WO2004111023A1 - Derive de 1-oxyde de thiadiazoline - Google Patents

Derive de 1-oxyde de thiadiazoline Download PDF

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Publication number
WO2004111023A1
WO2004111023A1 PCT/JP2004/008374 JP2004008374W WO2004111023A1 WO 2004111023 A1 WO2004111023 A1 WO 2004111023A1 JP 2004008374 W JP2004008374 W JP 2004008374W WO 2004111023 A1 WO2004111023 A1 WO 2004111023A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
lower alkyl
unsubstituted lower
acceptable salt
Prior art date
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PCT/JP2004/008374
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English (en)
Japanese (ja)
Inventor
Chikara Murakata
Yoji Ino
Kazuhiko Kato
Junichiro Yamamoto
Ryuichiro Nakai
Masahiro Hoshikawa
Koji Suzuki
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Fuji Photo Film Co., Ltd.
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Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd., Fuji Photo Film Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to JP2005506964A priority Critical patent/JPWO2004111023A1/ja
Publication of WO2004111023A1 publication Critical patent/WO2004111023A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • 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 thiadiazoline-l-oxide derivative or a pharmaceutically acceptable salt thereof, which is useful for treating a tumor.
  • Drugs such as bin-drugs, aldo-droids, and taxanes, which are clinically important anticancer drugs, bind to microtubules and have the effect of inhibiting the function of spindles that use microtubules as structural units.
  • Spindle function is essential for centrosome localization and accurate chromosome segregation during cell division (cell cycle M phase), and inhibition of its function impairs normal cell division and causes cell death in cancer cells.
  • Biochemicals, biophysical, research communications which are known to induce (Biochems. Biophys. Res.
  • microtubules are involved not only as constituent molecules of the M-phase spindle, but also in the maintenance of cell morphology, intracellular substance transport, and axonal transport of nerve fibers
  • anticancer drugs acting on microtubules act on cancer cells It also has side effects on normal cells as well. For example, as a side effect characteristic of microtubule agonists, peripheral neuropathy due to inhibition of axonal transport of nerve fibers has become a clinical problem. Therefore, drugs that act on molecules other than microtubules, which are important for the control of spindle function in the M phase of the cell cycle, and that inhibit spindle function in the same way as existing microtubule-acting anticancer drugs are the microtubules found in existing anticancer drugs. It is expected to be a new anticancer agent that avoids the above-mentioned side effects derived from its action.
  • M-phase kinesin is a protein involved in M-phase spindle control and plays an essential role in M-phase progression of the cell cycle. These proteins have the function of moving proteins along microtubules by utilizing the energy generated by ATP hydrolysis. A group of functional proteins called "molecular motors". In the M phase, it is deeply involved in the elongation and maintenance of the spindle and the formation of a structure called the spindle pole, and also controls the progress of correct cell division through the movement of chromosomes along spindle microtubules.
  • Eg5 M-phase kinesin easy five is one of the M-phase kinesins that forms an evolutionarily conserved subfamily.
  • Eg5 is a homotetrameric dipolar molecule that bridges two identically oriented microtubules and moves them toward the + (plus) end, between two antiparallel microtubules. It is known that by causing a sliding at a distance, one (minus) ends of microtubules are separated from each other, thereby separating the spindle poles and participating in the formation of a bipolar spindle structure.
  • the function of Eg5 has been elucidated from antibody transfection experiments and analysis of human cells using specific inhibitors [Cell (Ce 11), Vol. 83, p. 1159 (1995 ); Job ⁇ Cell ⁇ Biology
  • the gene is G enB an k a c c e s s io n numb er: X85137, NM004523,
  • Eg5 Eg5 in normal human tissues is limited to the testis and thymus, etc.Furthermore, analysis of the tissues of cancer patients shows that human Eg5 is It has been reported to show high expression [Proceedings.of the.Nashonanore 'Academy. Op.'Sciences.'ob'U.S.A. (Proc. Natl. Ac ad. Sci. USA ), Vol. 99, p. 4465 (2002), US 6414121 B 1].
  • M-phase kinesin E g5 is important as a target molecule for novel M-phase agonists, and its inhibitors are promising as therapeutic agents for diseases such as cancer caused by abnormal cell growth control. Conceivable.
  • Monasterol is a compound that exhibits human Eg5 enzyme inhibitory activity.
  • thiadiazoline derivatives those having a transcription factor stat 6 (STAT6) activation inhibitory activity and an integrin antagonistic action are known (JP-A-2000-229959, WO 01/56994).
  • STAT6 transcription factor stat 6
  • integrin antagonistic action those having antibacterial activity, ACE inhibitory activity, etc. are also known (W093Z22311, Journal of Banda Delish Chemical Society (J. Bangladesh).
  • malignant tumors breast, stomach, ovarian, colon, lung, brain, larynx, blood system cancers, urinary reproduction including bladder and prostate cancers
  • Thiadiazolin-l-oxide derivative or its pharmacologically acceptable which is useful for the treatment of vascular, renal, skin, liver, knee, uterine cancer, etc., restenosis, cardiac hypertrophy, immunological disease, etc.
  • the present invention relates to the following (1) to (28).
  • An unsubstituted heterocyclic group one COR 2Q (where R 2 ° represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, amino, substituted or unsubstituted lower alkylamino, substituted or Unsubstituted di-lower alkylamino or substituted or unsubstituted arylamino ) Or in one SO 2 R 21 (wherein, R 21 represents a a) synonymous with said R 9] or
  • R 15A, R 15B, 1 15 Jioyobi 1 1513 may be different or the same over, bonded to the adjacent two carbon atoms
  • R 6A wherein, W a and R 6 a is Each has the same meaning as W and R 6 described above).
  • R 1 is hydrogen
  • R 2 and R 3 are acetyl
  • R 4 is not hydrogen or methyl> a thiadiazoline-111-oxide derivative represented by the formula or a pharmaceutically acceptable salt thereof.
  • R 4 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted lower alkynyl
  • R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl A ring group or a substituted or unsubstituted aryl, or R 4 and R 5
  • R 4 and R 5 are linked together to represent one (CH 2 ) ml -Q- (CH 2 ) m2 — (wherein m 1, m 2 and Q are as defined above)
  • m 1, m 2 and Q are as defined above
  • R 6 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cyclo-alkyl (13) thiadiazoline one 1- Okishido according A derivative or a pharmacologically acceptable salt thereof.
  • R 1 and R 2 form a connexion substituted or unsubstituted multiple ring groups together with the adjacent nitrogen atom (1) thiadiazoline one 1-O key according to any one of the - (10) Sid derivatives or pharmacologically acceptable salts thereof.
  • W A is Chiajia gelsolin one 1- Okishido derivative or a pharmacologically acceptable salt thereof according to any one of an oxygen atom (18) to (20).
  • a medicament comprising, as an active ingredient, the thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (21).
  • An M-phase kinesin Eg5 inhibitor comprising, as an active ingredient, the thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (21).
  • An antitumor agent comprising, as an active ingredient, the thiadiazolin-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (21).
  • a method for inhibiting M-phase kinesin Eg5, which comprises administering an effective amount of the thiadiazolin-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (21). .
  • a method for treating a malignant tumor which comprises administering an effective amount of the thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (21).
  • the lower alkyl moiety of lower alkyl, lower alkoxy, lower alkylamino or lower alkylamino is, for example, straight-chain or branched alkyl having 1 to 10 carbon atoms, specifically methyl, ethyl, propyl Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentynole, isopentynole, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • the two lower alkyl moieties of the di-loweralkylamino may be the same or different.
  • alkenyl for example, a straight-chain or branched alkenyl having 2 to 10 carbon atoms, specifically, bininole, aryl, 1_propenyl, buteninole, penteninole, pentenyl, hexenyl, Heptul, Otatul, Nonenyl, Decenyl and the like.
  • lower alkynyl for example, linear or branched alkyl having 2 to 10 carbon atoms, specifically, ethininole, probel, butyninole, penture, hexinyl, heptinole, octinii / , Noninyl, and desininole.
  • cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl / le, cyclobutyl / le, cyclopentinole, cyclohexinole, cycloheptyl, cyclooctyl, and the like.
  • the aryl portion of aryl, aryloxy and arylamino includes, for example, feninole and naphthyl.
  • heterocyclic group examples include an aliphatic heterocyclic group and an aromatic heterocyclic group.
  • aliphatic heterocyclic group for example, a 5- or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are fused.
  • a condensed aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom such as azetidur, tetrahydrophenyl, and tetrahydrogen.
  • Dorothiopyral imidazolidinyl, pyrrolidinyl, oxazolinyl, dioxolanyl, piperidino, piperi Dinyl, piperazur, morpholino, morpholinyl, thiomorpholinyl, homopyridinyl, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuruel, tetrahydrovinylanil, dihydrobenzofuranyl, etc. .
  • aromatic heterocyclic group examples include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, A condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is a condensed bicyclic or tricyclic ring, and specifically, furyl, chenyl , Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxosazolyl, isoxazolyl, thiadiazolyl, oxaziazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzoinyl, benzoinyl, benzoinyl, benzoyl, benzoy
  • Examples of the heterocyclic group formed together with the adjacent nitrogen atom include an aliphatic heterocyclic group containing at least one nitrogen atom.
  • the aliphatic heterocyclic group containing at least one nitrogen atom may contain an oxygen atom, a sulfur atom or another nitrogen atom, for example, 1-pyrrolyl, pyrrolidinyl, morpholino, thiomorpholino, virazolidinyl, piperidino, Piperazinile, homopiperazinyl, aziridinyl, azetidur, azolidinyl, perhydroazebul, perhydroazosinyl, tetrahydroquinolinole, tetrahydroisoquinolinyl, indolyl, isoindolyl, 1,3-dihydroisoindolyl, pyrrolidinyl, sulcinyl And piperidonyl.
  • the cycloalkylene includes, for example, cycloalkylene having 3 to 8 carbon atoms, specifically, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclootylene and the like.
  • cycloalkylene having 3 to 8 carbon atoms, specifically, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclootylene and the like.
  • Nylene 1,2-phenylene, 1,3-phenylene and 1,4-phenylene.
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • the substituents in the substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted cycloalkyl, substituted lower alkoxy, substituted lower alkylamino and substituted dilower alkylamino are the same or different, for example, the number of substituents is 1 to substituted Possible number, preferably 1 to 3, of halogen, hydroxy, oxo, nitro, azide, cyano, carboxy,
  • Substituted or unsubstituted cycloalkyl (substituents (a) in the substituted cycloalkyl are the same or different, for example, having 1 to 3 substituents,
  • Substituted or unsubstituted lower alkoxy (substituent (b) in the substituted lower alkoxy may be the same or different, for example,
  • Halogen hydroxy, oxo, amino, nitro, azide, cyano, carboxy, lower alkoxy, hydroxy-substituted lower alkoxy, lower alkoxy-substituted lower alkoxy, amino-substituted lower alkoxy, lower alkylamino, di-lower alkylamino, hydroxy-substituted lower alkylamino, lower Alkoxy-substituted lower alkylamino, amino-substituted lower alkylamino, lower-alkanoylamino, lower-alkoxycarbonylamino, aralkylamino, aralkyloxy, aryl, aryloxy, heterocyclic group
  • Substituted or unsubstituted lower alkylthio (the substituent in the substituted lower alkylthio is the same as the substituent (b) in the above-mentioned substituted lower alkoxy), substituted or unsubstituted lower alkyl group (in the substituted lower alkyl group) location substituent is the same meaning as substituent (b) in the substituted lower alkoxy), in one NR 2 3 R 2 4 [wherein, R 2 3 and R 2 4 are the same or different,
  • R 23 and R 24 together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group (in a substituted heterocyclic group formed together with the adjacent nitrogen atom)
  • the substituent is the same as the substituent (b) in the lower alkoxy))]
  • Substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (a) in the above-mentioned substituted cycloalkyl),
  • Substituted or unsubstituted lower alkylamino substituted or unsubstituted lower alkylamino are the same as the substituents (a) in the substituted cycloalkyl), substituted or unsubstituted di-lower alkylamino (substituted di-lower alkylamino)
  • the substituent has the same meaning as the substituent (a) in the above-mentioned substituted cycloalkyl), substituted or unsubstituted lower alkyl ⁇ the substituent (c) in the substituted lower alkyl is, for example, ⁇ 3 of
  • Substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (a) in the substituted cycloalkyl), substituted or unsubstituted lower alkylthio (substituted in the substituted lower alkylthio) Is the same as the substituent (a) in the substituted cycloalkyl), a substituted or unsubstituted lower alkyl group (the substituent in the substituted lower alkyl group is the same as the substituent (a) in the substituted cycloalkyl group)
  • a substituted or unsubstituted lower alkoxycarbonyl (substituents in the substituted lower alkoxycarbonyl are the same as the substituents (a) in the substituted alkyl).
  • n represents an integer of 1 to 15, and R 27 represents a hydrogen atom or lower alkyl
  • Substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (a) in the above-mentioned substituted cycloalkyl),
  • Substituted or unsubstituted lower alkyl (substituent in the substituted lower alkyl is the same as the substituent (a) in the substituted cycloalkyl), substituted or unsubstituted lower alkenyl (substituent in the substituted lower alkenyl) Has the same meaning as the substituent (a) in the above-mentioned substituted cycloalkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (a) in the above-mentioned substituted cycloalkyl)
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl is the same as the substituent (a) in the substituted cycloalkyl);
  • a substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (Xii) in the substituted aryl described below),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the same as the substituent (Xiii) in the substituted heterocyclic group described later), a substituted or unsubstituted lower alkyl group (the substituted lower group)
  • the substituent in the aryl group has the same meaning as the substituent (a) in the above substituted cycloalkyl),
  • Substituted or unsubstituted lower alkoxycarbonyl (the substituent in the substituted lower alkoxycarbonyl has the same meaning as the substituent (a) in the above-mentioned substituted cycloalkyl),
  • Substituted or unsubstituted lower alkylsulfonyl (the substituent in the substituted lower alkylsulfonyl is the same as the substituent in the above-mentioned substituted alkyl)
  • Substituted or unsubstituted arylo (the substituent in the substituted arylo is synonymous with the substituent (Xii) in the substituted aryl described below),
  • a substituted or unsubstituted Ararukiru (the substituent in the substituted Ararukiru has the same meaning as the substituent (X ii) in later substituted Ariru), or R 2 8 and R 2 9 are summer together with the adjacent nitrogen atom
  • R 2 8 and R 2 9 are summer together with the adjacent nitrogen atom
  • -CONR 30 R 31 (wherein R 3 ° and R 31 are the same as R 28 and R 2, respectively)
  • Substituted or unsubstituted lower alkyl (substituent in the substituted lower alkyl is the same as the substituent (a) in the substituted cycloalkyl), substituted or unsubstituted lower alkenyl (substituent in the substituted lower alkenyl) Has the same meaning as the substituent (a) in the above-mentioned substituted cycloalkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (a) in the above-mentioned substituted cycloalkyl),
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl is the same as the substituent (a) in the above-mentioned substituted cycloalkyl),
  • a substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (Xii) in the substituted aryl described below),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group has the same meaning as the substituent (Xiii) in the substituted heterocyclic group described later), a substituted or unsubstituted lower alkoxy (in the substituted lower alkoxy,
  • the substituent in this is the same as the substituent (a) in the above-mentioned substituted cycloalkyl) or
  • R 33 and R 34 are each synonymous with the R 28 and R 2 9)
  • R 35 and R 36 are the same or different and represent lower alkyl, or a heterocyclic group wherein R 35 and R 36 are taken together with the adjacent nitrogen atom.
  • R 37 represents lower alkyl and X represents halogen
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (c) in the substituted lower alkyl);
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (C) in the substituted lower alkyl);
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl has the same meaning as the substituent (C) in the substituted lower alkyl);
  • Substituted or unsubstituted aryl substituted or unsubstituted aryl (substituents in the substituted aryl are the same as substituents (Xii) in the substituted aryls described below),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group has the same meaning as the substituent (Xiiii) in the substituted heterocyclic group described later),
  • Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is the same as the substituent (c) in the substituted lower alkyl), substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl is Substituted or unsubstituted lower alkynyl in the substituted lower alkyl (substituted lower alkynyl is the same as the substituent (C) in the substituted lower alkyl); Unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl has the same meaning as the substituent (C) in the substituted lower alkyl), substituted or unsubstituted aryl (the substituent in the substituted aryl is the substituent Synonymous with substituent (xii)),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the same as the substituent (xiiii) in the substituted heterocyclic group described later),
  • Substituted or unsubstituted lower alkoxy substituted or unsubstituted lower alkoxy (substituent in the substituted lower alkoxy is the same as the substituent (c) in the substituted lower alkyl), substituted or unsubstituted aryloxy (replacement in the substituted aryloxy)
  • the substituent is the same as the substituent (X ii) in the substituted aryl described below or the substituted or unsubstituted heterocyclic oxy (the substituent in the substituted heterocyclic oxy is the same as the substituent (X iii) in the substituted heterocyclic ring described later) Is)
  • R 39 and R 4 have the same meanings as R 28 and R 29 respectively), or
  • Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is the same as the substituent (c) in the substituted lower alkyl), substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl is The same as the substituent (c) in the substituted lower alkyl), the substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (C) in the substituted lower alkyl), Unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl has the same meaning as the substituent (C) in the substituted lower alkyl), substituted or unsubstituted aryl (the substituent in the substituted aryl is the substituent Substituent (synonymous with X ii)),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is synonymous with the substituent (xiiii) in the substituted heterocyclic group described later),
  • Substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (c) in the substituted lower alkyl) or -NR 42 R 43 (wherein R 42 and R 43 are each as defined above) Synonymous with R 28 and R 29 )
  • R 25 and R 26 form a substituted or unsubstituted heterocyclic group together with the nitrogen atom which is in contact with P (substituted heterocyclic group formed together with the adjacent nitrogen atom)
  • the substituent in the group has the same meaning as the substituent (X iii) in the substituted heterocyclic group described below. >)
  • Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is the same as the substituent (c) in the above-mentioned substituted lower alkyl),
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkyl has the same meaning as the substituent (c) in the substituted lower alkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (C) in the substituted lower alkyl);
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl has the same meaning as the substituent (C) in the substituted lower alkyl);
  • a substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (xii) in the substituted aryl below) or
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group has the same meaning as the substituent (Xiiii) in the substituted heterocyclic group described later)
  • Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is the same as the substituent (c) in the above-mentioned substituted lower alkyl),
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkyl has the same meaning as the substituent (c) in the substituted lower alkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (C) in the substituted lower alkyl);
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl has the same meaning as the substituent (C) in the substituted lower alkyl);
  • a substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (X ii) in the substituted aryl below),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group has the same meaning as the substituent (xiiii) in the substituted heterocyclic group described later),
  • Substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (c) in the substituted lower alkyl) or
  • Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is the same as the substituent (c) in the above-mentioned substituted lower alkyl),
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (c) in the substituted lower alkyl);
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (C) in the substituted lower alkyl);
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl has the same meaning as the substituent (C) in the substituted lower alkyl);
  • a substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (Xii) in the substituted aryl described below),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group has the same meaning as the substituent (xiiii) in the substituted heterocyclic group described later),
  • halogen is ⁇ , and the above is lower alkyl (i), lower alkenyl (ii), Synonymous with lower alkynyl (iii), cycloalkyl (iv) and halogen (i X), hydroxy-substituted lower alkoxy, amino-substituted lower alkoxy, lower alkoxy-substituted lower alk
  • the two lower alkyl moieties in the di-lower alkylamino may be the same or different.
  • aryl, aryloxy, aryloxycarbonyl and aryloyl, heterocyclic group and heterocyclic group in heteroaryloxy shown here they are formed together with the adjacent nitrogen atom.
  • V; aryl
  • V i the heterocyclic group
  • V ii the heterocyclic group
  • Examples of (x i) include aralkyl having 7 to 15 carbon atoms, specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.
  • Substituted aryl, substituted aryloxy, substituted arylamino and substituted phenylene have the same or different substituents, for example, having 1 to 3 substituents, such as halogen, hydroxy, nitro, cyano, azide, methylenedioxy,
  • Substituted or unsubstituted lower alkyl are Substituents in cycloalkyl (synonymous with ( a )),
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl is the same as the substituent (a) in the above cycloalkyl),
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl is the same as the substituent (a) in the above cycloalkyl),
  • Substituted or unsubstituted aryl (substituent (d) in the substituted aryl is the same or different and is, for example, 1 to 3 substituents,
  • Halogen hydroxy, amino, nitro, azido, cyano, carboxy, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, lower alkanoyl, lower alkanoyloxy, lower alkanoylamino, methylenedioxy, aryl, heterocyclic group
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the same as the substituent (d) in the above-mentioned substituted aryl);
  • Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is the same as the substituent (a) in the above cycloalkyl),
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (a) in the cycloalkyl),
  • a substituted or unsubstituted cycloalkyl (the substituent in the substituted alkyl is the same as the substituent (a) in the cycloalkyl),
  • a substituted or unsubstituted aryl (the substituents in the substituted aryl are Is the same as the substituent (d) on the reel) or
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the same as the substituent (d) in the above-mentioned substituted aryl)
  • Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is the same as the substituent (a) in the above cycloalkyl),
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl is the same as the substituent (a) in the cycloalkyl),
  • a substituted or unsubstituted lower alkyl group (the substituent in the substituted lower alkyl group is the same as the substituent (a) in the cycloalkyl);
  • a substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (d) in the substituted aryl),
  • Substituted or unsubstituted aralkyl (the substituent in the substituted aralkyl is the same as the substituent (d) in the substituted aralkyl) or
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the same as the substituent (d) in the above-mentioned substituted aryl)
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl is the same as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl is the same as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (a) in the cycloalkyl),
  • a substituted or unsubstituted lower alkyl group (the substituent in the substituted lower alkyl group is the same as the substituent (a) in the cycloalkyl);
  • Substituted or unsubstituted lower alkylsulfonyl (the substituent in the substituted lower alkylsulfonyl is the same as the substituent (a) in the cycloalkyl), substituted or unsubstituted aryl (the substituent in the substituted aryl is Is the same as the substituent (d) in the substituted aryl),
  • Substituted or unsubstituted aralkyl (the substituent in the substituted aralkyl is the same as the substituent (d) in the substituted aralkyl),
  • a substituted or unsubstituted aryloyl (the substituent in the substituted aryl is the same as the substituent (d) in the substituted aryl) or
  • R 65 and R 66 together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group (substituted heterocyclic group formed together with the adjacent nitrogen atom) Has the same meaning as the substituent (d) in the aryl.)], CONR 67 R 68 (wherein R 67 and R 68 have the same meanings as R 65 and R 66 , respectively), -SO 2 R 69 wherein R 69 is
  • Substituted or unsubstituted lower alkyl substituted lower alkyl (substituents in the substituted lower alkyl have the same meanings as the above-mentioned substituent (a) in cycloalkyl),
  • Substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the same as the substituent (a) in the cycloalkyl),
  • a substituted or unsubstituted cycloalkyl (the substituent in the substituted alkyl is the same as the substituent (a) in the cycloalkyl),
  • Substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (a) in the cycloalkyl),
  • a substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (d) in the substituted aryl),
  • Substituted or unsubstituted aralkyl (the substituent in the substituted aralkyl is the same as the substituent (d) in the substituted aralkyl),
  • a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the same as the substituent (d) in the above-mentioned substituted aryl) or
  • halogen is the lower alkyl (i), lower alkenyl (ii) and lower alkenyl, respectively.
  • the two lower alkyl moieties in di-lower alkylamino and the three lower alkyl moieties in tri-lower alkylsilyl are identical or different.
  • the aralkyl represented by the aryl and the aryl moiety of the aryl, the heterocyclic group, and the heterocyclic group formed together with the adjacent nitrogen atom, as well as the aralkyl are the aryl (v) and the heterocyclic group ( V i) has the same meaning as the heterocyclic group (V ii) and aralkyl (X i) formed together with the adjacent nitrogen atom.
  • the pharmacologically acceptable salts of compound (I) include, for example, pharmacologically acceptable caroyl salts with acids, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, citrate, etc.
  • Organic salts and the like, and pharmacologically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and the like.
  • Examples of the pharmacologically acceptable ammonium salts include zinc salts and the like.
  • Examples of the pharmacologically acceptable ammonium salts include salts of ammonium and tetramethylammonium
  • examples of the pharmacologically acceptable organic amine addition salts include morpholine.
  • Addition salts such as phosphorus and piperidine can be mentioned, and pharmacologically acceptable amino acid addition salts include, for example, lysine, glycine, fe / realanine, asparagine Acid addition salts such as glutamic acid.
  • Compound (I) can be produced according to the following production method.
  • Compound (I) is prepared by reacting compound (II) with a suitable oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide in a solvent inert to the reaction such as dichloromethane or water. It can be obtained by treating at a temperature between 100 ° C for 5 minutes to 48 hours.
  • a suitable oxidizing agent is preferably used in an amount of 1 to 100 equivalents, more preferably 1 to 4 equivalents, relative to compound (II).
  • Compound (II) can be produced according to the following Production Methods 2 to 12. Manufacturing method 2
  • R 2 is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted R 1 and R 2 together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group, or R 3 is _COR 6A A compound that is
  • (I I a) can be prepared in a known manner [for example, in Journal of Heterocyclic Chemistry (J. Heterocyclic Chem.), Vol. 21, p. 599.
  • R 1 represents each atom of chlorine, bromine or iodine
  • R 2a is one of the above-mentioned definitions of R 2 Hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Or R 1 and R 23 together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group)
  • RR 4 , R 5 , R 6 B and X 1 are each as defined above.
  • the compound (lie) in which R 2 is a hydrogen atom and R 3 is one COR 6B (where R 6B is as defined above) is a compound (lie) obtained by the production method 3.
  • I lb) can also be manufactured by the following process.
  • Compound (IIc) can be prepared by converting compound (I lb) in a suitable solvent such as water, ethanol, acetonitrile, N, N-dimethylformamide, or clotform, for example, sodium hydride, sodium hydroxide or hydrazine. It can be obtained by treating at a temperature between 110 ° C. and the boiling point of the solvent to be used in the presence of a suitable base such as a hydrate for 5 minutes to 24 hours.
  • the solvent can be used alone or as a mixture.
  • the base is preferably used in an amount of 1 to 200 equivalents, more preferably 1 to 10 equivalents, relative to compound (lib).
  • compound (IIc) can also be produced by the following method.
  • Compound (IIc) is prepared by converting compound (lib) to a solvent such as methanol or tert-butanol in the presence of a reducing agent such as sodium borohydride, if necessary, such as cerium chloride heptahydrate. It can be obtained by a treatment at a temperature of between 10 ° C. ( ⁇ 100 ° C.) for 5 minutes to 24 hours in the presence.
  • the reducing agent is preferably used in an amount of 1 to 200 equivalents based on compound (lib). Manufacturing method 5
  • the compound (IIe) in which R 2 is one COR 6 and R 3 is —COR 6c (wherein R 6c has the same meaning as the above R 6 ) is obtained by the production method 2
  • the compound (IIc-a) obtained by the production method 4 can also be produced by the following steps.
  • Compound (II e) is obtained by converting compound (II c—a) without solvent or acetone or ethyl acetate. , Acetonitrile, N, N-dimethylformamide, dichloromethane, etc. in a solvent inert to the reaction in the presence of a suitable base such as pyridine, 4- (dimethylamino) pyridine (DMAP), sodium hydride, etc. It can be obtained by reacting (VI e) or compound (VI f) at a temperature between 10 ° C and 150 ° C for 5 minutes to 24 hours. The compound (Vie) or the compound (VIf) is used in an amount of preferably 1 to 20 equivalents, more preferably 1 to 3 equivalents, to the compound (IIc_a), respectively.
  • the compound (IIf) wherein R 2 is —S0 2 R 14 and R 3 is one COR 6c is obtained from the compound (II ca) obtained by the production method 2 or 4.
  • it can be produced by a method described in, for example, Shin-Jikken Kagaku Koza, Vol. 14, p. 1803 (Maruzen Co., Ltd., 1978), or in accordance therewith.
  • the compound (II g) in which R 2 is one NRUR 12 and R 3 is —COR 6A is obtained from Indian Journal of Chemistry.
  • RR 4 , R 5 , R 6A , R 11 and R 12 are as defined above.
  • R 1 is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted cycloalkyl
  • the compound (IIe—b) which is a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group is a compound (lie) obtained by the production method 5 wherein R 1 is a hydrogen atom. From II e-a), it can also be manufactured by the following process.
  • R 4 , R 5 , R 6 , R 6A and X 1 are as defined above, and R la is a substituted or unsubstituted lower alkyl, substituted or unsubstituted in the definition of R 1 above.
  • R la represents lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group
  • Compound (IIe—b) is prepared by reacting compound (IIea) with compound (IX) in a solvent inert to a reaction such as N, N-dimethylformamide in the presence of a suitable base such as sodium hydride. And at a temperature between 110 ° C and the boiling point of the solvent to be used, for 5 minutes to 24 hours.
  • the base and the compound (IX) are preferably used in an amount of preferably 1 to 100 equivalents and 1 to 100 equivalents, more preferably 2 to 5 equivalents or 2 to 3 equivalents, respectively, based on the compound (IIe-a). . Manufacturing method 9
  • the compound (IIh) in which R 3 is a hydrogen atom is, for example, phosphorous sulfur and 'silicon' and the relatable 'element (.Phosphorus Su 1 fur & Si) 1 icon & Related Elements), Vol. 122, p. 307 (1997), Himika 'Berichte
  • compound (II j) is prepared by converting compound (I lk) into a solvent such as toluene, pyridine or tetrahydrofuran, and using a suitable sulfurizing agent such as 2,4-bis (4-methoxyphenyl) 1-1,3- Dithia-1,2,4-diphosphoethane-1,2,4-disulphide (Law sson's reagent), phosphorus pentasulfide, etc., at a temperature between -10 ° C and the boiling point of the solvent used for 5 minutes It can be obtained by treating for ⁇ 24 hours.
  • the sulfurizing agent is preferably used in an amount of 1 to 50 equivalents, more preferably 2 to 10 equivalents, relative to compound (Ilk).
  • the compound (II) wherein R 3 is one COR 6 and R 1 and R 2 together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group is The compound (IIn) obtained by the production method 2 or the production method 4 can also be produced by the following steps.
  • X 2 represents each atom of chlorine, bromine or iodine
  • R lb and R 23 ⁇ 4 are formed together with the adjacent nitrogen atom.
  • the heterocyclic group formed together with the adjacent nitrogen atom is a heterocyclic group formed together with the adjacent nitrogen atom.
  • the compound (IIp) is mixed with the compound (X) without solvent or in a solvent inert to a reaction such as dichloromethane, N, N-dimethylformamide at a temperature between 10 ° C and 200 ° C for 5 minutes. ⁇ 24 hours of reaction Wear.
  • Compound (X) is preferably used in an amount of 1 to 200 equivalents, more preferably 2 to 50 equivalents, based on compound (IIp).
  • the intermediate compound (I I p) can be obtained from compound (I In) by, for example, Chemi-Konore 'Communication (Chem. Commun.), Vol. 8, p. 873.
  • the compound (I Im) is a compound (IIe) obtained by the production method 5 in which R 1 is a hydrogen atom and R 6 is an alkyl group substituted with a carboxyl group.
  • II e—c for example, synthesis Suggard
  • the compound (I Im) is obtained from the compound (II e — d) in which R 1 is a hydrogen atom and R 6 is an alkyl group substituted with a halogen, among compounds (II e). , Vol. 14, p. 1174 (Maruzen Co., Ltd., 1978), etc., or according to them.
  • Intermediates and target compounds in the above-mentioned production methods can be purified by methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, high-performance liquid chromatography, thin-layer chromatography, silica gel chromatography, etc. It can be purified and isolated by various chromatographies. In addition, the intermediate can be subjected to the next reaction without particular purification.
  • Some compounds (I) may have stereoisomers such as positional isomers, geometric isomers, optical isomers, and tautomers, but the present invention includes all possible isomers. And the isomers and mixtures thereof.
  • compound (I) When it is desired to obtain a salt of compound (I), if compound (I) can be obtained in the form of a salt, it can be purified as it is, and if compound (I) can be obtained in a free form, compound (I) can be purified. What is necessary is just to dissolve or suspend in a suitable solvent, add an acid or a base to form a salt, and isolate.
  • the compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
  • Table 1 shows specific examples of the compound (I) obtained by the present invention. However, the compound of the present invention is not limited to these.
  • Test Example 1 Growth inhibitory activity against human colon cancer cell HCT116
  • HCT116 cells (ATCC number: CCL-247) were dispensed into 96-well microtiter plates (Nunc, 167008) at a rate of 1 ⁇ 10 3 cells / well. After culturing the plate in a 5% CO 2 incubator at 37 ° C for 24 hours, a serially diluted test compound is added thereto to make a total of 10 OmL Nowell, and further 37 ° C in a 5% CO 2 incubator. And cultured for 72 hours.
  • GI 5 Calculation method: The value obtained by subtracting the absorbance at 655 nm from the absorbance at 490 nm of each well (difference absorbance) was calculated. The concentration of the compound that inhibits cell growth by 50% by comparing the difference absorbance obtained with cells treated with a known concentration of compound with the difference absorbance obtained with cells not treated with the test compound as 100%. was calculated, and it was set as GI 50 .
  • Table 2 shows the results of representative compounds of the present invention obtained in this test.
  • Preparation of the recombinant full-length human Eg5 protein is carried out with reference to the literature [Cell (Ce 11), vol. 83, p. 1159 (1995)].
  • a baculovirus expressing full-length human Eg5 fused with a His tag at the N-terminus is used to infect S podopterafrugi-perda (S f) 9 insect cells. After culturing, the culture is centrifuged and the cells are centrifuged. Collect the precipitate. Suspend the cell pellet in buffer and collect the supernatant by centrifugation. The supernatant is passed through a nickel agarose column and Hi Eg5 with the s-tag fused to the N-terminus is affinity purified to obtain a partially purified sample.
  • E-6646 1 U / mL Purine nu cleo- sidephosphoryiase (Molecule Hoop Beads, Catalog No. E-6646) with 5 parts of Eg Prepare a reaction solution to which the purified sample has been added. Dispense the solution into a 96-well plate and carry out the enzymatic reaction for 30 minutes at 30 ° C Read the absorbance at 360 nm, which is an indicator of ATPase activity, into a plate reader (Molecular Depays, Inc.).
  • Compounds 1, 3 and 6 inhibited ATPase activity of Eg5 in a concentration-dependent manner, and its IC 5 .
  • the value was less than 5 ⁇ / L.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations.
  • the pharmaceutical preparations are used for animals or humans.
  • the pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient.
  • these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.
  • Examples of the administration form include tablets, injections and the like.
  • tablets suitable for oral administration include excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and fatty acid esters. And a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration comprise sterile aqueous preparations containing the active compound, which is preferably isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of saline and a glucose solution.
  • the excipients, disintegrants, lubricants, One or more scavenging components selected from binders, surfactants, plasticizers and diluents, preservatives, flappers and the like can also be added.
  • the compound (I) or a pharmaceutically acceptable salt thereof is used for the above purpose, it is usually administered systemically or locally, orally or parenterally.
  • the dosage and frequency of administration vary depending on the form of administration, the age and weight of the patient, the nature or severity of the condition to be treated, etc., but in the case of oral administration, it is usually 0.01 to 100 per adult per dose.
  • Omg preferably in the range of 0.05 to 500 mg, is administered once or several times a day.
  • parenteral administration such as intravenous administration, usually, the ability to administer 0.001 to 100 Omg, preferably 0.01 to 300 mg per adult once or several times a day, or in the range of 1 to 24 hours per day Administer intravenously continuously.
  • the dose and the number of administrations vary depending on the various conditions described above.
  • the proton nuclear magnetic resonance spectra (3 ⁇ 4-MR) used in the examples and reference examples were measured at 270 MHz or 300 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. .
  • As the notation of the multiplicity of a signal a commonly used signal is used, and br indicates that the signal is apparently wide.
  • Example 5 (Compound 5) Using the hydrochloride of compound 12a obtained in Reference Example 12 (74.8 mg, 0.170 bandol) and m-oral perbenzoic acid (29.3 mg, 0.170 mmol), the title compound was obtained in the same manner as in Example 1. Compound 5 (36.5 mg, 41%) was obtained as a diastereomeric mixture.
  • Table 3 shows the structures of the compounds 1a to 15a obtained in Reference Examples 1 to 15 below.
  • the 2- (methylsulfonylamino) acetophenone thiosemicarbazone (1.31 g, 4.36 mol) obtained above was dissolved in dichloromethane (5.0 mL), and pivaloyl cucumber lid (2.10 g, 17.4 mmol) and pyridine (1.38 g) were dissolved. g, 17.4 mmol) and stirred at room temperature for 5 hours. To the reaction solution was added a 2 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate.
  • Methanesulfonamide (0.476 g, 5.001! 111101) was dissolved in 1 [, N-dimethylformamide (10 mL), 60% sodium hydride (0.275 g, 5.00 ramol) was added, and the mixture was stirred under water cooling for 20 minutes. .
  • 3-Carbomethoxypropiophenone thiosemicarpazone (7.76 g, 29.2 mmol) obtained above was dissolved in dichloromethane (40 mL). Pyridine (11.3 mL, 140 mmol) and pivaloyl chloride (14.4 mL, 117 mmol) were added to this solution, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • 2-Aminoacetophenone hydrochloride (1.00 g, 5.85 mL) was dissolved in dichloromethane (50 mL), and triethylamine (2.50 mL, 17.9 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Was. After the reaction solution was cooled to 0 ° C., chloroethanesulfuryl chloride (0.92 mL, 8.8 mL) was added, and the mixture was stirred at the same temperature for 15 minutes. 2 mo 1 ZL hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform.
  • 4-carbomethoxybuty-mouth phenone thiosemi-force rubazone was obtained from 4-keto norevomethoxybuty-mouth phenone (0.588 g, 2.85 tmol) and thiosemicarbazide (0.260 g, 2.85 mmol). (0.700 g, 88%).
  • the compound 10a (4.44 g, 10.2 mmol) obtained in Reference Example 10 was dissolved in tert-butanol (100 mL) and heated to 80 ° C. To this solution, triethylamine (1.4 mL, 10.2 mmol) and diphenylphosphoryl azide (2.2 mL, 10.2 mol) were added, and the mixture was stirred at the same temperature for 9 hours. The mixture was concentrated under reduced pressure, added with water (100 mL), and extracted with ethyl acetate (300 mL).
  • N-tert-Putoxycanoleponi / le / 3-alanine 14.82 g, 78.32 mmol
  • Phenylboronic acid 11.46 g, 94.00 benzyl
  • palladium (II) acetate (1.05 g, 4.68 ramol
  • triphenylphosphine (2.88 g, ll. O mmol) were added to tetrahydrofuran (300 Water (3.52 mL, 196 mL) and trimethylacetic anhydride (23.8 mL, 117 mmol) were added, and the mixture was stirred at 60 ° C for 16 B.
  • the 3- (tert-butoxycarbonylamino) propiophenone (9.59 g, 38.5 mmol) obtained above was dissolved in a mixed solvent of methanol (100 mL) and water (25 mL), and the mixture was dissolved in thiosemione.
  • Carpazide hydrochloride (7.36 g, 57.7 mmol) was added, and the mixture was stirred at 40 ° C for 3 hours.
  • thiosemicarbazide hydrochloride (3.51 g, 27.5 ramol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
  • N, N-Dimethyl- ⁇ -aminobutyric acid hydrochloride (0.858 g, 5.12 mol), 1-hydroxybenzotriazole.
  • Monohydrate (0.823 g, 5.37 mmol) and 1- [3- (dimethylamino) [Propyl]-3-ethylcarboimide (0.715 mL, 4.67 mmol) was dissolved in N, N-dimethylformamide (40 ⁇ ) and stirred at 0 ° C for 15 minutes.
  • Compound 14a (1.00 g, 2.56 mmol) was added, and the mixture was stirred at room temperature for 15.5 hours.
  • a tablet having the following composition is prepared by a conventional method. 1,40 g of compound, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. The mixture is kneaded by a conventional method, granulated, dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate was added and mixed. The mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui) having a punch of 8 mm in diameter, and tablets (2 tablets of active ingredient per tablet) were added. Omg). Prescription compound] 20 mg
  • treatment of diseases involving cell proliferation for example, malignant tumors (breast cancer, stomach cancer, ovarian cancer, colorectal cancer, lung cancer, ⁇ tumor, larynx cancer, blood system cancer, urogenital tract including bladder cancer and prostate cancer)
  • malignant tumors breast cancer, stomach cancer, ovarian cancer, colorectal cancer, lung cancer, ⁇ tumor, larynx cancer, blood system cancer, urogenital tract including bladder cancer and prostate cancer
  • restenosis cardiac hypertrophy, immune disease, etc.

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Abstract

Dérivés de 1-oxyde de thiadiazoline de formule générale (I) dans laquelle R1, R2 et R4 représentent des atomes d'hydrogène, des alkyles inférieurs substitués ou non substitués ou analogues, R3 représente un atome d'hydrogène ou analogue et R5 représente un alkyle inférieur substitué ou non substitué ou analogue. La présente invention concerne également des sels acceptables sur le plan pharmaceutique desdits dérivés.
PCT/JP2004/008374 2003-06-10 2004-06-09 Derive de 1-oxyde de thiadiazoline WO2004111023A1 (fr)

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US7449486B2 (en) 2004-10-19 2008-11-11 Array Biopharma Inc. Mitotic kinesin inhibitors and methods of use thereof
US7759371B2 (en) 2001-12-11 2010-07-20 Kyowa Hakko Kinn Co., Ltd. Thiadiazoline derivative
US7795282B2 (en) 2005-05-02 2010-09-14 Array Biopharma Inc. Mitotic kinesin inhibitors and methods of use thereof
US7910611B2 (en) 2005-06-24 2011-03-22 Kyowa Hakko Kirin Co., Ltd. Therapeutic agent for restenosis
US8324257B2 (en) 2006-10-03 2012-12-04 Array Biopharma Inc. Mitotic kinesin inhibitors and methods of use thereof
US8796460B2 (en) 2007-10-19 2014-08-05 Mercky Sharp & Dohme Corp. Compounds for inhibiting KSP kinesin activity

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