WO2004032933A1 - Methode permettant de traiter le cancer - Google Patents

Methode permettant de traiter le cancer Download PDF

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Publication number
WO2004032933A1
WO2004032933A1 PCT/JP2003/013048 JP0313048W WO2004032933A1 WO 2004032933 A1 WO2004032933 A1 WO 2004032933A1 JP 0313048 W JP0313048 W JP 0313048W WO 2004032933 A1 WO2004032933 A1 WO 2004032933A1
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group
trimethoxyphenyl
pyridine
methyl
production example
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PCT/JP2003/013048
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English (en)
Japanese (ja)
Inventor
Chikage Mataki
Tatsuhiko Kodama
Takeshi Doi
Masahiro Tamura
Toshiaki Oda
Shunji Takemura
Masao Ohkuchi
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Kowa Co., Ltd.
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Priority to AU2003280558A priority Critical patent/AU2003280558A1/en
Publication of WO2004032933A1 publication Critical patent/WO2004032933A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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

Definitions

  • the present invention relates to novel cancer therapeutics and methods.
  • the present inventors have searched for a substance having an inhibitory effect on cancer cell growth by using a cultured cell system.
  • the group of compounds represented by the general formula (1) described below has been identified as 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.
  • a 2 represents one CH 2 —, one CH 2 CH 2 —, one CO— or _CH (CH 3 ) —;
  • R 1 represents hydrogen
  • R 2 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an arylalkyl group, a heteroarylalkyl group, a carboxyalkyl group, a carbamoylalkyl group, an aminoalkyl group or a guanidino atom;
  • Z represents an alkyl group;
  • Z represents the formula (2) or (3)
  • R 3 , RRR 7 and R 8 are the same or different and represent a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, or a nitro group;
  • R 5 is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom , A nitro group, a naphthyl group, or an alkyl group, an alkoxy group, a halogen atom, a nitro group and a phenyl group which may be substituted by 1 to 3 groups;
  • R 1 and R 2 are both hydrogen atoms, Z is not a 3,4,5-trimethoxyphenyl group! /. ]
  • 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 comprising the above cyclic diamine compound, its acid salt or a hydrate thereof as an active ingredient.
  • the present invention provides the above-mentioned cyclic diamine compound, and an acid thereof; ] It is intended to provide a medicament or composition for cancer treatment, comprising a mouth salt 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.
  • a C! -C 6 -alkyl group is preferable.
  • a hydroxy C i — C 6 -alkyl group is preferable, and specific examples thereof include a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxy-1-methylethyl group, and a 2-hydroxyethyl group.
  • Particularly preferred are a hydroxymethyl group, a 2-hydroxylethyl group, a 2-hydroxyl-1-methylethyl group, a 2-hydroxy-11,1-dimethylethyl group, and a 3-hydroxypropyl group.
  • An aryl C 1 -C 6 -alkyl group is preferred, and specific examples include phenyl CJ-C 6 -alkyl groups such as a benzyl group and a phenethyl group.
  • phenyl CJ-C 6 -alkyl groups such as a benzyl group and a phenethyl group.
  • heteroarylalkyl group a 5- or 6-membered heteroaryl-1-C 6 -alkyl group having 1 or 2 nitrogen atoms as a hetero atom is preferable. More preferably pyridyl-C, 1C W
  • alkyl group pyridinium Mijiru one C, - C 6 - alkyl group, imidazolyl one C "c 6 - alkyl group, pyrrolyl one d-c 6 -.
  • the alkyl group and the like Karubokishiaru kill group, carboxy one A Ci—Ce-alkyl group is preferred, and specific examples thereof include a carboxymethyl group, a carboxyl group, etc.
  • carbamoylalkyl group a carbamoyl-1-C 6 -alkyl group is preferred.
  • Cal Bamoirumechiru group is a force Rubamoiruechiru group, and the like amino group-amino C one C 6 -.!.
  • the guanidinoalkyl group is preferably a guanidino 1 d-c 6 -alkyl group, and specifically, a guanidinomethyl group, Examples include a nidinoethyl group and a guanidinopropyl group.
  • (CH 2) n methylene, ethylene and trimethylene styrene is preferred.
  • CO (CH 2 ) n is preferably CO 2 COCH 2 .
  • a 2 represents CH 2 , CH 2 CH 2 , CO or CH (CH 3 ), with CH 2 and CH 2 CH 2 being particularly preferred.
  • a C! -Ce-alkyl group is preferable, and specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert group
  • examples thereof include a monobutyl group, a pentyl group, and a hexyl group, and a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a tert-butyl group are particularly preferable.
  • a C 6 -alkoxy group is preferable, and specific examples include a methoxy group, an ethoxy group, an isopropoxy group, an n-butoxy group, and an isobutoxy group. Particularly, a methoxy group, an ethoxy group and an isopropoxy group are preferred.
  • halogen atom represented by R 3 to R 8 a chlorine atom, a bromine atom, Examples include a fluorine atom and an iodine atom.
  • R 5 may be a fuel group which may be substituted by 1 to 3 groups selected from an alkyl group, an alkoxy group, a halogen atom, a nitro group and a phenyl group, and the substituent on the phenyl group
  • alkyl group, the alkoxy group, and the halogen atom are the same as those described above.
  • the ring having X and Y in the formula (2) includes a benzene ring, a pyridine ring and a pyrimidine ring.
  • Z is not a 3,4,5-trimethoxyphenyl group.
  • the acid addition salt of the compound (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate.
  • acid addition salts of organic acids such as citrate and 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, for example, according to the following methods a to f.
  • R 9 represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group
  • R ′, R 2 , A 2 and Z are the same as above
  • ethyl 2-ethyl isonicotinate (4) was converted to 3,4,5-trimethoxyphenylboronic acid (5) at 0 ° C.
  • the compound (6) is obtained by reacting at a reflux temperature, preferably 90 ° C., for 10 minutes to several days, preferably overnight. It is preferably mixed with lithium aluminum hydride in THF at room temperature above 20 ° C, preferably at 0 ° C for several minutes to several hours. Or by reacting for 30 minutes to give the alcohol (7).
  • Alcohol (7) is treated with thionyl chloride in a solvent such as chlorophonolem, dichloromethane, ethyl acetate, ether, THF, dioxane or the like at room temperature above -20 ° C, preferably at 0 ° C for 1 hour to several days, preferably 5 hours.
  • Chlorine (8) is obtained by stirring for an hour.
  • the chloro form (8) and the diamine form (9) were converted from room temperature to 100 ° C. in the presence of carbon dioxide in a solvent such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or acetonitrile.
  • a solvent such as chlorophonolem, dichloromethane, ethyl acetate, ether, THF, dioxane or the like
  • Chlorine (8) is obtained by stirring for an hour.
  • the chloro form (8) and the diamine form (9) were converted from room temperature to 100 ° C. in
  • the monosubstituted product (10) is obtained by stirring at room temperature for preferably 1 hour to several days, preferably for 5 hours.
  • the compound (la) is obtained by condensing the compound (10) with the compound (11).
  • the condensation reaction is carried out by stirring in a solvent such as DMF, DMSO, and acetonitrile at room temperature to 100 ° C, preferably 70 ° C for 1 hour to several days, preferably 2 hours, in the presence of potassium carbonate.
  • the halogen atom represented by R 9 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 compound (11) is produced, for example, according to the following reaction formula.
  • R 1Q represents a hydrogen atom or a lower alkyl group
  • a la is (CH 2 ).
  • (CH 2 ) n CH CH, and Z and R 9 are the same as above]
  • the carboxylic acid compound or its ester derivative (12) is reduced using a reducing agent such as lithium aluminum hydride to obtain an alcohol compound (13).
  • the compound (11) is obtained by reacting a halogenating agent such as thionyl chloride with a methanesulfonylating agent.
  • the reduction reaction is performed in the same manner as in the synthesis of the compound (7).
  • thionyl chloride and alcohol (13) are used in a solvent such as chlorophonolem, dichloromethane, ethinole acetate, ethenole, THF, or dioxane.
  • methanesulfonylation methanesulfonyl chloride is used.
  • the stirring is carried out at 0 ° C for 1 hour to several days, preferably for 5 hours.
  • R 9 are the same as above.] That is, the compound (11) and the diamine derivative (9) are condensed to obtain a mono-substituted product (14), which is then reacted with the compound (8) to obtain a compound (la). In this reaction, the condensation reaction between the compound (11) and the diamine derivative (9) and the condensation reaction between the compound (14) and the compound (8) are respectively performed by the compound (10) and the compound (11). And the reaction of compound (8) with compound (9).
  • R 11 represents a halogen atom or a hydroxy group
  • R 1 R 2 , A 2 and Z are the same as above.
  • the compound (1b) is obtained by condensing the compound (10), which is an acid chloride or a carboxylic acid, with the compound (10).
  • the reaction between the acid chloride (15) and the compound (10) is carried out in a solvent such as chloroform and dichloromethane at 0 ° C. to a reflux temperature, preferably at room temperature for 1 hour to several days, preferably It is performed by stirring at B temple.
  • Carboxylic acid (15) and compound (10) For example, in a solvent such as chloroform and dichloromethane, dicyclohexyl carpoimidide, 1-ethyl-3- (3-dimethylaminopropyl) carbopimid 'hydrochloride (water-soluble carbodiimide hydrochloride)
  • a dehydrating condensing agent such as diisopropylpropylcarbodiimide at 0 ° C. to a reflux temperature, preferably at room temperature, for 10 minutes to several days, preferably for 6 hours.
  • a 2 is CH 2 , CH 2 CH 2 or CH (CH 3 ), and R 1 and R 2 are the same as above. ]
  • the compound (8) and the diamine derivative (9) are mixed with a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or acetonitrile in the presence of potassium carbonate from room temperature to 100 ° C, preferably 80 ° C.
  • a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or acetonitrile in the presence of potassium carbonate from room temperature to 100 ° C, preferably 80 ° C.
  • the compound (lc) is obtained by stirring at ° C for 1 hour to several days, preferably for 5 hours.
  • a 1 — Z is a 2- (3,4,5-trimethoxyphenyl) pyridylmethyl group and A 2 is CO.
  • the glycine methyl ester (16) is reacted with 2-2-trobenzene motivationfonyl chloride by a known method to obtain a 2-nitrobenzenesulfonyl compound (17).
  • the compound (17) is reacted with the compound (8) under the same conditions as described above to obtain the compound (18).
  • the compound (18) is treated by a known method to obtain a compound (19).
  • Compound (19) is reduced with lithium aluminum hydride in the same manner as described above to obtain alcohol (20).
  • Compound (20) is dissolved in a solvent such as dichloromethane, acetonitrile, DMF, or the like, in the presence of a base such as imidazole, triethylamine, 4-methylmorpholine, 4- (dimethylamino) pyridine, and tert-butyldimethylchlorosilane (TBD MS-C 1). And a reflux temperature of 0 ° C., preferably 50 ° C., for 1 hour to several days, preferably overnight, to obtain a TBDMS compound (21).
  • a solvent such as dichloromethane, acetonitrile, DMF, or the like
  • a base such as imidazole, triethylamine, 4-methylmorpholine, 4- (dimethylamino) pyridine, and tert-butyldimethylchlorosilane (TBD MS-C 1).
  • TBD MS-C tert-butyldimethylchlorosilane
  • Compound (21) was treated with 9-fluorenylmethoxycarbonyl amino acid (Fmoc-amino acid) (22) and dicyclohexylcarposimidate in a solvent such as chloroform, dichloromethane, acetonitrile, THF, DMF, DMSO, etc.
  • a solvent such as chloroform, dichloromethane, acetonitrile, THF, DMF, DMSO, etc.
  • the compound (24) is reacted with the above-mentioned 2-nitrobenzenesulfonyl chloride under the same conditions as described above to obtain a 2-nitrobenzenesulfonyl compound (25).
  • the compound (25) is treated by a known method to obtain an alcohol (26).
  • Compound (26) is dissolved in a solvent such as THF or dioxane, and triphenylphosphine and dimethyl ether carboxylate (DEAD) are refluxed at 0 ° C, preferably at room temperature for 1 hour to several days, preferably overnight.
  • the compound (27) is obtained by the reaction.
  • Compound (27) is subjected to de-2-nitrobenzenesulfonylation by a known method to obtain compound (28).
  • the compound (1d) is obtained by reacting the compound (28) with the above chlorinated compound (8) under the same conditions as described above.
  • N-benzylglycineethyl ester (29) is reacted with Fmoc-amino acid (N- (9-fluorenylmethoxycarbonyl) amino acid) (30) by a known method to obtain a dipeptide derivative (31).
  • Compound (31) undergoes de-Fmoc cyclization and cyclization simultaneously by a known method to obtain diketobiperazine derivative (32).
  • the compound (32) is treated by a known reduction method using lithium aluminum hydride or the like to obtain a piperazine derivative (33).
  • Compound (33) is subjected to debenzylation by known catalytic reduction using palladium monocarbon to obtain compound (34).
  • the compound (34) is reacted with the above-mentioned chlormouth (8) under the same conditions as described above to obtain a compound (1e).
  • 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 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 cancer therapeutic agent 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 can be appropriately selected depending on the purpose of treatment. , Oral, injection, suppository, ointment, inhalant, eye drop, nasal drop, patch, and the like. Can be produced by a known and commonly used formulation method.
  • 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.
  • Such additives may be those commonly used in the art, such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystals. Cellulose, silicic acid, etc.
  • binders water, ethanol, propanol, simple syrup, dextrose solution, starch solution, gelatin solution, carboxy methinoresenolerose, hydroxypropinoresenorelose, hydroxypropinoresoreryl, methinoreser Oral, ethylethylenolose, shellac, canolesum phosphate, polyvinylpyrrolidone, etc.Disintegrants include dried starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium laurinole sulfate, monoglyceride stearate, milk Etc., as lubricants purified talc, stearic emissions salt, borax, polyethylene glycol, sucrose as a flavoring agent, orange peel, click Examples thereof include citric acid and tartaric acid.
  • a flavoring agent When preparing an oral liquid preparation, add a flavoring agent, a buffer, a stabilizing agent, a flavoring agent, etc. 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 a flavoring agent
  • sodium citrate and the like are used as a buffer
  • tragacanth, acacia, gelatin and the like are used as a stabilizer.
  • a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to the compound (1), and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.
  • a 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 chloride, glucose and the like.
  • the compound (1) may be added to a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and, if necessary, Tween (registered trademark). After adding a suitable surfactant and the like, it can be produced by an ordinary method.
  • a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and, if necessary, Tween (registered trademark).
  • a base, a stabilizer, a wetting agent, a preservative, and the like which are usually used for the compound (1), are mixed as necessary, and mixed and formulated by a conventional method.
  • the base include liquid paraffin, white petrolatum, beeswax, octyldodecyl 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 which can be obtained by intensively treating various cancers, for example, pituitary adenoma, auditory schwannoma, glioma, brain tumor, etc., brain, nerve, eye cancer, oral cancer (tongue cancer, oral floor cancer , Gum 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-gallbladder and knee cancer, such as breast cancer such as dermatomas, gastric cancer,
  • Urinary cancer such as penile cancer, testicular tumor, renal pelvis and ureteral cancer, prostate cancer, renal cell cancer, bladder cancer, vulvar cancer, uterine cancer, cervix cancer, endometrial cancer (endometrial cancer), uterus Gynecological cancers, such as sarcomas, villous diseases, vaginal cancer, breast cancer, ovarian cancer, ovarian germ cell tumors, malignant melanoma (melanoma), mycosis fungoides, skin cancer, etc.
  • sarcomas such as penile cancer, testicular tumor, renal pelvis and ureteral cancer, prostate cancer, renal cell cancer, bladder cancer, vulvar cancer, uterine cancer, cervix cancer, endometrial cancer (endometrial cancer), uterus Gynecological cancers, such as sarcomas, villous diseases, vaginal cancer, breast cancer, ovarian cancer, ovarian germ cell tumors, malignant melanom
  • 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, rhabdomyosarcoma, angiosarcoma, vascular sarcoma, lymphatic sarcoma, neurosarcoma, malignant neuroepitheloma, soft tissue Ewing sarcoma, extraosseous chondrosarcoma, extraosseous Bone and muscle cancers such as osteosarcoma, alveolar soft tissue sarcoma, epithelioid sarcoma, and clear cell sarcoma), malignant lymphoma, malignant lymphoma (n
  • endocrine carcinomas such as cell tumors, knee endocrine tumors, parathyroid cancer and adrenal carcinoma
  • pediatric cancers such as soft tissue sarcomas, brain tumors, retinoblastoma, Wilms tumors, and other cancers of unknown primary origin.
  • 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. Usually, 1 to 100 mg of the compound (1) per day is 1 to adults. It is preferable to administer orally or parenterally once or several times.
  • Example 1 1-[[2— (3,4,5-trimethoxyphenyl) pyridine-14-yl] methyl] pidazine (172 mg) and 4-bromolipenyl benzene (97 mg) The title compound was obtained by reacting in the same manner as described above to obtain a maleate salt. Yield: 60 mg (17%)
  • Phenylboronic acid (147 mg) and ethyl 2-ethyl nicotinate (200 mg) were treated in the same manner as in Production Example 1 to obtain the title compound.
  • Lithium aluminum hydride (579 mg) was added to anhydrous THF (4 OmL) under an argon stream and ice-cooling, and then 5,6,7-trimethoxynaphthalene-1-carboxylic acid (4.0 g) was added.
  • An anhydrous THF solution (4 OmL) 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.
  • reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 56 1-[[2- (3,4,5-trimethoxyphenol) pyridine-4-yl] methyl] pidazine (103 mg) and 3,4,5-trimethoxycholic acid (65 m g) was reacted as in Example 56 to give the title compound as the free base.
  • Example 56 1-[[2- (3,4,5-trimethoxyphenyl) pyridine-14f1] methyl] piperazine (103 mg) and 2,3,4-trimethoxycholic acid (65 mg) were prepared in Example 56. The title compound was obtained as a free base.
  • the anti-reaction solution is concentrated under reduced pressure and reduced pressure, and the residue residue is added with ethityl acetic acid acetic acid to the residue to obtain saturated sodium bicarbonate bicarbonate.
  • the extract was washed, washed and washed with a saturated Japanese saline solution, dried and dried on anhydrous sodium sulfate sulfate, and concentrated under reduced pressure under reduced pressure. .
  • reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des médicaments thérapeutiques destinés au traitement du cancer. Ces médicaments contiennent, en tant que principe actif, des composés de diamine cyclique, représentés par la formule générale (1), des sels d'addition acides, ou des hydrates de ceux-ci; dans la formule, A1 représente (CH2)n , (CH2)n CH=CH-, -CO-(CH2)-, OU CO-(CH2)n-CH=CH- (n représentant un chiffre compris entre 0 et 3); A2 représente CH2-, -CH2CH2, -CO-, ou CH(CH3)-; R1 et R2 représentent, chacun, hydrogène, alkyle, ou un élément similaire; et Z est un groupe représenté par la formule générale (2) ou par la formule générale (3); dans ces formules, R3, R4, R5, R6, R7 et R8 représentent chacun, indépendamment les uns des autres, hydrogène, alkyle, ou un élément similaire; et X et Y représentent chacun, indépendamment l'un de l'autre =CH- ou =N-), pour autant que lorsque R1 et R2 représentent hydrogène, Z ne soit pas 3,4,5-triméthoxyphényl.
PCT/JP2003/013048 2002-10-11 2003-10-10 Methode permettant de traiter le cancer WO2004032933A1 (fr)

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AU2003280558A AU2003280558A1 (en) 2002-10-11 2003-10-10 Method for treatment of cancer

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US41759802P 2002-10-11 2002-10-11
US60/417,598 2002-10-11

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008147864A2 (fr) * 2007-05-22 2008-12-04 Xenon Pharmaceuticals Inc. Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium
US7767680B2 (en) 2004-11-03 2010-08-03 Vertex Pharmaceuticals Incorporated Ion channel modulators and methods of use
US8536186B2 (en) 2008-08-04 2013-09-17 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
RU2492163C9 (ru) * 2009-04-03 2013-12-27 Нэйчуруайз Байэутек & Медиклз Копэрейшн Соединения коричной кислоты (варианты), промежуточные соединения для их получения, фармацевтическая композиция на их основе, способ ингибирования гистоновой деацетилазы, способ лечения диабета, способ лечения опухоли или заболевания, связанного с пролиферацией клеток, способ усиления роста аксонов и способ лечения нейродегенеративных заболеваний и спинной мышечной атрофии
US8883785B2 (en) 2010-01-25 2014-11-11 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9428464B2 (en) 2011-08-30 2016-08-30 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9981918B2 (en) 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10258621B2 (en) 2014-07-17 2019-04-16 Chdi Foundation, Inc. Methods and compositions for treating HIV-related disorders
US10905687B2 (en) 2016-10-27 2021-02-02 Escalier Biosciences B.V. Substituted piperazines as ROR-gamma modulators
US11230555B2 (en) 2018-03-12 2022-01-25 Escalier Biosciences B.V. Bicyclic RORγ modulators
US11242350B2 (en) 2018-03-12 2022-02-08 Escalier Biosciences B.V. Spirocyclic ROR-gamma modulators

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US6509329B1 (en) * 2001-06-29 2003-01-21 Kowa Co., Ltd. Cyclic diamine compound with 6-membered ring groups
US20030022887A1 (en) * 2001-06-29 2003-01-30 Kowa Co., Ltd. Unsymmetrical cyclic diamine compound

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WO1993022303A1 (fr) * 1992-04-23 1993-11-11 Glaxo Group Limited Derives 1-piperazinacetiques utilises comme antagonistes de recepteur de fibrinogene
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
US6432957B1 (en) * 2001-06-29 2002-08-13 Kowa Co., Ltd. Piperazine derivative
US6509329B1 (en) * 2001-06-29 2003-01-21 Kowa Co., Ltd. Cyclic diamine compound with 6-membered ring groups
US20030022887A1 (en) * 2001-06-29 2003-01-30 Kowa Co., Ltd. Unsymmetrical cyclic diamine compound

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8546414B2 (en) 2004-11-03 2013-10-01 Vertex Pharmaceuticals Incorporated Ion channel modulators and methods of use
US7767680B2 (en) 2004-11-03 2010-08-03 Vertex Pharmaceuticals Incorporated Ion channel modulators and methods of use
US8236815B2 (en) 2004-11-03 2012-08-07 Vertex Pharmaceuticals Incorporated Ion channel modulators and methods of uses
WO2008147864A3 (fr) * 2007-05-22 2009-07-09 Xenon Pharmaceuticals Inc Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium
WO2008147864A2 (fr) * 2007-05-22 2008-12-04 Xenon Pharmaceuticals Inc. Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium
US9145373B2 (en) 2008-08-04 2015-09-29 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US8536186B2 (en) 2008-08-04 2013-09-17 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
RU2492163C9 (ru) * 2009-04-03 2013-12-27 Нэйчуруайз Байэутек & Медиклз Копэрейшн Соединения коричной кислоты (варианты), промежуточные соединения для их получения, фармацевтическая композиция на их основе, способ ингибирования гистоновой деацетилазы, способ лечения диабета, способ лечения опухоли или заболевания, связанного с пролиферацией клеток, способ усиления роста аксонов и способ лечения нейродегенеративных заболеваний и спинной мышечной атрофии
US8883785B2 (en) 2010-01-25 2014-11-11 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9428464B2 (en) 2011-08-30 2016-08-30 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9981918B2 (en) 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10258621B2 (en) 2014-07-17 2019-04-16 Chdi Foundation, Inc. Methods and compositions for treating HIV-related disorders
US10905687B2 (en) 2016-10-27 2021-02-02 Escalier Biosciences B.V. Substituted piperazines as ROR-gamma modulators
RU2753490C2 (ru) * 2016-10-27 2021-08-17 Эскальер Байосайенсес, Бв Модуляторы ror-гамма
US11230555B2 (en) 2018-03-12 2022-01-25 Escalier Biosciences B.V. Bicyclic RORγ modulators
US11242350B2 (en) 2018-03-12 2022-02-08 Escalier Biosciences B.V. Spirocyclic ROR-gamma modulators

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