JP2005232016A - Oxadiazoline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an agent which contains an oxadiazoline derivative or its pharmacologically acceptable salt as an active ingredient and used for treating and/or preventing cell proliferation-related diseases, such as tumors, restenosis, hypercardia and immunological diseases, and to provide the oxadiazoline derivative or its pharmacologically acceptable salt useful for treating the cell proliferation-related diseases. <P>SOLUTION: This anti-tumor agent contains the oxadiazoline derivative represented by formula (I) [R<SP>1</SP>is a substituted or unsubstituted lower alkyl, or the like; R<SP>2</SP>is -C(=W<SP>2</SP>)R<SP>19</SP>(W<SP>2</SP>is oxygen atom, or the like; R<SP>19</SP>is H, or the like); R<SP>3</SP>is H, or the like; R<SP>4</SP>is a substituted or unsubstituted lower alkyl, or the like] or its pharmacologically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a therapeutic and / or prophylactic agent for diseases associated with cell proliferation, such as tumors, restenosis, cardiac hypertrophy, immune diseases, etc. containing an oxadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient About.

  Drugs such as vinca alkaloids and taxanes, which are clinically important anticancer agents, bind to microtubules and have an action of inhibiting the function of spindles having microtubules as structural units. Spindle function is essential for centrosome localization and accurate chromosome segregation during cell division (cell cycle M phase). Inhibiting this function inhibits normal cell division and induces cell death in cancer cells. [Biochem. Biophys. Res. Commun., 263, p. 398 (1999)].

  Since microtubules are involved not only as constituent molecules of the M-phase spindle but also in maintaining cell morphology, intracellular substance transport, and nerve fiber axon transport, microtubule-acting anticancer agents act on cancer cells. Not only does it have side effects on normal cells. For example, as a side effect characteristic of microtubule agonists, peripheral neuropathy due to inhibition of nerve fiber axonal transport has become a clinical problem. Therefore, drugs other than microtubules that act on molecules important for controlling spindle function in the M phase of the cell cycle and inhibit spindle function as well as existing microtubule-acting anticancer agents are microtubules found in existing anticancer agents. It is expected to be a new anticancer agent that avoids the above-mentioned side effects resulting from the action.

  M-phase kinesin is a protein involved in M-phase spindle regulation, and plays an essential role in the M-phase progression of the cell cycle. These proteins have a function of moving proteins along microtubules using energy generated by ATP hydrolysis, and are a group of functional proteins generally 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 further controls the progression of correct cell division through the movement of chromosomes along the spindle microtubule.

  M-phase kinesin Easy Five (Eg5) is one of the M-phase kinesins that forms an evolutionarily conserved subfamily. Eg5 is a homotetrameric bipolar molecule that bridges two identically oriented microtubules and moves them toward the + (plus) end, sliding between two antiparallel aligned microtubules It is known that the spindle poles are separated by moving the-(minus) ends of the microtubules apart and are involved in the formation of a bipolar spindle structure. Such a function of Eg5 has been clarified from antibody introduction experiments and analysis of human cells using specific inhibitors [Cell, Volume 83, p. 1159 (1995), Journal of Cell Biology, 150, p. 975 (2000), Experimental Medicine, Vol. 17, p. 439 (1999)].

  The gene of human Eg5 was cloned in 1995, and expression of full-length human Eg5 recombinant protein using insect cells and functional analysis using the same have been reported [Cell, Vol. 83, p. 1159 (1995)]. The gene is registered in a public database as GenBank accession number: X85137, NM004523, U37426. Analysis using Eg5 derived from Xenopus having high homology to human Eg5 [Proc. Natl. Acad. Sci. USA], 96. [Procedures of the National Academy of Sciences of USA] Volume, p. 9106 (1999), Biochemistry, 35, p. 2365 (1996)], biochemical analysis and crystal structure analysis of Eg5 have been reported using the N-terminal part of human Eg5 expressed in E. coli [Journal of Biological]. -Chemistry (J. Biological Chemistry), 276, p. 25496 (2001), Chemistry & Biology, Vol. 9, p. 989 (2002)].

  Expression of Eg5 in normal human tissues is known to be limited to the testis and thymus, and from the results of analysis of cancer patient tissues, human Eg5 shows higher expression in cancer areas than in non-cancerous areas. [Procedure of the National Academy of Sciences of USA (Proc. Natl. Acad. Sci. USA), 99, p. 4465 (2002), US6414121 B1].

  As described above, M-phase kinesin Eg5 is important as a target molecule for a novel M-phase agonist, and its inhibitor is a disease associated with cell proliferation (eg, tumor, restenosis, cardiac hypertrophy, arthritis, immune disease, etc.). It is considered promising as a therapeutic agent [International Publication No. 01/98278, International Publication No. 02/56880, International Publication No. 02/57244, Trends in Cell Biology, 12 Volume, p. 585 (2002)].

  Compounds showing human Eg5 enzyme inhibitory activity include monasterol (Science), 286, p. 971 (1999)], quinazoline derivatives (International Publication No. 01/98278), phenathiazine derivatives (International Publication No. 02/057244), triphenylmethane derivatives (International Publication No. 02/056880), dihydropyrimidine derivatives (International Publication No. 02/079149, International Publication No. 02/079169) and dihydropyrazole derivatives (International Publication No. 03/079973) have been reported.

On the other hand, as oxadiazoline derivatives, those having an integrin antagonistic action (for example, see Patent Document 1), those having an antimycobacterial action (for example, see Patent Document 2), those having an antibacterial action (for example, non-patents) Documents 1 and 2), those having a pest control action (for example, see Patent Documents 3 and 4), those having antitumor activity (for example, see Non-Patent Document 3), and the like are known. Further, those having an acetyl group at the 4-position (for example, see Patent Document 2 and Non-Patent Documents 1 and 4 to 28), and those having a benzoyl group at the 4-position (for example, Patent Document 5 and Non-Patent Documents 26, 28 and 29) and those having a diphenylacetyl group at the 4-position (see, for example, Non-Patent Document 30).
International Publication No. 01/56994 Pamphlet International Publication No. 02/43668 Pamphlet JP 2000-159756 A US Pat. No. 6,235,762 US Pat. No. 3,146,232 “Pharmacazie”, 1983, vol. 38, p. 833 “Indian Journal of Heterocyclic Chemistry”, 2001, Vol. 10, p. 253 “Journal of Medicinal Chemistry”, 2001, vol. 44, p. 4416 “Journal of the Chinese Chemical Society”, 2001, Vol. 48, p. 913 “Archives of Pharmaceutical Research”, 2001, Vol. 24, p. 263 “Yoji Huaxue”, 2000, Vol. 20, p. 499 “Gaodeng Xueiao Huaxue Xuebao”, 1999, Vol. 20, p. 1242 “Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion, Medicinal Chemistry (Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion, Medicinal Chemistry, Vol. 35, B). 980 “Egyptian Journal of Pharmaceutical Sciences (1985), Volume of Date (Egyptian Journal of Pharmaceutical Sciences (1985), Volume Date)”, 1983, Vol. 24, p. 57 "Mansour Journal of Pharmaceutical Sciences", 1996, Vol. 12, p. 256 “Journal of the Indian Chemical Society”, 2000, vol. 77, p. 168 “Yuji Huaxue”, 1999, Vol. 19, p. 316 “Chinese Journal of Chemistry”, 1999, Vol. 17, p. 62 “Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion, Medicinal Chemistry (Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion, Vol. 41, B, year 200). 2176 “Synthetic Communications”, 2003, Vol. 33, p. 143 “Carbohydrate Research”, 1988, Volume 182, p. 19 “Bulletin of Pharmaceutical Sciences, Associate University”, 1994, Vol. 17, p. 17 “Egyptian Journal of Pharmaceutical Sciences”, 1994, Vol. 35, p. 21 “Archidder Pharmazine”, 1990, Vol. 323, p. 595 “Journal of the Chemical Society of Pakistan”, 1987, Vol. 9, p. 87 “Egyptian Journal of Pharmaceutical Sciences (1983), Volume of Date (Egyptian Journal of Pharmaceutical Sciences (1983), Volume Date)”, 1981, Vol. 22, p. 199 “Acta Pharmaceuticals Jugoslavica”, 1972, Vol. 22, p. 97 “Liebigs Analen der Chemie”, 1994, Vol. 6, p. 623 "Tetrahedron", 1992, 48, p. 9355 “Hauxue Tongbao”, 2000, Vol. 1, p. 38 “Tetrahedron Letters”, 1988, Vol. 29, p. 3581 “Chemiche Berichte”, 1986, Vol. 119, p. 2963 “Tetrahedron”, 1985, vol. 41, p. 5187 “Gazetta Chimica Italiana”, 1965, vol. 95, p. 33 “Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion, Medicinal Chemistry (Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion Medicinal Chemistry, Vol. 39, B). 554

  An object of the present invention is to treat and / or prevent diseases involving cell proliferation, such as tumors, restenosis, cardiac hypertrophy, immune diseases, etc., which contain an oxadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient. It is to provide an agent. Another object is to provide an oxadiazoline derivative or a pharmacologically acceptable salt thereof useful for the treatment of the above-mentioned diseases involving cell proliferation.

The present invention relates to the following (1) to (16).
(1) General formula (I)

<In the formula, R ¹ is 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 -C (= W) R ⁵ {wherein W represents an oxygen atom or a sulfur atom, R ⁵ represents -YR ⁶ (wherein Y represents a bond, an oxygen atom or a sulfur atom, R ⁶ represents 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 complex. ring group represents a) or -NR ⁷ R ⁸ [wherein, R ⁷ and R ⁸ are the same or different, a hydrogen atom, a substituted or unsubstituted lower alkyl, location Or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, in -OR ⁹ (wherein, R ⁹ is the R ⁶ synonymous) or -NR ¹⁰ R ¹¹ (wherein, R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Represents a substituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, or R ¹⁰ and R ¹¹ together with the adjacent nitrogen atom are substituted or unsubstituted form a heterocyclic group) or represents, or R ⁷ and R ⁸ is a substituted or unsubstituted together with the adjacent nitrogen atom a heterocyclic Represents a] forming a}

Or —NR ¹² R ¹³ {wherein R ¹² and R ¹³ are the same or different and each represents 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 heterocyclic group or —C (═W ¹ ) R ¹⁴ [wherein W ¹ has the same meaning as W above, and R ¹⁴ represents 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 heterocyclic group,- NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ have the same meanings as R ¹⁰ and R ¹¹ , respectively), —OR ¹⁷ (wherein R ¹⁷ is substituted or unsubstituted) Or substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group) or —SR ¹⁸ (Wherein R ¹⁸ has the same meaning as R ¹⁷ above), or R ¹² and R ¹³ together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group} Represents

R ² is —C (═W ² ) R ¹⁹ , wherein W ² is as defined above, and R ¹⁹ 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 heterocyclic group, —NR ²⁰ R ²¹ (wherein R ²⁰ and R ²¹ are the same as R ¹⁰ And R ¹¹ ), —OR ²² (wherein R ²² has the same meaning as R ¹⁷ ) or —SR ²³ (wherein R ²³ has the same meaning as R ¹⁷ )). Represent,

R ³ 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 Represents a heterocyclic group of

R ⁴ represents 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 heterocycle Represents a group,

Or R ³ and R ^{4 taken} together — (CR ^24A R ^24B ) _m1 -Q- (CR ^24C R ^24D ) _m2 — {wherein Q represents a single bond, substituted or unsubstituted phenylene or cycloalkylene. , M1 and m2 are the same or different and each represents an integer of 0 to 4, m1 and m2 are not 0 at the same time, and R ^24A , R ^24B , R ^24C and R ^24D are the same or different and represent a hydrogen atom, halogen , Substituted or unsubstituted lower alkyl, —OR ²⁵ [wherein R ²⁵ represents 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 heterocyclic group, -CONR ²⁶ R ²⁷ (wherein, R ²⁶ and R ²⁷ the same or different and each represents a hydrogen atom, a substituted if Represents an 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, or a substituted or unsubstituted heterocyclic group; Or R ²⁶ and R ²⁷ together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group), —SO ₂ NR ²⁸ R ²⁹ (wherein R ²⁸ and R ²⁹ are each the above-mentioned R ²⁶ and R ²⁷ ) or —COR ³⁰ (wherein R ³⁰ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Represents a substituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group)],

—NR ³¹ R ³² [wherein R ³¹ and R ³² are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, —COR ³³ (wherein R ³³ represents 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 heterocyclic group, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, amino, Substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino During a substituted or unsubstituted arylamino), or -SO ₂ R ³⁴ (wherein other, R ³⁴ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted Or a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), or R ³¹ and R ³² together with the adjacent nitrogen atom are substituted or unsubstituted. Forms a heterocyclic group] or —CO ₂ R ³⁵ , wherein R ³⁵ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted substituted cycloalkyl, or represents represents) a substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, or R ^24A, Represents R ^24B or R ^24C and R ^24D is an oxygen atom together, when m1 or m2 is 2 or more integer, each of R ^24A, R ^24B, even if R ^24C and R ^24D are the same or different than Well, R ^24A , R ^24B , R ^24C and R ^24D bonded to two adjacent carbon atoms may each form a bond}
An M-phase kinesin easy 5 (Eg5) inhibitor comprising an oxadiazoline derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient.

(2) The M-phase kinesin easy 5 (Eg5) inhibitor according to (1), wherein R ⁴ is substituted or unsubstituted phenyl.
(3) General formula (IA)

<In the formula, R ^1A represents 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 -C (= W) R ⁵ (wherein W and R ⁵ are as defined above) or -NR ¹² R ¹³ (wherein R ¹² and R ¹³ are as defined above), Represent)
R ^2A is —C ( ^{═W 2} ) R ^19A , wherein W ² is as defined above, and R ^19A is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or non-substituted Substituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, —NR ^20A R ^21A (wherein R ^20A and R ^21A are the same or different, hydrogen Represents an atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group, or R ^20A and R ^21A together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group), - oR ²² (wherein, R ²² is as defined above) the -SR ²³ (wherein, R ²³ has the same meaning as defined above) represents' represents a

R ^3A represents 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 Represents

R ^4A represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group,
Or R ^3A and R ^{4A taken} together — (CR ^24AA R ^24BA ) _m1A -Q ^A — [wherein Q ^A represents substituted or unsubstituted phenylene, m1A represents an integer of 1 to 4; R ^24AA and R ^24BA are the same or different and are a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, —OR ²⁵ (wherein R ²⁵ is as defined above), —NR ³¹ R ³² (wherein R ³¹ and R ³² are as defined above) or —CO ₂ R ³⁵ (wherein R ³⁵ is as defined above), or R ^24AA and R ^24BA are combined to form an oxygen atom. represents, when m1A is an integer of 2 or more, each of R ^24aa and R ^24ba may be the same or different, a bond respectively R ^24aa and R ^24ba are bonded to adjacent two carbon atoms together May be formed]

However,
(A) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is phenyl, R ^1A is pyridyl, substituted benzodiazepinyl, substituted methyl, 2-acetoxy-3,5-dibromophenyl , Substituted triazolyl, 5-methyl-3-isoxazolyl and 2- (phenothiazinyl) ethyl,
(B) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is 4-substituted phenyl, R ^1A is phenyl, 2-acetoxy-3,5-dibromophenyl, 4- (substituted methoxy) ) Instead of phenyl and substituted methyl

(C) when R ^2A is acetyl, R ^3A is methyl and R ^4A is 2-thienyl, R ^1A is not 2-bromo-5-methoxyphenyl,
(D) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is substituted phenyl, R ^1A is not substituted quinolyl,
(E) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is benzopyranyl or substituted oxadiazolyl, R ^1A is not methyl, substituted or unsubstituted phenyl and 4-pyridyl;

(F) When R ^2A is acetyl, R ^3A is phenyl, and R ^4A is phenyl, R ^1A is not phenyl and methyl;
(G) when R ^2A is benzoyl, R ^3A is phenyl, and R ^4A is phenyl, R ^1A is not phenyl;
(H) R ^1A is not diphenylmethyl when R ^2A is diphenylacetyl, R ^3A is substituted or unsubstituted phenyl, and R ^4A is substituted or unsubstituted phenyl. A diazoline derivative or a pharmacologically acceptable salt thereof.

(4) The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to (3), wherein R ^4A is a substituted or unsubstituted aromatic heterocyclic group.
(5) The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to (3), wherein R ^4A is substituted or unsubstituted phenyl.

(6) The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (5), wherein R ^1A is substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group. .
(7) The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (5), wherein R ^1A is substituted or unsubstituted phenyl.

(8) In any one of (3) to (5), R ^1A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl The oxadiazoline derivative or a pharmacologically acceptable salt thereof.
(9) The oxadiazoline derivative according to any one of (3) to (8), wherein R ^2A is —C (═O) R ^19B (wherein R ^19B represents a substituted or unsubstituted lower alkyl). Or a pharmacologically acceptable salt thereof.

(10) The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (8), wherein R ^2A is pivaloyl.
(11) The oxadiazoline derivative according to any one of (3) to (10), wherein R ^3A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted lower alkynyl, or a derivative thereof Pharmacologically acceptable salt.

(12) The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (10), wherein R ^3A is substituted lower alkyl.
(13) A medicament comprising the oxadiazoline derivative or a pharmacologically acceptable salt thereof according to any one of (3) to (12) as an active ingredient.
(14) An M-phase kinesin easy five (Eg5) inhibitor comprising as an active ingredient the oxadiazoline derivative or the pharmacologically acceptable salt thereof according to any one of (3) to (12).

(15) A therapeutic agent for a disease involving cell proliferation, comprising as an active ingredient the oxadiazoline derivative or a pharmacologically acceptable salt thereof according to any one of (3) to (12).
(16) An antitumor agent comprising the oxadiazoline derivative or a pharmacologically acceptable salt thereof according to any one of (3) to (12) as an active ingredient.
Hereinafter, the compound represented by general formula (I) and the compound represented by general formula (IA) are referred to as compound (I) and compound (IA), respectively. The same applies to the compounds of other formula numbers.

  According to the present invention, there is provided a therapeutic and / or prophylactic agent for diseases associated with cell proliferation containing an oxadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient, such as tumors, restenosis, cardiac hypertrophy and immune diseases. Provided. In addition, an oxadiazoline derivative or a pharmacologically acceptable salt thereof useful for the treatment of the above-mentioned diseases involving cell proliferation is provided.

In the definition of each group of general formula (I) and general formula (IA):
(I) Lower alkyl part of lower alkyl, lower alkoxy, lower alkylamino and di-lower alkylamino includes, for example, linear or branched alkyl having 1 to 10 carbon atoms, specifically methyl, ethyl, propyl, isopropyl Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. The two lower alkyl moieties of the di-lower alkylamino may be the same or different.

(Ii) As the lower alkenyl, for example, linear or branched alkenyl having 2 to 10 carbon atoms, specifically vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. can give.
(Iii) Examples of lower alkynyl include linear or branched alkynyl having 2 to 10 carbon atoms, specifically ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.

Examples of (iv) cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
(V) Examples of the aryl moiety of aryl, aryloxy and arylamino include phenyl, naphthyl and the like.

(Vi) As the aromatic heterocyclic group, for example, 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; Examples thereof include condensed bicyclic or tricyclic condensed rings containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, specifically, furyl, thienyl, Benzothienyl, pyrrolyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyrimidinyl, indolyl, isoindolyl, benzothiazolyl, benzoimidazolyl, benzotriazolyl, quinolylisoquinolyl, quinolyl , Quinazolinyl, pirani , Phenothiazinyl, such as benzopyranyl, and the like.

(Vii) Examples of the heterocyclic group include an aliphatic heterocyclic group and the aromatic heterocyclic group shown above. As the aliphatic heterocyclic group, for example, a 5-membered 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 condensed. And a condensed aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, such as pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl. , Morpholinyl, thiomorpholinyl, piperidino, morpholino, oxazolinyl, dioxolanyl, tetrahydropyranyl and the like.

(Viii) 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 other nitrogen atom, such as pyrrolidinyl, morpholino, thiomorpholino, pyrazolidinyl, piperidino, piperazinyl, homopiperazinyl, aziridinyl, Examples thereof include azetidinyl, azolidinyl, perhydroazepinyl, perhydroazosinyl, succinimide, phthalimide, pyrrolidonyl, glutarimide, piperidonyl and the like.

Examples of (ix) cycloalkylene include cycloalkylene having 3 to 8 carbon atoms, specifically cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, and the like. 1,2-phenylene, 1,3-phenylene and 1,4-phenylene.
(X) Halogen means each atom of fluorine, chlorine, bromine or iodine.

(Xi) Substituents in substituted lower alkyl, substituted lower alkoxy, substituted lower alkenyl, substituted lower alkynyl, substituted cycloalkyl, substituted lower alkylamino and substituted dilower alkylamino may be the same or different and may have, for example, 1 to 1 substituents. Any number, preferably 1 to 3, of halogen, hydroxy, oxo, nitro, azide, cyano, substituted or unsubstituted cycloalkyl [substituent (b) in the substituted cycloalkyl is the same or different, for example substituted A halogen atom, hydroxy, oxo, carboxy, cyano, substituted or unsubstituted lower alkoxy (the substituent (a) in the substituted lower alkoxy is the same or different, for example, Hydroxy, oxo, carboxy, lower alkoxy, Secondary alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, aryl, heterocyclic group and the like), lower alkanoyloxy, substituted or unsubstituted lower alkylthio (the substituent in the substituted lower alkylthio is the above-mentioned substitution) The same as the substituent (a) in lower alkoxy), aryl, aryloxy, heterocyclic group, amino, substituted or unsubstituted lower alkylamino (substituent in the substituted lower alkyl is substitution in the above substituted lower alkoxy) The same as the group (a)), substituted or unsubstituted di-lower alkylamino (the substituent in the substituted lower alkyl is the same as the substituent (a) in the substituted lower alkoxy), etc.] Substituted or unsubstituted aryl (substitution in the substituted aryl) Is synonymous with the substituent (xii) in the substituted aryl described later), a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the substituent (xiii) in the substituted heterocyclic group described later). Synonymous),

-CONR ³⁶ R ³⁷ <In the formula, R ³⁶ and R ³⁷ are the same or different, and a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl {the substituent (c) in the substituted lower alkyl is the same or different. For example, halogen, hydroxy, oxo, carboxy, cyano, substituted or unsubstituted lower alkoxy having 1 to substitutable number, preferably 1 to 3 (the substituent in the substituted lower alkoxy is the same as in the substituted cycloalkyl). Substituted or unsubstituted lower alkylthio (the substituent in the substituted lower alkylthio has the same meaning as substituent (b) in the substituted cycloalkyl), substituted or unsubstituted lower Alkylsulfonyl (the substituent in the substituted lower alkylsulfonyl is the above 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 later), a substituted or unsubstituted heterocycle 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 aryloxy (the substituent in the substituted lower aryloxy is described later in The same as the substituent (xii) in the substituted aryl), —NR ³⁸ R ³⁹ , wherein R ³⁸ and R ³⁹ are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl (in the substituted lower alkyl, The substituent is the same as the substituent (b) in the above substituted cycloalkyl), a substituted or unsubstituted lower alkenyl (the substituted lower alkenyl Definitive substituents are as defined in substituent (b) in the substituted cycloalkyl),

Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl has the same meaning as the substituent (b) in the above substituted cycloalkyl), substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkynyl is , The same as the substituent (b) in the substituted cycloalkyl), a substituted or unsubstituted substituted aryl (the substituent in the substituted aryl is the same as the substituent (xii) in the substituted aryl described later), 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) or a substituted or unsubstituted lower alkylsulfonyl (the substituted lower alkyl The substituent in the sulfonyl has the same meaning as the substituent (b) in the substituted cycloalkyl. Or it represents, or R ³⁸ and the substituent in the substituted heterocyclic group R ³⁹ may be formed together with the adjacent nitrogen atom together a substituted or unsubstituted Hajime Tamaki (said adjacent nitrogen atom , Which is synonymous with the substituent (xiii) in the substituted heterocyclic group formed together with the adjacent nitrogen atom described later]]

A substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (b) in the substituted cycloalkyl), a substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is , Which is synonymous with the substituent (b) in the substituted cycloalkyl), substituted or unsubstituted cycloalkyl (the substituent in the substituted cycloalkyl is synonymous with the substituent (b) in the substituted cycloalkyl. ), Substituted or unsubstituted aryl (the substituent in the substituted aryl has the same meaning as the substituent (xii) in the substituted aryl described later) or a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group) may represent a substituent in below the substituted heterocyclic group (xiii) as synonymous) or R ^36, Substituents in the substituted heterocyclic group R ³⁷ may be formed together with the adjacent nitrogen atom together a substituted or unsubstituted Hajime Tamaki (said adjacent nitrogen atom, and later the adjacent nitrogen atom Forming a substituent (xiii) in a substituted heterocyclic group formed together>

—CO ₂ R ⁴⁰ wherein R ⁴⁰ is a hydrogen atom, a substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl has the same meaning as the substituent (c) in the substituted lower alkyl), a substituted Or an unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (c) in the substituted lower alkyl), a 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 is synonymous with the substituent (c) in the substituted lower alkyl) Substituted or unsubstituted aryl (the substituent in the substituted aryl is the substituent (xii) in substituted aryl described below) Or 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)], -COR ⁴¹ (formula R ⁴¹ is as defined above for R ⁴⁰ ),

—NR ⁴² R ⁴³ <In the formula, R ⁴² and R ⁴³ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl {the substituent (d) in the substituted lower alkyl is the same or different, for example A halogen atom, a hydroxy group, an oxo group, a carboxy group, a cyano group, a substituted or unsubstituted lower alkoxy group having a substitutable number, preferably 1 to 3 (the substituent in the substituted lower alkoxy is the substituent in the substituted alkyl described above) (Same as (c)), substituted or unsubstituted lower alkylthio (the substituent in the substituted lower alkylthio has the same meaning as the substituent (c) in the substituted alkyl), substituted or unsubstituted aryl (the The substituent in the substituted aryl has the same meaning as the substituent (xii) in the substituted aryl described later), substituted or non-substituted (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 aryloxy (the substituent in the substituted aryloxy is Substituent (xii) in the substituted aryl described later has the same meaning), —O (CH ₂ CH ₂ O) _n R ⁴⁴ (wherein n represents an integer of 1 to 15 and R ⁴⁴ represents lower alkyl) , —SO ₂ R ⁴⁵ [wherein, R ⁴⁵ represents a substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl has the same meaning as the substituent (c) in the substituted alkyl), a lower alkenyl, a lower Alkynyl, substituted or unsubstituted aryl (the substituent in the substituted aryl has the same meaning as the substituent (xii) in substituted aryl described later), a substituted or unsubstituted heterocyclic group (the substituted Substituents on heterocyclic groups are as defined in substituent (xiii) in the later of the substituted heterocyclic group), amino, a lower alkylamino or di-lower alkylamino,

-NR ⁴⁶ R ⁴⁷ (wherein R ⁴⁶ and R ⁴⁷ are as defined above for R ³⁸ and R ³⁹ , respectively), etc.}, substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl is A substituted or unsubstituted lower alkynyl group (the substituent group in the substituted lower alkynyl group has the same meaning as the substituent group (c) in the substituted lower alkyl group). ), Substituted or unsubstituted cycloalkyl (the substituent in the substituted lower 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 synonymous with the substituent (xii) in the substituted aryl described below), a substituted or unsubstituted heterocyclic group (into the substituted heterocyclic group, Kicking substituents are as defined in substituent (xiii) in the later of the substituted heterocyclic group),

—COR ⁴⁸ {wherein R ⁴⁸ is a hydrogen atom, substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl has the same meaning as the substituent (c) in the substituted lower alkyl), substituted or unsubstituted Lower alkenyl (the substituent in the substituted lower alkenyl has the same meaning as the substituent (c) in the substituted lower alkenyl), substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is 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 cycloalkyl Unsubstituted aryl (the substituent in the substituted aryl has the same meaning as the substituent (xii) in the substituted aryl described later) 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),

-NR ⁴⁹ R ⁵⁰ (wherein, R ⁴⁹ and R ⁵⁰ are each synonymous with the for R ³⁸ and R ³⁹⁾ or -OR ⁵¹ [wherein, R ⁵¹ is a substituted or unsubstituted lower alkyl (said substituted lower The substituent in the alkyl has the same meaning as the substituent (c) in the substituted lower alkyl), the substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl is the substituent in the substituted lower alkyl (c ), Substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl has the same meaning as the substituent (c) in the substituted lower alkyl), substituted or unsubstituted cycloalkyl (including The substituent in the substituted cycloalkyl has the same meaning as the substituent (c) in the above substituted lower alkyl), substituted or unsubstituted aryl The substituent in aryl has the same meaning as the substituent (xii) in the substituted aryl described later) or a substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is the substituent in the substituted heterocyclic group described later ( represents the same as xiii)] or —SO ₂ R ⁵² (wherein R ⁵² is as defined above for R ⁴⁸ ), or R ⁴² and R ⁴³ are adjacent nitrogen atoms. Together with a heterocyclic group or a substituted heterocyclic group (the substituent in the substituted heterocyclic group formed with the adjacent nitrogen atom is formed with the adjacent nitrogen atom described later) The same as the substituent (xiii) in the substituted heterocyclic group),

^{-N + R 53 R 54 R 55} X - ( wherein, R ⁵³ and R ⁵⁴ are the same or different and each represents lower alkyl, or R ⁵³ and R ⁵⁴ together with the adjacent nitrogen atom a heterocyclic Forming a group, R ⁵⁵ represents lower alkyl, X represents each atom of chlorine, bromine or iodine), —OR ⁵⁶ [wherein R ⁵⁶ represents a substituted or unsubstituted lower alkyl (in the substituted lower alkyl, The substituent is synonymous with the substituent (d) in the above substituted lower alkyl), the substituted or unsubstituted lower alkenyl (the substituent in the substituted lower alkenyl is the substituent (c) in the above substituted lower alkyl) A substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl has the same meaning 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 above substituted lower alkyl), substituted or unsubstituted aryl (the substituent in the substituted aryl is described later) Or 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). ) representing a], - SR ⁵⁷ (wherein, R ⁵⁷ has the same meaning as above _{^{R 56), - SO 2 R}} 58 [ wherein, R ⁵⁸ is the substituted or unsubstituted lower alkyl (said substituted lower alkyl The substituent is synonymous with the substituent (d) in the above-mentioned 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), substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl has the same meaning 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 above substituted lower alkyl), substituted or unsubstituted aryl (the substituent in the substituted aryl is described later) The same as the substituent (xii) in the substituted aryl of (2), 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 in the above substituted lower alkyl). Or -NR ⁵⁹ R ⁶⁰ (wherein R ⁵⁹ and R ⁶⁹ are respectively synonymous with the aforementioned R ³⁸ and R ³⁹ )], -OSO ₂ R ⁶¹ (formula) R ⁶¹ is the same as R ⁵⁸ described above).

  The lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylamino, dilower alkylamino and lower alkanoyloxy, lower alkanoyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl and aryloxy moieties shown here , A heterocyclic group, a heterocyclic group formed together with an adjacent nitrogen atom, and halogen are the lower alkyl (i), lower alkenyl (ii), lower alkynyl (iii) and cycloalkyl (iv), respectively. , Aryl (v), heterocyclic group (vii), heterocyclic group (viii) formed together with the adjacent nitrogen atom and halogen (x), and two lower alkyls of di-lower alkylamino The portions may be the same or different.

(Xii) Substituents in substituted aryl, substituted aryloxy, substituted arylamino, substituted phenylene, and substituted aromatic heterocyclic group are the same or different, for example, halogen, hydroxy, carboxy, formyl, nitro having 1 to 3 substituents. , Cyano, methylenedioxy, substituted or unsubstituted lower alkyl [substituent (e) in the substituted lower alkyl is the same or different, for example, halogen, hydroxy, oxo, carboxy, substituted or Unsubstituted lower alkoxy (the substituent (f) in the substituted lower alkoxy is the same or different, for example, halogen, hydroxy, oxo, carboxy, lower alkoxy, amino, lower alkylamino, di-lower, having 1 to 3 substituents) Alkylamino, aryl, heterocyclic groups, etc. Amino, substituted or unsubstituted lower alkylamino (the substituent in the substituted lower alkylamino has the same meaning as the substituent (f) in the substituted lower alkoxy), substituted or unsubstituted di-lower alkyl Amino (the substituent in the substituted di-lower alkylamino has the same meaning as the substituent (f) in the substituted lower alkoxy), aryl, heterocyclic group, etc.], substituted or unsubstituted lower alkenyl (including The substituent in the substituted lower alkenyl has the same meaning as the substituent (e) in the substituted lower alkyl, and the substituted or unsubstituted lower alkynyl (the substituent in the substituted lower alkynyl is the substituent in the substituted lower alkyl). (Same as (e)), substituted or unsubstituted cycloalkyl (the substituted cycloalkyl). In the above substituted lower alkyl is the same as the substituent (e) in the above substituted lower alkyl), substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the substituent (e) in the above substituted lower alkyl) Is synonymous with

Substituted or unsubstituted lower alkylthio (the substituent in the substituted lower alkylthio has the same meaning as the substituent (e) in the substituted lower alkyl), amino, substituted or unsubstituted lower alkylamino (the substituted lower alkylamino The substituent in is the same as the substituent (e) in the substituted lower alkyl), substituted or unsubstituted di-lower alkylamino (the substituent in the substituted di-lower alkylamino is a substituent in the substituted lower alkyl) The same as or different from, for example, 1 to 3 halogen, hydroxy, carboxy, cyano, nitro, which are the same or different. Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is The same as the substituent (f) in the substituted lower alkoxy), the substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is the same as the substituent (f) in the substituted lower alkoxy), amino Substituted or unsubstituted lower alkylamino (the substituent in the substituted lower alkylamino has the same meaning as the substituent (f) in the substituted lower alkoxy), substituted or unsubstituted dilower alkylamino (the substituted dialkylamino) Examples of the substituent in the lower alkylamino are the same as the substituent (f) in the substituted lower alkoxy)]

A substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group has the same meaning as the substituent (g) in the substituted aryl), a substituted or unsubstituted aryloxy (the substituent in the substituted aryloxy) Is synonymous with the substituent (g) in the substituted aryl), substituted or unsubstituted arylamino (the substituent in the substituted arylamino is synonymous with the substituent (g) in the substituted aryl) Substituted or unsubstituted arylthio (the substituent in the substituted arylthio has the same meaning as the substituent (g) in the substituted aryl), substituted or unsubstituted arylsulfonyl (the substituent in the substituted arylsulfonyl is The same as the substituent (g) in the substituted aryl, and a substituted or unsubstituted heterocyclic oxy ( The substituent in the substituted heterocyclic oxy has the same meaning as the substituent (g) in the above substituted aryl), a substituted or unsubstituted heterocyclic amino (the substituent in the substituted heterocyclic amino is a substituent in the above substituted aryl) Group (g) and substituted or unsubstituted heterocyclic thio (the substituent in the substituted heterocyclic thio has the same meaning as the substituent (g) in the substituted aryl).

  The lower alkyl part of lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino and di-lower alkylamino shown here has the same meaning as the above lower alkyl (i), and lower alkenyl, lower alkynyl, cycloalkyl and halogen are respectively The lower alkenyl (ii), lower alkynyl (iii), cycloalkyl (iv) and halogen (x) have the same meaning, and the two lower alkyl moieties of the di-lower alkylamino may be the same or different. Further, the aryl part of aryl, aryloxy, arylthio, arylamino and arylsulfonyl shown here has the same meaning as the above aryl (v), and the heterocyclic group, heterocyclicthio, heterocyclicamino and heterocyclicoxy of heterocyclicoxy The group part is synonymous with the heterocyclic group (vii).

  (Xiii) The substituent in the substituted aromatic heterocyclic group among the substituted heterocyclic groups has the same meaning as the substituent (xii) in the substituted aryl, and the substituted aliphatic heterocyclic group in the substituted heterocyclic group and Examples of the substituent in the substituted heterocyclic group formed together with the adjacent nitrogen atom include oxo and the like in addition to the groups exemplified for the substituent (xii) in the substituted aryl.

  The pharmacologically acceptable salt of compound (I) includes, for example, a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt, amino acid addition salt and the like. Examples of the pharmacologically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, citrate, and the like. Examples of the pharmacologically acceptable metal salt include organic acid salts and the like, such as alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of pharmacologically acceptable ammonium salts include ammonium and tetramethylammonium salts. Examples of pharmacologically acceptable organic amine addition salts include morpholine and piperidine. Examples of pharmacologically acceptable amino acid addition salts include lysine, glycine, phenylalanine, aspartic acid, and glutamate. Addition salts, such as phosphate, and the like.

Next, the manufacturing method of compound (I) is demonstrated.
In the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the method, a method for introducing and removing a protective group commonly used in organic synthetic chemistry [for example, Protective Groups in Organic Synthesis, by TW Greenes, John Wiley & Sons Inc. (1981). Protective Groups in Organic Synthesis, TW Greenes, John Wiley & Sons Inc. (1981) Etc. can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.

Compound (I) can be produced according to the following reaction steps.
Manufacturing method 1
Compound (I) was obtained from Compound (II) from Indian Journal of Heterocyclic Chemistry, Vol. 10, p. 253 (2001) or the like, or according to them, or according to the following steps.

Wherein W ² , R ¹ , R ² , R ³ , R ⁴ and R ¹⁹ are each as defined above, X ¹ represents a chlorine atom or a bromine atom, and R ^19a represents the definition of R ¹⁹ 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 heterocycle Represents a group)

Step 1-1
Compound (IV) is obtained by removing Compound (II) in the absence of a solvent or in a suitable solvent in the presence of 0.5 to 50 equivalents of Compound (III) and optionally 0.1 to 50 equivalents of an appropriate acid. , By reacting at a temperature between −50 ° C. and 150 ° C. for 5 minutes to 72 hours.
Compound (II) may be a commercially available product or New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds II, p. 1220, Maruzen (1977), etc., or according to them. Compound (III) can be obtained as a commercially available product or from Experimental Chemistry Course 4th edition 21, Organic Synthesis III, p. 1 or by a method described in Maruzen (1991) or the like.

  Suitable solvents include, for example, methanol, ethanol, dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP). , Water, dimethyl sulfoxide (DMSO) and the like, and these can be used alone or in combination. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.

Step 1-2
Compound (I) is compound (IV) obtained in the above step 1-1 without solvent or in a suitable solvent, 1 to 50 equivalents of compound (Va), compound (Vb) or compound (Vc), If necessary, it can be produced by reacting at a temperature between −50 ° C. and 150 ° C. for 5 minutes to 120 hours in the presence of 0.1 to 50 equivalents of a suitable base.
Compound (Va) can be obtained as a commercially available product or from Experimental Chemistry Course 4th Edition 22, Organic Synthesis IV, p. 115, Maruzen (1992), or the like. Compound (Vb) can be obtained as a commercially available product or from Experimental Chemistry Course 4th Edition 22, Organic Synthesis IV, p. 127, Maruzen (1992), or the like. Compound (Vc) can be obtained as a commercially available product or from Experimental Chemistry Course 4th Edition 20, Organic Synthesis II, p. 473, Maruzen (1992), or the like.

  Suitable solvents include, for example, dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, acetone and the like, and these can be used alone or in combination. Suitable bases include, for example, pyridine, 4- (dimethylamino) pyridine (DMAP), triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), sodium hydride and the like. Can be given.

Manufacturing method 2
In the compound (I), R ³ is —Y ^a —NH ₂ (wherein Y ^a is obtained by removing one hydrogen atom from the lower alkyl portion of the substituted or unsubstituted lower alkyl in the definition of R ³ above). Compound (Ib), which represents a group, is R ³ is —Y ^a —NHCO ₂ C (CH ₃ ) ₃ (wherein Y ^a is as defined above), which is obtained by the above Production Method 1. It can also be produced from compound (Ia) according to the following steps.

(Wherein R ¹ , R ² , R ⁴ and Y ^a are as defined above)
Process 2
Compound (Ib) is obtained by treating Compound (Ia) with no solvent or in a suitable solvent with 0.1 to 300 equivalents of acid at a temperature between −50 ° C. and 150 ° C. for 5 minutes to 72 hours. Can be manufactured.
Suitable solvents include, for example, methanol, ethanol, dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, water, DMSO and the like, either alone or in combination. Can be used. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.
Compound (Ib) can also be obtained as an acid addition salt with the acid used above.

Production method 3
In the compound (I), R ³ is —Y ^a —NHR ^42a [wherein Y ^a is as defined above, and R ^42a is —COR ⁴⁸ (wherein R ⁴⁸ is as defined above) or — Compound (Ic) which is SO ₂ R ⁵² (wherein R ⁵² represents the same as defined above) can also be produced from compound (Ib) obtained by Production Method 2 according to the following steps. .

^{Wherein, R 1, R 2, R} 4, R 42a, R 48, R 52, Y a and X ¹ have the same meanings as defined above, R ^48a is among the definition of the R ^48, -NR ⁴⁹ R ⁵⁰ (in the formula, each of R ⁴⁹ and R ⁵⁰ is the same as defined above)
Process 3
Compound (Ic) is obtained by adding 1 to 50 equivalents of Compound (Vd), Compound (Ve) or Compound (Vf) in the absence of a solvent or in a suitable solvent, and optionally 0.1 to 50 It can be produced by reacting at a temperature between −50 ° C. and 120 ° C. for 5 minutes to 100 hours in the presence of an equivalent amount of a suitable base.

Examples of suitable solvents include dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, acetone, water and the like, and these can be used alone or in combination. . Suitable bases include, for example, pyridine, DMAP, triethylamine, diisopropylethylamine, DBU and the like.
Compound (Vd) can be obtained as a commercially available product or from Experimental Chemistry Course 4th Edition 22, Organic Synthesis IV, p. 115, Maruzen (1992), or the like. Compound (Ve) can be obtained as a commercially available product or from Experimental Chemistry Course 4th Edition 22, Organic Synthesis IV, p. 127, Maruzen (1992), or the like. Compound (Vf) can be obtained as a commercially available product or from Experimental Chemistry Course 4th Edition 20, Organic Synthesis II, p. 473, Maruzen (1992), or the like.

Alternatively, as the compound (Ic-a) in which R ³ is —Y ^a —NHCOR ^48a (wherein Y ^a and R ^48a have the same meanings as described above), the compound (Ib) can be used without a solvent or In a suitable solvent, in the presence of 1 to 30 equivalents of a suitable condensing agent, optionally in the presence of 0.1 to 30 equivalents of a suitable additive, 1 to 300 equivalents of R ^48a CO ₂ H (wherein , R ^48a has the same ^{meaning as} described above) and can be produced by reacting at a temperature between −30 ° C. and 150 ° C. for 5 minutes to 72 hours.

Suitable solvents include, for example, dichloromethane, chloroform, acetonitrile, toluene, xylene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP and the like, and these can be used alone or in combination. Suitable condensing agents include, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), N, N′-dicyclohexylcarbodiimide. 1,1′-carbonyldiimidazole and the like. Suitable additives include, for example, N-hydroxysuccinimide, DMAP, 1-hydroxybenzotriazole (HOBt), 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O), and the like.

The conversion of the functional group contained in R ¹ , R ² , R ³ or R ⁴ in the compound (I) may be carried out by other known methods [for example, Comprehensive Organic Transformations (for example, Comprehensive Organic Transformations). Transformations), R.A. C. The method described in Larock (1989) or the like] or in accordance with them.
Moreover, the compound (I) which has a desired functional group in a desired position can be obtained by implementing combining said method suitably.

The intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. The intermediate can be subjected to the next reaction without any particular purification.
Some compounds (I) may have stereoisomers such as positional isomers, geometric isomers, optical isomers, tautomers, etc., but the antitumor agent of the present invention includes these isomers. All possible isomers and mixtures thereof can be used, including

When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be isolated or purified by dissolving or suspending and forming a salt by adding an acid or a base.
Further, Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used in the antitumor agent of the present invention. can do.
Specific examples of the compound (I) used in the present invention or obtained by the present invention are shown in Table 1. However, the compounds used in the present invention or the compounds of the present invention are not limited thereto.

Next, the pharmacological activity of the representative compound (I) will be described with reference to test examples.
Test Example 1: Growth inhibitory activity against human colon cancer cells HCT 116 HCT 116 cells (ATCC number: CCL-247) were dispensed at a rate of 1 × 10 ³ cells / well into a 96-well microtiter plate (Nunk, 167008). . After incubating the plate in a 5% carbon dioxide incubator for 24 hours at 37 ° C., a test compound diluted in stages was added thereto to make a total of 100 μL / well, and further in a 5% carbon dioxide incubator at 37 ° C. for 72 hours. Cultured. In this culture medium, XTT {3 ′-[1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (4-methoxy-6-nitro) benzenesulfonate sodium hydrate (Sodium 3 ′-[ 1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (4-methyoxy-6-nitro) benzonesulfuric acid hydrate} labeling mixture (Roche Diagnostics, 1465015) was dispensed at 50 μL / well. After that, the cells were cultured in a 5% carbon dioxide incubator at 37 ° C. for 1 hour, and the absorbance at 490 nm and 655 nm was measured using a microplate spectrophotometer (Biorad, Model 550). Cytostatic activity was expressed by 50% growth inhibitory concentration GI _50.

Calculation method of GI ₅₀ : A value (difference absorbance) obtained by subtracting the absorbance at 655 nm from the absorbance at 490 nm of each well was calculated. Calculate the concentration of the compound that inhibits cell growth by 50% by comparing the difference absorbance obtained in cells treated with a known concentration of the compound with the difference absorbance obtained in cells not treated with the test compound as 100%. It was designated as GI ₅₀ .
The results are shown in Table 2.

Test Example 2: Inhibition Test for Eg5 Enzyme Preparation of the full-length human Eg5 recombinant was performed in the literature [Cell, Volume 83, p. 1159 (1995)]. Baculovirus expressing full-length human Eg5 fused with His tag at the N-terminus is infected with Spodoptera frugiperda (Sf) 9 insect cells, and after culturing, the culture solution is centrifuged to collect the cell precipitate. Suspend the cell pellet in buffer and collect the supernatant by centrifugation. The supernatant is passed through a nickel agarose column, and Eg5 fused with a His tag at the N-terminus is affinity purified to obtain a partially purified preparation.

The measurement of the ATPase activity of Eg5 was performed in the literature [The Embo Journal, Vol. 13, p. 751 (1994), Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. USA), 89, p. . 4884 (1992)]. 25 mmol / L piperazine N, N′-bis (ethanesulfonic acid) (PIPES) / KOH (pH 6.8), 1 mmol / L ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA), 2 mmol / L MgCl ₂ , 1 mmol / L dithiothreitol (DTT), 100 μg / mL bovine serum albumin (BSA), 5 μmol / L paclitaxel, 25 μg / mL tubulin (Cytoskeleton, catalog number TL238), 200 μmol / L L MESG substrate (2-amino-6-mercapto-7-methylpurine riboside) (Molecular Probes, catalog number E-6646), 1 U / mL purine nucleoside phosphorylase (Purine nuc) A reaction solution is prepared by adding a partially purified Eg5 sample together with a test compound serially diluted to 1 mmol / L ATP (Leoside phosphorase) (Molecular Probes, catalog number E-6646). A 96-well plate is used for the enzyme reaction, and the reaction is performed at 30 ° C. for 30 minutes. Absorbance at 360 nm, which is an index of ATPase activity, is measured with a plate reader (Molecular Device, SpectraMax 340PC ³⁸⁴ ). The relative activity is calculated with the absorbance in the absence of the test compound in the presence of Eg5 as 100% and the absorbance in the absence of the test compound in the absence of Eg5 as 0%, and the IC ₅₀ value is calculated.

By the above test, the inhibitory action of the compound (I) on the Eg5 enzyme can be confirmed.
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. These pharmaceutical preparations are used for animals or humans.
The pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.

As the administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
Examples of the dosage form include tablets and injections.
Suitable for oral administration, such as tablets, excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and surface activity such as fatty acid esters And a plasticizer such as glycerin.

Formulations suitable for parenteral administration preferably comprise a sterile aqueous solution containing the active compound that is 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 salt water and a glucose solution.
Also in these parenteral agents, one kind selected from excipients, disintegrating agents, lubricants, binders, surfactants, plasticizers and diluents, preservatives, flavors and the like exemplified in the oral preparations. Or more auxiliary components can be added.

  Compound (I) or a pharmaceutically acceptable salt thereof is usually administered systemically or locally in an oral or parenteral form when used for the above purpose. The dose and frequency of administration vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc., but usually oral, 0.01 to 1000 mg per adult, The dose is preferably in the range of 0.05 to 500 mg once to several times a day. In the case of parenteral administration such as intravenous administration, usually 0.001-1000 mg, preferably 0.01-300 mg per adult is administered once to several times a day, or in the range of 1-24 hours per day. Administer intravenously. However, the dose and the number of doses vary depending on the various conditions described above.

Hereinafter, the present invention will be described in detail by way of examples.
Proton nuclear magnetic resonance spectra ( ¹ H-NMR) used in the examples are those measured at 270 MHz or 300 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. In addition, although what is used normally is used as description of the multiplicity of a signal, br represents that it is an apparent wide signal.

(Compound 1)
Process 1
Tetrahedron Letters, 43, p. 8223 (2002) tert-butyl (2-oxo-2-phenylethyl) carbamate (29 mg, 0.19 mmol) and 2-fluorobenzhydrazide (30 mg, 0.13 mmol) obtained by methanol ( 1 mL), concentrated hydrochloric acid (0.021 mL) was added, and the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform / methanol = 20/1) to give [2-[(2-fluorobenzoyl) hydrazono] -2-phenylethyl] carbamine. The acid tert-butyl (46 mg, yield 92%) was obtained.

Process 2
[2-[(2-Fluorobenzoyl) hydrazono] -2-phenylethyl] carbamate tert-butyl (45 mg, 0.12 mmol) obtained above was dissolved in dichloromethane (1 mL) and pyridine (0.050 mL, 0.62 mmol) and trimethylacetyl chloride (0.060 mL, 0.49 mmol) were added, and the mixture was stirred at room temperature for 30 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform / methanol = 40/1) to obtain Compound 1 (45 mg, yield 82%).
APCI-MS m / z: 456 [M + H] ⁺ ; ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.30 (s, 9H), 1.43 (s, 9H), 4.21 (dd, J = 6.9, 14.8 Hz, 1H), 4.48 (dd, J = 6.4, 14.8 Hz, 1H), 5.03 (br t, 1H), 7.06-7.25 (m, 2H), 7.30-7.58 (m, 6H), 7.79 (m, 1H).

(Compound 2)
A 4 mol / L hydrogen chloride-ethyl acetate solution (1 mL) was added to compound 1 (45 mg, 0.10 mmol) obtained in Example 1, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain Compound 2 (42 mg, quantitative).
APCI-MS m / z: 356 [M + H] ⁺ ; ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.39 (s, 9H), 4.01 (br d, 1H), 4.45 (br d, 1H) , 6.95-7.68 (m, 8H), 7.86 (m, 1H), 8.70 (br, 3H).

(Compound 3)
Compound 2 (42 mg, 0.10 mol) obtained in Example 2 was dissolved in dichloromethane (1 mL), and triethylamine (0.060 mL, 0.43 mmol) and methanesulfonyl chloride (0.017 mL, 0.22 mmol) were added under ice cooling. The mixture was further stirred at room temperature for 1.5 hours. Furthermore, triethylamine (0.060 mL, 0.43 mmol) and methanesulfonyl chloride (0.017 mL, 0.22 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform / methanol = 20/1) to obtain Compound 3 (23 mg, yield 54%).
APCI-MS m / z: 434 [M + H] ⁺ ; ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (s, 9H), 2.87 (s, 3H), 4.16 (dd, J = 6.8, 14.6 Hz, 1H), 4.56 (dd, J = 7.3, 14.6 Hz, 1H), 4.92 (br t, J = 7.0 Hz, 1H), 7.12-7.29 (m, 2H), 7.35-7.56 (m, 6H) , 7.80 (ddd, J = 1.8, 7.4, 7.4 Hz, 1H).

(Compound 4)
Acetophenone (0.330 mL, 2.83 mmol) was dissolved in ethanol (10 mL), benzhydrazide (406 mg, 2.98 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Then, the solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane (10 mL), pyridine (1.00 mL, 12.4 mmol) and trimethylacetyl chloride (1.40 mL, 11.4 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (n-hexane / ethyl acetate = 9/1) to obtain Compound 4 (239 mg, yield 26%).
APCI-MS m / z: 323 [M + H] ⁺ ; ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.38 (s, 9H), 2.27 (s, 3H), 7.30-7.56 (m, 8H) , 7.82-7.90 (m, 2H).

(Compound 5)
Acetophenone (0.117 mL, 1.00 mmol) was dissolved in methanol (5 mL), semicarbazide hydrochloride (124 mg, 1.11 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Subsequently, the solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane (10 mL), pyridine (0.500 mL, 6.21 mmol) and trimethylacetyl chloride (0.700 mL, 5.68 mmol) were added, and the mixture was stirred at room temperature for 96 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (n-hexane / ethyl acetate = 2/1) to obtain Compound 5 (135 mg, yield 45%).
APCI-MS m / z: 303 [M + H] ⁺ ; ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.27 (s, 9H), 1.29 (s, 9H), 2.12 (s, 3H), 7.28 -7.46 (m, 5H).

Formulation Example 1: Tablet (Compound 1)
A tablet having the following composition is prepared by a conventional method. Compound 1, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 120 g of 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this was added 1.2 g of magnesium stearate, mixed, and tableted with a tableting machine (RT-15 model, manufactured by Kikusui Co., Ltd.) having a 8 mm diameter punch to contain tablets (containing 20 mg of active ingredient per tablet). To get).
Formulation Compound 1 20 mg
Lactose 143.4 mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
200 mg

Formulation Example 2: Tablet (Compound 3)
The title tablet (containing 20 mg of active ingredient per tablet) is obtained in the same manner as in Formulation Example 1 using 40 g of Compound 3.
Formulation Compound 3 20 mg
Lactose 143.4 mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
200 mg

Formulation Example 3: Injection (Compound 2)
An injection having the following composition is prepared by a conventional method. Compound 2, 1 g and 5 g of D-mannitol are added to and mixed with distilled water for injection. Further, hydrochloric acid and sodium hydroxide aqueous solution are added to adjust the pH to 6, and then the total volume is made up to 1000 mL with distilled water for injection. . The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial).
Formulation Compound 2 2 mg
D-mannitol 10 mg
Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount
Distilled water for injection
2.00 mL

Claims (16)

Formula (I)

<In the formula, R ¹ is 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 -C (= W) R ⁵ {wherein W represents an oxygen atom or a sulfur atom, R ⁵ represents -YR ⁶ (wherein Y represents a bond, an oxygen atom or a sulfur atom, R ⁶ represents 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 complex. ring group represents a) or -NR ⁷ R ⁸ [wherein, R ⁷ and R ⁸ are the same or different, a hydrogen atom, a substituted or unsubstituted lower alkyl, location Or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, in -OR ⁹ (wherein, R ⁹ is the R ⁶ synonymous) or -NR ¹⁰ R ¹¹ (wherein, R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Represents a substituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, or R ¹⁰ and R ¹¹ together with the adjacent nitrogen atom are substituted or unsubstituted form a heterocyclic group) or represents, or R ⁷ and R ⁸ is a substituted or unsubstituted together with the adjacent nitrogen atom a heterocyclic During} or -NR ¹² R ¹³ {wherein represents a form] a, R ¹² and R ¹³ are the same or different, a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Substituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or —C (═W ¹ ) R ¹⁴ wherein W ¹ is as defined above for W. R ¹⁴ 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 A substituted heterocyclic group, —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ have the same meanings as R ¹⁰ and R ¹¹ , respectively), —OR ¹⁷ (wherein R ¹⁷ represents 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. Or -SR ¹⁸ (wherein R ¹⁸ is as defined above for R ¹⁷ ), or R ¹² and R ¹³ together with the adjacent nitrogen atom are substituted or unsubstituted Represents a cyclic group},
R ² is —C (═W ² ) R ¹⁹ , wherein W ² is as defined above, and R ¹⁹ 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 heterocyclic group, —NR ²⁰ R ²¹ (wherein R ²⁰ and R ²¹ are the same as R ¹⁰ And R ¹¹ ), —OR ²² (wherein R ²² has the same meaning as R ¹⁷ ) or —SR ²³ (wherein R ²³ has the same meaning as R ¹⁷ )). Represent,
R ³ 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 Represents a heterocyclic group of
R ⁴ represents 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 heterocycle Represents a group,
Or R ³ and R ^{4 taken} together — (CR ^24A R ^24B ) _m1 -Q- (CR ^24C R ^24D ) _m2 — {wherein Q represents a single bond, substituted or unsubstituted phenylene or cycloalkylene. , M1 and m2 are the same or different and each represents an integer of 0 to 4, m1 and m2 are not 0 at the same time, and R ^24A , R ^24B , R ^24C and R ^24D are the same or different and represent a hydrogen atom, halogen , Substituted or unsubstituted lower alkyl, —OR ²⁵ [wherein R ²⁵ represents 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 heterocyclic group, -CONR ²⁶ R ²⁷ (wherein, R ²⁶ and R ²⁷ the same or different and each represents a hydrogen atom, a substituted if Represents an 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, or a substituted or unsubstituted heterocyclic group; Or R ²⁶ and R ²⁷ together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group), —SO ₂ NR ²⁸ R ²⁹ (wherein R ²⁸ and R ²⁹ are each the above-mentioned R ²⁶ and R ²⁷ ) or —COR ³⁰ (wherein R ³⁰ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Represents a substituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), -NR ³¹ R ³² [wherein R represents ³¹ and R ³² are the same or different and each represents 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 heterocyclic group, —COR ³³ (wherein R ³³ represents 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 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 An arylamino), or -SO ₂ R ³⁴ (wherein, R ³⁴ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, Represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), or R ³¹ and R ³² together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group] Or —CO ₂ R ³⁵ (wherein R ³⁵ 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 Represents an unsubstituted aryl or a substituted or unsubstituted heterocyclic group), or R ^24A and R ^24B or R ^24C and R ^{24 When D} together represents an oxygen atom and m1 or m2 is an integer of 2 or more, each R ^24A , R ^24B , R ^24C and R ^24D may be the same or different, and two adjacent carbons R ^24A , R ^24B , R ^24C and R ^24D bonded to an atom may be combined together to form a bond}
An M-phase kinesin easy 5 (Eg5) inhibitor comprising an oxadiazoline derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient. The M phase kinesin easy 5 (Eg5) inhibitor according to claim 1, wherein R ⁴ is substituted or unsubstituted phenyl. Formula (IA)

<In the formula, R ^1A represents 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 -C (= W) R ⁵ (wherein W and R ⁵ are as defined above) or -NR ¹² R ¹³ (wherein R ¹² and R ¹³ are as defined above), Represent)
R ^2A is —C ( ^{═W 2} ) R ^19A , wherein W ² is as defined above, and R ^19A is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or non-substituted Substituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, —NR ^20A R ^21A (wherein R ^20A and R ^21A are the same or different, hydrogen Represents an atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group, or R ^20A and R ^21A together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group), - oR ²² (wherein, R ²² is as defined above) the -SR ²³ (wherein, R ²³ has the same meaning as defined above) represents' represents a
R ^3A represents 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 Represents
R ^4A represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group,
Or R ^3A and R ^{4A taken} together — (CR ^24AA R ^24BA ) _m1A -Q ^A — [wherein Q ^A represents substituted or unsubstituted phenylene, m1A represents an integer of 1 to 4; ^24AA and R ^24BA are the same or different and are a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, —OR ²⁵ (wherein R ²⁵ is as defined above), —NR ³¹ R ³² (wherein R ^{25 31} and R ³² are each as defined above) or —CO ₂ R ³⁵ (wherein R ³⁵ is as defined above), or R ^24AA and R ^24BA together represent an oxygen atom. when m1A is an integer of 2 or more, each of R ^24aa and R ^24ba may be the same or different, a bond respectively R ^24aa and R ^24ba are bonded to adjacent two carbon atoms are taken together form May be]
However,
(A) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is phenyl, R ^1A is pyridyl, substituted benzodiazepinyl, substituted methyl, 2-acetoxy-3,5-dibromophenyl , Substituted triazolyl, 5-methyl-3-isoxazolyl and 2- (phenothiazinyl) ethyl,
(B) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is 4-substituted phenyl, R ^1A is phenyl, 2-acetoxy-3,5-dibromophenyl, 4- (substituted methoxy) ) Instead of phenyl and substituted methyl
(C) when R ^2A is acetyl, R ^3A is methyl and R ^4A is 2-thienyl, R ^1A is not 2-bromo-5-methoxyphenyl,
(D) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is substituted phenyl, R ^1A is not substituted quinolyl,
(E) When R ^2A is acetyl, R ^3A is methyl, and R ^4A is benzopyranyl or substituted oxadiazolyl, R ^1A is not methyl, substituted or unsubstituted phenyl and 4-pyridyl;
(F) When R ^2A is acetyl, R ^3A is phenyl, and R ^4A is phenyl, R ^1A is not phenyl and methyl;
(G) when R ^2A is benzoyl, R ^3A is phenyl, and R ^4A is phenyl, R ^1A is not phenyl;
(H) R ^1A is not diphenylmethyl when R ^2A is diphenylacetyl, R ^3A is substituted or unsubstituted phenyl, and R ^4A is substituted or unsubstituted phenyl. A diazoline derivative or a pharmacologically acceptable salt thereof. The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein R ^4A is a substituted or unsubstituted aromatic heterocyclic group. The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein R ^4A is substituted or unsubstituted phenyl. The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 5, wherein R ^1A is a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group. ^R1A is substituted or unsubstituted phenyl, The oxadiazoline derivative in any one of Claims 3-5, or its pharmacologically acceptable salt. The oxadiazoline according to any one of claims 3 to 5, wherein R ^1A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl. A derivative or a pharmacologically acceptable salt thereof. R ^2A is —C (═O) R ^19B (wherein R ^19B represents a substituted or unsubstituted lower alkyl), or an oxadiazoline derivative or a pharmacological thereof according to any one of claims 3 to 8 Acceptable salt. ^R2A is pivaloyl, The oxadiazoline derivative or pharmacologically acceptable salt thereof according to any one of claims 3 to 8. ^R3A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted lower alkynyl, or an oxadiazoline derivative according to any one of claims 3 to 10, or a pharmacologically acceptable salt thereof Salt. The oxadiazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 10, wherein R ^3A is substituted lower alkyl. The pharmaceutical which contains the oxadiazoline derivative in any one of Claims 3-12, or its pharmacologically acceptable salt as an active ingredient. An M-phase kinesin easy five (Eg5) inhibitor comprising the oxadiazoline derivative or a pharmacologically acceptable salt thereof according to any one of claims 3 to 12 as an active ingredient. A therapeutic agent for a disease involving cell proliferation, comprising as an active ingredient the oxadiazoline derivative or a pharmacologically acceptable salt thereof according to any one of claims 3 to 12. The antitumor agent which contains the oxadiazoline derivative in any one of Claims 3-12, or its pharmacologically acceptable salt as an active ingredient.