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JP-7857035-B2 - PSMA ligands for imaging and internal radiotherapy

JP7857035B2JP 7857035 B2JP7857035 B2JP 7857035B2JP-7857035-B2

Inventors

  • ウェスター，ハンス－ユルゲン
  • シュミット，アレクサンデル
  • パーツィンガー，マラ

Assignees

  • テクニシェ ユニバーシタット ミュンヘン

Dates

Publication Date
20260512
Application Date
20241003
Priority Date
20171211

Claims (14)

  1. Compounds of formula (I) or pharmaceutically acceptable salts thereof (In the formula, m is an integer between 2 and 6; n is an integer between 2 and 6; R1L is CH2 , NH or O; R 2L is C or P(OH); R 3L is CH 2 , NH or O; X1 is selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds; L1 is a divalent linking group having a structure selected from oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether), oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea), and oligo(thioester-urea); A linking group is a group in which 2 to 10 subunits are linked by a type of bond specified by the same term. The linking group may have an EDS group; X2 is selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds; R2 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens and -OH groups; R3 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens and -OH groups; r is either 0 or 1; p is either 0 or 1; q is either 0 or 1; R4 is selected from optionally substituted aryl groups and EDS groups, and the aryl group may be substituted on its aromatic ring with one or more substituents selected from halogens, -OH, and -NH2 ; X3 is an amide bond, ether bond, thioether bond, ester bond, thioester bond, urea crosslink, amine bond, and formula A group is selected from the following groups, in which the carbonyl group marked bond attaches X3 to RM , and the other marked bond attaches X3 to the remainder of the compound of formula (I); RM is: 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y, 89 Y, 94m Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, Cations of 149 Pm , 151 Pm, 149 Tb, 153 Sm, 157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 177 Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac, and 227 Th, or 18 A chelate group containing a chelated radioactive cation, selected from cationic molecules containing F; Furthermore, the EDS group possessed by L 1 and/or represented by R 4 in the formula is contained at least once in the compound of formula (I), (E-1A), (E-1B), (E-2A), and (E-2B): Having a structure selected from, During the ceremony, This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); s is 1, 2, or 3; t is 1, 2, or 3; R 5A is independently an electron-withdrawing substituent selected from -NO 2 and -COOH for each occurrence where s > 1, and the bond between R 5A and the phenyl ring represents s R 5A groups substituting s hydrogen atoms at any position on the phenyl ring; R 5B is independently a substituent with a lone pair of electrons at an atom directly attached to the phenyl ring represented by formula (E-1B) for each occurrence where s > 1, the substituent is selected from -OH and -NH 2 , and the bond between R 5B and the phenyl ring represents s R 5B groups substituting s hydrogen atoms at any position on the phenyl ring; R 6A is independently an electron-withdrawing substituent selected from -NO₂ and -COOH for each occurrence when t > 1, and the bond between R 6A and the phenyl ring represents t R 6A groups substituting t hydrogen atoms at any position on the phenyl ring; and R 6B is independently an substituent with a lone pair of electrons at an atom directly attached to the phenyl ring shown in formula (E-2B) for each occurrence when t > 1, and the substituent is selected from -OH and -NH₂ , and the bond between R 6B and the phenyl ring represents t R 6B groups substituting t hydrogen atoms at any position on the phenyl ring).
  2. The compound or salt according to claim 1, wherein m is 2, n is 2 or 4, R 1L is NH, R 2L is C, and R 3L is NH.
  3. The compound or salt according to claim 1 or 2, wherein L1 is a divalent linking group having a structure selected from oligoamides containing a total of 1 to 5 amide bonds in their main chain, and oligo(ester-amides) containing a total of 2 to 5 amide and ester bonds in their main chain, and the linking group may have an EDS group.
  4. The part in equation (I) -X 2 -L 1 -X 1 - is *-C(O)-NH-R 7 -NH-C(O)-R 8 -C(O)-NH- (L-1), *-C(O)-NH-R 9A -NH-C(O)-R 10A -C(O)-NH-R 11A -NH-C(O)- (L-2A), and *-C(O)-NH-R 9B -C(O)-NH-R 10B -C(O)-NH-R 11B -NH-C(O)- (L-2B) A compound or salt according to any one of claims 1 to 3 having a structure selected from (wherein the formula, the amide bond marked with * is attached to the carbon atom having R 2 in formula (I), R7 , R8 , R9A , R9B , R11A , and R11B are independently selected from optionally substituted C2-C10 alkanediyl groups, and each alkanediyl group may be independently substituted with one or more substituents selected from -OH, -OCH3 , -COOH, -COOCH3 , -NH2 , -NHC(NH) NH2 , and EDS groups, and R10A and R10B are selected from optionally substituted C2-C10 alkanediyl and optionally substituted C6-C10 arenediyl groups, and each alkanediyl and arenediyl group may be independently substituted with -OH, -OCH3 , -COOH, -COOCH3 , -NH2 , -NHC(NH)NH (May be substituted with one or more substituents selected from groups 2 and EDS).
  5. Part -X 2 -L 1 -X 1 - is *-C(O)-NH-CH(COOH)-R 12 -NH-C(O)-R 13 -C(O)-NH- (L-3), *-C(O)-NH-CH(COOH)-R 14 -NH-C(O)-R 15 -C(O)-NH-R 16 -CH(COOH)-NH-C(O)- (L-4), and *-C(O)-NH-CH(COOH)-R 17 -C(O)-NH-R 18 -C(O)-NH-R 19 -CH(COOH)-NH-C(O)- (L-5) A compound or salt according to claim 4 having a structure selected from (wherein the formula, the bond marked with * is attached to the carbon atom having R 2 in formula (I), R12 and R14 are independently selected from linear C2-C6 alkanediyl groups. R 13 is a straight-chain C2-C10 alkanediyl, R15 and R16 are independently selected from linear C2-C6 alkanediyl molecules. Each of R13 and R15 has one EDS group as a substituent. R 17 is a straight-chain C2-C6 alkanediyl, R18 is a phenylene group, and R19 is a linear C2-C6 alkanediyl.
  6. The compound or salt according to any one of claims 1 to 5, wherein R 2 is an optionally substituted aralkyl group selected from optionally substituted -CH 2 -phenyl and optionally substituted -CH 2 -naphthyl, and the phenyl and naphthyl groups are optionally substituted with substituents selected from halogens.
  7. The compound or salt according to any one of claims 1 to 6, wherein R3 is an optionally substituted aralkyl group selected from optionally substituted -CH2 -phenyl and optionally substituted -CH2 -naphthyl, and the phenyl and naphthyl groups are optionally substituted with substituents selected from halogens and -OH.
  8. The compound or salt according to any one of claims 1 to 7, wherein r is 1, R4 is selected from optionally substituted phenyl, optionally substituted naphthyl, and EDS groups, and the phenyl and naphthyl groups are optionally substituted with substituents selected from halogen, -OH, and -NH2 .
  9. X3 is an amide bond or formula A compound or salt according to any one of claims 1 to 8, which is the base of (wherein the carbonyl group, the marked bond attaches X3 to RM , and the other marked bond attaches X3 to the remainder of the molecule).
  10. The compound or salt according to any one of claims 1 to 9, wherein the compound of formula (I) contains one EDS group of the linking group L1 , or one is represented by R4 and the other contains two EDS groups of L1 .
  11. Formula (E-2A): A compound or salt according to any one of claims 1 to 10, containing an EDS group having (wherein, The marker indicates a bond that attaches the EDS group to the remainder of the compound of formula (I); and t is 1 or 2, and R 6A is selected from -NO 2 or -COOH).
  12. The following formula: A compound or salt according to any one of claims 1 to 11, having one of the above.
  13. One or more compounds or salts according to any one of claims 1 to 12 (where R M is 225 Ac, 161 Tb, or 212 Pb, and the following formula A pharmaceutical or diagnostic composition comprising or consisting of compounds or salts having the same (excluding compounds or salts having the same) .
  14. (a) cancer, including prostate cancer; or (b) a compound or salt thereof according to any one of claims 1 to 12 for use in a method for diagnosing and/or treating angiogenesis/angiogenesis.

Description

This disclosure relates to imaging and internal radiotherapy for diseases involving prostate-specific membrane antigen (PSMA). Compounds are provided that bind to or inhibit PSMA and have at least one moiety suitable for radiolabeling. Medical uses of such compounds are also provided. This specification incorporates references to several documents, including patent applications and manufacturer's descriptions. While the disclosures of these documents are not considered relevant to the patentability of the present invention, they are incorporated herein by reference in their entirety. More specifically, all relevant documents are incorporated by reference to the same degree as to indicate that each individual document is incorporated specifically and individually by reference. Prostate cancer (PCa) remains the most common malignant disease in men, with a high rate of poor survival rates over the past few decades. Prostate-specific membrane antigen (PSMA) or glutamate carboxypeptidase II (GCP II), due to its overexpression in prostate cancer (Silver, D.A. et al., Prostate-specific membrane antigen expression in normal and malicious human tissues. Clinical Cancer Research, 1997.3(1): pp. 81-85), has demonstrated its suitability as an excellent target for the development of highly sensitive radiolabeling agents for internal radiotherapy and imaging of prostate cancer (Afshar-Oromieh, A. et al., The diagnostic value of PET/CT imaging with the 68Ga-labeled PSMA). ligand HBED-CC in the diagnosis of current prostate cancer. European journal of nuclear medicine and molecular imaging, 2015.42(2): pages 197-209; Benesova, M. Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. Journal of Nuclear Medicine, 2015. 56(6): pp. 914-920; Robu, S. et al., Preclinical evaluation and first patient application of 99mTc-PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer. Journal of Nuclear Medicine, 2016: jnumed. 116. 178939; Weineisen, M. et al., Development and first in human evaluation of PSMA I&T-A ligand for diagnostic imaging and endorradiotherapy of prostate cancer. Journal of Nuclear Medicine, 2014.55 (Supplement 1): pages 1083-1083; Rowe, S. et al., PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges. Prostate cancer and prosstatic diseases, 2016; Maurer, T. et al., Current us e of PSMA-PET in prostate cancer management. Nature Reviews Urology, 2016). Prostate-specific membrane antigen is an extracellular hydrolase whose catalytic center contains two zinc(II) ions with a cross-linked hydroxide ligand. Although prostate-specific membrane antigen is very upregulated in metastatic and hormone-refractory prostate cancer, its physiological expression has also been reported in the kidneys, salivary glands, small intestine, brain, and, to a lesser extent, in healthy prostate tissue. In the intestine, PSMA promotes folate absorption by converting pteroylpoly-γ-glutamic acid to pteroylglutamic acid (folate). In the brain, PSMA hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and glutamate. The enzymatic function of PSMA in normal and pathological prostates has not been elucidated. PSMA-targeting molecules typically consist of a P1' glutamate moiety (Maculkin, A.E. et al., Small-molecular PSMA ligands. Current state, SAR and perceptions. Journal of drug targeting, 2016: pp. 1-15) linked to urea (Zhou, J. et al., NAAG peptide inhibitors and their potential for diagnosis and therapy. Nature Reviews Drug). Discovery, 2005.4(12): pp. 1015–1026), contains a binding unit that includes a zinc-binding group (such as a phosphinate or phosphoramide), the binding unit ensuring high affinity and specificity to PSMA, and is typically further linked to an effector functional group. The effector portion is more mobile and to some extent resistant to structural modification. The entrance tunnel of PSMA contains two distinct and notable structural properties that are important for ligand binding. The first is a positively charged region on the wall of the entrance tunnel, an arginine patch that provides a structural explanation for the preference of negatively charged functional groups at the P1 site of PSMA. Upon binding, the concerted repositioning of the arginine side chain can lead to the opening of the S1 hydrophobic accessory pocket, a second important structural feature that has been shown to accept the iodobenzyl group of several urea-based inhibitors. This thus contributes to its high affinity for PSMA (Barinka, C. et al., Interactions between Human Glutamate Carboxypeptides II and Urea-Based Inhibitors: Structural Characterization†. Journal of Medicinal Chemistry, 2008. 51(24): pp. 7737-7743). Zhang et al. discovered a remote binding site on prostate-specific membrane antigen that can utilize a bidentate binding mode. Revealed by an