JP6292568B2 - Urea derivative compound and radiopharmaceutical containing the same - Google Patents
Urea derivative compound and radiopharmaceutical containing the same Download PDFInfo
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- JP6292568B2 JP6292568B2 JP2013230229A JP2013230229A JP6292568B2 JP 6292568 B2 JP6292568 B2 JP 6292568B2 JP 2013230229 A JP2013230229 A JP 2013230229A JP 2013230229 A JP2013230229 A JP 2013230229A JP 6292568 B2 JP6292568 B2 JP 6292568B2
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- Prior art keywords
- compound
- acid
- formula
- carboxy
- urea derivative
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- -1 Urea derivative compound Chemical class 0.000 title claims description 60
- 239000012217 radiopharmaceutical Substances 0.000 title claims description 8
- 229940121896 radiopharmaceutical Drugs 0.000 title claims description 8
- 230000002799 radiopharmaceutical effect Effects 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 83
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 50
- 230000002285 radioactive effect Effects 0.000 claims description 46
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 36
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 32
- 239000011737 fluorine Substances 0.000 claims description 31
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 239000012216 imaging agent Substances 0.000 claims description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- NSTREUWFTAOOKS-COJKEBBMSA-N 2-fluoranylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[18F] NSTREUWFTAOOKS-COJKEBBMSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- VNDHYTGVCGVETQ-COJKEBBMSA-N 4-fluoranylbenzamide Chemical compound NC(=O)C1=CC=C([18F])C=C1 VNDHYTGVCGVETQ-COJKEBBMSA-N 0.000 claims 1
- 241000255925 Diptera Species 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 238000000746 purification Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000004007 reversed phase HPLC Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 description 11
- 230000014759 maintenance of location Effects 0.000 description 11
- ISEYJGQFXSTPMQ-UHFFFAOYSA-N 2-(phosphonomethyl)pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CP(O)(O)=O ISEYJGQFXSTPMQ-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000002600 positron emission tomography Methods 0.000 description 8
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 6
- 206010060862 Prostate cancer Diseases 0.000 description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 6
- 150000002431 hydrogen Chemical group 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000012746 preparative thin layer chromatography Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 5
- 230000035508 accumulation Effects 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LSSQMISUDUUZCC-DWSYCVKZSA-N (2,5-dioxopyrrolidin-1-yl) 4-fluoranylbenzoate Chemical compound C1=CC([18F])=CC=C1C(=O)ON1C(=O)CCC1=O LSSQMISUDUUZCC-DWSYCVKZSA-N 0.000 description 4
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000007259 addition reaction Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000002222 fluorine compounds Chemical class 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 3
- AHLAQJXELUHIEW-UHFFFAOYSA-N 1-(5-aminopentyl)pyrrole-2,5-dione Chemical compound NCCCCCN1C(=O)C=CC1=O AHLAQJXELUHIEW-UHFFFAOYSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108090000369 Glutamate Carboxypeptidase II Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- PFTTUAZTMZVAGO-UHFFFAOYSA-N [Cl-].O=C1N(C(C=C1)=O)CCCCCNC(CCCC[NH3+])=O Chemical compound [Cl-].O=C1N(C(C=C1)=O)CCCCCNC(CCCC[NH3+])=O PFTTUAZTMZVAGO-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000012911 assay medium Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 3
- LSSQMISUDUUZCC-UHFFFAOYSA-N n-succinimidyl 4-fluorobenzoate Chemical compound C1=CC(F)=CC=C1C(=O)ON1C(=O)CCC1=O LSSQMISUDUUZCC-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 2
- VNDHYTGVCGVETQ-UHFFFAOYSA-N 4-fluorobenzamide Chemical compound NC(=O)C1=CC=C(F)C=C1 VNDHYTGVCGVETQ-UHFFFAOYSA-N 0.000 description 2
- BDROKDOQKWRLRF-UHFFFAOYSA-N 5-[(4-fluorobenzoyl)amino]pentanoic acid Chemical compound OC(=O)CCCCNC(=O)C1=CC=C(F)C=C1 BDROKDOQKWRLRF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- NZSQBRZWARZNQH-ZWOACCQCSA-N C1(CC1)NC(=O)O[C@H]1C(C2CC[C@]3([C@@]4(CC[C@@]5(C(C4CCC3[C@]2(CC1)C)[C@@H](CC5)[C@H](C)O)C(=O)O)C)C)(C)C Chemical compound C1(CC1)NC(=O)O[C@H]1C(C2CC[C@]3([C@@]4(CC[C@@]5(C(C4CCC3[C@]2(CC1)C)[C@@H](CC5)[C@H](C)O)C(=O)O)C)C)(C)C NZSQBRZWARZNQH-ZWOACCQCSA-N 0.000 description 2
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- RDYCGXZTWVQNLF-UHFFFAOYSA-N CN(C)C=O.ON1C(=O)CCC1=O Chemical compound CN(C)C=O.ON1C(=O)CCC1=O RDYCGXZTWVQNLF-UHFFFAOYSA-N 0.000 description 2
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
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- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
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Description
本発明は、前立腺特異的膜抗原（ＰＳＭＡ）に親和性を有するウレア誘導体化合物、及び、該化合物を含有する放射性医薬に関する。 The present invention relates to a urea derivative compound having affinity for prostate-specific membrane antigen (PSMA), and a radiopharmaceutical containing the compound.
前立腺特異的膜抗原（ＰＳＭＡ）は、グルタミン酸カルボキシペプチダーゼII（ＧＣＰＩＩ）として知られている酵素(EC 3.4.17.21)である。ＰＳＭＡは、N-アセチル-L-アスパルチル-L-グルタマーテペプチダーゼI(ＮＡＡＬＡＤａｓｅ I)、又は葉酸ヒドロラーゼとも呼ばれることがある。 Prostate specific membrane antigen (PSMA) is an enzyme (EC 3.4.17.21) known as glutamate carboxypeptidase II (GCPII). PSMA may also be referred to as N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I), or folate hydrolase.
従来、米国では、ＰＳＭＡを標的としたモノクローナル抗体をIn-111で標識したProstataScintなる商標のイメージング剤が臨床で使用されているが、この抗体はＰＳＭＡの膜内に位置するエピトープを認識するものであり、死滅または乾燥した前立腺癌細胞にしか結合しないと考えられており、広く普及するには至っていない（非特許文献１）。また、ＰＳＭＡの膜外領域に結合するモノクローナル抗体をIn-111で標識したものも開発され、前立腺癌を移植したマウスに集積したことが報告されている（非特許文献２）。しかし、これらのモノクローナル抗体を利用したイメージング剤は、循環血漿中の半減期が長く、抗体の体内動態が遅く、固体腫瘍、特に骨転移部への浸透性が低く、In-111による画像が不鮮明になるなどの欠点を有している。 Conventionally, in the United States, a prostataScint trademark imaging agent labeled with In-111 monoclonal antibody targeting PSMA has been used clinically. This antibody recognizes an epitope located in the PSMA membrane. It is thought that it binds only to dead or dried prostate cancer cells, and has not spread widely (Non-patent Document 1). In addition, a monoclonal antibody labeled with In-111 that binds to the extramembrane region of PSMA has been developed and reported to accumulate in mice transplanted with prostate cancer (Non-patent Document 2). However, imaging agents using these monoclonal antibodies have a long half-life in circulating plasma, slow antibody pharmacokinetics, low permeability to solid tumors, especially bone metastases, and In-111 images are unclear. Has the disadvantages of becoming.
そこで、ＰＳＭＡに親和性の低分子化合物をＰＳＭＡプローブとして用いたイメージング剤が既に幾つか提案されている（特許文献1及び２）。本発明者も、チオールとマレイミドとの間の求核共役付加反応を利用して合成したウレア誘導体をＩ-123標識したＰＳＭＡプローブが、合成の容易さとＰＳＭＡに対する親和性の点で有望であることを見出している（非特許文献３）。
Therefore, several imaging agents using a low molecular weight compound having affinity for PSMA as a PSMA probe have already been proposed (
しかし、Ｉ-123で標識したＰＳＭＡプローブの場合、シングル・フォト・エミッションＣＴ（ＳＰＥＣＴ）で撮像することになるため、空間分解能や定量性の点で限界があり、ポジトロン・エミッション・トモグラフィー（ＰＥＴ）で撮像できるＰＳＭＡプローブが望まれている。 However, in the case of a PSMA probe labeled with I-123, imaging is performed with single photo emission CT (SPECT), so there are limitations in terms of spatial resolution and quantification, and positron emission tomography (PET). A PSMA probe that can be used for imaging is desired.
本発明は、フッ素基を有しつつ、ＰＳＭＡへの親和性が維持又は向上された、ウレア誘導体化合物を提供することを目的とする。 An object of the present invention is to provide a urea derivative compound having a fluorine group and having an affinity for PSMA maintained or improved.
本発明は、一局面によれば、下記式（１）：
（式（１）中、ｍは０又は１、ｎは１〜４の整数、Ｒは水素又はカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す。）
で表わされるウレア誘導体化合物又はその塩を提供する。
According to one aspect of the present invention, the following formula (1):
(In formula (1), m represents 0 or 1, n represents an integer of 1 to 4, R represents hydrogen or a carboxyl group, and F represents non-radioactive fluorine or radioactive fluorine.)
The urea derivative compound or its salt represented by these is provided.
また、本発明は、他の局面によれば、上記のウレア誘導体化合物又はその塩を含有する、放射性医薬を提供する。 According to another aspect, the present invention provides a radiopharmaceutical containing the above urea derivative compound or a salt thereof.
また、本発明は、他の局面によれば、上記のウレア誘導体化合物又はその塩を有効成分として含有する、前立腺特異的膜抗原（ＰＳＭＡ）の放射性イメージング剤を提供する。 According to another aspect of the present invention, there is provided a radioactive imaging agent for prostate specific membrane antigen (PSMA) containing the above urea derivative compound or a salt thereof as an active ingredient.
さらに、本発明は、下記式（２）：
（式（２）中、ｍは０又は１、ｎは１〜４の整数、Ｒは水素又はカルボキシル基を示す。）
で表される化合物と、Ｎ−スクシンイミジル フルオロベンゾエートとを反応させる第１工程と、
前記第１工程で得られる反応生成物と、２−［３−［１−カルボキシ‐２−メルカプトエチル］ウレイド ペンタン二酸とを反応させて、上記式（１）で表されるウレア誘導体化合物を得る第２工程と、
を含む、ウレア誘導体化合物の製造方法を提供する。
Furthermore, the present invention provides the following formula (2):
(In Formula (2), m is 0 or 1, n is an integer of 1-4, R shows hydrogen or a carboxyl group.)
A first step of reacting a compound represented by: N-succinimidyl fluorobenzoate;
The reaction product obtained in the first step is reacted with 2- [3- [1-carboxy-2-mercaptoethyl] ureidopentanedioic acid to give a urea derivative compound represented by the above formula (1). A second step of obtaining,
A method for producing a urea derivative compound is provided.
本発明によれば、フッ素基を有しつつ、ＰＳＭＡへの親和性が維持又は向上された、ウレア誘導体化合物が提供される。 According to the present invention, there is provided a urea derivative compound having a fluorine group and maintaining or improving the affinity for PSMA.
（本発明の化合物またはその塩）
本発明の化合物は、上記式（１）で表される化合物である。式（１）中、ｍは０又は１を示すが、ＰＳＭＡに対する親和性が高く、かつ、非特異的吸着が少ない観点から、ｍ＝０が好ましい。
(Compound of the present invention or a salt thereof)
The compound of the present invention is a compound represented by the above formula (1). In formula (1), m represents 0 or 1, and m = 0 is preferable from the viewpoint of high affinity for PSMA and low nonspecific adsorption.
また、式（１）中、ｎは１〜４の整数を示すが、ＰＳＭＡに対する親和性が高い観点から、ｎは４の整数が好ましい。 In formula (1), n represents an integer of 1 to 4, but n is preferably an integer of 4 from the viewpoint of high affinity for PSMA.
また、式（１）中、Ｒは水素又はカルボキシル基（ＣＯＯＨ基）であるが、ＰＳＭＡに対する親和性が高い観点から、カルボキシル基が好ましい。 In formula (1), R is hydrogen or a carboxyl group (COOH group), and a carboxyl group is preferred from the viewpoint of high affinity for PSMA.
式（１）中、Ｆは非放射性フッ素又は放射性フッ素を示す。本明細書において、非放射性フッ素はフッ素−１９であり、放射性フッ素とはフッ素の放射性同位体である。Ｆは放射性フッ素が好ましく、ＰＥＴプローブとしてＰＳＭＡの非侵襲的画像化が可能になる観点から、フッ素−１８がより好ましい。 In formula (1), F represents non-radioactive fluorine or radioactive fluorine. In this specification, non-radioactive fluorine is fluorine-19, and radioactive fluorine is a radioactive isotope of fluorine. F is preferably radioactive fluorine, and fluorine-18 is more preferable from the viewpoint of enabling noninvasive imaging of PSMA as a PET probe.
本発明に係るウレア標識化合物は、ＰＳＭＡに対する親和性が向上する観点から光学異性体であることが好ましい。具体的には、下記式（３）で表される化合物が好ましい。
（式（３）中、ｍは０又は１、ｎは１〜４の整数、Ｒは水素又はカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す。）
The urea-labeled compound according to the present invention is preferably an optical isomer from the viewpoint of improving the affinity for PSMA. Specifically, a compound represented by the following formula (3) is preferable.
(In formula (3), m represents 0 or 1, n represents an integer of 1 to 4, R represents hydrogen or a carboxyl group, and F represents non-radioactive fluorine or radioactive fluorine.)
本発明の化合物として、具体的には、以下のウレア誘導体化合物が挙げられる。
・２−（３−（１−カルボキシ−２−（（１−（５−カルボキシ−５−（４−フルオロベンズアミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（１）中、ｍは０、Ｒはカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・２−（３−（１−カルボキシ−２−（（１−（５−（４−フルオロベンズアミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（１）中、ｍは０、Ｒは水素、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・２−（３−（１−カルボキシ−２−（（１−（５−カルボキシ−５−（２−（４−フルオロベンズアミド）アセタミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（１）中、ｍは１、ｎは１、Ｒはカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・２−（３−（１−カルボキシ−２−（（１−（５−（２−（４−フルオロベンズアミド）アセタミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（１）中、ｍは１、ｎは１、Ｒは水素、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）
・２−（３−（１−カルボキシ−２−（（１−（５−カルボキシ−５−（５−（４−フルオロベンズアミド）ペンタミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（１）中、ｍは１、ｎは４、Ｒはカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・２−（３−（１−カルボキシ−２−（（１−（５−（５−（４−フルオロベンズアミド）アセタミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（１）中、ｍは１、ｎは４、Ｒは水素、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）。
Specific examples of the compound of the present invention include the following urea derivative compounds.
2- (3- (1-carboxy-2-((1- (5-carboxy-5- (4-fluorobenzamido) pentyl-2,5-dioxopyrrolidin-3-yl) thio) ethyl) ureido) Pentanedioic acid (in the formula (1), m is 0, R is a carboxyl group, F is a non-radioactive fluorine or a compound showing radioactive fluorine);
2- (3- (1-carboxy-2-((1- (5- (4-fluorobenzamido) pentyl) -2,5-dioxopyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid (In the formula (1), m is 0, R is hydrogen, F is a non-radioactive fluorine or a compound showing radioactive fluorine);
2- (3- (1-carboxy-2-((1- (5-carboxy-5- (2- (4-fluorobenzamido) acetamido) pentyl-2,5-dioxopyrrolidin-3-yl) thio ) Ethyl) ureido) pentanedioic acid (in formula (1), m is 1, n is 1, R is a carboxyl group, F is a non-radioactive fluorine or a compound showing radioactive fluorine);
2- (3- (1-carboxy-2-((1- (5- (2- (4-fluorobenzamido) acetamido) pentyl-2,5-dioxopyrrolidin-3-yl) thio) ethyl) ureido ) Pentanedioic acid (in formula (1), m is 1, n is 1, R is hydrogen, F is a non-radioactive or radioactive fluorine compound)
2- (3- (1-carboxy-2-((1- (5-carboxy-5- (5- (4-fluorobenzamido) pentamido) pentyl) -2,5-dioxopyrrolidin-3-yl) Thio) ethyl) ureido) pentanedioic acid (in the formula (1), m is 1, n is 4, R is a carboxyl group, F is a non-radioactive fluorine or a compound showing radioactive fluorine);
2- (3- (1-carboxy-2-((1- (5- (5- (4-fluorobenzamido) acetamido) pentyl) -2,5-dioxopyrrolidin-3-yl) thio) ethyl) (Ureido) pentanedioic acid (in the formula (1), m is 1, n is 4, R is hydrogen, and F is a non-radioactive fluorine or a compound showing radioactive fluorine).
ＰＳＭＡに対する親和性が向上する観点からは、下記のウレア誘導体化合物が好ましい。
・（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（（Ｓ）−５−カルボキシ−５−（４−フルオロベンズアミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（３）中、ｍは０、Ｒはカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（５−（４−フルオロベンズアミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（３）中、ｍは０、Ｒは水素、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（Ｓ）−５−カルボキシ−５−（２−（４−フルオロベンズアミド）アセタミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（３）中、ｍは１、ｎは１、Ｒはカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（５−（２−（４−フルオロベンズアミド）アセタミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（３）中、ｍは１、ｎは１、Ｒは水素、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）
・（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（（Ｓ）−５−カルボキシ−５−（５−（４−フルオロベンズアミド）ペンタミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（３）中、ｍは１、ｎは４、Ｒはカルボキシル基、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）；
・（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（５−（５−（４−フルオロベンズアミド）アセタミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（式（３）中、ｍは１、ｎは４、Ｒは水素、Ｆは非放射性フッ素又は放射性フッ素を示す化合物）。
From the viewpoint of improving the affinity for PSMA, the following urea derivative compounds are preferred.
(2S) -2- (3-((1R) -1-carboxy-2-((1-((S) -5-carboxy-5- (4-fluorobenzamido) pentyl-2,5-dioxo Pyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid (in the formula (3), m is 0, R is a carboxyl group, F is a non-radioactive fluorine or a compound showing radioactive fluorine);
(2S) -2- (3-((1R) -1-carboxy-2-((1- (5- (4-fluorobenzamido) pentyl) -2,5-dioxopyrrolidin-3-yl) thio ) Ethyl) ureido) pentanedioic acid (in formula (3), m is 0, R is hydrogen, F is a non-radioactive fluorine or a compound showing radioactive fluorine);
(2S) -2- (3-((1R) -1-carboxy-2-((1- (S) -5-carboxy-5- (2- (4-fluorobenzamido) acetamido) pentyl-2, 5-dioxopyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid (in the formula (3), m is 1, n is 1, R is a carboxyl group, and F is a non-radioactive or radioactive fluorine compound. );
(2S) -2- (3-((1R) -1-carboxy-2-((1- (5- (2- (4-fluorobenzamido) acetamido) pentyl-2,5-dioxopyrrolidine-3) -Yl) thio) ethyl) ureido) pentanedioic acid (wherein m is 1, n is 1, R is hydrogen, F is a non-radioactive or radioactive fluorine compound)
(2S) -2- (3-((1R) -1-carboxy-2-((1-((S) -5-carboxy-5- (5- (4-fluorobenzamido) pentamido) pentyl)-) 2,5-dioxopyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid (wherein m is 1, n is 4, R is a carboxyl group, F is non-radioactive fluorine or radioactive fluorine) Compounds shown);
(2S) -2- (3-((1R) -1-carboxy-2-((1- (5- (5- (4-fluorobenzamide) acetamido) pentyl) -2,5-dioxopyrrolidine- 3-yl) thio) ethyl) ureido) pentanedioic acid (in formula (3), m is 1, n is 4, R is hydrogen, and F is a non-radioactive or radioactive fluorine compound).
本発明のウレア誘導体化合物は、上記式（１）の化合物が、塩の形態であってもよい。
上記一般式（１）で表される化合物が塩基である場合、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸などの無機酸、又は、酢酸、トリフルオロ酢酸、マレイン酸、コハク酸、マンデル酸、フマル酸、マロン酸、ピルビン酸、シュウ酸、グリコール酸、サリチル酸、ピラノシジル酸（グルクロン酸、ガラクツロン酸など）、α‐ヒドロキシ酸（クエン酸、酒石酸など）、アミノ酸（アスパラギン酸、グルタミン酸など）、芳香族酸（安息香酸、ケイ皮酸など）、スルホン酸（ｐ‐トルエンスルホン酸、エタンスルホン酸など）などの有機酸から誘導される塩にすることができる。
In the urea derivative compound of the present invention, the compound of the above formula (1) may be in the form of a salt.
When the compound represented by the general formula (1) is a base, for example, inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, trifluoroacetic acid, maleic acid, succinic acid , Mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid (glucuronic acid, galacturonic acid etc.), α-hydroxy acid (citric acid, tartaric acid etc.), amino acid (aspartic acid, glutamic acid) Etc.), aromatic acids (benzoic acid, cinnamic acid, etc.), sulfonic acids (p-toluenesulfonic acid, ethanesulfonic acid, etc.), and the like.
また、上記式（１）で表される化合物が酸である場合、例えば、アミノ酸（グリシン、アルギニンなど）、アンモニア、第一級、第二級及び第三級アミン及び環状アミン（ピペリジン、モルホリン、ピペラジンなど）などの有機塩基、又は、水酸化ナトリウム、水酸化カルシウム、水酸化カリウム、水酸化マグネシウム、水酸化マンガン、水酸化鉄、水酸化銅、水酸化亜鉛、水酸化アルミニウム、水酸化リチウムなどの無機塩基から誘導される塩にすることができる。 When the compound represented by the above formula (1) is an acid, for example, amino acids (glycine, arginine, etc.), ammonia, primary, secondary and tertiary amines and cyclic amines (piperidine, morpholine, Organic bases such as piperazine) or sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, manganese hydroxide, iron hydroxide, copper hydroxide, zinc hydroxide, aluminum hydroxide, lithium hydroxide, etc. Or a salt derived from an inorganic base.
（本発明の化合物またはその塩の製造方法）
本発明のウレア誘導体化合物の製造方法は、上記式（２）で表される化合物と、Ｎ−スクシンイミジル フルオロベンゾエートとを反応させる工程（第１工程）と、第１工程で得られる反応生成物と、２−［３−［１−カルボキシ‐２−メルカプトエチル］ウレイド ペンタン二酸（Ｃｙｓ−ＣＯ−Ｇｌｕ）とを反応させて、上記式（１）で表されるウレア誘導体化合物を得る工程（第２工程）とを含むものである。
(Method for producing the compound of the present invention or a salt thereof)
The method for producing a urea derivative compound of the present invention includes a step of reacting a compound represented by the above formula (2) with N-succinimidyl fluorobenzoate (first step), and a reaction product obtained in the first step. , 2- [3- [1-carboxy-2-mercaptoethyl] ureido pentanedioic acid (Cys-CO-Glu) is reacted to obtain a urea derivative compound represented by the above formula (1) (first step) 2 steps).
上記式（２）で表される化合物は、アミニウム基を有するが、カウンターアニオンとしては、例えば、塩化物イオン、臭化物イオン、又はヨウ化物イオンといったハロゲンイオン、硫酸イオン、硝酸イオン、リン酸イオン、酢酸イオンなどの無機イオン；トリフルオロ酢酸イオン、マレイン酸イオン、コハク酸イオン、マンデル酸イオン、フマル酸イオン、マロン酸イオン、ピルビン酸イオン、シュウ酸イオン、グリコール酸イオン、サリチル酸イオン、ピラノシジル酸イオン（グルクロン酸イオン、ガラクツロン酸イオンなど）、α‐ヒドロキシ酸イオン（クエン酸イオン、酒石酸イオンなど）、スルホン酸イオン（ｐ‐トルエンスルホン酸イオン、エタンスルホン酸イオンなど）などの有機酸イオンが挙げられる。 The compound represented by the above formula (2) has an aminium group, and examples of the counter anion include halogen ions such as chloride ion, bromide ion, or iodide ion, sulfate ion, nitrate ion, phosphate ion, Inorganic ions such as acetate ion; trifluoroacetate ion, maleate ion, succinate ion, mandelate ion, fumarate ion, malonate ion, pyruvate ion, oxalate ion, glycolate ion, salicylate ion, pyranosidate ion Organic acid ions such as (glucuronic acid ion, galacturonic acid ion, etc.), α-hydroxy acid ion (citrate ion, tartrate ion, etc.), sulfonic acid ion (p-toluenesulfonic acid ion, ethanesulfonic acid ion, etc.) It is done.
第１工程は、例えば、アセトニトリルなどの非プロトン性極性溶媒中、Ｎ，Ｎ−ジイソプロピルエチルアミンなどの三級アミンを存在下に実行することができる。これにより、一方の末端にフルオロフェニル基を備え、他方の末端にマレイミド基を備える化合物を得ることができる。 The first step can be carried out in the presence of a tertiary amine such as N, N-diisopropylethylamine in an aprotic polar solvent such as acetonitrile. Thereby, a compound having a fluorophenyl group at one end and a maleimide group at the other end can be obtained.
第２工程は、第１工程の後に、Ｃｙｓ−ＣＯ−Ｇｌｕをそのまま加えればよいが、このとき、Ｃｙｓ−ＣＯ−Ｇｌｕの水溶液を添加すると好ましい。これにより、チオールとマレイミドとの間の求核共役付加反応を生起させることができる。その後、固相カートリッジや高速液体クロマトグラフィーなどの、通常の精製法を採用することにより、上記式（１）で表されるウレア誘導体化合物を得ることができる。 In the second step, Cys-CO-Glu may be added as it is after the first step, but at this time, it is preferable to add an aqueous solution of Cys-CO-Glu. Thereby, the nucleophilic conjugate addition reaction between thiol and maleimide can be caused. Then, the urea derivative compound represented by the above formula (1) can be obtained by employing a normal purification method such as a solid phase cartridge or high performance liquid chromatography.
以下、図１、３、４を例に取りつつ、具体的に説明する。
上記式（１）中、ｍ＝０の化合物は、例えば、図１、３のスキームに従って製造することができる。上記式（２）（ただし、ｍ＝０）の化合物は、まず、プトレシンまたはオルニチンなどのジアミンのα炭素位のアミノ基をBoc基等のアミノ酸保護基で保護し、Ｎ−カルボキシマレイミドと反応させた後、上記アミノ酸保護基を脱保護し、２−アミノ−６−（２，５−ジヒドロ−２，５−ジオキソ−１Ｈ−ピロール）−１‐へキサン酸の酸性塩（上記式（２）中、ｍは０、Ｒはカルボキシル基の化合物）、又は、Ｎ−（５−アミノペンチル）マレイミド酸性塩の（上記式（２）中、ｍは０、Ｒは水素の化合物）を得ることができる。これらの化合物の具体的な製造方法は、既報（非特許文献３等）に記載されている。一方、Ｎ−スクシンイミジル フルオロベンゾエートは、フルオロ安息香酸とＮ‐ヒドロキシスクシンイミドを反応させることにより得ることができる。これらの化合物の具体的な製造方法は、既報（Nat Protoc. 2006;1:1655-1661）に記載されている。
Hereinafter, a specific description will be given with reference to FIGS.
In the above formula (1), the compound of m = 0 can be produced, for example, according to the scheme of FIGS. In the compound of the above formula (2) (where m = 0), first, the amino group at the α-carbon position of a diamine such as putrescine or ornithine is protected with an amino acid protecting group such as a Boc group and reacted with N-carboxymaleimide. Then, the amino acid protecting group is deprotected, and an acid salt of 2-amino-6- (2,5-dihydro-2,5-dioxo-1H-pyrrole) -1-hexanoic acid (the above formula (2) Wherein m is 0 and R is a carboxyl group compound) or an N- (5-aminopentyl) maleimide acid salt (wherein m is 0 and R is a hydrogen compound in the above formula (2)). it can. Specific production methods of these compounds are described in the previous reports (
そして、式（２）で表される化合物のアミニウム基と、Ｎ−スクシンイミジル フルオロベンゾエートとの間にアミド結合を形成させることにより、一方の末端にフルオロフェニル基を備え、他方の末端にマレイミド基を備える化合物を得る（第１工程）。そして、マレイミド基に、Ｃｙｓ−ＣＯ−Ｇｌｕを作用させて、チオールとマレイミドとの間の求核共役付加反応を生起させることにより、上記式（１）の化合物（ただし、ｍ＝０）を製造することができる（第２工程）。 Then, by forming an amide bond between the aminium group of the compound represented by the formula (2) and N-succinimidyl fluorobenzoate, a fluorophenyl group is provided at one end and a maleimide group is provided at the other end. A compound provided is obtained (first step). Then, a compound of the above formula (1) (where m = 0) is produced by causing Cys-CO-Glu to act on the maleimide group to cause a nucleophilic conjugate addition reaction between thiol and maleimide. (Second step).
上記式（１）の化合物（ただし、ｍ＝１）は、図４のスキームに従って製造することができる。具体的には、アミノ吉草酸のような脂肪族アミノカルボン酸のα位のアミノ基をBoc基等のアミノ酸保護基で保護し、これとＮ−ヒドロキシスクシンイミドを反応させて２，５−ジオキソピロリジン−１−イル ５−アミノペンタノエートのアミノ保護体を得る。そして、２，５−ジオキソピロリジン−１−イル ５−アミノペンタノエートのアミノ保護体と、２−アミノ−６−（２，５−ジヒドロ−２，５−ジオキソ−１Ｈ−ピロール）−１‐へキサン酸又はＮ−（５−アミノペンチル）マレイミドとを反応させた後、アミノ基の保護基を脱保護し、５−（（１−カルボキシ−５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル）アミノ−５−オキソペンタン−１−アミニウム（上記式（２）中、ｍは１、ｎは１、Ｒはカルボキシル基の化合物）や、５−（（５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル）アミノ）−５−オキソペンタン−１−アミニウム（上記式（２）中、ｍは１、ｎは１、Ｒは水素の化合物）を得る。そして、これら式（２）で表される化合物と、Ｎ−スクシンイミジル フルオロベンゾエートとを反応させた後（第１工程）、Ｃｙｓ−ＣＯ−Ｇｌｕを混合して反応条件を与えて、チオールとマレイミドとの間の求核共役付加反応を生起させることにより、上記式（１）の化合物（ただし、ｍ＝１）を製造することができる（第２工程）。 The compound of the above formula (1) (where m = 1) can be produced according to the scheme of FIG. Specifically, the amino group at the α-position of an aliphatic aminocarboxylic acid such as aminovaleric acid is protected with an amino acid protecting group such as a Boc group, and this is reacted with N-hydroxysuccinimide to produce 2,5-dioxo. An amino protected form of pyrrolidin-1-yl 5-aminopentanoate is obtained. An amino protected form of 2,5-dioxopyrrolidin-1-yl 5-aminopentanoate and 2-amino-6- (2,5-dihydro-2,5-dioxo-1H-pyrrole) -1 -After reacting with -hexanoic acid or N- (5-aminopentyl) maleimide, the protecting group of the amino group is deprotected, and 5-((1-carboxy-5- (2,5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) pentyl) amino-5-oxopentane-1-aminium (wherein m is 1, n is 1, R is a carboxyl group compound) and 5 -((5- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) pentyl) amino) -5-oxopentane-1-aminium (wherein m is 1 , N is 1 and R is hydrogen). After reacting these compounds represented by the formula (2) with N-succinimidyl fluorobenzoate (first step), Cys-CO-Glu is mixed to give reaction conditions, and between thiol and maleimide. The compound of the above formula (1) (where m = 1) can be produced by causing the nucleophilic conjugate addition reaction of (second step).
なお、図１、３、４ではＮ−スクシンイミジル フルオロベンゾエートとしてＮ−スクシンイミジル ４−フルオロベンゾエートを用いた例が示されているが、Ｎ−スクシンイミジル ２−フルオロベンゾエートまたはＮ−スクシンイミジル ３−フルオロベンゾエートを使用することにより、これに対応してフェニル基の２位又は３位にフッ素原子が結合した式（１）の化合物を得ることができる。 In addition, although the example using N-succinimidyl 4-fluorobenzoate as N-succinimidyl 4-fluorobenzoate is shown in FIGS. 1, 3, and 4, N-succinimidyl 2-fluorobenzoate or N-succinimidyl 3-fluorobenzoate is used. Accordingly, a compound of the formula (1) in which a fluorine atom is bonded to the 2-position or 3-position of the phenyl group can be obtained.
また、上記式（１）中、Ｆが放射性フッ素のウレア誘導体化合物又はその塩を得るときは、第１工程において、Ｎ−スクシンイミジル フルオロベンゾエートとして、Ｎ−スクシンイミジル［１８Ｆ］フルオロベンゾエートを用いればよい。中でも、Ｎ−スクシンイミジル ４−［１８Ｆ］フルオロベンゾエートを用いることが好ましい。Ｎ−スクシンイミジル ４−［１８Ｆ］フルオロベンゾエートの具体的な製造方法は、既報（Nat Protoc. 2006;1:1655-1661）に記載されている。 In the above formula (1), when F is a radioactive derivative urea derivative compound or a salt thereof, N-succinimidyl [ 18 F] fluorobenzoate may be used as N-succinimidyl fluorobenzoate in the first step. . Among these, N-succinimidyl 4- [ 18 F] fluorobenzoate is preferably used. A specific method for producing N-succinimidyl 4- [ 18 F] fluorobenzoate is described in a previous report (Nat Protoc. 2006; 1: 1655-1661).
（本発明の放射性医薬）
本発明の放射性医薬は、式（１）中、Ｆが放射性フッ素のウレア誘導体化合物又はその塩を含有するものである。この放射性医薬は、他の一般に知られている放射性医薬と同様に、上記式（１）の化合物を所望により適当なｐＨに調整された水又は生理食塩水若しくはリンゲル液等に配合させた液として調製することができる。この場合における上記式（１）の化合物の濃度は、配合された当該化合物の安定性が得られる濃度以下とする必要がある。上記式（１）の化合物の投与量は、薬効を示すために十分な濃度であれば特に限定されない。上記式（１）の化合物は、被験者の状態に応じた必要量を、静脈投与又は局所投与して使用することができる。
(Radiopharmaceutical of the present invention)
The radiopharmaceutical of the present invention contains a urea derivative compound or a salt thereof in which F is a radioactive fluorine in formula (1). This radiopharmaceutical is prepared as a liquid in which the compound of the above formula (1) is mixed with water, physiological saline, Ringer's solution or the like adjusted to an appropriate pH as required, as with other generally known radiopharmaceuticals. can do. In this case, the concentration of the compound of the above formula (1) needs to be not more than a concentration at which the stability of the compounded compound is obtained. The dose of the compound of the above formula (1) is not particularly limited as long as it is a sufficient concentration to show a medicinal effect. The compound of the above formula (1) can be used by intravenously or locally administering a necessary amount according to the condition of the subject.
（本発明の放射性イメージング剤）
本発明の放射性イメージング剤は、式（１）中、Ｆが放射性フッ素のウレア誘導体化合物又はその塩を含有するものである。上記式（１）の化合物はＰＳＭＡに特異的に集積するので、該化合物を有効成分として含有する本発明の放射性イメージング剤は、例えば、ＰＥＴ用プローブとして有効であり、ＰＳＭＡが多量に発現する前立腺癌細胞を特異的に検出できるだけでなく、ＰＳＭＡの発現を伴う各種疾患の診断に使用することができる。
(Radioimaging agent of the present invention)
The radioactive imaging agent of the present invention contains a urea derivative compound or a salt thereof in which F is a radioactive fluorine in formula (1). Since the compound of the above formula (1) specifically accumulates in PSMA, the radioimaging agent of the present invention containing the compound as an active ingredient is effective, for example, as a probe for PET, and a prostate in which PSMA is expressed in a large amount. In addition to specifically detecting cancer cells, it can be used for diagnosis of various diseases associated with PSMA expression.
以下、実施例により、本発明を更に具体的に説明するが、本発明は下記の実施例のみに限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited only to the following Example.
なお、以下の実施例において、実験材料及び操作は下記のとおり行った。
（Ｓ）−２−［３−［（Ｒ）−１−カルボキシ−２−メルカプトエチル］ウレイド−ペンタン二酸（化合物１）、（２Ｓ）−２−アミノ−６−（２，５−ジヒドロ−２，５−ジオキソ−１Ｈ−ピロール）−１‐へキサン酸・塩酸塩（化合物５ａ）及びＮ−（５−アミノペンチル）マレイミド・塩酸塩（化合物５ｂ）は、既報（非特許文文献３）の記載に従って調製した化合物を使用した。Ｎ−スクシンイミジル ４−フルオロベンゾエート（化合物６）及びＮ−（４−フルオロベンゾイル）−グリシン（化合物９ａ）は既報（J Labelled Compd RAD, 53(4), 186-191; 2010）の記載に従って調製した化合物を使用した。 中圧分取液体クロマトグラフにはＷ−Ｐｒｅｐ ２ＸＹ（ＹＡＭＡＺＥＮ社製）を使用した。
分取薄層クロマトグラフィー（ＰＴＬＣ）には、ＰＬＣ Ｓｉｌｉｃａ ｇｅｌ ６０ Ｆ２５４，０．５ｍｍ（メルク社製）を使用した。
実施例中使用した水は、ＭＱ Ｉｎｔｅｇｒａ１５（日本ミリポア社製）で調製した。
逆相高速液体クロマトグラフィー（逆相ＨＰＬＣ）は、ＬＣ−２０ＡＤ（島津製作所社製）、ＳＰＤ−２０Ａ ＵＶ検出器（波長２２０ｎｍ及び２５４ｎｍ）（島津製作所社製）、放射線検出器（ＮＤＷ−３５１（日立アロカメディカル社製）、カラムとしてＹＭＣ Ｐａｃｋ−ＯＤＳ ＡＱ（２０×２５０ｍｍ）を使用し、移動相はメタノールと水（共に０．１体積％トリフルオロ酢酸を含有）を用い、流速５ｍＬ／ｍｉｎ、メタノール濃度のグラディエントは３０体積％‐８０体積％（６０分）とした。
１Ｈ−ＮＭＲスペクトルは、ＬＮＭ−ＡＬ５００（ＪＥＯＬ社製）を用いて測定した。溶媒としては、重クロロホルム（ＣＤＣｌ３）、ジメチルスルホキシド−ｄ６（ＤＭＳＯ−ｄ６），重メタノール（ＣＤ３ＯＤ），重水（Ｄ２Ｏ）を用い、テトラメチルシラン（Ｅｕｒｉｓｏ−ｔｏｐ社製）を内部標準とした。
マススペクトルは、ＬＣＭＳ−２０１０ ＥＶ（島津製作所社製），ＧＣＭＳ−ＱＰ２０１０ Ｐｌｕｓ（島津製作所社製），又はＪＭＳ−ＳＸ １０２Ａ ＱＱ（ＪＥＯＬ社製）を使用した。
ヒト前立腺がん細胞：ＬＮＣａＰ（ＰＳＭＡ陽性）、及び、ＰＣ−３は、ＤＳファーマバイオメディカル社から購入し、１０％ウシ胎児血清、グルタミン、抗体（ペニシリン／ストレプトマイシン）ロスウェルパーク記念研究所１６４０培地（ＲＰＭＩ培地）で、高湿度ＣＯ２インキュベーター（３７℃／５％二酸化炭素）内にて培養した。
Ｃ．Ｂ．−１７／Ｉｃｒ ＋／＋ Ｊｃｌマウス、及び、Ｃ．Ｂ．−１７／Ｉｃｒ ｓｃｉｄ／ｓｃｉｄ Ｊｃｌマウス（いずれも雄性）は、日本クレア社から購入したものを使用した。
腫瘍移植マウスとしては、上記培養したヒト前立腺がん細胞を２．５ｇ／Ｌトリプシン／１ｍｍｏｌ／Ｌエチレンジアミンテトラ酢酸で処理し、リン酸バッファー生理食塩液で再懸濁したものと、ＢＤマトリゲルＴＭ基底膜マトリックスとの混合物（１：１、１００μＬ）を１〜５×１０６細胞／匹ずつ、５週齢のＣ．Ｂ．−１７／Ｉｃｒ ｓｃｉｄ／ｓｃｉｄ Ｊｃｌマウスに移植（右脚にＰＣ−３、左脚にＬＮＣａＰ）して、腫瘍の大きさが約５〜１０ｍｍになるまで飼育したものを使用した。
In the following examples, experimental materials and operations were performed as follows.
(S) -2- [3-[(R) -1-carboxy-2-mercaptoethyl] ureido-pentanedioic acid (compound 1 ), (2S) -2-amino-6- (2,5-dihydro- 2,5-dioxo-1H-pyrrole) -1-hexanoic acid / hydrochloride (compound 5a ) and N- (5-aminopentyl) maleimide / hydrochloride (
For preparative thin layer chromatography (PTLC), PLC Silica gel 60 F 254 , 0.5 mm (Merck) was used.
The water used in the examples was prepared with MQ Integra 15 (Nippon Millipore).
Reversed phase high performance liquid chromatography (reverse phase HPLC) is LC-20AD (manufactured by Shimadzu Corporation), SPD-20A UV detector (wavelengths 220 nm and 254 nm) (manufactured by Shimadzu Corporation), radiation detector (NDW-351 ( Hitachi Aloka Medical Co., Ltd.), YMC Pack-ODS AQ (20 × 250 mm) was used as the column, methanol and water (both containing 0.1% by volume trifluoroacetic acid) were used as the mobile phase, and the flow rate was 5 mL / min. The gradient of methanol concentration was 30% to 80% by volume (60 minutes).
1 H-NMR spectrum was measured using LNM-AL500 (manufactured by JEOL). As a solvent, deuterated chloroform (CDCl 3 ), dimethyl sulfoxide-d6 (DMSO-d6), deuterated methanol (CD 3 OD), and deuterated water (D 2 O) were used, and tetramethylsilane (manufactured by Euroso-top) was used. Standard.
For mass spectrum, LCMS-2010 EV (manufactured by Shimadzu Corporation), GCMS-QP2010 Plus (manufactured by Shimadzu Corporation), or JMS-SX 102A QQ (manufactured by JEOL) was used.
Human prostate cancer cells: LNCaP (PSMA positive) and PC-3 were purchased from DS Pharma Biomedical, 10% fetal bovine serum, glutamine, antibody (penicillin / streptomycin) Roswell Park Memorial Institute 1640 medium ( (RPMI medium) in a high humidity CO 2 incubator (37 ° C./5% carbon dioxide).
C. B. -17 / Icr + / + Jcl mice and C.I. B. -17 / Icr scid / scid Jcl mice (both male) were purchased from CLEA Japan.
As tumor transplanted mice, the cultured human prostate cancer cells were treated with 2.5 g / L trypsin / 1 mmol / L ethylenediaminetetraacetic acid, resuspended in phosphate buffer physiological saline, and BD Matrigel TM basal. Mix with membrane matrix (1: 1, 100 μL) at 1-5 × 10 6 cells / mouse at 5 weeks of age. B. -17 / Icr scid / scid Jcl mice were transplanted (PC-3 on the right leg, LNCaP on the left leg) and reared until the tumor size was about 5-10 mm.
実施例１：（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（（Ｓ））−５−カルボキシ−５−（４−フルオロベンズアミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）ウレイド）ペンタン二酸（８ａ）の調製
図１のスキームに従い、下記（１）〜（２）の手順で調製した。
Example 1: (2S) -2- (3-((1R) -1-carboxy-2-((1-((S)))-5-carboxy-5- (4-fluorobenzamido) pentyl-2, Preparation of 5-dioxopyrrolidin-3-yl) thio) ureido) pentanedioic acid (8a) The following procedures (1) to (2) were prepared according to the scheme of FIG.
（１）（Ｓ）−６−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）−２−（４−フルオロベンズアミド）ヘキサン酸（７ａ）の調製
化合物６（４５ｍｇ）のアセトニトリル溶液（１ｍＬ）に化合物５ａ（５０ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（４９ｍｇ）を加えて、室温（２５℃）下６時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液に注ぎ込み、酢酸エチルで抽出した。硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。ＰＴＬＣ（クロロホルム：メタノール＝１０：１（体積比））で粗精製を行い、その後に逆相ＨＰＬＣで精製し、化合物７ａ（７．５ｍｇ，収率１１％）を得た。ＨＰＬＣ保持時間：５２分。
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，５００ＭＨｚ）δ：１．３９−１．４６（ｍ，２Ｈ），１．４７−１．６９（ｍ，２Ｈ），１．８１−２．０３（ｍ，２Ｈ），３．５１（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），４．５４（ｍ，２Ｈ），６．７７（ｓ，２Ｈ），７．１９（ｍ，２Ｈ），７．９０（ｍ，２Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：３４９［Ｍ＋Ｈ］＋。
(1) Preparation of (S) -6- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) -2- (4-fluorobenzamido) hexanoic acid (7a) Compound 6 (45 mg Compound 5a (50 mg) and N, N-diisopropylethylamine (49 mg) were added to an acetonitrile solution (1 mL) and stirred at room temperature (25 ° C.) for 6 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Crude purification was performed with PTLC (chloroform: methanol = 10: 1 (volume ratio)), followed by purification with reverse phase HPLC to obtain compound 7a (7.5 mg, yield 11%). HPLC retention time: 52 minutes.
1 H-NMR (CD 3 OD, 500 MHz) δ: 1.39-1.46 (m, 2H), 1.47-1.69 (m, 2H), 1.81-2.03 (m, 2H) ), 3.51 (t, J = 6.87 Hz, 2H), 4.54 (m, 2H), 6.77 (s, 2H), 7.19 (m, 2H), 7.90 (m, 2H).
ESI-MS m / z: 349 [M + H] < +>.
（２）化合物（８ａ）の調製
化合物７ａ（７．５ｍｇ）のアセトニトリル溶液（０．１ｍＬ）に化合物１（６．３ｍｇ）の水溶液（０．７ｍＬ）を加え、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ７にした。室温（２５℃）下２時間撹拌した後、逆相ＨＰＬＣで精製し、化合物８ａ（７．３ｍｇ，収率５２％）を得た。ＨＰＬＣ保持時間：４３分。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：１．２０−１．３４（ｍ，２Ｈ），１．４５−１．５６（ｍ，２Ｈ），１．７０−２．０８（ｍ，４Ｈ），２．３７（ｄｔ，Ｊ＝４．０１，７．４５Ｈｚ，２Ｈ），２．４６（ｍ，１Ｈ），２．７７−３．１７（ｍ，３Ｈ），３．４０（ｔ，Ｊ＝６．３０Ｈｚ，２Ｈ），３．８６（ｍ，１Ｈ），４．１５（ｍ，１Ｈ），４．３５−４．４３（ｍ，２Ｈ），７．１２（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．７１（ｄｄ，Ｊ＝８．５９，５．７３Ｈｚ，２Ｈ）。
ＦＡＢ−ＭＳ ｍ／ｚ：６４３［Ｍ＋Ｈ＋］。
ＨＲＦＡＢ＋−ＭＳ：ｃａｌｃｄ ｆｏｒ Ｃ２６Ｈ３２Ｎ４Ｏ１２ＦＳ，６４３．１７２５［Ｍ＋Ｈ＋］；ｆｏｕｎｄ ６４３．１７２１。
(2) Preparation of Compound (8a) An aqueous solution (0.7 mL) of Compound 1 (6.3 mg) was added to an acetonitrile solution (0.1 mL) of Compound 7a (7.5 mg), and a 2 mol / L aqueous sodium hydroxide solution was added. The pH was adjusted to 7. After stirring at room temperature (25 ° C.) for 2 hours, purification was conducted by reversed-phase HPLC to obtain Compound 8a (7.3 mg, yield 52%). HPLC retention time: 43 minutes.
1 H-NMR (D 2 O, 500 MHz) δ: 1.20-1.34 (m, 2H), 1.45-1.56 (m, 2H), 1.70-2.08 (m, 4H) ), 2.37 (dt, J = 4.01, 7.45 Hz, 2H), 2.46 (m, 1H), 2.77-3.17 (m, 3H), 3.40 (t, J = 6.30 Hz, 2H), 3.86 (m, 1H), 4.15 (m, 1H), 4.35-4.43 (m, 2H), 7.12 (t, J = 8.59 Hz) , 2H), 7.71 (dd, J = 8.59, 5.73 Hz, 2H).
FAB-MS m / z: 643 [M + H + ].
HRFAB + -MS: calcd for C 26 H 32 N 4 O 12 FS, 643.1725 [M + H + ]; found 643.1721.
実施例２： （２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（５−（４−フルオロベンズアミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（８ｂ）の調製
図１のスキームに従い、下記（１）〜（２）の手順で調製した。
Example 2: (2S) -2- (3-((1R) -1-carboxy-2-((1- (5- (4-fluorobenzamido) pentyl) -2,5-dioxopyrrolidine-3- Preparation of yl) thio) ethyl) ureido) pentanedioic acid (8b) According to the scheme of FIG. 1, it was prepared by the following procedures (1) to (2).
（１）Ｎ−（５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル−４−フルオロベンズアミド（７ｂ）の調製
化合物６（５４ｍｇ）のアセトニトリル溶液（１．５ｍＬ）に化合物５ｂ（５０ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（３０ｍｇ）を加えて、室温（２５℃）下４時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液に注ぎ込み、酢酸エチルで抽出した。硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。中圧分取液体クロマトグラフ（ヘキサン：酢酸エチル＝１：１（体積比））で精製し、化合物７ｂ（５４ｍｇ，収率７７％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，５００ＭＨｚ）δ：１．３７（ｍ，２Ｈ），１．６６（ｍ，４Ｈ），３．４４（ｄｔ，Ｊ＝６．３０，５．７３Ｈｚ，２Ｈ），３．５５（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），６．０９（ｂｒｏａｄ ｓ，１Ｈ），６．６７（ｓ，２Ｈ），７．１１（ｍ，２Ｈ），７．７８（ｍ，２Ｈ）。
ＥＩ−ＭＳ ｍ／ｚ：３０４［Ｍ］＋，１２３（１００），９５（２５）。
(1) Preparation of N- (5- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) pentyl-4-fluorobenzamide (7b) Compound 6 (54 mg) in acetonitrile solution (1
1 H-NMR (CDCl 3 , 500 MHz) δ: 1.37 (m, 2H), 1.66 (m, 4H), 3.44 (dt, J = 6.30, 5.73 Hz, 2H), 3 .55 (t, J = 6.87 Hz, 2H), 6.09 (broad s, 1H), 6.67 (s, 2H), 7.11 (m, 2H), 7.78 (m, 2H) .
EI-MS m / z: 304 [M] <+> , 123 (100), 95 (25).
（２）化合物（８ｂ）の調製
化合物７ｂ（６．２ｍｇ）のアセトニトリル溶液（０．１５ｍＬ）に化合物１（６．０ｍｇ）の水溶液（０．７５ｍＬ）を加え、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ７にした。室温（２５℃）下４時間撹拌した後、逆相ＨＰＬＣで精製し、化合物８ｂ（５．５ｍｇ，収率４５％）を得た。ＨＰＬＣ保持時間：４８分。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：１．１９（ｔｔ，Ｊ＝８．０２，７．４５Ｈｚ，２Ｈ），１．４９（ｍ，４Ｈ），１．８４７（ｍ，１Ｈ），２．０４（ｍ，１Ｈ），２．３８（ｍ，２Ｈ），２．４８（ｍ，１Ｈ），２．８０−３．１６（ｍ，３Ｈ），３．２４（ｔ，Ｊ＝６．５９Ｈｚ，２Ｈ），３．４０（ｔ，Ｊ＝６．５９Ｈｚ，２Ｈ），３．８７（ｍ，１Ｈ），４．１５（ｍ，１Ｈ），４．３６（ｄｄ，Ｊ＝６．８７，５．１６Ｈｚ，１Ｈ），７．１１（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．６５（ｄｄ，Ｊ＝８．５９，５．１６Ｈｚ，２Ｈ）。
ＦＡＢ−ＭＳ ｍ／ｚ：５９９［Ｍ＋Ｈ＋］。
ＨＲＦＡＢ＋−ＭＳ：ｃａｌｃｄ ｆｏｒ Ｃ２５Ｈ３２Ｎ４Ｏ１０ＦＳ，５９９．１８２８［Ｍ＋Ｈ＋］；ｆｏｕｎｄ ５９９．１８２３。
(2) Preparation of Compound (8b) To an acetonitrile solution (0.15 mL) of Compound 7b (6.2 mg) was added an aqueous solution (0.75 mL) of Compound 1 (6.0 mg), and a 2 mol / L aqueous sodium hydroxide solution was added. The pH was adjusted to 7. The mixture was stirred at room temperature (25 ° C.) for 4 hours and then purified by reverse phase HPLC to obtain Compound 8b (5.5 mg, yield 45%). HPLC retention time: 48 minutes.
1 H-NMR (D 2 O, 500 MHz) δ: 1.19 (tt, J = 8.02, 7.45 Hz, 2H), 1.49 (m, 4H), 1.847 (m, 1H), 2.04 (m, 1H), 2.38 (m, 2H), 2.48 (m, 1H), 2.80-3.16 (m, 3H), 3.24 (t, J = 6. 59 Hz, 2H), 3.40 (t, J = 6.59 Hz, 2H), 3.87 (m, 1H), 4.15 (m, 1H), 4.36 (dd, J = 6.87, 5.16 Hz, 1H), 7.11 (t, J = 8.59 Hz, 2H), 7.65 (dd, J = 8.59, 5.16 Hz, 2H).
FAB-MS m / z: 599 [M + H + ].
HRFAB + -MS: calcd for C 25 H 32 N 4 O 10 FS, 599.1828 [M + H + ]; found 599.1833.
実施例３：（２Ｓ）−２−（３−（１Ｒ）−１−カルボキシ−２−（（１−（Ｓ）−５−カルボキシ−５−（２−（４−フルオロベンズアミド）アセタミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（１２ａ）の調製
図２のスキームに従い、下記（１）〜（３）の手順で調製した。
Example 3: (2S) -2- (3- (1R) -1-carboxy-2-((1- (S) -5-carboxy-5- (2- (4-fluorobenzamido) acetamido) pentyl- Preparation of 2,5-dioxopyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid (12a) The following procedures (1) to (3) were prepared according to the scheme of FIG.
（１）Ｎ−［２−［（２，５−ジオキソ−１−ピロリジニル）オキシ］−２−オキソエチル］−４−フルオロベンズアミド（１０ａ）の調製
化合物９ａ（２００ｍｇ）のＮ，Ｎ−ジメチルホルムアミド溶液（３ｍＬ）にＮ−ヒドロキシスクシンイミド（１１７ｍｇ）と水溶性カルボジイミド塩酸塩（１９４ｍｇ）を加えて室温（２５℃）下１時間撹拌した。反応溶液を飽和炭酸水素ナトリウム水溶液に注ぎ込み、酢酸エチルで抽出した。硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。生じた沈殿を濾取し、クロロホルムで洗浄した。（１２７ｍｇ, 収率４３％）
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，５００ＭＨｚ）δ：２．８１（ｓ，４Ｈ），４．４３（ｄ，Ｊ＝５．７３Ｈｚ，２Ｈ），７．３４（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．９５（ｍ，２Ｈ），９．２０（ｔ，Ｊ＝５．７３Ｈｚ，１Ｈ）。
(1) Preparation of N- [2-[(2,5-dioxo-1-pyrrolidinyl) oxy] -2-oxoethyl] -4-fluorobenzamide (10a) Compound 9a (200 mg) in N, N-dimethylformamide N-hydroxysuccinimide (117 mg) and water-soluble carbodiimide hydrochloride (194 mg) were added to (3 mL) and stirred at room temperature (25 ° C.) for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting precipitate was collected by filtration and washed with chloroform. (127 mg, 43% yield)
1 H-NMR (DMSO-d6, 500 MHz) δ: 2.81 (s, 4H), 4.43 (d, J = 5.73 Hz, 2H), 7.34 (t, J = 8.59 Hz, 2H) ), 7.95 (m, 2H), 9.20 (t, J = 5.73 Hz, 1H).
（２）（Ｓ）−６−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）−２−（２−（４−フルオロベンズアミド）アセタミド）ヘキサン酸（１１ａ）の調製
化合物１０ａ（７４ｍｇ）のアセトニトリル溶液（２．５ｍＬ）に化合物５ａ（６６ ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（６５ｍｇ）を加えて室温（２５℃）下６時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液に注ぎ込み、酢酸エチルで抽出した。硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。ＰＴＬＣ（クロロホルム：メタノール＝１０：１（体積比））で粗精製を行い、その後に逆相ＨＰＬＣで精製し、化合物１１ａ（３３ｍｇ，収率３３％）を得た。
ＨＰＬＣ保持時間：４８分。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，５００ＭＨｚ）δ：１．２６（ｍ，２Ｈ），１．４８（ｍ，２Ｈ），１．５９（ｍ，１Ｈ），１．７２（ｍ，１Ｈ），３．３８（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），３．８７（ｄ，Ｊ＝５．７３Ｈｚ，２Ｈ），３．９３（ｍ，２Ｈ），４．１７（ｍ，１Ｈ），６．９９（ｓ，２Ｈ），７．３１（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．９４（ｍ，２Ｈ），８．１４（ｄ，Ｊ＝８．０２Ｈｚ，１Ｈ），８．７０（ｔ，Ｊ＝５．７３Ｈｚ，１Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：４０６［Ｍ＋Ｈ］＋。
(2) of (S) -6- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) -2- (2- (4-fluorobenzamido) acetamido) hexanoic acid (11a) Compound 5a (66 mg) and N, N-diisopropylethylamine (65 mg) were added to an acetonitrile solution (2.5 mL) of the prepared compound 10a (74 mg), and the mixture was stirred at room temperature (25 ° C.) for 6 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Crude purification was performed with PTLC (chloroform: methanol = 10: 1 (volume ratio)), followed by purification with reverse phase HPLC to obtain compound 11a (33 mg, 33% yield).
HPLC retention time: 48 minutes.
1 H-NMR (DMSO-d6, 500 MHz) δ: 1.26 (m, 2H), 1.48 (m, 2H), 1.59 (m, 1H), 1.72 (m, 1H), 3 .38 (t, J = 6.87 Hz, 2H), 3.87 (d, J = 5.73 Hz, 2H), 3.93 (m, 2H), 4.17 (m, 1H), 6.99 (S, 2H), 7.31 (t, J = 8.59 Hz, 2H), 7.94 (m, 2H), 8.14 (d, J = 8.02 Hz, 1H), 8.70 (t , J = 5.73 Hz, 1H).
ESI-MS m / z: 406 [M + H] < +>.
（３）化合物（１２ａ）の調製
化合物１１ａ（１３．８ｍｇ）のアセトニトリル溶液（０．３ｍＬ）に化合物１（１０ｍｇ）の水溶液（０．７５ｍＬ）を加え、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ７にした。室温（２５℃）下３時間撹拌し、逆相ＨＰＬＣで精製して、化合物１２ａ（９．０ｍｇ，収率３９％）を得た。ＨＰＬＣ保持時間：４１分。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：１．２３（ｍ，２Ｈ），１．４９（ｍ，２Ｈ），１．６６（ｍ，１Ｈ），１．８４（ｍ，２Ｈ），２．０６（ｍ，１Ｈ），２．３９（ｍ，２Ｈ），２．５６（ｍ，１Ｈ），２．９５−３．２６（ｍ，３Ｈ），３．４２（ｔ，Ｊ＝６．８２Ｈｚ，２Ｈ），３．９４（ｍ，１Ｈ），４．０３（ｍ，２Ｈ），４．１７（ｍ，１Ｈ），４．３０（ｍ，１Ｈ），４．４４（ｍ，１Ｈ），７．１６（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．７７（ｍ，２Ｈ）。
ＦＡＢ−ＭＳ ｍ／ｚ：７００［Ｍ＋Ｈ＋］。
ＨＲＦＡＢ＋−ＭＳ：ｃａｌｃｄ ｆｏｒ Ｃ２８Ｈ３５Ｎ５Ｏ１３ＦＳ，７００．１９４２［Ｍ＋Ｈ＋］；ｆｏｕｎｄ ７００．１９３６。
(3) Preparation of Compound (12a) An aqueous solution (0.75 mL) of Compound 1 (10 mg) was added to an acetonitrile solution (0.3 mL) of Compound 11a (13.8 mg), and the pH was adjusted to 7 with a 2 mol / L aqueous sodium hydroxide solution. did. The mixture was stirred at room temperature (25 ° C.) for 3 hours and purified by reverse phase HPLC to obtain Compound 12a (9.0 mg, yield 39%). HPLC retention time: 41 minutes.
1 H-NMR (D 2 O, 500 MHz) δ: 1.23 (m, 2H), 1.49 (m, 2H), 1.66 (m, 1H), 1.84 (m, 2H), 2 .06 (m, 1H), 2.39 (m, 2H), 2.56 (m, 1H), 2.95-3.26 (m, 3H), 3.42 (t, J = 6.82 Hz) , 2H), 3.94 (m, 1H), 4.03 (m, 2H), 4.17 (m, 1H), 4.30 (m, 1H), 4.44 (m, 1H), 7 .16 (t, J = 8.59 Hz, 2H), 7.77 (m, 2H).
FAB-MS m / z: 700 [M + H + ].
HRFAB + -MS: calcd for C 28 H 35 N 5 O 13 FS, 700.1942 [M + H + ]; found 700.1936.
実施例４：（２Ｓ）−２−（３−（１Ｒ）−１−カルボキシ−２−（（１−（５−（２−（４−フルオロベンズアミド）アセタミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（１２ｂ）の調製
図２のスキームに従い、下記（１）〜（２）の手順で調製した。
Example 4: (2S) -2- (3- (1R) -1-carboxy-2-((1- (5- (2- (4-fluorobenzamido) acetamido) pentyl-2,5-dioxopyrrolidine) Preparation of -3-yl) thio) ethyl) ureido) pentanedioic acid (12b) The following procedure (1) to (2) was performed according to the scheme of FIG.
（１）Ｎ−（２−（（５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル）アミノ−２−オキソエチル）−４−フルオロベンズアミド（１１ｂ）の調製
実施例３（１）と同じ方法で合成した化合物１０ａ（５０ｍｇ）のアセトニトリル溶液（２ｍＬ）に化合物５ｂ（３７ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（４４ｍｇ）を加えて室温（２５℃）下３時間撹拌した。反応溶液を飽和塩化アンモニウム溶液に注ぎ込み、酢酸エチルで抽出した。飽和食塩水で有機相を洗浄し、硫酸ナトリウムで乾燥させた。減圧下溶媒を留去し、中圧分取液体クロマトグラフ（クロロホルム：メタノール＝１０：１（体積比））で精製し、化合物１１ｂ（３７ｍｇ，収率６０％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，５００ＭＨｚ）δ：１．３１（ｍ，２Ｈ），１．５９（ｍ，４Ｈ），３．３０（ｍ，２Ｈ），３．５２（ｔ，Ｊ＝７．１６Ｈｚ，２Ｈ），４．１０（ｄ，Ｊ＝５．１６Ｈｚ，２Ｈ），６．１０（ｂｒｏａｄ ｓ，１Ｈ），６．６９（ｓ，２Ｈ），６．９８（ｂｒｏａｄ ｓ，１Ｈ），７．１３（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．８５（ｍ，２Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：３６２［Ｍ＋Ｈ］＋。
(1) N- (2-((5- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) pentyl) amino-2-oxoethyl) -4-fluorobenzamide (11b)
1 H-NMR (CDCl 3 , 500 MHz) δ: 1.31 (m, 2H), 1.59 (m, 4H), 3.30 (m, 2H), 3.52 (t, J = 7.16 Hz) , 2H), 4.10 (d, J = 5.16 Hz, 2H), 6.10 (broad s, 1H), 6.69 (s, 2H), 6.98 (broad s, 1H), 7. 13 (t, J = 8.59 Hz, 2H), 7.85 (m, 2H).
ESI-MS m / z: 362 [M + H] < +>.
（２）化合物（１２ｂ）の調製
化合物１１ｂ（８．６ｍｇ）のアセトニトリル溶液（０．１５ｍＬ）に化合物１（７．０ｍｇ）の水溶液（０．７５ｍＬ）を加え、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ７にした。室温（２５℃）下２時間撹拌した。逆相ＨＰＬＣで精製し、化合物１２ｂ（６．０ｍｇ，収率３８％）を得た。ＨＰＬＣ保持時間：４４分。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：１．１５（ｍ，２Ｈ），１．４３（ｍ，４Ｈ），１．８５（ｍ，１Ｈ），２．０６（ｍ，１Ｈ），２．３９（ｍ，２Ｈ），２．５８（ｍ，１Ｈ），２．９５−３．２４（ｍ，６Ｈ），３．３９（ｔ，Ｊ＝７．１６Ｈｚ，２Ｈ），３．９４（ｓ，２Ｈ），４．１６（ｄｄ，Ｊ＝５．１６，９．１６Ｈｚ，１Ｈ），４．４２（ｍ，１Ｈ），７．１６（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．７７（ｍ，２Ｈ）。
ＦＡＢ−ＭＳ ｍ／ｚ：６５６［Ｍ＋Ｈ＋］。
ＨＲＦＡＢ＋−ＭＳ：ｃａｌｃｄ ｆｏｒ Ｃ２７Ｈ３４Ｎ５Ｏ１１ＦＳ，６５６．２０４０［Ｍ＋Ｈ＋］；ｆｏｕｎｄ ６５６．２０３８。
(2) Preparation of Compound (12b) An aqueous solution (0.75 mL) of Compound 1 (7.0 mg) was added to an acetonitrile solution (0.15 mL) of
1 H-NMR (D 2 O, 500 MHz) δ: 1.15 (m, 2H), 1.43 (m, 4H), 1.85 (m, 1H), 2.06 (m, 1H), 2 .39 (m, 2H), 2.58 (m, 1H), 2.95-3.24 (m, 6H), 3.39 (t, J = 7.16 Hz, 2H), 3.94 (s) , 2H), 4.16 (dd, J = 5.16, 9.16 Hz, 1H), 4.42 (m, 1H), 7.16 (t, J = 8.59 Hz, 2H), 7.77. (M, 2H).
FAB-MS m / z: 656 [M + H + ].
HRFAB + -MS: calcd for C 27 H 34 N 5
実施例５： （２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（（Ｓ）−５−カルボキシ−５−（５−（４−フルオロベンズアミド）ペンタミド）ペンチル）−２，５−ジオキサピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（１２ｃ）の調製
図２のスキームに従い、下記（１）〜（４）の手順で調製した。
Example 5: (2S) -2- (3-((1R) -1-carboxy-2-((1-((S) -5-carboxy-5- (5- (4-fluorobenzamide)) pentamide) Preparation of pentyl) -2,5-dioxapyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid (12c) The following procedures (1) to (4) were prepared according to the scheme of FIG.
（１）５−［（４−フルオロベンゾイル）アミノ］ペンタン酸（９ｂ）の調製
化合物６（４６０ｍｇ）のアセトニトリル溶液（５ｍＬ）に５−アミノ吉草酸（２５０ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（２７５ｍｇ）を加えて室温（２５℃）下４時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液に注ぎ込み、酢酸エチルで抽出した。硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。生じた沈殿を濾取してクロロホルムで洗浄した。（２９８ｍｇ，収率６４％）
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，５００ＭＨｚ）δ:１．６７（ｍ，４Ｈ），２．３５（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），３．３９（ｍ，２Ｈ），７．１７（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ）， ７．８６（ｍ，２Ｈ），８．４６（ｓ，１Ｈ）.
ＥＩ−ＭＳ ｍ／ｚ：２３８［Ｍ］＋，１８０（１３）,１６６（４），１５２（８），１２３（１００），９５（２８）。
(1) Preparation of 5-[(4-fluorobenzoyl) amino] pentanoic acid (9b) Compound 6 (460 mg) in acetonitrile (5 mL) was added 5-aminovaleric acid (250 mg) and N, N-diisopropylethylamine (275 mg). ) Was added and stirred at room temperature (25 ° C.) for 4 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting precipitate was collected by filtration and washed with chloroform. (298 mg, 64% yield)
1 H-NMR (CD 3 OD, 500 MHz) δ: 1.67 (m, 4H), 2.35 (t, J = 6.87 Hz, 2H), 3.39 (m, 2H), 7.17 ( t, J = 8.59 Hz, 2H), 7.86 (m, 2H), 8.46 (s, 1H).
EI-MS m / z: 238 [M] + , 180 (13), 166 (4), 152 (8), 123 (100), 95 (28).
（２）Ｎ−［５−［（２，５−ジオキソ−１−ピロリジニル）オキシ］−５−オキソペンチル］−４−フルオロベンズアミド（１０ｂ）の調製
化合物９ｂ（２９７ｍｇ）のＮ，Ｎ−ジメチルホルムアミド溶液（７ｍＬ）にＮ−ヒドロキシスクシンイミド（１４３ｍｇ）とＮ，Ｎ´−ジイソプロピルカルボジイミド（１５７ｍｇ）を加えて室温（２５℃）下一晩撹拌した。反応溶液を飽和炭酸水素ナトリウム水溶液に注ぎ込み、酢酸エチルで抽出した。硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製して化合物１０ｂを得た（２１１ｍｇ，収率５０％）。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，５００ＭＨｚ）δ：１．７６（ｍ，２Ｈ），１．８７（ｍ，２Ｈ），２．６９（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），２．８５（ｓ，４Ｈ），３．５０（ｄｄ，Ｊ＝６．８７，１２．６Ｈｚ），７．１０（ｍ，２Ｈ），７．７９（ｍ，２Ｈ）．
ＥＩ−ＭＳ ｍ／ｚ：３３６［Ｍ］＋，３３３（４），１８０（９），１２３（１００），９５（１９）．
(2) Preparation of N- [5-[(2,5-dioxo-1-pyrrolidinyl) oxy] -5-oxopentyl] -4-fluorobenzamide (10b) Compound 9b (297 mg) of N, N-dimethylformamide N-hydroxysuccinimide (143 mg) and N, N′-diisopropylcarbodiimide (157 mg) were added to the solution (7 mL), and the mixture was stirred overnight at room temperature (25 ° C.). The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (hexane: ethyl acetate = 1: 1) gave compound 10b (211 mg, yield 50%).
1 H-NMR (CDCl 3 , 500 MHz) δ: 1.76 (m, 2H), 1.87 (m, 2H), 2.69 (t, J = 6.87 Hz, 2H), 2.85 (s , 4H), 3.50 (dd, J = 6.87, 12.6 Hz), 7.10 (m, 2H), 7.79 (m, 2H).
EI-MS m / z: 336 [M] + , 333 (4), 180 (9), 123 (100), 95 (19).
（３）（Ｓ）−６−（２，５−ジオキソ−ジヒドロ−１Ｈ−ピロール−１−イル）−２−（５−（４−フルオロベンズアミド）ペンタミド）ヘキサン酸（１１ｃ）の調製
化合物１０ｂ（８０ｍｇ）のアセトニトリル溶液（２ｍＬ）に化合物５ａ（６２ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（６１ｍｇ）を加えて室温（２５℃）下４時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液に注ぎ込み、酢酸エチルで抽出した。硫酸ナトリウムで乾燥させ、減圧下溶媒を留去した。ＰＴＬＣ（クロロホルム：メタノール＝１０：１（体積比））で粗精製を行い、その後に逆相ＨＰＬＣで精製し、化合物１１ｃ（４０ｍｇ，収率３７％）を得た。ＨＰＬＣ保持時間：５３分。
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，５００ＭＨｚ）δ：１．３７（ｍ，２Ｈ），１．５３−１．８９（ｍ，８Ｈ），２．２９（ｔ，Ｊ＝７．１６Ｈｚ，２Ｈ），３．３８（ｍ，２Ｈ），３．４７（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），４．３３（ｄｔ，Ｊ＝４．５８，９．１６Ｈｚ，１Ｈ），６．７７（ｓ，２Ｈ），７．１６（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．８６（ｍ，２Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：４４８［Ｍ＋Ｈ］＋。
(3) Preparation of (S) -6- (2,5-dioxo-dihydro-1H-pyrrol-1-yl) -2- (5- (4-fluorobenzamido) pentamido) hexanoic acid (11c) Compound 10b ( Compound 5a (62 mg) and N, N-diisopropylethylamine (61 mg) were added to an acetonitrile solution (2 mL) of 80 mg) and stirred at room temperature (25 ° C.) for 4 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Crude purification was performed with PTLC (chloroform: methanol = 10: 1 (volume ratio)), followed by purification with reverse-phase HPLC to obtain Compound 11c (40 mg, yield 37%). HPLC retention time: 53 minutes.
1 H-NMR (CD 3 OD, 500 MHz) δ: 1.37 (m, 2H), 1.53-1.89 (m, 8H), 2.29 (t, J = 7.16 Hz, 2H), 3.38 (m, 2H), 3.47 (t, J = 6.87 Hz, 2H), 4.33 (dt, J = 4.58, 9.16 Hz, 1H), 6.77 (s, 2H) ), 7.16 (t, J = 8.59 Hz, 2H), 7.86 (m, 2H).
ESI-MS m / z: 448 [M + H] < +>.
（４）化合物（１２ｃ）の調製
化合物１１ｃ（１０ｍｇ）のアセトニトリル溶液（０．２ｍＬ）に化合物１（６．６ｍｇ）の水溶液（０．８ｍＬ）を加え、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ７にした。室温（２５℃）下２時間撹拌した。逆相ＨＰＬＣで精製し、化合物１２ｃ（９．０ｍｇ，収率５５％）を得た。ＨＰＬＣ保持時間：４６分。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：１．２０（ｍ，２Ｈ），１．４３（ｍ，２Ｈ），１．５２−１．６５（ｍ，５Ｈ），１．７４−１．９０（ｍ，２Ｈ），２．０７（ｍ，１Ｈ），２．２５（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），２．３９（ｍ，２Ｈ），２．４１−２．５３（ｍ，３Ｈ），２．９４−３．１８（ｍ，３Ｈ），３．９２（ｍ，１Ｈ），４．２０（ｍ，２Ｈ），４．４５（ｍ，１Ｈ），７．１２（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．６８（ｍ，２Ｈ）。
ＦＡＢ−ＭＳ ｍ／ｚ：７４２［Ｍ＋Ｈ＋］。
ＨＲＦＡＢ＋−ＭＳ：ｃａｌｃｄ ｆｏｒ Ｃ３１Ｈ４１Ｎ５Ｏ１３ＦＳ，７４２．２４１３［Ｍ＋Ｈ＋］；ｆｏｕｎｄ ７４２．２４０６。
(4) Preparation of Compound (12c) An aqueous solution (0.8 mL) of Compound 1 (6.6 mg) was added to an acetonitrile solution (0.2 mL) of Compound 11c (10 mg), and the pH was adjusted to 7 with a 2 mol / L aqueous sodium hydroxide solution. did. The mixture was stirred at room temperature (25 ° C.) for 2 hours. Purification by reverse phase HPLC gave compound 12c (9.0 mg, 55% yield). HPLC retention time: 46 minutes.
1 H-NMR (D 2 O, 500 MHz) δ: 1.20 (m, 2H), 1.43 (m, 2H), 1.52-1.65 (m, 5H), 1.74-1. 90 (m, 2H), 2.07 (m, 1H), 2.25 (t, J = 6.87 Hz, 2H), 2.39 (m, 2H), 2.41-2.53 (m, 3H), 2.94-3.18 (m, 3H), 3.92 (m, 1H), 4.20 (m, 2H), 4.45 (m, 1H), 7.12 (t, J = 8.59 Hz, 2H), 7.68 (m, 2H).
FAB-MS m / z: 742 [M + H + ].
HRFAB + -MS: calcd for C 31 H 41 N 5 O 13 FS, 742.2413 [M + H + ]; found 742.2406.
実施例６：（２Ｓ）−２−（３−（（１Ｒ）−１−カルボキシ−２−（（１−（５−（５−（４−フルオロベンズアミド）ペンタミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸（１２ｄ）の調製
図２のスキームに従い、下記（１）〜（２）の手順で調製した。
Example 6: (2S) -2- (3-((1R) -1-carboxy-2-((1- (5- (5- (4-fluorobenzamido) pentamido) pentyl) pentyl) -2,5-di Preparation of Oxopyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid (12d) The following procedures (1) to (2) were prepared according to the scheme of FIG.
（１）Ｎ−（５−（（５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル）アミノ）−５−オキソペンチル）−４−フルオロベンズアミド（１１ｄ）の調製
実施例５（１）〜（２）の方法で合成した化合物１０ｂ（５０ｍｇ）のアセトニトリル溶液（１．３ｍＬ）に化合物５ｂ（３３ｍｇ）、及び、Ｎ，Ｎ−ジイソプロピルエチルアミン（３８ｍｇ）を加えて室温（２５℃）下３時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液に注ぎ込み、酢酸エチルで抽出した。飽和食塩水で有機相を洗浄し、硫酸ナトリウムで乾燥させた。減圧下溶媒を留去し、中圧分取液体クロマトグラフ（クロロホルム：メタノール＝１０：１（体積比））で精製し、化合物１１ｄ（５６ｍｇ，収率９３％）。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，５００ＭＨｚ）δ：１．３０（ｍ，２Ｈ），１．５０−１．６９（ｍ，６Ｈ），１．７５（ｍ，２Ｈ），２．２５（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），３．２５（ｍ，２Ｈ），３．４６（ｍ，２Ｈ），３．５１（ｔ，Ｊ＝７．１６Ｈｚ，２Ｈ），５．６２（ｂｒｏａｄ ｓ，１Ｈ），６．６８（ｓ，２Ｈ），６．７４（ｂｒｏａｄ ｓ，１Ｈ），７．１０（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．８４（ｍ，２Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：４０４［Ｍ＋Ｈ］＋。
(1) N- (5-((5- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) pentyl) amino) -5-oxopentyl) -4-fluorobenzamide (11d )
1 H-NMR (CDCl 3 , 500 MHz) δ: 1.30 (m, 2H), 1.50-1.69 (m, 6H), 1.75 (m, 2H), 2.25 (t, J = 6.87 Hz, 2 H), 3.25 (m, 2 H), 3.46 (m, 2 H), 3.51 (t, J = 7.16 Hz, 2 H), 5.62 (broad s, 1 H) 6.68 (s, 2H), 6.74 (broad s, 1H), 7.10 (t, J = 8.59 Hz, 2H), 7.84 (m, 2H).
ESI-MS m / z: 404 [M + H] < +>.
（２）化合物（１２ｄ）の調製
化合物１１ｄ（８．３ｍｇ）のアセトニトリル溶液（０．１５ｍＬ）に化合物１（６．０ｍｇ）の水溶液（１．０ｍＬ）を加え、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ７にした。室温（２５℃）下２時間撹拌した。逆相ＨＰＬＣで精製し、化合物１２ｄ（５．７ｍｇ，収率４０％）を得た。ＨＰＬＣ保持時間：４９分。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：１．１２（ｍ，２Ｈ），１．３７（ｍ，４Ｈ），１．５３（ｍ，４Ｈ），１．８６（ｍ，１Ｈ），２．０５（ｍ，１Ｈ），２．１６（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），２．３９（ｄｄ，Ｊ＝４．５８，６．８７Ｈｚ，２Ｈ），２．５２（ｍ，１Ｈ），２．９３−３．１７（ｍ，５Ｈ），３．２９（ｍ，４Ｈ），３．９１（ｍ，１Ｈ），４．１６（ｄｄ，Ｊ＝５．１６，８．５９Ｈｚ，１Ｈ），４．４３（ｂｒｏａｄ ｓ，１Ｈ），７．１２（ｔ，Ｊ＝８．５９Ｈｚ，２Ｈ），７．６７（ｍ，２Ｈ）。
ＦＡＢ−ＭＳ ｍ／ｚ： ６９８［Ｍ＋Ｈ＋］。
ＨＲＦＡＢ＋−ＭＳ：ｃａｌｃｄ ｆｏｒ Ｃ３０Ｈ４１Ｎ５Ｏ１１ＦＳ，６９８．２５０４［Ｍ＋Ｈ＋］；ｆｏｕｎｄ ６９８．２５０７。
(2) Preparation of Compound (12d) An aqueous solution (1.0 mL) of Compound 1 (6.0 mg) was added to an acetonitrile solution (0.15 mL) of Compound 11d (8.3 mg), and 2 mol / L aqueous sodium hydroxide solution was added. The pH was adjusted to 7. The mixture was stirred at room temperature (25 ° C.) for 2 hours. Purification by reverse phase HPLC gave compound 12d (5.7 mg, 40% yield). HPLC retention time: 49 minutes.
1 H-NMR (D 2 O, 500 MHz) δ: 1.12 (m, 2H), 1.37 (m, 4H), 1.53 (m, 4H), 1.86 (m, 1H), 2 .05 (m, 1H), 2.16 (t, J = 6.87 Hz, 2H), 2.39 (dd, J = 4.58, 6.87 Hz, 2H), 2.52 (m, 1H) 2.93-3.17 (m, 5H), 3.29 (m, 4H), 3.91 (m, 1H), 4.16 (dd, J = 5.16, 8.59 Hz, 1H) 4.43 (broad s, 1H), 7.12 (t, J = 8.59 Hz, 2H), 7.67 (m, 2H).
FAB-MS m / z: 698 [M + H + ].
HRFAB + -MS: calcd for C 30 H 41 N 5 O 11 FS, 698.2504 [M + H + ]; found 698.2507.
実施例７：（Ｓ）−５−（（１−カルボキシ−５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル）アミノ−５−オキソペンタン−１−アミニウム塩化物（１５ａ）の調製
図４のスキームに従い、下記（１）〜（３）の手順で調製した。
Example 7: (S) -5-((1-carboxy-5- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) pentyl) amino-5-oxopentane-1- Preparation of aminium chloride (15a) According to the scheme of FIG. 4, it prepared by the procedure of following (1)-(3).
（１）２，５−ジオキソピロリジン−１−イル ５−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ペンタノエート（１３）の調製
５−アミノ吉草酸の１，４−ジオキサン溶液（３３３ｍｇ，３ｍＬ）に、二炭酸ジ−ｔｅｒｔ−ブチル（０．７５ｇ）と２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２３ｇ，３ｍＬ）を０℃で加えた。室温（２５℃）で１６時間撹拌し、１ｍｏｌ／Ｌ塩酸と酢酸エチルで抽出し、有機相を飽和塩化ナトリウム水溶液で洗浄した。減圧下溶媒を留去し、得られた無色の油状物質をジメチルホルムアミド（６ｍＬ）に溶解させた。Ｎ，Ｎ′−ジイソプロピルカルボジイミド（０．３５ｇ）とＮ−ヒドロキシスクシンイミド（０．３２ｇ）を加えて室温下１６時間撹拌した。飽和炭酸水素ナトリウム水溶液と酢酸エチルで抽出し、有機相を硫酸ナトリウムで乾燥させた。減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１（体積比））で精製し、化合物１３（０．４８ｇ，収率５４％）を得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，５００ＭＨｚ）δ：６．８２（ｔ，Ｊ＝５．１６Ｈｚ，１Ｈ），２．９３（ｍ，２Ｈ），２．８１（ｓ，４Ｈ），２．６６（ｔ，Ｊ＝７．４５Ｈｚ，２Ｈ），１．５９（ｔｔ，Ｊ＝７．４５Ｈｚ，７．４５Ｈｚ，２Ｈ），１．４６（ｔｔ，Ｊ＝７．４５Ｈｚ，７．４５Ｈｚ，２Ｈ）。
(1) Preparation of 2,5-dioxopyrrolidin-1-yl 5-((tert-butoxycarbonyl) amino) pentanoate (13) To a 1,4-dioxane solution (333 mg, 3 mL) of 5-aminovaleric acid, Di-tert-butyl dicarbonate (0.75 g) and a 2 mol / L aqueous sodium hydroxide solution (0.23 g, 3 mL) were added at 0 ° C. The mixture was stirred at room temperature (25 ° C.) for 16 hours, extracted with 1 mol / L hydrochloric acid and ethyl acetate, and the organic phase was washed with a saturated aqueous sodium chloride solution. The solvent was distilled off under reduced pressure, and the resulting colorless oily substance was dissolved in dimethylformamide (6 mL). N, N′-diisopropylcarbodiimide (0.35 g) and N-hydroxysuccinimide (0.32 g) were added and stirred at room temperature for 16 hours. Extraction was performed with a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic phase was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 (volume ratio)) to obtain Compound 13 (0.48 g, yield 54%).
1 H-NMR (DMSO-d6,500 MHz) δ: 6.82 (t, J = 5.16 Hz, 1H), 2.93 (m, 2H), 2.81 (s, 4H), 2.66 ( t, J = 7.45 Hz, 2H), 1.59 (tt, J = 7.45 Hz, 7.45 Hz, 2H), 1.46 (tt, J = 7.45 Hz, 7.45 Hz, 2H).
（２）（Ｓ）−２−（５−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ペンタナミド）−６−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ヘキサン酸（１４ａ）の調製
化合物１３のアセトニトリル溶液（１２６ｍｇ／４ｍＬ）に化合物５ａ（１０５ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（１０３ｍｇ）を加えて室温（２５℃）で６時間撹拌した。飽和塩化ナトリウム水溶液と酢酸エチルで抽出し、有機相を硫酸ナトリウムで乾燥させた。減圧下溶媒を留去し、ＰＴＬＣ（クロロホルム／メタノール＝９／１（体積比））で精製し、化合物１４ａ（３５ｍｇ，収率２１％）を得た。
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，５００ＭＨｚ）δ：６．７９（ｓ，２Ｈ），４．１３（ｓ，１Ｈ），３．４９（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），３．０５（ｔ，Ｊ＝７．４５Ｈｚ，２Ｈ），２．２５（ｔ，Ｊ＝７．４５Ｈｚ，２Ｈ），１．８６（ｍ，１Ｈ），１．６４（ｍ，５Ｈ），１．４９（ｍ，２Ｈ），１．４２（ｓ，９Ｈ），１．３６（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：４２６［Ｍ＋Ｈ＋］。
(2) (S) -2- (5-((tert-butoxycarbonyl) amino) pentanamide) -6- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) hexanoic acid ( Preparation of 14a) Compound 5a (105 mg) and N, N-diisopropylethylamine (103 mg) were added to an acetonitrile solution (126 mg / 4 mL) of
1 H-NMR (CD 3 OD, 500 MHz) δ: 6.79 (s, 2H), 4.13 (s, 1H), 3.49 (t, J = 6.87 Hz, 2H), 3.05 ( t, J = 7.45 Hz, 2H), 2.25 (t, J = 7.45 Hz, 2H), 1.86 (m, 1H), 1.64 (m, 5H), 1.49 (m, 2H), 1.42 (s, 9H), 1.36 (t, J = 6.87 Hz, 2H).
ESI-MS m / z: 426 [M + H <+ >].
（３）化合物（１５ａ）の調製
化合物１４ａ（３５ｍｇ）に４ｍｏｌ／Ｌ塩酸の酢酸エチル溶液（４ｍＬ）を加えて、室温（２５℃）下で容器を振とうさせた。生じた白色沈殿を濾取して酢酸エチルで洗浄した後、逆相ＨＰＬＣで精製し、化合物１５ａ（２２ｍｇ，収率７４％）を得た。ＨＰＬＣ保持時間：２５分。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：６．７１（ｓ，２Ｈ），４．１８（ｍ，１Ｈ），３．３６（ｍ，２Ｈ），２．８９（ｍ，２Ｈ），２．２３（ｍ，２Ｈ），１．７６（ｍ，２Ｈ），１．４４−１．５５（ｍ，６Ｈ），１．２３（ｍ，２Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：３２６［Ｍ＋Ｈ＋］。
(3) Preparation of Compound (15a) A 4 mol / L hydrochloric acid ethyl acetate solution (4 mL) was added to Compound 14a (35 mg), and the container was shaken at room temperature (25 ° C.). The resulting white precipitate was collected by filtration, washed with ethyl acetate, and purified by reverse phase HPLC to give compound 15a (22 mg, yield 74%). HPLC retention time: 25 minutes.
1 H-NMR (D 2 O, 500 MHz) δ: 6.71 (s, 2H), 4.18 (m, 1H), 3.36 (m, 2H), 2.89 (m, 2H), 2 .23 (m, 2H), 1.76 (m, 2H), 1.44-1.55 (m, 6H), 1.23 (m, 2H).
ESI-MS m / z: 326 [M + H <+ >].
実施例８：５−（（５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル）アミノ）−５−オキソペンタン−１−アミニウム塩化物（１５ｂ）の調製
図４のスキームに従い、下記（１）〜（２）の手順で調製した。
Example 8: of 5-((5- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) pentyl) amino) -5-oxopentane-1-aminium chloride (15b) Preparation According to the scheme of FIG. 4, preparation was performed by the following procedures (1) to (2).
（１）ｔｅｒｔ−ブチル（５−（（５−（２，５−ジオキソ−２，５−ジヒドロ−１Ｈ−ピロール−１−イル）ペンチル）アミノ）−５−オキソペンチル）カルバメート（１４ｂ）の調製
実施例７（１）で得られた化合物１３のアセトニトリル溶液（８０ｍｇ／２．５ｍＬ）に化合物５ｂ（５６ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（６６ｍｇ）を加えて室温（２５℃）で５時間撹拌した。飽和塩化ナトリウム水溶液と酢酸エチルで抽出し、有機相を硫酸ナトリウムで乾燥させた。減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１（体積比））で精製し、化合物１４ｂ（９２ｍｇ，収率９５％）を得た。
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，５００ＭＨｚ）δ：７．９０（ｂｒｏａｄ ｓ，１Ｈ），６．８０（ｓ，２Ｈ），６．５８（ｂｒｏａｄ ｓ，１Ｈ），３．４９（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），３．１４（ｍ，２Ｈ），３．０４（ｍ，２Ｈ），２．１７（ｔ，Ｊ＝７．４５Ｈｚ，２Ｈ），１．４５-１．６３（ｍ，６Ｈ），１．４２（ｓ，９Ｈ），１．２９（ｍ，２Ｈ）。
ＥＳＩ−ＭＳ ｍ／ｚ：３８２［Ｍ＋Ｈ＋］。
(1) Preparation of tert-butyl (5-((5- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) pentyl) amino) -5-oxopentyl) carbamate (14b)
1 H-NMR (CD 3 OD, 500 MHz) δ: 7.90 (broad s, 1H), 6.80 (s, 2H), 6.58 (broad s, 1H), 3.49 (t, J = 6.87 Hz, 2H), 3.14 (m, 2H), 3.04 (m, 2H), 2.17 (t, J = 7.45 Hz, 2H), 1.45-1.63 (m, 6H), 1.42 (s, 9H), 1.29 (m, 2H).
ESI-MS m / z: 382 [M + H <+ >].
（２）化合物（１５ｂ）の調製
化合物１４ｂ（７０ｍｇ）に４ｍｏｌ／Ｌ塩酸の酢酸エチル溶液（１０ｍＬ）を加えて、室温（２５℃）下で容器を振とうさせた。生じた白色沈殿を濾取して酢酸エチルで洗浄し、化合物１５ｂ（２２ｍｇ，収率３８％）を得た。
１Ｈ−ＮＭＲ（Ｄ２Ｏ，５００ＭＨｚ）δ：６．７４（ｓ，２Ｈ），３．４０（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），３．０６（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），２．９１（ｔ，Ｊ＝６．３０Ｈｚ，２Ｈ），２．１７（ｔ，Ｊ＝６．８７Ｈｚ，２Ｈ），１．３８−１．５６（ｍ，８Ｈ），１．１８（ｍ，２Ｈ）。
(2) Preparation of compound (15b) A 4 mol / L hydrochloric acid ethyl acetate solution (10 mL) was added to compound 14b (70 mg), and the container was shaken at room temperature (25 ° C). The resulting white precipitate was collected by filtration and washed with ethyl acetate to obtain Compound 15b (22 mg, yield 38%).
1 H-NMR (D 2 O, 500 MHz) δ: 6.74 (s, 2H), 3.40 (t, J = 6.87 Hz, 2H), 3.06 (t, J = 6.87 Hz, 2H) ), 2.91 (t, J = 6.30 Hz, 2H), 2.17 (t, J = 6.87 Hz, 2H), 1.38-1.56 (m, 8H), 1.18 (m , 2H).
実施例９：放射化学合成
前駆体として化合物５ａ，化合物５ｂ，化合物１５ａ，化合物１５ｂを用い、図３及び図４のスキームに従い、下記の通り、それぞれに対応する［１８Ｆ］フッ素標識化合物；［１８Ｆ］８ａ，［１８Ｆ］８ｂ，［１８Ｆ］１２ｃ，［１８Ｆ］１２ｄを調製した。まず、Ｎ−スクシンイミジル ４−［１８Ｆ］フルオロベンゾエートを、既報（Nat Protoc. 2006;1:1655-1661）記載の方法を用いて合成した。各前駆体０．５ｍｇにＮ−スクシンイミジル ４−［１８Ｆ］フルオロベンゾエートのアセトニトリル溶液（６−６００ＭＢｑ、５０μＬ）とＮ，Ｎ−ジイソプロピルエチルアミン（１０μＬ）を加えて室温（２５℃）で５分反応させた。反応溶液に化合物１（１．２ｍｇ）の水溶液（１００μＬ）を加えて室温で５分反応させた。反応後に１ｍｏｌ／Ｌ塩酸を５０μＬ加えて逆相ＨＰＬＣで精製した。精製後はＳｅｐ−Ｐａｋ Ｌｉｇｈｔ Ｃ１８ Ｃａｒｔｒｉｄｇｅに吸着させて水１ｍＬで洗浄、メタノールで抽出した。窒素ガス気流下メタノールを除去し、生理食塩水に溶解させて各実験にて使用した。いずれの［１８Ｆ］フッ素標識化合物も放射化学的純度９５％以上で得た。各［１８Ｆ］フッ素標識化合物の放射化学的収率（ＲＣＹ，減衰補正）とＨＰＬＣ保持時間（ｔＲ）を以下の表１に示す。
なお、保持時間（ｔＲ）は、下記条件の保持時間である。
カラム：ＣＯＳＭＯＣＩＬ ５Ｃ１８ ＡＲ−ＩＩ ４．６×１５０ｍｍ（ナカライテスク社製）。
流速：１ｍｌ/ｍｉｎ
移動相：水、メタノール（共に０．１％トリフルオロ酢酸を含む）。
グラディエント：メタノール３０％−８０％（６０ｍｉｎ）。
各［１８Ｆ］フッ素標識化合物は１−オクタノールと０．１ｍｍｏｌ／Ｌリン酸バッファー（ｐＨ７．４）を用いて分配計数（ｌｏｇ Ｄ）を算出した。結果は以下の表１に併せて表記した。
Example 9: Using compound 5a ,
The holding time (t R ) is a holding time under the following conditions.
Column: COSMOCIL 5C18 AR-II 4.6 × 150 mm (manufactured by Nacalai Tesque).
Flow rate: 1 ml / min
Mobile phase: water, methanol (both containing 0.1% trifluoroacetic acid).
Gradient: methanol 30% -80% (60 min).
Each [ 18 F] fluorine-labeled compound was calculated for partition count (log D) using 1-octanol and 0.1 mmol / L phosphate buffer (pH 7.4). The results are shown in Table 1 below.
実施例１０：親和性評価
ヒト前立腺がん細胞（ＬＮＣａＰ）を用いた結合阻害実験にて、実施例１〜６で得られた６つのウレア誘導体化合物；８ａ，８ｂ，１２ａ，１２ｂ，１２ｃ，１２ｄの親和性を評価した。ポジティブコントロールとして、２−（ホスホノメチル）ペンタン二酸（２−ＰＭＰＡ、Ｔｏｃｒｉｓ Ｂｉｏｓｃｉｅｎｃｅ社製、以下同じ）の親和性を評価した。Ｎ−［Ｎ−［（Ｓ）−１，３−ジカルボキシプロピル］カルバモイル］−Ｓ−３−ヨード−Ｌ−チロシン（［１２５Ｉ］ＤＣＩＴ、非特許文献３と同じ方法で調製）を放射性リガンドとして用いた。１２ウェルプレート（４×１０５細胞／ウェル）に播種したＬＮＣａＰ細胞を５％二酸化炭素雰囲気下、３７℃で４８時間インキュベートした。培地を取り去り、それぞれのウェルを５００μＬアッセイ培地（０．５％ウシ血清アルブミンが付加されたＲＰＭＩ１６４０培地）で２度洗浄した。［１２５Ｉ］ＤＣＩＴのアッセイ培地溶液（２９．６ｋＢｑ／ｍＬ）を５００μＬ／ｍＬと、各ウレア誘導体化合物を加え、３７℃で１時間インキュベートした。非特異的結合は、２−ＰＭＰＡを０．５ｍｍｏｌ／Ｌを加えることによって評価した。インキュベーションした後、各ウェルは５００μＬの上記アッセイ培地で二度洗浄し、細胞を０．２ｍｏｌ／Ｌ水酸化ナトリウム水溶液に溶解した。細胞に結合した放射能は、γカウンターで測定した。ＩＣ５０値をＧｒａｐｈＰａｄ Ｐｒｉｓｍ５プログラム（ＧｒａｐｈＰａｄ Ｓｏｆｔｗａｒｅ社製）で計算し、Ｋｉ値をＣｈｅｎｇ−Ｐｒｕｓｏｆｆ式を用いて計算した。６つのウレア誘導体化合物の親和性は以下の表２に示す通りとなった。
Example 10: Affinity evaluation Six urea derivative compounds obtained in Examples 1 to 6 in a binding inhibition experiment using human prostate cancer cells (LNCaP); 8a , 8b , 12a , 12b , 12c , 12d The affinity of was evaluated. As a positive control, the affinity of 2- (phosphonomethyl) pentanedioic acid (2-PMPA, manufactured by Tocris Bioscience, the same applies hereinafter) was evaluated. N- [N-[(S) -1,3-dicarboxypropyl] carbamoyl] -S-3-iodo-L-tyrosine ([ 125 I] DCIT, prepared in the same manner as in Non-Patent Document 3) as a radioligand Used as. LNCaP cells seeded in 12-well plates (4 × 10 5 cells / well) were incubated at 37 ° C. for 48 hours in a 5% carbon dioxide atmosphere. The medium was removed and each well was washed twice with 500 μL assay medium (RPMI 1640 medium supplemented with 0.5% bovine serum albumin). [ 125 I] DCIT assay medium solution (29.6 kBq / mL) and 500 μL / mL of each urea derivative compound were added and incubated at 37 ° C. for 1 hour. Nonspecific binding was assessed by adding 0.5 mmol / L of 2-PMPA. After incubation, each well was washed twice with 500 μL of the above assay medium, and the cells were dissolved in 0.2 mol / L aqueous sodium hydroxide solution. Radioactivity bound to the cells was measured with a γ counter. IC50 values were calculated with GraphPad Prism 5 program (GraphPad Software) and Ki values were calculated using the Cheng-Prusoff equation. The affinity of the six urea derivative compounds was as shown in Table 2 below.
実施例１１：血漿中安定性
実施例９に示す方法で調製した［１８Ｆ］フッ素標識化合物；［１８Ｆ］８ａ，［１８Ｆ］８ｂ，［１８Ｆ］１２ｃ，［１８Ｆ］１２ｄのインビトロでの安定性を、マウス血漿を用いて評価した。マウス血漿は、Ｃ．Ｂ．−１７／Ｉｃｒ ＋／＋ Ｊｃｌ雄性マウス（２０〜２２ｇ）をイソフルランで麻酔し、心臓から血液を収集して遠心分離（１５００×ｇ）にかけ、上澄みを‐８０℃で保存したものを使用した。［１８Ｆ］フッ素標識化合物（２０μＬ、０．６−１．５ＭＢｑ）をそれぞれマウス血漿１００μＬに加え、３７℃で１時間インキュベートした。インキュベーション後、メタノール（１５０μＬ）を加え、遠心分離（５０００×ｇ）にかけた。上澄みを回収し、コスモナイスフィルター（Ｓ）（０．４５μｍ、４ｍｍ）でろ過して、ろ液の分析を高速液体クロマトグラフィーで行った。このときの分析条件は、実施例９で示したものを用いた。その結果、各［１８Ｆ］フッ素標識化合物；［１８Ｆ］８ａ，［１８Ｆ］８ｂ，［１８Ｆ］１２ｃ，［１８Ｆ］１２ｄはいずれも、分解物を認めず９５％以上が安定に存在した。
Example 11: Plasma stability [ 18 F] Fluorine labeled compound prepared by the method shown in Example 9; [ 18 F] 8a , [ 18 F] 8b , [ 18 F] 12c , [ 18 F] 12d in vitro Was evaluated using mouse plasma. Mouse plasma was obtained from C.I. B. -17 / Icr + / + Jcl male mice (20-22 g) were anesthetized with isoflurane, blood was collected from the heart, centrifuged (1500 × g), and the supernatant stored at −80 ° C. was used. [ 18 F] fluorine-labeled compound (20 μL, 0.6-1.5 MBq) was added to 100 μL of mouse plasma, respectively, and incubated at 37 ° C. for 1 hour. After incubation, methanol (150 μL) was added and centrifuged (5000 × g). The supernatant was collected and filtered through a Cosmonis filter (S) (0.45 μm, 4 mm), and the filtrate was analyzed by high performance liquid chromatography. The analysis conditions at this time were the same as those shown in Example 9. As a result, each [ 18 F] fluorine-labeled compound; [ 18 F] 8a , [ 18 F] 8b , [ 18 F] 12c , and [ 18 F] 12d do not show any decomposition products, and 95% or more is stable. Were present.
実施例１２：体内分布実験
実施例９に示す方法で調製した［１８Ｆ］フッ素標識化合物［１８Ｆ］８ａ，［１８Ｆ］８ｂ，［１８Ｆ］１２ｃ，［１８Ｆ］１２ｄの生体内分布を、ヒト前立腺がん細胞（ＬＮＣａＰ，ＰＣ−３）を前述の方法で移植した腫瘍移植マウス（２２〜２５ｇ）を用いて評価した。生理食塩水に溶解させた各［１８Ｆ］フッ素標識化合物（１００μＬ、３７ｋＢｑ）をマウス（ｎ＝４）に尾静脈投与して、投与後２，１５，６０分後の各組織における放射能量を組織摘出法にて評価した。各［１８Ｆ］フッ素標識化合物の生体内分布は以下の表３−１及び表３−２に示す通りとなった。表３−１及び表３−２の数値は平均±標準偏差として表記、単位は％ＩＤ／ｇとして示した（胃のみ％ＩＤ）。何れもＬＮＣａＰに集積し、中でも［１８Ｆ］８ａが最も高い集積を示した。ＰＳＭＡ非発現腫瘍（ＰＣ−３）への集積は認められなかった。
Example 12: Biodistribution experiment Biodistribution of [ 18 F] fluorine-labeled compound [ 18 F] 8a , [ 18 F] 8b , [ 18 F] 12c , [ 18 F] 12d prepared by the method shown in Example 9 Was evaluated using tumor-transplanted mice (22-25 g) transplanted with human prostate cancer cells (LNCaP, PC-3) by the method described above. Each [ 18 F] fluorine-labeled compound (100 μL, 37 kBq) dissolved in physiological saline was administered to the mouse (n = 4) via the tail vein, and the amount of radioactivity in each tissue was measured 2, 15, 60 minutes after administration. Evaluation was made by tissue extraction. The biodistribution of each [ 18 F] fluorine-labeled compound was as shown in Tables 3-1 and 3-2 below. The numerical values in Table 3-1 and Table 3-2 are expressed as mean ± standard deviation, and the unit is shown as% ID / g (% ID of stomach only). All accumulated in LNCaP, and [ 18 F] 8a showed the highest accumulation. Accumulation in PSMA non-expressing tumor (PC-3) was not observed.
実施例１３： インビボブロッキング評価
最も高い腫瘍集積（ＬＮＣａＰ）を認めた化合物［１８Ｆ］８ａ（１００μＬ、３７ｋＢｑ）と２−ＰＭＰＡ（５０ｍｇ／ｋｇ）を、腫瘍移植マウス（２２−２４ｇ）に同時に尾静脈投与し、３０分後に断頭して、実施例１２の結果に対する腫瘍集積の変化を評価した。結果を図５に示す。図５から明らかなように、２−ＰＭＰＡと同時投与を行った場合、ＬＮＣａＰと血中放射能量の比は０．９５となり、［１８Ｆ］８ａ単独投与の場合の値１６．９よりも有意に低下した。
Example 13: In vivo blocking evaluation Compound [ 18 F] 8a (100 μL, 37 kBq) and 2-PMPA (50 mg / kg) with the highest tumor accumulation (LNCaP) were simultaneously tailed to tumor-implanted mice (22-24 g). It was administered intravenously and decapitated 30 minutes later to evaluate the change in tumor accumulation relative to the results of Example 12. The results are shown in FIG. As is clear from FIG. 5, when 2-PMPA was co-administered, the ratio of LNCaP to blood radioactivity was 0.95, which was more significant than the value 16.9 obtained with [ 18 F] 8a alone. Declined.
実施例１４：ＰＥＴ撮像
放射性フッ素標識化合物［１８Ｆ］８ａと放射性フッ素標識化合物［１８Ｆ］１２ｃのＰＥＴ／ＣＴ撮像を行った。ＰＥＴ／ＣＴ装置は、Gamma Medica-Ideas, Inc.製のものを用いた。腫瘍移植マウス（２０〜２５ｇ）を２．５％イソフルラン／空気で麻酔し、温熱パッドに置いて体温を維持した。各放射性フッ素標識化合物（３．７−１１．１ＭＢｑ）を尾静脈投与した。競合実験は、［１８Ｆ］８ａと、２−ＰＭＰＡ（５０ｍｇ／ｋｇ）とを含む生理食塩液（０．１０ｍＬ）を尾静脈投与することにより行った。ＣＴスキャンの後、ＰＥＴスキャンを３０〜６４分収集した。
結果を図６及び図７に示す。図６、７中、矢印で指す部位がＬＮＣａＰの移植部位であり、破線で囲んだ部分がＰＣ−３の移植部位である。図６及び図７から明らかなように、いずれのプローブもＬＮＣａＰを明瞭に描出した。放射性化合物［１８Ｆ］８ａは肝臓から速やかに消失し、投与１時間後（６０〜６５分）には腎臓、膀胱、ＬＮＣａＰに高い集積を認めた。一方、放射性化合物［１８Ｆ］１２ｃは投与１時間後においても肝臓に放射能の集積を認めた。
２−ＰＭＰＡと放射性化合物［１８Ｆ］８ａを同時に投与した結果を図８に示す。この場合、図８から明らかなように、腎臓とＬＮＣａＰにおける集積が阻害され、投与１時間後にはほぼ全ての放射能が膀胱に移行した。
Example 14: PET imaging PET / CT imaging of radioactive fluorine-labeled compound [ 18 F] 8a and radioactive fluorine-labeled compound [ 18 F] 12c was performed. A PET / CT apparatus manufactured by Gamma Medica-Ideas, Inc. was used. Tumor transplanted mice (20-25 g) were anesthetized with 2.5% isoflurane / air and placed on a heating pad to maintain body temperature. Each radioactive fluorine-labeled compound (3.7-11.1 MBq) was administered via the tail vein. The competition experiment was performed by administering a tail vein of physiological saline (0.10 mL) containing [ 18 F] 8a and 2-PMPA (50 mg / kg). After the CT scan, a PET scan was collected for 30-64 minutes.
The results are shown in FIGS. In FIGS. 6 and 7, the site indicated by the arrow is the LNCaP transplant site, and the portion surrounded by the broken line is the PC-3 transplant site. As is apparent from FIGS. 6 and 7, LNCaP was clearly depicted with any probe. The radioactive compound [ 18 F] 8a rapidly disappeared from the liver, and high accumulation was observed in the kidney, bladder and
The results of simultaneous administration of 2-PMPA and radioactive compound [ 18 F] 8a are shown in FIG. In this case, as is apparent from FIG. 8, accumulation in the kidney and LNCaP was inhibited, and almost all radioactivity was transferred to the
本発明の化合物は、ＰＳＭＡへ特異的に集積するので、ＰＳＭＡの発現が関与する各種疾患の診断に有用であり、放射性画像診断薬の分野で広く利用できる。 Since the compound of the present invention specifically accumulates in PSMA, it is useful for diagnosis of various diseases in which PSMA expression is involved, and can be widely used in the field of radiological diagnostic imaging.
Claims (7)
で表わされるウレア誘導体化合物又はその塩。 Following formula (1):
Or a salt thereof.
・２−（３−（１−カルボキシ−２−（（１−（５−カルボキシ−５−（４−［ １８ Ｆ］フルオロベンズアミド）ペンチル−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸；又は、
・２−（３−（（１−カルボキシ−２−（（１−（５−カルボキシ−５−（５−（４−［ １８ Ｆ］フルオロベンズアミド）ペンタミド）ペンチル）−２，５−ジオキソピロリジン−３−イル）チオ）エチル）ウレイド）ペンタン二酸
である、請求項１に記載のウレア誘導体化合物又はその塩。 The compound represented by the formula (1) is
2- (3- (1-carboxy-2-((1- (5-carboxy-5- (4- [ 18 F] fluorobenzamido) pentyl-2,5-dioxopyrrolidin-3-yl) thio) Ethyl) ureido) pentanedioic acid; or
- 2- (3 - ((1-carboxy-2 - ((1- (5-carboxy -5- (5- (4- [18 F ] fluoro-benzamide) Pentamido) pentyl) -2,5-dioxo-pyrrolidine The urea derivative compound or a salt thereof according to claim 1, which is -3-yl) thio) ethyl) ureido) pentanedioic acid.
で表される化合物と、Ｎ−スクシンイミジル ［ １８ Ｆ］フルオロベンゾエートとを反応させる第１工程と、
前記第１工程で得られる反応生成物と、２−［３−［１−カルボキシ‐２−メルカプトエチル］ウレイド ペンタン二酸とを反応させて、下記式（１）：
で表されるウレア誘導体化合物を得る第２工程と、
を含む、ウレア誘導体化合物の製造方法。
Following formula (2):
A first step of reacting a compound represented by : N-succinimidyl [ 18 F] fluorobenzoate;
The reaction product obtained in the first step and 2- [3- [1-carboxy-2-mercaptoethyl] ureidopentanedioic acid are reacted to form the following formula (1):
A second step of obtaining a urea derivative compound represented by:
A process for producing a urea derivative compound, comprising:
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