JP5372096B2 - 新規な抗腫瘍化合物 - Google Patents
新規な抗腫瘍化合物 Download PDFInfo
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- JP5372096B2 JP5372096B2 JP2011214682A JP2011214682A JP5372096B2 JP 5372096 B2 JP5372096 B2 JP 5372096B2 JP 2011214682 A JP2011214682 A JP 2011214682A JP 2011214682 A JP2011214682 A JP 2011214682A JP 5372096 B2 JP5372096 B2 JP 5372096B2
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- kahalalide
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- FXHGMKSSBGDXIY-UHFFFAOYSA-N heptanal Chemical compound CCCCCCC=O FXHGMKSSBGDXIY-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 150000002430 hydrocarbons Chemical group 0.000 description 1
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- FXHCFPUEIDRTMR-UHFFFAOYSA-N hydron;1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;chloride Chemical compound Cl.C1=CC=C2CNC(C(=O)O)CC2=C1 FXHCFPUEIDRTMR-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 108010090761 kahalalide O Proteins 0.000 description 1
- NEXGSZAIWOZENU-UHFFFAOYSA-N kahalalide O Natural products N1C(=O)C(NC(=O)CNC(=O)CCCC(C)C)C(C)OC(=O)C(C(C)C)NC(=O)C(C(C)CC)NC(=O)C(C(C)O)NC(=O)C(CC=2C3=CC=CC=C3NC=2)NC(=O)C1CC1=CC=C(O)C=C1 NEXGSZAIWOZENU-UHFFFAOYSA-N 0.000 description 1
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- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
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- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
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- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- PUPKPAZSFZOLOR-UHFFFAOYSA-N n,n-dimethylformamide;toluene Chemical compound CN(C)C=O.CC1=CC=CC=C1 PUPKPAZSFZOLOR-UHFFFAOYSA-N 0.000 description 1
- NEXGSZAIWOZENU-CDKWWZSLSA-N n-[2-[[(3s,6s,9s,12r,15r,18s,19r)-6-[(2s)-butan-2-yl]-9-[(1r)-1-hydroxyethyl]-15-[(4-hydroxyphenyl)methyl]-12-(1h-indol-3-ylmethyl)-19-methyl-2,5,8,11,14,17-hexaoxo-3-propan-2-yl-1-oxa-4,7,10,13,16-pentazacyclononadec-18-yl]amino]-2-oxoethyl]-5-methylhexa Chemical compound C([C@@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(=O)N[C@H](C(N[C@H](C(=O)O[C@H](C)[C@H](NC(=O)CNC(=O)CCCC(C)C)C(=O)N1)C(C)C)=O)[C@@H](C)CC)[C@@H](C)O)C1=CC=C(O)C=C1 NEXGSZAIWOZENU-CDKWWZSLSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 125000005561 phenanthryl group Chemical group 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
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- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
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- 238000000159 protein binding assay Methods 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- OWBFRQWDQDYNNF-IBTYICNHSA-N tert-butyl (2s,3r)-2-amino-3-hydroxybutanoate;hydrochloride Chemical compound Cl.C[C@@H](O)[C@H](N)C(=O)OC(C)(C)C OWBFRQWDQDYNNF-IBTYICNHSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
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- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Description
本発明はまた、末端脂肪酸基が他のアシル基によって置換されているか、又は除去されている、式1で表される化合物に係る。
本発明はまた、脂肪族メチルヘキサン酸のアシル基が他のアシル基によって置換されているか、除去されている、式1で表される化合物に係る。
本発明の好ましい化合物は、環外鎖の1個又は複数のアミノ酸が他の天然又は非天然のアミノ酸によって置換されているか、有機基によってマスクされているか、又は除去されている、式1で表される化合物を含む。
本発明の他の好ましい化合物は、環状鎖の1個又は複数のアミノ酸が他の天然又は非天然のアミノ酸によって置換され、有機基によってマスクされ又は除去された式1で表される化合物を含む。
環外鎖及び/又は環状部分のアミノ酸の修飾に加え、環外鎖の末端アシル基において修飾を有する化合物であってもよい。
-炭素原子数26までで、1個又は複数の置換基、特に、4-メチルシクロヘキシル等の場合によって置換されたシクロアルキル;アルキル、特にメチル等の短鎖アルキル;場合によって置換されたアリール、特にジフルオロフェニル等のフェニル;パーフルオロまでのフルオロ等のハロ;オキソ;アミノ;又はイミノから選択された置換基を有する直鎖アルカノイル、
-場合によって置換されたベンゾイル、例えばベンゾイル自体、p-メチルベンゾイル酸、p-トリフルオロメチルベンゾイル酸、ピペロニロイル、
-好ましくはアルケノイル中に2個の炭素原子を有するアリールアルケノイル基、特にp-トリフルオロメチルシンナモイル等のシンナモイル基、
を含む。
環外アミノ酸、環状アミノ酸及び末端アシル基における可能な変化は組合せることができる。
-8位のL-Ornの代わりにGlu又はLysであり;
-11位のL-Valの代わりにGly、Phe、Ala、Leu、D-Val、Pro、Gln、Orn、Thr又はGluであり;
-12位のL-Thrの代わりにVal又はD-Thrであり;
-13位のD-Valの代わりにGly、D-Ala、D-Leu、D-Phe、D-Pro、Val、D-Glu、D-Gln又はD-Thrであり;
-11位のL-Valの代わりにhCh、及び/又は13位のD-Valの代わりにD-Chaであり;
-12位のL-Thrの代わりにAla、Gly、Leu、Pro、Glu、Orn又はGlnであり、及び13位のアミノ酸が存在せず;
-7位のD-allo-Ileの代わりにD-Ile又はD-Valであり;
-8位のL-Ornの代わりにD-Ornであり、及び9位のD-Proの代わりにL-Proであり;
-7位のD-allo-Ileの代わりにD-Cysであり、及び11位のL-Valの代わりにL-Cysであり;又は
-7位のD-allo-Ileの代わりにD-Cys又はD-homo-Cysであり、及び10位のD-Valの代わりにD-Cys又はD-homo-Cysであり;
-14位の5-MeHexの代わりにIcos、(c/t)-4-Me-cHexa、Und、(4R)-MeHex、(4RS)-MeHex、(4S)-MeHex、Oct、p-MeBza、Bza、p-CF3Bza、3,5-dFPhAc、Pipe、p-CF3Cinn、p-CF3PhAc、Pfh、6-OHep、6,6-dFHep、4-GuBut、AM、AO又はC(=N(CH3)2)であり、及び場合によって8位のL-Ornの代わりにLysであり;
-9位のD-Proの代わりにPro、D-Pip、D-Tic又は(5R)-Ph-Proであり、及び14位の5-MeHexの代わりに(4S)-MeHexであり;
-8位のL-Ornの代わりにN(Me)2,N'(Me)2-Arg、N(Me,Ph),N'(Me)2-Arg、N(CH2)4,N'(Me)2-Arg、N(CH2)4,N'(CH2)4-Arg、Nδ(CHN(CH2)4,N'(CH2)4)-Orn、Nε(Me)3-Lys、Orn(NδTfa)又はOrn(Biot)であり、及び場合によって14位の5-MeHexの代わりに(4S)-MeHexであり、及び場合によって12位のL-Thrの代わりにThr(OTfa)であり;
-12位のL-Thrの代わりにThr(OTfa)であり、及び14位の5-MeHexの代わりに(4S)-MeHex又はLit(OTfa)であり;
-13位のD-Valの代わりにN-(Hep)2-D-Valであり、及び14位の5-MeHexが存在せず;又は
-11、12及び13位のアミノ酸が存在せず、及び場合によって14位の5-MeHexの代わりにMstであり;
-2位のZ-Dhbの代わりにDha又はE-Dhbであり;
-2位のThrの代わりにD,L-Ser、Gly又はAibであり、水素化した類似体であり;
-1位のL-Valの代わりにD-Valであり;
-3位のL-Pheの代わりにTrpであり;
-6位のD-alo-Thrの代わりにD-Thr又はD-Serであり;
-3位のL-Pheの代わりにhCh、Phe(3,4-Cl2)、Phe(F5)、Phe(4-I)、Phe(4-NO2)、Phe(4-F)、Tyr(Me)、Thi、Tic、Tyr、Oic、NMePhe、Phe(2-Cl)、Phe(3-Cl)、Phe(4-Cl)、Phe(3,4-F2)、NaI、Bip又はPhgであり、及び場合によって14位の5-MeHexの代わりに(4S)-MeHex又はp-CF3Cinnであり、
-5及び7位のD-alo-Ileの代わりにD-Val又はD-Chaであり、及び場合によって4位のD-Valの代わりにD-Chaであり;又は
-1位のL-Valの代わりにD-Valであり、3位のL-Pheの代わりにD-Pheであり、4位のD-Valの代わりにValであり、5位のD-alo-Ileの代わりにL-alo-Ileであり、6位のD-alo-Thrの代わりにL-alo-Thrであり、7位のD-alo-Ileの代わりにL-alo-Ileであり、8位のL-Ornの代わりにD-Ornであり、9位のD-Proの代わりにL-Proであり、10位のD-Valの代わりにL-Valであり、11位のL-Val代わりにD-Valであり、12位のL-Thrの代わりにD-Thrであり、及び13位のD-Valの代わりにL-Valである。
(a)クロロトリチルクロロ樹脂上にFmoc-D-Val-OHを組み込み、エステル結合を形成し;
(b)Fmoc/tBuストラテジーを用い、3個のアミノ酸[DaIle,DaThr(遊離OH),DaIle]によりペプチド鎖を延長し;
(c)Alloc/tBuストラテジーを用い、[Val(1)]を組み込み;
(d)Fmoc/tBuストラテジーを用い、残存するアミノ酸及び脂肪族カルボン酸によりペプチド鎖を延長し;
(e1)溶液中で結合し脱水した、ジペプチドAlloc-Phe-ZDhb-OHを組み込み;
(e2a)2個のアミノ酸、好ましくはThr及びPheによりペプチド鎖を延長する。ThrのOHは保護されておらず、Pheのアミノ基又はその置換体はFmoc又は好ましくはAllocにより保護されており;Fmocにより保護されているいくつかの場合において、これが除去されAllocが固相に導入され;
(e2b)固相における脱水によりジデヒドロペプチドを生成し;
(f)Phe、又はその置換体のAlloc/Fmoc基を除去し、一方、ペプチドはなお固体支持体に結合しており;
(g)固体支持体からペプチドを保護した側鎖を切断し;
(h)溶液中でペプチドを環化し;
(i)TFAの不安定な側鎖保護基を除去し;
(j)さらに溶液相で官能基を修飾する。
Fmoc-D-Val-OHを好ましくはクロロトリチルポリスチレン樹脂に組み込み、Barlos, K.; Gatos, D.; Schafer, W. Angew. Chem. Int. Ed. Engl. 1991, 30, 590〜593頁参照、DIPEAの存在下、置換のレベルを約0.5mmol/gに維持する。より高い挿入量の使用は最終生成物中に終端となったペプチドの存在をもたらす、Chiva, C.; Vilaseca, M.; Giralt, E.; Albericio, F. J. Pept. Sci. 1991, 5, 131〜140頁参照。
Cl-TrtCl-樹脂、保護されたFmoc-アミノ酸誘導体、HOBt、HOAtは、ABI(Framingham, MA)、Bachem(Bubendorf, Switzerland)、NovaBiochem(Laufelfingen, Switzerland)から、4-MeHex誘導体はNarchemから、HATU及び他のグアニジル化誘導体はABI(Framingham, MA)から入手するか、del Fresno, M.; El-Faham, A.; Carpino, L.A.; Royo, M.; Albericio, F. Organic Lett., 2000, 2, 3539〜3542頁に従って調製した。
(4S)-MeHex-D-Val-ThrVal-D-Val-D-Pro-Orn-D-allo-Ile-cyclo[D-allo-Thr-D-allo-Ile-D-Val-Phe-(Z)Dhb-Val], [(4S)-MeHex14]-カハラリドF(化合物1)
Cl-TrtCl-樹脂(1g、1.64mmol/g)をポリエチレンフィルターディスクを取り付けた20mLのポリプロピレンシリンジ内に設置した。次に樹脂をCH2Cl2で洗浄し(5x0.5分)、Fmoc-D-Val-OH(238mg、0.7mmol、0.7当量)及びDIPEA(0.41mL)を含むCH2Cl2(2.5mL)溶液を加え、混合物を15分間撹拌し、DIPEA(0.81mL、合計7当量、7mmol)を追加し、及び混合物を45分間撹拌した。10分間撹拌した後MeOH(800μL)を添加することにより反応を停止させた。Fmoc-D-Val-O-TrtCl-樹脂を、一般的手順に記載されているようにCH2Cl2(3x0.5分)、DMF(3x0.5分)、ピペリジン、及びDMF(5x0.5分)により洗浄/処理した。Fmoc測定により計算された挿入量は0.50mmol/gであった。
Fmoc-D-allo-Ile-OH(707mg、2mmol、4当量)、Fmoc-D-allo-Thr-OH(遊離の水酸基)(683mg、2mmol、4当量)、及びFmoc-D-allo-Ile-OH(707mg、2mmol、4当量)を、DMF(2.5mL)中のDIPCDI(310μL、2mmol、4当量)及びHOBt(307mg、2mmol、4当量)を用い、上で得られたH-D-Val-O-TrtCl-樹脂に順次加えた。すべての場合において、90分間のカップリング後、ニンヒドリン試験は陰性であった。Fmoc基の除去及び洗浄は、一般的手順の記載に従って行った。Alloc-Val-OH(502mg、2.5mmol、5当量)は、DMAP(30.6mg、0.25mmol、0.5当量)及びDIPEA(88μL、0.5mmol、1当量)の存在下、45分間DIPCDI(387mg、2.5mmol、5当量)とカップリングした。このカップリングは同一の条件で2回繰り返した。ペプチジル-樹脂の一定量をTFAで処理し、そして蒸発後に得られた粗生成物のHPLC(tR7.8分、条件S、カラムD)は>98%の純度を示した。ESMS、C45H63N5O11に対する計算値は、849.45である。実測値:m/z 850.1[M+H]+。
Fmoc基が除去され、Fmoc-Orn(Boc)-OH(912mg、2mmol、4当量)、Fmoc-D-Pro-OH(843mg、2.5mmol、5当量)、及びFmoc-D-Val-OH(255mg、2.5mmol、5当量)を、DIPCDI(2.0mmol及び4当量に対し310μL;2.5mmol、5当量に対し388μL)及びHOBt(2.0mmol及び4当量に対し307mg;2.5mmol、5当量に対し395mg)を90分間用い、上で得られたペプチジル-樹脂(工程2)に順次添加した。Orn及びD-Proを組み込んだ後のニンヒドリン試験は陰性であった。D-Valを組み込んだ後のクロルアニルはわずかに陽性であった。したがってこの残基の再カップリングをFmoc-D-Val-OH(678mg、2.0mmol、4当量)、DIPCDI(310μL、2.0mmol、4当量)及びHOBt(307mg、2.0mmol、4当量)を用い90分間行った。ペプチジル-樹脂の一定量をTFAで処理し、そして蒸発後に得られた粗生成物のHPLC(tR10.1分、条件S、カラムD)は>98%の純度を示した。MALDI-TOF-MS、C65H97N9O16に対する計算値は、1,259.71である。実測値:m/z 1,282.16[M+Na]+。
Fmoc基が除去され、Fmoc-Val-OH(678mg、2mmol、4当量)、Fmoc-Thr(tBu)-OH(992mg、2.5mmol、5当量)、Fmoc-D-Val-OH(678mg、2mmol、4当量)、及び(4S)-MeHex-OH(195mg、1.5mmol、3当量)を、DIPCDI(1.5mmol及び3当量に対し233μL;2mmol及び4当量に対し310μL、及び2.5mmol及び5当量に対し388μL)及びHOBt(1.5mmol及び3当量に対し230mg;2mmol及び4当量に対し307mg、及び2.5mmol及び5当量に対し395mg)を90分間用い、上記のペプチジル-樹脂(工程3)に順次添加した。すべての場合において、90分のカップリング後、ニンヒドリン試験は陰性であった。Fmoc基の除去及び洗浄は一般的手順の記載に従って行った。
Alloc基をAr雰囲気中、PhSiH3(617μL、5mmol、10当量)の存在下でPd(PPh3)4(58mg、0.05mmol、0.1当量)により除去し、Alloc-Phe-Z-Dhb-OH(666mg、2mmol、4当量)及びHOAt(273mg、2mmol、4当量)をDMF(1.25mL)中に溶解し、ペプチジル樹脂に加え、次いでDIPCDI(310μL、2mmol、4当量)を加え、混合物を5時間撹拌したところ、ニンヒドリン試験は陰性であった。DMF及びCH2Cl2により洗浄後、ペプチジル樹脂の一定量をTFA-H2O(1:99)で1分間処理し、生成物の特徴をMALDI-TOF-MSにより調べた。C88H146N14O21に対する計算値は、1,735.08である。実測値:m/z 1,758.67[M+Na]+、1,774.62[M+K]+。
DMF及びCH2Cl2により洗浄後、Alloc基をAr雰囲気中、PhSiH3(617μL、5mmol、10当量)の存在下でPd(PPh3)4(58mg、0.05mmol、0.1当量)により除去した。保護されたペプチドをTFA-CH2Cl2(1:99)により樹脂から切断した(5x30秒)。ろ液をH2O(4mL)に集め、H2Oをロータベーパーにより一部除去した。次いでACNを加え、H2O除去中に析出した固体を溶解し、溶液を凍結乾燥し、639mg(387μmol、収率77%)の標記化合物をHPLC(条件R、カラムC、tR10.5分)による試験で>95%の純度で得た。
保護されたペプチド(工程6)(639mg、387μmol)をCH2Cl2(390mL、1mM)に溶解し、HOBt(237mg、1.55mmol)をHOBtの溶解に必要な最少量のDMFに溶解し、DIPEA(203μL、1.16mmol、3当量)、及びDIPCDI(240μL、1.55mmol、4当量)を加えた。混合物を1時間撹拌し、次いで環化工程の経過をHPLCにより調べた。溶媒を減圧下で蒸発させることにより除去した。保護された環状ペプチドをTFA-H2O(19:1、85mL)に溶解し、混合物を1時間撹拌した。溶媒を減圧下で蒸発させることにより除去し、ジオキサン(30mL)を加え、溶媒を減圧下で蒸発させることにより除去し(このプロセスを3回繰り返した)、次にH2O(40mL)を加え、凍結乾燥した。粗生成物をHPLC(Kromasil C8 5μm、205x50mm)、水(+0.05% TFA)に溶かした44%アセトニトリル(+0.05% TFA)を用いたイソクラティックで、55mL/時間、220nm検出により精製し、標記生成物(192mg、0.13mmol、収率26%、92.3%)を得た。MALDI-TOF-MS、C75H124N14O16に対する計算値は、1,476.93である。実測値:m/z 1,500.12[M+Na]+、1,515.97[M+K]+。1H-NMR(2.5mM、500KHz、H2O-D2O(9:1)化合物のスペクトルを表IIに示す)。
表IIIに示す類似体は、欄(工程)に示された工程[残基(A)は他の残基(B)によって置き換えられたか除去(none)されている]である以外、実施例1に記載の実験手順と同様にして合成した。
5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo[D-allo-Thr-D-alo-Ile-D-Val-hCh-(Z)-Dhb-Val](化合物63)
工程4において(4S)-MeHexを5-MeHexにより置換し、かつ工程5を以下の実験手順に従って行った以外、実施例1に記載の実験手順と同様にした:
5-MeHex-D-Val-Thr(tBu)-Val-D-Val-D-Pro-Orn(Boc)-D-allo-Ile-D-alo-Thr(Val-Alloc)-D-allo-Ile-D-Val-O-2-Clorotrityl-Ps(250mg、初期挿入量=0.5mmol/g樹脂)からAlloc基を、上記と同様にAr雰囲気中、PhSiH3の存在下でPd(PPh3)4により除去した。Fmoc-Thr-OH(遊離の水酸基)(213.2mg; 0.63mmol; 5当量)及びFmoc-hCha-OH(254.0mg; 0.63mmol; 5当量)を、DMF中のDIPCDI(96.8mg; 0.63mmol; 5当量)及びHOBt(85mg; 0.63mmol; 5当量)を用い、上記のペプチジル-樹脂に順次添加した。DMFにより十分に洗浄後(5x30秒)、該ペプチジル-樹脂をCH2Cl2-DMF(1:9)中のEDC-HCl(479mg、2,5mmol、20当量)、CuCl(184mg、1,5mmol、12当量)により6日間処理した。DMF、CH2Cl2、及びDMFで十分に洗浄後、実施例1に記載の実験手順に従い、KF類似体を得た。
表IVに記載の類似体を、工程4の(4S)-MeHexを5-MeHexにより置換し、工程5を実施例3に記載と同様に行った以外、実施例1に記載の実験手順に従って合成し、ただしFmoc-hCh-OHの代わりにFmoc-Phe-OHを組み込み、及び欄(工程)に示された工程において、残基(A)は他の残基(B)により置換されたか、除去(none)された。類似体64〜66において、該類似体は水素化されているため、脱水反応は採用しなかった。
表Vに記載の類似体は、工程5を実施例3における記載と同様に行った以外、実施例1に記載の実験手順に従って合成し、及び欄(工程)に示された工程において、残基(A)は他の残基(B)により置換された。さらに、固相を脱水する前に、Fmoc基を一般的手順における記載に従って除去し、アミノ基をDIPEA(5当量)の存在下、溶媒としてDMFを用い、Alloc-OSu(5当量)との反応(2時間)によりAllocの形態で保護した。
[N(Me)2,N'(Me)2-Arg8]-カハラリドF(化合物89)
DIPEA(1.73μL; 10.17μmol)及びHATU(3.86mg; 10.15μmol)をDMF(5ml)に溶解したカハラリドF(10.0mg; 6.76μmol)に添加した。反応をHPLCにより追跡し、4時間後、DMFを減圧下で除去し、残渣をCH3CN-H2O-AcOH(4.5:4.5:1、20ml)に溶解し、凍結乾燥し、粗精製HPLCにより精製し、標記の類似体(4.5mg、40%)を得た。
[N(Me,Ph),N'(Me)2-Arg8]-カハラリドF(化合物90)
HATU:1.63mg、12%の代わりにHAPyU(4.87mg、10.15μmol)を用いた以外、実施例6に記載の実験手順を用いた。
[N(CH2)4,N'(Me)2-Arg8]-カハラリドF(化合物91)
HATU:5.2mg、46%の代わりにM2A(4.12mg、10.14μmol)を用いた以外、実施例6に記載の実験手順を用いた。
[N(CH2)4,N'(CH2)4-Arg8]-カハラリドF(化合物92a)及び[Nδ(CHN(CH2)4,N'(CH2)4)-Orn8]-カハラリドF(化合物92b)
HATUの代わりにBTFFH(約50%の1,1'-(フルオロメチレン)ジピロリジン)(3.16mg; 10.16μmを含有する)を用いた以外、実施例6に記載の実験手順を用いた。2つの生成物、92a及び92b、が得られ、それら(1:1の比率の4.0mgの混合物、35.6%)を分離することができなかった。
[Nε(Me)3-Lys8,(4S)-MeHex14]-KF(化合物93)
DIPEA(10μL; 58.8μmol)及びMeI(6μL;0.100mmol)をDMF/DCM(1:1、5ml)に溶解した[Lys8、(4S)-MeHex14]-カハラリドF(化合物30)(5.0mg; 3.35μmol)に加えた。反応をHPLCにより追跡し、12時間後、溶媒を減圧下で除去し、残渣をCH3CN-H2O-AcOH(4.5:4.5:1、20ml)に溶解し、凍結乾燥し、粗精製HPLCにより精製し、標記の類似体(2.2mg、44%)を得た。
[Thr(OTfa)12,4(S)MeHex14]-カハラリドF(化合物94)
[4(S)MeHex14]-カハラリドF(化合物1;10.0mg; 6.7μmol)をTFA-DCM(1:1、20mL)に溶解し、室温で3日間撹拌した。次に、溶媒を減圧下で除去し、残渣をH2O-CH3CN(1:9)に溶解し、試料が水に溶解している時間を最小限にするように直ちに精製した。標記の類似体に対応する分画を液体N2に没入させた丸底フラスコに集め、凍結乾燥した(2.5mg; 25%)。
[Orn(NδTfa)8, Thr(OTfa)12,4(S)MeHex14]-カハラリドF(化合物95)
[4(S)-MeHex14]-KF(化合物1;10mg; 6.7μmol)をDCM(8mL)に溶解し;TFAA(18.9μL; 134μmol)及びDIPEA(22.8μL; 134μmol)を加え、12時間反応させた。次に、溶媒を減圧下で除去し、H2O-CH3CN(1:1)に再溶解し、及び直ちに精製した(2.0mg; 20%)。
[Orn(NδTfa)8,4(S)MeHex14]-カハラリドF(化合物96)
精製前に、類似体をH2O-CH3CN(1:1)に溶解し、溶液中に2時間放置し、精製した(4.3mg; 43%)以外、実施例12に記載の実験手順を用いた。
[Thr(OTfa)12,Lit(OTfa)14]-カハラリドF(化合物97)
工程4において(4S)-MeHexをLit-OHによって置き換え、工程7において環状ペプチドをTFA-DCM(1:1、20ml)に溶解し、室温で3日間撹拌した以外、実施例1に記載の実験手順を用いた。この時間の後、一定量(10%)から溶媒を減圧下で除去し、固体残渣をH2O-CH3CN(1:9)に溶解し、試料がH2Oに溶解している時間を最小限にするように直ちに精製した。標記の類似体に対応する分画を液体N2に没入させた丸底フラスコに集め、凍結乾燥した(5.6mg; 出発樹脂からの収率6%)。
[no5-MeHex14-N-(Hep)2-D-Val13]-カハラリドF(化合物98)
工程4において、DMF-AcOH(99:1; 2mL)に溶解したヘプタンアルデヒド(60.65μL; 0.75mmol; 5当量)をH-D-Val-Thr(tBu)-Val-D-Val-D-Pro-Orn(Boc)-D-allo-Ile-D-alo-Thr(Val-Alloc)-D-allo-Ile-D-Val-O-2-クロロトリチル-Ps(300mg; 初期挿入量=0.5mmol/g樹脂)に加え及び5分後、DMF-AcOH(99:1; 1mL)に溶解したNaBH3CN(28.28mg; 0.45mmol; 3当量)を加えた以外、実施例1に記載の実験手順を用い、混合物を2時間反応させた。HPLCにより反応を観察しながらこの処理をさらに2回繰り返した。
[Orn(Biot)8]-カハラリドF(化合物99)
カハラリドF(150.0mg; 94.3μmol)、d-ビオチン(37.0mg、151.5μmol)及びHATU(114.0mg、299.8μmol)をAr雰囲気中で無水DCM(6.0ml)に溶解し、NMM(58μl、524.0μmol)を加えた。混合物を20時間撹拌した。次に、溶媒を減圧下で除去し、残渣をMeOH中に溶解し、精製した。標記の類似体に対応する分画を凍結乾燥した(74.0mg; 43%)。
特性を表VI及びVIIに示す。表VI中のEMはMALDI-TOFに対応し、正確な質量はChemwind 6.0により計算し、及び表VII中のEMはpositive modeでのAPCIに対応する。
本発明の化合物の生物学的活性を以下に記載の方法に従って得られた下記の表の結果により示す。この分析の最終的な判断は、細胞を試験試料に継続して提示する方法により、「in vitro」の腫瘍細胞培養の成長を中断させることによって判断した。
Claims (4)
- 請求項1に記載の化合物、及び薬学上許容される担体、賦形剤又は希釈剤を含む医薬組成物。
- 医薬としての使用のための、請求項1に記載の化合物または請求項2に記載の医薬組成物。
- 癌の処置における使用のための、請求項1に記載の化合物または請求項2に記載の医薬組成物。
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JP2011214680A Pending JP2012051899A (ja) | 2003-09-09 | 2011-09-29 | 新規な抗腫瘍化合物 |
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JP2006525886A Expired - Fee Related JP4874796B2 (ja) | 2003-09-09 | 2004-09-09 | 新規な抗腫瘍化合物 |
JP2011214681A Pending JP2012031187A (ja) | 2003-09-09 | 2011-09-29 | 新規な抗腫瘍化合物 |
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Country Status (23)
Country | Link |
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US (1) | US20070117743A1 (ja) |
EP (6) | EP1664093B8 (ja) |
JP (4) | JP4874796B2 (ja) |
KR (1) | KR20060073618A (ja) |
CN (2) | CN100467482C (ja) |
AT (1) | ATE393776T1 (ja) |
AU (2) | AU2004270471B2 (ja) |
CA (1) | CA2537128A1 (ja) |
CY (1) | CY1108226T1 (ja) |
DE (1) | DE602004013454T2 (ja) |
DK (2) | DK1664093T3 (ja) |
ES (2) | ES2305843T3 (ja) |
GB (1) | GB0321066D0 (ja) |
HR (1) | HRP20080330T3 (ja) |
HU (1) | HUE025308T2 (ja) |
IL (1) | IL173929A (ja) |
MX (1) | MXPA06002741A (ja) |
NZ (4) | NZ545700A (ja) |
PL (1) | PL1664093T3 (ja) |
PT (1) | PT1664093E (ja) |
RU (2) | RU2395520C2 (ja) |
SI (1) | SI1664093T1 (ja) |
WO (1) | WO2005023846A1 (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0002952D0 (en) * | 2000-02-09 | 2000-03-29 | Pharma Mar Sa | Process for producing kahalalide F compounds |
GB0304367D0 (en) | 2003-02-26 | 2003-04-02 | Pharma Mar Sau | Methods for treating psoriasis |
US7507708B2 (en) | 2003-02-26 | 2009-03-24 | Pharma Mar, S.A.U. | Antitumoral compounds |
EP2207561A2 (en) * | 2007-10-19 | 2010-07-21 | Pharma Mar, S.A. | Improved antitumoral treatments |
EP2252315A1 (en) * | 2008-01-30 | 2010-11-24 | Pharma Mar, S.A. | Improved antitumoral treatments |
WO2009109649A1 (en) * | 2008-03-07 | 2009-09-11 | Pharma Mar, S.A. | Improved antitumoral treatments |
CN101519437B (zh) * | 2009-04-09 | 2012-05-02 | 中国人民解放军第二军医大学 | 西沙海绵中一种环七肽类化合物及其用途 |
CN104725266B (zh) * | 2014-04-10 | 2016-08-10 | 申俊 | 酰亚胺类化合物的合成方法 |
JOP20190254A1 (ar) | 2017-04-27 | 2019-10-27 | Pharma Mar Sa | مركبات مضادة للأورام |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CU22545A1 (es) * | 1994-11-18 | 1999-03-31 | Centro Inmunologia Molecular | Obtención de un anticuerpo quimérico y humanizado contra el receptor del factor de crecimiento epidérmico para uso diagnóstico y terapéutico |
US4943533A (en) * | 1984-03-01 | 1990-07-24 | The Regents Of The University Of California | Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor |
JPS6178719A (ja) * | 1984-09-25 | 1986-04-22 | Tanabe Seiyaku Co Ltd | 総合輸液剤 |
JP3854306B2 (ja) * | 1991-03-06 | 2006-12-06 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | ヒト化及びキメラモノクローナル抗体 |
AU661533B2 (en) * | 1992-01-20 | 1995-07-27 | Astrazeneca Ab | Quinazoline derivatives |
US6274551B1 (en) * | 1994-02-03 | 2001-08-14 | Pharmamar, S.A. | Cytotoxic and antiviral compound |
GB9302046D0 (en) | 1993-02-03 | 1993-03-24 | Pharma Mar Sa | Antiumoral compound-v |
US5705511A (en) * | 1994-10-14 | 1998-01-06 | Cephalon, Inc. | Fused pyrrolocarbazoles |
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
US5747498A (en) * | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
PT912559E (pt) * | 1996-07-13 | 2003-03-31 | Glaxo Group Ltd | Compostos heterociclicos fundidos como inibidores de proteina tirosina quinase |
US6235883B1 (en) * | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
RS49779B (sr) * | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze |
US6200598B1 (en) * | 1998-06-18 | 2001-03-13 | Duke University | Temperature-sensitive liposomal formulation |
EE200100271A (et) * | 1998-11-19 | 2002-10-15 | Warner-Lambert Company | N-[4-(3-kloro-4-fluorofenüülamino)-7-(3-morfoliin-4-üülpropoksü)kinasoliin-6-üül]ak rüülamiid kui türosiinkinaaside pöördumatu inhibiitor |
US7311924B2 (en) * | 1999-04-01 | 2007-12-25 | Hana Biosciences, Inc. | Compositions and methods for treating cancer |
UA74803C2 (uk) * | 1999-11-11 | 2006-02-15 | Осі Фармасьютікалз, Інк. | Стійкий поліморф гідрохлориду n-(3-етинілфеніл)-6,7-біс(2-метоксіетокси)-4-хіназолінаміну, спосіб його одержання (варіанти) та фармацевтичне застосування |
GB0002952D0 (en) * | 2000-02-09 | 2000-03-29 | Pharma Mar Sa | Process for producing kahalalide F compounds |
WO2002036145A2 (en) * | 2000-10-31 | 2002-05-10 | Pharma Mar, S.A. | Kahalalide f formulation |
CA2462639A1 (en) | 2001-10-19 | 2003-04-24 | Pharma Mar, S.A. | Kahalalide compounds for use in cancer therapy |
EP1572726B1 (en) * | 2002-10-18 | 2010-12-08 | Pharma Mar, S.A.U. | 4-methylhexanoic kahalalide f compound |
DK1572726T3 (da) * | 2002-10-18 | 2011-03-28 | Pharma Mar Sau | 4-methylhexansyre-kahalalid F-forbindelse |
GB0304367D0 (en) * | 2003-02-26 | 2003-04-02 | Pharma Mar Sau | Methods for treating psoriasis |
US7507708B2 (en) * | 2003-02-26 | 2009-03-24 | Pharma Mar, S.A.U. | Antitumoral compounds |
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- 2004-09-09 JP JP2006525886A patent/JP4874796B2/ja not_active Expired - Fee Related
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