WO2004024141A1

WO2004024141A1 - Hsp90 FAMILY PROTEIN INHIBITORS

Info

Publication number: WO2004024141A1
Application number: PCT/JP2003/011087
Authority: WO
Inventors: Tsutomu Agatsuma; Yutaka Kanda; Hideyuki Onodera; Noriko Matsushita; Tatsuhiro Ogawa; Shiro Akinaga; Shiro Soga
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 2002-08-29
Filing date: 2003-08-29
Publication date: 2004-03-25
Also published as: AU2003264356A1; JPWO2004024141A1

Abstract

It is intended to provide an Hsp90 family protein inhibitor, etc. comprising as the active ingredient a cyclic phenylacetic acid derivative represented by the following general formula (I), which is useful as drugs such as an antitumor agent, or its pharmacologically acceptable salt: (I) wherein R1, R2, R3 and R4 are the same or different and each represents hydrogen, hydroxy, optionally substituted lower alkyl, etc.; X represents oxygen, sulfur, -N(R5)- or -CH2-; a represents -CRa1Ra2-, optionally substituted arylene, an optionally substituted divalent heterocyclic group or a bond; b represents -(CRb1Rb2)m- or -CHRb3CRb4Rb5-; c represents -(CRc1Rc2)n(CHRc3CRc4Rc5)p-; d represents -(CRd1CRd2)q- or -CHRd3CRd4Rd5-; and e represents -CRe1Re2-.

Description

Specification

Hsp90 family protein inhibitor Technical field

The present invention relates to a heat shock protein 90 (Hsp90) family protein inhibitor which contains a cyclic phenylacetic acid derivative as an active ingredient and is useful as a pharmaceutical such as an antitumor agent. Background art

Conventionally, as compounds that bind to the Hsp90 family protein, benzoquinone ansamycin antibiotics such as geldanamycin and harpimycin and radicicol (Radicicol) are known [Cell 'Stress & Chaperones ( Cell Stress & Chaperones), 100-108 (1998), Journal-Bob Medicinal Chemistry (J. Med. Chem.), 42, 260-266 (1999)]. It has been reported that all of these compounds bind to the Hsp90 family protein and exhibit pharmacological activities such as antitumor activity by inhibiting the function of the Hsp90 family protein. Therefore, compounds that bind to the Hsp90 family protein are useful as therapeutic agents for diseases involving the Hsp90 family protein or the protein to which the Hsp90 family protein binds (Hsp90 client protein).

Further, a geldanamycin derivative [17 -. AAG, in Vu Est game conditioner Honoré ■ two U Drugs _{(. L nves t New Drugs)} , 17, 361-373 (1999)] Oyopi Radi Shikoru derivatives [Cancer 'Research (Cancer Research), 59, 2931-2938 (1999), Blood, 96, 2284-2291 (2000), Cancer ■ Cancer Chemotherapy and Pharmacology, 48, 435-445 (Cancer Chemotherapy and Pharmacology) 2001), W096 / 33989, WO98 / 18780, W099 / 55689, WO02 / 16369] have been reported to exhibit antitumor effects.

In addition, novobiocin and PU3 have been reported as compounds that bind to the Hsp90 family protein [Journal of National Cancer Institute, Journal of National Cancer Institute, 92, 242-248. (2000), Chemistry & Biology, 8, 289-299 (2001)].

Known Hsp90 family proteins include Hsp90a protein, Hsp90B protein, grp94, hsp75 / TRAPl, etc. [Pharmacology & Therapeutics, 79, 129-168 (1998), Molecular And Molecular Endocrinology, 13, 1435-1448 (1999)]. On the other hand, as a cyclic phenylacetic acid derivative represented by the general formula (I), curvularin (Curvularin) and the like are known [for example, Tetrahedron, 54, 15937-15958 (1998)].

Curvularin

Disclosure of the invention

An object of the present invention is to provide an Hsp90 family protein inhibitor and the like, which contains a cyclic phenylacetic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient, which is useful as a pharmaceutical such as an antitumor agent. .

The present invention relates to the following (1) to (24). (1) General formula (I)

(Wherein RR ² , R ³ and: R ⁴ are the same or different and each represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, halogen Substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted lower alkoxyl-poeroxy, di-rubamoyloxy, substituted Or unsubstituted lower alkylaminocarbonylcarbonyl, substituted or unsubstituted di-lower alkylaminocarboxy, amino, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, substituted or Unsubstituted lower Al-Noil Amino, substituted or unsubstituted lower alkylsulfonylamino, rubamoylamino, substituted or unsubstituted lower alkylcarbamoylamino, substituted or unsubstituted di-lower alkyl rubamoylamino, substituted or unsubstituted lower alkoxycarbonylamino, Droxyamino, substituted or unsubstituted lower alkylthio, nitro, cyano, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted arylo, substituted or unsubstituted Represents a substituted or unsubstituted aralkyl,

X represents an oxygen atom, a sulfur atom, one NOR ⁵ ) — (wherein R ⁵ represents a hydrogen atom or a substituted or unsubstituted lower alkyl) or one CH ₂ —,

a is CR ^al R ^a2 — wherein 1 and Ra2 are the same or different and each represents a hydrogen atom, a hydroxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted Substituted aryloxy, substituted or unsubstituted aryloxy,

(Wherein Ra ³ is a substituted or unsubstituted lower alkyl, Substituted or unsubstituted lower alkoxy, amino, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, substituted or unsubstituted arylamino or substituted or unsubstituted aralkylamino), substituted or unsubstituted Represents an aryl group or a substituted or unsubstituted heterocyclic group, or Ral and Ra ² together form an oxygen atom (= 0), = NOR ^a 4 (where R ^a4 is a hydrogen atom, a substituted or unsubstituted lower group) Alkyl, represents a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl) or one O (CH ₂ ) _r O—, wherein r represents 2 or 3], substituted or unsubstituted Represents an arylene, a substituted or unsubstituted divalent heterocyclic group or a bond;

b is — (CIi ^bl Ii ^b2 ) _m — [wherein _m represents an integer from 0 to 5, and R ^bl and: R ^b2 are the same or different and are a hydrogen atom, hydroxy, substituted or unsubstituted Represents a lower alkoxy, a substituted or unsubstituted lower alkanoyloxy or a substituted or unsubstituted lower alkyl, or Rbl together with an oxygen atom (representing =) or one CHR ^b3 CR ^b4 R ^b5 — (Wherein, R ^b3 , R ^b4 and R ^b5 are the same or different and each represents a hydrogen atom, hydroxy, halogen, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkoxyalkyl, amino Substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted lower alkylthio, substituted or unsubstituted arylalkyl , Substituted or unsubstituted lower alkyl, substituted or either properly represent unsubstituted Ariru or substituted or unsubstituted heterocyclic group, and R ^b3: or R ^b4 represents together a connexion bond or an oxygen atom, or R ^b4 and: R ^b5 together represent an oxygen atom (= 0),

c is one (CRdRc ^ CHRcsCR Rc — (wherein, n and p have the same meanings as m, Rcl and Re ² have the same meanings as Ral and Ra2, respectively, and _R c3, Rc4 and R ^c5 have the same meanings as Ral and Ra2, respectively) R ^b3 , R ^b4 and R ^b5 have the same meanings),

d is — (CRdiCR ^d2 ) _q — (wherein q has the same meaning as m, R ^dl and R ^d2 have the same meanings as R ^al and R ^a2 , respectively) or one CHR ^d3 CR ^d4 R ^d5 — ( In the formula, R ^d3 , R ^d4 and R ^d5 represent the above-mentioned R ^¾3 , respectively: R ^b4 and R ^b5 ),

e is one CR ^e ¾ ^e2 — (wherein R ^el and; R ^e2 are the same or different and each represents a hydrogen atom or A heat-shock protein 90 (Hsp90) family protein inhibitor comprising, as an active ingredient, a cyclic phenylacetic acid derivative represented by}, which represents substituted or unsubstituted lower alkyl).

(2). R ² and R ⁴ are the same or different and each is hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aryloyloxy, substituted or unsubstituted The Hsp90 family protein inhibitor according to the above (1), which is an aralkyloxy, lower alkoxyl propylonyloxy, rubamoyloxy, lower alkylaminocarboxy or di-lower alkylamino propyloxy.

(3) The Hsp90 family protein inhibitor according to the above (1), wherein R ² and R ⁴ are hydroxy or substituted or unsubstituted lower alkoxy.

(4) The Hsp90 family protein inhibitor according to any one of the above (1) to (3), wherein Ri and R ³ are hydrogen atoms.

(5) X is an oxygen atom, a guard CR ^a ¾ ^a2 - a (wherein, R ^al and R ^a2 are the same as defined, respectively therewith the), b gar CHR ^b 3CR ^b4 R ^¾5 - (Wherein R ^b3 , H ^b4 and Rb5 are as defined above, respectively), and c is one CR ^c iRc2— (where R _C I and

Rc2 are the same meanings as defined above, respectively), d gar CHRd3 _C Rd4 _R d5 i (wherein, _R d3,

Rd ⁴ and Rds is the same meanings as defined above, respectively), and _e gar CH (CH ₃₎ - a above (1) to according to any one (4): Bsp90 family protein inhibitor.

(6) X is an oxygen atom, a is a substituted or unsubstituted divalent heterocyclic group, b and C represents a bond, d gar CHRd3CRd4 _R d5 i (wherein,; Rd3, Rd4 and Rd5 each have the same meanings as defined above) and., Hsp90 Fuamiri protein inhibitor according to any one of e is one CH (CH ₃₎ a _ the above (1) to (4).

(7) — General formula (I)

(Wherein, RR ² , R ³ , -RX, a, b, c, d and e have the same meanings as described above) or a pharmacologically acceptable derivative thereof. A therapeutic agent for diseases involving Hsp90 family protein containing a salt as an active ingredient or a protein to which Hsp90 family protein binds (Hsp90 client protein).

(8) and R ⁴ are the same or different and are hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted aralkyloxy, lower The protein (Hsp90 client) to which the Hsp90 family protein or Hsp90 family protein according to the above (7) is an alkoxycanoleponinoleoxy, carbamoinoleoxy, lower alkylaminocanolebonyloxy or di-lower alkylaminocarboxy-loxy. A therapeutic agent for diseases involving protein).

(9) The therapeutic agent for a disease involving the Hsp90 family protein or the protein to which the Hsp90 family protein binds (Hsp90 client protein) according to the above (7), wherein R ² and R ⁴ are hydroxy or substituted or unsubstituted lower alkoxy. .

(10) The Hsp90 family protein or the protein to which the Hsp90 family protein according to any one of the above (7) to (9), wherein Ri and R ³ are hydrogen atoms.

(Hsp90 client protein).

(1 1) X is an oxygen atom, (wherein, Ral and it respectively the same meanings as defined above) a is _ CRalRa2- a, b is one CKRb3 _CR b4 _R b ₅ _ (wherein, _R b3, Rb4 Oyo Pi Rb ⁵ are each the same meanings as defined above), C is one CR ^cl Ii ^c2 - a (wherein, Rei and R ^c2 are the same meanings as defined above, respectively), d isー CHR ^d3 CR ^d4 R ^d5 — (where,

Rd 3, Rd 4 and Rd5 are the same meanings as defined above, respectively), and e is one CH (CH ₃₎ - a is the (7) ~ (1 0 Hsp90 family one protein according to any one of) or A therapeutic agent for diseases involving Hsp90 family proteins (Hsp90 client protein).

(12) X is an oxygen atom, a is a substituted or unsubstituted divalent heterocyclic group, b and c represent a bond, d is -CHR ^d3 CR ^d4 R ^d5 — (wherein, R ^d3 , R ^d4 and R ^d5 are as defined above, respectively, and e is -CH (CH ₃ )-

(10) The Hsp90 family protein or Hsp90 family protein according to any of (10).

— Ό 一 A therapeutic agent for diseases involving protein-bound proteins (Hsp90 client protein). (1 3) General formula (I)

(Wherein, Ri, R ² , R ³ , R ⁴ , a, b, c, d and e are as defined above) or a pharmaceutically acceptable salt thereof. An antitumor agent containing as an active ingredient.

(14) R ² and R ⁴ are the same or different and are hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted (13) The antitumor agent according to the above (13), which is aralkyl oxy, lower anorecoxy canoleboninoleoxy, canolebamoinoleoxy, lower alkynoleamino liponyloxy or di-lower alkylamino carboxy.

(15) The antitumor agent according to the above (13), wherein R ² and R ⁴ are hydroxy or substituted or unsubstituted lower alkoxy.

The antitumor agent according to any one of (16) and said R ³ is a hydrogen atom (1 3) - (1 5).

(17) X is an oxygen atom, a is —CR ^al R ^a2 — (wherein, R ^al and R ^a2 have the same meanings as above), and b is —CHR ^b3 CRb4Rb5 (formula _Wherein , _R b3, Rb4 and R ^b5 are as defined above, and c is —CR ^cl R ^c2 — (wherein Rci and ぴ R ^c2 are as defined above, respectively). Wherein d is —CHRd ³ CRd ⁴ Rd ⁵ — (wherein K ^d3 . R ^d4 and R ^d5 are each as defined above), and e is —CH (CH ₃ ) — ) The antitumor agent according to any one of (1) to (16).

(18) X is an oxygen atom, a is a substituted or unsubstituted divalent heterocyclic group, b and c represent a bond, d is one CH ^d3 CR ^d4 R ^d5 — (wherein, R ^d3 , Rd4 and Hd ₅ are the same as defined above, respectively, and e is one CH (CH ₃ ) — -The antitumor agent _{c according} to any of (16);

(19) — General formula (I)

(Wherein, II ¹ , R ² , R ³ , R ⁴ , X, a, b, c, d and e have the same meanings as described above) or a pharmacology thereof. A method for inhibiting Hsp90 family protein, which comprises administering an effective amount of a commercially acceptable salt.

(20) — General formula (I)

(Wherein, I ¹ , R ² , R ³ , R ⁴ , X, a, b, c, d and e have the same meanings as described above) or a pharmacology thereof. A method for treating a disease involving the Hsp90 family protein or a protein to which the Hsp90 family protein binds (Hsp90 client protein), comprising administering an effective amount of a commercially acceptable salt.

(21) — General formula (I)

(Wherein, Ri, R ² , R ³ , R 4, χ, _a , b, c, d and e are as defined above) or a pharmacologically acceptable derivative thereof. Salty A method for treating a malignant tumor, which comprises administering an effective amount.

(22) General formula (I) for the production of Hsp90 family protein inhibitors

(Wherein, RR ² , R \ E ⁴ , X, a, b, c, d and e are as defined above) or a pharmacologically acceptable salt thereof. Use of.

(23) General formula (I) for production of a therapeutic agent for a disease involving Hsp90 family protein or a protein to which Hsp90 family protein binds (Hsp90 client protein)

(Wherein, II ¹ , R ² , R ³ , H ⁴ , X, a, b, c, d, and e have the same meanings as described above) or a pharmacologically acceptable derivative thereof. Use of acceptable salts.

(24) General formula for the production of an antitumor agent (I)

(Wherein, RR ² , H ³ , R ⁴ , X, a, b, c, d and e are as defined above) or a pharmacologically acceptable derivative thereof. Salt use.

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

Lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylamino, di-lower alkylamino, lower alkylaminocarbonyloxy, di-lower alkylaminocarbonyloxy, lower alkyl-based rubamoylamino, di-lower alkyl-based rubamoylamino, lower alkoxycarbonyl Examples of the lower alkyl moiety of amino, lower alkylsulfonylamino, lower alkylthio and lower alkoxycarboxy include, for example, straight-chain or branched alkyl having 1 to 8 carbon atoms, more specifically methyl, ethyl. Propyl, isopropyl, butyl, sec-butyl, tert-butyl / pentyl, pentinole, isopenpentole, neopentynole, hexyl, heptyl, octyl, etc., and, for example, cycloalkyl having 3 to 8 carbon atoms, more specifically Examples include cyclopropynole, cyclopentinole, cyclopentinole, cyclohexyl, cyclohexyl, cyclooctyl, and the like. The two lower alkyl moieties in the di-lower alkylamino, di-lower alkylaminocarbonyldioxy and lower dialkyl moieties may be the same or different. As the lower alkenyl, for example, a straight-chain or branched alkenyl having 2 to 8 carbon atoms, more specifically, vinyl, aryl, 1-propenyl, methacrylic, crotyl, 1-butenyl, 3-butane , Teninole, 2-pentenigle, 4-pentenole, 2-hexenyl, 5-hexenyl, 2-heptur, 2-octenyl, and the like. The lower alkynyl includes, for example, straight-chain or branched alkynole having 2 to 8 carbon atoms, more specifically, ethur, propynole, butcher, pentinole, hexinyl, heptur, otatur and the like. .

Examples of the lower alkanoyl moiety of lower alkanol, lower alkanol and lower alkanol include, for example, straight-chain or branched alkanol having 1 to 7 carbon atoms, more specifically formyl, acetyl, propioel, Butyryl, isoptyryl, norrelyl, isovaleryl, vivaloyl, hexanoyl, heptanyl and the like.

Aryl, aryloxy, arylamino, arylthio, arylo and aryloyl of aryloyl include, for example, aryl having 6 to 14 carbon atoms, More specifically, phenyl, indenyl, naphthyl, anthryl and the like can be mentioned.

Examples of the aralkyl moiety of aralkyl, aralkyloxy and aralkylamino include aralkyl having 7 to 15 carbon atoms, more specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.

Examples of the heterocyclic group include an aromatic heterocyclic group and an alicyclic heterocyclic group. Examples of the aromatic heterocyclic group include at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. 6-membered or 6-membered monocyclic aromatic heterocyclic group, 3- or 8-membered fused bicyclic or tricyclic fused ring containing at least one atom selected from nitrogen, oxygen and sulfur And more specifically, pyridyl, pyrazinyl, pyrimidinyl, pyridazyl, quinoliel, isoquinolinyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, virazolyl, imidazolyl, azomidyl Tetrazolyl, chenyl, frill, thiazolyl, oxazolyl, indolyl, indazolinole, Benzoimidazolinole, benzotriazolinole, benzothiazolinole, benzoxazolyl, purinyl and the like. Examples of the alicyclic heterocyclic group include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, a 3- to 8-membered ring And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically a pyrrolidinyl group. , Piperidino, piperazinyl, morpholino, thiomorpholino, homopiberidino, homopiperazyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranil, tetrahydrofuranil, tetrahydroviranyl, dihydrobenzofuranole and the like.

Halogen means atoms of fluorine, chlorine, bromine and iodine.

Arylene represents a group in which one hydrogen atom has been removed from aryl, and a divalent heterocyclic group represents a group in which one hydrogen atom has been removed from the heterocyclic group.

Substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkoxy, substituted lower alkanoyloxy, substituted lower alkoxy carboxy , Substituted lower alkylamino, substituted diloweralkylamino, substituted lower alkanoylamino, substituted lower alkanoyl, substituted lower alkylaminocarboxyloxy, substituted dilower alkylaminocarbonyloxy, substituted lower alkylsulfonylamino, substituted lower alkylaminoylamino The substituents in the substituted di-lower alkyl group rubamoylamino, the substituted lower alkoxycarbonylamino, the substituted lower alkylthio and the substituted lower alkoxycarbonyl are, for example, the same or different, and have 1 to 3 substituents such as hydroxy, cyano, Examples include carboxy, substituted or unsubstituted lower alkoxy, and the like. The substitution position of the substituent is not particularly limited. Here, the lower alkoxy has the same meaning as described above, and examples of the substituent in the substituted lower alkoxy include, for example, hydroxy having the number of substitution:! As a substituent in substituted aryloxy, substituted arylalkyl, substituted aryl, substituted aryloyl, substituted arylalkyl, substituted aryloxy, substituted arylamino, substituted arylalkylamino, substituted arylthio, substituted heterocyclic group, substituted arylene and substituted divalent heterocyclic group Are the same or different and are, for example, hydroxy, substituted, unsubstituted, cyano, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, di-lower alkylamino, lower alkanol, substituted or unsubstituted Lower alkyl, substituted or unsubstituted lower alkoxy, etc. The substitution position of the substituent is not particularly limited, where halogen, lower alkoxycarbonyl, lower alkylamino, di-lower alkylamino, lower alkylamino, and the like. , Lower alkyl and lower ^ alkoxy have the same meanings as described above, and the substituents in substituted lower alkyl and substituted lower alkoxy are, for example, the same or different, and have 1 to 3 substituents such as hydroxy and halogen. And halogen is as defined above.

Hereinafter, the compound represented by the general formula (I) is referred to as compound (I).

Pharmaceutically acceptable salts of compound (I) include, for example, pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.

Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, and the like. Organic salts such as citrate can be mentioned, and pharmacologically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and potassium salt, and the like. Aluminum salts, zinc salts, and the like, and pharmacologically acceptable ammonium salts include, for example, salts of ammonium and tetramethylammonium, and pharmacologically acceptable organic amines. Examples of the addition salts include addition salts such as morpholine and piperidine, and examples of the pharmacologically acceptable amino acid addition salts include addition salts such as glycine, phenylalanine, lysine, aspartic acid, and glutamic acid. can give.

Hsp90 family protein inhibition means inhibiting the binding between Hsp90 family protein and a protein to which Hsp90 family protein binds (Hsp90 client protein).

Examples of Hsp90 family proteins include Hsp90a protein, Hsp90B protein, grp94, hsp75 / TRA: P1 and the like.

The protein to which the Hsp90 family protein binds may be any protein as long as it is a protein to which the Hsp90 family protein binds.For example, EGFR, Erb-B2, Bcr-Abl, src, raf-l, AKT, Flt_3, PLK, Weel, FAE: cMET, hTERT, HIFl-a _N variant p53, estrogen receptor, androgen receptor, etc. [Expert Opinion 'on' Biological 'Therapy (Expert Opinion on Biological Therapy), 2, 3-24 (2002)].

Diseases involving the Hsp90 family protein or the protein to which the Hsp90 family protein binds (Hsp90 client protein) include, for example, solid cancers (eg, retinal blast fibrosis, osteosarcoma, colorectal cancer, breast cancer, gastric cancer, bladder cancer, prostate cancer) , Multi-cellular carcinoma, human papillomavirus cervical cancer, small cell lung cancer, etc., blood cancer (eg, acute myeloblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, multiple myeloma, Rennel T lymphoma, etc.) Malignant tumors, such as osteoporosis, atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, Hashimoto's thyroiditis, severe myasthenia, multiple sclerosis, systemic sclerosis, Behcet's disease, nodularity Periarteritis, ulcerative colitis, active chronic hepatitis, chronic glomerulonephritis, osteoarthritis, gout, Ciddaren syndrome, psoriasis, Phi dermatitis, asthma, allergic rhinitis, Jin'asa Rash, food allergies, various encephalitis, endotoxin shock, sepsis, inflammatory bowel disease, diabetes, pneumonia, rejection associated with organ transplantation, encephalomyelitis, anorexia, acute hepatitis, drug-toxic liver injury, alcoholic Hepatitis, viral hepatitis, jaundice, cirrhosis, liver failure, atrial myxoma Castleman syndrome, mesangial proliferative nephritis, ischemic reperfusion injury, subarachnoid hemorrhage, restenosis, cachexia, cytomegaloviral Pneumonia, cytomegalovirus retinopathy, adenoviral cold, adenoviral pool fever, adenoviral ophthalmitis, AIDS, pulmonary disease with granulomas, etc. [e.g. Pharmacology Review] The

(Pharmacological Reviews), 50, 493-514 (1998)].

Manufacturing method>

The compound (I) is described, for example, in the literature [Japanese Patent Laid-Open No. 2000-287697, Tetrahedron, 54, 15937-15958 (1998), Chinese 'Chemical' Letters (Chin. Chem. Lett.), 5, 481. -484 (1994), Heterocycles, 32, 307-310 (1991), Tetrahedron Lett., 30, 2241-2244 (1989), Chemistry Letters ), 589-592 (1990), Journal of Nippon Dani Gakkai, 5, 883-885 (1981), Agricultural 'and-noological' chemistry (Agrc. Biol. Chem.), 40, 1663-1664 ( 1976), Journal of Chemical 'Society C (J. Chem. Soc. C), 10, 947-948 (1967), etc.] or a method analogous thereto. it can.

In addition, each functional group is identified by known methods commonly used in organic synthetic chemistry [eg, Comprehensive Organic Transformations, RC Larock (1989)]. Various compounds (I) can be produced by conversion. Also, if necessary, protection and deprotection of each functional group [for example, Protective Groups in Organic Synthesis ■ Protective Groups in Organic Synthesis, by TW Greene, John 'Wiley' and · John Wiley & Sons Inc. (1999), etc.] can be used to produce target compounds having various functional groups. Some compounds (I) A specific example of the production of is described in Reference Examples described later.

Intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. can do. Further, the intermediate can be subjected to the next reaction without purification.

Some of the compounds (I) may have stereoisomers such as geometric isomers and optical isomers. In the present invention, all possible isomers, including these, and mixtures thereof are included. Can be used.

When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is. When compound (I) is obtained in a free form, compound (I) may be converted to an appropriate solvent. Dissolve or suspend, add acid or base, and isolate and purify.

Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts may be used in the present invention. it can.

Table 1 shows specific examples of the compound (I).

Table 1

Next, the pharmacological action of compound (I) will be specifically described with reference to test examples. Test Example 1 Hsp90 protein binding activity test

(1) Hsp90 protein (58% purity) purified from cereal brain according to the method described in Archives of Biochemistry and Biophysics, 282, 290-296 (1990) Was diluted with Tris-buffered saline (TBS, pH 7.4) to a concentration of 1 μg / mL, and aliquoted at 75 / L / well into a 96-well ELISA Assay plate manufactured by Sumitomo Bei-Clait. After the injection, it was left at 4 ° C for 1 hour to solidify.

(2) The supernatant was removed, and blocking was performed by dispensing 300 L / μl of Tris-buffered saline containing 1% calcium serum albumin (BSA).

(3) After removing the blocking solution, the operation of adding 500 // L / well of Tris-buffered saline (TBST) containing 0.05% Tween 20 and washing the solid phase was repeated three times.

(4) A test compound (compounds 1 to 12) was diluted with TBST from a maximum concentration of 0.5 mmol / L to “10-fold dilution in 8 steps” to prepare a solution in another container. 80 / ZL / well TBST containing protease inhibitor complete EDTA-free (Roche) and Fablock SC (Pefabloc SC, Roche) at a concentration of 1 tablet / 40 mL and 0.4 mmol / L, respectively. Add 20 / iL / well to the Atsell plate previously dispensed in step 1 and leave at room temperature for 1 hour, where dimethylsulfoxide was used as a positive control for the final concentration of lL / well and a negative control. Radicicol was used at a final concentration of 0.25 / iinol / L, and the same operation as in the case of using the test compound arranged on the same plate as the test compound was performed.

(5) Add biotinylated radicicol represented by the formula (II) to a final concentration of 0.1 / xmol / L, leave it at room temperature for 1 hour, and bind the test compound to the immobilized Hsp90 protein. A competitive reaction was performed.

(6) After removing the reaction solution in (5), the operation of adding TBST in an amount of 500 // L / well and washing the solid phase was repeated three times.

(7) Dilute youpium-labeled streptavidin [Wallac Oy] with a buffer for Atssei [Wallac Oy] to a final concentration of 0.1 / zg / mL. After dispensing in an amount of / xL / well, the mixture was allowed to stand at room temperature for 1 hour to perform a biotin-avidin binding reaction.

(8) After removing the reaction solution of (7), the operation of adding 500 L / well of TBST and washing the solid phase was repeated three times.

(9) Add 100 µl of the fluorescence enhancement solution [Perak Oy] to perform a color reaction at room temperature for 5 minutes, and add a multi-label counter [ARVO ™, Perlac Oy]. Time-resolved fluorescence was measured at an excitation wavelength of 340 nm and a measurement wavelength of 615 nm.

Assuming that the measured value of the time-resolved fluorescence of the positive control is 100% of the binding rate and the measured value of the negative control is 0%, the binding rate of the well containing the test compound is calculated from the measured value of each well. did.

Compounds 1 to 4 and 6 to 12 inhibited the binding of biotinylated radicicol to Hsp90 protein by 50% or more at concentrations of ΙΟΟμηιοΙ / L or less, indicating that they have binding activity to Hsp90 protein. . In particular, compound 8 inhibited the binding of 16 μmol / L biotinylated radicicol to Hsp90 by 50%.

Test Example 2 Cell proliferation inhibitory activity against human colon cancer cell HCT116

1X10 ³ Z-well HCT116 cells were dispensed into a 96-well microtiter plate (MS-8196F, manufactured by Sumitomo Beit-Client) and cultured in a 5% CO 2 incubator at 37 ° C for 24 hours. . Thereafter, the test compound diluted stepwise is added. The cells were cultured at 37 ° C for 72 hours in a 5% carbon dioxide gas incubator. XTT so that it becomes lmg / mL.

L 2,3-bis (2-metlioxy-4-nitro-5-suliophenyi) -2H-tetrazolium-5-carboxanilide sodium salt] standard reagent (Roche Diagnostics) is dispensed into the culture medium did. After culturing at 37 ° C for 2 hours in a 5% carbon dioxide gas incubator, the absorbance at 490ηιη (reference wavelength 650 nm) was measured using a microplate plate spectrophotometer Emax (manufactured by Molecular Devices).

Compound 1 and Compound 11 inhibited cell proliferation by 50% or more at a concentration of 100 // mol / L or less.

Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. The pharmaceutical preparations are used for animals and humans.

The pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmacologically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient. it can. In addition, such pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmaceutically acceptable carriers, and by any method well known in the technical field of pharmaceuticals.

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

Dosage forms include, for example, tablets, injections and the like.

Suitable for oral administration, for example, tablets are excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, fatty acid esters, etc. It can be produced by using a surfactant such as a plasticizer such as glycerin.

Formulations suitable for parenteral administration comprise sterile aqueous solutions containing the active compound, which is preferably isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of saline and a glucose solution.

Also, in these parenteral preparations, the excipients, disintegrants, One or more auxiliary ingredients selected from agents, binders, surfactants, plasticizers and the like can also be added.

The dosage and frequency of compound (I) or a pharmacologically acceptable salt thereof will vary depending on the mode of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. 0.01 mg to lg, preferably 0.05 to 50 mg, per adult is administered once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to: LOmg per adult is administered once to several times a day. However, the dose and the number of administrations vary depending on the various conditions described above.

Hereinafter, embodiments of the present invention will be described with reference examples and examples. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the wavy line in the structural formula indicates that it is a mixture of stereoisomers.

Reference Example 1: Compound 1, Compound 2, Compound 3, and Compound 4

Compound 3 Compound 4 ^ iZ / ws genus filamentous fungus MPC1009 strain [Accession No. BPBP-7900; Deposit with Higashi 1-chome No. 1 1 Chuo No. 6)] from the agar slant medium, add 50 mL of each platinum loop to the primary seed medium (mash potato 3%, glucose 10%, yeast extract o.5%, pH 6.5) Inoculate four 300 mL Erlenmeyer flasks containing Culture was performed on a rotary stirrer at 28 ° C for 4 days to obtain a primary seed culture solution. Secondary seed medium (2% glucose the primary seed culture 75 mL 2.5 L, mashed 2%, 0.5% peptone, ΚΗ ₂ Ρθ4 θ.5%, adjusted to _{ρΗ 6.0, Mg 3 (P04)} 2 · 8Η ₍ 0.05% added) was inoculated into a 5 L jar armmenter, and aerated with aeration at 25 ° C for 24 hours. The resulting secondary-seed production medium broth 450 mL of 15 L (2% glucose, mashed 2%, 0.5% peptone, KH2 PO4 0.5%, adjusted to pH 6.0, Mg ₃ (P_rei_4) 2 · 8H ₂ O 2 (containing 0.05% O) was inoculated into a 30 L jar fermenter and cultured with aeration and stirring at 25 ° C for 5 days. After completion of the culture, the culture solution (30 L) is separated into cells and supernatant by suction filtration, and the culture supernatant is subjected to column chromatography using Diaion HP20 (1.5 L, Mitsubishi Chemical) previously filled with 30% methanol. After washing with 50% methanol, the mixture was eluted with 100% methanol. The eluate was concentrated, extracted with ethyl acetate, and the extract was concentrated to dryness to obtain 10.4 g of an extract. By repeatedly subjecting the obtained extract to silica gel column chromatography (chloroform-methanol and ethyl acetate-methanol), Compound 1 (1.0 g), Compound 2 (9.2 mg), Compound 3 (23 mg) and Compound 3 (23 mg) were obtained. 4 (680 mg) was obtained.

Compound 1: trans-dehydrocurvularm

Ή NMR (CD3OD, 300MHz) 6 (ppm) 1.18 (3H, d, J = 6.4 Hz), 1.52- 1.64 (2H, m), 1.81-2.01 (2H, m), 2.24-2.42 (2H; m), 3.45 (1H, d, J = 16.7 Hz), 3.73 (IH, d, J = 16.7 Hz), 4.81 (IH, m), 6.24 (lH, d, J = 2.2 Hz), 6.28 (lH, d, J = 2.2 Hz), 6.50 (IH, d, J = 15.6 Hz), 6.59 (lH, ddd, J = 5.1, 5.5, 15.6 Hz); FAB -MS m / z 291 [M + H] ⁺ ; [ah ²⁸ "67.2 ° (c 1.06, C2H5OH)

Compound 2: cis-dehy droc rvularin

iH NMR (CDsOD, 300MHz) δ (ppm) 1.12 (3H, d, J = 6.4 Hz), 1.49-1.58 (2H, m), 1.77 (2H, m), 2.20-2.27 (2H, m), 3.62 ( lH, d, J = 14.5 Hz), 3.70 (lH, d, J = 14.5 Hz), 4.80 (IH, m), 5.93 (lH, ddd, J = 12.1, 7.7, 7.7 Hz), 6.22 (lH, d , J = 2.2 Hz), 6.24 (IH, d, J = 2.2 Hz), 6.49 (IH, ddd, J = 12.1, 1.7, 1.7 Hz); FAB-MS m / z 291 [M + H] +

Yi Danigao 3: 12-oxocurvularin Ή NMR (CDsOD, 300MHz) 5 (ppm) 1.10 (3H, d, J = 6.2 Hz), 1.69 (IH, m), 2.02 (IH, HI), 2.23 (lH, ddd, J = 2.9, 8.1, 16.5 Hz), 2.64 (IH, m), 2.69 (lH, m), 2.97 (2H, m), 3.36 (1H, m), 3.51 (lH, d, J = 15.8 Hz), 3.60 (lH, d, J = 15.8 Hz), 4.92 (lH, m), 6.17 (lH, d, J = 2.2 Hz), 6.23 (lH, d, J = 2.2 Hz); FAB -MS m / z 307 [M + H] ⁺

Compound 4: 11-hydroxycurvularin (¾2: 1 mixture of stereoisomers)

NMR (CD3OD, 300MHz, major isomer) 6 (ppm) 1.13 (3H, d, J = 6.1 Hz),

1.38- 1.65 (6H, m), 3.22 (2H, d, J = 7.6 Hz), 3.58 (lH, d, J = 15.6 Hz), 3.96

(IH, d, J = 15.6 Hz), 4.07 (IH, m), 4.98 (lH, m), 6.21 (1H, d, J = 2.1 Hz),

6.27 (IH, d, J = 2.1 Hz); FAB -MS m / z 309 [M + H] ⁺

Reference Example 2: Compound 5 and compound 6

Compound 1 Compound 5 Compound 6 Compound 1 (101.7 mg, 0.351 mmol) obtained in Reference Example 1 was dissolved in 4 mL of methanol, and sodium carbonate (85 mg, 0.80 mmol) and 30% hydrogen peroxide ( 1 mL) and stirred for 2 hours while cooling with ice. The reaction solution was poured into ice water and extracted with ethyl acetate (50 mL × 2). The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure was separated and purified by preparative thin-layer chromatography on silica gel (0.5 mm x 20 cm x 20 cm, chloroform: methanol = 10: 1) to give Compound 5.

(12.2 mg, 11%) and compound 6 (5.5 mg, 5%).

Compound 5

Ή NMR (CDCla, 300MHz) 5 (ppm) 1.27 (3H, d, J = 6.8 Hz), 1.60-2.15 (6H, m), 3.08 (IH, brd, J = 7.0 Hz), 3.69 (1H, d, J = 18.3 Hz), 3.97 (lH, d, J = 1.8 Hz), 4.17 (IH, d, J = 18.3 Hz), 5.10 (IH, m), 6.24 (1H, d, J = 2.6 Hz), 6.26 (IH, d, J = 2.6 Hz), 7.51 (lH, brs), 12.49 (1H, brs); FAB -MS m / z 307 [M + H] ⁺ , 305 [Μ-Η] ·

Compound 6

Ή NMR (CDCls, 300MHz) δ (ppm) 1.28 (3H, d, J = 6.2 Hz), 1.55-1.83 (4H, m), 2.09-2.19 (2H, m), 3.31 (lH, ddd, J = 4.7 , 2.9, 2.2 Hz), 3.70 (IH, d, J = 17.2 Hz), 3.76 (lH, d, J = 2.2 Hz), 3.78 (1H, d, J = 17.2 Hz), 5.07 (lH, m), 6.31 (IH, d, J = 2.2 Hz), 6.34 (lH, d, 2.2 Hz), 6.61 (lH, brs), 11.13 (1H, brs); FAB-MS m / z 307 [M + H] +, 305 [MH] "

Reference Example 3: Compound 7

To a solution of compound 1 (65.0 mg, 0.224 mmol) obtained in Reference Example 1 in tetrahydrofuran (3 mL) was added triethylamine (75 / zL, 0.54 mmol) and aniline (50 μL, 0.55 mmol). The mixture was stirred at 70 ° C for 1 hour. The reaction solution was poured into a 0.1 mol / L aqueous hydrochloric acid solution, and extracted with ethyl acetate (20 mL × 2). The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue (48.7 mg) concentrated under reduced pressure was separated and purified by silica gel preparative thin layer chromatography to obtain Compound 7 (18.0 mg, 21%) which was a mixture having a stereoisomer ratio of about 2: 1.

Compound 7

Ή NMR (Aseton -d _6, 300 MHz, major isomer) 5 (ppm) 1.20 (3H , d, J = 6.6 Hz), 1.28-1.90 (6H, m), 2.83 (lH, m), 3.45 (1H, m), 3.66 (1H, m), 3.81 (IH, d, J = 15.4 Hz), 4.04 (IH, d, J = 15.4 Hz), 5.10 (lH, m), 6.48 (lH, d, J = 2.2 Hz), 6.54 (IH, d, J = 2.2 Hz), 6.61-6.79 (3H, m), 7.12-7.20 (2H, m), 8.96 (1H, brs); FAB -MS m / z 384 (M + H] +, 382 [MH] "

Reference Example 4: Compound 8

Compound 1 Compound 8 To a solution of compound 1 (35.0 mg, 0.121 mmol) obtained in Reference Example 1 in acetone (3 mL) was added lithium carbonate (60 mg, 0.43 mmol) and methyl iodide (15 // L, 0.2 mmol) and stirred at 60 ° C. After 30 minutes, methyl iodide (20 L, 0.32 mmol) was further added, and the mixture was stirred at 70 ° C for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate (20 mL × 2). The extract was washed with a 0.5 mol / L aqueous hydrochloric acid solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. The residue (38.3 mg) concentrated under reduced pressure was separated and purified by silica gel preparative thin-layer chromatography (0.5 mm X 20 cm X 20 cm, n-hexane: ethyl acetate = 2: 1) to give Compound 8 (7.6 mg, 21 %).

Compound 8

Ή NMR (CDCls, 300ΜΗζ) δ (ppm) 1.24 (3H, d, J = 6.2 Hz), 1.58.1.70 (2H, m), 1.85-2.04 (2H, m), 2.27-2.52 (2H, m), 3.54 (1H, d, J = 17.8 Hz), 3.82 (3H, s), 4.04 (1H, d, J = 17.8 Hz), 4.85 (1H, m), 6.32 (lH, d, J = 2.4 Hz), 6.41 (1H, d, J = 2.4 Hz), 6.63 (lH, dd, J = 15.6, 3.9 Hz), 6.68 (lH, d, J = 15.6 Hz), 12.8 (1H, s); FAB-MS m / z 305 [M + H] +

Reference Example 5: Compound 9

Cerium chloride heptahydrate (53.4 mg, 0.143 mmol) and sodium borohydride (8.1 mg, 8 mL) were added to an ethanol solution (2 mL) of Compound 1 (32.4 mg, 0.112 mmol) obtained in Reference Example 1 while cooling with ice. 0.214 mmol) and stir for 1 hour while continuing to cool on ice. Stirred. The reaction solution was poured into water and extracted with ethyl acetate (50 mL × 2). The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue (34.1 mg) obtained by concentration under reduced pressure was separated and purified by silica gel preparative thin-layer chromatography (0.5 mm X 20 cm X 20 cm, chloroform: methanol = 10: 1) to give compound 9 (3.5 mg). , 9.8%).

Compound 9

Ή NMR (CD ₃ OD, 300MHz) 5 (ppm) 1.15 (3H, d, J = 6.4 Hz), 1.16 (3H, t, J

= 7.0 Hz), 1.44-1.66 (6H, m), 3.42 (1H, d, J = 17.2 Hz), 3.59 (2H, q, J = 7.0

Hz), 3.68 (1H, ddd, J = 7.7, 7.7, 3.7 Hz), 3.90 (lH, d, J = 17.2 Hz), 5.06 (lH, m), 5.73 (1H, dd, J = 16.5, 7.7 Hz) ), 6.16 (lH, d, J = 2.2 Hz), 6.24 (1H, d, J =

2.2 Hz), 6.39 (1H, d, J = 16.5 Hz); FAB-MS m / z 319 [Μ-Η], 273

[MC ₂ H ₅ OH-H]-Reference Example 6: Compound 10

Compound 3 Compound 10 Camphorsulfonic acid (27 mg, 0.116 mmol) was added to a toluene solution (3 mL) of compound 3 (15.0 mg, 0.0490 mmol) obtained in Reference Example 1, and the mixture was heated under an atmosphere of argon gas for 2 hours. Refluxed. The residue obtained by concentrating the reaction mixture was separated and purified by silica gel preparative thin-layer mouth chromatography (0.5 mm x 20 cm x 20 cm, mouth-mouth: methanol = 10: 1) to give Compound 1. 0 (3.5 mg, 25%) was obtained.

Yi Danigao 1 0: citreofuran

NMR (CD ₃ OD, 300ΜΗζ) δ (ppm) 1.22 (3H, d, J = 6.6 Hz), 1.76 (1H, m), 2.03 (1H, m), 2.66 (1H, ddd, J = 3.3, 11.0, 15.0 Hz), 2.84 (1H, ddd, J = 2.9, 5.9, 15.0 Hz), 3.09 (lH, d, J = 14.3 Hz), 3.20 (1H, d, J = 14.3 Hz), 5.15 (1H, m) , 6.09 (1H, d, J = 2.6 Hz), 6.20 (lH, d, J = 2.6 Hz), 6.29 (lH, d, J = 2.2 Hz), 6.33 (1H, d, J = 2.2 Hz); FAB -MS m / z 289 [M + H]

Reference Example 7: Compound 11 and Compound 12

Compound 11 and compound 12 were obtained according to the method described in Agricultural-and 'Bio-mouthed' Chemistry (Agrc. Biol. Chem.), 52, 3119-3121 (1998). The physicochemical data of both compounds are described below.

Compound 1 1: curv larm

Ή NMR (CDsOD, 300MHz) δ (ppm) 1.12 (3H, d, J = 6.2 Hz), 1.28-1.59 (8H, m), 2.74 (IH, ddd, J = 2.9, 9.4, 15.0 Hz), 3.21 ( lH, ddd, J = 2.8, 9.0, 15.0 Hz), 3.62 (IH, d, J = 15.8 Hz), 3.86 (1H, d, J = 15.8 Hz), 4.91 (1H, m), 6.21 (IH, d , J = 2.2 Hz), 6.25 (1H, d, J = 2.2 Hz); FAB-MS m / z 293 [M + H] ⁺ compound 12: 11-methoxycurvularin (about 3: 1 mixture of stereoisomers)

NMR (CDCls, 300 MHz, major isomer) δ (ppm) 1.18 (3H, d, J = 6.1 Hz), 1.40-1.72 (6H, m), 3.01 (lH, dd, J = 13.6, 7.9 Hz), 3.36 (3H, s), 3.49 (IH, d, J = 18.3 Hz), 3.72 (lH, m), 3.79 (lH, m), 3.89 (lH, d, J = 18.3 Hz), 4.93 (lH, m ), 6.22 (IH, brs), 6.29 (IH, brs), 7.69 (lH, brs), 8.46 (lH, brs); FAB-MS m / z 323 [M + H] ⁺

Example 1: Tablet

A tablet having the following composition is prepared by a conventional method. Compound 140 g, lactose 286.8 g, and potato starch 60 g are mixed, and 120 g of a 10% aqueous solution of hydroxypropyl cellulose is added thereto. The mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate was added and mixed. The mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui) having a punch of 8 mm in diameter, and tablets (20 mg of active ingredient per tablet) Is obtained. Formulation compound 20 mg

Lactose 143.4 mg

όΌ mg

Hydroxypropinoresenolerose 6 mg

Magnesium stearate 0.6 ιης

200 mg

Example 2: Tablet

A disintegrant having the following composition is prepared by a conventional method. Compound 40 (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, and thereto is added a 10% aqueous solution of hydroxypropylcellulose (120 g). The mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate was added and mixed. The mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui) having a punch of 8 mm in diameter, and tablets (20 mg of active ingredient per tablet) Is obtained.

Formulation Compound 5 20 mg

Lactose 143.4 mg

30 mg

Hydroxypropinoresenolerose 6 mg

Magnesium stearate _ 0.6 mg

200 mg

Example 3: Injection

An injection having the following composition is prepared by a conventional method. Compound 101 g is dissolved in purified soybean oil 100 g, and purified egg yolk lecithin 12 g and glycerin 25 g for injection are added. After sterile filtration this mixture with Day Supoza Bull type membrane filter of _c obtained dispersion 0.2 // m to kneading and emulsified as 1000 mL with distilled water for injection by a conventional method, by 2 mL to the glass vials Fill aseptically to give an injection (containing 2 mg of active ingredient per vial). Formulation Compound 102 mg

Refined soybean oil 200 mg

Purified egg yolk lecithin 24 mg

Glycerin for injection 50 mg

1.72 mL of distilled water for injection

2.00 mL industrial availability

According to the present invention, there is provided an Hsp90 family protein inhibitor and the like containing a cyclic acetic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient, which is useful as a pharmaceutical such as an antitumor agent.

Claims

The scope of the claims

General formula (I)

(Wherein, II ¹ , R \ R ³ and R ⁴ are the same or different and each represent a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Halogen, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted lower alkoxycarboxy-loxy, carbamoyloxy Substituted or unsubstituted lower alkylaminocarbonyloxy, substituted or unsubstituted di-lower alkylaminocarbonyloxy, amino, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, Substituted or unsubstituted lower Al Amino, substituted or unsubstituted lower alkylsulfonylamino, rubamoylamino, substituted or unsubstituted lower alkylcarbamoylamino, substituted or unsubstituted di-lower alkyl rubamoylamino, substituted or unsubstituted lower alkoxycarbonylamino, Droxyamino, substituted or unsubstituted lower alkylthio, nitro, cyano, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted arylo, substituted or unsubstituted arylyl Or represents a substituted or unsubstituted aralkyl,

X represents an oxygen atom, a sulfur atom, one N (R ⁵ ) _ (where R ⁵ represents a hydrogen atom or a substituted or unsubstituted lower alkyl) or —CH ₂ —,

a is CR ^al R ^a2 — wherein R ^al and R ^a2 are the same or different and each represents a hydrogen atom, a hydroxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy, a substituted or Unsubstituted arylalkyl, substituted or unsubstituted aryl Luoxy, one

(Wherein, is a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, amino, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, substituted or unsubstituted arylamino or substituted or unsubstituted arylamino. Represents an unsubstituted aralkylamino), represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, or Ral and Ra2 together represent an oxygen atom (

(Wherein 4 represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl) or one O (CH ₂ ) _r O— (where r is Represents 2 or 3), represents a substituted or unsubstituted arylene, a substituted or unsubstituted divalent heterocyclic group or a bond,

b is one (CR ^bl R ^b2 ) _m — wherein m represents an integer from 0 to 5, and R ^bl and R ^b2 are the same or different and each represents a hydrogen atom, a hydroxy, a substituted or unsubstituted Represents lower alkoxy, substituted or unsubstituted lower alkanoyloxy or substituted or unsubstituted lower alkyl, or: R ^bl and R ^b2 together represent an oxygen atom (= 0)] or — CHR ^b3 CR ^b4 R ^b5 — (wherein R ^¾3 , R ^b4 and R ^b5 are the same or different and each represents a hydrogen atom, hydroxy, halogen, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkyl, Nyloxy, amino, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted lower alkylthio, substituted or unsubstituted amino One Lucio, substituted or unsubstituted lower alkyl, or substituted or represents unsubstituted Ariru or substituted or unsubstituted heterocyclic group, or R ^b3 and R ^b4 represents together a connexion bond or an oxygen atom, Or R ^b4 and R ^b5 together represent an oxygen atom (= 0),

c is one (CRciRc ^ CHI ^ CI ^ R ^ p— (wherein, n and p have the same meanings as the above m, R ^cl and R ^c2 have the same meanings as the above R ^al and Ra ² , respectively, R ^c3 , R ^c4 and R ^c5 represent the same as the above R ^b3 , respectively: R ^b4 and ¹³⁵ ),

d is one (CR ^d iCR ^d2 ) _q — (where q is the same as m, Rdi and _R d2 are the same as Ral and Ra2, respectively) or one CHR ^d3 CR ^d4 R ^d5 — (formula Wherein, R ^d3 , and! Id ⁵ represent the same as Rb ³ ,: and _R b ⁵ , respectively. is (wherein, H ^el and R ^e2 are the same or different, represent a hydrogen atom or a substituted or unsubstituted lower alkyl) Single CR ^el R ^e2 _ e cyclic full sulfonyl acid derivative or represented by represents a} A heat shock protein 90 (Hsp90) family protein inhibitor comprising a pharmacologically acceptable salt as an active ingredient.

2.H ² and R ⁴ are the same or different and each is hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted 2. The Hsp90 family protein inhibitor according to claim 1, which is an arylalkyloxy, a lower alkoxycarbonyloxy, a rubamoyloxy, a lower alkylamino liponyloxy or a di-lower alkylaminocarbonyloxy.

3. The Hsp90 family protein inhibitor according to claim 1, wherein R ² and R ⁴ are hydroxy or substituted or unsubstituted lower alkoxy.

4. Hsp90 Fuamiri one protein inhibitor according to any one of claims 1-3 claims wherein R ¹ and R ³ are hydrogen atoms.

5. X is an oxygen atom, a is one CR ^a ¾ ^a2 — (wherein, R ^al and R ^a2 are each as defined above), and b is —CHR ^b3 CRb4 _R b5 (formula Medium, _R b3, Rb4 and

R ^b5 is as defined above, and c is _CR ^c ¾ ^c2 — (where R ^cl and

Rc2 are the same meanings as defined above, respectively), d is in one CHRd3C¾d4 _R d ₅ i (wherein, _R d3, and Rds is the same meanings as defined above, respectively), and _e is one CH (CH ₃₎ - The Hsp90 family protein inhibitor according to any one of claims 1 to 4, wherein

6. X is an oxygen atom, a is a substituted or unsubstituted divalent heterocyclic group, b and c represent a bond, and d is _CHR ^d3 CIi ^d4 Il ^d5 — (where R ^d3 , and Rd5 are the same meanings as defined above, respectively), e gar CH (CH ₃₎ - Hsp90 Fuamiri protein inhibitor according to any one of claims 1 to 4 wherein a.

7. General formula (I)

(Wherein, II ¹ , R ² , R ³ , R ⁴ , X, a, b, c, d and e are as defined above) or a pharmacologically active derivative thereof. A therapeutic agent for a disease involving Hsp90 family protein or an Hsp90 family protein-binding protein (Hsp90 client protein) containing an acceptable salt as an active ingredient.

8. When R ² and R ⁴ are the same or different, they are hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted A protein to which the Hsp90 family protein or the Hsp90 family protein described in claim 4 is an arylalkyloxy, a lower alkoxycarbonyloxy, a rubamoyloxy, a lower alkylaminoaminocarbonyl or a di-lower alkylaminocarbonyloxy. Therapeutic agent for diseases involving client protein).

9. R ² and R ⁴ are hydroxy or substituted or unsubstituted lower alkoxy Hsp90 Fuamiri protein of sheet in claims 7 wherein is or Hsp90 Fuamiri one protein protein binds (Hs _P 90 client protein) disease is involved Therapeutic agent.

10. The Hsp90 family protein or the protein to which the Hsp90 family protein according to any one of claims 7 to 9, wherein R ¹ and H ³ are hydrogen atoms.

(Hsp90 client protein).

11. X is an oxygen atom, a is —CR ^{a a2} — (wherein, R ^al and R ^a2 are each as defined above), and b is —CHRb3 _CR b4 _R b5— (wherein , _R b3, Rb4 and R ^b5 are each as defined above, and c is one CR ^cl R ^c2 — (wherein ^,: ^cl and R ^c2 are each as defined above). And d is —CHRd ³ CRd ⁴ Rd ⁵ — (wherein Rd ³ and Rds are each as defined above), and _e is

— An agent for treating a disease involving a protein to which an Hsp90 family protein or an Hsp90 family protein binds (Hsp90 client protein) according to any one of claims 7 to 10, which is CH (CH ₃ ) —.

12. X is an oxygen atom, a is a substituted or unsubstituted divalent heterocyclic group, b and c represent a bond, d is one CHR ^d3 CR ^d4 : R ^d5 — ^d3, R ^d4 and Ras are the same meanings as defined above, respectively), e is one CH (CH ₃₎ - an Hsp90 family protein or Hsp90 family蛋according to any one of claims 7-10 according to which Therapeutic agent for diseases involving proteins to which white matter binds (Hsp90 client protein). '

13. General formula (I)

(Wherein, I ¹ , RR ³ , R ⁴ , a, b, c, d and e are as defined above) or a pharmacologically acceptable salt thereof is effective. An antitumor agent contained as a component.

14.R ² and R ⁴ are the same or different and are hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted aralkyloxy 14. The antitumor agent according to claim 13, which is a lower alkoxycarbonyloxy, a rubamoyloxy, a lower alkylamino liponyloxy or a di-lower alkylaminocarbonylcarbonyl.

15. The antitumor agent according to claim 13, wherein R ² and R ⁴ are hydroxy or substituted or unsubstituted lower alkoxy.

The antitumor agent of the mounting serial to any one of 16. H ¹ and R ³ in the range 13-15 according hydrogen atom.

17. X is an oxygen atom, a is one CR ^{a a2} — (wherein R ^al and R ^a2 are as defined above, respectively), and b is _ CHR ^b3 CRb4 _R b5 one (wherein , _R b3: and R ^b5 are as defined above, and c is —CR ^cl R ^c2 — (wherein, R ^cl and R ^c2 are as defined above, respectively). And d is —CHR ^d3 CR ^d4 R ^d5 — (wherein, Rds and Rds are as defined above), and _e is one CH (CH ₃ ) —. The antitumor agent according to any one of the above.

18. X is an oxygen atom, a is a substituted or unsubstituted divalent heterocyclic group, b and c represent a bond, d is -CHR ^d3 CR ^d4 R ^d5 — (wherein, R ^d3 , R ^d4 and Rd5 are the same as defined above, respectively, and e is -CH (CH ₃ )-. The antitumor agent _{c according} to any one of the above 16

19. General formula (I)

(Wherein, RR ² , R ³ , R ⁴ , X, a, b, c, d and e have the same meanings as described above) or a pharmacologically acceptable derivative thereof. A method for inhibiting Hsp90 family protein, which comprises administering an effective amount of a salt.

20. General formula (I)

(Wherein, II ¹ , R ² , R ³ , R ⁴ , X, a, b, c, d and e are as defined above) or a pharmacologically active derivative thereof. A method for treating a disease involving an Hsp90 family protein or a protein to which the Hsp90 family protein binds (Hsp90 client protein), which comprises administering an effective amount of an acceptable salt.

21. General formula (I)

(Wherein Ri, R ² , R ³ , H ⁴ , X, a, b, c, d and e are as defined above) or a pharmacologically acceptable derivative thereof. Of salt A method for treating a malignant tumor, which comprises administering an effective amount.

22. General formula (I) for production of Hsp90 family protein inhibitors

(Wherein, II ¹ , R \ R \ R ⁴ , X, a, b, c, d and e have the same meanings as described above), respectively, or a pharmacologically acceptable derivative thereof. Use of salt. ,

23. General formula for the manufacture of a therapeutic agent for diseases involving Hsp90 family protein or a protein to which Hsp90 family protein binds (Hsp90 client protein)

(I)

_{^{(Wherein, Ri, R2 N R 3,}} R 4, X, a, b, c, d and e are each the and Ru synonymous der) cyclic full represented by - Le acid derivative or a pharmacologically Use of acceptable salts.

24. General formula (I) for the production of an antitumor agent

Wherein Ri, R ² , H ³ , RX, a, b, c, d and e have the same meanings as defined above, or a pharmacologically acceptable derivative thereof. Salt ^