JP2014051442A - Nuclear medicine imaging probe capable of diagnosing prostatic cancer - Google Patents
Nuclear medicine imaging probe capable of diagnosing prostatic cancer Download PDFInfo
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- JP2014051442A JP2014051442A JP2012195399A JP2012195399A JP2014051442A JP 2014051442 A JP2014051442 A JP 2014051442A JP 2012195399 A JP2012195399 A JP 2012195399A JP 2012195399 A JP2012195399 A JP 2012195399A JP 2014051442 A JP2014051442 A JP 2014051442A
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LOTBYPQQWICYBB-UHFFFAOYSA-N methyl n-hexyl-n-[2-(hexylamino)ethyl]carbamate Chemical compound CCCCCCNCCN(C(=O)OC)CCCCCC LOTBYPQQWICYBB-UHFFFAOYSA-N 0.000 description 1
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- DPLOGSUBQDREOU-UHFFFAOYSA-N tert-butyl n-(5-aminopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCCN DPLOGSUBQDREOU-UHFFFAOYSA-N 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
本開示は、前立腺がんを診断可能な核医学イメージングプローブに関する。 The present disclosure relates to a nuclear medicine imaging probe capable of diagnosing prostate cancer.
前立腺がんは、世界中で多くの男性が罹患しているがん種である。前立腺がんの診断方法としてはＰＳＡ(Prostate Specific Antigen)検査があるが、この方法は確定診断に侵襲的な生検を必要とする。また、その他の診断方法として、ＳＰＥＣＴ（Single Photon Emission Computed Tomography）や、ＰＥＴ（Positoron Emission Tomography）等といった核医学イメージングプローブを用いたイメージング法を用いた方法が提案されている。 Prostate cancer is a cancer type that affects many men worldwide. There is a PSA (Prostate Specific Antigen) test as a method for diagnosing prostate cancer, but this method requires an invasive biopsy for a definitive diagnosis. As another diagnostic method, a method using an imaging method using a nuclear medicine imaging probe such as SPECT (Single Photon Emission Computed Tomography) or PET (Positoron Emission Tomography) has been proposed.
ＰＳＭＡ（Prostate Specific Membrane Antige）は、前立腺がん、特にアンドロゲン非依存性の前立腺がん細胞の表面に大量に発現するII型内在性膜タンパク質である。このため、ＰＳＭＡを標的とするイメージング剤及び癌の治療のための薬剤が提案されている（例えば、非特許文献１、２及び３）。非特許文献１には、N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[125I]iodo-L-tyrosine([125I]DCIT)が記載されている。非特許文献２には、(S)-2-(3-((S)-1-carboxy-5-(3-(4-[125I]iodophenyl)ureido)pentyl)ureido)pentanedioic acid([125I]MIP-1095)及び(S)-2-(3-((S)-1-carboxy-5-(4-[125I]iodobenzylamino)pentyl)ureido)pentanedioic acid([125I]MIP-1072)が記載されている。非特許文献３には、N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-Lcysteine([18F]DCFBC)が記載されている。 PSMA (Prostate Specific Membrane Antige) is a type II integral membrane protein that is expressed in large amounts on the surface of prostate cancer, particularly androgen-independent prostate cancer cells. For this reason, imaging agents targeting PSMA and agents for cancer treatment have been proposed (for example, Non-Patent Documents 1, 2, and 3). Non-Patent Document 1 describes N- [N-[(S) -1,3-dicarboxypropyl] carbamoyl] -S-3- [ 125 I] iodo-L-tyrosine ([ 125 I] DCIT). Yes. Non-Patent Document 2 includes (S) -2- (3-((S) -1-carboxy-5- (3- (4- [ 125 I] iodophenyl) ureido) pentyl) ureido) pentanedioic acid ([ 125 I] MIP-1095) and (S) -2- (3-((S) -1-carboxy-5- (4- [ 125 I] iodobenzylamino) pentyl) ureido) pentanedioic acid ([ 125 I] MIP-1072 ) Is described. Non-Patent Document 3 describes N- [N-[(S) -1,3-Dicarboxypropyl] carbamoyl] -4- [ 18 F] fluorobenzyl-Lcysteine ([ 18 F] DCFBC).
前立腺がんは、アメリカにおいて男性が罹りやすいがんであり、また日本においてもその罹患率が年々増加している。このため、前立腺がんを診断可能な新たなプローブが求められている。本開示は、前立腺がんを診断可能な新たなプローブを提供する。 Prostate cancer is a cancer susceptible to men in the United States, and its incidence is increasing year by year in Japan. For this reason, a new probe capable of diagnosing prostate cancer is required. The present disclosure provides a new probe capable of diagnosing prostate cancer.
本開示は、一又は複数の態様において、式(I)で表される化合物又は式(I)で表される化合物の製薬上許容される塩に関する。
Ｌは、リンカー、又は結合手を示し、
Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示し、
ｍは、０、１、２、３、４、又は５である。
In one or more embodiments, the present disclosure relates to a compound represented by formula (I) or a pharmaceutically acceptable salt of a compound represented by formula (I).
L represents a linker or a bond,
Each Z independently represents a hydrogen atom or C 1-4 alkyl;
m is 0, 1, 2, 3, 4, or 5.
本開示は、一又は複数の態様において、式(II)で表される化合物又は式(II)で表される化合物の製薬上許容される塩に関する。
Ｐは、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示し、
Ｘ及びＹは、それぞれ独立して、Ｃ1-8アルキレン、Ｃ2-8アルケニル、Ｃ2-8アルキニル、Ｃ1-8ヘテロアルキル、Ｃ2-8ヘテロアルケニル、Ｃ2-8ヘテロアルキニル、Ｃ1-8アルコキシ、又は結合手を示し、
Ｑは、天然アミノ酸、−ＮＨ−、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示し、
Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示し、
ｍは、０、１、２、３、４、又は５である。
In one or more embodiments, the present disclosure relates to a compound represented by formula (II) or a pharmaceutically acceptable salt of a compound represented by formula (II).
P is, -O -, - CO-NH -, - CO 2 -NH -, - NH -, - S -, - SO 2 -, - CO 2 -, - NH-CO -, - NH-CO 2 - Or -CH = CH-
X and Y are each independently C 1-8 alkylene, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 2-8 heteroalkenyl, C 2-8 heteroalkynyl, C 2 1-8 alkoxy or a bond
Q is a natural amino acid, -NH -, - O -, - CO-NH -, - CO 2 -NH -, - S -, - SO 2 -, - CO 2 -, - NH-CO -, - NH- CO 2- or -CH = CH-
Each Z independently represents a hydrogen atom or C 1-4 alkyl;
m is 0, 1, 2, 3, 4, or 5.
本開示によれば、一又は複数の態様において、前立腺がんを診断可能な新たなプローブを提供できる。 According to the present disclosure, in one or a plurality of aspects, a new probe capable of diagnosing prostate cancer can be provided.
ＰＳＭＡはＧＣＰ−ＩＩ（glutamate carboxypeptidase-II）活性を有している。ＧＣＰ−ＩＩは腎臓に高発現しているため、ＰＳＭＡイメージングプローブは腎臓に多く集積する。従来のプローブは、腎臓に集積した後、時間経過とともに膀胱へ流出する傾向が見られる。膀胱は前立腺の近傍臓器であることから、膀胱へのプローブの集積は、前立腺がんのイメージングに影響を及ぼす恐れがある。本開示は、プローブのＰＳＭＡに対する親和性を向上させることができれば、前立腺がん組織への迅速且つ高い集積が期待できるとともに、腎臓での滞留時間を延長させて膀胱へのプローブの流出を遅らせることができる、との知見に基く。 PSMA has GCP-II (glutamate carboxypeptidase-II) activity. Since GCP-II is highly expressed in the kidney, many PSMA imaging probes accumulate in the kidney. Conventional probes tend to flow out into the bladder over time after accumulating in the kidney. Since the bladder is a nearby organ of the prostate, probe accumulation in the bladder may affect prostate cancer imaging. If the affinity of the probe for PSMA can be improved, the present disclosure can be expected to be rapidly and highly accumulated in prostate cancer tissue, and the retention time in the kidney is extended to delay the outflow of the probe to the bladder. Based on the knowledge that it is possible.
本開示によれば、ＰＳＭＡとの親和性が向上された化合物を提供できる。本開示の化合物はＰＳＭＡに対して優れた親和性を示すことから、本開示によれば、一又は複数の態様において、前立腺がんのイメージングプローブ及び又は治療用の薬剤を提供できる。また、ＰＳＭＡは、前立腺がん細胞以外の腫瘍に発現していること、及び血管形成等に関与すること等が知られている。このため、本開示によれば、一又は複数の態様において、前立腺がん以外のＰＳＭＡが発現するがんのイメージングプローブ及び又は治療用の薬剤を提供できる。 According to the present disclosure, a compound having improved affinity with PSMA can be provided. Since the compound of the present disclosure exhibits excellent affinity for PSMA, according to the present disclosure, in one or a plurality of embodiments, an imaging probe for prostate cancer and / or a therapeutic agent can be provided. In addition, PSMA is known to be expressed in tumors other than prostate cancer cells and to be involved in angiogenesis. Therefore, according to the present disclosure, in one or a plurality of aspects, it is possible to provide an imaging probe and / or therapeutic agent for cancer in which PSMA other than prostate cancer is expressed.
本開示の化合物により、ＰＳＭＡとの親和性が向上された化合物を提供できる理由は明らかではないが、式(I)又は(II)で表される化合物における３−チオ−２，５−ジオキソピロリジン（例えば、下記式において破線で囲まれた部分の構造）がＰＳＭＡに対する親和性に何らかの影響を及ぼし、これによりＰＳＭＡに対する親和性が向上しているものと考える。但し、本開示はこれらのメカニズムに限定されるものではない。
本明細書において、式(I)〜(VIII)で表される化合物は少なくとも１又は２個の不斉炭素原子をもっており、各々少なくとも２、３又は４種の光学異性体が存在する。このため、式(I)〜(VIII)で表される化合物は、いずれも、これらの光学異性体の全て及びこれらの混合物の全てを包含するものである。 In the present specification, the compounds represented by formulas (I) to (VIII) have at least one or two asymmetric carbon atoms, and there are at least 2, 3 or 4 optical isomers, respectively. For this reason, all the compounds represented by the formulas (I) to (VIII) include all of these optical isomers and all of mixtures thereof.
本明細書において「製薬上許容される塩」とは、薬理上及び／又は医薬上許容される塩を含有し、例えば、無機酸塩、有機酸塩、無機塩基塩、有機塩基塩、酸性又は塩基性アミノ酸塩等が挙げられる。 As used herein, the term “pharmaceutically acceptable salt” includes pharmacologically and / or pharmaceutically acceptable salts, and includes, for example, inorganic acid salts, organic acid salts, inorganic basic salts, organic basic salts, acidic or Examples include basic amino acid salts.
本明細書において「放射性同位元素又はその同位体」は、放射性同位元素及び非放射性同位元素を含む。放射性同位元素としては、特に限定されないが、一又は複数の実施形態において、11Ｃ、13Ｎ、15Ｏ、18Ｆ、64Ｃｕ、67Ｇａ、68Ｇａ、75Ｂｒ、76Ｂｒ、77Ｂｒ、82Ｒｂ、99mＴｃ、111Ｉｎ、123Ｉ、124Ｉ、125Ｉ、131Ｉ、186Ｒｅ、188Ｒｅ、及び90Ｙ等が挙げられる。非放射性同位元素は、一又は複数の実施形態において、上述する放射性同位元素の非放射性同位元素であり、例えば、13Ｃ、14Ｎ、16Ｏ、17Ｆ、63Ｃｕ、70Ｇａ、80Ｂｒ、99mＴｃ、115Ｉｎ、及び127Ｉ等が挙げられる。 As used herein, “radioisotope or its isotope” includes radioactive isotopes and non-radioactive isotopes. Radioisotopes include, but are not limited to, in one or more embodiments, 11 C, 13 N, 15 O, 18 F, 64 Cu, 67 Ga, 68 Ga, 75 Br, 76 Br, 77 Br, 82 Examples include Rb, 99m Tc, 111 In, 123 I, 124 I, 125 I, 131 I, 186 Re, 188 Re, and 90 Y. The non-radioactive isotope is a non-radioactive isotope of the above-mentioned radioisotope in one or a plurality of embodiments, for example, 13 C, 14 N, 16 O, 17 F, 63 Cu, 70 Ga, 80 Br, 99m Tc, 115 In, 127 I and the like.
本明細書において「Ｃ1-4アルキル」、又は「Ｃ1-6アルキル」とは、炭素数が１〜４個、又は１〜６個の直鎖、分岐、又は環状の飽和脂肪族炭化水素をいう。これらのアルキルとしては、一又は複数の実施形態において、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、第３級ブチル、ペンチル、及びヘキシル等が挙げられる。Ｃ1-4アルキル及びＣ1-6アルキルは、一又は複数の実施形態において、１以上の置換基によって置換されていてもよい。 In the present specification, “C 1-4 alkyl” or “C 1-6 alkyl” means a linear, branched or cyclic saturated aliphatic hydrocarbon having 1 to 4 carbon atoms or 1 to 6 carbon atoms. Say. These alkyls include, in one or more embodiments, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. C 1-4 alkyl and C 1-6 alkyl may be substituted with one or more substituents in one or more embodiments.
本明細書において「Ｃ6-12アリール」とは、共役π電子系を有する少なくとも１つの環を有する炭素数が６〜１２個の芳香族基をいう。Ｃ6-12アリールとしては、一又は複数の実施形態において、フェニル、ナフチル、及び１，２，３，４−テトラヒドロナフチル等があげられる。本明細書において「ハロゲン置換されたＣ6-12アリール」は、少なくとも１つの炭素原子がハロゲンによって置換されている炭素数が６〜１２のアリールをいう。ハロゲンは、放射性ハロゲンであってもよいし、非放射性ハロゲンであってもよい。放射性ハロゲンとしては、一又は複数の実施形態として、123Ｉ、124Ｉ、125Ｉ、131Ｉ、18Ｆ、75Ｂｒ、76Ｂｒ、及び77Ｂｒが挙げられる。非放射性ハロゲンとしては、17Ｆ、80Ｂｒ、及び127Ｉ等が挙げられる。ハロゲン置換されたＣ6-12アリールは、一又は複数の態様において、ハロゲン以外の１以上の置換基によって置換されていてもよい。置換基としては、一又は複数の態様において、トリハロメチル、ヒドロキシメチル、ＳＨ、ＯＨ、ＮＯ2、アミン、シアノ、アルキル、アルコキシ、及びアミノ等が挙げられる。 As used herein, “C 6-12 aryl” refers to an aromatic group having 6 to 12 carbon atoms and having at least one ring having a conjugated π electron system. C 6-12 aryl includes phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and the like in one or more embodiments. As used herein, “halogen-substituted C 6-12 aryl” refers to aryl having 6 to 12 carbon atoms in which at least one carbon atom is substituted with halogen. The halogen may be a radioactive halogen or a non-radioactive halogen. The radioactive halogen includes 123 I, 124 I, 125 I, 131 I, 18 F, 75 Br, 76 Br, and 77 Br as one or more embodiments. Non-radioactive halogens include 17 F, 80 Br, 127 I and the like. The halogen-substituted C 6-12 aryl may be substituted with one or more substituents other than halogen in one or more embodiments. Examples of the substituent include trihalomethyl, hydroxymethyl, SH, OH, NO 2 , amine, cyano, alkyl, alkoxy, amino and the like in one or more embodiments.
本明細書において「Ｃ4-12へテロアリール」とは、少なくとも１つのヘテロ原子を含む炭素数が４〜１２のアリールをいう。ヘテロ原子としては、一又は複数の実施形態として、酸素、硫黄、及び窒素が上げられる。Ｃ4-12へテロアリールとしては、一又は複数の実施形態として、チオフェン、フラン、ピロール、イミダゾール、ピラゾール、イソチアゾール、イソオキサゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、フラニル、ピリジル、ピロリル、イミダゾリル、キノリン、及びベンゾフラン等が挙げられる。本明細書において、「ハロゲン置換されたＣ4-12へテロアリール」は、少なくとも１つの炭素原子がハロゲンによって置換されている炭素数が６〜１２のヘテロアリールをいう。ハロゲン置換されたＣ6-12アリールは、一又は複数の態様において、ハロゲン以外の１以上の置換基によって置換されていてもよい。置換基は、上記の通りである。 As used herein, “C 4-12 heteroaryl” refers to aryl having 4 to 12 carbon atoms and containing at least one heteroatom. Heteroatoms include oxygen, sulfur, and nitrogen as one or more embodiments. C 4-12 heteroaryl includes, as one or more embodiments, thiophene, furan, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, furanyl, pyridyl, pyrrolyl, imidazolyl, quinoline , And benzofuran. As used herein, “halogen-substituted C 4-12 heteroaryl” refers to a heteroaryl having 6 to 12 carbon atoms in which at least one carbon atom is substituted with a halogen. The halogen-substituted C 6-12 aryl may be substituted with one or more substituents other than halogen in one or more embodiments. The substituents are as described above.
本明細書において「ハロゲン置換されたＣ1-6アルキル」は、少なくとも１つの炭素原子がハロゲンによって置換されている炭素数が１〜６のアルキルをいう。ハロゲン置換されたＣ1-6アルキルは、一又は複数の実施形態において、１以上の置換基によって置換されていてもよい。 As used herein, “halogen-substituted C 1-6 alkyl” refers to an alkyl having 1 to 6 carbon atoms in which at least one carbon atom is substituted with halogen. The halogen-substituted C 1-6 alkyl may be substituted with one or more substituents in one or more embodiments.
本明細書において「Ｃ2-8アルケニル」とは、炭素数が２〜８個のアルケンをいう。Ｃ2-8アルケニルとしては、一又は複数の実施形態において、ビニル、アリル、プロペニル、２−メチルー１−プロペニル、及び２−ブテニル等が挙げられる。本明細書において「Ｃ2-8ヘテロアルケニル」とは、少なくとも１つのヘテロ原子を含む炭素数が２〜８のアルケニルをいう。 As used herein, “C 2-8 alkenyl” refers to an alkene having 2 to 8 carbon atoms. C 2-8 alkenyl includes, in one or more embodiments, vinyl, allyl, propenyl, 2-methyl-1-propenyl, 2-butenyl, and the like. As used herein, “C 2-8 heteroalkenyl” refers to alkenyl having 2 to 8 carbon atoms and containing at least one heteroatom.
本明細書において「Ｃ2-8アルキニル」とは、炭素数が２〜８個のアルキンをいう。Ｃ2-8アルキニルとしては、一又は複数の実施形態において、エチニル、プロピニル、及びブチニル等が挙げられる。本明細書において「Ｃ2-8ヘテロアルキニル」とは、少なくとも１つのヘテロ原子を含む炭素数が２〜８のアルキニルをいう。 As used herein, “C 2-8 alkynyl” refers to alkyne having 2 to 8 carbon atoms. C 2-8 alkynyl includes, in one or more embodiments, ethynyl, propynyl, butynyl, and the like. As used herein, “C 2-8 heteroalkynyl” refers to alkynyl having 2 to 8 carbon atoms and containing at least one heteroatom.
本明細書において「Ｃ1-8ヘテロアルキル」とは、炭素原子の少なくとも１つがヘテロ原子に置換された炭素数が１〜８のアルキルをいう。 As used herein, “C 1-8 heteroalkyl” refers to an alkyl having 1 to 8 carbon atoms in which at least one carbon atom is substituted with a heteroatom.
本明細書において「Ｃ1-8アルコキシ」とは、直鎖又は分岐鎖状の炭素数が１〜８個の環を含むアルキルオキシをいう。Ｃ1-8アルコキシとしては、一又は複数の実施形態において、メトキシ、メトキシ、プロピルオキシ、イソプロピルオキシ、及びブチルオキシ等が挙げられる。 In this specification, “C 1-8 alkoxy” refers to a linear or branched alkyloxy containing a ring having 1 to 8 carbon atoms. C 1-8 alkoxy includes, in one or more embodiments, methoxy, methoxy, propyloxy, isopropyloxy, butyloxy, and the like.
本明細書において「Ｃ1-8アルキレン」とは、直鎖又は分岐鎖状の炭素数が１〜８個を含むアルキレンをいう。Ｃ1-8アルキレンとしては、一又は複数の実施形態において、メチレン基、エチレン基、プロピレン基、ブチレン基、ペンチル基、及びヘキシル基が挙げられる。 In this specification, “C 1-8 alkylene” refers to a linear or branched alkylene having 1 to 8 carbon atoms. C 1-8 alkylene includes, in one or more embodiments, a methylene group, an ethylene group, a propylene group, a butylene group, a pentyl group, and a hexyl group.
本明細書において「天然アミノ酸」としては、一又は複数の実施形態において、グリシン、リジン、グルタミン酸、チロシン、及びシステイン等が挙げられる。 As used herein, “natural amino acid” includes, in one or more embodiments, glycine, lysine, glutamic acid, tyrosine, cysteine, and the like.
［式(I)で表される化合物］
本開示は、一又は複数の実施形態において、式(I)で表される化合物又は式(I)で表される化合物の製薬上許容される塩（以下、「本開示の化合物(I)」という）に関する。
In one or a plurality of embodiments, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt of a compound represented by formula (I) (hereinafter, “compound (I) of the present disclosure”). Said).
式(I)において、Ｒは、放射性同位元素又はその同位体を含む置換基を示す。放射性同位元素又はその同位体を含む置換基は、少なくとも放射性同位元素又はその同位体を含んでいればよい。置換基としては、一又は複数の実施形態において、公知の放射性標識基、及び放射性金属同位元素を含むキレート化合物等が挙げられる。置換基としては、一又は複数の実施形態において、ハロゲン置換されたＣ6-12アリール等が挙げられる。 In the formula (I), R represents a radioisotope or a substituent containing an isotope thereof. The radioisotope or the substituent containing the isotope only needs to contain at least the radioisotope or the isotope. Examples of the substituent include, in one or a plurality of embodiments, chelate compounds containing a known radiolabeled group and a radiometal isotope. Examples of the substituent include halogen-substituted C 6-12 aryl in one or more embodiments.
式(I)において、Ｌは、リンカー、又は結合手を示す。リンカーとしては、一又は複数の実施形態において、−ＣＯＮＲ2（ＣＨ2）n1ＣＯＮＲ3（ＣＨＲ1）n2（ＣＨ2）n3−、−ＣＯＮＲ2（ＣＨ2）n1ＣＯＮＲ3（ＣＨ2）n2−、−（ＣＨ2）n1ＣＯＮＲ2（ＣＨ2）n2−、−（ＣＨ2）n1ＮＲ2ＣＯ（ＣＨ2）n2−、−（ＣＨ2）n1ＮＲ3ＣＯＮＲ2（ＣＨ2）n2−、−（ＣＨ2）n1ＣＯＮＲ3（ＣＨ2）n3ＣＯＮＲ2（ＣＨ2）n2−、−（ＣＨ2）n1ＣＯＮＲ3（ＣＨ2）n3（ＣＨＲ4）n4ＣＯＮＲ2（ＣＨ2）n2−、−（ＣＨ2）n1−、−（ＣＨ2）n1Ｓ（ＣＨ2）n2−、−（ＣＨ2）n1Ｏ（ＣＨ2）n2−、−（ＣＨ2）n1ＮＲ2（ＣＨ2）n2−、−（ＣＨ2）n1ＣＯ２（ＣＨ2）n2−等が挙げられる。前記式中、ｎ１、ｎ２、ｎ３及びｎ４はそれぞれ０又は１〜５の整数であり、Ｒ1は、水素原子、低級アルキル基。カルボキシル基、又はフェニル基であり、Ｒ2、Ｒ3及びＲ4は、それぞれ、水素原子、低級アルキル基又はフェニル基である。 In the formula (I), L represents a linker or a bond. Linkers, in one or more embodiments, -CONR 2 (CH 2) n1 CONR 3 (CHR 1) n2 (CH 2) n3 -, - CONR 2 (CH 2) n1 CONR 3 (CH 2) n2 - , - (CH 2) n1 CONR 2 (CH 2) n2 -, - (CH 2) n1 NR 2 CO (CH 2) n2 -, - (CH 2) n1 NR 3 CONR 2 (CH 2) n2 -, - (CH 2) n1 CONR 3 ( CH 2) n3 CONR 2 (CH 2) n2 -, - (CH 2) n1 CONR 3 (CH 2) n3 (CHR 4) n4 CONR 2 (CH 2) n2 -, - ( CH 2) n1 -, - ( CH 2) n1 S (CH 2) n2 -, - (CH 2) n1 O (CH 2) n2 -, - (CH 2) n1 NR 2 (CH 2) n2 -, - (CH 2 ) n1 CO2 (CH 2 ) n2 — and the like. In the above formula, n1, n2, n3 and n4 are each 0 or an integer of 1 to 5, and R 1 is a hydrogen atom or a lower alkyl group. It is a carboxyl group or a phenyl group, and R 2 , R 3 and R 4 are a hydrogen atom, a lower alkyl group or a phenyl group, respectively.
式(I)において、Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示す。式(I)において、ｍは、０、１、２、３、４、又は５である。 In the formula (I), each Z independently represents a hydrogen atom or C 1-4 alkyl. In the formula (I), m is 0, 1, 2, 3, 4, or 5.
[式(II)で表される化合物]
本開示は、一又は複数の実施形態において、式(II)で表される化合物又は式(II)で表される化合物の製薬上許容される塩（以下、「本開示の化合物(II)」という）に関する。
In one or a plurality of embodiments, the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt of a compound represented by formula (II) (hereinafter, “compound (II) of the present disclosure”). Said).
式(II)中、Ｒ’は、ハロゲン置換されたＣ6-12アリール、ハロゲン置換されたＣ4-12へテロアリール、又はハロゲン置換されたＣ1-6アルキルを示し、中でも、ハロゲン置換されたＣ6-12アリールが好ましい。 In the formula (II), R ′ represents halogen-substituted C 6-12 aryl, halogen-substituted C 4-12 heteroaryl, or halogen-substituted C 1-6 alkyl. C 6-12 aryl is preferred.
式(II)中、Ｐは、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示す。 Wherein (II), P is, -O -, - CO-NH -, - CO 2 -NH -, - NH -, - S -, - SO 2 -, - CO 2 -, - NH-CO-, —NH—CO 2 — or —CH═CH— is shown.
式(II)中、Ｘ及びＹは、それぞれ独立して、Ｃ1-8アルキレン、Ｃ2-8アルケニル、Ｃ2-8アルキニル、Ｃ1-8ヘテロアルキル、Ｃ2-8ヘテロアルケニル、Ｃ2-8ヘテロアルキニル、Ｃ1-8アルコキシ、又は結合手を示す。 In formula (II), X and Y are each independently C 1-8 alkylene, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 2-8 heteroalkenyl, C 2. -8 heteroalkynyl, C 1-8 alkoxy, or a bond.
式(II)中、Ｑは、天然アミノ酸、−ＮＨ−、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示す。 Wherein (II), Q is a natural amino acid, -NH -, - O -, - CO-NH -, - CO 2 -NH -, - S -, - SO 2 -, - CO 2 -, - NH- CO -, - NH-CO 2 -, or an -CH = CH-.
式(II)中、Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示す。 In the formula (II), each Z independently represents a hydrogen atom or C 1-4 alkyl.
式(II)中、ｍは、０、１、２、３、４、又は５である。 In the formula (II), m is 0, 1, 2, 3, 4, or 5.
本開示の化合物(II)としては、一又は複数の実施形態において、式(III)〜(VIII)のいずれかで表される化合物又はそれらの化合物の製薬上許容される塩等が挙げられる。式(III)〜(VIII)中、*Iは、放射性ヨウ素原子を示す。
[イメージング用組成物]
本開示は、一又は複数の実施形態において、本開示の化合物を含むイメージング用組成物（以下、「本開示のイメージング用組成物」ともいう）に関する。本開示のイメージング用組成物は、一又は複数の実施形態において、ＰＳＭＡ及び／又はＧＣＰ−ＩＩのイメージングに用いることができる。また、本開示のイメージング用組成物は、一又は複数の実施形態において、前立腺がん、又は前立腺がん以外のＰＳＭＡが発現するがんのイメージングに用いることができる。
[Imaging composition]
In one or a plurality of embodiments, the present disclosure relates to an imaging composition including the compound of the present disclosure (hereinafter, also referred to as “imaging composition of the present disclosure”). In one or more embodiments, the imaging composition of the present disclosure can be used for imaging of PSMA and / or GCP-II. In one or a plurality of embodiments, the imaging composition of the present disclosure can be used for imaging of prostate cancer or cancer expressing PSMA other than prostate cancer.
本開示のイメージング用組成物の形態は、特に限定されるものではないが、一又は複数の実施形態において、溶液又は粉末が挙げられる。イメージング用組成物は、担体等の医薬品添加物を含んでいてもよい。本開示において医薬品添加物は、日本薬局方、アメリカ薬局方及び／又はヨーロッパ薬局方等で医薬品添加物として許認可を受けている化合物をいう。担体としては、例えば、水性溶媒及び非水性溶媒が使用できる。水性溶媒としては、例えば、リン酸カリウム緩衝液、生理食塩水、リンゲル液、及び蒸留水等が挙げられる。非水性溶媒としては、例えば、ポリエチレングリコール、植物性油脂、エタノール、グリセリン、ジメチルスルホキサイド、及びプロピレングリコール等が挙げられる。 Although the form of the composition for imaging of this indication is not specifically limited, In one or some embodiment, a solution or a powder is mentioned. The imaging composition may contain a pharmaceutical additive such as a carrier. In the present disclosure, a pharmaceutical additive refers to a compound that has been approved as a pharmaceutical additive in the Japanese Pharmacopoeia, the American Pharmacopoeia, and / or the European Pharmacopoeia. As the carrier, for example, an aqueous solvent and a non-aqueous solvent can be used. Examples of the aqueous solvent include potassium phosphate buffer, physiological saline, Ringer's solution, and distilled water. Examples of the non-aqueous solvent include polyethylene glycol, vegetable oil, ethanol, glycerin, dimethyl sulfoxide, and propylene glycol.
[医薬組成物]
本開示は、一又は複数の実施形態において、本開示の化合物を含む医薬組成物に関する。本開示の医薬組成物は、一又は複数の実施形態において、前立腺がん、又は前立腺がん以外のＰＳＭＡが発現するがんの治療に用いることができる。
[Pharmaceutical composition]
The present disclosure, in one or more embodiments, relates to a pharmaceutical composition comprising a compound of the present disclosure. In one or a plurality of embodiments, the pharmaceutical composition of the present disclosure can be used for treatment of prostate cancer or cancer expressing PSMA other than prostate cancer.
［イメージング方法］
本開示は、一又は複数の実施形態において、本開示の化合物を用いたＰＳＭＡのイメージング方法に関する。本開示は、一又は複数の実施形態において、本開示の化合物を投与された被検体から前記化合物の放射性シグナルを検出することを含む、イメージング方法に関する。被検体は、特に限定されないが、一又は複数の実施形態において、ヒト、ヒト以外の哺乳類、培養細胞、及びＰＳＭＡが存在しうる対象から選択される。
[Imaging method]
In one or more embodiments, the present disclosure relates to a method for imaging PSMA using a compound of the present disclosure. The present disclosure, in one or more embodiments, relates to an imaging method comprising detecting a radioactive signal of the compound from a subject administered the compound of the present disclosure. The subject is not particularly limited, but in one or more embodiments, the subject is selected from humans, non-human mammals, cultured cells, and subjects in which PSMA can exist.
本開示にかかるイメージング方法は、第１の態様として、本開示の化合物を予め投与された被検体から該ポリペプチドの放射性シグナルを検出することを含む。シグナルの検出は、例えば、本開示の化合物を投与後、シグナルの検出に十分な時間が経過後に行うことが好ましい。本開示にかかるイメージング方法は、一又は複数の実施形態において、検出されたシグナルを再構成処理して画像に変換し表示すること、及び／又は検出されたシグナルを数値化して集積量を提示することを含む。本開示において「表示すること」は、一又は複数の実施形態において、モニタに表示すること、及び／又は印字することを含む。本開示において「提示すること」は、一又は複数の実施形態において、算出した集積量を保存すること、及び／又は外部に出力することを含む。 The imaging method according to the present disclosure includes, as a first aspect, detecting a radioactive signal of the polypeptide from a subject previously administered with the compound of the present disclosure. The signal detection is preferably performed, for example, after administration of the compound of the present disclosure and after a sufficient time for signal detection has elapsed. In one or a plurality of embodiments, an imaging method according to the present disclosure reconstructs a detected signal, converts it into an image and displays it, and / or quantifies the detected signal to present an accumulation amount. Including that. In the present disclosure, “displaying” includes displaying on a monitor and / or printing in one or more embodiments. In the present disclosure, “presenting” includes storing the calculated accumulation amount and / or outputting the accumulated amount in one or a plurality of embodiments.
シグナルの検出は、使用する本開示の化合物に含まれる放射性同位元素の種類に応じて適宜決定でき、例えば、PET及びSPECT等を用いて行うことができる。SPECTは、例えば、本開示の化合物を投与された被検体から放出されるγ線をガンマカメラにより測定することを含む。ガンマカメラによる測定は、例えば、本開示の化合物の放射性同位元素から放出される放射線（γ線）を一定時間単位で測定することを含み、好ましくは放射線が放出される方向及び放射線数量を一定時間単位で測定することを含む。本開示にかかるイメージング方法は、放射線の測定により得られた測定されたオ本開示の化合物の分布を断面画像として表すこと、及び得られた断面画像を再構成することをさらに含んでいてもよい。PETは、例えば、オリゴペプチドを投与された被検体から、ポジトロンと電子との対消滅により生成するガンマ線をPET用検出器で同時計数することを含み、さらに、計測した結果に基づきポジトロンを放出する放射性核種の位置の三次元分布を描写することを含んでいてもよい。 The detection of the signal can be appropriately determined according to the type of radioisotope contained in the compound of the present disclosure to be used, and can be performed using, for example, PET and SPECT. SPECT includes, for example, measuring gamma rays emitted from a subject administered a compound of the present disclosure with a gamma camera. The measurement by the gamma camera includes, for example, measuring radiation (γ rays) emitted from the radioisotope of the compound of the present disclosure in a certain time unit. Preferably, the direction and the quantity of radiation are emitted for a certain time. Includes measuring in units. The imaging method according to the present disclosure may further include representing the measured distribution of the compound of the present disclosure obtained by measurement of radiation as a cross-sectional image, and reconstructing the obtained cross-sectional image. . PET includes, for example, simultaneous counting of gamma rays generated by pair annihilation of positron and electrons from a subject administered with an oligopeptide with a PET detector, and further releases positrons based on the measured results. It may include rendering a three-dimensional distribution of radionuclide positions.
SPECT又はPETによる測定にあわせて、X線CT及び／又はMRIの測定を行ってもよい。これにより、例えば、SPECT又はPETにより得られた画像（機能画像）と、CT又はMRIにより得られた画像（形態画像）とを融合させた融合画像を得ることができる。 X-ray CT and / or MRI measurement may be performed in accordance with measurement by SPECT or PET. Thereby, for example, a fused image obtained by fusing an image (functional image) obtained by SPECT or PET and an image (morphological image) obtained by CT or MRI can be obtained.
本開示にかかるイメージング方法は、第２の形態として、本開示の化合物を被検体に投与すること、及び投与された被検体から本開示の化合物の放射性シグナルを検出することを含む。シグナルの検出、及び再構成処理等は、第１の態様と同様に行うことができる。 The imaging method concerning this indication includes administering the compound of this indication to a subject as a 2nd form, and detecting the radioactive signal of the compound of this indication from the administered subject. Signal detection, reconstruction processing, and the like can be performed in the same manner as in the first embodiment.
被検体への本開示の化合物の投与は、局所的であってもよく、全身的であってもよい。投与経路は、被検体の状態等に応じて適宜決定できるが、例えば、静脈、動脈、皮内、腹腔内への注射又は輸液等が挙げられる。本開示の化合物の投与量（用量）は、特に制限されず、イメージングのために所望のコントラストを得るために十分な量を投与すればよく、一又は複数の実施形態において、１μｇ以下とすることができる。本開示の化合物は、一又は複数の実施形態において、担体等の医薬品添加物とともに投与される。医薬品添加物は上述のとおりである。投与から測定までの時間は、例えば、本開示の化合物のＰＳＭＡへの結合時間、本開示の化合物の種類及び本開示の化合物の分解時間等に応じて適宜決定できる。 Administration of a compound of the present disclosure to a subject can be local or systemic. The administration route can be appropriately determined according to the condition of the subject, and examples thereof include intravenous, arterial, intradermal, intraperitoneal injection or infusion. The dose (dose) of the compound of the present disclosure is not particularly limited, and may be an amount sufficient to obtain a desired contrast for imaging. In one or a plurality of embodiments, the dose is 1 μg or less. Can do. In one or more embodiments, the compounds of the present disclosure are administered with a pharmaceutical additive such as a carrier. The pharmaceutical additives are as described above. The time from administration to measurement can be appropriately determined according to, for example, the binding time of the compound of the present disclosure to PSMA, the type of the compound of the present disclosure, the decomposition time of the compound of the present disclosure, and the like.
［治療方法］
本開示は、一又は複数の実施形態において、治療上有効な放射性同位元素又はその同位体を含む本開示のいずれかに記載の化合物を、治療有効量投与することを含む、腫瘍の治療方法（以下、「本開示の治療方法」という）に関する。本開示の治療方法は、一又は複数の実施形態において、前立腺がん、又は前立腺がん以外のＰＳＭＡが発現するがんの治療に用いることができる。
[Method of treatment]
In one or more embodiments, the present disclosure provides a method of treating a tumor, comprising administering a therapeutically effective amount of a therapeutically effective radioisotope or a compound according to any of the present disclosure containing the isotope thereof ( Hereinafter, it is referred to as “the treatment method of the present disclosure”). In one or a plurality of embodiments, the treatment method of the present disclosure can be used for treatment of prostate cancer or cancer expressing PSMA other than prostate cancer.
本開示は、以下の一又は複数の実施形態に関しうる；
〔１〕 式(I)で表される化合物又は式(I)で表される化合物の製薬上許容される塩。
Ｌは、リンカー、又は結合手を示し、
Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示し、
ｍは、０、１、２、３、４、又は５である。
〔２〕 式(II)で表される化合物又は式(II)で表される化合物の製薬上許容される塩。
Ｐは、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示し、
Ｘ及びＹは、それぞれ独立して、Ｃ1-8アルキレン、Ｃ2-8アルケニル、Ｃ2-8アルキニル、Ｃ1-8ヘテロアルキル、Ｃ2-8ヘテロアルケニル、Ｃ2-8ヘテロアルキニル、Ｃ1-8アルコキシ、又は結合手を示し、
Ｑは、天然アミノ酸、−ＮＨ−、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示し、
Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示し、
ｍは、０、１、２、３、４、又は５である。
〔３〕 前記ハロゲンは、123Ｉ、124Ｉ、125Ｉ、131Ｉ、18Ｆ、75Ｂｒ、76Ｂｒ、又は77Ｂｒである、〔２〕記載の化合物。
〔４〕 前記Ｒ’は、ハロゲン置換されたＣ6-12アリールであり、好ましくはハロゲン置換されたフェニルである、〔２〕又は〔３〕記載の化合物。
〔５〕 前記Ｐは、−ＣＯ−ＮＨ−である、〔２〕から〔４〕のいずれかに記載の化合物。
〔６〕 前記Ｑは、グリシン、リジン、又は−ＣＯ−ＮＨ−である、〔２〕から〔５〕のいずれかに記載の化合物。
〔７〕 前記Ｘは、メチレン、エチレン、又はプロピレンである、〔２〕から〔６〕のいずれかに記載の化合物。
〔８〕 前記Ｙは、プロピレン、ブチレン、ペンチル、又はヘキシルである、〔２〕から〔７〕のいずれかに記載の化合物。
〔９〕 前記Ｚは、水素原子である、〔２〕から〔８〕のいずれかに記載の化合物。
〔１０〕 式(III)〜(VIII)のいずれかで表される化合物又はそれらの化合物の製薬上許容される塩。
〔１１〕 〔１〕から〔１０〕のいずれかに記載の化合物を含む、イメージング用組成物。
〔１２〕 ＰＳＭＡのイメージング方法であって、
〔１〕から〔１０〕のいずれかに記載の化合物を投与された被検体から前記化合物の放射性シグナルを検出することを含む、イメージング方法。
〔１３〕 前記検出されたシグナルを再構成処理して画像に変換し表示することを含む、〔１２〕記載のイメージング方法。
〔１４〕 前立腺がんのイメージング方法であって、
〔１〕から〔１０〕のいずれかに記載の化合物を投与された被検体から前記化合物の放射性シグナルを検出することを含む、イメージング方法。
〔１５〕 ＰＳＭＡ及び又はＧＣＰ−ＩＩをイメージングするための〔１〕から〔１０〕のいずれかに記載の化合物の使用。
〔１６〕 治療上有効な放射性同位元素又はその同位体を含む〔１〕から〔１０〕のいずれかに記載の化合物を、治療有効量投与することを含む、腫瘍の治療方法。
The present disclosure may relate to one or more of the following embodiments;
[1] A compound represented by formula (I) or a pharmaceutically acceptable salt of a compound represented by formula (I).
L represents a linker or a bond,
Each Z independently represents a hydrogen atom or C 1-4 alkyl;
m is 0, 1, 2, 3, 4, or 5.
[2] A compound represented by formula (II) or a pharmaceutically acceptable salt of a compound represented by formula (II).
P is, -O -, - CO-NH -, - CO 2 -NH -, - NH -, - S -, - SO 2 -, - CO 2 -, - NH-CO -, - NH-CO 2 - Or -CH = CH-
X and Y are each independently C 1-8 alkylene, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 2-8 heteroalkenyl, C 2-8 heteroalkynyl, C 2 1-8 alkoxy or a bond
Q is a natural amino acid, -NH -, - O -, - CO-NH -, - CO 2 -NH -, - S -, - SO 2 -, - CO 2 -, - NH-CO -, - NH- CO 2- or -CH = CH-
Each Z independently represents a hydrogen atom or C 1-4 alkyl;
m is 0, 1, 2, 3, 4, or 5.
[3] The halogen, 123 I, 124 I, 125 I, 131 I, 18 F, 75 Br, 76 Br, or 77 is Br, [2] the compound according.
[4] The compound according to [2] or [3], wherein R ′ is halogen-substituted C 6-12 aryl, preferably halogen-substituted phenyl.
[5] The compound according to any one of [2] to [4], wherein the P is —CO—NH—.
[6] The compound according to any one of [2] to [5], wherein Q is glycine, lysine, or —CO—NH—.
[7] The compound according to any one of [2] to [6], wherein X is methylene, ethylene, or propylene.
[8] The compound according to any one of [2] to [7], wherein Y is propylene, butylene, pentyl, or hexyl.
[9] The compound according to any one of [2] to [8], wherein Z is a hydrogen atom.
[10] A compound represented by any one of formulas (III) to (VIII) or a pharmaceutically acceptable salt of the compound.
[11] An imaging composition comprising the compound according to any one of [1] to [10].
[12] A PSMA imaging method,
[1] An imaging method comprising detecting a radioactive signal of the compound from a subject administered with the compound according to any one of [10].
[13] The imaging method according to [12], including reconstructing the detected signal, converting the signal into an image, and displaying the image.
[14] A method for imaging prostate cancer,
[1] An imaging method comprising detecting a radioactive signal of the compound from a subject administered with the compound according to any one of [10].
[15] Use of the compound according to any one of [1] to [10] for imaging PSMA and / or GCP-II.
[16] A method for treating a tumor, comprising administering a therapeutically effective amount of a therapeutically effective radioisotope or a compound according to any one of [1] to [10] containing the isotope thereof.
以下に、実施例を用いて本発明をさらに説明する。但し、本発明は以下の実施例に限定して解釈されない。 The present invention will be further described below with reference to examples. However, the present invention is not construed as being limited to the following examples.
本明細書の記載において、以下の略語を使用する。
ＤＭＦ：Ｎ，Ｎ’−ジメチルホルムアミド
ＰＭＢ：ｐ−メトキシベンジル
ＤＣＭ：ジクロロメタン
ＴＦＡ：トリフルオロ酢酸
ＷＳＣＤ：水溶性カルボジイミド
ＤＭＤ：ジメチルジオキシラン
ＤＩＣ：ジイソプロピルカルボジイミド
The following abbreviations are used in the description of the present specification.
DMF: N, N′-dimethylformamide PMB: p-methoxybenzyl DCM: dichloromethane TFA: trifluoroacetic acid WSCD: water-soluble carbodiimide DMD: dimethyldioxirane DIC: diisopropylcarbodiimide
（製造例１）式(III’)で表される化合物の製造
下記スキームにしたがい、式(III’)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
化合物(1-2)の合成
氷冷した化合物(1-1)(5.0g)のDMF溶液(20mL)に、０℃で1,1,4,4-tetramethylguanidine(7.9g)を滴下した。2時間攪拌したあと、ethyl acetoacetate(4.5g)を加え、化合物(1-1)が溶解するまで室温で攪拌した。p-methoxybenzyl chloride(10.7g)及びpotassium carbonateを加え、室温で12時間攪拌した。反応混合物に酢酸エチルを加えて希釈し、水、1N NaHCO3及び乾燥Na2SO4で順次洗浄し、化合物(1-2)（Bis-4-methoxybenzylglutamate hydrochloride、10.9g、74.9％）を得た。TLC Rf=0.16(1/1 hexane/ethyl acetate)
1H NMR (500 MHz, CD3OD) δ; 2.13-2.18 (m, 2H), 2.42-2.56 (m, 2H), 3.77 (s, 3H), 3.78 (s, 3H), 4.10 (t, J = 6.87 Hz, 1H), 5.04 (dd, J =12.03, 13.17 Hz, 2H), 5.15-5.21 (m, 2H), 6.88-6.90 (m, 4H), 7.27 (dd, J = 2.29, 6.87 Hz, 2H), 7.31-7.33 (m, 2H). 13C NMR (125 MHz, CDCl3) δ； 25.3, 29.8, 52.5, 55.11, 55.13, 66.3, 68.0, 113.8, 113.9, 126.7, 127.8, 129.9, 130.3, 159.5, 159.7, 169.1, 172.1. ESI-MS; 388 [M + H]+ for C21H26NO6. [α]D; 1.03 (MeOH, c = 1.00, 21 ℃).
Synthesis of Compound (1-2) 1,1,4,4-tetramethylguanidine (7.9 g) was added dropwise at 0 ° C. to an ice-cooled DMF solution (20 mL) of Compound (1-1) (5.0 g). After stirring for 2 hours, ethyl acetoacetate (4.5 g) was added, and the mixture was stirred at room temperature until compound (1-1) was dissolved. p-methoxybenzyl chloride (10.7 g) and potassium carbonate were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water, 1N NaHCO 3 and dry Na 2 SO 4 to obtain compound (1-2) (Bis-4-methoxybenzylglutamate hydrochloride, 10.9 g, 74.9%). . TLC Rf = 0.16 (1/1 hexane / ethyl acetate)
1 H NMR (500 MHz, CD 3 OD) δ; 2.13-2.18 (m, 2H), 2.42-2.56 (m, 2H), 3.77 (s, 3H), 3.78 (s, 3H), 4.10 (t, J = 6.87 Hz, 1H), 5.04 (dd, J = 12.03, 13.17 Hz, 2H), 5.15-5.21 (m, 2H), 6.88-6.90 (m, 4H), 7.27 (dd, J = 2.29, 6.87 Hz, 2H), 7.31-7.33 (m, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ; 25.3, 29.8, 52.5, 55.11, 55.13, 66.3, 68.0, 113.8, 113.9, 126.7, 127.8, 129.9, 130.3, 159.5, 159.7, 169.1, 172.1. ESI-MS; 388 [M + H] + for C 21 H 26 NO 6. [α] D ; 1.03 (MeOH, c = 1.00, 21 ° C).
化合物(1-4)の合成
化合物(1-3)(Nα-Fmoc-S-tert-butyl-L-cysteine（1.0g)のDMF溶液(8mL)に、p-methoxybenzyl chloride(0.4g)及びpotassium carbonate(0.35g)を加えた。懸濁液を室温で窒素気流下４時間攪拌した。懸濁液を濾過後、固体をCH2Cl2で洗浄した。酢酸エチルを加え、水で抽出した。有機層を水で2回洗浄し、無水硫酸マグネシウムで乾燥後、濾過してロータリーエバポレータで一晩濃縮し、ヘキサン／酢酸エチルで再結晶化し、化合物(1-4)((R)-4-Methoxybenzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butylthio)propanoate、0.76g、57.5％)を得た。TLC Rf=0.56(2/1 hexane/ethyl acetate)
1H NMR (500 MHz, DMSO-d6) δ; 1.25 (s, 9H), 2.79 (m, 1H), 2.89 (m, 1H), 3.71 (s, 3H), 4.24 (m, 4H), 5.06 (s, 2H), 6.88 (d, J = 8.59 Hz, 2H), 7.29 (d, J = 8.59 Hz, 2H), 7.32 (d, J = 7.45 Hz, 2H), 7.42 (t, J = 7.45 Hz, 2H), 7.71 (d, J = 7.45 Hz, 2H), 7.89 (d, J = 7.45 Hz, 2H), 7.91 (s, 1H). 13C-NMR (125 MHz, CDCl3) δ； 30.8, 39.3, 42.6, 47.1, 53.7, 55.3, 67.2, 67.4, 114.0, 119.9, 125.1, 127.1, 127.2, 127.7, 130.3, 141.3, 143.7, 155.7, 159.8, 170.6. ESI-MS; 542 [M + Na]+ for C30H33NO5NaS.
Compound (1-4) Synthesis Compound (1-3) (Nα-Fmoc-S-tert-butyl-L-cysteine (1.0 g) in DMF solution (8 mL), p-methoxybenzyl chloride (0.4 g) and potassium Carbonate (0.35 g) was added, and the suspension was stirred at room temperature under a nitrogen stream for 4 hours, and the suspension was filtered, and the solid was washed with CH 2 Cl 2. Ethyl acetate was added, and the mixture was extracted with water. The organic layer was washed twice with water, dried over anhydrous magnesium sulfate, filtered, concentrated on a rotary evaporator overnight, recrystallized from hexane / ethyl acetate, and compound (1-4) ((R) -4- Methoxybenzyl 2-(((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (tert-butylthio) propanoate, 0.76 g, 57.5%) was obtained.TLC Rf = 0.56 (2/1 hexane / ethyl acetate)
1 H NMR (500 MHz, DMSO-d6) δ; 1.25 (s, 9H), 2.79 (m, 1H), 2.89 (m, 1H), 3.71 (s, 3H), 4.24 (m, 4H), 5.06 ( s, 2H), 6.88 (d, J = 8.59 Hz, 2H), 7.29 (d, J = 8.59 Hz, 2H), 7.32 (d, J = 7.45 Hz, 2H), 7.42 (t, J = 7.45 Hz, 2H), 7.71 (d, J = 7.45 Hz, 2H), 7.89 (d, J = 7.45 Hz, 2H), 7.91 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ) δ; 30.8, 39.3 , 42.6, 47.1, 53.7, 55.3, 67.2, 67.4, 114.0, 119.9, 125.1, 127.1, 127.2, 127.7, 130.3, 141.3, 143.7, 155.7, 159.8, 170.6. ESI-MS; 542 [M + Na] + for C 30 H 33 NO 5 NaS.
化合物(1-5)の合成
20% piperidineのDMF溶液(4.9mL)を、化合物(1-4)(0.56g)に加えた。室温で1.6時間攪拌した後、酢酸エチルを加えて分液し、水で3回、飽和NaClで1回洗浄した。有機層を回収し、硫酸ナトリウムで乾燥後、ろ過して濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(シリカゲル：W-Prep 2XY、展開溶媒：hexane/ethyl acetate)にて精製し、化合物(1-5)((R)-4-Methoxybenzyl 2-amino-3-(tert-butylthio)propanoate、0.29g、90.6％)を得た。TLC Rf=0.16(1/1 hexane/ethyl acetate)
1H NMR (500 MHz, DMSO-d6) δ; 1.23 (s, 9H), 2.69 (m, 1H), 2.75 (m, 1H), 3.50 (m, 1H), 3.75 (s, 3H), 5.04 (s, 2H), 6.92 (d, J = 8.59 Hz, 2H), 7.32 (d, J = 8.59 Hz, 2H). 13C-NMR (125 MHz, CDCl3) δ； 30.9, 33.4, 42.4, 54.6, 55.2, 66.7, 113.9, 127.6, 130.2, 159.7, 173.9. ESI-MS; 298 [M + H]+ for C15H24NO3S.
Synthesis of compound (1-5)
20% piperidine in DMF (4.9 mL) was added to compound (1-4) (0.56 g). After stirring at room temperature for 1.6 hours, ethyl acetate was added for liquid separation, and the mixture was washed 3 times with water and once with saturated NaCl. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (silica gel: W-Prep 2XY, developing solvent: hexane / ethyl acetate), and compound (1-5) ((R) -4-Methoxybenzyl 2-amino-3- ( tert-butylthio) propanoate, 0.29 g, 90.6%). TLC Rf = 0.16 (1/1 hexane / ethyl acetate)
1 H NMR (500 MHz, DMSO-d6) δ; 1.23 (s, 9H), 2.69 (m, 1H), 2.75 (m, 1H), 3.50 (m, 1H), 3.75 (s, 3H), 5.04 ( s, 2H), 6.92 (d, J = 8.59 Hz, 2H), 7.32 (d, J = 8.59 Hz, 2H). 13 C-NMR (125 MHz, CDCl 3 ) δ; 30.9, 33.4, 42.4, 54.6, 55.2, 66.7, 113.9, 127.6, 130.2, 159.7, 173.9. ESI-MS; 298 [M + H] + for C 15 H 24 NO 3 S.
化合物(1-6)の合成
化合物(1-2)(0.56g)をCH2Cl2(4mL)に溶解し、ついで窒素気流下-78℃に冷却した。triphosgene(0.14g)を加え、ついでtriethylamine(0.61mL)を慎重に加えた。反応物を-78℃で0.5時間攪拌した後、室温まで昇温させ、室温で2時間攪拌した。化合物(1-5)(0.43g)のCH2Cl2溶液(4mL)を加え、室温で一晩攪拌後、CH2Cl2で抽出し、水で2回洗浄し、鹹水で1回洗浄した。有機層を回収し、硫酸ナトリウムで乾燥後、濾過し、濃縮した。組成生物をシリカゲルカラムクロマトグラフィー(シリカゲル：W-Prep 2XY、展開溶媒：hexane/ethyl acetate)にて精製し、化合物(1-6)((S)-Bis(4-methoxybenzyl) 2-(3-((R)-3-(tert-butylthio)-1-((4-methoxybenzyl)
oxy)-1-oxopropan-2-yl)ureido)pentanedioate、0.97g、93.8％)を得た。TLC Rf=0.50(1/1 hexane/ethyl acetate)
1H NMR (500 MHz, DMSO-d6)δ; 1.22 (s, 9H), 1.85 (broad m, 2H), 2.
33 (m, 2H), 2.79 (m, 2H), 3.74 (m, 9H), 4.21 (dd, J = 8.02, 5.73 Hz, 1H), 4.42 (dd, J = 8.02, 5.73 Hz, 1H), 5.02 (m, 6H), 6.43 (d, J = 8.02 Hz, 1H), 6.73 (d, J = 8.02 Hz, 1H), 6.90 (m, 6H), 7.28 (m, 6H). 13C-NMR (125 MHz, CDCl3) δ; 28.1, 30.3, 30.8, 31.1, 42.5, 52.5, 52.8, 55.2, 676.2, 67.1, 67.2, 113.9, 114.0, 127.4, 128.0, 130.0, 130.1, 130.2, 156.2, 159.6, 159.7, 171.4, 172.6, 172.8. ESI-MS; 733 [M + Na]+ for C37H46N2O10NaS. FAB-HRMS. [α]D. IR (/cm); 721, 827, 959, 1113, 1227, 1304, 1348, 1366, 1383, 1464, 1516, 1680, 1736, 2338, 2359, 2940, 2963, 3009, 3422.
Synthesis of Compound (1-6) Compound (1-2) (0.56 g) was dissolved in CH 2 Cl 2 (4 mL), and then cooled to −78 ° C. under a nitrogen stream. Triphosgene (0.14 g) was added followed by the careful addition of triethylamine (0.61 mL). The reaction was stirred at −78 ° C. for 0.5 hour, then warmed to room temperature and stirred at room temperature for 2 hours. A CH 2 Cl 2 solution (4 mL) of compound (1-5) (0.43 g) was added and stirred at room temperature overnight, then extracted with CH 2 Cl 2 and washed twice with water and once with brine. . The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The component organism was purified by silica gel column chromatography (silica gel: W-Prep 2XY, developing solvent: hexane / ethyl acetate), and compound (1-6) ((S) -Bis (4-methoxybenzyl) 2- (3- ((R) -3- (tert-butylthio) -1-((4-methoxybenzyl)
oxy) -1-oxopropan-2-yl) ureido) pentanedioate, 0.97 g, 93.8%). TLC Rf = 0.50 (1/1 hexane / ethyl acetate)
1 H NMR (500 MHz, DMSO-d6) δ; 1.22 (s, 9H), 1.85 (broad m, 2H), 2.
33 (m, 2H), 2.79 (m, 2H), 3.74 (m, 9H), 4.21 (dd, J = 8.02, 5.73 Hz, 1H), 4.42 (dd, J = 8.02, 5.73 Hz, 1H), 5.02 (m, 6H), 6.43 (d, J = 8.02 Hz, 1H), 6.73 (d, J = 8.02 Hz, 1H), 6.90 (m, 6H), 7.28 (m, 6H). 13 C-NMR (125 MHz, CDCl 3 ) δ; 28.1, 30.3, 30.8, 31.1, 42.5, 52.5, 52.8, 55.2, 676.2, 67.1, 67.2, 113.9, 114.0, 127.4, 128.0, 130.0, 130.1, 130.2, 156.2, 159.6, 159.7, 171.4 , 172.6, 172.8. ESI-MS; 733 [M + Na] + for C 37 H 46 N 2 O 10 NaS. FAB-HRMS. [Α] D. IR (/ cm); 721, 827, 959, 1113, 1227, 1304, 1348, 1366, 1383, 1464, 1516, 1680, 1736, 2338, 2359, 2940, 2963, 3009, 3422.
化合物(1-7)の合成
TFA(1mL)とAnisole(80μL)とを含む溶液を化合物(1-6)(0.16g)に加え、化合物(1-6)が溶解するまで0℃で攪拌した。得られた溶液にHg(OAc)2(88mg)を加え、0℃で1時間攪拌した後、室温で減圧濃縮した。水銀付加物をエチルエーテルを添加することによって抽出し、濾過後、減圧乾燥した。これをさらに精製することなく、水銀付加物をDMFに溶解した後、H2Sを室温で12時間撹拌した。得られたスラリーを濾過し、メタノール及び水で洗浄した。減圧下で濃縮後、生成物をメタノールに溶解し、濾過後、濾過物を濃縮した。このプロセスを水で繰り返した。得られた濾過物を逆相HPLCで精製し、化合物(1-7)((S)-2-[3-[(R)-1-carboxy-2-mercaptoethyl]ureido]-pentanedioic acid、60mg、88.9%)を得た。
1H-NMR (500 MHz, DMSO-d6) δ; 1.72 (dt, J = 8.59, 14.3 Hz, 1H), 1.92 (m, 1H), 2.17 (m, 1H), 2.20-2.30 (m, 2H), 2.83 (dd, J = 5.16, 13.7 Hz,), 4.10 (m, 1H), 4.36 (m, 1H), 6.44 (d, J = 8.02 Hz, 1H), 6.58 (d, J = 8.02 Hz, 1H). 13C-NMR (125 MHz, CD3CN) δ; 26.7, 27.2, 30.1, 52.6, 54.9, 158.3, 173.2, 175.1, 175.7. ESI-MS; 294 [M]+ for C9H14N2O7S.
Synthesis of compound (1-7)
A solution containing TFA (1 mL) and Anisole (80 μL) was added to compound (1-6) (0.16 g), and the mixture was stirred at 0 ° C. until compound (1-6) was dissolved. Hg (OAc) 2 (88 mg) was added to the resulting solution, stirred at 0 ° C. for 1 hour, and concentrated under reduced pressure at room temperature. The mercury adduct was extracted by adding ethyl ether, filtered and dried under reduced pressure. Without further purification, the mercury adduct was dissolved in DMF, and H 2 S was stirred at room temperature for 12 hours. The resulting slurry was filtered and washed with methanol and water. After concentration under reduced pressure, the product was dissolved in methanol, and after filtration, the filtrate was concentrated. This process was repeated with water. The obtained filtrate was purified by reverse phase HPLC, and compound (1-7) ((S) -2- [3-[(R) -1-carboxy-2-mercaptoethyl] ureido] -pentanedioic acid, 60 mg, 88.9%).
1 H-NMR (500 MHz, DMSO-d6) δ; 1.72 (dt, J = 8.59, 14.3 Hz, 1H), 1.92 (m, 1H), 2.17 (m, 1H), 2.20-2.30 (m, 2H) , 2.83 (dd, J = 5.16, 13.7 Hz,), 4.10 (m, 1H), 4.36 (m, 1H), 6.44 (d, J = 8.02 Hz, 1H), 6.58 (d, J = 8.02 Hz, 1H 13 C-NMR (125 MHz, CD3CN) δ; 26.7, 27.2, 30.1, 52.6, 54.9, 158.3, 173.2, 175.1, 175.7. ESI-MS; 294 [M] + for C 9 H 14 N 2 O 7 S.
既知の合成法(J Med Chem 1997, 40, 2643-52)に従い、上記スキームに示す順序で化合物(1-19)((S)-6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-(2-(3-iodobenzamido)acetamido)hexanoic acid)を合成した。 According to a known synthesis method (J Med Chem 1997, 40, 2643-52), compound (1-19) ((S) -6- (2,5-Dioxo-2,5-dihydro- 1H-pyrrol-1-yl) -2- (2- (3-iodobenzamido) acetamido) hexanoic acid) was synthesized.
化合物(1-9)の合成
化合物(1-8)(3.0g)のDMF懸濁液(12mL)に、N,N,N',N'-tetramethylguanidine(4.7g)を0℃で加え、0℃で2時間攪拌した後、ethyl acetoacetate(5.3g)を添加した。室温で一晩攪拌した後、p-methoxybenzyl chloride(6.7g)を加え、室温で一晩攪拌した。酢酸エチルによって抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下で除去し、10%HCl/methanol(35mL)を加え、残渣が溶解するまで穏やかに振盪した。減圧下で溶媒を除去後、化合物(1-9)をジエチルエーテルで再結晶化した(6.8g,72.8%). TLC Rf=0.58(80/20 chloroform/methanol)。
1H-NMR (500 MHz, DMSO-d6) δ; 3.76 (s,3H), 3.84 (s, 2H), 5.17 (s, 2H), 6.95 (d, J = 8.59 Hz, 2H), 7.35 (d, J = 8.59 Hz, 2H), 8.28 (bs, 3H). 13C-NMR (125 MHz, CD3OD) δ; 41.1, 55.8, 68.8, 115.0, 128.4, 131.6, 161.5, 168.4. EI-MS; 195 [M]+ for C10H13NO3.
Synthesis of Compound (1-9) To DMF suspension (12 mL) of Compound (1-8) (3.0 g), N, N, N ′, N′-tetramethylguanidine (4.7 g) was added at 0 ° C., 0 After stirring at 0 ° C. for 2 hours, ethyl acetoacetate (5.3 g) was added. After stirring overnight at room temperature, p-methoxybenzyl chloride (6.7 g) was added and stirred overnight at room temperature. Extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, the solvent was removed under reduced pressure, 10% HCl / methanol (35 mL) was added, and gently shaken until the residue dissolved . After removing the solvent under reduced pressure, the compound (1-9) was recrystallized with diethyl ether (6.8 g, 72.8%). TLC Rf = 0.58 (80/20 chloroform / methanol).
1 H-NMR (500 MHz, DMSO-d6) δ; 3.76 (s, 3H), 3.84 (s, 2H), 5.17 (s, 2H), 6.95 (d, J = 8.59 Hz, 2H), 7.35 (d , J = 8.59 Hz, 2H), 8.28 (bs, 3H). 13 C-NMR (125 MHz, CD 3 OD) δ; 41.1, 55.8, 68.8, 115.0, 128.4, 131.6, 161.5, 168.4. EI-MS; 195 [M] + for C 10 H 13 NO 3 .
化合物(1-11)の合成
化合物(1-10)(3.0g)のDMF溶液に、化合物(1-9)(3.0g)、トリエチルアミン（5.mL）及びWSCD/HCl(2.5g)を室温で加え、室温で一晩攪拌した。酢酸エチルによって抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下で除去し、化合物(1-11)をヘキサン/酢酸エチルで再結晶化した(3.7g,68.4%). TLC Rf=0.35(2/1 hexane/ethyl acetate).
1H-NMR (500 MHz, DMSO-d6) δ; 3.75 (s, 3H), 4.03 (d, J = 5.73 Hz, 2H), 5.08 (s, 2H), 6.91-6.94 (m, 2H), 7.29-7.33 (m, 3H), 7.87 (m, 1H), 7.92 (m, 1H), 8.20 (m, 1H), 9.06 (m, 1H). 13C-NMR (125 MHz, CDCl3) δ; 41.9, 55.3, 67.3, 94.2, 114.0, 126.2, 127.1, 130.2, 130.3, 135.6, 136.1, 140.6, 159.9, 165.8, 169.8. EI-MS; 425 [M]+ for (C17H16NO4I).
Synthesis of Compound (1-11) Compound (1-9) (3.0 g), triethylamine (5 mL) and WSCD / HCl (2.5 g) were added to a DMF solution of compound (1-10) (3.0 g) at room temperature. And stirred at room temperature overnight. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, the solvent was removed under reduced pressure, and compound (1-11) was recrystallized from hexane / ethyl acetate (3.7 g, 68.4%). TLC Rf = 0.35 (2/1 hexane / ethyl acetate).
1 H-NMR (500 MHz, DMSO-d6) δ; 3.75 (s, 3H), 4.03 (d, J = 5.73 Hz, 2H), 5.08 (s, 2H), 6.91-6.94 (m, 2H), 7.29 -7.33 (m, 3H), 7.87 (m, 1H), 7.92 (m, 1H), 8.20 (m, 1H), 9.06 (m, 1H). 13 C-NMR (125 MHz, CDCl 3 ) δ; 41.9 , 55.3, 67.3, 94.2, 114.0, 126.2, 127.1, 130.2, 130.3, 135.6, 136.1, 140.6, 159.9, 165.8, 169.8. EI-MS; 425 [M] + for (C 17 H 16 NO 4 I).
化合物(1-12)の合成
化合物(1-11)(2.1g)のジクロロメタン溶液(17mL)に、TFA(3.7mL)を室温で加え、室温で15分間攪拌した後、溶媒を減圧下で除去し、化合物(1-12)をクロロホルムで再結晶化した(1.5g,96.3%). TLC Rf=0.37(10/1/1 chloroform/methanol/acetic acid).
1H-NMR (500 MHz, DMSO-d6) δ; 3.92 (d, J = 5.73 Hz, 2H), 7.30 (t, J = 8.02 Hz, 1H), 7.87 (m, 1H), 7.88 (m, 1H), 7.91 (m, 1H), 7.93 (m, 1H), 8.22 (t, J = 1.72 Hz, 1H), 8.95 (m, 1H). 13C-NMR (125 MHz, CD3OD) δ; 42.3, 94.7, 127.7, 131.4, 137.1, 137.5, 141.8, 168.7, 173.0. ESI-MS; 304 [M - H]- for C9H7NO3I.
Synthesis of compound (1-12) To a dichloromethane solution (17 mL) of compound (1-11) (2.1 g), TFA (3.7 mL) was added at room temperature and stirred at room temperature for 15 minutes, and then the solvent was removed under reduced pressure. Compound (1-12) was recrystallized with chloroform (1.5 g, 96.3%). TLC Rf = 0.37 (10/1/1 chloroform / methanol / acetic acid).
1 H-NMR (500 MHz, DMSO-d6) δ; 3.92 (d, J = 5.73 Hz, 2H), 7.30 (t, J = 8.02 Hz, 1H), 7.87 (m, 1H), 7.88 (m, 1H ), 7.91 (m, 1H) , 7.93 (m, 1H), 8.22 (t, J = 1.72 Hz, 1H), 8.95 (m, 1H) 13 C-NMR (125 MHz, CD 3 OD) δ;. 42.3 , 94.7, 127.7, 131.4, 137.1 , 137.5, 141.8, 168.7, 173.0 ESI-MS;. 304 [M - H] - for C 9 H 7 NO 3 I.
化合物(1-13)の合成
化合物(1-12)(1.1g)のDMD溶液(8mL)に、N-hydroxysuccinimide(0.4g)及びDIC(0.44g)を室温で加え、室温で8時間攪拌した。酢酸エチル及び炭化水素ナトリウムで抽出後、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させた。減圧下で溶媒を除去後、化合物(1-13)をクロロホルムで再結晶化した(0.81g,57.9%)。TLC Rf=0.46(10/1 chloroform/methanol).
1H-NMR (500 MHz, DMSO-d6) δ; 2.81 (s, 4H), 4.42 (d, J = 5.73 Hz, 2H), 7.31 (t, J = 8.02 Hz, 1H), 7.88 (m, 1H), 7.92 (m, 1H), 8.22 (m, 1H), 9.27 (t, J = 5.73 Hz, 1H). 13C-NMR (125 MHz, ACETN-d6) δ; 26.2, 39.8, 94.4, 127.5, 131.4, 136.7, 137.1, 141.4, 166.2, 166.9, 170.1. EI-MS; 402 [M]+ for C13H11N2O5I.
Synthesis of Compound (1-13) To DMD solution (8 mL) of Compound (1-12) (1.1 g), N-hydroxysuccinimide (0.4 g) and DIC (0.44 g) were added at room temperature and stirred at room temperature for 8 hours. . After extraction with ethyl acetate and sodium hydrocarbon, the organic layer was washed with saturated brine and dried over sodium sulfate. After removing the solvent under reduced pressure, the compound (1-13) was recrystallized from chloroform (0.81 g, 57.9%). TLC Rf = 0.46 (10/1 chloroform / methanol).
1 H-NMR (500 MHz, DMSO-d6) δ; 2.81 (s, 4H), 4.42 (d, J = 5.73 Hz, 2H), 7.31 (t, J = 8.02 Hz, 1H), 7.88 (m, 1H ), 7.92 (m, 1H) , 8.22 (m, 1H), 9.27 (t, J = 5.73 Hz, 1H) 13 C-NMR (125 MHz, ACETN-d6) δ;. 26.2, 39.8, 94.4, 127.5, 131.4, 136.7, 137.1, 141.4, 166.2, 166.9, 170.1. EI-MS; 402 [M] + for C 13 H 11 N 2 O 5 I.
化合物(1-16)の合成
化合物(1-14)(4.1g)の酢酸エチル溶液(12mL)に、N-methylmorpholine(4.0mL)を0℃で加えた後、攪拌し、化合物(1-15)(3.3mL)を0℃で滴下した。室温で一晩攪拌した後、濾過して沈殿物を除去し、ろ過して濃縮し、粗生成物をシリカゲルカラムクロマトグラフィー(シリカゲル：W-Prep 2XY、展開溶媒：hexane/ethyl acetate)にて精製し、化合物(1-16)(1.9g,88.7%).TLC Rf=0.54(2/1 toluene/THF).
1H NMR (500 MHz, CDCl3) δ; 3.99 (s, 3H), 6.84 (s, 2H). 13C NMR (125 MHz, CDCl3) δ; 54.3, 135.2, 148.1, 165.6. EI-MS; 155 [M]+ for C6H5NO4.
Synthesis of Compound (1-16) To an ethyl acetate solution (12 mL) of Compound (1-14) (4.1 g), N-methylmorpholine (4.0 mL) was added at 0 ° C., and the mixture was stirred to give Compound (1-15) ) (3.3 mL) was added dropwise at 0 ° C. After stirring overnight at room temperature, the precipitate is removed by filtration, filtered and concentrated, and the crude product is purified by silica gel column chromatography (silica gel: W-Prep 2XY, developing solvent: hexane / ethyl acetate). Compound (1-16) (1.9 g, 88.7%). TLC Rf = 0.54 (2/1 toluene / THF).
1 H NMR (500 MHz, CDCl 3 ) δ; 3.99 (s, 3H), 6.84 (s, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ; 54.3, 135.2, 148.1, 165.6. EI-MS; 155 [M] + for C 6 H 5 NO 4 .
化合物(1-17)の合成
化合物(1-16)(1.0g)及びBoc-Lys-OH(1.6g)の混合物に、飽和炭酸ナトリウム溶液を室温で加え、0℃で1時間攪拌した後、室温で2時間攪拌し、ついでその混合物に6N HClを加えpH2〜4に調整した。クロロホルムで抽出後、有機層を硫酸ナトリウムで乾燥させた。溶媒を減圧下で除去した後、粗生成物をシリカゲルカラムクロマトグラフィー(シリカゲル：W-Prep 2XY、展開溶媒：hexane/methanol)にて精製し、化合物(1-17)( 1.7 g, 76.1 %). TLC Rf = 0.23 (10/1 chloroform/methanol).
1H NMR (500 MHz, CDCl3) δ; 1.40 (m, 2H), 1.45 (s, 9H), 1.64 (m, 2H), 1.70-1.90 (m, 2H), 3.53 (m, 2H), 4.27 (bs, 1H), 5.00 (bs, 1H), 6.69 (s, 2H). 13C-NMR (125 MHz, CDCl3) δ; 22.5, 28.0, 28.3, 31.8, 37.4, 53.1, 80.2, 134.1, 155.6, 170.8, 176.7. ESI-MS; 325 [M - H]- for C15H21N2O6.
Synthesis of compound (1-17) To a mixture of compound (1-16) (1.0 g) and Boc-Lys-OH (1.6 g), a saturated sodium carbonate solution was added at room temperature, and the mixture was stirred at 0 ° C for 1 hour. The mixture was stirred at room temperature for 2 hours, and then 6N HCl was added to the mixture to adjust the pH to 2-4. After extraction with chloroform, the organic layer was dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography (silica gel: W-Prep 2XY, developing solvent: hexane / methanol) to obtain compound (1-17) (1.7 g, 76.1%) TLC Rf = 0.23 (10/1 chloroform / methanol).
1 H NMR (500 MHz, CDCl 3 ) δ; 1.40 (m, 2H), 1.45 (s, 9H), 1.64 (m, 2H), 1.70-1.90 (m, 2H), 3.53 (m, 2H), 4.27 . (bs, 1H), 5.00 (bs, 1H), 6.69 (s, 2H) 13 C-NMR (125 MHz, CDCl 3) δ; 22.5, 28.0, 28.3, 31.8, 37.4, 53.1, 80.2, 134.1, 155.6 , 170.8, 176.7 ESI-MS; . 325 [M - H] - for C 15 H 21 N 2 O 6.
化合物(1-18)の合成
化合物(1-17)(0.97g)と4N HCl/酢酸エチル(4.5mL)とを室温で混合した後、濾過し、白色の沈殿物をジエチルエーテルで洗浄した。減圧下で乾燥後、得られた組成生物(化合物1-18)をさらに精製することなく使用した(0.51g,65.5%). TLC Rf=0.69(RP-18 F254S, 1/2 methanol/water).
1H NMR (500 MHz, DMSO-d6) δ; 1.24-1.40 (m, 2H), 1.51 (m, 2H), 1.77 (m, 2H), 3.39 (t, J = 6.87 Hz, 2H), 3.86 (bs, 1H), 7.02 (s, 2H), 8.25 (bs, 3H). 13C-NMR (125MHz, CD3OD) δ; 23.1, 29.0, 30.9, 37.9, 53.7, 135.4, 171.7, 172.6.
Synthesis of Compound (1-18) Compound (1-17) (0.97 g) and 4N HCl / ethyl acetate (4.5 mL) were mixed at room temperature, then filtered, and the white precipitate was washed with diethyl ether. After drying under reduced pressure, the resulting organism (compound 1-18) was used without further purification (0.51 g, 65.5%). TLC Rf = 0.69 (RP-18 F254S, 1/2 methanol / water) .
1 H NMR (500 MHz, DMSO-d6) δ; 1.24-1.40 (m, 2H), 1.51 (m, 2H), 1.77 (m, 2H), 3.39 (t, J = 6.87 Hz, 2H), 3.86 ( . bs, 1H), 7.02 ( s, 2H), 8.25 (bs, 3H) 13 C-NMR (125MHz, CD 3 OD) δ; 23.1, 29.0, 30.9, 37.9, 53.7, 135.4, 171.7, 172.6.
化合物(1-19)の合成
化合物(1-13)(0.44mg)のアセとニトリル溶液(5mL)に、化合物(1-18)(0.29mg)及びジイソプロピレンアミン(0.38mL)を室温で加え、室温で1時間攪拌した。減圧下で溶媒を除去後、シリカゲルカラムクロマトグラフィーによって化合物(1-19)((S)-6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-(2-(3-iodobenzamido)acetamido)
hexanoic acid)を得た(57mg,10.1%). TLC Rf=0.54 (50/10/1 chloroform/methanol/acetic acid).
1H-NMR (500 MHz, CD3OD) δ; 1.37 (m, 2H), 1.54-1.65 (m, 2H), 1.70-1.94 (m, 2H), 3.49 (t, J = 7.16 Hz, 2H), 4.08 (m, 2H), 4.41 (m, 2H), 6.78 (s, 2H), 7.23 (t, J = 7.74 Hz, 1H), 7.72 (m, 2H), 8.24 (m, 1H). 13C-NMR (125 MHz, CD3OD) δ; 23.9, 29.0, 32.1, 38.2, 43.8, 53.5, 94.7, 127.8, 131.4, 135.3, 137.2, 137.6, 141.8, 168.7, 171.5, 172.6, 175.2. ESI-MS; 514 [M + H]+ for C19H21N3O5I. HPLC保持時間 (tR); 25.2min.
Synthesis of Compound (1-19) Compound (1-18) (0.29 mg) and diisopropyleneamine (0.38 mL) were added at room temperature to an acetonitrile solution (5 mL) of Compound (1-13) (0.44 mg). The mixture was further stirred at room temperature for 1 hour. After removing the solvent under reduced pressure, the compound (1-19) ((S) -6- (2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl) -2- (2- (3-iodobenzamido) acetamido)
hexanoic acid) (57 mg, 10.1%). TLC Rf = 0.54 (50/10/1 chloroform / methanol / acetic acid).
1 H-NMR (500 MHz, CD3OD) δ; 1.37 (m, 2H), 1.54-1.65 (m, 2H), 1.70-1.94 (m, 2H), 3.49 (t, J = 7.16 Hz, 2H), 4.08 (m, 2H), 4.41 (m, 2H), 6.78 (s, 2H), 7.23 (t, J = 7.74 Hz, 1H), 7.72 (m, 2H), 8.24 (m, 1H). 13 C-NMR (125 MHz, CD3OD) δ; 23.9, 29.0, 32.1, 38.2, 43.8, 53.5, 94.7, 127.8, 131.4, 135.3, 137.2, 137.6, 141.8, 168.7, 171.5, 172.6, 175.2. ESI-MS; 514 [M + H] + for C 19 H 21 N 3 O 5 I. HPLC retention time (t R ); 25.2 min.
化合物(III’)の合成
化合物(1-7)(6.8mg)の水溶液(0.2mL)と、化合物(1-19)(11.9mg)のアセトニトリル(0.15mL)溶液を混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で2時間攪拌し、HPLCにより精製して、目的とする化合物(III’)を得た。HPLCの分析にはCosmosil(R) 5C18-AR-II 4.6x150mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速1mL/min、B濃度30%一定（0-10min）、30%-60%（10-20min）、60%一定（20-30min）とした。
1H-NMR (500 MHz, D2O) δ; 1.21 (t, J = 7.45 Hz, 2H), 1.48 (m, 2H), 1.65 (m, 1H), 1.83 (m, 2H), 2.05 (m, 1H), 2.38 (dt, J = 2.86, 7.45 Hz, 2H), 2.56 (m, 1H), 2.95-3.35 (m, 3H), 3.39 (t, J = 6.87 Hz, 2H), 3.93 (m, 1H), 3.99-4.07 (m, 2H), 4.15 (m, 1H), 4.28 (broad s, 1H), 4.39 (t, J = 5.73 Hz, 1H), 7.21 (dd, J = 7.45, 8.02 Hz, 1H), 7.71 (d, J = 7.45 Hz, 1H), 7.90 (d, J = 8.02 Hz, 1H), 8.10 (s, 1H). ESI-MS; 808 [M + H]+ for C28H35N5O13SI.
Synthesis of Compound (III ′) An aqueous solution (0.2 mL) of Compound (1-7) (6.8 mg) and a solution of Compound (1-19) (11.9 mg) in acetonitrile (0.15 mL) were mixed, and then the mixture was mixed. 2N NaOH was added to adjust to pH7. The mixture was stirred at room temperature for 2 hours and purified by HPLC to obtain the target compound (III ′). A Cosmosil (R) 5C18-AR-II 4.6x150mm column was used for HPLC analysis, and 0.1% trifluoroacetic acid-added water (mobile phase A) and methanol (mobile phase B) were used as the mobile phase. The program was set at a flow rate of 1 mL / min, a B concentration of 30% constant (0-10 min), 30% -60% (10-20 min), and 60% constant (20-30 min).
1 H-NMR (500 MHz, D 2 O) δ; 1.21 (t, J = 7.45 Hz, 2H), 1.48 (m, 2H), 1.65 (m, 1H), 1.83 (m, 2H), 2.05 (m , 1H), 2.38 (dt, J = 2.86, 7.45 Hz, 2H), 2.56 (m, 1H), 2.95-3.35 (m, 3H), 3.39 (t, J = 6.87 Hz, 2H), 3.93 (m, 1H), 3.99-4.07 (m, 2H), 4.15 (m, 1H), 4.28 (broad s, 1H), 4.39 (t, J = 5.73 Hz, 1H), 7.21 (dd, J = 7.45, 8.02 Hz, 1H), 7.71 (d, J = 7.45 Hz, 1H), 7.90 (d, J = 8.02 Hz, 1H), 8.10 (s, 1H). ESI-MS; 808 [M + H] + for C 28 H 35 N 5 O 13 SI.
（製造例２）式(IV’)で表される化合物の製造
下記スキームにしたがい、式(IV’)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
化合物（2-3）の合成
既知化合物（2-2, J Org Chem 1999, 64, 7094-7100）（280mg,0.84mmol）のDMF溶液（5mL）にN-hydroxysuccinimide（97mg,0.84mmol）とN,N'-diisopropylcarbodiimide（131μL,0.84mmol）を加え、室温で1時間攪拌した。反応終了後、反応液を水に注ぎ込み、ethyl acetateで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、溶媒を留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（カラム：Hi FlashTM 40 mm 60 Å (Yamazen)、展開溶媒：chloroform/methanol=10/1）で精製し、化合物（2-3）（240mg,62.0%）を得た。
Synthesis of Compound (2-3) N-hydroxysuccinimide (97 mg, 0.84 mmol) and N in DMF solution (5 mL) of known compound (2-2, J Org Chem 1999, 64, 7094-7100) (280 mg, 0.84 mmol) , N′-diisopropylcarbodiimide (131 μL, 0.84 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (column: Hi Flash TM 40 mm 60 mm (Yamazen ), Developing solvent: chloroform / methanol = 10/1) to obtain compound (2-3) (240 mg, 62.0%).
化合物（2-4）の合成
化合物（2-3）（58mg,0.13mmol）のアセトニトリル溶液（2mL）に化合物（1-18）（35mg,0.13mmol）とN,N'-diisopropylethylamine（46μL,0.27mmol）を加えた。室温で3.5時間攪拌した後、反応液を飽和塩化アンモニウム水溶液に注ぎ込み、ethyl acetateで抽出した。得られた有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を留去して得られた粗生成物をpreparative TLC（TLC：Kieselgel 60 F-254 plats 0.5mm（Merck）、展開溶媒：chloroform/methanol=10/1）とHPLCにより精製して、化合物（2-4）（12mg,17%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、62.0minであった。
Synthesis of Compound (2-4) Compound (1-18) (35 mg, 0.13 mmol) and N, N'-diisopropylethylamine (46 μL, 0.27) were added to acetonitrile (2 mL) of Compound (2-3) (58 mg, 0.13 mmol). mmol) was added. After stirring at room temperature for 3.5 hours, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off. The resulting crude product was prepared by preparative TLC (TLC: Kieselgel 60 F-254 plats 0.5 mm (Merck), developing solvent: chloroform / Methanol = 10/1) and purification by HPLC gave compound (2-4) (12 mg, 17%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 30% -80% (0-60 min). The HPLC retention time was 62.0 min.
化合物（IV'）の合成
化合物（1-7）（6mg,20.4μmol）の水溶液（0.9mL）と、化合物（2-4）（11mg,20.3mmol）のアセトニトリル（0.9mL）溶液を混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で1時間攪拌し、HPLCにより精製して、目的とする化合物（IV'）（12.1mg,72.5%）を得た。分取HPLCには、YMC-Pack ODS 20x250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、42.8minであった。
Synthesis of Compound (IV ′) An aqueous solution (0.9 mL) of Compound (1-7) (6 mg, 20.4 μmol) and an acetonitrile (0.9 mL) solution of Compound (2-4) (11 mg, 20.3 mmol) were mixed, The mixture was then adjusted to pH 7 by adding 2N NaOH. The mixture was stirred at room temperature for 1 hour and purified by HPLC to obtain the target compound (IV ′) (12.1 mg, 72.5%). For preparative HPLC, a YMC-Pack ODS 20x250mm column was used. Water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. Min, B concentration 30% -80% (0-60min). The HPLC retention time was 42.8 min.
（製造例３）式(V’)で表される化合物の製造
下記スキームにしたがい、式(V’)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。なお、化合物(3-2)の合成は、既知の合成法（J Am Chem Soc 1964, 86,1839-42）を参考に行った。
化合物（3-1）の合成
化合物（2-1）（600 mg,1.74mmol）のアセトニトリル溶液（6 mL）にβ-aranine（170mg,1.91mmol）とN,N'-diisopropylethylamine（0.33mL,1.91mmol）を加え、室温で11時間攪拌した。反応終了後、反応液を塩化アンモニウム水溶液に注ぎ込み、ethyl acetateで抽出した。得られた有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を留去した。得られた粗生成物をchloroformで洗浄し、化合物（3-1）（214mg,39%）を得た。
Synthesis of Compound (3-1) Compound (2-1) (600 mg, 1.74 mmol) in acetonitrile solution (6 mL) and β-aranine (170 mg, 1.91 mmol) and N, N'-diisopropylethylamine (0.33 mL, 1.91) mmol) and stirred at room temperature for 11 hours. After completion of the reaction, the reaction solution was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off. The obtained crude product was washed with chloroform to obtain compound (3-1) (214 mg, 39%).
化合物（3-2）の合成
化合物（3-1）（186mg,0.58mmol）のDMF溶液（4mL）にN-hydroxysuccinimide（67mg,0.58mmol）とN,N'-diisopropylcarbodiimide（90μL,0.58mmol）を加え、室温で14時間攪拌した。反応終了後、反応液を水に注ぎ込み、ethyl acetateで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、溶媒を留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（カラム：Hi FlashTM 40mm 60Å(Yamazen)、展開溶媒：chloroform/methanol=10/1）で精製し、化合物（3-2）（112mg,46%）を得た。
Synthesis of compound (3-2) N-hydroxysuccinimide (67 mg, 0.58 mmol) and N, N'-diisopropylcarbodiimide (90 μL, 0.58 mmol) were added to DMF solution (4 mL) of compound (3-1) (186 mg, 0.58 mmol). The mixture was further stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and then the solvent was distilled off. The resulting crude product was subjected to silica gel column chromatography (column: Hi Flash TM 40mm 60 mm (Yamazen), The compound (3-2) (112 mg, 46%) was obtained by purification with a developing solvent: chloroform / methanol = 10/1).
化合物（3-3）の合成
化合物（3-2）（110mg,0.26mmol）のアセトニトリル溶液（4mL）に化合物（1-18）（69mg,0.26mmol）とN,N'-diisopropylethylamine（91μL,0.53mmol）を加えた。室温で3.5時間攪拌した後、反応液を飽和塩化アンモニウム水溶液に注ぎ込み、ethyl acetateで抽出した。得られた有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を留去して得られた粗生成物をpreparative TLC（TLC：Kieselgel 60 F-254 plats 0.5mm（Merck）、展開溶媒：chloroform/methanol=9/1）とHPLCにより精製して、化合物（3-3）（19mg,14%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、60.3minであった。
Synthesis of compound (3-3) Compound (1-18) (69 mg, 0.26 mmol) and N, N'-diisopropylethylamine (91 μL, 0.53) were added to acetonitrile (4 mL) of compound (3-2) (110 mg, 0.26 mmol). mmol) was added. After stirring at room temperature for 3.5 hours, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off. The resulting crude product was prepared by preparative TLC (TLC: Kieselgel 60 F-254 plats 0.5 mm (Merck), developing solvent: chloroform / Purification by methanol and 9/1) gave compound (3-3) (19 mg, 14%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 30% -80% (0-60 min). The HPLC retention time was 60.3 min.
化合物（V'）の合成
化合物（1-7）（6.1mg,20.7μmol）の水溶液（0.6mL）と、化合物（3-3）（11mg,20.9mmol）のアセトニトリル（0.4mL）溶液を混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で1.5時間攪拌し、HPLCにより精製して、目的とする化合物（V'）（9.9mg,57.6%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、51.7minであった。
Synthesis of Compound (V ′) An aqueous solution (0.6 mL) of Compound (1-7) (6.1 mg, 20.7 μmol) and an acetonitrile (0.4 mL) solution of Compound (3-3) (11 mg, 20.9 mmol) were mixed. Then, 2N NaOH was added to the mixture to adjust the pH to 7. The mixture was stirred at room temperature for 1.5 hours and purified by HPLC to obtain the target compound (V ′) (9.9 mg, 57.6%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 30% -80% (0-60 min). The HPLC retention time was 51.7 min.
（製造例４）式(VI’)で表される化合物の製造
下記スキームにしたがい、式(VI’)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
化合物（4-2）の合成
N-(Tert-butoxycarbonyl)-1,5-diaminopentane（488mg,2.41mmol）を飽和炭酸水素ナトリウム水溶液（10mL）と1,4-dioxane（2mL）の混合溶液に溶解した後、氷冷下N-methoxycarbonyl maleimide（412mg,2.66 mmol）を加えた。室温で2時間攪拌した後、反応液をchloroformで抽出した。得られた有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（カラム：Hi FlashTM 40 mm 60 Å(Yamazen)、展開溶媒：n-hexane/ethyl acetate=2/1）で精製し、化合物（4-2）（390mg,57%）を得た。
Synthesis of compound (4-2)
N- (Tert-butoxycarbonyl) -1,5-diaminopentane (488 mg, 2.41 mmol) is dissolved in a mixed solution of saturated aqueous sodium hydrogen carbonate (10 mL) and 1,4-dioxane (2 mL), and then N- ( Methoxycarbonyl maleimide (412 mg, 2.66 mmol) was added. After stirring at room temperature for 2 hours, the reaction solution was extracted with chloroform. The obtained organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off. The resulting crude product was subjected to silica gel column chromatography (column: Hi Flash TM 40 mm 60 mm (Yamazen), developing solvent: n Purification with -hexane / ethyl acetate = 2/1) gave compound (4-2) (390 mg, 57%).
化合物（4-3）の合成
化合物（4-2）（390mg,1.38mmol）に4N 塩酸/dioxane溶液（10mL）を加えた。徐々に析出した沈殿物をろ取、ethyl acetateで洗浄し、化合物（4-3）（125mg,41%）を得た。
Synthesis of Compound (4-3) A 4N hydrochloric acid / dioxane solution (10 mL) was added to Compound (4-2) (390 mg, 1.38 mmol). The gradually deposited precipitate was collected by filtration and washed with ethyl acetate to obtain Compound (4-3) (125 mg, 41%).
化合物（4-4）の合成
化合物（4-3）（52mg,0.24mmol）のアセトニトリル懸濁液（3mL）に化合物（1-13）（96mg,0.24mmol）とN,N'-diisopropylethylamine（41μL,0.24mmol）を加えた。室温で1時間攪拌した後、反応液を飽和塩化アンモニウム水溶液に注ぎ込み、ethyl acetateで抽出した。得られた有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（カラム：Hi FlashTM 40 mm 60Å(Yamazen)、展開溶媒：chloroform/methanol=10/1）で精製し、化合物（4-4）（51mg,45%）を得た。
Synthesis of Compound (4-4) Compound (1-13) (96 mg, 0.24 mmol) and N, N'-diisopropylethylamine (41 μL) in acetonitrile suspension (3 mL) of Compound (4-3) (52 mg, 0.24 mmol) 0.24 mmol) was added. After stirring at room temperature for 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off. The resulting crude product was subjected to silica gel column chromatography (column: Hi Flash TM 40 mm 60 mm (Yamazen), developing solvent: chloroform / Purification with methanol = 10/1) gave Compound (4-4) (51 mg, 45%).
化合物（VI'）の合成
化合物（1-7）（14mg,47.6μmol）の水溶液（0.3mL）と、化合物（4-4）（23mg,49.0mmol）のアセトニトリル（0.3mL）溶液を混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で1時間攪拌し、HPLCにより精製して、目的とする化合物（VI'）（16mg,42.8%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度40%-90%（0-60min）とした。HPLCの保持時間は、41〜43minであった。
ESI-MS m/z; 764 [M + H]+. 1H-NMR (CD3OD) δ; 1.32 (m, 2H), 1.56 (m, 4H), 1.89 (m, 1H), 2.14 (m, 1H), 2.42 (m, 2H), 2.50 (m, 1H), 3.20 (m, 4H), 3.48 (m, 3H), 3.98 (m, 3H), 4.31 (m, 1H), 4.61 (m, 1H), 7.25 (t, J = 8.02 Hz, 1H), 7.89 (m, 2H), 8.26 (t, J = 1.72 Hz, 1H).
Synthesis of Compound (VI ′) An aqueous solution (0.3 mL) of Compound (1-7) (14 mg, 47.6 μmol) and a solution of Compound (4-4) (23 mg, 49.0 mmol) in acetonitrile (0.3 mL) were mixed, The mixture was then adjusted to pH 7 by adding 2N NaOH. The mixture was stirred at room temperature for 1 hour and purified by HPLC to obtain the target compound (VI ′) (16 mg, 42.8%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 40% -90% (0-60 min). HPLC retention time was 41-43 min.
ESI-MS m / z; 764 [M + H] + . 1 H-NMR (CD 3 OD) δ; 1.32 (m, 2H), 1.56 (m, 4H), 1.89 (m, 1H), 2.14 (m , 1H), 2.42 (m, 2H), 2.50 (m, 1H), 3.20 (m, 4H), 3.48 (m, 3H), 3.98 (m, 3H), 4.31 (m, 1H), 4.61 (m, 1H), 7.25 (t, J = 8.02 Hz, 1H), 7.89 (m, 2H), 8.26 (t, J = 1.72 Hz, 1H).
（製造例５）式(VII’)で表される化合物の製造
下記スキームにしたがい、式(VII’)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
化合物（5-3）の合成
上記のスキームにしたがい既知の合成法で作製した化合物（5-2）（100mg,0.23mmol）のアセトニトリル溶液（2mL）に化合物（1-18）（59mg,0.22mmol）とN,N'-diisopropylethylamine（77μL,0.45mmol）を加えた。室温で2時間攪拌した後、反応液を飽和塩化アンモニウム水溶液に注ぎ込み、ethyl acetateで抽出した。得られた有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を留去して得られた粗生成物をpreparative TLC（TLC：Kieselgel 60 F-254 plats 0.5mm（Merck）、展開溶媒：chloroform/methanol= 10/1）とHPLCにより精製して、化合物（5-3）（30mg,25%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、63.1minであった。
Synthesis of Compound (5-3) Compound (1-18) (59 mg, 0.22 mmol) in acetonitrile solution (2 mL) of Compound (5-2) (100 mg, 0.23 mmol) prepared by a known synthesis method according to the above scheme ) And N, N′-diisopropylethylamine (77 μL, 0.45 mmol) were added. After stirring at room temperature for 2 hours, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off. The resulting crude product was prepared by preparative TLC (TLC: Kieselgel 60 F-254 plats 0.5 mm (Merck), developing solvent: chloroform / Purification by HPLC with methanol = 10/1) gave compound (5-3) (30 mg, 25%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 30% -80% (0-60 min). The HPLC retention time was 63.1 min.
化合物（VII'）の合成
化合物（1-7）（9mg,30.6μmol）の水溶液（0.6mL）と、化合物（5-3）（17mg,30.6mmol）のアセトニトリル（1mL）溶液を混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で2時間攪拌し、HPLCにより精製して、目的とする化合物（VII'）（6mg,23.1%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、54.9minであった。
Synthesis of Compound (VII ′) An aqueous solution (0.6 mL) of Compound (1-7) (9 mg, 30.6 μmol) and an acetonitrile (1 mL) solution of Compound (5-3) (17 mg, 30.6 mmol) were mixed, and then The mixture was adjusted to pH 7 by adding 2N NaOH. The mixture was stirred at room temperature for 2 hours and purified by HPLC to obtain the target compound (VII ′) (6 mg, 23.1%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 30% -80% (0-60 min). The HPLC retention time was 54.9 min.
（製造例６）式(IX)で表される化合物の製造
下記スキームにしたがい、式(IX)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
化合物（6-4）の合成
既知化合物（6-3, Aust J Chem 1978, 31, 439-43）（100mg,0.36mmol）を、化合物（1-18）（95mg,0.36mmol）とN,N'-diisopropylethylamine（125μL,0.73mmol）のアセトニトリル溶液（3mL）に加えた。室温で3時間攪拌した後、反応液を飽和塩化アンモニウム水溶液に注ぎ込み、ethyl acetateで抽出した。得られた有機層を硫酸ナトリウムで乾燥し、ろ過後、溶媒を留去して得られた粗生成物をpreparative TLC（TLC：Kieselgel 60 F-254 plats 0.5mm（Merck）、展開溶媒：chloroform/methanol=9/1）とHPLCにより精製して、化合物（6-4）（6mg,4%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、44.0minであった。
Synthesis of Compound (6-4) Known Compound (6-3, Aust J Chem 1978, 31, 439-43) (100 mg, 0.36 mmol) was converted to Compound (1-18) (95 mg, 0.36 mmol) and N, N It added to the acetonitrile solution (3 mL) of '-diisopropylethylamine (125 microliters, 0.73 mmol). After stirring at room temperature for 3 hours, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off. The resulting crude product was prepared by preparative TLC (TLC: Kieselgel 60 F-254 plats 0.5 mm (Merck), developing solvent: chloroform / Purification by methanol and 9/1) and HPLC gave Compound (6-4) (6 mg, 4%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 30% -80% (0-60 min). The HPLC retention time was 44.0 min.
化合物（IX）の合成
化合物（1-7）（4.8mg,16.3μmol）の水溶液（0.4mL）と、化合物（6-4）（6.3mg,16.3mmol）のアセトニトリル（0.6mL）溶液を混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で1時間攪拌し、HPLCにより精製して、目的とする化合物（IX）（5.9mg,54.1%）を得た。分取HPLCには、YMC-Pack ODS 20×250mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速5ml/min、B濃度30%-80%（0-60min）とした。HPLCの保持時間は、37.4minであった。
ESI-MS m/z; 682 [M + H]+. 1H-NMR (CD3OD) δ; 1.39 (m, 2H), 1.61 (m, 2H), 1.73 (m, 1H), 1.89 (m, 2H), 2.14 (m, 1H), 2.40 (m, 2H), 2.48 (m, 1H), 3.19 (m, 2H), 3.50 (m, 2H), 4.01 (m, 1H), 4.11 (m, 2H), 4.32 (m, 1H), 4.42 (m, 1H), 4.61 (m, 1H), 7.47 (t, J = 7.45 Hz, 2H), 7.55 (t, J = 7.73 Hz, 1H), 7.88 (m, 2H).
Synthesis of Compound (IX) An aqueous solution (0.4 mL) of Compound (1-7) (4.8 mg, 16.3 μmol) and a solution of Compound (6-4) (6.3 mg, 16.3 mmol) in acetonitrile (0.6 mL) were mixed. Then, 2N NaOH was added to the mixture to adjust the pH to 7. The mixture was stirred at room temperature for 1 hour and purified by HPLC to obtain the target compound (IX) (5.9 mg, 54.1%). For preparative HPLC, a YMC-Pack ODS 20 x 250 mm column was used, and water (mobile phase A) and methanol (mobile phase B) with 0.1% trifluoroacetic acid were used as the mobile phase. The concentration was 5 ml / min and the B concentration was 30% -80% (0-60 min). The HPLC retention time was 37.4 min.
ESI-MS m / z; 682 [M + H] + . 1 H-NMR (CD 3 OD) δ; 1.39 (m, 2H), 1.61 (m, 2H), 1.73 (m, 1H), 1.89 (m , 2H), 2.14 (m, 1H), 2.40 (m, 2H), 2.48 (m, 1H), 3.19 (m, 2H), 3.50 (m, 2H), 4.01 (m, 1H), 4.11 (m, 2H), 4.32 (m, 1H), 4.42 (m, 1H), 4.61 (m, 1H), 7.47 (t, J = 7.45 Hz, 2H), 7.55 (t, J = 7.73 Hz, 1H), 7.88 ( m, 2H).
（製造例７）式(X)で表される化合物の製造
下記スキームにしたがい、式(X)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
化合物(1-7)(6.2mg)の水溶液(0.5mL)と化合物(7-1)のメタノール(0.6mL)溶液とを混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で1時間攪拌し、HPLCにより精製して、目的とする化合物(X)((2S)-2-(3-((1R)-1-carboxy-2-((1-(3-iodophenyl)-2,5-dioxopyrrolidin-3-yl)thio)ethyl)ureido)pentanedioic acid)を得た(2.4mg、収量18%)。HPLCの分析には化合物(III')と同じ条件とした。
ESI-MS; 594 [M + H]+ for C19H20N3O9SI.
An aqueous solution (0.5 mL) of compound (1-7) (6.2 mg) and a solution of compound (7-1) in methanol (0.6 mL) were mixed, and then 2N NaOH was added to the mixture to adjust to pH7. Stir at room temperature for 1 hour and purify by HPLC to obtain the desired compound (X) ((2S) -2- (3-((1R) -1-carboxy-2-((1- (3-iodophenyl) -2,5-dioxopyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid) was obtained (2.4 mg, 18% yield). The HPLC analysis was performed under the same conditions as for the compound (III ′).
ESI-MS; 594 [M + H] + for C 19 H 20 N 3 O 9 SI.
（製造例８）式(XI)で表される化合物の製造
下記スキームにしたがい、式(XI)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
既知の合成法に従い、上記スキームに示す順番で化合物(8-7)を合成した（放射化学的純度(未精製)：74.9±3.7%、HPLC保持時間(tR);25.4min）。化合物(1-7)(6.8mg)の水溶液(0.2mL)と、化合物(8-7)(11.9mg)のアセトニトリル(0.15mL)溶液を混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で2時間攪拌し、HPLCにより精製して、目的とする化合物(XI)を放射化学的収率63.3％、放射科学的純度＞95％で得た。HPLCの分析にはCosmosil(R) 5C18-AR-II 4.6x150mmカラムを使用し、移動相には0.1%トリフルオロ酢酸を加えた水（移動相A）とメタノール（移動相B）を用い、タイムプログラムは流速1mL/min、B濃度30%一定（0-10min）、30%-60%（10-20min）、60%一定（20-30min）とした。 Compound (8-7) was synthesized according to a known synthesis method in the order shown in the above scheme (radiochemical purity (unpurified): 74.9 ± 3.7%, HPLC retention time (t R ); 25.4 min). Mix an aqueous solution (0.2 mL) of compound (1-7) (6.8 mg) with a solution of compound (8-7) (11.9 mg) in acetonitrile (0.15 mL), and then add 2N NaOH to the mixture to adjust to pH 7. did. Stirring at room temperature for 2 hours and purification by HPLC afforded the desired compound (XI) in radiochemical yield 63.3%, radiochemical purity> 95%. A Cosmosil (R) 5C18-AR-II 4.6x150mm column was used for HPLC analysis, and 0.1% trifluoroacetic acid-added water (mobile phase A) and methanol (mobile phase B) were used as the mobile phase. The program was set at a flow rate of 1 mL / min, a B concentration of 30% constant (0-10 min), 30% -60% (10-20 min), and 60% constant (20-30 min).
（製造例９）式(XII)で表される化合物の製造
下記スキームにしたがい、式(XII)で表される化合物を製造した。以下に、当該スキームを具体的に説明する。
化合物(1-7)(6.2mg)の水溶液(0.5mL)と化合物(9-1)のメタノール(0.6mL)溶液とを混合し、ついでその混合物に2N NaOHを加えpH7に調整した。室温で1時間攪拌し、HPLCにより精製して、目的とする化合物(XII)((2S)-2-(3-((1R)-1-carboxy-2-((1-(3-[125I]iodophenyl)-2,5-dioxopyrrolidin-3-yl)thio)ethyl)ureido)pentanedioic acid)を放射化学的収率36.5％、放射科学的純度＞95％で得た。HPLCの分析には化合物(X)と同じ条件とした。 An aqueous solution (0.5 mL) of compound (1-7) (6.2 mg) and a solution of compound (9-1) in methanol (0.6 mL) were mixed, and then 2N NaOH was added to the mixture to adjust to pH7. Stir at room temperature for 1 hour and purify by HPLC to obtain the desired compound (XII) ((2S) -2- (3-((1R) -1-carboxy-2-((1- (3- [ 125 I] iodophenyl) -2,5-dioxopyrrolidin-3-yl) thio) ethyl) ureido) pentanedioic acid) was obtained with a radiochemical yield of 36.5% and a radiological purity of> 95%. The HPLC analysis was performed under the same conditions as for the compound (X).
［in vitro安定性］
C.B.-17/Icr +/+ Jclマウス(雄性、20〜20g)より採取した血漿サンプル(100μL)に、20μLの化合物(XI)又は化合物(XII)を加え、37℃で1,3,又は6時間インキュベートした。インキュベート後、150μLのメタノールを加え、5,000×gで遠心分離した。上清を回収し、Cosmonice Filter(R) (S)(0.45μm,4mm)で濾過紙、濾過物をHPLCで分析した。
[In vitro stability]
To a plasma sample (100 μL) collected from CB-17 / Icr + / + Jcl mice (male, 20-20 g), 20 μL of compound (XI) or compound (XII) is added, and 1, 3, or 6 at 37 ° C. Incubated for hours. After incubation, 150 μL of methanol was added and centrifuged at 5,000 × g. The supernatant was recovered and filtered with Cosmonice Filter® (S) (0.45 μm, 4 mm), and the filtrate was analyzed by HPLC.
図１に示すように、化合物(XII)は時間依存的な分解が観察され、1時間後には化合物の50％、3時間後には72％、6時間後には89％が分解した。これに対し、化合物(XI)は6時間インキュベートしても分解物はほとんど見られなかった。よって、化合物(XI)は、化合物(XII)と比較して血漿中で優れた安定性を示すことが確認できた。 As shown in FIG. 1, compound (XII) showed time-dependent degradation, with 50% of the compound being degraded after 1 hour, 72% after 3 hours, and 89% after 6 hours. In contrast, compound (XI) showed almost no degradation product even after 6 hours of incubation. Therefore, it was confirmed that the compound (XI) showed excellent stability in plasma compared with the compound (XII).
[in vitro細胞結合アッセイ]
化合物(XI)、及び既知のPSMA阻害剤である[125I]DCIT(N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[125I]iodo-L-tyrosine)と[125I]MIP-1072((S)-2-(3-((S)-1-carboxy-5-((4-[125I]idobenzyl)amino)pentyl)ureido)pentanedionic acid)について、PSMAに対する親和性を細胞結合アッセイによりKd値として評価した。
[In vitro cell binding assay]
Compound (XI) and a known PSMA inhibitor [ 125 I] DCIT (N- [N-[(S) -1,3-dicarboxypropyl] carbamoyl] -S-3- [ 125 I] iodo-L- tyrosine) and [ 125I ] MIP-1072 ((S) -2- (3-((S) -1-carboxy-5-((4- [ 125I ] idobenzyl) amino) pentyl) ureido) pentanedionic acid) Were evaluated as K d values by cell binding assay.
測定には、PSMA発現ヒト前立腺がん細胞としてLNCaPを用いた。LNCaPを12wellディッシュに播いて(4x105cells/well)、CO2インキュベーターにて48時間培養した。培地を除去し、下記表1の化合物を種々の濃度加えて37℃で1時間インキュベートした。非特異的結合は過剰量の2-PMPAを加えることで評価した。インキュベート後にウェルを洗浄して0.2N NaOHで細胞を溶解させ、結合放射能を測定した。その結果を下記表１に示す。 For the measurement, LNCaP was used as PSMA-expressing human prostate cancer cells. LNCaP was seeded in a 12-well dish (4 × 10 5 cells / well) and cultured in a CO 2 incubator for 48 hours. The medium was removed and various concentrations of the compounds in Table 1 below were added and incubated at 37 ° C. for 1 hour. Nonspecific binding was assessed by adding an excess of 2-PMPA. After incubation, the wells were washed and the cells were lysed with 0.2N NaOH and bound radioactivity was measured. The results are shown in Table 1 below.
表１に示すように、化合物(XI)は、既知のPSMA阻害剤であるDCIT及びMIP-1072よりも高い親和性を示した。このように、化合物(XI)は、臨床試験が進んでいるMIP-1072よりも高い親和性を有しており、効果的なPSMAイメージングプローブとして機能する可能性が示唆された。 As shown in Table 1, compound (XI) showed higher affinity than the known PSMA inhibitors DCIT and MIP-1072. Thus, compound (XI) has a higher affinity than MIP-1072, which is undergoing clinical trials, suggesting the possibility of functioning as an effective PSMA imaging probe.
また、既知のGCP-II阻害剤である2-PMPA（(2RS,4S)-2-fluoro-4-phosphonomethyl-pentanedioic acid）、化合物(1-7)、化合物(III')、(IV')、（V'）、（VI'）、（VII'）及び(IX)について、同様にPSMAに対する親和性を評価した。その結果を下記表２に示す。 In addition, known GCP-II inhibitor 2-PMPA ((2RS, 4S) -2-fluoro-4-phosphonomethyl-pentanedioic acid), compound (1-7), compound (III '), (IV') , (V ′), (VI ′), (VII ′) and (IX) were similarly evaluated for affinity to PSMA. The results are shown in Table 2 below.
表２に示すように、化合物(III')、(IV')、（V'）、（VI'）、（VII'）及び(IX)は、既知のGCP-II阻害剤である2-PMPAよりも高い親和性を示した。 As shown in Table 2, compounds (III ′), (IV ′), (V ′), (VI ′), (VII ′) and (IX) are 2-PMPA, which are known GCP-II inhibitors. Higher affinity.
［体内分布実験］
化合物(XI)を用いてマウスの体内分布実験を行った。PC-3及びLNCaPをC.B-17 Icr scid/scidマウスの肩に移植したモデルマウスを作製した。100μLの化合物(XI)を無麻酔のモデルマウス（22〜24g）に静脈注射(尾静脈)により投与した。投与２分後、３０分後、６０分後、１８０分後、３６０分後に各臓器を摘出した。各臓器の放射能を測定し、各臓器あたりの放射能の集積量（%dose/g）を算出した（n＝3〜6）。その結果の一例を下記表３に示す。
[Body distribution experiment]
A mouse biodistribution experiment was conducted using compound (XI). A model mouse was prepared by transplanting PC-3 and LNCaP to the shoulder of a CB-17 Icr scid / scid mouse. 100 μL of compound (XI) was administered by intravenous injection (tail vein) to unanesthetized model mice (22-24 g). Each organ was removed 2 minutes, 30 minutes, 60 minutes, 180 minutes, and 360 minutes after administration. The radioactivity of each organ was measured, and the amount of radioactivity accumulated per organ (% dose / g) was calculated (n = 3 to 6). An example of the results is shown in Table 3 below.
表３に示すように、化合物(XI)は血液クリアランスに優れ、筋肉への集積も低かった。また、化合物(XI)は、PSMAが発現しているLNCaP腫瘍及び腎臓を含む臓器に特異的に集積したが、PSMAが発現していないPC-3腫瘍への集積は少なかった。この特異的な臓器への集積は、少なくとも６時間にわたって維持された。また、LNCaP/PC-3比が時間の経過に伴い上昇したことから、化合物(XI)はPSMAを特異的に認識して、結合・集積していることが確認できた。さらに、腎臓への高い集積が少なくとも６時間にわたって維持されていることから、化合物(XI)は腎臓での滞留時間が長く、膀胱への流出を遅らせることができることが示唆された。 As shown in Table 3, compound (XI) was excellent in blood clearance and low in muscle accumulation. Compound (XI) was specifically accumulated in LNCaP tumors expressing PSMA and organs including kidney, but was rarely accumulated in PC-3 tumors not expressing PSMA. This specific organ accumulation was maintained for at least 6 hours. Further, since the LNCaP / PC-3 ratio increased with the passage of time, it was confirmed that the compound (XI) specifically recognized PSMA and was bound and accumulated. Furthermore, the high accumulation in the kidney was maintained for at least 6 hours, suggesting that compound (XI) has a long residence time in the kidney and can delay the outflow to the bladder.
［Blocking Study］
100μLの化合物(XI)と、GCP-II阻害剤である2-PMPA(50mg/kg weight)とを、腫瘍を有するマウス(22〜24g)に尾静脈より同時投与した。注射30分後、各臓器を摘出し、各臓器の放射能を測定し、各臓器あたりの放射能の集積量（%dose/g）を算出した。また、化合物(XI)のみを投与した以外は、上記と同様にして測定を行い、各臓器あたりの放射能の集積量（%dose/g）を算出した。それらの結果の一例を図２に示す。
[Blocking Study]
100 μL of compound (XI) and 2-PMPA (50 mg / kg weight), a GCP-II inhibitor, were simultaneously administered to tumor-bearing mice (22-24 g) from the tail vein. Thirty minutes after the injection, each organ was removed, the radioactivity of each organ was measured, and the amount of radioactivity accumulated in each organ (% dose / g) was calculated. Further, measurement was carried out in the same manner as described above except that only compound (XI) was administered, and the amount of radioactivity accumulated per organ (% dose / g) was calculated. An example of the results is shown in FIG.
図２に示すように、LNCaP腫瘍及び腎臓は、過剰の2-PMPAによって集積が抑制された。また、2-PAMAを同時に投与したグループ（図２の2-PAMA(+)）でのLNCaP腫瘍における集積(0.55±0.05%ID/g)は、2-PAMAを同時に投与していないグループ(図２の2-PAMA(-))でのPC-3腫瘍における集積(0.94±0.26%ID/g)と同程度のレベルまで阻害されていた。この結果により、体内分布実験において得られたLNCaP腫瘍及び腎臓への化合物(XI)の集積は非特異的なものではなく、化合物(XI)はPSMAに特異的に結合していることが確認できた。 As shown in FIG. 2, accumulation of LNCaP tumors and kidneys was suppressed by excess 2-PMPA. In addition, the accumulation (0.55 ± 0.05% ID / g) in LNCaP tumors in the group to which 2-PAMA was administered simultaneously (2-PAMA (+) in FIG. 2) 2 (2-PAMA (-)) was inhibited to a level similar to the accumulation (0.94 ± 0.26% ID / g) in PC-3 tumors. This result confirms that the accumulation of compound (XI) in LNCaP tumors and kidneys obtained in biodistribution experiments is not nonspecific and that compound (XI) specifically binds to PSMA. It was.
[SPECT/CT撮像]
下記化合物(XIII)を用いて、SPECT/CT撮像を行った。
SPECT / CT imaging was performed using the following compound (XIII).
LNCaP及びPC-3腫瘍を肩に移植したマウス(20〜25g)を麻酔し、化合物(XIII)(25.9MBq in 生理食塩水(0.10mL))を静脈注射(尾静脈)により投与した。SPECT/CT撮像は、FX3300(SII NanoTechnology Inc., USA)を用いて行った。SPECT撮像は投与後30〜64分にわたって行い、ついでCT撮像を行った(spatial resolution, 50μm; 60kV; 310μA)。SPECT撮像は、回転半径（ROR）35mm、収集角度360°、1方向あたりの収集時間60秒、32投影角で行い、シングルピンホールコリメータ（直径：1.0mm、焦点距離：9.0mm）を用いた。得られたSPECT画像は、3D-OSEM(３D ordered subsets expectation maximization)を用いて再構築した。得られたCT画像は、改変した3D cone beam Feldkamp algorithmを用いて再構築した。得られたSPECTデータ及びCTデータをAMIRA software (version 5.1)を用いて処理した。また、競合実験として、2-PMPA(50mg/kg weight in 生理食塩水(0.10mL))と同時注入した以外は、上記と同様にして、SPECT/CT撮像を行った。比較例として、化合物(XIII)に代えて[123I]DCITを投与した以外は、上記と同様にして、SPECT/CT撮像を行った。これらにより得られた画像を図３に示す。画像は、投与30分後のものである。 Mice (20-25 g) transplanted with LNCaP and PC-3 tumors on the shoulder were anesthetized, and compound (XIII) (25.9 MBq in physiological saline (0.10 mL)) was administered by intravenous injection (tail vein). SPECT / CT imaging was performed using FX3300 (SII NanoTechnology Inc., USA). SPECT imaging was performed for 30 to 64 minutes after administration, followed by CT imaging (spatial resolution, 50 μm; 60 kV; 310 μA). SPECT imaging was performed using a single pinhole collimator (diameter: 1.0 mm, focal length: 9.0 mm) with a radius of rotation (ROR) of 35 mm, a collection angle of 360 °, a collection time of 60 seconds per direction, and a projection angle of 32. . The obtained SPECT image was reconstructed using 3D-OSEM (3D ordered subsets expectation maximization). The obtained CT images were reconstructed using a modified 3D cone beam Feldkamp algorithm. The obtained SPECT data and CT data were processed using AMIRA software (version 5.1). As a competitive experiment, SPECT / CT imaging was performed in the same manner as described above except that 2-PMPA (50 mg / kg weight in physiological saline (0.10 mL)) was co-injected. As a comparative example, SPECT / CT imaging was performed in the same manner as described above except that [ 123 I] DCIT was administered instead of the compound (XIII). The image obtained by these is shown in FIG. Images are from 30 minutes after administration.
図３Ａは化合物(XIII)のみを投与して得られた横断像のSPECT/CT画像であり、図３Ｂは化合物(XIII)と2-PAMAを同時に投与して得られた横断像のSPECT/CT画像であり、図３Ｃは化合物(XIII)のみを投与して得られた冠状断像のSPECT/CT画像であり、図３Ｄは[123I]DCITを投与して得られた冠状断像のSPECT/CT画像である。図３ＡからＤにおいて、白丸がLNCaP腫瘍の位置を示し、破線の白丸がPC-3腫瘍の位置を示す。図３Ａ及びＢに示すように、化合物(XIII)は、LNCaP腫瘍に非常に特異的に取り込まれ、この取り込みは2-PMPAの同時投与によって完全に抑制された。また、図３Ｃ及びＤに示すように、化合物(XIII)を投与して得られた画像では、既知のPSMA阻害剤である[123I]DCITと同等又はそれ以上にLNCaP腫瘍を明瞭に描出できた。 FIG. 3A is a cross-sectional SPECT / CT image obtained by administering compound (XIII) alone, and FIG. 3B is a cross-sectional SPECT / CT image obtained by simultaneously administering compound (XIII) and 2-PAMA. FIG. 3C is a SPECT / CT image of a coronal image obtained by administering compound (XIII) alone, and FIG. 3D is a SPECT of the coronal image obtained by administering [ 123 I] DCIT. / CT image. 3A to 3D, white circles indicate the position of the LNCaP tumor, and broken white circles indicate the position of the PC-3 tumor. As shown in FIGS. 3A and B, compound (XIII) was very specifically taken up by LNCaP tumors and this uptake was completely suppressed by co-administration of 2-PMPA. In addition, as shown in FIGS. 3C and 3D, in the image obtained by administering Compound (XIII), the LNCaP tumor can be clearly depicted to be equal to or more than [ 123 I] DCIT, which is a known PSMA inhibitor. It was.
Claims (9)
Ｌは、リンカー、又は結合手を示し、
Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示し、
ｍは、０、１、２、３、４、又は５である。 A compound represented by formula (I) or a pharmaceutically acceptable salt of a compound represented by formula (I).
L represents a linker or a bond,
Each Z independently represents a hydrogen atom or C 1-4 alkyl;
m is 0, 1, 2, 3, 4, or 5.
Ｐは、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示し、
Ｘ及びＹは、それぞれ独立して、Ｃ1-8アルキレン、Ｃ2-8アルケニル、Ｃ2-8アルキニル、Ｃ1-8ヘテロアルキル、Ｃ2-8ヘテロアルケニル、Ｃ2-8ヘテロアルキニル、Ｃ1-8アルコキシ、又は結合手を示し、
Ｑは、天然アミノ酸、−ＮＨ−、−Ｏ−、−ＣＯ−ＮＨ−、−ＣＯ2−ＮＨ−、−Ｓ−、−ＳＯ2―、―ＣＯ2−、−ＮＨ−ＣＯ−、−ＮＨ−ＣＯ2−、又は−ＣＨ＝ＣＨ−を示し、
Ｚは、それぞれ独立して、水素原子又はＣ1-4アルキルを示し、
ｍは、０、１、２、３、４、又は５である。 A pharmaceutically acceptable salt of the compound represented by formula (II) or the compound represented by formula (II).
P is, -O -, - CO-NH -, - CO 2 -NH -, - NH -, - S -, - SO 2 -, - CO 2 -, - NH-CO -, - NH-CO 2 - Or -CH = CH-
X and Y are each independently C 1-8 alkylene, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 2-8 heteroalkenyl, C 2-8 heteroalkynyl, C 2 1-8 alkoxy or a bond
Q is a natural amino acid, -NH -, - O -, - CO-NH -, - CO 2 -NH -, - S -, - SO 2 -, - CO 2 -, - NH-CO -, - NH- CO 2- or -CH = CH-
Each Z independently represents a hydrogen atom or C 1-4 alkyl;
m is 0, 1, 2, 3, 4, or 5.
請求項１から４のいずれかに記載の化合物を投与された被検体から前記化合物の放射性シグナルを検出することを含む、イメージング方法。 An imaging method of PSMA (Prostate Specific Membrane Antige),
An imaging method comprising detecting a radioactive signal of the compound from a subject administered with the compound according to claim 1.
請求項１から４のいずれかに記載の化合物を投与された被検体から前記化合物の放射性シグナルを検出することを含む、イメージング方法。 A method for imaging prostate cancer,
An imaging method comprising detecting a radioactive signal of the compound from a subject administered with the compound according to claim 1.
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| JP2015089881A (en) * | 2013-11-06 | 2015-05-11 | 国立大学法人京都大学 | Urea derivative compound and radiopharmaceutical containing the same |
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| CN110770212A (en) * | 2017-06-19 | 2020-02-07 | 未来化学株式会社 | 18F-labeled compound for diagnosis of prostate cancer and application thereof |
| JP2021513979A (en) * | 2018-02-22 | 2021-06-03 | ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Chemical conjugates of Evans blue derivatives and their use as radiation therapy and contrast agents to target prostate cancer |
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| JP2015089881A (en) * | 2013-11-06 | 2015-05-11 | 国立大学法人京都大学 | Urea derivative compound and radiopharmaceutical containing the same |
| KR101918285B1 (en) | 2015-06-17 | 2018-11-13 | 주식회사 엘지화학 | Preparation method for super absorbent polymer |
| CN110770212A (en) * | 2017-06-19 | 2020-02-07 | 未来化学株式会社 | 18F-labeled compound for diagnosis of prostate cancer and application thereof |
| CN110770212B (en) * | 2017-06-19 | 2022-11-22 | 未来化学株式会社 | 18F-labeled compounds for prostate cancer diagnosis and uses thereof |
| JP2021513979A (en) * | 2018-02-22 | 2021-06-03 | ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Chemical conjugates of Evans blue derivatives and their use as radiation therapy and contrast agents to target prostate cancer |
| JP7449864B2 (en) | 2018-02-22 | 2024-03-14 | ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Chemical conjugates of Evans blue derivatives and their use as radiotherapy and contrast agents to target prostate cancer |
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