Alternatively, it can be obtained by subjecting it to an oxidation reaction.
  • the compound (2) having a quinazoline skeleton can be produced according to the following reaction formula.
  • the compound (1) is obtained by condensing the carboxylic acid (4) with the cyclic diamine (3) and reducing the obtained amide (7).
  • the condensation reaction of carboxylic acid (4) with cyclic diamine (3) is carried out, for example, in toluene, benzene, dichloromethane, chloroform, tetrahydrofuran (THF), Dehydration condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide hydrochloride) in a solvent such as xane or acetonitrile using 41- (dimethylamino) pyridine as a catalyst
  • THF tetrahydrofuran
  • Dehydration condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide hydrochloride) in a solvent such as xane or acetonitrile
  • the reduction reaction of the amide form (7) is carried out, for example, by using a reducing agent such as lithium aluminum hydride in THF or getyl ether at a temperature of reflux from 0 ° C., preferably from 1 hour to several days at room temperature.
  • the reaction is preferably carried out for 6 hours.
  • the compound (1) can be obtained by the above-mentioned method, and can be further purified by a usual purification means such as a recrystallization method and column chromatography, if necessary. If necessary, the desired salt or solvate can be prepared by a conventional method.
  • the compound (1) has an asymmetric carbon, the present invention includes all stereoisomers.
  • the compound (1) thus obtained, or a salt or solvate thereof, exhibits an excellent inhibitory action on cancer cell growth as described in Examples below, and is useful as a therapeutic agent for cancer of human-containing animals.
  • the therapeutic agent for cancer of the present invention comprises the compound (1), a salt thereof or a solvate thereof as an active ingredient
  • the administration form is not particularly limited and may be appropriately selected depending on the purpose of treatment.
  • oral, injection, suppository, ointment, inhalant, eye drop, nasal drop, or patch, and the composition suitable for these administration forms is compounded with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, it can be produced by a conventional formulation method known to those skilled in the art.
  • an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added to the compound (1), and then a conventional method is used.
  • a conventional method is used.
  • tablets, coated tablets, granules, powders, capsules and the like can be produced.
  • additives may be those commonly used in the art.
  • excipients include lactose, sucrose, sodium salt, glucose, starch, calcium carbonate Gum, kaolin, microcrystalline cellulose, silicic acid, etc .
  • binders are water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch , Methinoresenololose, ethinoresenorelose, shellac, canolaresic phosphate, polypyrrolidone, etc .
  • disintegrants are dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearin Acid monoglyceride, lactose, etc.
  • lubricating agents include purified talc, stearate, borax, polyethylene glycol, etc.
  • flavoring agents include sucrose, orange peel, citric acid, tartaric acid, etc.
  • a flavoring agent, a buffering agent, a stabilizing agent, a flavoring agent, etc. are added to the compound (1) to produce an oral solution, a syrup, an elixir, etc. in a conventional manner.
  • vanillin and the like are used as flavoring agents
  • sodium citrate and the like are used as buffering agents
  • tragacanth, gum arabic and gelatin are used as stabilizers.
  • a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the compound (1), and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.
  • the pH adjusting agent and the buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
  • the stabilizer include sodium bisulfite, EDTA, thioglycolic acid, and thiolactic acid.
  • Local anesthetics include proforce hydrochloride, lidocaine hydrochloride and the like.
  • the isotonic agent include sodium salt sodium, glucose and the like.
  • the compound (1) When preparing a suppository, the compound (1) may be added to a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, a fatty acid triglyceride, and, if necessary, Tween (registered trademark). After adding a surfactant such as described above, it can be produced by a conventional method.
  • a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, a fatty acid triglyceride, and, if necessary, Tween (registered trademark).
  • bases, stabilizers, and the like usually used for the compound (1) are used.
  • Wetting agents, preservatives, etc. are blended as necessary, and mixed and formulated by ordinary methods.
  • the base include liquid paraffin, white petrolatum, beeswax, otatyl dodecyl alcohol, paraffin and the like.
  • the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, p-hydroxybenzoate and the like.
  • inhalants In addition to the above, inhalants, eye drops, and nasal drops can be prepared by conventional methods.
  • the cancer therapeutic agent of the present invention can be used for various cancers such as pituitary adenoma, auditory schwannoma, glioma, brain tumor, etc., brain cancer, nerve cancer, eye cancer, oral cancer (tongue cancer, oral floor cancer, gingival cancer) Cancer, mucosal cancer, hard palate cancer), pharyngeal cancer (nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), laryngeal cancer (glottic, supraglottic, subglottic), maxillary, thyroid (papillary) , Follicular carcinoma, medullary carcinoma, undifferentiated carcinoma, malignant lymphoma), head and neck cancer such as salivary gland carcinoma (parotid carcinoma, submandibular carcinoma, sublingual carcinoma), thymoma, breast cancer, lung cancer, medium Liver cancer, stomach cancer, esophageal cancer, gastrointestinal cancer cancer such as colorectal cancer, hepato
  • Urinary cancers such as penile cancer, testicular tumor, renal pelvis and ureteral cancer, prostate cancer, renal cell cancer, bladder cancer, vulvar cancer, uterine cancer, cervical cancer, and child cancer (Endometrial cancer), uterine sarcoma, trophoblastic disease, vaginal cancer, breast cancer, ovarian cancer, ovarian germ cell tumors and other gynecological cancers, malignant melanoma (melanoma), mycosis fungoides, skin cancer and other skin Cancer, malignant bone tumor (osteosarcoma, paraosseous osteosarcoma, periosteal osteosarcoma, malignant fibrous histiocytoma, chordoma, Ewing sarcoma, adamancinoma, chondrosarcoma), malignant soft tissue tumor (malignant fibrous histiocytoma) , Liposarcoma, synovial sarcoma, leiomyosarcoma,
  • the dose of the cancer therapeutic agent of the present invention varies depending on the age, body weight, symptoms, administration form, number of administrations, and the like, but it is usually 1 to 1000 mg once or several times a day as the compound (1) for adults. It is preferable to administer orally or parenterally in divided doses.
  • Lithium aluminum hydride (579 mg) was added to anhydrous THF (4 OmL) under an argon stream under ice-cooling, followed by 5,6,7-trimethoxynaphthalene_2-carboxylic acid (4.0 g). Was added dropwise, and the mixture was stirred at room temperature for 4 hours.
  • Ether (15 OmL) was added to the reaction solution, sodium sulfate decahydrate was added, and the mixture was stirred for 15 minutes.
  • methyltriphenylphosphonium bromide (2.8 g) was suspended in anhydrous THF (1 OmL).
  • THF 1 OmL
  • 1.7 M tert-butyllithium hexane solution (3.3 mL) was added.
  • anhydrous THF 3 OmL
  • 5,6,7-trimethoxynaphthalene-12-carbaldehyde (1.26 g) was added.
  • the solution was added dropwise and stirred at room temperature overnight.
  • the solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • reaction solution was diluted with ethyl acetate, washed with 2M hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the title compound was obtained by treating 4,5,6-trimethoxyindole-2-methyl ribonate (70 Omg) in the same manner as in Production Example 36.
  • Methyl 3- (2,3,4-trimethoxyphenyl) -12-azidopropenoate (799 mg), potassium tert-butoxide (438 mg), and 18-crown-16 (7 lmg) were dissolved in anhydrous benzene (60 mL). Stirred for minutes. Then, methane (0.28 mL) was added, and the mixture was stirred overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.
  • N-methyl-1,4,5,6-trimethoxyindole-2-methyl carboxylate (19 Omg) was treated in the same manner as in Production Example 36 to give the title compound.
  • N-Methyl-1,5,6-trimethoxyindole-2-caprolubonic acid 200 mg was reacted with piperazine (35 mg) in the same manner as in Production Example 37 to give the title compound.
  • N-methyl-4,5,6-trimethoxyindole-1-carboxylic acid 130 mg
  • homopiperazine 24 mg
  • 4,5,6-Trimethoxyindole-Methyl 2-carboxylate (533 mg), benzene bromide (0.22 mL), copper oxide (64 mg), potassium hydroxide (336 mg) were added to anhydrous DMF (1 OmL ) And stirred under reflux for 6 hours under an argon stream. After cooling, the reaction solution was dissolved in water (100 mL) and filtered through celite. The filtrate was extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the title compound was obtained by reacting 1-phenyl 4,5,6-trimethoxyindole_2-carboxylic acid (91 mg) and homopyrazine (14 mg) in the same manner as in Production Example 37.
  • N, N'-bis (1-phenyl_4,5,6-trimethoxyindole-2-carboehl) homopidazine (99 mg) was treated in the same manner as in Example 18 and labeled. The compound was obtained as the free base.
  • N-Ethoxycanoleponyl 2--2-troth 3,4,5-trimethoxyaniline (2.8 g) was treated in the same manner as in Preparation 49 to give the title compound.
  • 1,2-Diamino-3,4,5-trimethoxybenzene (675 mg) and triethylamine (1.4 mL) are dissolved in dry dichloromethane (25 mL), and the mixture is cooled under ice-cooling. 34 mL), and the mixture was stirred as it was for 4 hours.
  • the reaction solution was extracted with chloroform, and the organic layer was washed with diluted hydrochloric acid, aqueous potassium carbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the isomeric title compound was isolated from the silica gel preparative TLC of Production Example 67.
  • Oxalyl chloride (0.78 mL) was dissolved in dichloromethane (10 mL), and DMSO (1.49 mL) was added dropwise at ⁇ 78 ° C., followed by stirring for 30 minutes.
  • a solution of 2-hydroxymethyl-5,6,7-trimethoxybenzothiazole (1.53 g) in dichloromethane (10 mL) was added dropwise at 180 ° C, and the mixture was stirred for 1 hour.
  • Ndiloxyacetic acid (6 '' Nitro 1 2 ', 3'',4' (Zinyl) ester (1.38 g) was dissolved in methanol (40 mL), 10% palladium carbon (560 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction solution was filtered, and the filtrate was concentrated. . The residue was dissolved in xylene (50 mL), p-toluenesulfonic acid monohydrate (350 mg) was added, and the mixture was stirred under reflux for 1 hour.
  • 1,2,3,4-Trimethoxybenzaldehyde (1.6 g) was dissolved in DMF (15 mL), and potassium carbonate (1.28 g) was added thereto. Under ice cooling, methyl thioglycolate (0.68 mL) was added dropwise, and the mixture was stirred for 40 minutes. The mixture was then stirred at room temperature for 4 hours. Water was added to the mixture, extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Slurry residue Purification by force gel column chromatography (ethyl acetate: hexane 1: 4) gave the title compound.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un médicament thérapeutique contre le cancer, contenant comme ingrédient actif un composé diamine cyclique représenté par la formule générale suivante (1) [dans laquelle R1 et R2 représentent chacun hydrogène ou méthoxy, à condition que lorsque R2 représente hydrogène, R1 représente alors méthoxy, et que lorsque R2 représente méthoxy, R1 représente alors hydrogène; A représente l'oxygène, le soufre, -CH=CH-, -CH=N-, ou -NR3- (R3 représentant hydrogène, alkyle inférieur, hydroxy(alkyle inférieur), (alkoxy inférieur)alkyle inférieur, aryle, ou aryle(alkyle inférieur)); B représente l'azote, =CH-, ou =CR4- (R4 représentant hydrogène, alkyle inférieur, hydroxy(alkyle inférieur),(alkoxy inférieur)alkyle inférieur, aryle, ou aryle(alkyle inférieur); m est 1 ou 2; et n est un nombre de 1 à 5], un sel d'addition acide dudit composé, ou un hydrate d'un des deux.
PCT/JP2003/013046 2002-10-11 2003-10-10 Metrode de traitement du cancer Ceased WO2004032930A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003272972A AU2003272972A1 (en) 2002-10-11 2003-10-10 Method of treatment for cancer

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US41763502P 2002-10-11 2002-10-11
US60/417,635 2002-10-11

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WO2004032930A1 true WO2004032930A1 (fr) 2004-04-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005095389A1 (fr) * 2004-03-31 2005-10-13 Zenyaku Kogyo Kabushiki Kaisha Composé hétérocylique et agent de tumeur anti-maligne contenant celui-ci comme ingrédient actif
US7750001B2 (en) 2005-03-11 2010-07-06 Zenyaku Kogyo Kabushikikaisha Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient
WO2012176878A1 (fr) * 2011-06-23 2012-12-27 学校法人自治医科大学 Inhibiteur du protéasome

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Publication number Priority date Publication date Assignee Title
EP0774257A2 (fr) * 1995-11-20 1997-05-21 Kowa Co. Ltd. Dérivés de pipérazine et homopipérazine pour l'inhibition de l'adhésion et l'infiltration cellulaire
WO2000032590A1 (fr) * 1998-11-25 2000-06-08 Aventis Pharmaceuticals Products Inc. COMPOSES OXOAZAHETEROCYCLYLE SUBSTITUE INHIBITEURS DU FACTEUR Xa
WO2001007436A2 (fr) * 1999-07-28 2001-02-01 Aventis Pharmaceuticals Inc. Composes d'oxoazaheterocyclyle substitue
WO2003002532A1 (fr) * 2001-06-29 2003-01-09 Kowa Co., Ltd. Composes de diamine cyclique possedant des groupes a noyau fusionne

Patent Citations (4)

* Cited by examiner, † Cited by third party
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EP0774257A2 (fr) * 1995-11-20 1997-05-21 Kowa Co. Ltd. Dérivés de pipérazine et homopipérazine pour l'inhibition de l'adhésion et l'infiltration cellulaire
WO2000032590A1 (fr) * 1998-11-25 2000-06-08 Aventis Pharmaceuticals Products Inc. COMPOSES OXOAZAHETEROCYCLYLE SUBSTITUE INHIBITEURS DU FACTEUR Xa
WO2001007436A2 (fr) * 1999-07-28 2001-02-01 Aventis Pharmaceuticals Inc. Composes d'oxoazaheterocyclyle substitue
WO2003002532A1 (fr) * 2001-06-29 2003-01-09 Kowa Co., Ltd. Composes de diamine cyclique possedant des groupes a noyau fusionne

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* Cited by examiner, † Cited by third party
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WO2005095389A1 (fr) * 2004-03-31 2005-10-13 Zenyaku Kogyo Kabushiki Kaisha Composé hétérocylique et agent de tumeur anti-maligne contenant celui-ci comme ingrédient actif
US7855199B2 (en) 2004-03-31 2010-12-21 Zenyaku Kogyo Kabushiki Kaisha Heterocyclic compound and anti-malignant-tumor agent containing the same as active ingredient
US7750001B2 (en) 2005-03-11 2010-07-06 Zenyaku Kogyo Kabushikikaisha Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient
US8338414B2 (en) 2005-03-11 2012-12-25 Zenyaku Kogyo Kabushikikaisha Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient
WO2012176878A1 (fr) * 2011-06-23 2012-12-27 学校法人自治医科大学 Inhibiteur du protéasome
JPWO2012176878A1 (ja) * 2011-06-23 2015-02-23 学校法人自治医科大学 プロテアソーム阻害剤

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