WO2004111023A1

WO2004111023A1 - Thiadiazoline-1-oxide derivative

Info

Publication number: WO2004111023A1
Application number: PCT/JP2004/008374
Authority: WO
Inventors: 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.
Priority date: 2003-06-10
Filing date: 2004-06-09
Publication date: 2004-12-23
Also published as: JPWO2004111023A1

Abstract

Disclosed are thiadiazoline-1-oxide derivatives represented by the general formula (I): (I) (wherein R1, R2 and R4 represent hydrogen atoms, substituted or unsubstituted lower alkyls or the like; R3 represents a hydrogen atom or the like; and R5 represents a substituted or unsubstituted lower alkyl or the like) and pharmacologically acceptable salts thereof.

Description

Thiadiazoline-l-oxide derivative Technical field

The present invention relates to a thiadiazoline-l-oxide derivative or a pharmaceutically acceptable salt thereof, which is useful for treating a tumor. Background art

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.

Commun.), Volume 263, Page 398 (1999)].

Because 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.

M-phase kinesin easy five (E g 5) 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

(J. Cell Biol.), Vol. 150, p. 975 (2000); Experimental Medicine, Vol. 17, p. 439 (1999)].

The human Eg5 gene was cloned in 1995, and the expression of full-length human Eg5 recombinant protein in insect cells and functional analysis using it have been reported [Cell

(Ce11), Vol. 83, pp. 1159 (1995)]. The gene is G enB an k a c c e s s io n numb er: X85137, NM004523,

Registered in the public database as U37426. Analysis using Eg5 derived from African Megafrog, which is highly homologous to human Eg5 [Proceedings. Of the National "Academy" Op. "Sciences" of Ob. Roc. Natl. Ac ad. Sci. USA), 96, 9106 (1999); Biochemistry, 35, 2365

(1996)], using the N-terminal part of human Eg5 expressed using Escherichia coli, biochemical analysis and crystal structure analysis of Eg5 have been reported [ Journal 'OB Biological. Chemistry

(J. Biological Chemistry), Volume 276, Page 25496 (2001); Chemistry 'Biology (Ch em istry & Biology), 9 volumes, 989 pages (2002)].

It is known that the expression of 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].

As described above, 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.

(Monastrom) [Science (Scienc), vol. 286, p. 971 (1999)], quinazoline derivatives (WO01 / 98278), phenathiazine derivatives (WO 02/057244), triphenyl methane derivatives (WO 02 /

056880) and dihydroxypyrimidine derivatives (WO 02/079149, WO 02/079169) and the like.

As the 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). In addition, those having antibacterial activity, ACE inhibitory activity, etc. are also known (W093Z22311, Journal of Banda Delish Chemical Society (J. Bangladesh).

Chem. Soc.), Vol. 5, p. 127 (1992)). Also, thiadiazoline-1-oxide derivatives are described in US Pat. No. 6,235,762; European Patent No. 1004241; Tetrahedron Letters, Vol. 37, p. 3569 (1973), etc. A thiadiazoline-1-oxide derivative having a substituent at the 2-position via a nitrogen atom is also known [Journal of the Chemicals Society] [Chemicals] J. Chem. Soc. Chem. Commun., 16 volumes, 901 pages (1982), Heterocycles; 24 volumes, 21 pages (1986)] .

Disclosure of the invention

It is an object of the present invention to treat diseases involving cell proliferation, such as 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. To provide salt.

The present invention relates to the following (1) to (28).

(1) General formula (I)

(I)

Wherein R ¹ and R ⁴ are the same or different and each 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 cycloalkyl, Represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, wherein R ² is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkyl; , A substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, — C (= W) R ⁶ [wherein W represents an oxygen atom or a sulfur atom, R ⁶ is a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substitution if Unsubstituted cycloalkyl, substituted or unsubstituted Ariru, substitution also properly unsubstituted heterocyclic group, in one NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are the same or different, a hydrogen atom, a substituted or Unsubstituted lower alkyl, substituted or unsubstituted lower alkyl A substituted or unsubstituted lower alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, or R ⁷ and R ⁸ together with an adjacent nitrogen atom To form a substituted or unsubstituted heterocyclic group), —OR ⁹ (where R ⁹ is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl) Represents a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, or one SR ^1D (wherein, R ^1Q has the same meaning as R ⁹ above) the representative, in -NR ^{1 X} R ¹² {wherein, R ¹¹ and R ¹² are the same or different, a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted Properly is unsubstituted lower Arukieru, substituted or unsubstituted cycloalkyl Le, a substituted or unsubstituted Ariru, in a substituted or unsubstituted heterocyclic group or -COR ¹³ [wherein, R ¹³ is a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted also properly unsubstituted consequent opening alkyl, substituted or unsubstituted Ariru, substituted or unsubstituted heterocyclic group, one NR ^7A R ^8A (wherein, R ⁷ A and R ^{8 A} have the same meanings as R ⁷ and R ⁸ , respectively), one OR ^9A (where R ^9A has the same meaning as R ⁹ above) or one ^Represents SR ^{1 () A} (wherein, R ^1GA is as defined above for R ⁹ )] or ^—S0 ₂ R ¹⁴ (where R ¹⁴ is as defined above for R ⁹ ) It represents or R ¹ and also together such connexion replaced with the nitrogen atom to which R ² is adjacent Ku form an unsubstituted heterocyclic group, R ⁵ is laid substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, and substituted Represents an unsubstituted aryl or a substituted or unsubstituted heterocyclic group, or R ⁴ and R ⁵ together form one (CR ^15A R ^15B ) _ml -Q- (CR ^15C R ^15D ) _m2 — { In the formula, Q represents a single bond, substituted or unsubstituted phenylene or cycloalkylene, and m1 and m2 are the same or different and each represents an integer of 0 to 4.m1 and m2 are simultaneously 0 and R ^15A , R ^15B , R ^15C and R ^15D are the same or different and each is hydrogen atom, halogen, substituted or unsubstituted lower alkyl, OR ¹⁶ [where R ¹⁶ is water Elemental atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, (wherein, R ^7B and R ^8B are the same meanings as the above R ⁷ and R ⁸⁾ one ^{^{_{CONR 7B R 8B, -S0 2 NR}}} 7C R 8C ( wherein, R ^7C and R ^8C each As defined above for R ⁷ and R ⁸ ) or one COR ¹⁷ (wherein R ¹⁷ 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 aryl or substituted or unsubstituted heterocyclic group).] NR ¹⁸ R ^{19 wherein} R ¹⁸ and R ¹⁹ are the same Or different 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 cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aryl. 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

-Represents CO ₂ R ²² (wherein R ²² is as defined above for R ¹⁷ ), or R ^15A and R ^15B or R ^15C and R ^15D together represent an oxygen atom, ^ 11 or when 012 is 2 or more integer, each of R ^15A, R ^15B, 1 ¹⁵ Jioyobi 1 ¹⁵¹³ may be different or the same over, bonded to the adjacent two carbon atoms R ^15A, R ^15B, represents the R ^15G and R ^15D may form together a connexion bond respectively}, R ³ is a hydrogen atom or a ^{- C (= W a) R} 6A ( wherein, W ^a and R ^{6 a} is Each has the same meaning as W and R ⁶ described above). Where R ¹ is hydrogen, R ² and R ³ are acetyl, And when R ⁵ is phenyl, R ⁴ is not hydrogen or methyl> a thiadiazoline-111-oxide derivative represented by the formula or a pharmaceutically acceptable salt thereof.

(2) R ⁴ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted lower alkynyl, and 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

-(CR ^15A R ^15B ) _ml -Q- (CR ^15C R ^15D ) _m2 — (wherein, R ^15A , R ^15B , R ^15C , R ^15D , ml, m 2 and Q are each as defined above) The thiadiazoline-1-oxide derivative according to (1) or a pharmacologically acceptable salt thereof.

(3) The thiadiazoline-1-oxide described in (1), wherein R ⁵ is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, or a substituted or unsubstituted cycloalkyl. Derivatives or pharmacologically acceptable salts thereof.

(4) The thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to (1) or (2), wherein R ⁵ is a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group. '

(5) The thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to (1) or (2), wherein R ⁵ is substituted or unsubstituted phenyl or substituted or unsubstituted phenyl.

(6) The thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein R ⁴ is a substituted or unsubstituted lower alkyl.

(7) The thiaziazoline-111-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein R ⁴ is substituted lower alkyl.

(8) R ⁴ and R ⁵ are connected together

― (CR ^15A R ^15B ) _ml -Q- (CR ^15C R ^15D ) _m2 — (wherein, R ^15A , R ^15B , R ^15C , R ^15D , ml, m 2 and Q are as defined above) (1) Or a pharmacologically acceptable salt thereof.

(9) 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) (1) The thiadiazolin-1 monooxide derivative or the pharmaceutically acceptable salt thereof according to the above.

(10) The thiadiazoline-l-oxide derivative or the pharmaceutically acceptable salt thereof according to (8) or (9), wherein Q is substituted or unsubstituted phenylene.

(11) The thiadiazoline-1-oxide derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein R ¹ is a hydrogen atom or a substituted or unsubstituted lower alkyl.

(12) The thiadiazoline-11-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein R ¹ is a hydrogen atom.

(13) R ² is one C (= W) R ⁶ (wherein W and R ⁶ have the same meanings as described above), respectively. An oxide derivative or a pharmacologically acceptable salt thereof.

(14) 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.

(15) The thiadiazoline-l-oxide derivative or the pharmaceutically acceptable salt thereof according to (13), wherein R ⁶ is lower alkyl.

(16) The thiadiazoline-11-oxide derivative or the pharmaceutically acceptable salt thereof according to any of (13) to (15), wherein W is an oxygen atom.

(1 7) 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.

(18) The thiadiazoline according to any one of (1) to (17), wherein R ^{3 is} —C (= W ^A ) R ^6A (wherein W ^A and R ^6A are each as defined above). 1—Oki Sid derivatives or pharmacologically acceptable salts thereof.

(19) The thiadiazoline according to (18), wherein R ^{6 A} is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkynyl, or a substituted or unsubstituted cycloalkyl. 1-oxide derivative or pharmacologically acceptable salt thereof.

(20) The thiadiazoline-1-oxo derivative or the pharmaceutically acceptable salt thereof according to (18), wherein R ^6A is lower alkyl.

(21) 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).

(22) 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).

(23) 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).

(24) 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).

(25) 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). .

(26) 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).

(27) Use of the thiadiazoline-111-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (21) for the production of an M-phase kinesin E g5 inhibitor.

(28) Use of the thiadiazolin-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (21) for the manufacture of an antitumor agent. Hereinafter, the compound represented by the general formula (I) is referred to as compound (I). The same applies to compounds having other formula numbers.

In the definition of each group of the general formula (I),

(i) 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.

(ii) As the lower 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.

(iii) As 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.

(iv) Examples of the cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl / le, cyclobutyl / le, cyclopentinole, cyclohexinole, cycloheptyl, cyclooctyl, and the like.

(V) The aryl portion of aryl, aryloxy and arylamino includes, for example, feninole and naphthyl.

(vi) Examples of the heterocyclic group include an aliphatic heterocyclic group and an aromatic heterocyclic group. As the 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. . Examples of the aromatic heterocyclic group 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, benzoyl, benzoyl, benzoyl, benzoylamine , Benzimidazolinole, Benzothiazolyl, Benzo Riazoriru, purinyl, quinolyl, isoquinolyl, quinazolinyl, Futarajuru, quinoxalinyl, naphthyridinyl, benzodioxanyl § benzindolyl, Fuenochi azinyl, benzopyranyl, cinnolinyl, etc. Biraniru the like.

(V i i) 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.

(viii) The cycloalkylene includes, for example, cycloalkylene having 3 to 8 carbon atoms, specifically, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclootylene and the like. As Nylene, 1,2-phenylene, 1,3-phenylene and 1,4-phenylene. (ix) Halogen means each atom of fluorine, chlorine, bromine and iodine.

(x) 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,

Halogen, hydroxy, oxo, amino, nitro, azide, cyano, carboxy,

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

Etc.),

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,

Hydrogen atom, substituted or unsubstituted lower alkyl (substituted lower alkyl And the substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl has the same meaning as the substituent (b) in the substituted lower alkoxy). A) substituted or unsubstituted lower alkyl group (the substituent in the substituted lower alkyl group is the same as the substituent (b) in the substituted lower alkoxy group), aralkyl, aryl or heterocyclic group

Or 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))],

Aryl, heterocyclic group

},

_NR ²⁵ R ²⁶ <wherein, R ²⁵ and R ²⁶ are the same or different,

Hydrogen atom, hydroxy, amino,

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 (substituents in the substituted 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

Halogen, hydroxy, oxo, nitro, azido, cyano, carboxy, substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl is the same as the substituent (a) in the substituted cycloalkyl), substituted or unsubstituted Substituted aryl (the substituent in the substituted aryl is the same as the substituent (Xii) 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 (Xiii) 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 (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).

— O (CH ₂ CH ₂ 0) _n R ²⁷ (where n represents an integer of 1 to 15, and R ²⁷ represents a hydrogen atom or lower alkyl),

I NR ²⁸ R ^{29 wherein} R ²⁸ and R ²⁹ are the same or different,

Hydrogen atom, hydroxy, amino, lower alkylamino, di-lower alkylamino,

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)

(synonymous with (a)),

Substituted or unsubstituted arylo (the substituent in the substituted arylo is synonymous with the substituent (Xii) in the substituted aryl described below),

Substituted or unsubstituted aryloxycarbonyl (the substituent in the substituted aryloxycarbonyl is the substituent in the substituted aryl described below)

(Synonymous with (Xii)) or

Or 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 To form a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group formed together with the adjacent nitrogen atom is the same as the substituent (xiii) in the substituted heterocyclic group described later) )], -CONR ³⁰ R ³¹ (wherein R ³ ° and R ³¹ are the same as R ²⁸ and R ^2, respectively)

Synonymous with ⁹ ),

-SO ₂ R ³² [where R ³² is

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 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

- NR ³³ R ³⁴ (wherein, R ³³ and R ³⁴ are each synonymous with the R ²⁸ and R ² ⁹⁾

Represents],

I N + R ³⁵ R ³⁶ R ³⁷ X_ (wherein, 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 (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),

-COR ³⁸ [where R ³⁸ is

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 (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)

Represents],

— CONR ³⁹ R ⁴ . (Wherein, R ³⁹ and R ⁴ have the same meanings as R ²⁸ and R ²⁹ respectively), or

-S0 ₂ R ⁴¹ [where R ⁴¹ is

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 )

Represents

Or 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. >)

One of CONR ⁴⁴ R ⁴⁵ (wherein R ⁴⁴ and R ⁴⁵ have the same meanings as R ²⁵ and R ²⁶ , respectively);

-COR ⁴⁶ [where R ⁴⁶ is

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),

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)

Represents],

-COO ⁴⁷ (wherein, R ⁴⁷ has the same meaning as R ⁴⁶ ),

-S0 ₂ R ⁴⁸ [where R ⁴⁸ is

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),

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 49 _R 50 (wherein R 49 and R 5 have the same meanings as R 28 and R 29, respectively)

Represents],

— OR ⁵¹ [where R ⁵¹ is

-COR ⁵² (wherein, R ⁵² is as defined above for R ⁴⁸ ),

-SO ₂ R ⁵³ (wherein, R ⁵³ has the same meaning as R ⁴⁸ ) or

— Represents Si R ⁵⁴ R ⁵⁵ R ⁵⁶ (wherein R ⁵⁴ , R ⁵⁵ and R ⁵⁶ are the same or different and represent a hydrogen atom, hydroxy, lower alkyl or lower alkoxy)], — SR ⁵⁷ (wherein R ⁵⁷ is as defined above for R ⁵¹ ),

One N + R ⁵⁸ R ⁵⁹ R ⁶ . X— (wherein, R ⁵⁸ , R ⁵⁹ , R ⁶ and X have the same meanings as R ³⁵ , R ³⁶ , R ³⁷ and X, respectively) and the like.

Lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, lower alkoxycarbonyl, lower alkanol, lower alkenyloxy, lower alkylamino, lower alkoxy-substituted lower alkoxy, lower alkoxy-substituted lower alkylamino shown here In the case of lower alkylaminoyl, lower alkoxycarbonylamino and lower alkyl moiety of lower alkylsulfonyl, lower alkenyl, lower alkynyl and cycloalkyl, halogen is ぴ, 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 alkoxy , Hydroxy-substituted lower Arukiruamino the alkylene moiety of Amino substituted lower Arukiruamino and lower § alkoxy substituted lower Arukiruamino has the same meaning as the group formed by removing one hydrogen atom from the groups mentioned in the definition of the lower alkyl (i). The two lower alkyl moieties in the di-lower alkylamino may be the same or different. In the case of aryl, aryloxy, aryloxycarbonyl and aryloyl, heterocyclic group and heterocyclic group in heteroaryloxy shown here, they are formed together with the adjacent nitrogen atom. Are the same as the aryl (V;), the heterocyclic group (V i) and the heterocyclic group (V ii) formed together with the adjacent nitrogen atom, respectively. Aralkyl and aralkyl part of aralkyl

Examples of (x i) include aralkyl having 7 to 15 carbon atoms, specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.

(Xii) 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 (substituents in the substituted 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 lower alkynyl (the substituent in the substituted lower alkynyl 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

Etc.),

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);

One C OR ⁶¹ [where R ⁶¹ is

Hydrogen atom,

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)

Represents],

-COOR ⁶² (wherein R ⁶² is as defined above for R ⁶¹ ),

-OR ⁶³ [where R ⁶³ is

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);

Tri-lower alkylsilyl,

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

Represents],

-SR ⁶⁴ (wherein R ⁶⁴ is as defined above for R ⁶³ ),

I NR ⁶⁵ R ^{66 wherein} R ⁶⁵ and R ⁶⁶ are the same or different,

Hydrogen atom, hydroxy, 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 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),

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

'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 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 (substituents in the substituted lower alkyl have the same meanings as the above-mentioned substituent (a) in cycloalkyl),

Substituted or unsubstituted aryloyl (the substituent in the substituted aryl is the same as the substituent (d) in the above substituted aryl),

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

-NR ⁷⁰ R ⁷¹ (wherein, R ⁷ and R ⁷¹ are as defined above for R ⁶⁵ and R ⁶⁶ , respectively)

Represents].

The lower alkyl portion of the lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, dilower alkylamino, tri lower alkylsilyl, lower allylyl, lower allyloxy, lower allylamino and lower alkylsulfonyl shown here, In the case of lower alkenyl, lower alkynyl and cycloalkyl, halogen is the lower alkyl (i), lower alkenyl (ii) and lower alkenyl, respectively. Synonymous with nil (iii), cycloalkyl (iv) and halogen (ix), the two lower alkyl moieties in di-lower alkylamino and the three lower alkyl moieties in tri-lower alkylsilyl are identical or different. Yeah. In addition, 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.

(X iii) As the substituent in the substituted heterocyclic group and the substituted heterocyclic group formed together with the adjacent nitrogen atom, in addition to the groups defined in the definition of the substituent (X ii) in the above-mentioned substituted aryl, And oxo.

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, and 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.

Next, the production method of compound (I) will be described.

In the following production methods, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the method, methods for introducing and removing protecting groups commonly used in organic synthetic chemistry [for example, , Protective Groups' In Organic Synthesis Synthesis), Green (TW Greenes), John Wiley & Sons Incorporated (1981)] to produce target compounds can do. In addition, the order of reaction steps such as introduction of a substituent can be changed as necessary.

Compound (I) can be produced according to the following production method.

Manufacturing method 1

(I I) (I)

(Wherein, I ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above)

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

In the compound (II), 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.

(1984) and the like, or compound (III) and compound (IV) From compound (V).

(I I I) (IV) (V)

R ^6A COX ¹ or (R ^6A CO) ₂₀

(Via) (VIb)

(I I a)

(Wherein, I ¹ , R ⁴ , R ⁵ and R ^6A have the same meanings as above, X ¹ represents each atom of chlorine, bromine or iodine, and 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)

Manufacturing method 3

Among the compounds (II), a compound (IIb) wherein R ² and R ³ are the same and one COR ^6B (where R ^6B has the same meaning as R ^{6 above} ) is obtained by the production method 1. Compound (Va) and compound (Vic) or compound (Vic) wherein R ^2a is a hydrogen atom

From (VI d), in a known manner [for example, J. Bangladesh Chem. Soc., Vol. 5, p. 127 (1992), Journal 'Ob' Organic Chemistry (J. Org. Chem.), Vol. 45, p. 1473 (1980), East German Patent

243930 or the like] or according to them.

(Va) (I I b)

Wherein RR ⁴ , R ⁵ , R ^{6 B} and X ¹ are each as defined above.

In the compound (II), 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.

(l i b) (l i e)

(Wherein, I ¹ , R ⁴ , R ⁵ and R ^6B are as defined above)

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).

Further, 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

In the compound (II), 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 Alternatively, the compound (IIc-a) obtained by the production method 4 can also be produced by the following steps.

(I I c-a) (l i e)

(Wherein RR ⁴ , R ⁵ , R ⁶ , R ^6c and X ¹ are the same as defined above). 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.

Manufacturing method 6

Of the compound (II), 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. For example, 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.

(Wherein, I ¹ , R ⁴ , R ⁵ , R ^6c , R ¹⁴ and X ¹ are each as defined above).

Among the compounds (II), 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.

(Indian J. Chem.), Section B, 31B (8), Vol. 547 (1992), from the compound (VIII) obtained in a manner analogous thereto, for example from the Indian Journal. Ob Chemistry (Indian J. Chem.), Section B, 31B (8), pp. 547 (1992), Phosphorus Sulfur and Silicone and The Relatable Element. It can be produced by the method described in, for example, osphorus Sul1 Fur & Silicon & Related Elements), Vol. 122, p. 307 (1997) or according to the method.

Wherein RR ⁴ , R ⁵ , R ^6A , R ¹¹ and R ¹² are as defined above.

In the compound (II e) obtained by the production method 5, 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 And 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. COR ^6A R ^A X ¹ COR ^6A

_R 4 NN (I) _R4 -N

To R5 s input r " ^{1 a}

To R5 s ^^

COR ⁶ COR ⁶

(I I e-a) (I I e— b)

(Wherein, 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. 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

Among the compounds (II), 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

(Chem. Ber.), Vol. 123, p. 691 (1990), etc., or according to them.

Manufacturing method 10

Among the compounds (II), the compound (II j) wherein R ² and / or R ³ are each C (= S) R ⁶ and ぴ Z or —C (= S) R ^6A is prepared according to the above production method 2 Of the compounds (IIa) to (IIh) obtained from the compounds (IIa) to (9h), wherein the corresponding R ² and Z or R ³ are one COR ⁶ and Z or one COR ^6A , respectively. k) by sulfidation.

For example, 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).

Manufacturing method 1 1

Among the compounds (II), the compound (I Im) 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.

(Wherein, R ⁴ , R ⁵ and R ⁶ have the same meanings as above, X ² represents each atom of chlorine, bromine or iodine, and R ^lb and R ^2¾ 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.

(vii) is the same as defined above, and the substituent in the substituted heterocyclic group formed together with the adjacent nitrogen atom is the same as the substituent (xiii) in the above heterocyclic group. 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.

(1998) or according to them. Alternatively, 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

(Synthesis-Stuttgart), Vol. 5, p. 420 (1991), etc., or according to them.

Further, 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.

Manufacturing method 12

Among the compounds (II), compounds wherein R ^{3 is} —C (= S) R ^6A and R ¹ and R ² together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group ( II j-a) can be produced from compound (I Im) in the same manner as in Production Method 10.

(I Im) (I I j -a)

(Wherein, R ^lb , R ^2b , RR ⁵ and R ⁶ are the same as defined above.) The conversion of the functional group contained in I ¹ , R ² , R ³ , R ⁴ or R ⁵ in the compound (I) is as follows. In addition to the above steps, other known methods [for example, by Comprehensive Organic Transformations (RC Rock, Larock)] (1989), etc.] or according to them. In addition, a compound (I) having a desired functional group at a desired position can be obtained by appropriately combining and carrying out the above methods.

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.

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.

Table 1

Examples Compound

Number

COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ CH2NHSO2CH3

2 2 COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ (CH ₂ ) 2NHS0 ₂ CH3 3 COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ (CH ₂ ) ₃ N (CH ₂ CH ₃ ) 2 4 4 COC ( CH ₃ ) ₃ COC (CH ₃ ) ₃ CH ₂ NHS 0 ₂ (CH ₂ ) ₂ NHCH ₂ CH ₃ 5 COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ (CH ₂ ) ₃ NH ₂

6 6 COC (CH ₃ ) 3 COC (CH ₃ ) ₃ (CH ₂ ) 2NHCO (CH ₂ ) ₃ N (CH ₃ ) ₂

Next, the pharmacological activity of a representative compound (I) will be described in Test Examples.

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. In this culture medium, XTT {3 '-[1— (phenylaminocarbonyl) -1,3,4-tetrazo [Rium] -bis (4-methoxy-1-6-nitro) benzenesulfonate sodium hydrate (Sodium 3, ― [1— (pheny l amino carbo nyl) ― 3,4—tetrazolium] bis, 4— me tho xy— 6— nitro) —benzenesulfonicacid hy drate)} labeling mixture (Roche Diagnostics, 1465015)

After dispensing each Z-well, incubate at 37 ° C for 1 hour in a 5% CO2 incubator, and measure the absorbance at 490 nm and 655 nm using a microplate spectrophotometer (Pioradne clay, Mode 1 550) did. Cytostatic activity of 50% growth inhibition concentration GI _5. Indicated by.

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.

Table 2

(Compound No.GI ₅₀ μmol / L)

1 0.13 Test example 2: Inhibition test for Eg5 enzyme (1)

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.

The measurement of the ATPase activity of Eg5 is described in the literature [Embo Journal (Th e

EMBO J ournal), Volume 13, Page 75 (1994), Proceeding of the National Academy of Sciences of the State of the State USA, Proc. Natl. Acc. Sci. USA, Vol. 89, p. 4884 (1992)]. 25 mMol / L piperazine N, N, monobis (ethanesulfonic acid) (PI PES) / KOH (H6.8), lmmol / L ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA ) ゝ₂ mmo 1 / L Mg C 12, 1 mmo 1 ZL dithiothreitol (DTT), 100 μg / mL ゥ serum albumin (BSA), 5 μπιο 1 / L paclitaxel (P ac 1 itae 1 25 μ g, L Tu bu 1 in (Cytoskenoreton, catalog number TL 238), and SOO mol ZL ME SG substrate (2-amino-6-mercapto-7-methylpurine riboside) ) (Molekiura Probes, Catalog No. 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.).

Measure with Spectr aMa x 340 PC ³⁸⁴ ). E g 5 presence test compound Absorbance 1 100% in the absence, the relative activity to calculate the absorbance in the absence E g 5 absence test compound as 0%, IC _5. Calculate the value.

The above test confirms the inhibitory effect of compound (I) on the Eg5 enzyme. Test Example 3 Inhibition test on Eg5 enzyme (2)

Preparation of Recombinant Human Eg5 Motor Domain Protein by Literature Radiochemistry (Biochemistry), 35 volumes, 2365 pages (1996)]. A plasmid expressing the human Eg5 motor domain was constructed and transformed into E. coli BL21 (DE3). The transformants were cultured at 25 ° C, 0D _6fl . Was 0.74, isopropyl 1 / 3-D-thiogalactoside was added to the mixture so that the final concentration was 0.5 mmol / L. After further culturing for 4 hours, the culture was centrifuged to collect the cells. The cells were suspended in a buffer, sonicated, and the supernatant was collected by centrifugation. The supernatant was purified by cation exchange column chromatography to obtain a partially purified sample. Furthermore, the partially purified sample was purified by gel filtration column chromatography to obtain a final purified sample.

Measurement of the ATPase activity of Eg5 the literature [Enbo Journal (EMBO Journal) _s 13 Certificates, 751 pages (1994), Proceedings, O blanking the National Academy O blanking Sciences * O blanking THE · United 'States of America' (Proc. Natl. Acad. Sci. USA), Vol. 89, p. 4884 (1992)]. The following two types of solutions were prepared. 25 bandol ol / L piperazine N, N, monobis (ethanesulfonate) (PIPES) / K0H (pH 6.8), 1 ramol / L ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA ), 2 mmol / L MgCl ₂ , 1 mmol / L dithiothreitol (DTT), 5 μmol / L paclitaxel (Paclitaxel), 167 // g / mL ゥ serum albumin (BSA), 41.7 ^ g / niL Tubulin (Cytoskeleton, catalog number TL238), 333 μmol / L MESG substrate (2-amino-6-mercapto-17-methylpurine riboside) (Molecular Probes, catalog number E-6646), 1.67 U / mL Purine nucleoside phosphorylase (Molecular Probes, catalog number E-6646) and 1.33 μg / mL Solution A consisting of purified human Eg5 motor domain preparation was prepared. 25 mmol / L piperazine N, N, monobis (ethanesulfonic acid) (PIPES) / K0H (ρΗ6.8), 1 mmol / L ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA), 2 mmol / L MgCl ₂ , 1 mmol / L dithiothreitol (DTT), 5 μmol / L paclitaxel

(Paclitaxel) and a solution B composed of 2.5 mmol / L ATP was prepared. Solution A was dispensed into a 96-well plate at 45 A per well (L). The compound was serially diluted. Each 30 zL of the diluted test compound solution was mixed with the solution A dispensed into the above 96-well plate, and the enzyme reaction was started. The enzyme reaction was performed at 30 ° C for 30 minutes. The absorbance at 360 nm, which is an indicator of ATPase activity, was measured with a plate reader (Molecular Devices, SpectraMax 340PC ³⁸⁴ ). Eg5 presence of 100% and the absorbance in the absence the test compound, the relative activity was calculated Eg5 absence, the test compound and the absorbance in the absence as 0%, IC _5. Values were calculated.

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 μπιοΙ / 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. . In addition, 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.

It is desirable to use the most effective route for administration, and it can be oral or parenteral, for example, intravenous.

Examples of the administration form include tablets, injections and the like.

For example, 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. For example, in the case of an injection, 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. Also, in these parenteral preparations, 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.

When 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. In the case of 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. However, the dose and the number of administrations vary depending on the various conditions described above. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to Examples, Reference Examples, and Formulation Examples.

The proton nuclear magnetic resonance spectra (¾-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 1 (Compound 1)

Compound 1a (300 mg, 0.66 mmol) obtained in Reference Example 1 was dissolved in dichloromethane (10 mL) and cooled to 0 ° C. To this solution was added m-chloroperbenzoic acid (182 mg, 1.06 mmol), and the mixture was stirred at the same temperature for 5 hours. After pouring water (10 mL) into the reaction solution and extracting with ethyl acetate (25 mL), the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL). It was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from a mixed solvent of 2-propanol and water (10: 1) (32 mL), and the obtained crystals were dried by heating under reduced pressure to give the title compound 1 ( 265 mg, 85%).

_{¾NMR (300 MHz, CDC1 3)} δ (ppm): 1.30 (s, 9H), 1.44 (s, 9H), 2.93 (s, 3H), 4.42 (dd, J = 3.3, 13.8 Hz, 1H), 4.71 ( dd, J = 11.1, 13.8 Hz, 1H), 5.88 (dd, J = 3.3, 11.1 Hz, 1H), 7.10-7.12 (m, 2H), 7.36-7.42 (m, 3H), 8.21 (br s) AP -MS (m / z): 493 (If + Na)

Example 2 (Compound 2)

Using compound 2a (80 mg, 0.17 mmol) obtained in Reference Example 2 and m-chloroperbenzoic acid (35 mg, 0.21 mmol), the title compound 2 (74 mg, 89% ).

_{¾NMR (270 MHz, CD 3 0D} ) δ (ppm): 1.25 (s, 9H), 1.46 (s, 9H), 2.93 (s, 3H), 2.99 (m, 1H), 3.12 (m, 1H), 3.23 (m, 1H), 3.53 (m, 1H), 7.13 (m, 2H), 7.30-7.43 (m, 3H) AP-MS (m / z): 483 (Wl)

Example 3 (Compound 3)

Using compound 6a (102 mg, 0.190 mmol) obtained in Reference Example 6 and m-chloroperbenzoic acid (34.3 mg, 0.190 mmol), the title compound 3 (67.7 mg, 64 mg) was obtained in the same manner as in Example 1. %).

AP-MS (m / z): 477 (M ++ 1)

Example 4 (Compound 4)

Using compound 8a (27.0 mg, 61.2 bandol) obtained in Reference Example 8 and m-chloroperbenzoic acid (10.6 mg, 61.2 mmol), the title compound 4 (20 mg, 85 mg) was obtained in the same manner as in Example 1. %) Was obtained as a diastereo mixture.

_{¾NMR (270 MHz, CDC1 3)} δ (ppm): 1.04-1.13 (m, 3H), 1.27 (s, 9H), 1.38 (s, 9H), 2.61-2.93 (m, 2H), 3.00-3.33 (m , 2H), 3.36--3.57 (m, 2H), 4.01 and 4.05 (2 Xd, J = 13.0 Hz, 1H), 4.58 and 4.60 (2Xd, J = 13.0 Hz, 1H), 7.20-7.41 (m, 5H) , 7.95-8.00 (br s, 1H)

AP-MS (m / z): 528 (M ⁺ + l)

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.

¾賺_{(270 MHz, CDC1 3) δ} (ppm):. 1.30 and 1.34 (2xs, 9H), 1.42 and 1.44 (2xs, 9H), 1.44-1 6 (m, IH), 1.69-1.75 (m, IH ), 2.83-3.06 (m, 2H), 3.09-3.27 (m, 2H), 7.00-7.08 (m, 2H), 7.20-7.40 (m, 3H)

AP-MS (m / z): 421 (WT + 1)

Example 6 (Compound 6)

The hydrochloride (30 mg, 0.056 mmol) of compound 15a obtained by treating compound 15a obtained in Reference Example 15 with 4 mo 1 ZL hydrogen chloride monoethyl acetate solution and m-chloroperbenzoic acid (12 mg, 0.068 mmol) to give the title compound 6 (10 mg, 34%) in the same manner as in Example 1.

_{¾NMR (270 MHz, CDC1 3)} δ (ppm): 1.29 (s, 9H), 1.31 (s, 9H), 1.80 (m, 2H), 2.23 (t, J = 7.2 Hz, 2H), 2.26 (s, 6H), 2.35 (t, J = 6.8 Hz, 2H), 2.54 (m, 1H), 3.14-3.35 (m, 2H), 3.82 (m, IH), 6.68 (br t, IH), 7.19-7.40 ( m, 5H), 8.08 (br, IH)

AP-MS (m / z): 520 (M ++ 1)

Table 3 shows the structures of the compounds 1a to 15a obtained in Reference Examples 1 to 15 below.

Table 3

Reference example Compound

R '

Number

1 1 a COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ CH2NHSO2CH3

2 2 a COC (CH ₃ ) ₃ COC (CH ₃ ) 3 (CH ₂ ) ₂ NHS0 ₂ CH ₃

3 3 a COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ (CH ₂ ) ₂ COOCH ₃

4 4 a COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ (CH ₂ ) 2CH ₂ OH

"

5 5 a COC (CH3) 3 COC (CH3) 3 (CH2) 2CHO

6 6 a COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ (CH ₂ ) ₃ N (CH ₂ CH ₃ ) ₂

7 7 a COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ CH2NHS0 ₂ CH = CH2

_{8 8 a COC (CH 3)} 3 COC (CH 3) 3 CH 2 NHS0 2 (CH 2) 2 NHCH 2 CH 3

9 9 a COC (CH ₃ ) ₃ COC (CH ₃ ) 3 (CH ₂ ) ₃ COOCH ₃

1 0 1 0 a COC (CH ₃ ) ₃ COC (CH ₃ ) 3 (CH ₂ ) ₃ COOH

1 1 1 1 a COC (CH ₃ ) ₃ COC (CH ₃ ) ₃ (CH ₂ ) ₃ NHCOOC (CH ₃ ) ₃

1 2 1 2 a COC (CH ₃ ) 3 COC (CH ₃ ) ₃ (CH ₂ ) ₂ CH ₂ NH ₂

1 3 1 3 a COC (C) 3 COC (CH ₃ ) ₃ (CH2) 2NHCOOC (CH ₃ ) ₃

14 14 a COC (CH ₃ ) 3 COC (CH ₃ ) ₃ CH2CH2NH2

1 5 1 5 a COC (CH ₃ ) 3 COC (CH ₃ ) ₃ CH2CH ₂ NHCO (CH ₂ ) ₃ N (CH3) 2 Reference Example 1 (Compound la)

Process 1

2-Aminoacetophenone hydrochloride (6.10 g, 35.5 gol) was dissolved in dichloromethane (60 mL), and triethylamine (7.56 g, 74.9 mmol) was added. This solution is 0. (The mixture was cooled to (:), methanesulfoyl chloride (2.84raL, 36.5 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes, and then stirred at room temperature for 2 hours. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.The residue was suspended in chloroform (5 mL), stirred, and the crystals were collected by filtration. 2- (Methylsulfonylamino) acetophenone (4.58 g, 57%) was obtained.

Process 2

2- (Methylsulfonylamino) acetophenone (4.58 g, 20.2 mmol) and thiosemicarbazide (1.84 g, 20.2 benzyl) obtained above were dissolved in methanol (30 mL). Hydrochloric acid (0.1 mL) was added to this solution, and the mixture was vigorously stirred at room temperature for 15 hours. Water (30 mL) was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with water and diisopropyl ether, and then dried to obtain 2- (methylsulfonylamino) acetophenone == thiosemiforce rubazone (3.08 g, 51%).

Process 3

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. The organic layer was washed with a saturated aqueous sodium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate Zn-hexane = 1/2) to give the title compound 1a (1.81 g, 91%).

¾賺_{(270 MHz, CDC1 3) δ} (ppm): 1.30 (s, 9H), 1.36 (s, 9H), 2.97 (s, 3H), 3.98 (dd, J = 5.3, 13.8 Hz, 1H), 4.64 (dd, J = 8.5, 13.8 Hz, 1H), 5.10 (br dd, J = 5.3, 8.5 Hz, 1H), 7.25-7.i39 (m, 5H), 7.93 (br s, 1H)

AP-MS (m / z): 453 (If-1)

Reference Example 2 (Compound 2a)

Process 1

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. . To the reaction solution was added 3-chloropropiophenone (843 mg, 5.00 mol), and the mixture was stirred under water cooling for 1 hour, and further stirred at room temperature for 15 hours. Water was added to the reaction solution, which was 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. The residue was purified by silica gel column chromatography (black port Holm _/ / methanol = 20/1) to give 3- (methylsulfonyl Amino) propiophenone (240 mg, 21%).

Process 2

In the same manner as in Step 2 of Reference Example 1, from 3- (methylsulfonylamino) propiophenone (388 mg, 1.71 mmol) and thiosemicarbazide (156 mg, 1.71 ramol) obtained above, Sulfonylamino) Propiofenone = thiosemicarpazone (219 mg, 45%) was obtained.

Process 3

In the same manner as in Step 3 of Reference Example 1, 3- (methylsulfonylamino) propiophenone-thiosemicarbazone (200 mg, 0.696 mraol), pivaloyl chloride (342 2.78 mmol) and The title compound 2a (218 mg, 86%) was obtained from pyridine (219 μί, 2.78 mmol).

_{¾NMR (300 fflz, CDC1 3)} 8 (ppm): 1.30 (s, 9H), 1.34 (s, 9H), 2.56-2.65 (m, 1H), 2.94 (s, 3H), 3.21-3.44 (m, 2H ), 3.58-3.70 (m, 1H), 4.45 (br s, 1H), 7.28-7.37 (m, 5H), 7.97 (br s, 1H)

AP-MS (m / z): 467 (M—-1)

Reference Example 3 (Compound 3a) Process 1

Thiosemiccarbazide (3.86 g, 42.3 mmol) was dissolved in methanol (50 mL). To this solution, 3-carboxymethoxypropionofenone (8.13 g, 42.3 t ol) and concentrated hydrochloric acid (1.00 mL, 12.0 t ol) were added, and the mixture was stirred at room temperature for 11 hours. The precipitated solid was collected by filtration, and the obtained solid was washed with methanol and dried to obtain 3-force lupomethoxypropiophenone == thiosemicarbazone (10.6 g, 94%).

Process 2

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. Diisopropyl ether (50 mL) was added to the residue, and the suspension was stirred for 1 hour and filtered. The crystals collected by filtration were washed with diisopropyl ether and dried to give the title compound 3a (9.70 g, 77%).

_{¾NMR (270 MHz, CDC1 3)} δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 2.37 (m, 1H), 2.67 (m, 1H), 2.79 (m, 1H), 3.42 ( m, 1H), 3.70 (s, 3H), 7.22-7.40 (m, 5H), 7.89 (br s, 1H)

Reference Example 4 (Compound 4a)

Compound 3a (1.50 g, 3.46 mmol) obtained in Reference Example 3 was dissolved in tetrahydrofuran (10 mL). After cooling the solution to 0 ° C, the diisobutylaluminum hydride

0.93mo1ZL hexane solution (12.5mL, 11.6mL) was added, and the mixture was stirred for 2.5 hours. Anhydrous sodium sulfate and a saturated aqueous solution of sodium sulfate were added to the reaction solution, and the mixture was further stirred for 1 hour and then filtered. Water was added to the filtrate, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to obtain the title compound 4a (1.49 g, 100%).

AP-MS (m / z): 404 (¾Γ-1)

Reference Example 5 (Compound 5a)

Compound 4a (1.00 g, 2.47 nunol) obtained in Reference Example 4 was dissolved in dichloromethane (50 mL). To this solution was added pyridinium dichromate (2.94 g, 7.81 mmol), and the mixture was stirred at room temperature for 60 hours. After the reaction solution was filtered, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound 5a (517 mg, 52% ).

Reference Example 6 (Compound 6a)

Compound 5a (66.5 mg, 0.165 mmol) obtained above was dissolved in 1,2-dichloroethane (5 mL). Acetic acid (0.0587 mL, 1.03 mmol), getylamine (0.0886 mL, 0.855 mmol) and sodium triacetoxyborohydride (175 mg, 0.824 mmol) were sequentially added to this solution. The mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated by preparative thin-layer chromatography (chloroform / methanol Z concentrated aqueous ammonia =

Purification was carried out with 100 10/1) to give the title compound 6a (47.4 mg, 62%).

AP-MS (m / z): 461

Reference Example 7 (Compound 7a)

Process 1

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. 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. Ethyl acetate and n-hexane The mixed solvent was added for crystallization to obtain 2_ (vinylsulfonylamino) acetophenone (0.442 g, 32%).

Process 2

2- (Bursulfonylamino) acetophenone (0.32 g, 1.42 mmol) and thiosemicarbazide hydrochloride (0.27 g, 2.13 mmol) obtained above were dissolved in methanol (20 mL). Concentrated hydrochloric acid (2 drops) was added to this solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue to carry out liquid separation. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / n-hexane = 1/1) to give 2- (vinylsulfonylamino) acetophenone = thiosemicarbazone (0.25 g, 58%). .

Process 3

The 2_ (Burus / lefonylamino) acetophenone = thiosemicanolebazone (0.25 g, 0.83 mmol) obtained above was dissolved in acetone (10 mL), and pyridine (0.34 mL, 4.17 mmol) and pivaloyl chloride (0.31 mL, 2.50 t) were dissolved. ol) and stirred at room temperature for 30 minutes. Acetic anhydride (0.16 mL, 1.66 mmol) was added to the reaction solution, and the mixture was further stirred at room temperature for 3 days. The reaction solution was concentrated, and ethyl acetate and 2mo 1ZL hydrochloric acid were added to the residue to separate the solution. 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. The residue was purified by silica gel column chromatography (ethyl acetate Zn-hexane = 1/1) to obtain the title compound 7a (0.10 g, 26%).

_{¾NMR (300 MHz, CDC1 3)} δ (ppm): 1.29 (s, 9H), 1.33 (s, 9H), 3.85 (dd, J = 13.5, 4.8 Hz, 1H), 4. 9 (dd, J = 13.5 , 8.1 Hz, 1H), 5.29 (br s, 1H), 5.93 (br d, J = 9.9 Hz, 1H), 6.27 (br d, J = 16.5 Hz, 1H), 6.53 (br dd, J = 16.4, 9.6 Hz, 1H), 7.27-7.34 (m, 5H), 8.06 (br s, 1H)

AP-MS (m / z): 466 (M ⁺ )

Reference Example 8 (Compound 8a)

Compound 7a (0.05 g, 0.11 mmol) obtained in Reference Example に was added to acetonitrile (3 mL). After dissolution, a 70% aqueous solution of ethylethylamine (0.10 mL) was added, and the mixture was stirred at 80 ° C for 2 hours. After concentrating the reaction solution, the residue was purified by silica gel gel column chromatography (cloform formethanol = 10-1) to obtain the title compound 8a (0.01 g, 26%).

_{¾NMR (300 MHz, CDC1 3)} δ (ppm): 1.18 (m, 3H), 1.28 (s, 9H), 1.34 (s, 9H), 2.63

(quin, J = 7.0 Hz, 2H), 2.73 (br q, J = 6.3 Hz, 1H), 2.84 (br q, J = 6.2 Hz,

1H), 3.18 (br t, J = 6.6 Hz, 2H), 4.02 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 13.2

Hz, 1H), 5.85 (br s, 1H), 7.27—7.35 (m, 5H), 8.02 (br s, 1H)

AP-MS (m / z): 512

Reference Example 9 (Compound 9a)

Process 1

In the same manner as in Step 2 of Reference Example 4, 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%).

Process 2

In the same manner as in Step 3 of Reference Example 4, 4-carbomethoxybutyl phenone = thiosemicarbazone, piperoyl chloride (0.549 mL, 4.45 ramol) and pyridine (0.431 mL, 5.3 tmol) obtained above were obtained. From this, the title compound 9a (318 mg, 64%) was obtained.

_{¾NMR (300 MHz, CDC1 3)} δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.51-1.60 (m, 1H), 2.10-2.30 (m, 2H), 2.44 (m, 2H ), 3.03—3.17 (m, 1H), 3.68 (s, 3H), 7.20-7.36 (m, 5H), 7.95 (br s, 1H)

Reference Example 10 (Compound 10a)

Sodium hydroxide (2.68 g, 66, 9 mmol) was dissolved in water (2 mL), and 1,4-dioxane (4 mL) was added and stirred, and the compound 9a obtained in Reference Example 9 was further added. (9.65 g, 22.3 mmol) was added. After reacting at room temperature for 5 hours, 1 mo 1, L hydrochloric acid (20 mL) and water (30 mL) were added, and the precipitated white crystals were collected by filtration. The obtained white crystals were washed with water and diisopropyl ether, and dried under reduced pressure to obtain the title compound 10a (9.18 g, 95%). _{¾NMR (270 MHz, CDC1 3)} δ (ppm) 1.29 (s, 9H), 1.32 (s, 9H), 1.65-1.75 (m, 1H), 2.10-2.35 (m, 2H), 2.50 (m, 2H) , 3.10—3.20 (m, 1H), 7.23-7.35 (m, 6H), 7.92 (br s, 1H)

Reference Example 11 (Compound 11a)

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). The organic layer was washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1). Thus, the title compound 11a (1.91 g, 3.78 mmol) was obtained.

_{¾ NMR (270 MHz, CDC1 3} ) δ (ppm): 1.29 (s, 9H), 1.31 (s, 9H), 1.45 (s, 9H), 1.47-1.54 (m, 1H), 1.91-2.04 (m, 1H), 2.17—2.31 (m, 1H), 3.07-3.34 (m, 3H), 4.57-4.69 (m, 1H), 7.19-7.38 (m, 5H), 7.89 (s, 1H)

AP-MS (m / z): 505 (M ++ 1)

Reference Example 12 (Compound 12a)

The compound 11a (1.91 g, 3.78 mmol) obtained in Reference Example 11 was dissolved in 4 mol 1 ^ L hydrogen chloride-methanol solution (50 mL) and allowed to stand at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the title compound 12a (1.43 g, 3.24 mol) as a hydrochloride.

_{¾NMR (270 MHz, CDC1 3)} δ (ppm): 1.27 (s, 9H), 1.31 (s, 9H), 1.68-1.86 (m, 1H), 1.05-2.22 (m, 1H), 2.41-2.55 (m , 1H), 2.98-3.11 (m, 2H), 3.21-3.36 (m, 1H), 7.17-7.35 (m, 3H), 7.39-7.46 (m, 2H), 8.02 (s, 1H), 8.33-8 , 50 (m, 3H) AP-MS (m / z): 405 + l)

Reference Example 13 (Compound 13a)

Process 1

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) and 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. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 3- (tert-butoxycarbonylamino) propiophenone (9.59). g, 49%). Process 2

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. Furthermore, 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. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (200 mL), pyridine (10.2 mL, 126 mL) and pivaloyl chloride (12.9 mL, 105 mmol) were added at 0 ° C, and the mixture was stirred at room temperature for 19 hours. . Furthermore, 0. Pyridine (10.2 mL, 126 bilol) and pivaloyl chloride (12.9 mL, 105 bilol) were added at C, and the mixture was stirred at room temperature for 23 hours, water was added, and the mixture was extracted with chloroform. . The organic layer was sequentially washed with 1 mol 1 ZL hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with disopropyl ether to give the title compound 13a (9.28 g, 90%).

AP-MS (m / z): 491 (M ++ 1)

Reference Example 14 (Compound 14a)

Compound 13a (6.00 g, 12.2 mmol) obtained in Reference Example 13 was dissolved in dichloromethane (30 mL), trifluoroacetic acid (60 mL) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. Stirred. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After washing the organic layer with a saturated aqueous sodium chloride solution, anhydrous sodium sulfate is added. It was dried over a lime and the solvent was distilled off under reduced pressure. The residue was triturated with disopropyl ether to give compound 14a (4.49 g, 94%).

¾賺_{(270 MHz, CDC1 3) δ} (ppm): 1.29 (s, 9H), 1.31 (s, 9H), 2.43 (m, 1H), 2.82

(m, 1H), 3.12-3.3 (m, 2H), 7.17-7.46 (m, 5H)

AP-MS (m / z): 391 (M + 1) ⁺

Reference Example 15 (Compound 15a)

N, N-Dimethyl-γ-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 虬) 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 saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the title compound 15a (0.980 g, 98%).

AP-MS (m / z): 504 (M ++ 1)

Formulation Example 1 Tablet (Compound 1)

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

Lactose 43.4 mg

30 mg

Hydroxypropinoresenolerose 6 mg

Magnesium stearate --- 0.6 mg

200 mg industrial availability

According to the present invention, treatment of diseases involving cell proliferation, for example, malignant tumors (breast cancer, stomach cancer, ovarian cancer, colorectal cancer, lung cancer, 胭 tumor, larynx cancer, blood system cancer, urogenital tract including bladder cancer and prostate cancer) Thiadiazoline-l-oxide derivative or pharmacologically acceptable salt thereof useful for the treatment of cancer, kidney cancer, skin cancer, liver cancer, ovarian cancer, uterine cancer, etc.), restenosis, cardiac hypertrophy, immune disease, etc. Is done.

Claims

1. General formula (I)

Wherein R ¹ and R ⁴ are the same or different and are each 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 R ² represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group; unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Ariru, substituted or unsubstituted heterocyclic group, in one C (-W) R ⁶ [wherein, W is an oxygen atom or a sulfur atom represents, R ⁶ is a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, location Or unsubstituted cycloalkyl, substituted or unsubstituted Ariru, substituted or unsubstituted heterocyclic group, _NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are the same or different, a hydrogen atom, a substituted or unsubstituted Represents a substituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, or R ⁷ and R ⁸ together with an adjacent nitrogen atom form a substituted or unsubstituted complex ring group), -OR ⁹ (where R ⁹ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted) Substituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted Represents a substituted heterocyclic group) or one SR ^1G (wherein, R ^1G is as defined above for R ⁹ )], one NRHR ¹² (where R ¹¹ and R ¹² are the same or different, Hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Heterocyclic group or one co

R ¹³ wherein R ¹³ 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 of Ariru, substituted or unsubstituted heterocyclic group, - NR ^7A R ^8A (in the formula, R ^7A and R ^8A are the same meanings as the above R ⁷ and R ^8), in one oR ^9A (wherein, R ^9A is as defined above for R ⁹ ) or one SR ^10A (wherein, R ^1QA is as defined above for R ⁹ )] or one S0 ₂ R ¹⁴ (where R ¹⁴ is or represents a a) synonymous with said R ^9, or R ¹ and R ² form a heterocyclic group of the connexion substituted or unsubstituted, such together with the nitrogen atom it adjacent, R ⁵ is properly also substituted non Substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl Represents a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, or a combination of R ⁴ and R ⁵ (CR ^15A R ^15B ) _ml — Q— (CR ^15C R ^15D ) _m2 — {wherein Q represents a single bond, substituted or unsubstituted phenylene or cycloalkylene, and m 1 and m 2 are the same or different and represent an integer of 0 to 4 However, m 1 and m 2 are not simultaneously 0, and R ^15A , ^15B _S R ^15C and R ^15D are the same or different and each represents a hydrogen atom, a halogen, a substituted or unsubstituted lower alkyl, —OR ¹⁶ [wherein And R ¹⁶ 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 aryl, substituted or unsubstituted aryl. Unsubstituted Ring group, (wherein, R ^7B and R ^8B are the same meanings as the above R ⁷ and R ⁸⁾ one ^{^{_{CONR 7B R 8B, -SO 2 NR}}} 7C R 8c ( wherein, R ^7C and R ^8C are Is as defined above for R ⁷ and R ⁸ ) or one COR ¹⁷ (where R ¹⁷ is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted Lower alkynyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl Or -NR ¹⁸ R ^{19 wherein} R ¹⁸ and R ¹⁹ are the same or different and are a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or Unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, one COR ² ° ² ° is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Unsubstituted heterocyclic group, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, amino, substituted or unsubstituted lower alkyl Amino, during a substitution or an unsubstituted di-lower Arukiruamino or substituted or unsubstituted Ariruamino) or a S0 ₂ R ²¹ (wherein, R ²¹ represents a a) synonymous with said R ^9] or

— Represents CO ₂ R ²² (wherein R ²² is as defined above for R ¹⁷ ) or R ^15A and R ^15B or R ^15C and R ^15D represent an oxygen atom, and m 1 Or when m 2 is an integer greater than or equal to 2, each R ^15A , R ^15B,! ^ ぉ! ^^ may be the same or different, and R ^15A , R ^15B , R ^15C and R ^15D bonded to two adjacent carbon atoms may each be taken together to form a bond}, R ³ represents a hydrogen atom or a ^{^{C (= W a) R 6A}} ( wherein, W ^a and R ⁶ a is the same meaning as W and R ⁶ above). Provided that when R ¹ is hydrogen, R ² and R ³ are acetyl, and R ⁵ is phenyl, R ⁴ is not hydrogen or methyl, or a thiadiazoline 1-oxide derivative represented by> Acceptable salts.

2. R ⁴ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted lower alkynyl, and R ⁵ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle A group or a substituted or unsubstituted aryl, or R ⁴ and R ⁵

― (CR ^15A R ^15B ) _ml -Q- (CR ^15C R ^15D ) _m2 _ (wherein, R ^15A , R ^15B , R ^15C , R ^15D , ml, m2 and Q are as defined above) Billing The thiaziazoline-111-oxide derivative or the pharmacologically acceptable salt thereof according to item (1).

3. The thiadiazoline according to claim 1, wherein R ⁵ is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, or a substituted or unsubstituted cycloalkyl. 1-oxide derivative or pharmacologically acceptable salt thereof.

4. The thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ⁵ is a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group.

5. The thiadiazoline-1-oxide derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ⁵ is substituted or unsubstituted phenyl or substituted or unsubstituted phenyl.

6. The thiadiazoline-1-oxide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ⁴ is a substituted or unsubstituted lower alkyl.

7. The thiadiazoline-111-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ⁴ is substituted lower alkyl.

8. R ⁴ and R ⁵ together

Represents a ^{^{(wherein, R 15A, R 15B, R}} 15C, R 15D, ml, m2 and Q each have the same meanings as defined above) - A ^{^{_{(CR 15A R 15B) ml -Q-}}} (CR 15C R 15D) m2 The thiadiazoline-1-oxide derivative according to claim 1, or a pharmacologically acceptable salt thereof.

9. A claim wherein R ⁴ and R ^{5 are}緖 to represent 1 (CH ₂ ) _ml -Q- (CH ₂ ) _m2 — wherein m 1, m 2 and Q are as defined above. 3. The thiadiazoline-111-oxide derivative or the pharmaceutically acceptable salt thereof according to item 1.

10. The thiadiazoline-11-oxide derivative or the pharmaceutically acceptable salt thereof according to claim 8 or 9, wherein Q is substituted or unsubstituted phenylene.

11. The thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims ¹ to 10, wherein R ¹ is a hydrogen atom or a substituted or unsubstituted lower alkyl.

12. The thiaziazoline-111-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims ¹ to 10, wherein R ¹ is a hydrogen atom.

1 3. R ² gar C (= W) R ⁶ (wherein, W and R ⁶ are as defined above, respectively Ru der) according to any of claims the 1 to 1 2, wherein a Chiajiazorin 1-oxo derivative or a pharmacologically acceptable salt thereof.

14. The method according to claim 13, wherein R ⁶ is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, or a substituted or unsubstituted cycloalkyl. A thiadiazoline-1-oxide derivative or a pharmacologically acceptable salt thereof.

15. The thiadiazoline 1-oxide derivative or a pharmaceutically acceptable salt thereof according to claim 13, wherein R ⁶ is lower alkyl.

16. The thiadiazolin-1-oxide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 13 to 15, wherein W is an oxygen atom.

. 1 7 R ¹ and R ² are as defined in any range the 1 to 1 0 the preceding claims for forming the adjacent nitrogen atom and the a connexion substituted or unsubstituted heterocyclic group together thiadiazoline - 1 one Okishido derivatives Or a pharmacologically acceptable salt thereof.

1 8. R ³ gar ^{^{C (= W A) R 6}} A ( wherein, W ^A and R ^{6 A} are each the same meanings as defined above) in any of claims the 1 to 1 7, wherein a Or a pharmacologically acceptable salt thereof.

19. The method according to claim 18, wherein R ⁶ A is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkynyl, or a substituted or unsubstituted cycloalkyl. Thiadiazoline 1-oxide derivative or a pharmacologically acceptable salt thereof.

20. The thiadiazoline according to claim 18, wherein R ⁶ A is lower alkyl. 1 A monooxide derivative or a pharmacologically acceptable salt thereof.

2 1. W ^A is thia Jiazorin one 1- Okishido derivative or a pharmacologically acceptable salt thereof according to any one of claims first 8-2 0 of claims is an oxygen atom.

22. A medicament comprising the thiadiazoline-l-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 as an active ingredient.

23. M-phase kinesin easy-form (E g) containing the thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 as an active ingredient. 5) Inhibitor.

24. An antitumor agent comprising the thiadiazoline-11-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 as an active ingredient.

25. An M-phase kinesin, comprising administering an effective amount of the thiadiazoline_1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21. Eg5 inhibition method.

26. A malignant Jfi tumor characterized by administering an effective amount of the thiadiazoline-1-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21. Treatment method.

27. Use of a thiadiazoline-l-oxide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 for the manufacture of an M-phase kinesin Eg5 inhibitor. .

28. Use of the thiadiazoline-l-oxide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 for the manufacture of an anti-JB ulcer agent.