WO1999055689A1

WO1999055689A1 - Radicicol derivatives

Info

Publication number: WO1999055689A1
Application number: PCT/JP1999/002138
Authority: WO
Inventors: Yoji Ino; Nobuyoshi Amishiro; Mayumi Miyata; Tsutomu Agatsuma; Chikara Murakata; Shiro Akinaga; Shiro Soga; Yukimasa Shiotsu
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 1998-04-24
Filing date: 1999-04-22
Publication date: 1999-11-04
Also published as: AU3534499A

Abstract

Compounds represented by general formula (I) which show a tyrosine kinase inhibitory activity or salts thereof, wherein R?1 and R2¿ represent each hydrogen, alkanoyl, etc.; Y represents optionally substituted alkylene; R3 represents NR5R6 (wherein R5 represents hydrogen, optionally substituted lower alkyl, etc.; and R6 represents substituted alkyl, etc.), NR7COR8 [wherein R7 represents hydrogen, optionally substituted alkyl, etc.; and R8 represents substituted lower alkyl, substituted lower alkoxy, NR9R10 (wherein R?9 and R10¿ represent each hydrogen, optionally substituted lower alkyl, etc.)], NR11COR12 (wherein R11 represents optionally substituted lower alkyl, etc.; and R12 represents lower alkyl, lower alkoxy, etc.), substituted lower alkoxy, optionally substituted alkenyloxy, etc.; X represents halogeno or forms together with R4 a single bond; and R4 forms together with X a single bond or represents hydrogen, alkanoyl, etc.

Description

Specification

Radicicol derivative

Technical field

The present invention relates to a radicicol derivative or a pharmacologically acceptable salt thereof, which exhibits a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive action.

Background art

Radicicol, which is represented by the formula (B) and is a metabolite of microorganisms, has antifungal and anticancer effects [Nature, 171: 344 (1953); Neoplasma

(Neoplasia), vol. 24, p. 21 (1977)], immunosuppressive action (JP-A-6-298764), morphological normalizing action of ras and mos cancerous cells [Oncogene

(Oncogene), vol. 11, p. 161 (1995)], or is known to have an inhibitory effect on the expression of cyclooxygenase-2 and inflammatory cytotoxicity (W096 / 25928).

It is known that a radicicol derivative in which a phenolic hydroxyl group is modified with various acyl groups has an antitumor effect (Japanese Patent Application Laid-Open No. 4226991). Furthermore, a radicicol derivative in which the phenolic hydroxyl group is modified with an acyl group or an alkyl group has an inhibitory effect on angiogenesis (JP-A-6-279279) or an inhibitory effect on interleukin-11 production (JP-A-8-40893). ) Is disclosed.

In addition, it has been disclosed that the oxime derivative of genone of the radicicol derivative represented by the formula (C) exhibits an antitumor effect and an immunosuppressive effect (W096 / 33989).

It has been disclosed that the radicicol derivative represented by (D) exhibits an antitumor effect (JP-A-9-202781).

(In the formula, R ^1P and R ^2P represent hydrogen, alkanoyl, alkenoyl or tert-butyldimethylsilyl, Y ^p represents hydrogen or substituted or unsubstituted lower alkyl, R ^4P represents hydrogen, alkanoyl or alkenoyl, etc. X ^p represents a single bond together with a halogen atom or R ^4P )

(Wherein, R ^1Q and R ^2Q represent a hydrogen atom or acyl, and X ^Q represents a halogen atom, hydroxy or lower alkoxy)

The ansamycin antibiotic geldanamycin of the formula (E) [The Journal of Antibiotics, 23, 44 (1970)] is a tyrosine kinase. It is known to have inhibitory activity and antitumor activity [Cancer's Research (Cancer Research), Vol. 52, 1721 ぺ-ジ (1992) and Cancer Research (Cancer Research), Vol. 54, 2724 ぺ-ジ(1994) etc.]. These effects are due to the binding of geldanamycin to the molecular chaperone Hsp (heat shock / stress protein) 90, which forms a complex with Hsp90 to express functions, such as Src, ErbB-2, and Lck. Has been shown to inhibit the activation of the tyrosine kinase and the serine / threonine kinase Raf-l in the Procedurals of the National Academy of Sciences of the · Proceedings of the National Academy of Science of the US, Vol. 91, p. 8324 (1994) and The Journal of Biological Chemistry, Vol. 270, p. 24585 (1995), etc.). Therefore, drugs that act on Hsp90 are also included in tyrosine kinase inhibitors, and are useful for the prevention and treatment of various diseases such as osteoporosis and immunological diseases, including antitumor agents. It has also recently been shown that radiscol has a destabilizing effect on Raf-1 [The Journal of Biological Chemistry, vol. 273, 822 pages (1998)].

Tyrosine kinase is an enzyme that catalyzes the transfer of its arsenic acid group to the hydroxyl group of a specific tyrosine residue of a substrate protein using ATP as a phosphate donor, and plays an important role in the regulatory mechanism in intracellular signal transduction Is responsible for. Various tyrosine kinase families are known, and the activity of each tyrosine kinase such as Src in colorectal cancer, ErbB-2 in breast cancer and gastric cancer, and Abl in leukemia is known. An uncontrolled increase in tyrosine kinase activity causes abnormalities in cell differentiation and proliferation. Therefore, a specific inhibitor of tyrosine kinase is useful for prevention and treatment of various diseases including antitumor agents.

Lck is a cytosine kinase that is activated when T lymphocytes are activated by antigen stimulation, and inhibitors of this enzyme are useful as immunosuppressants. Src is known to be involved in bone resorption in osteoclasts, and this tyrosine kinase inhibitor is thought to act as a bone resorption inhibitor, and is useful as a therapeutic agent for osteoporosis. In addition, various growth factor receptor tyrosine kinases, EGF-R (epithelial cells) Vesicle growth factor receptor: epidermal growth factor receptor, FGF-R (fibroblast growth factor receptor), PDGF-R (platelet-derived growth factor receptor), etc. Are useful as a solid cancer growth inhibitor, an angiogenesis inhibitor, a vascular smooth muscle growth inhibitor, and the like. Disclosure of the invention

An object of the present invention is to provide a novel radicicol derivative or a pharmacologically acceptable salt thereof which exhibits a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive activity.

The present invention provides a compound represented by the general formula (I)

Wherein R ¹ and R ² are the same or different and represent hydrogen, alkanoyl, alkenoyl, alkadienol, alkatrienoyl, trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl. , Y represents a substituted or unsubstituted alkylene, and R ³ is NR ⁵ R ⁶ (where R ⁵ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted Represents a lower cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, wherein R ⁶ is a substituted lower alkyl, a substituted or unsubstituted higher alkyl, a substituted or unsubstituted lower cycloalkyl , Represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), NR ⁷ C〇R ⁸ [wherein R ⁷ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; ⁸ is substituted lower alkyl, substituted lower α Alkoxy, substituted alkenyloxy, substituted alkadienyloxy, substituted alkyl trienyloxy, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyloxy or NR ⁹ R ^{1 G} (wherein, R ⁹ and R ^{1 Q} are the same or different and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aromatic heterocyclic group. Or R ⁹ and R ^{1 Q} together with an adjacent N form a substituted or unsubstituted nitrogen-containing heterocyclic group), NRUCOR ¹² (where R ¹¹ is substituted or unsubstituted) Represents lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group. And R ¹² represents lower alkyl, lower alkoxy, lower alkenyloxy, lower alkadienyloxy or lower alkatrienyloxy), substituted lower alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkatrienyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkadienyl, substituted or unsubstituted alkatrienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted Substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted Desperately Unsubstituted isothiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted oxazolidonyl, substituted or unsubstituted piperidonyl, substituted or unsubstituted perhydroazepino Substituted or unsubstituted succinimides, substituted or unsubstituted phthalimides, substituted or unsubstituted phthalimides, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinedionyl, substituted or unsubstituted Oxopyrrolidonyl, substituted or unsubstituted maleimide, substituted or unsubstituted thiazolidonyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazolidinedionyl, substituted or unsubstituted 2-oxo- 3-pyrrolini , Substituted or unsubstituted Okisazoroni Le, a substituted or unsubstituted pyrazolonyl, substituted or unsubstituted Isookisazoroni Le, a substituted or unsubstituted Chiazoroniru, Okisazorijiniri substituted or unsubstituted Represents a substituted or unsubstituted pyrrolinyl, a substituted or unsubstituted imidazolidinyl, a substituted or unsubstituted imidazolinyl, a substituted or unsubstituted oxadiazolyl or a substituted or unsubstituted virazolidinyl, and X represents a halogen atom or is integrated with R ⁴ Or represents a single bond, and R ⁴ represents a single bond together with X, or hydrogen, alkanoyl, alkenol, alkadienoyl, alkatrienoyl, or SO—Z (where Z is the formula (A)

[Wherein, R ¹ A and R ^{2 A} have the same meanings as R ¹ and R ² , respectively, X ^A represents an octogen atom, W represents 〇 or N—O—Y ^A —R ^{3 A} (formula among relates Y ^a and R ^{3 a} salts previous SL Y and R ³ and the Radishiko Le derivative or a pharmaceutically represented by representing] a a a) representing the representative] a} synonymous allowable respectively.

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 in the general formula (I), lower means up to 1 to 8 carbon atoms and higher means up to 9 to 30 carbon atoms, unless otherwise specified.

The alkanoyl includes straight or branched ones having 1 to 30 carbon atoms, for example, formyl, acetyl, propanoyl, isopropanol, bushynoyl, forceproyl, lauroyl, myristoyl, palmitoyl, stearoyl and the like. Alkenols include straight-chain or branched ones having 3 to 30 carbon atoms, such as acryloyl, methacryloyl, crotonyl, isocrotonyl, and palmitoleyl. Alkadienoyl is a straight or branched chain having 5 to 30 carbon atoms, for example, 2,4-diene dienol, 2,4-hexadienol, 3,5-hepadienol, linoleoyl, 3,5-diene Decadienol, 10, 12-Penya Decadienol and 12,15-Henikosagenol are included. Alkatrienoyl is a straight or branched chain having 7 to 30 carbon atoms, for example, 2,4,6-hepnotrienol, linolenoyl, 2,4,6-docosatri. Enol, 8,11,14-icosatrienoyl and 12,15,18-hexosatrienoyl are included.

Lower alkyl and the alkyl moiety of lower alkoxy include straight-chain or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terbutyl, pentyl, isopentyl, neopentyl, hexyl, Heptyl, octyl, isooctyl and the like are included, and one of the carbon atoms may be replaced by a silicon atom.The alkylene portion of aralkyloxy is a group obtained by removing one hydrogen atom from these lower alkyl groups. Included.

The alkyl part of the trialkylsilyl, monoalkyldiarylsilyl and dialkylmonoarylsilyl has the same meaning as the lower alkyl.

Higher alkyls include straight-chain or branched, for example, decyl, dodecyl and hexadecyl.

Examples of aryl include phenyl, naphthyl and anthranyl having 6 to 14 carbon atoms. The aryl moiety in aralkyloxy, triarylsilyl, monoalkyldiarylsilyl and dialkylmonoarylsilyl has the same meaning as the above aryl.

Examples of the alkenyl moiety in alkenyl and alkenyloxy include straight-chain or branched having 2 to 30 carbon atoms, for example, vinyl, aryl, toprobenyl, 2-butenyl, 1-pentenyl, 2-hexenyl, dodecenyl and Hexadecenyl and the like are included. Examples of the lower alkenyl moiety in lower alkenyloxy include those having 2 to 8 carbon atoms in the alkenyl, for example, vinyl, aryl, toprobenyl, 2-butenyl, 1-pentenyl, 2-hexenyl and the like. Include. Examples of the alkadienyl moiety in alkadienyl and alkadienyloxy include 1,3-pentagenenyl, 1,3-hexadenyl, 2,4-hexadenyl, having 4 to 30 carbon atoms, linoleyl, 2,4-decadenyl, .9, 1-tetradecadienyl, 11, 14-icosagenyl and the like are included. Examples of the lower alkadienyl moiety in the lower alkadienyloxy include those having 4 to 8 carbon atoms in the alkadienyl, for example, 1,3-pentenyl, 1,3-hexenyl, and 2,4-hexenyl. . The alkatrienyl moiety in al-trienyl and al-trienyloxy includes 1,3,5-hexatriene having 6 to 30 carbon atoms. Nyl, linolenyl, 1,3,5-docosatrienyl, 7,10,13-nonadecatrienyl, 11,14,17-icosatrienyl and the like. Examples of the lower alkenyl group in the lower alkarylenyl group include those having 6 to 8 carbon atoms in the above alkenyl group, such as 1,3,5-hexatrienyl.

Lower cycloalkyl includes those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. The heterocyclic group includes an alicyclic heterocyclic group and an aromatic heterocyclic group. Examples of the alicyclic heterocyclic group include, for example, 2-pyridonyl, 3-pyridonyl, 4-pyridonyl, 2-pyrrolidonyl, 3-pyrrolidonyl, dioxolanyl, pyrrolidinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, piperazinyl, pyridolinidinyl, piperidinyl Homopiperazinyl, piperidyl, imidazolinyl, imidazolidinyl, 2-oxazolidonyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-piperidonyl, 3-piperidonyl, 4-piperidonyl, pahydro-2-azepinonyl, perhydro-3-azepinonyl, pahydro 1-hydro-4-azepinonyl, succinimide, phthalimide, gluimide, hydantoinyl, thiazolidinedionyl, 3-oxopyrrolidonyl, 4-oxopyrrolidonyl, maleimide, 2-thiazolidonyl 4-thiazolidonyl, 5-thiazolidonyl, oxazolidinedionyl, 2-oxo-3-pyrrolinyl, 2 (3H) -oxazolonyl, 4 (5H) -oxazolonyl, 4-pyrazolonyl, 5-pyrazolonyl, 4-isoxoxa Zolonyl, 4-thiazolonyl, oxazolidinyl, 2-pyrolinyl and the like are included. Examples of the aromatic heterocyclic group include peracylyl, pyrrolyl, tetrazolyl, phenyl, pyridyl, pyrazolyl, pyrazinyl, indolyl, isoindolyl, furyl, quinolyl, phthalazinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, thiazolyl, and thiazolyl. Etc. are included. A nitrogen-containing heterocyclic group formed integrally with adjacent N (the nitrogen-containing heterocyclic group formed integrally with adjacent N may further include 〇, S, or another N ) Includes, for example, pyrrolidinyl, morpholino, thiomorpholino, piperazinyl, virazolidinyl, pyrazolinyl, piperidino, homopiperazinyl, indolinyl, isoindolinyl, perhydroazepinyl, perhydroazosinyl, indolyl, isoindrill and the like. As the alkylene, the lower alkyl or higher alkyl It includes groups obtained by removing one hydrogen atom from alkyl. The halogen atom includes fluorine, chlorine, bromine and iodine atoms.

Substituents in the substituted lower alkyl, substituted higher alkyl and substituted lower alkoxy are the same or different and have 1 to 3 substituents, such as hydroxy, lower cycloalkyl, lower cycloalkenyl, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxy. Lucanoyloxy, azide, di-lower alkanoylamino, lower alkenyloxy-power luponylamino, lower alkadienyloxycarbonylamino, lower alkatrienylyloxycarbonylamino, halogen atom, lower alkanol, substituted or unsubstituted aryl, A substituted or unsubstituted heterocyclic group, a substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted daltarimide, C RNR ^13A R ^14A (where R ^13A and R ^14A are the same or Differently, water Element, hydroxy, lower alkyl, lower cycloalkyl, higher alkyl, alkenyl, lower alkoxy, aryl, heterocyclic group or NR ^15A R ^16A (wherein R ^15A and R ^16A are the same or different, and hydrogen, lower alkyl, lower cycloalkyl, Ariru, heterocyclic group, lower Arukanoiru, Aroiru, or a heterocyclic represents the bound carbonyl or Ariru force Rubamoiru a), a substituted or unsubstituted together with N to R ^13A and R ^14A are adjacent to form a nitrogen-containing heterocyclic group], and in C0 ₂ R ^17A (wherein, R ^17A is hydrogen, lower alkyl, higher alkyl, lower cycloalkyl, alkenyl, substituted or unsubstituted Ariru or substituted or unsubstituted heterocyclic represents a _{_{group), (OCH 2 CH 2)}} n O CH 3 ( wherein, n represents an integer of 1 to 10), in NR ^18A R ^19A (wherein, R ^18A and R ^19A are One or differently, hydrogen, lower alkyl, higher alkyl, lower Shikuroa alkyl, Ariru or a heterocyclic group, R ^18A and R ^19A is a substituted or unsubstituted become adjacent N toe body nitrogen-containing heterocycle Or NR ^2GA COR ^21A

^Wherein R ^2GA represents hydrogen, lower alkyl, higher alkyl, lower cycloalkyl, aryl or heterocyclic group, and R ^21A represents hydrogen, lower alkyl, aryl, aromatic heterocyclic group, lower alkoxy, aralkyloxy. or NR ^22A R ^23A (wherein, R ^22A and R ^23A are the same or different, hydrogen, lower alkyl, or represents Ariru or aromatic heterocyclic group, the N integral with R ²² a and R ²³ a are adjacent To form a substituted or unsubstituted nitrogen-containing heterocyclic group). Substituents in the substituted alkylene may be the same or different and have 1 to 3 substituents, such as hydroxy, lower alkoxy, lower alkanoyloxy, azide, di-lower alkanoylamino, lower alkenyloxyl-ponylamino, lower alkadenyloxy. Carbonylamino, lower alkatrienyloxycarbonylamino, halogen atom, lower alkanoyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkadienyl, substituted or unsubstituted alkatrienyl, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkadienyloxy, substituted or unsubstituted alkatrienyloxy, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridonyl, substituted or unsubstituted Substituted pyrrolidonyl, substituted or unsubstituted peracylyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted morpholino, substituted or unsubstituted morpholinyl, substituted Or unsubstituted piperazino, substituted or unsubstituted piperazinyl, substituted or unsubstituted thiomorpholino, substituted or unsubstituted dioxolanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted phenyl Substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, Substituted or unsubstituted tetrazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted oxazolidonyl, substituted or unsubstituted piperidonyl, substituted or unsubstituted perhydroazepinonyl, Substituted or unsubstituted succinimides, substituted or unsubstituted phthalimides, substituted or unsubstituted dalyl imides, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinedionyl, substituted or unsubstituted oxopyrrolides Donyl, substituted or unsubstituted maleimide, substituted or unsubstituted thiazolidonyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazolidinedionyl, substituted or unsubstituted 2-oxo-3 -Pyrrolinyl, substituted or unsubstituted Kisazoroniru, substituted or unsubstituted pyrazolonyl, substituted or unsubstituted I Soo hexa Zorro cycloalkenyl, substituted or unsubstituted Chiazoroniru, substituted or unsubstituted Okisazorijiniru, substituted or unsubstituted pyrrolinyl, substituted Or unsubstituted imidazolidinyl, substituted or unsubstituted imidazolinyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted oxadiazolyl, CO NR ^13B R ^14B (wherein, R ^13B and R ^14B are the above-mentioned R ^13A and R ^14A and each synonymous) in C0 ₂ R ^17B (wherein, R ^17B has the same meaning as defined above for R ^17A), (〇 CH ₂ CH ₂₎ _na 〇_CH ₃ (wherein, na is defined as above for n ), NR ^18B R ^19B (where! ^^ and! ^^ are synonymous with! ^^ and! ^^, respectively) or NR ^20B COR ^21B (where R ^2QB and R ^21B are wherein respectively synonymous with R ^2QA and R ^21A of) are included.

Substituted alkenyloxy, substituted alkadienyloxy, substituted alkatrienyloxy, substituted lower cycloalkyl, substituted aryl, substituted aralkyloxy, substituted heterocyclic group, substituted aromatic heterocyclic group, substituted alkenyl, substituted alkadienyl, substituted Alkatrienyl, substituted pyridyl, substituted pyridonyl, substituted pyrrolidonyl, substituted peracylyl, substituted piperidyl, substituted piperidino, substituted pyrrolidinyl, substituted morpholino, substituted morpholinyl, substituted piperazino, substituted piperazinyl, substituted thiomorpholino, substituted dioxoxo Furyl, substituted phenyl, substituted pyrazolyl, substituted imidazolyl, substituted oxazolyl, substituted isooxazolyl, substituted thiazolyl, substituted isothiazolyl, substituted tetrazolyl, substituted pyrimidinyl, substituted Substituted pyrazinyl, substituted oxazolidonyl, substituted piperidonyl, substituted perhydroazepinonyl, substituted succinimide, substituted phthalimide, substituted darylimide, substituted hydantoinyl, substituted thiazolidine dionyl, substituted oxopyrrolidonyl, substituted maleimide, substituted thiazolidinyl, substituted pyridinyl , Substituted oxazolidinedionyl, substituted 2-oxo-3-pyrolinyl, substituted oxazolonyl, substituted pyrazolonyl, substituted isooxazolonyl, substituted thiazolonyl, substituted oxazolidinyl, substituted pyrrolinyl, substituted imidazolidinyl, substituted imidazolinyl, substituted virazolinyl Substituents in the substituted oxaziazolyl and the substituted nitrogen-containing heterocyclic group formed together with the adjacent N are the same or different and have 1 to 3 substituents, such as hydroxy and lower. Alkyl, higher alkyl, alkenyl, alkadienyl, alkatrienyl, lower cycloalkyl, lower cycloalkenyl, lower alkoxy, lower alkoxy lower alkoxy, lower alkanoyloxy, azide, di-lower alkanoylamino, lower alkenyloxycarbonyl Amino, lower Arkadie 2 Roxycarbonylamino, lower alkatrienyloxycarbonylamino, halogen atom, lower alkanoyl, aryl, heterocyclic group, CONR ^13C R ^{14C wherein} R ^13C and R ^14C are the same or different, hydrogen, Hydroxy, lower alkyl, lower cycloalkyl, higher alkyl, alkenyl, lower alkoxy, aryl, heterocyclic group or NR ^15A1 R ^16A1 (wherein, R ^15A1 and R ^16A1 have the same ^meanings as R ^15A and R ^16A , respectively) Or R ^13C and R ^14C together with an adjacent N form a nitrogen-containing heterocyclic group], C〇 ₂ R ^17C (wherein, R ^17C has the same meaning as R ^17A described above.) ), NR ^18C R ^19C (wherein R ^18C and R ^19C are the same or different and represent hydrogen, lower alkyl, higher alkyl, lower cycloalkyl, aryl or heterocyclic group, or R ^18C and R ^19G Is integrated with adjacent N And it forms a nitrogen-containing heterocyclic group), NR ^2GC C0R ^21C (wherein, R ^2GC and R ^21C are Ru same meanings der and R ^2QA and R ^21A described above) or S_〇 ₂ NR ^24C R ^25C ( Wherein R ^24C and R ^25C are the same or different and represent hydrogen or lower alkyl).

For lower alkyl, higher alkyl, lower cycloalkyl, lower alkoxy, halogen atom, aryl, heterocyclic group, aromatic heterocyclic group, nitrogen-containing heterocyclic group formed integrally with adjacent N, alkenyl and alkenyloxy The alkenyl moiety, the alkadienyl moiety in alkadienyl and alkadienyloxy, the alkatrienyl moiety in alkatrienyl and alkatrienyloxy, and aralkyloxy are as defined above, respectively. The lower alkyl moiety in the lower alkoxy lower alkoxy has the same meaning as the lower alkyl, and the lower alkylene moiety represents a group obtained by removing one hydrogen atom from the lower alkyl. Examples of the lower alkenyl in the lower alkenyloxycarbonylamino include those having 2 to 8 carbon atoms in the alkenyl, for example, vinyl, aryl, topropropenyl, 2-butenyl, 1-pentenyl, 2-hexenyl and the like. Examples of the lower alkadienyl in the lower alkadienyloxycarbonylamino include those having 4 to 8 carbon atoms in the alkadienyl, for example, 1,3-pentenyl, 1,3-hexenyl, 2,4-hexenyl. Etc. are included. The lower alkenyl group in the lower alkenyl group includes those having 6 to 8 carbon atoms, for example, 1,3,5-hexatrienyl and the like in the alkatrienyl. Lower cycloalkenyl includes those having 4 to 8 carbon atoms, for example, Includes 2-cyclopentenyl, 2-cyclohexenyl and 1,3-cyclopentenyl. The lower alkanol in the lower alkanol, lower alkanoyloxy and di-lower alkanoylamino includes straight-chain or branched C 1-8 carbon atoms in the above-mentioned alkanoyl, for example, formyl, acetyl, propanol, isopropanol, and the like. And the like. The aryl portion in arylo and arylcarbamoyl is as defined above. The heterocyclic group moiety in the carbonyl bonded to the heterocycle has the same meaning as described above. Examples of the group including carbonyl include fluoryl, tenyl, nicotinol, and isonicotinoyl.

One embodiment of the present invention is a compound in which X is a halogen atom in compound (I).

Another embodiment of the present invention is a compound (I) in which X is a single bond together with R ⁴ . Among compounds in which X is a single bond with R ⁴ , a compound in which R ¹ and R ² are hydrogen is a preferred example. More preferably, but in a compound is a single bond together with R ^4, R ¹ and R ² are hydrogen, R ³ is substitution or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted Or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted Or unsubstituted tetrazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted oxazolidonyl, substituted or unsubstituted piperidonyl, substituted or unsubstituted monohydroazepinonyl, substituted Or unsubstituted succinimide, substituted or unsubstituted Substituted phthalimide, substituted or unsubstituted dalyl imide, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinedionyl, substituted or unsubstituted oxopyrrolidonyl, substituted or unsubstituted maleimide , Substituted or unsubstituted thiazolidonyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted 2-oxo-3-pyrolinyl, substituted or unsubstituted oxazolonyl, substituted Or unsubstituted pyrazolonyl, substituted or unsubstituted isoxazolonyl, substituted or unsubstituted thiazolonyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted And unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted imidazolinyl, substituted or unsubstituted oxadiazolyl or substituted or unsubstituted pyrazolidinyl.

Most preferably, among the compounds in which X is a single bond together with R ⁴ , R ¹ and R ² are hydrogen and R ³ is substituted or unsubstituted oxazolidonyl, substituted or unsubstituted piperidonyl, substituted Or unsubstituted perhydroazepinonyl, substituted or unsubstituted succinimide, substituted or unsubstituted phthalimide, substituted or unsubstituted dalyl imide, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinediamine Examples of the compound include oxonyl, substituted or unsubstituted oxopyrrolidonyl, substituted or unsubstituted maleimide, substituted or unsubstituted thiazolidonyl, and substituted or unsubstituted oxazolidinedionyl. it can.

The pharmacologically acceptable salts of compound (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts, and the acid addition salts include hydrochloride and odor. Inorganic acid salts such as hydride, sulfate and phosphate, formate, acetate, oxalate, benzoate, methanesulfonate, P-toluenesulfonate, maleate, fumarate And organic acid salts such as tartrate, citrate, succinate and lactate. Examples of metal salts include alkali metal salts such as lithium salt, sodium salt and potassium salt, and alkali metals such as magnesium salt and calcium salt. Examples include earth metal salts, aluminum salts and zinc salts, etc., and ammonium salts include salts such as ammonium and tetramethylammonium. Include addition salts such as phosphorus and piperidine, Examples of the amino acid addition salts of glycine, phenylene Ruaranin, § scan aspartic acid, Dar evening include addition salts such as tromethamine acid and lysine.

In the compound of the present invention, some of the compounds (I) usually produced from radicicol as starting compounds may include various stereoisomers, positional isomers, tautomers and the like. The present invention includes all of these possible isomers and mixtures thereof, and the mixing ratio may be in any ratio. Next, a method for producing the compound (I) will be described.

The production process of compound (I) mainly includes oximation (Production method 1), alkylation, Consists of the following reaction steps: substitution reaction (Production method 2), halohydrination (Production method 3), desilylation (Production method 4), or acylation (Production method 5). It can be manufactured in combination.

In the following production methods, if the defined groups change under the conditions of the method or are inappropriate for carrying out the method, methods for introducing and removing protecting groups commonly used in organic synthetic chemistry are used. [For example, Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons Inc. (1981) ) Reference] can be used to obtain the target compound. Further, the order of the reaction steps such as introduction of a substituent may be changed as necessary.

Manufacturing method 1

Radicicol or a compound (F) obtained by a method known from radicicol (Japanese Patent Laid-Open No. 4-226991), or radicicol or one of the phenolic hydroxyl groups of radicicol substituted with alkanoyl, alkenoyl, alkadienyl or alkatrienoyl. A method known from Radicicol [for example, Journal of the Americas, Chemical, Society (Journal of the

American Chemical Society), Vol. 94, p. 6190 (1972)], a compound (Ia) obtained by oxidizing genone carbonyl of compound (G) obtained according to the following reaction step. it can.

(F) Process 1

Or

(Wherein, R ^la and R ^2a, wherein R ¹ and trialkylsilyl from R ^2, Toriari - Rushiriru a monoalkyl di § Li one Rushiriru and a group remaining after removing dialkyl mono ants one Rushiriru, scale ¹¹⁵ and Shaku ²¹⁾ has the same meaning as R ¹ and R ² , respectively, wherein at least one of R ¹ and R ² is trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl. R ¹ R ² , R ³ and Y are as defined above.

Process 1

Compound (Ia) is prepared by converting compound (F) or compound (G) in the presence or absence of an acid in the presence of H ₂ N—〇—Y—R ³ (II) (wherein R ³ and Υ are as defined above) The compound (II) represented by the following formula (II) or an acid addition salt thereof can be obtained.

As a reaction solvent, pyridine, chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, etc. are used alone or in combination, and pyridine or ethyl acetate is preferred. _c Acids include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid and the like, and preferably 0.1 to 10 equivalents to compound (F) or compound (G). Examples of the acid addition salts of compound (II) include hydrochloride, hydrobromide, sulfate, nitrate, formate, acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, and benzoic acid. Acid salts, oxalates, fumarates, maleates, tartrates and the like are used.

When an acid addition salt of the salt compound (II) is used, one or more equivalents, preferably 1 to 10 equivalents of a base, for example, pyridine, triethylamine, diisopropylethylamine are used based on the acid addition salt of the compound (II). Amines such as amines, N, N-dimethylaniline and N, N-ethylylaniline; and alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium bicarbonate. Preferably, Ν, Ν-dimethylaniline or Ν, Ν-ethylylaniline is used, or pyridine is used also as a solvent. The compound (II) or an acid addition salt thereof is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (F) or the compound (G). The reaction is usually carried out at −20 to 100 t, preferably at 20 to 60 ° C., and is completed in 1 to 80 hours.

Manufacturing method 2

Compound (Ia) is obtained by subjecting a hydroxyl group of compound (H) or compound (J) obtained according to a method known from Radicicol (W096 / 33989) to another functional group by alkylation or substitution reaction. Can also be obtained by the step of converting to

(Wherein, R ¹ R ² , R ³ and Y are as defined above)

Process 2

Compound (Ia) is obtained by reacting compound (H) with compound (III) represented by HO—Y—R ³ (III) (wherein R ³ and Y are as defined above) in the presence of a condensing agent. It can be obtained by reacting.

In the compound (Ia), R ³ is a substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted daryl imide, a substituted or unsubstituted hydantoinyl, a substituted or unsubstituted thiazolidine Compounds that are dionyl, substituted or unsubstituted maleimide, substituted or unsubstituted oxopyrrolidonyl or substituted or unsubstituted oxazolidinedionyl can be prepared by subjecting compound (J) to the presence of a condensing agent. A substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted hydantoin, a substituted or unsubstituted thiazolidinedione, a substituted or unsubstituted maleimide, It can be obtained by reacting with a substituted or unsubstituted oxopyrrolidone or a substituted or unsubstituted oxazolidinedione.

As a reaction solvent, toluene, THF, dichloromethane or the like is used alone or as a mixture. As the condensing agent, a mixture of a trivalent phosphorus compound such as triphenylphosphine and tributylphosphine and an azo compound such as getyl azodicarboxylate (DEAD) and 1,1- (azodicarbonyl) dipiperidine are used.

The compound (III) and the condensing agent are each used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (H).

Substituted or unsubstituted succinimide, substituted or unsubstituted phthalimide, substituted or unsubstituted dalyl imide, substituted or unsubstituted hydantoin, substituted or unsubstituted thiazolidinedione, substituted or unsubstituted maleimide, substituted Alternatively, the unsubstituted oxopyrrolidone or the substituted or unsubstituted oxazolidinedione and the condensing agent are each used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on Compound (J).

The reaction is usually carried out at -20 to 80 ° C, preferably 0 to 30 and is completed in 5 minutes to 48 hours.

Manufacturing method 3

The compound (Ib) can be obtained by opening the epoxide of the compound (Ia) to a halohydrin or the like.

Wherein R ¹ R ² , R ³ and Y are as defined above, X ^a is a halogen atom, R ^4a is hydrogen, formyl, or SO—Z (where Z is as defined above) ) Process 3 _ 1

Among the compounds (Ib), those in which R ^4a is hydrogen can be obtained by reacting the compound (Ia) with an acid such as hydrochloric acid or hydrobromic acid or with a Lewis acid such as titanium tetrachloride. it can.

As the solvent, dioxane, THF, ether, black form, dichloromethane, DMF, acetonitrile, methanol, ethyl acetate or the like is used alone or as a mixture. The acid or Lewis acid is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, relative to compound (Ia). The reaction is usually carried out at -20 to 40 ° C, preferably at 0 to 40, and is completed in 10 minutes to 48 hours.

Process 3-2

Among the compounds (Ib), a compound wherein ^R4a is formyl can be obtained by reacting the compound (Ia) with a phosphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide in DMF. The phosphorus oxyhalide is used in an amount of 1 equivalent or more, preferably 2 to 5 equivalents, relative to compound (Ia). The reaction is usually carried out at -10 to 40 ° C, preferably at 0 to 40, and is completed in 1 to 48 hours.

Process 3 _ 3

In the compound (lb), the dimer compound in which R ^4a is SO—Z (where Z is as defined above) is obtained by converting the compound (Ia) to a halogenated thiol such as thionyl chloride or thionyl bromide. Can be obtained by reacting with carbonyl. As the solvent, DMF, chloroform, dichloromethane, dimethylsulfoxide (DMS0), acetonitrile and the like are used alone or as a mixture. The thionyl halide is used in an amount of 1 equivalent or more, preferably 2 to 10 equivalents, based on compound (Ia). The reaction is usually carried out at -10 to 40 ° C, preferably at 0 to 40 ° C, and is completed in 1 to 48 hours.

Manufacturing method 4

Compound (Ic) in which at least one of R ¹ and R ² of compound (I) is substituted with trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl is removed. Compound (Id) can be obtained by silylation.

(Wherein, R ^lb , R ^2b , R ³ , RY and X are as defined above, and R ^lc and R ^2c are the above trialkylsilyl, triarylsilyl, monoalkyldiaryl in R ^lb and R ^2b ) Where at least one of silyl or dialkylmonoarylsilyl has been replaced by hydrogen)

Process 4

Compound (Id) can be obtained by reacting compound (Ic) with a desilylating agent.

As the solvent, THF, chloroform, dichloromethane, toluene, water, methanol and the like are used alone or as a mixture. Tetrabutylammonium fluoride (TBAF), sodium fluoride, hydrofluoric acid, and the like are used as the desilylation agent. The reaction may be performed by increasing the pH by adding an acid such as acetic acid or hydrochloric acid. The desilylating agent is used in an amount of 0.1 equivalent or more, preferably 1 to 10 equivalents, relative to compound (Ic). The reaction is usually performed at -20 to 50 ° C, and is completed in 5 minutes to 24 hours.

Manufacturing method 5

Compound (I f) in which at least one of R ¹ R ² and R ⁴ in compound (I) is alkanoyl, alkenoyl, alkadienol or alkatrienoyl is obtained by acylating the following compound (I e) be able to.

(Wherein, R ³ , Y and X are as defined above, and R ^ld , R ^2d and R ^4b are as defined above for R ¹ , R ² and R ⁴ , but at least one of them is hydrogen R ^le , R ^{2 e} and R ^{4 c} are those wherein at least one of the hydrogens in the above R ^{1 d} , R ^{2 d} and R ^{4 b} is replaced by alkanoyl, alkenoyl, alkadienoyl or alkatrienoyl. is there)

Process 5

Compound (IO is a compound (Ie) comprising at least one equivalent, preferably 1 to 100 equivalents of an acid halide, an acid anhydride or a mixed anhydride containing a desired alkanol, alkenoyl, alkadienoyl or alkatrienoyl, etc. And in the presence of a base.

As the solvent, DMF, DMS0, chloroform, dichloromethane, toluene and the like are used alone or as a mixture. An arbitrary hydroxyl group can be modified by appropriately introducing and removing a protective group for a hydroxyl group, but a plurality of hydroxyl groups can be simultaneously modified. As the base, pyridine, triethylamine, N, N-dimethylaniline, Ν, Ν-getylaniline and the like are used in an amount of 1 equivalent or more, preferably 1 to 200 equivalents, relative to compound (Ie). Further, a base such as pyridine can be used also as a solvent. Further, dimethylaminopyridine (DMAP) or the like can be added in an amount of 0.1 to 4 equivalents to the compound (Ie) to promote the reaction. The reaction is usually performed at -20 to 50, and is completed in 5 minutes to 24 hours.

In the production of the compound (I), the conversion of the functional group of RR ² , R ³ , RY or X may be performed by a known method other than the above-mentioned method [for example, Comprehensive Organic Transformations (Comprehensive Organic Transformations, R · C · Larock (1989)].

The isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like. In addition, the intermediate can be subjected to the next reaction without purification.

When it is desired to obtain a salt of compound (I), the compound (I) may be purified as it is when a salt thereof is obtained, or may be dissolved or suspended in a suitable solvent when obtained in a free form, An acid or a base may be added to form a salt.

Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Specific examples of the compound (I) are shown in Tables 1 (1) to 1 (3) and 2 (1) to 2 (2). Incidentally, Me, Et, ^l Bu is each methyl in the table described below, Echiru means tert- butyl.

Table 1 (1) Specific examples of compound (I)

Compound YR ³ Compound Y-R:

8

3 1 0

Four

^{4 N} '1 1

Me, N

Table 1 (2) Specific examples of compounds

Compound YR ³ Compound YR ³

1 8 2 5

0, N

Table 1 (3) Specific examples of compound (I)

Compound YR ³

I

o

(Z JO) N H H L 2

; Man

^ co en (L) zeiZ0 / 66Jf / lDd Table 2 (2) Specific examples of compounds

Compound R ¹ YR ³

Next, the activity of compound (I) as an antitumor agent / immunosuppressant will be specifically described in test examples using representative compounds.

<Test Example 1> Intracellular tyrosine kinase activity inhibition test

SR-3Y1 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS), supplemented with radicicol derivatives at each test concentration, and cultured at 37 t: 5% CO2 for 40 hours. Lysis buffer [50 niM Hepes NaOH, H 7.4, 25 m salt (NaCl), 1% nonidet Ρ-40 (ΝΡ40), 0.1 ナトリウム sodium dodecyl sulfonate (SDS) mM Dithiothreitol, 1 mM Ethylenediaminetetraacetic acid (EDTA), 1 mM Phenylmethylsulfonyl fluoride

(PMSF), 20 ug / ml leupeptin, 1 mM sodium fluoride (NaF), 10 mM / 3-glycerophosphate (] 3-glycerophosphate), 1 mM sodium orthovanadate (Na ₃ V0 ₄ )] at 4 ° C for 20 minutes, and then centrifuged at 15000 G for 10 minutes. The protein concentration of the obtained supernatant was measured, and the same protein After preparing a sample to obtain the same amount, spot the same amount on a polypinylidene difluoride (PVDF) membrane (Millipore), and use mouse mouse polyclonal phosphotyrosine antibody MX-pTYR (Kyowa Medix) as the primary antibody. Was added to a mouse IgG antibody (BIO-RAD) bound to alkaline phosphatase (Alkaline Phosphatase) as a secondary antibody, and reacted with the protein on the membrane. Detection was performed using an ECF reagent (Vistra), and the amount of tyrosine phosphorylated protein was quantified by density scanning of the spots obtained on a fluoroimager (Molecular Dynamics). Tyrosine phosphorylation inhibitory activity of La Defense Ishikoru derivatives, can be represented by a derivative such as the percentage of protein as compared to the case without the addition of drug has tyrosine phosphorylation is halved concentration (IC _{5 0).}

Table 3 shows the results.

Table 3 Inhibition of intracellular tyrosine kinase activity

Compound Ι 0 ₅₀ (μΜ)

3 0. 02

8 0. 02

1 4 0. 06

1 7 0. 03

25 0. 08

27 0. 08

According to Table 3, the test compound shows a strong inhibitory activity on intracellular tyrosine kinase activity, and compound (I) is useful as an inhibitor of tyrosine kinase.

Test example 2> Rat normal fibroblast 3 μΒ cell line and its growth inhibition test on V-src oncogene transformed cell SR-3Y1 cell line

In a 96-well microplate (Nunc # 167008), 1000 rat normal fibroblast 3Y1-B cell lines or a V-s rc oncogene-transformed cell SR-3Y1 cell line per well were spread. The cells were pre-cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS) in a 5% carbon dioxide incubator at 37 ° C for 24 hours. Then, the DMS0 solution of each test compound adjusted to 10 mM was serially diluted in a culture medium, and 501 was added to each well. Then, the cells were cultured in a 5% CO 2 incubator at 37 for 72 hours. The 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolidine dissolved in the culture medium was adjusted to a final concentration of 1 mg / ml 5 hours before the end of the culture. Dembromide (3- (4,5-dimethylthiazol-2-y 0 -2,5-diphenyl tetrazolium bromide (manufactured by Sigma), hereinafter abbreviated as MTT)) is 50 i 1 per well. After culturing, DMS0 was dispensed at 150 1 per well, and vigorously stirred using a plate mixer. MTT-formazan crystals were completely dissolved. Then, the difference in absorbance between 550 nM and 630 nM was measured using a microplate reader (manufactured by Wako Pure Chemical Industries, Ltd.).

The cell growth inhibitory activity was calculated as the 50% growth inhibitory concentration (IC ₅ ) using the formula of the measurement software (Soft Max Pro) attached to the microplate reader.

The results are shown in Table 4.

Table 4 Rat normal fibroblast 3Y1-B cell line and

The V-src oncogene transform cells

Growth inhibitory activity against SR-3Y1 cell line against CD

Tosa

Compound Cell growth inhibitory activity II. (ΜΜ)

3Υ1-Β SR-3Y1

3 0.04 0.012

8 0.037 0.018

18 0.014

20 0.15 0.023

27 0.019

28 0.048 0.008

32 Not measured 0.009

35 Not measured 0.009

According to Table 4, the test compound showed stronger cell strength in SR-3Y1 cells compared to 3Y1-B cells. Compound (I) is useful as an antitumor agent since it exhibits vesicle growth inhibitory activity.

<Test Example 3> Anti-tumor test against MX-1 solid tumor transplanted from nude mouse transplanted human breast cancer Human breast cancer cells passaged in nude mice (BALB / c nu / nu mice: CLEA Japan) Better growth than MX-1 tumor mass The portion shown was selected, and a 2 mm square fragment was cut out and transplanted subcutaneously into the ventral side of a nude mouse, male, 7-9 weeks old, with Troia curl. 13 days after tumor implantation were measured tumor size, tumor good proliferating tumor volume 100-300 mm ³ {[(longer diameter) X (minor) ^2] calculated from the calculation formula of X 0. 5} After selection, the mice are arbitrarily divided into groups of 5 mice, and 7.5% cremophor EL (Sigma) / 5% dimethylacetamide (DMA) /87.5% concentration in saline solution The test compound dissolved at 10 mg / ml was administered intravenously to mice at a dose of 100 mg / kg once daily for 5 days.

The antitumor activity of the test compound was represented by the ratio (TZC) of the tumor volume (T) of the test compound-administered group to the tumor volume (C) of the non-drug-treated control group on day 7 after administration of the test compound.

Table 5 shows the results.

Table 5 Anti-tumor activity against human mammary carcinoma MX-1 solid tumor transplanted in nude mice

Compound T / C (¾) Measurement date (after administration of test compound)

1 4 3 1 7

According to Table 5, the test compound shows excellent antitumor activity, and compound (I) is useful as an antitumor agent.

Test Example 4> Intracellular Raf-1 protein reduction activity and Erk2 phosphorylation inhibitory activity Activated K-ras transgenic rat renal epithelial cells KNRK 5.2 Cells contain 10% fetal calf serum (FCS) Dulbecco Radase at each test concentration in denatured Eagle's medium (DMEM) Isicol derivative was added, and the cells were cultured at 37 under 5% carbon dioxide for 40 hours. Lysis buffer with cooled cells [HEPES 50 mM NaOH, pH 7.4, 250 mM NaCl

(NaCl), 1 mM ethylenediaminetetraacetic acid (EDTA), 1% nonidet P-40 (NP40), 1 m dithiothreitol (DTT), 1 mM phenylmethylsulfonyl fluoride

(PMSF), 5 p. G / ml Roipe leptin (leupeptin), 2 mM Orutobanajin acid sodium © beam _{_{(Na 3 V0 4), 1}} mM sodium fluoride (NaF), 10 mM 3- glycerin port phosphate (beta -glycerophosphate)] at 4 ° C for 30 minutes, and centrifuged at 30,000 G for 10 minutes. The protein concentration of the obtained supernatant was measured, and samples were prepared so as to have the same protein content in each lane. Then, the proteins were separated by SDS-PAGE. The separated protein samples were transferred to a polyvinylidene difluoride (PVDF) membrane (Millipore or ATT0), and then used as primary antibodies as anti-phosphorylated MAPK antibodies (anti-phospho MAPK, New England Biolabs), Anti-Erk2 antibody (ant Erk2, Upstate

Biotechnology), Anti-Raf-1 antibody Canti-Raf-1 (C-12), Santa Cruz

Biotechnology) and reacted with the protein on the membrane. Then, as a secondary antibody, a horseradish peroxidase-labeled primary antibody that reacts with each of the primary antibodies (anti-horse Ig antibody, or anti-mouse Ig antibody,

(Amersham). Detection is performed using an ECL reagent (Amersham), and the bands obtained on the X-ray film are subjected to density scanning to quantify the phosphorylated Erk2 protein, Erk2 total protein, and Raf-1 protein, respectively. did. The Erk2 phosphorylation inhibitory activity of a radicicol derivative was calculated by calculating the ratio of phosphorylated Erk2 protein (phosphorylated Erk2 protein mass / Erk2 total protein mass) from the results obtained from samples at each drug concentration. It can be indicated by the derivative concentration (IC ₅₀ ) such that the ratio is reduced by half compared to the case where no drug is added. Regarding the Raf-1 protein reduction effect, the ratio of Raf-1 protein to Erk2 protein (Raf-1 protein mass / Erk2 total protein mass), which does not change the protein mass due to drug treatment, was determined from the sample at each drug concentration. It can be calculated from the results obtained, and can be indicated by the derivative concentration (IC _5Q ) that halves the ratio compared to the case where no drug is added.

The results are shown in Table 6. Table 6 Intracellular Raf-1 protein reduction activity and Erk2 phosphorylation inhibitory activity

Raf-1 protein content Erk2 phosphorylation

Compound reducing effect Inhibitory activity

Ι0 ₅₀ ( _μ ) I 'so, μ "

0.22 0.48

18 0.28 0.14

27 0.48 0.16

28 0.03 0.06

According to Table 6, the test compound showed an effect of reducing intracellular Raf-1 protein content and an effect of inhibiting Erk2 phosphorylation.

Compound (I) or a pharmaceutically acceptable salt thereof is administered as it is or orally or parenterally as various pharmaceutical compositions. Examples of the dosage form of such a pharmaceutical composition include tablets, pills, powders, granules, capsules, suppositories, injections, and drops.

For the preparation of the above dosage forms, generally known methods are applied, for example, various excipients, lubricants, binders, disintegrants, suspending agents, isotonic agents, emulsifiers, or absorption enhancers Etc. may be contained.

Carriers used in pharmaceutical compositions include, for example, water, distilled water for injection, physiological saline, glucose, fructose, sucrose, mannitol, lactose, starch, corn starch, cellulose, methylcellulose, carboxymethylcellulose, Hydroxy Propylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, or glycerin fatty acid ester, etc., depending on the type of preparation. It is appropriately selected.

The dose and frequency of administration of the compound (I) used for the above purpose vary depending on the intended therapeutic effect, administration method, treatment period, age, body weight, etc., and are orally administered or parenterally administered (for example, Injection, infusion, rectal administration by suppository, dermal application, etc.), the dose is usually 0.01 to 20 mg / kg per day for adults, and the frequency of administration is once or several times a day.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments of the present invention will be described with reference to Reference Examples and Examples.

The peak position (δ) of the proton nuclear magnetic resonance spectrum (MR) used in Reference Examples and Examples is expressed in parts per million (ppm) from tetramethylsilane to the lower magnetic field side. These were measured at 270 MHz, and the observed shape, coupling constant, and number of protons are shown in parentheses after the δ value of each signal. The peak shape is expressed as follows.

s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: brod.

Example 1 (Compound 1)

0.41 mmol of the trifluoroacetic acid salt of the compound a (see Reference Example 1) was dissolved in 1 ml of pyridine, 60 mg of radicicol was added, and the mixture was stirred at room temperature for 45 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) to obtain 74 mg of compound 1. Compound 1 was a mixture of isomers (約 2: 1) based on oxime rather than Ή- 丽 R.

FAB-MS m / z: 530 [M + H] ⁺

Main _{component: Ή-NMR (CD 3 0D} ) δ (ppm): 1.16 (d, J = 6.9 Hz, 3H), 1.60 (m, 1H), 2.09 (m, 2H), 2.42 (m, 1H), 3.15 (m, 1H), 3.31 (m, 2H), 3.35 (m, 1H), 3.68 (s, 3H), 3.82 (d, J = 16.2 Hz, 1H), 3.93 (d, J = 16.2 Hz, 1H), 4.20 (s,

2H), 4.24 (m, 2H), 5.29 (m, 1H), 5.61 (dd, J = 3.0, 10.6 Hz, 1H), 6.05 (m, 1H), 6.06 (m, 1H), 6.28 (m, 1H ), 6.43 (s, 1H), 6.69 (d, J = 16.2 Hz, 1H), 6.72 (m, 1H), 7.25 (dd, J = 11.2, 16.2 Hz, 1H).

Example 2: L 0

Hereinafter, Compounds 2 to 10 were obtained from radicicol and trifluoroacetate or hydrochloride of Compounds b to j according to Example 1.

Example 2 (Compound 2)

The isomer ratio was about 2: 1.

FAB-MS m / z: 517 [M + H] ⁺

Main _{component: 'H-NMR (CD 3} 0D) <5 (ppm): 1.36 (m, 6H), 1.52 (d, J = 6.3 Hz, 3H), 1.59 (m, 1H), 1.85 (m, 2H) , 2.10 (m, 4H), 2.43 (dd, J = 3.6, 14.5 Hz, 1H),

2.90-3.10 (m, 2H), 3.16 (m, 2H), 3.35 (m, 1H), 3.82 (d, J = 16.2 Hz, 1H),

3.96 (d, J-16.2 Hz, 1H), 4.25 (m, 2H), 5.29 (m, 1H), 5.61 (dd, J = 3.6, 10.6 Hz, 1H), 6.16 (m, 1H), 6.45 (s , 1H), 6.73 (d, J = 16.2 Hz, 1H), 7.25 (dd, J = 11.2, 16.2 Hz, 1H).

Example 3 (Compound 3)

The isomer ratio was about 2: 1.

FAB-MS m / z: 528 [M + H] ⁺

Main _{component: 'H - NMR (CD 3} 0D) δ (ppm): 1.52 (d, J = 6.6 Hz, 3H), 1.61 (ddd, J 3.6, 9.2, 13.9 Hz, 1H), 1.70- 1.80 (m, 4H), 2.42 (dt, J = 3.5, 14.5 Hz, 1H), 2.69-2.74 (m, 2H), 3.00 (m, 1H), 3.35 (m, 1H), 3.84 (d, J = 15.8 Hz, 1H ), 3.90 (s, 2H), 3.93 (d, J-15.8 Hz, 1H), 4.10-4.20 (m, 2H), 5.30 (m, 1H), 5.59 (dd, J = 3.6, 10.6 Hz, 1H) , 6.12 (dd, J = 10.6, 11.9 Hz, 1H),

6.41 (s, 1H), 6.70 (d, J = 16.5 Hz, 1H), 7.24 (dd, J = 10.9, 15.8 Hz, 1H),

7.43 (d, J = 5.9 Hz, 2H), 8.48 (d, J = 5.9 Hz, 2H).

Example 4 (Compound 4)

The isomer ratio was about 2: 1.

FAB-MS m / z: 556 [MIH] ⁺ Main component: 'H-NMR (CDCI3) δ (ppm): 1.56 (d, J = 7.0 Hz, 3H), 1.73 (m, 4H), 1.96 (m, 1H), 2.24 (s, 3H), 2.30 ( m, 1H), 2.38 (m, 2H), 2.96 (m, 1H), 3.19 (m, 1H), 3.51 (s, 2H), 3.96 (m, 1H), 4.17 (m, 2H), 4.74 (m , 1H), 5.50 (m, 1H), 5.62 (m, 1H), 6.14 (m, 1H), 6.56 (s, 1H), 6.66 (d, J: 16.2 Hz, 1H),

7.14 On, 1H), 7.34 (m, 2H), 8.52 (m, 2H).

Example 5 (Compound 5)

The isomer ratio was about 8: 1.

FAB-MS m / z: 531 YL] +

Main _{component: Ή-NMR (CD 3 0D} ) δ (ppm): 1.51 (d, J = 6.6 Hz, 3H), 1.65 (m, 1H),

1.76 (m, 4H), 2.42 (dt, J = 3.6, 14.5 Hz, 1H), 2.91 On, 2H), 3.01 (m, 1H), 3.31 (m, 1H), 3.82 (d, J = 15.8 Hz, 1H), 3.94 (d, J = 15.8 Hz, 1H), 4.05-

4.15 (m, 4H), 5.31 (m, 1H), 5.59 (dd, J = 3.3, 10.2 Hz, 1H), 6.13 (m, 1H),

6.44 (s, 1H), 6.70 (d, J = 16.2 Hz, 1H), 7.09 (s, 2H), 7.24 (dd, J = 11.2, 15.8 Hz, 1H).

Example 6 (Compound 6)

The isomer ratio was about 4: 1.

FAB-MS m / z: 544 [M + H] ⁺

Main _{component: 'H - NMR (CD 3} 0D) δ (ppm): 1.51 (d, J = 6.3 Hz, 3H), 1.61 (m, 1H),

2.42 (dt, J = 3.6, 1.5 Hz, 1H), 2.68 (m, 1H), 2.82 (m, 1H), 2.99 (m, 1H),

3.36 (m, 1H), 3.82 (d, J = 16.2 Hz, 1H), 3.91 (s, 2H), 3.93 (d, J = 16.2 Hz, 1H), 4.10-4.20 (m, 3H), 5.30 (m , 1H), 5.60 (dd, J = 3.3, 10.6 Hz, 1H), 6.12 (m, 1H), 6.43 (s, 1H), 6.72 (d, J = 16.2 Hz, 1H), 7.23 (dd, J = 11.6, 16.2 Hz, 1H), 7.44 (m, 2H), 8.46 (dd, J = 1.3, 4.6 Hz, 2H).

Example 7 (Compound 7)

The isomer ratio was about 8: 1.

FAB-MS m / z: 556 [M + H] ⁺

Main components:-NMR (CD3OD) δ (ppm): 1.52 (d, J = 6.3 Hz, 3H), 1.58 (m, 1H),

1.77 (m, 4H), 2.42 (dt, J = 3.3, 14.2 Hz, 1H), 3.00 (m, 1H), 3.35 (m, 1H),

3.45 (m, 2H), 3.79 (d, J = 16.2 Hz, 1H), 3.82 (m, 2H), 3.92 (d, J = 16.2 Hz, 111), 5.28 (m, 1H), 5.58 (dd, J = 3.6, 10.6 Hz, 1H), 6.13 (dd, J = 10.6, 10.9 Hz, 1H), 6.43 (s, 1H), 6.73 (d , J = 16.2 Hz, 1H), 7.23 (dd, J = 10.8,

15.8 Hz, 1H), 7.78 (dd, J = 1.7, 4.6 Hz, 2H), 8.67 (dd, J = 1.7, 4.6 Hz, 2H).

Example 8 (Compound 8)

The isomer ratio was about 2: 1.

FAB-MS m / z: 508 [M + H] ⁺

Main _{component: Ή-NMR (CD 3 0D} ) 6 (ppm): 1.52 (d, J = 6.3 Hz, 3H), 1.60 (m, 3H), 1.73 (m, 1H), 2. 2 (dt, J = 3.6, 14.5 Hz, 1H), 2.69 (s, 3H), 3.00 (dd, J = 3.3, 5.6 Hz, 1H), 3.15 (t, J = 6.9 Hz, 2H), 3.34 (m, 1H), 3.79 ( d, J =

16.2 Hz, 1H), 3.92 (d, J = 16.2 Hz, 1H), 4.15 On, 2H), 5.30 (m, 1H), 5.59 (dd, J = 3.6, 10.6 Hz, 1H), 6.13 (m, 1H ), 6.43 (s, 1H), 6.73 (d, J = 16.2 Hz, 1H), 7.24 (dd, J = 11.2, 16.2 Hz, 1H).

Example 9 (Compound 9)

The isomer ratio was about 2: 1.

FAB-MS m / z: 551 [MIH] ⁺

Main _{component: Ή - NMR (CDC1 3)} δ (ppm): 1.46 (m, 12H), 1.58 (d, J = 6.9 Hz, 3H), 1.98 (m, 1H), 2.35 (m, 1H), 2.99 ( m, 1H), 3.21 (m, 1H), 3.49 (m, 4H), 4.05 (br, 1H), 4.22 (m, 2H), 4.73 (br d, J = 14.9 Hz, 1H), 5.53 (m, 1H), 5.66 (m, 1H), 6.16 (t, J = 11.9 Hz, 1H), 6.62 (s, 1H), 6.66 (d, J = 16.2 Hz, 1H), 7.20 (dd, J = 11.9, 16.2 Hz, 1H), 10.99 (br s, 1H).

Example 10 (Compound 10)

The isomer ratio was about 1.9: 1.

FAB-MS m / z: 585 [M + H] ⁺

Main _{component: 'H- MR (CDC1 3)} δ (ppm): 1.13 (br, 3H), 1.58 (d, J = 6.6 Hz, 3H), 1.94 (m, 1H), 2.34 (m, 1H), 2.96 (m, 1H), 3.20 (m, 1H), 3.37 (m, 2H), 3.58 (m, 2H), 4.00 (br, 1H), 4.31 (m, 2H), 4.70 (br, 1H), 5.15 ( m, 2H), 5.49 (m, 1H), 5.64 (m, 1H), 6.11 (t, J = 10.2 Hz, 1H), 6.60 (s, 1H), 6.63 (d, J 15.5 Hz, 1H), 7.16 (dd, J = 10.2, 15.5 Hz, 1H), 7.35 (m, 5H), 11.00 (br s, 1H).

Example 11 (Compound 11)

Compound 1.00 g was dissolved in pyridine (3 ml), concentrated hydrochloric acid (0.5 ml) and radisitol (0.55 g) were added, and the mixture was stirred at room temperature for 45 hours. The reaction solution was post-treated in the same manner as in Example 1 to obtain 0.71 g of compound 11. The isomer ratio was about 1.5: 1.

FAB-MS m / z: 525 [M + H] ⁺

Main _{component: Ή- MR (CDC1 3) (} 5 (ppm): 1.56 (d, J - 6.9 Hz, 3H), 1.96 (ddd, J = 3.6, 8.8, 14.9 Hz, 1H), 2.33 (m, 1H) , 2.97 (dt, J = 2.3, 8.6 Hz, 1H), 3.19 (m, 1H), 3.37 (s, 3H), 3.56 (m, 2H), 3.60 — 3.70 (m, 6H), 3.79 (m, 2H ), 3.98 (br, 1H), 4.31 (m, 2H), 4.70 (d, J = 15.8 Hz, 1H), 5.49 (m, 1H), 5.63 (dd, J = 2.6, 10.2 Hz, 1H), 6.14 (dd, J = 10.2, 10.9 Hz, 1H), 6.62 (s, 1H), 6.72 (d, J = 16.2 Hz, 1H), 7.17 (dd, J = 11.6, 15.5 Hz, 1H).

Example 12 (Compound 12)

According to Example 1, compound 12 was obtained from radicicol and the hydrochloride of compound m. The isomer ratio was about 1.7: 1.

FAB-MS m / z: 557 [M + H] ⁺

Main _{component: Ή-NR (CDC1 3)} δ (ppm): 1.55 (d, J = 6.6 Hz, 3H), 1.87 - 2.03 (m, 3H), 2.33 (ddd, J = 3.3, 6.9, 15.2 Hz, 1H ), 2.82 (m, 2H), 2.53 (s, 3H), 2.96 (ddd, J = 2.3, 3.0, 5.6 Hz, 1H), 3.22 (br, 1H), 3.50 (t, J = 6.4 Hz, 2H) , 3.73 (m, 2H), 4.05 (br, 1H), 4.28 (m, 2H), 4.70 (d, J = 13.9 Hz, 1H), 5.48 (m, 1H), 5.63 (dd, J = 2.6, 10.6 Hz, 1H), 6.14 (dd, J = 10.6, 11.2 Hz, 1H), 6.51 (s, 1H), 6.73 (d, J = 16.2 Hz, 1H), 7.01 (br d, J = 7.6 Hz, 2H) , 7.17 (dd, J = 11.9, 16.2 Hz, 1H), 7.52 (ddd, J = 1.7, 7.6, 7.6 Hz, 1H). Example 13 (Compound 13)

Compound 13 was obtained from radicicol and compound n according to Example 11. The isomer ratio was about 2: 1.

FAB-MS m / z: 496 [M + H] ⁺

Main _{component: 'Η- NMR (CDC1 3)} δ (ppm): 1.51 (d, J = 6.3 Hz, 3H), 1.58 (ddd, J = 4.4, 8.9, 13.8 Hz, 1H), 2.40 (ddd, J = 3.3, 3.6, 14.2 Hz, 1H), 3.01 (m, 1H), 3.33 (m, 1H), 3.92 (d, J = 16.3 Hz, 1H), 4.17 (d, J = 16.3 Hz, 1H),

5.35 (m, 1H), 5.77 (dd, J = 3.3, 10.6 Hz, 1H), 6.22 (t, J = 10.9 Hz, 1H),

6.31 (dt, J-6.2, 15.8 Hz, 1H), 6.47 (s, 1H), 6.56 (d, J-15.8 Hz, 1H), 6.60 (d, J = 16.3 Hz, 1H), 7.10-1 7.40 (m , 6H).

Example 14 (Compound 14)

Compound 14 was obtained from radicicol and compound o according to Example 11. The isomer ratio was about 2: 1.

FAB-MS m / z: 473 [M + H] ⁺

Main ^{_{component: 1 H- NMR (CD 3 0D}} ) 6 (ppm): 1.52 (d, J = 6.3 Hz, 3H), 1.57 (m, 1H), 2.41 (dt, J = 3.3, 14.2 Hz, 1H), 2.98 (m, 1H), 3.35 On, 1H), 3.67 (s, 3H), 3.80 (d, J = 16.2 Hz, 1H), 3.92 (d, J = 16.2 Hz, 1H), 5.09 (s, 2H) , 5.29 (m, 1H), 5.57 (dd, J = 3.6, 10.6 Hz, 1H), 5.96 (dd, J = 2.6, 6.3 Hz, 1H), 6.10-6.21 (m, 2H), 6.41 (s, 1H ), 6.66 (dd, J = 2.0 ₍ 4.3 Hz, 1H), 6.70 (d, J = 15.8 Hz, 1H), 7.22 (dd, J = 11.9, 16.8 Hz, 1H).

Examples 15 to 22

Hereinafter, Compounds 15 to 22 were obtained from radicicol and hydrochloride salts of Compounds P to w according to Example 1.

Example 15 (Compound 15)

The isomer ratio was about 2: 1.

FAB-MS m / z: 474 [M + H] ⁺

Main _{component: Ή - NMR (CDC1 3)} 6 (ppm): 1.56 (d, J = 6.6 Hz, 3H), 2.32 (m, 1H), 2.95 (m, 1H), 3.19 (br s, 1H), 3.90 (s, 3H), 4.02 (m, 1H), 4.74 (br d, 1H),

5.07 (s, 2H), 5.50 (m, 1H), 5.64 (dd, J = 2.6, 10.2 Hz, 1H), 6.12 (m, 1H),

6.58 (s, 1H), 6.65 (d, J = 16.0 Hz, 1H), 7.15 (dd, J: 11.6, 16.0 Hz, 1H), 7.45 (s, 1H), 7.57 (s, 1H), 10.80 (br , 1H).

Example 16 (Compound 16)

The isomer ratio was about 1.7: 1.

FAB-MS m / z: 460 [M + H] ⁺

Main component: Ή-NMR (CDCI3) δ (ppm): 1.52 (d, J = 6.6 Hz, 3H), 1.59 (m, 1H), 2.41 On, 1H), 3.00 (m, 1H), 3.30 (m, 1H), 3.82 (d, J = 15.8 Hz, 1H), 3.94 (d, J = 15.8 Hz, 1H), 5.10 (s, 2H) , 5.30 (m, 1H), 5.58 (dd, J = 3.6, 10.6 Hz, 1H), 6.13 (m, 1H), 6.2 (s, 1H), 6.74 (d, J = 16.2 Hz, 1H), 7.17 (m, 1H), 7.22 (dd, J = 10.9, 16.2 Hz, 1H), 7.68 (m, 1H).

Example 17 (Compound 17)

The isomer ratio was about 2: 1.

FAB-MS m / z: 474 [M + H] ⁺

Main _{component: Ή- NMR (CDC1 3) <} 5 (ppm): 1.54 (d, J = 6.9 Hz, 3H), 1.92 (m, 1H), 2.28 (m, 1H), 2.95 On, 1H), 3.18 ( m, 1H), 3.75 (m, 1H), 3.78 (s, 3H), 4.11 (m, 1H), 5.24 (m, 2H), 5.41 (m, 1H), 5.60 (m, 1H), 6.07 (m , 1H), 6.58 (s, 1H), 6.63 (d, J = 16.2 Hz, 1H), 6.93 (m, 1H), 7.03 (m, 1H), 7.11 On '1H) .Example 18 (Compound 18)

The isomer ratio was about 1.8: 1.

FAB-MS m / z: 461 [M + H] +

Main _{component: Ή-NMR (CDC1 3)} δ (ppm): 1.56 (d, J - 6.6 Hz, 3H), 1.95 (m, 1H), 2.31 (m, 1H), 2.95 On, 1H), 3.17 (m , 1H), 3.97 (m, 1H), 4.72 (m, 1H), 5.25 (m, 2H), 5.49 (m, 1H), 5.62 (m, 1H), 6.10 (m, 1H), 6.58 (s, 1H), 6.70 (d, J-16.5 Hz, 1H), 7.12 (m, 1H), 7.16 (d, J = 0.9 Hz, 1H), 7.70 (d, J = 0.9 Hz, 1H), 10.90 (br, 1H).

Example 19 (Compound 19)

The isomer ratio was about 1.5: 1.

FAB-MS m / z: 489 [M + H] ⁺

Main _{component: 'H - NMR (CDC1 3} ) (5 (ppm): 1.57 (d, J = 6.6 Hz, 3H), 1.96 (m, 1H), 2.32 On, 1H), 2.33 (s, 3H), 2.45 (s, 3H), 2.95 (m,-1H), 3.19 (br s, 1H), 3.96 (m, 1H), 4.70 (m, 1H), 4.93 (m, 1H), 5.50 (m, 1H), 5.66 (dd, J = 1.3, 9.6 Hz, 1H), 6.10 On, 1H), 6.58 (s, 1H), 6.58 (d, J = 16.2 Hz, 1H), 7.15 (dd, J = 10.6, 16.2 Hz, 1H), 11.00 (br, 1H).

Example 2 O (Compound 2 O)

The isomer ratio was about 3: 1. FAB-MS m / z: 505 [M + H] ⁺

Main _{component: Ή-NMR (CDC1 3)} (3 (ppm): 1.58 (d, J = 6.6 Hz, 3H), 1.98 (m, 1H), 2.35 (m, 1H), 2.42 (s, 3H), 2.95 (m, 1H), 3.20 On, 3H), 4.04 (m, 1H), 4.34 (m, 2H), 4.74 (br d, 1H), 5.51 (m, 1H), 6.68 (dd, J = 2.0, 9.9 Hz, 1H), 6.15 (m, 1H), 6.57 (s, 1H), 6.70 (d, J = 16.4 Hz, 1H), 7.19 (dd, J = 9.6, 16.4 Hz, 1H), 8.60 (s, 1H ), 11.00 (br, 1H).

Example 21 (Compound 21)

The isomer ratio was about 3: 1.

FAB-MS m / z: 554 [M + H] ⁺

Main component: Ή-NMR (CDCl ₃ ) δ (ppm): 1.57 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H),

2.33 (m, 1H), 2.79 (m, 1H), 3.20 (m, 1H), 4.04 On, 1H), 4.77 (m, 1H), 5.39 (s, 2H), 5.51 (m, 1H), 5.68 ( m, 1H), 6.17 (t, J = 11.9 Hz, 1H), 6.57 (s, 1H), 6.78 (d, J-16.2 Hz, 1H), 7.18 (m, 1H), 7.37 (s, 1H), 7.42 (m, 1H), 8.28 (dt, J = 1.8, 7.9 Hz, 1H), 8.65 (dd, J = 1.8, 5.0 Hz, 1H), 9.17 (dd,

J = 1.0, 1.3 Hz, 1H).

Example 22 (Compound 22)

The isomer ratio was about 1.7: 1.

FAB-MS m / z: 462 [M + H] ⁺

Main _{component: Ή-NMR (CDC1 3)} δ (ppm): 1.58 (d, J = 7.3 Hz, 3H), 1.98 (m, 1H), 2.34 (m, 1H), 2.96 (m, 1H), 3.19 On , 1H), 4.02 (m, 1H), 4.75 (m, 1H), 5.33 (d, J-13.9 Hz, 1H), 5.39 (d, J = 13.9 Hz, 1H), 5.51 (m, 1H), 5.63 (m, 1H), 6.15 (m, 1H), 6.59 (s, 1H), 6.73 (d, J = 15.8 Hz, 1H), 7.18 On, 1H), 8.76 (s, 1H), 11.04 (br s, 1H).

Example 23 (Compound 23)

Compound 23 was obtained from radicicol and compound x according to Example 11. The isomer ratio was about 1.6: 1.

FAB-MS m / z: 476 [M + H] ⁺

Main _{component: Ή-NMR (CDC1 3)} δ (ppm): 1.59 (d, J = 6.3 Hz, 3H), 1.96 (m, 1H),

2.34 (m, 1H), 2.96 On, 1H), 3.21 (m, 1H), 3.99 (m, 1H), 4.18 (s, 3H), 4.66 (m, 1H), 5.50 (m, 3H), 5.67 (m, 1H), 6.10 (m, 1H), 6.28 (m, 1H), 6.59 (s, 1H), 6.61 (d, J = 16.3 Hz, 1H), 7.09 (dd, J = 11.1, 16.3 Hz, 1H), 10.97 (br, 1H).

Examples 24 to 26

Hereinafter, Compound 24 to Compound 26 were obtained from radicicol and the hydrochloride of Compound y to Compound aa according to Example 1.

Example 24 (Compound 24)

The isomer ratio was about 2.5: 1.

FAB-MS m / z: 476 [M + H] ⁺

Main _{component: Ή - NMR (CDC1 3)} δ (ppm): 1.56 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 2.34 (m, 1H), 2.97 (m, 1H), 3.19 ( br s, 1H), 4.00 (br d, 1H), 4.38 (s, 3H),

4.69 (br d, 1H), 5.42 (m, 2H), 5.48 (m, 1H), 5.66 (dd, J = 2.6, 10.2 Hz, 1H), 6.12 (m, 1H), 6.56 (s, 1H), 6.70 (d, J = 15.8 Hz, 1H), 7.17 (dd, J = 10, 9, 15.8 Hz, 1H), 11.00 (br, 1H).

Example 25 (Compound 25)

The isomer ratio was about 1.7: 1.

FAB-MS m / z: 472 [MIH] ⁺

Main _{component: 'H - NMR (CDC1 3} ) δ (ppm): 1.57 (d, J - 6.6 Hz, 3H), 1.98 (ddd, J = 4.1, 8.7, 15.5 Hz, 1H), 2.34 (ddd, J = 3.2, 6.7, 15.5 Hz, 1H), 2.99 (br d, J = 8.6 Hz, 1H), 3.20 (br, 1H), 3.97 (br, 1H), 4.76 (br, 1H), 5.37 (s, 2H) ,

5.53 1 5.61 (m, 1H), 5.69 (br d, J-10.6 Hz, 1H), 6.17 (dd, J = 9.6, 11.6 Hz, 1H), 6.57 (s, 1H), 6.77 (d, J = 16.2 Hz, 1H), 7.02 (br, 1H), 7.22 (dd, J-11.2, 15.5 Hz, 1H), 8.53 (m, 1H), 8.59 On, 1H), 8.73 (s, 1H), 11.02 (br, 1H).

Example 26 (Compound 26)

The isomer ratio was about 2.5: 1.

FAB-MS m / z: 518 [M + H] ⁺

Main _{component: 'Η- NMR (CDC1 3)} δ (ppm): 1.53 (d, J = 6.6 Hz, 3H), 1.97 (ddd, J = 4.1, 8.7, 14.9 Hz, 1H), 2.31 (br d, J = 15.2 Hz, 1H), 2.95 (br d, J = 8.6 Hz, 1H), 3.18 (br, 1H), 3.93 (br, 1H), 4.00 (s, 3H), 4.63 (br, 1H), 5.07 (d, J = 11.6 Hz, 1H), 5.19 (d, J = 11.2 Hz, 1H), 5.46 (m, 1H), 5.61 (br d, J = 10.6 Hz, 1H), 6.10 (dd, J = 9.9, 10.6 Hz, 1H), 6.51 (s, 1H), 6.65 ( d, J = 16.2 Hz, 1H), 7.10 (dd, J = 11.5, 15.8 Hz, 1H), 11.00 (br, 1H), 8.12 (s, 1H).

Example 27 (Compound 27)

Compound 27 was obtained from radicicol and the compound according to Example 11. The isomer ratio was about 2: 1.

FAB-MS m / z: 493 [M + H] ⁺

Main _{component: Ή-NMR (CD 3 0D} ) δ (ppm): 1.52 (d, J = 6.0 Hz, 3H), 1.60 (m, 1H), 2.42 (dd, J = 3.3, 14.5 Hz, 1H), 3.00 (m, 1H), 3.31 (m, 1H), 3.60 (m, 2H), 3.72 (m, 2H), 3.83 (d, J = 16.2 Hz, 1H), 3.95 (d, J = 16.2 Hz, 1H) , 4.20-4.40 (m, 4H), 5.30 (m, 1H), 5.60 (dd, J = 3.3, 10.6 Hz, 1H), 6.15 On, 1H), 6.44 (s, 1H), 6.72 (d, J = 15.8 Hz, 1H), 7.25 (dd, J = 11.2, 15.8 Hz, 1H). Example 28 (Compound 28)

0.51 g of radicicol, 2.00 g of the compound trifluoroacetate cc and 4.30 ml of N, N-diethylaniline were dissolved in 10 ml of ethyl acetate and stirred at room temperature for 23 hours. The reaction solution was post-treated in the same manner as in Example 1 to obtain 0.34 g of Compound 28. The isomer ratio was about 1.4: 1.

FAB-MS m / z: 505 [M + H] ⁺

Main _{component: 'Η - NMR (CDC1 3} ) δ (ppm): 1.57 (d, J = 6.6 Hz, 3H), 1.78 (m, 1H), 1.97 (m, 1H), 2.33 (m, 1H), 2.42 (m, 2H), 2.98 (m, 1H), 3.21 (m, 1H), 3.0 (m, 2H), 3.70 (m, 2H), 4.06 (br, 1H), 4.35 (m, 2H), 4.71 (br d, J = 12.9 Hz, 1H), 5.50 (m, 1H), 5.65 (dd, J = 2.6, 12.5 Hz, '1H), 6.10 (dd, J = 11.9, 12.5 Hz, 1H), 6.60 (s, 1H), 6.63 (d, J = 16.5 Hz, 1H), 7.18 (dd, J = 11.9, 16.5 Hz, 1H).

Example 29 (Compound 29)

Compound 29 was obtained from radicicol and trifluoroacetate of compound dd according to Example 28. The isomer ratio was about 1.7: 1. FAB-MS m / z: 519 [M † H] ⁺

Main component: Ή-NMR (CDCI3) δ (ppm): 1.56 (d, J = 6.6 Hz, 3H), 1.70 (m, 6H), 1.96 (m, 1H), 2. 34 (m, 1H), 2.56 (m, 2H), 2.96 (m, 1H), 3.21 (br, 1H), 3.46 (br, 2H), 3.74 (m, 2H) ), 4.00 (br, 1H), 4.27 (m, 2H), 4.67 (br d, J = 14.9 Hz, 1H), 5.49 (m, 1H), 5.63 ( m, 1H), 6.10 (t, J = 11.5 Hz, 1H), 6.60 (s, 1H), 6.64 (d, J = 15.8 Hz, 1H), 7.18 ( dd, J = 11.5, 15.8 Hz, 1H).

Example 30 (Compound 30)

Dissolve 2.94 g of compound K obtained in Reference Example 30 and 3.55 g of triphenylphosphine in 60 ml of THF, add 6.12 ml of DEAD and 1.34 g of succinimide under ice-cooling, and add room temperature. For 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / n-hexane = 4/1) to obtain 4.90 g of compound 30.

FAB-MS m / z: 733 [M + H] ⁺ .

Example 31 (Compound 31 and Compound 32)

4.90 g of compound 30 was dissolved in 60 ml of THF, and thereto was added a solution of TBAF 20.0 mKl M in THF adjusted to pH 6 with acetic acid under ice-cooling, followed by stirring at the same temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.The organic layer was washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried over anhydrous sodium sulfate. The solvent was removed. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/1) to obtain 1.46 g of a mixture of compound 31 and compound 32.

High-performance liquid chromatography of 1.48 g of a mixture of compound 31 and compound 32 (column: YMC-Pack ODS AM, SH-365-10A, 500 × 30 mml. D., eluent: 50 mM phosphate buffer) Solution (pH 7.3) / acetonitrile = 73/27, flow rate: 40 ml / min, detection: UV 276 nm), extract each eluate with ethyl acetate, and wash the organic layer with saturated sodium bicarbonate. After washing with an aqueous solution and then with a saturated saline solution, the resultant was dried with anhydrous sodium sulfate, and the solvent was removed. The residue was triturated from a mixed solvent of ethanol and water to obtain 167 mg of compound 31 (high polarity) and 347 mg of compound 32 (low polarity).

Compound 3 1

FAB-MS m / z: 505 [M + H] ⁺ Ή-NMR (CDCI3) δ (ppm): 1.59 (d, J = 6.6 Hz, 3H), 1.99 (m, 1H), 2.34 (m, 1H), 2.65 (s, 4H), 3.00 (m, 1H) , 3.19 (s, 1H), 3.86 (m, 2H), 3.96 (m, 1H), .30 (m, 2H), 4.70 (m, 1H), 5.52 (m, 1H), 5.65 (dd, J- 3.3, 9.9 Hz, 1H), 6.13 (t, J = 11.2 Hz, 1H), 6.57 (d, J = 16.4 Hz, 1H), 6.59 (s, 1H), 7.15 (dd, J = 11.1, 16.4 Hz, 1H), 10.84 (m, 1H).

Compound 32

FAB-MS m / z: 505 闺 +

_{Ή-NMR (CDC1 3) 6} (ppm): 1.59 (d, J = 6.9 Hz, 3H), 1.83 (m, 1H), 2.33 (d, J = 15.2 Hz, 1H), 2.70 (s, 4H), 2.92 (d, J = 9.9 Hz, 1H), 3.08 (s, 1H), 3.90 (m, 2H), 4.31 n, 2H), 4.23 (d, J = 16.5 Hz, 1H), 4.37 (d, J = 16.5 Hz, 1H), 5.53 (m, 1H), 5.59 (d, J = 10.9 Hz, 1H), 6.10 (t, J = 10.4 Hz, 1H), 6.11 (d, J = 16.2 Hz, 1H), 6.51 (s, 1H), 7.06 (dd, J-11.2, 16.2 Hz, 1H), 11.02 (s, 1H).

Example 32 (Compound 33)

According to Example 30, compound 33 was obtained from the compound, triphenylphosphine, DEAD and 2,4-thiazolidinedione.

FAB-MS m / z: 751 [M + H] ⁺ .

Example 33 (Compound 34 and Compound 35)

According to Example 31, compound 33 was treated with TBAF and then separated by high performance liquid chromatography to obtain compound 34 (high polarity) and compound 35 (low polarity).

Compound 34

FAB-MS m / z: 523 [M + H] ⁺

_{Ή-NMR (CDC1 3) δ} (ppm): 1.59 (d, J = 7.3 Hz, 3H), 1.97 (m, 1H), 2.34 (m, 1H), 2.98 (m, 1H), 3.19 (br s, 1H), 3.95 (s, 2H), 3.96 (m, 1H), 3.98 (m, 2H), 4.33 (m, 2H), 4.75 (m, 1H), 5.52 (m, 1H), 5.65 (m, 1H ), 6.14 (m, 2H), 6.59 (s, 1H), 7.14 (m, 1H), 11.04 (m, 1H).

Compound 35

FAB-MS m / z: 523 [M + H] ⁺

Ή-NMR (CDCI3) δ (ppm): 1.59 (d, J = 6.9 Hz, 3H), 1.94 On, 1H), 2.32 (m, 1H), 2.94 (m, 1H), 3.08 (s, 1H), 3.93 (s, 2H), 3.99 (m, 2H), 4.30 (d, J = 16.7 Hz, 1H), 4.38 (m, 2H), 4.44 (d, J = 16.7 Hz, 1H), 5.53 (m, 1H), 5.59 (d, J = 10.2 Hz, 1H), 6.11 (t, J = 10.2 Hz, 1H), 6.12 (d, J = 16.0 Hz, 1H), 6.59 (s, 1H), 7.06 (dd, J = 11.2, 16.0 Hz, 1H), 11.04 (s, 1H).

Example 34 (Compound 36)

According to Example 30, compound 36 was obtained from the compound, triphenylphosphine, DEAD and trimethylhydantoin.

FAB-MS m / z: 748 [M + H] ⁺ .

Example 35 (Compound 37)

Compound 36 was treated with TBAF according to Example 31 to give compound 37.

FAB-MS m / z: 520 麵] +. In Table 7 (1) and Table 7 (2), the compounds H ₂ N 例 —Y ^B —R ^3B (Y ^B and R ^3B have the same meanings as Y and R ³ , respectively).

Table 7 (1) Reference example

H ₂ NO-Y ^B -R ^B

Compound Y ^B -R ^3B Compound Y ^B -R ^3B

Table 7 (2) Reference example

H ₂ NO-Y ^B -R ^B

Compound Y ^B -R 3B Compound Y ^B -R ^3B

Reference Example 1 {3-[(Trimethyl-2-pyrrolyl) methylamino] propoxy} amine (Compound a)

Process 1— 1

1.50 g of tert-butyl N-hydroxycarbamate was dissolved in 15 ml of DMF, 2.08 g of potassium carbonate and 3.03 g of N- (3-bromopropyl) furimide were added, and the mixture was stirred at 80 ° C. for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 1.00 g of tert-butyl N- [3- (phthalimido) propoxy] rubbamate.

FAB-MS m / z: 321 [M + H] +.

Process 1 1 2

2.00 g of tert-butyl N- [3- (phthalimido) propoxy] rubbamate was dissolved in 15 ml of ethanol, 0.20 ml of hydrazine monohydrate was added, and the mixture was stirred at 80 for 3 hours. After cooling the reaction solution, the resulting precipitate was filtered off and the solvent was removed under reduced pressure. To the residue was added a 1N aqueous solution of sodium hydroxide, and the mixture was extracted with a mixed solvent of chloroform and methanol (9/1). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 0.49 g of tert-butyl N- (3-aminopropoxy) rubinate.

FAB-MS m / z: 191 [M + H] ⁺ .

Process 1-3

Dissolve 120 mg of tert-butyl N- (3-aminopropoxy) rubrate in 2 ml of 1,2-dichloroethane, 0.075 ml of trimethyl-2-pyrrolylcarpoxyaldehyde, sodium triacetoxyborohydride 155 mg and acetic acid 0.04 ml were added, and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with chloroform. The foam layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (form: form / solvent = 7/1), and tert-butyl N- {3-[(trimethyl-2-pyrrolyl) methylamino] propoxy} mg was obtained. FAB-MS m / z: 284 meetings] +.

Process 1 _ 4

N- {3-[(Trimethyl-2-pyrrolyl) methylamino] propoxy} force 117 mg of tert-butyl rubamate was dissolved in 0.5 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain a trifluoroacetic acid salt of compound a.

Reference Example 2 [3- (cyclohexylamino) propoxy] amine (Compound b)

According to steps 1-3 of Reference Example 1, the N- [3- (3-aminopropoxy) tert-butyl rubamate and cyclohexanone obtained in Steps 1-2 of Reference Example 1 were converted to N- [3- ( After obtaining tert-butyl cyclohexylamino) propoxy] rubbamate, a trifluoroacetate of the compound b was obtained according to step 114 of Reference Example 1.

Reference Example 3-[(4-pyridylmethyl) amino] butyroxy} amine (Compound c) In accordance with Step 11 of Reference Example 1, tert-butyl N-hydroxycarbamate and N- (4-bromobutyl) phthalimide were used. After obtaining tert-butyl N- [4- (phthalimido) butyroxy] potassium rubinate, tert-butyl N- (4-aminobutyroxy) potassium rubamate was obtained according to Steps 1-2 of Reference Example 1. .

Then, N- {4-[(4-pyridylmethyl) amino] was obtained from tert-butyl N- (4-aminobutyroxy) amine and 4-pyridinecarboxaldehyde according to steps 113 of Reference Example 1. After obtaining tert-butyl ptyroxyl, a trifluoroacetate of compound c was obtained according to Steps 1-4 of Reference Example 1.

Reference Example 4 {4- [N-methyl-N- (4-pyridylmethyl) amino] butyroxy} amine (Compound d)

According to steps 13 of Reference Example 1, the N-{-[N- [N] -N- {4-[(4-pyridyl) methylamino] butyroxy} amine obtained in Reference Example 3 was obtained from tert-butyl rubamate and an aqueous solution of formalin. -Methyl-N- (4-pyridylmethyl) amino] butyroxy} tert-butyl rubamate was obtained, and then trifluoroacetate of the compound d was obtained according to Steps 1-4 of Reference Example 1. Reference Example 5 {4-[(2-Imidazolylmethyl) amino] butyroxy} amine (Compound e) The N- (4-aminobutyroxy) power obtained in Reference Example 3 according to Steps 13 of Reference Example 1 Lubamine Tert-butyl acid and 2-imidazole carboxyaldehyde give N- [4- After obtaining tert-butyl (2-imidazolylmethylamino) butyl oxalate] rubbamate, a trifluoroacetate salt of the compound e was obtained according to Steps 1-4 of Reference Example 1.

Reference Example 6 {2-hydroxy-3-[(4-pyridylmethyl) amino] propoxy} amine

Process 6-1

According to step 1-1 of Reference Example 1, 659 mg of tert-butyl N- (aryloxy) carboxylate obtained from tert-butyl N-hydroxycarbamate, sodium hydride and aryl bromide in 10 ml of dichloromethane. After dissolution, 886 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 24 hours. After filtering the reaction solution, a 1 N aqueous solution of sodium hydroxide was added to the filtrate, and the mixture was extracted with chloroform. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain 447 mg of tert-butyl N- (2,3-epoxypropoxy) rubinate.

FAB-MS m / z: 190 random] +.

Process 6-2

245 mg of tert-butyl N- (2,3-epoxypropoxy) rubbamate was dissolved in 1 ml of methanol, 0.13 ml of 4- (aminomethyl) pyridine was added, and the mixture was stirred at room temperature for 14 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with chloroform. The foam layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain about 8 mg of tert-butyl N- {2-hydroxy-3-[(4-pyridylmethyl) amino] propoxy} rubbamate.

FAB-MS m / z: 298 [M + H] ⁺ .

Process 6-3

According to steps 114 of Reference Example 1, trifluoroacetate of compound f was obtained from tert-butyl N- {2-hydroxy-3-[(4-pyridyl) methylamino] propoxy} potassium rubinate.

Reference Example 7 [4- (Isonicotinoylamino) petit-mouth] [Compound g] Step 7-1

N- (4-aminobutyroxy) tert-butyl rubamate 200 mg obtained in Reference Example 3 Was dissolved in 2 ml of dichloromethane, 174 mg of isonicotinoyl chloride hydrochloride and 0.27 ml of triethylamine were added under ice-cooling, and the mixture was stirred at room temperature for 2 hours and further heated under reflux for 1 hour. After cooling the reaction solution, a saturated aqueous solution of ammonium chloride was added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (form / formanol = 20/1) to obtain 182 mg of tert-butyl N- [4- (isonicotinylamino) butyroxy] potassium.

FAB-MS m / z: 310 [MIH] ⁺ .

Process 7-2

According to Steps 1-4 of Reference Example 1, N- [4- (isonicotinylamino) pentoxy] force From tert-butyl rubamate, a trifluoroacetate of Compound g was obtained.

Reference Example 8 [4- (Methylureido) butyl] xamine (Compound h)

Process 8-1

130 mg of tert-butyl N- (4-aminobutyroxy) carbamate obtained in Reference Example 3 was dissolved in 1 ml of dichloromethane, and 0.037 ml of methyl isocyanate was added under ice-cooling. Stir for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The foam layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to obtain 120 mg of tert-butyl N- [4- (methylperido) butyl] xylcarbamate.

FAB-MS m / z: 262 [M + H] +

Process 8-2

According to Steps 1-4 in Reference Example 1, a trifluoroacetate salt of Compound h was obtained from tert-butyl N- [4- (methylperido) butyl] x-hydroxylbamate.

Reference Example 9 [2- (N-tert-butoxycarboxyl N-ethylamino) ethoxy] amine

(Compound i)

Process 9-1

2 ml of 2- (ethylamino) ethanol was dissolved in 50 ml of THF, and 5.00 g of N- (tert-butoxycalponyloxy) furimide was added, followed by stirring at room temperature for 4 hours. Reaction solution After filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to obtain 3.50 g of tert-butyl N-ethyl-N- (2-hydroxyethyl) carbamate. .

FAB-MS m / z: 190 varieties] +.

Process 9 1 2

3.50 g of N-ethyl-N- (2-hydroxyethyl) tert-butyl rubamate, 2.90 g of N-hydroxyphthalimide and 4.70 g of triphenylphosphine were dissolved in 50 ml of THF. Under ice cooling, 2.80 ml of DEAD dissolved in 10 ml of THF was gradually added. After stirring at the same temperature for 1 hour, the mixture was further stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and n-hexane was added. The resulting precipitate was filtered off and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methyl alcohol = 97/3) to obtain 3.50 g of tert-butyl N-ethyl-N- [2- (phthalimidoxy) ethyl] potassium. Was.

FAB-MS m / z: 335 [M + H] ⁺ .

Process 9 1 3

N-Ethyl-N- [2- (phthalimidoxy) ethyl] tert-butyl rubamate (3.50 g) was dissolved in 30 ml of chloroform and added with 0.60 ml of hydrazine monohydrate. Stir for 15 minutes. The resulting precipitate was separated by filtration, and 3.00 ml of a 4N hydrogen chloride / ethyl acetate solution was added to the filtrate. The solvent was removed under reduced pressure to obtain 2.60 g of the compound i hydrochloride.

FAB-MS m / z: 205 [M + H] ⁺ .

Reference Example 10 0 [2- (N-benzyloxycarbonyl_N-ethylamino) ethoxy] amine (Compound j)

Process 1 0-1

1.25 ml of 2- (ethylamino) ethanol was dissolved in 20 ml of THF, 3.00 g of N- (benzyloxycarbonyloxy) succinimide was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 100 ml of ethyl acetate, washed with water, 0.5 N hydrochloric acid, and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 2.70 g of benzyl N-ethyl-N- (2-hydroxykisethyl) rubbamate.

FAB-MS m / z: 224 [M + H] ⁺ .

Process 1 0-2 According to Step 9-2 of Reference Example 9, N-ethyl-N-ethyl-N- (2-hydroxyethyl) carbamate is obtained from N-ethyl-N- (2-hydroxyethyl) carbamate, N-hydroxyfurimide, triphenylphosphine and DEAD. After obtaining [2- (phthalimidoxy) ethyl] benzyl rubbamate, the hydrochloride of compound j was obtained according to Steps 9-13 of Reference Example 9.

FAB-MS m / z: 239 [M † H] ⁺ .

Reference Example 1 1 {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} amine (Compound k)

According to Step 9_2 of Reference Example 9, triethylenedalicol monomethyl ether, N-hydroxyphthalimide, triphenylphosphine and DEAD gave N- {2- [2- (2- obtained N- {2- 1.80 g of [2- (2-methoxyethoxy) ethoxy] ethoxy} phthalimide was dissolved in 5 ml of ethanol, 0.30 ml of hydrazine monohydrate was added, and the mixture was stirred at 80 ° C. for 1 hour. The precipitate was filtered off, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (form / chloroform = 20/1) to obtain 1.05 g of compound k.

EI-MS m / z: 179 [M + H] ⁺ .

Reference Example 1 2 {2- [3- (6-Methyl-2-pyridyl) propoxy] ethoxy} amine (Compound m)

According to Step 9_2 of Reference Example 9, 2- [3- (6-methyl-2-pyridyl) propoxy] ethanol, N-hydroxyfurimide, triphenylphosphine and N- {2- [ After obtaining 3-(6-methyl-2-pyridyl) propoxy] ethoxy} phthalimide, a hydrochloride of the compound m was obtained according to Step 9-13 of Reference Example 9.

Reference Example 13 3 (Cinnamyloxy) amine (Compound n)

According to Step 9-12 of Reference Example 9, N- (cinnamyloxy) furimide was obtained from cas alcohol, N-hydroxyphenylimide, triphenylphosphine and DEAD, and then the compound was prepared according to Reference Example 11. got n.

Reference Example 14 [(trimethyl-2-pyrrolyl) methoxy] amine (Compound o)

Process 1 4 1 1

Dissolve 0.50 ml of trimethyl-2-pyrrolecarboxaldehyde in 10 ml of methanol Then, 176 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with chloroform. The foam layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to obtain 503 mg of 2-hydroxymethyl-trimethylpyrrole.

Process 1 4 1 2

According to Step 9-12 of Reference Example 9, 2-hydroxymethyl-trimethylpyrrolyl, N-hydroxyphthalimide, triphenylphosphine and DEAD were used to obtain N-[(trimethyl-2-pivalyl) methoxy]. After obtaining phthalimide, compound o was obtained according to Reference Example 11.

EI-MS m / z: 126 [M + H] ⁺ .

Reference Example 15 [(Trimethyl-4-pyrazolyl) methoxy] amine (Compound p)

Process 1 5-1

518 mg of 4-pyrazolcarboxylic acid was dissolved in 10 ml of DMF, 1.28 g of potassium carbonate and 0.64 ml of methyl iodide were added, and the mixture was stirred at 60 ° C for 7 hours. After cooling the reaction solution, water was added, and the mixture was extracted with chloroform. The foam layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 599 mg of methyl 1-methyl-4-pyrazolecarboxylate.

FAB-MS m / z: 140 [M + H] ⁺ .

Process 1 5-2

598 mg of methyl trimethyl-4-pyrazolecarboxylate was dissolved in 15 ml of THF, 326 mg of lithium aluminum hydride was gradually added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. After cooling the reaction mixture with ice, 0.93 ml of a saturated aqueous sodium sulfate solution was added, and the mixture was stirred at the same temperature for 1 hour. After the reaction solution was filtered with a radio light, the solvent was removed under reduced pressure. The residue was repeatedly subjected to toluene azeotrope twice to obtain 401 mg of 4-hydroxymethyl-1-methylpyrazole.

FAB-MS m / z: 113 varieties] +.

Process 1 5— 3

According to Step 9-12 of Reference Example 9, 4-hydroxymethyl-trimethylvirazole, N- 4-[(phthalimidoxy) methyl] -trimethylvirazole was obtained from hydroxyfurimide, triphenylphosphine and DEAD.

Process 1 5 _ 4

250 mg of 4-[(phthalimidoxy) methyl] -trimethylvirazole was dissolved in 10 ml of dichloromethane, and 0.052 ml of hydrazine monohydrate was added, followed by stirring at room temperature for 1 hour. The resulting precipitate was filtered off and the solvent was removed under reduced pressure. 10 ml of ethyl acetate was added to the residue, and the insoluble material was filtered off. To the filtrate, 0.53 ml of a 4N hydrogen chloride / ethyl acetate solution was added, followed by stirring at room temperature for 30 minutes. The resulting precipitate was collected by filtration to give the hydrochloride of compound p (111 mg).

FAB-MS m / z: 128 [M + H] ⁺ .

Reference Example 16 [(4-imidazolyl) methoxy] amine (Compound Q)

Process 1 6— 1

964 mg of 4-imidazolemethanol hydrochloride was gradually added to 2.50 ml of thionyl chloride, and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added chloroform, stirred for 50 minutes, and the resulting precipitate was collected by filtration to obtain 1.06 g of 4- (chloromethyl) imidazole hydrochloride.

FAB-MS m / z: 117 [M + H] ⁺ .

Process 1 6-2

According to Step 11 of Reference Example 1, 4- [chloromethyl) imidazole hydrochloride, N-hydroxy phthalimide and 1,8-diazabicyclo [5,4,0] -7-indene (Phthalimidoxy) methyl] imidazole was obtained.

FAB-MS m / z: 244 [M + H] ⁺ .

Process 1 6— 3

According to Step 15-4 of Reference Example 15, a hydrochloride of Compound Q was obtained from 4-[(phthalimidoxy) methyl] imidazole.

FAB-MS m / z: 144 [M + H] ⁺ .

Reference Example 17 [(Tomethyl-2-imidazolyl) methoxy] amine (Compound r) Step 17-1

According to the step 15_1 of Reference Example 15, trimethyl-2-imidazole carboxyaldehyde was obtained from 2-imidazolecarboxaldehyde, carboxylamide and methyl iodide. FAB-MS m / z: 111 [M + H] ⁺ .

Process 1 7— 2

According to Step 14-1 of Reference Example 14, 2-hydroxymethyl-1-methylimidazole was obtained from trimethyl-2-imidazolecarboxyaldehyde.

According to Step 9-2 of Reference Example 9, 2-hydroxymethyl-1-methylimidazole, N-hydroxyphthalimide, triphenylphosphine, and N-[(trimethyl-2-imidazolyl) methoxy] phenol were obtained from DEAD. After obtaining the imide, a hydrochloride of the compound r was obtained according to Step 15-4 of Reference Example 15.

FAB-MS m / z: 127 [M + H] ⁺ .

Reference Example 18 [(2-oxazolyl) methoxy] amine (compound s)

Process 1 8— 1

3.70 g of triazole was dissolved in 10 ml of toluene, 2.13 ml of chloroacetyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 13 hours. The resulting precipitate was filtered off and the solvent was removed under reduced pressure. 20 ml of sulfolane was added to the residue, and the mixture was stirred at 150 for 2.5 hours. After cooling the reaction solution, the sublimation product was eluted from the condenser with acetone, and the solvent was removed under reduced pressure to obtain 0.59 g of 2- (chloromethyl) oxazole.

Process 1 8— 2

After obtaining 2- (phthalimidoxy) methyloxazole from 2- (chloromethyl) oxazole according to Step 1-1 of Reference Example 1, the compound was prepared according to Step 15-5-4 of Reference Example 15. s hydrochloride was obtained.

FAB-MS m / z: 115 [M + H] ⁺ .

Reference Example 1 9 [(3,5-Dimethyl-4-isoxazolyl) methoxy] amine (compound) According to Step 1-1 of Reference Example 1, 4-chloromethyl-3,5-dimethylisoxazole was used. After obtaining 4-[(phthalimidoxy) methyl] -3,5-dimethylisoxazole, a hydrochloride of compound t was obtained according to Step 15-4 of Reference Example 15.

FAB-MS m / z: 143 [M + H] ⁺ .

Reference Example 20 [2- (4-methyl-5-thiazolyl) ethoxy] amine (Compound u)

According to Step 9-2 of Reference Example 9, 5- (2-hydroxyethyl) -4-methylthiazole, N-hydroxyphthalimide, triphenylphosphine and DEAD were used to give [2- (phthalyl) After obtaining [midoxy) ethyl] -4-methylthiazole, a hydrochloride of compound u was obtained according to Step 15-4 of Reference Example 15.

FAB-MS m / z: 158 [M + H] ⁺ .

Reference Example 21 {[2- (3-pyridyl) -5-thiazolyl] methoxy} amine (Compound V) Step 21-1

4.51 g of 2- (3-pyridyl) thiazol-5-carboxylic acid was suspended in a mixed solvent of 180 ml of dichloromethane and 90 ml of methanol, and 13.5 ml of a 2.0 M (trimethylsilyl) diazomethane / hexane solution was added. The mixture was stirred at room temperature for 40 minutes. Further, 3.3 ml of a 2.0 M (trimethylsilyl) diazomethane / hexane solution was added, and the mixture was stirred at room temperature for 20 minutes. After removing the solvent under reduced pressure, 200 ml of ethyl acetate was added, and the resulting precipitate was filtered off. The solvent was removed under reduced pressure to obtain 3.34 g of methyl 2- (3-pyridyl) thiazol-5-carboxylate.

Process 2 1-2

Reference Example 15 After obtaining 5-hydroxymethyl-2- (3-pyridyl) thiazol from methyl 2- (3-pyridyl) thiazole-5-carboxylate according to Step 15_2 of Reference Example 5, According to Step 9-12 of 9, 5- (phthalimidoxy) methyl-2- (3-pyridyl) thiazole was obtained.

Next, the hydrochloride of Compound V was obtained from 5- (phthalimidoxy) methyl-2- (3-pyridyl) thiazole according to Step 15-4 of Reference Example 15.

FAB-MS m / z: 208 [M + H] ⁺ .

Reference Example 22 [(1,2,4-oxaziazol-3-yl) methoxy] amine (Compound w) According to Step 11 of Reference Example 1, 3- (chloromethyl) -1,2,4- After obtaining oxaziazole or 3-[(phthalimidoxy) methyl] -1,2,4-oxaziazole, the hydrochloride of compound w was obtained according to Step 15-4 of Reference Example 15.

FAB-MS m / z: 116 [M + H] ⁺ .

Reference Example 23 [(Trimethyltetrazol-5-yl) methoxy] amine (Compound X) Step 23-1

According to Step 1-1 in Reference Example 1, 5-[(phthalimidoxy) methyl] -2- (triphenylmethyl) tetramer was obtained from 5- (chloromethyl) -2- (triphenylmethyl) tetrazole. A sol was obtained.

FAB-MS m / z: 244 [M + H] ⁺ .

Process 23-2

Dissolve 2.42 g of 5-[(phthalimidoxy) methyl] -2- (triphenylmethyl) tetrazole in a mixed solvent of 50 ml of 1,2-dichloroethane and 25 ml of methanol, and add 5 ml of acetic acid. For 2.5 hours. After cooling the reaction solution, the solvent was removed under reduced pressure, and the residue was triturated with ethyl acetate to obtain 0.90 g of 5-[(phthalimidoxy) methyl] tetrazole.

FAB-MS m / z: 246 [MiH] ⁺ .

Process 23-3

According to Step 15-1 of Reference Example 15, 5-[(phthalimidoxy) methyl] tetrazole was used to give 5-[(phthalimidoxy) methyl] -trimethyltetrazole and 5-[(phthalimidoxy) methyl]- 2-Methyltetrazole was obtained.

Process 23—4

According to Reference Example 11, compound X was obtained from 5-[(phthalimidoxy) methyl] -trimethyltetrazole.

FAB-MS m / z: 130 strokes ⁺ .

Reference Example 24 [(2-Methyltetrazol-5-ylyl) methoxy] amine (Compound y) According to Step 15-4 of Reference Example 15, 5-[obtained in Step 23-3 of Reference Example 23 From ((phthalimidoxy) methyl] -2-methyltetrazole, a hydrochloride of compound y was obtained.

FAB-MS m / z: 130 [M † H] ⁺ .

Reference Example 25 [(2-pyrazinyl) methoxy] amine (Compound z)

According to Step 15-2 of Reference Example 15, 2- (hydroxymethyl) pyrazine was obtained from methyl 2-pyrazinecarboxylate. According to Step 9-2 of Reference Example 9, 2-[(phthalimidoxy) ) After obtaining methyl] pyrazine, a hydrochloride of compound z was obtained according to Step 9-3 of Reference Example 9.

Reference Example 26 [(6-hydroxy-4-methoxypyrimidin-5-yl) methoxy] amine (compound aa) According to the step 15-2 of Reference Example 15, 5-hydroxymethyl-4-methoxy-6- [2- -4-methoxy-6- [2- (trimethylsilyl) ethoxy] -5-pyrimidinecarboxaldehyde (Trimethylsilyl) ethoxy] pyrimidine was obtained.

Next, according to Step 9-2 of Reference Example 9, 5- (furimidoxy) methyl-4-methoxy-6- from 5-hydroxymethyl-4-methoxy-6- [2- (trimethylsilyl) ethoxy] pyrimidine. After obtaining [2- (trimethylsilyl) ethoxy] pyrimidine, a hydrochloride of the compound aa was obtained according to Step 9-3 of Reference Example 9.

Reference Example 2 7 [2- (2-oxazolidone-3-yl) ethoxy] amine (compound bb) According to Step 9-2 described in Reference Example 9, 3- (2-hydroxyethyl) -2-oxazolide After obtaining 3- [2- (phthalimidoxy) ethyl] -2-oxazolidone from

Compound bb was obtained according to 11.

FAB-MS m / z: 146 [M + H] ⁺ .

Reference Example 2 8 [2- (2-pyridone-tolyl) ethoxy] amine (compound c c)

Process 2 8 _ 1

Dissolve 2.48 g of 2-azido-enol and 2.50 ml of cyclopeninone in 100 ml of dichloromethane, and slowly add 7.00 l of boron trifluoride ether complex under ice-cooling, and add the same temperature for 20 minutes. Stirred. After further stirring at room temperature for 18 hours, the solvent was removed under reduced pressure, THF cooled to -78 ° C was added to the residue, and the resulting precipitate was collected by filtration, dissolved in 50 ml of dichloromethane, and dissolved in N-hydroxyfurimide 2 30 g and 1,8-diazabicyclo

[5, 4, 0] -7-Pendecene (4.20 ml) was added, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 1.50 g of tri [2- (phthalimidoxy) ethyl] -2-piperidone.

FAB-MS m / z: 289 [M + H] ⁺ .

Process 2 8— 2

1.80 g of 1- [2- (phthalimidoxy) ethyl] -2-piperidone was dissolved in 50 ml of chloroform, 0.42 ml of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered off, and 1.50 ml of trifluoroacetic acid was added to the filtrate. The solvent was removed under reduced pressure to obtain 2.50 g of compound cc in trifluoroacetate. FAB-MS m / z: 1 59 [M + H] ⁺ .

Reference Example 2 9 [2- (2-Ph-hydroazepinone-tolyl) ethoxy] amine (compound d d)

According to step 28-1 and step 28-2 of Example 28, trifluoroacetate of compound dd was obtained using cyclohexanone instead of cyclopentanone.

FAB-MS m / z: 173 [M + H] ⁺ .

Reference Example 30 (Compound)

Process 3 0— 1

According to step 1-1 described in Reference Example 1, N- (2-hydroxyethoxy) furimide was obtained from 2-bromoethanol, N-hydroxyphthalimide and potassium carbonate. Process 3 0-2

6.27 g of N- (2-hydroxyethoxy) phthalimide was dissolved in 48 ml of methanol, 1.61 ml of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered off, the solvent was removed, and 50 ml of ethyl acetate was added to the residue. After filtering off the insoluble matter, add 2.80 ml of trifluoroacetic acid to the filtrate, extract with water, wash the aqueous layer with ethyl acetate, remove the solvent, and remove 2- (aminooxy) ethanol trifluoroacetic acid salt. 5. 03 g was obtained.

Ή-NMR (DMS0-d ₆ ) δ (pm): 3.62 (t, J-4.7 Hz, 2H), 3.92 (t, J = 4.7 Hz, 2H).

Process 3 0— 3

Dissolved 7.75 g of bis (tert-butyldimethylsilyl) form of radicicol, 6.24 g of 2- (aminooxy) ethanol trifluoroacetate and 10.4 ml of N, N-ethylethylaniline in 124 ml of ethyl acetate Then, the mixture was stirred at room temperature for 25 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 6.10 g of compound K. The isomer ratio was about 1.9: 1.

FAB-MS m / z: 652 [M + H] ⁺ .

The structure of compound K is as follows: / ⁰ Ί

Me '0 (K)

Industrial applicability

The present invention provides a novel radicicol derivative or a pharmacologically acceptable salt thereof, which has a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive activity.

Claims

The scope of the claims

(1) General formula (I)

[Wherein, R ¹ and R ² are the same or different and represent hydrogen, alkanoyl, alkenoyl, alkadienol, alkatrienoyl, trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl, Y represents a substituted or unsubstituted alkylene; R ³ is NR ⁵ R ⁶ (where R ⁵ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted Represents a lower cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, wherein R ⁶ is a substituted lower alkyl, a substituted or unsubstituted higher alkyl, a substituted or unsubstituted lower cycloalkyl, Represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), NR ⁷ C〇R ⁸ R ⁷ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group; ⁸ is a substituted lower alkyl, a substituted lower alkoxy, a substituted alkenyloxy, a substituted alkadienyloxy, a substituted alkyl trienyloxy, a substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group Wherein R ⁹ and R ^1Q are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyloxy or NR ⁹ R ^1D Represents a substituted aromatic heterocyclic group, or a substituted or unsubstituted nitrogen-containing group in which R ⁹ and R ^{1 Q} are combined with an adjacent N A NRUCOR ¹² (wherein R ¹¹ is a substituted or unsubstituted lower radical) Alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, and R ¹² represents lower alkyl, lower alkoxy, lower alkenyl. Represents substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkenylenyl, substituted or unsubstituted alkenylenyl, Xy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkadienyl, substituted or unsubstituted alkatrienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl Unsubstituted pyrazolyl, Substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted pyrimidinyl Substituted or unsubstituted pyrazinyl, substituted or unsubstituted oxazolidonyl, substituted or unsubstituted piperidonyl, substituted or unsubstituted perhydroazepinonyl, substituted or unsubstituted succinimide, substituted or unsubstituted phthalimide, substituted or unsubstituted Substituted darylimide, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinedionyl, substituted or unsubstituted oxopyrrolidonyl, substituted or unsubstituted maleimide, substituted Or unsubstituted thiazolidonyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted 2-oxo-3-pyrrolinyl, substituted or unsubstituted oxazolonyl, Substituted or unsubstituted pyrazolonyl, substituted or unsubstituted isoxazolonyl, substituted or unsubstituted thiazolonyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted pyrrolinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted imidazolinyl, a substituted or unsubstituted Okisajiazoriru or substituted or unsubstituted Birazorijiniru, X represents a single bond is either a halogen atom, or R ⁴ and integrated, display the R ⁴ is a single bond is X and integral Water, hydrogen, alkanoyl, alkenoy , Arukajienoiru, alk triethyl Noi le or SO - Z {wherein, Z is Formula (A)

[Wherein, R ^{1 A} and R ^{2 A} have the same meanings as R ¹ and R ² , respectively, X ^A represents a halogen atom, and W represents 〇 or N—〇—Y ^A —R ^{3 A} (wherein , Y ^A and R ^{3 A} have the same meanings as Y and R ³ ), respectively.] Represents a)] represents a radicicol derivative or a pharmaceutically acceptable salt thereof.

(2) The radicicol derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein X is a halogen atom.

(3) The radicicol derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein X is a single bond together with R ⁴ .

(4) The radicicol derivative or the pharmaceutically acceptable salt thereof according to claim 3, wherein R ¹ and R ² are hydrogen.

(5) R ³ force substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted Or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted oxazolidonyl, Substituted or unsubstituted piperidonyl, substituted or unsubstituted perhydroazepinonyl, substituted or unsubstituted succinimide, substituted or unsubstituted phthalimide, substituted or unsubstituted dalyl imide, substituted or unsubstituted hydan Toynyl, substituted or unsubstituted thiazolidinedionyl, substituted or unsubstituted oxopyrrolidonyl, substituted or unsubstituted maleimide, substituted or unsubstituted thiazolidonyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazolyl Gindionyl, substituted or unsubstituted 2-oxo-3-pyrolinyl, substituted or unsubstituted oxazolonyl, substituted or unsubstituted pyrazolonyl, substituted or unsubstituted isoxax Zolonyl, substituted or unsubstituted thiazolonyl, substituted or unsubstituted oxazolidinyl, substituted or unsubstituted pyrrolinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted imidazolinyl, substituted or unsubstituted oxaziazolyl or substituted or unsubstituted 5. The radicicol derivative or the pharmaceutically acceptable salt thereof according to claim 4, which is a substituted pyrazolidinyl.

(6) R ³ is a substituted or unsubstituted oxazolidonyl, a substituted or unsubstituted piperidonyl, a substituted or unsubstituted monohydroazepinonyl, a substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted phthalimide, Unsubstituted gulimide, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinedionyl, substituted or unsubstituted oxopyrrolidonyl, substituted or unsubstituted maleimide, substituted or unsubstituted thiazolidonyl or substituted 5. The radicicol derivative or the pharmaceutically acceptable salt thereof according to claim 4, which is unsubstituted oxazolidinedionyl.

(7) A medicament comprising at least one radicicol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

(8) An antitumor agent comprising at least one radicicol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

(9) An immunosuppressant comprising at least one radicicol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

(10) A tyrosine kinase inhibitor comprising at least one radicicol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

(11) A therapeutic agent comprising at least one radicicol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, for a disease associated with tyrosine kinase.

(12) A therapeutic agent comprising at least one radicicol derivative or a pharmaceutically acceptable salt thereof according to claim 11, wherein the disease involving tyrosine kinase is a malignant tumor.

(13) a radicicol derivative or a pharmaceutically acceptable salt thereof according to claim 11, wherein the disease involving tyrosine kinase is a disease involving immunity. Containing therapeutic agent.