RU2796538C2 - Diagnosis, treatment and prevention of conditions associated with the neurotensin receptor - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention describes the compound of formula (I).

The invention relates to a compound of formula (I), optionally in the form of a pharmaceutically acceptable salt thereof

where R¹ is selected from -(C_1-6 alkyl), R² is selected from -(C_1-6 alkyl), R³ is selected from 2-amino-2-adamantanecarboxylic acid, and Z is -(linker group)-( chelator group), where the linker group is -C_1-6 alkylene-N(R⁴)-C_1-6 alkylene-N(R⁴)-, where each R⁴ is independently selected from hydrogen and C_1-6 alkyl, and each C_1-6 alkylene is independently optionally substituted with one substituent selected from OH, where the chelator group is selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 6-hydrazinonicotinic acid (HYNIC) and 2-amino-3-(1-(2-carboxyethyl)-1H-1,2,3-triazol-4-yl)propanoic acid, as well as a compound complex with one or more diagnostically or therapeutically effective radionuclides selected from Cu-62, Cu-64, Cu-67, Tc-99m, Lu-177 and Ac-225, as well as pharmaceutical compositions based on it for the diagnosis and/or treatment of a disorder involving the neurotensin 1 receptor.

EFFECT: obtaining new compounds and complexes that can be used for the diagnosis and/or treatment of a disorder involving the neurotensin 1 receptor.

11 cl, 2 tbl, 3 dwg

Description

Technical field

This invention relates to chemical compounds containing radionuclides that have activity on neurotensin receptors, which can be used in the diagnosis, treatment and prevention of a variety of conditions, and their precursors, which do not contain a radionuclide. Moreover, this invention relates to a process for the preparation of chemical compounds having such an effect, and to the medical use of these compounds in the diagnosis, treatment and prevention of a variety of conditions.

State of the art

Cancer is one of the leading causes of death worldwide. Mortality is especially high among patients suffering from cancer of the prostate, rectum and colon, pancreas, lung, bronchi and breast carcinoma. Although there has been some progress in the past few years, the development of more powerful compounds for diagnosing, treating and preventing cancer is still a high priority, and the growing number of deaths from cancer must be addressed.

Neurotensin receptors are transmembrane receptors that bind the neurotransmitter neurotensin. Among the three subtypes of the neurotensin receptor (NTS1-3), the G protein-coupled receptor NTS1 has the most suitable prerequisites to serve as a drug target (non-patent document 1). The NTS1 receptor is involved in a variety of pathophysiological processes, including neurodegenerative diseases such as schizophrenia (non-patent document 2) and Parkinson's disease (non-patent document 3). Overexpression of NTS1 has been demonstrated in various tumor types such as prostate, pancreatic, colon and small cell lung carcinoma. Selective overexpression of NTS1 in tumors, in addition to apparently low expression in corresponding healthy tissues, offers an outstanding opportunity for targeting tumors. This is supported by various publications discussing NTS1 as a biomarker for predicting various types of cancer (non-patent document 4) and providing evidence for NTS1 overexpression in multiple cell types both in vitro and in vivo (non-patent documents 5 and 6).

The ability to selectively treat tumors overexpressing NTS1 in vivo is also supported by several publications using radiolabeled agents to visualize NTS1 receptors via positron emission tomography (PET) (submitted: non-patent documents 7-9). Treatment of small cell lung cancer with a small molecule NTS1 antagonist (Meklinertant, SR48692) has failed due to lack of efficacy, demonstrating that tumor therapy by blocking NTS1 receptors with an antagonist as a mechanism of action is not successful. However, SR48692 is able to sensitize tumors for radiotherapy (non-patent document 10).

A non-peptide ¹⁸ F-labeled NTS1 indicator for PET imaging of NTS1 positive tumors is described by the present inventors (non-patent document 11), and a non-peptide SPECT indicator labeled with In-111 is described by Schulz et al. (not Patent Document 12).

The presence of dopamine receptors in pancreatic tumors has been described (Non-Patent Document 13). Therefore, radiotracers that bind to both dopamine receptors and NTS1 cannot be reliably used to study or stage NTS1 positive tumors due to an interfering signal from dopamine receptor binding.

non-patent documents

Non-Patent Document 1: Cancer Chemistry and Cell: Molecules that interact with Neurotensin receptors; Myers, Rebecca M.; Shearman, James W.; Kitching, Matthew O.; Ramos-Montoya, Antonio; Neal, David E.; Ley, Steven V.; ACS Chemical Biology (2009), 4(7), 503-525.

Non-Patent Document 2: Neurotensin, schizophrenia, and antipsychotic drug action; Kinkead, Becky; Nemeroff, Charles B.; International Review of Neurobiology (2004), 59, 327-349.

Non-Patent Document 3: Emerging evidence for neurotensin receptor 1 antagonists as novel pharmaceutics in neurodegenerative disorders; Ferraro, L.; Tomasini, M. C.; Beggiato, S.; Guerrini, R.; Salvadori, S.; Fuxe, K.; Calza, L.; Tanganelli, S.; Antonelli, T.; Mini-Reviews in Medicinal Chemistry (2009), 9(12), 1429-1438.

Non-Patent Document 4: The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers; Dupouy, Sandra; Mourra, Najat; Doan, Van Kien; Gompel, Anne; Alifano, Marco; Forgez, Patricia.; Biochimie (2011), 93(9), 1369-1378.

Non-Patent Document 5: Prostate cancer targeting motifs: Expression of α _ν β ₃ , neurotensin receptor 1, prostate specific membrane antigen, and prostate stem cell antigen in human prostate cancer cell lines and xenografts; Taylor, Robert M.; Severns, Virginia; Brown, David C.; Bisoffi, Marco; Sillerud, Laurel O.; Prostate (2012), 72(5), 523-532.

Non-Patent Document 6: Altered Expression of Neurotensin receptors Is Associated with the Differentiation State of Prostate Cancer; Swift, Stephanie L., Burns, Julie E., Maitland, Norman J.; Cancer Research (2010), 70(1), 347-356.

Non-Patent Document 7: Synthesis of a ⁶⁸ Ga-Labeled Peptoid-Peptide Hybrid for Imaging of Neurotensin receptor Expression in Vivo; Maschauer, Simone; Einsiedel, Jurgen; Hocke, Carsten; Hübner, Harald; Kuwert, Torsten; Gmeiner, Peter; Prante, Olaf; ACS Medicinal Chemistry Letters (2010), 1(5), 224-228.

Non-Patent Document 8: [ ^99m Tc] Demotensin 5 and 6 in the NTS1-R-targeted imaging of tumors: synthesis and preclinical results; Maina, Theodosia; Nicolopoulou, Anastasia; Stathopoulou, Eleni; Galanis, Athanassios S.; Cordopatis, Paul; Nock, Berthold A; European Journal of Nuclear Medicine and Molecular Imaging (2007), 34(11), 1804-1814.

Non-Patent Document 9: ¹⁸ F- and ⁶⁸ Ga-labeled Neurotensin Peptides for PET Imaging of Neurotensin receptor 1; Maschauer S., Einsiedel J., Hübner H., Gmeiner P., Prante O.; Journal of Medicinal Chemistry (2016).

Non-Patent Document 10: Inhibition of Neurotensin receptor 1 Selectively Sensitizes Prostate Cancer to Ionizing Radiation; Valerie, Nicholas C. K.; Casarez, Eli V.; DaSilva, John O.; Dunlap-Brown, Marya E.; Parsons, Sarah J.; Amorino, George P.; Dziegielewski, Jaroslaw; Cancer Research (2011), 71(21), 6817-6826.

Non-Patent Document 11: Synthesis and Evaluation of a ¹⁸ F-Labeled Diarylpyrazole Glycoconjugate for the Imaging of NTS1-Positive Tumors; Lang, Christopher; Maschauer, Simone; Hübner, Harald; Gmeiner, Peter; Prante, Olaf; Journal of Medicinal Chemistry (2013), 56(22), 9361-9365.

Non-Patent Document 12: Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications; Schulz, J., Rohracker, M., Stiebler, M., Goldschmidt, J., Grosser, O., Osterkamp, F., Pethe, A., Reineke, U., Smerling, C., and Amthauer, H. ; Journal of Nuclear Medicine (2016), 57, 1120-1123.

Non-Patent Document 13: The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumors opens new therapeutic strategies; O'Toole, D., Saveanu, A., Couvelard, A., Gunz, G., Enjalbert, A., Jaquet, P., Ruszniewski, P., Barlier, A.; European Journal of Endocrinology (2006), 155, 849-857.

The essence of the invention

This invention relates to compounds of formula (I) containing a non-peptidic NTS1 antagonist and a chelator that is associated with the antagonist.

In view of the problems of the prior art, the object of this invention is the development of radiopharmaceuticals that show low binding to dopamine receptors and improved selectivity for NTS1. The present inventors have developed novel compounds that overcome these problems and exhibit improved selectivity for NTS1 receptors over dopamine receptors. This increased selectivity not only confers more efficient action, but also allows the diagnosis and imaging of NTS1-positive tumors, for example, by reducing interference caused by dopamine receptor binding.

The present inventors have surprisingly found that the triazolyl group reduces the affinity of these compounds for dopamine receptors and results in increased inhibition of tumor growth in vivo compared to the corresponding amide analogues.

Moreover, the compounds of the present invention exhibit subnanomolar affinity for NTS1, low affinity for dopamine receptors, selective ligand concentration in tumors overexpressing NTS1, rapid clearance from healthy tissues, and high uptake in the tumor resulting in a high dose of delayed radioactivity in the tumor. with concomitant acceptable doses in healthy tissues.

Brief description of the drawings

In FIG. 1 shows the accumulation of radioactivity in NTS1 receptor positive tumors (HT29, PC3, AsPC1) which is high at 24 and 48 h after injection with excellent retention in the tumor over time, while uptake in non-target tissue (e.g. blood , liver and bones) was significantly lower and a fast elimination rate was demonstrated.

In FIG. 2 shows the results of a therapy study using PC3 xenograft nude mice treated with ¹⁷⁷ Lu-14 (group B) or saline (control, group A). Left: Evolution of tumor size (tumor diameter) normalized on the day of initiation of therapy. Right: Survival curves of ¹⁷⁷ Lu-14 treated animals compared to untreated controls. The arrow indicates the start of radiotherapy.

In FIG. 3 shows data from the FAUC Lu469 endoradiotherapy experiment in nude mice bearing an AsPC-1 pancreatic tumor. Single dose administration (Group B, 1x28 MBq/animal) versus double dose administration (Group C, 2x29 MBq/animal) and untreated control animals (Group A).

Definitions

As used herein, the term "alkyl" refers to a monovalent saturated acyclic (ie, non-cyclic) hydrocarbon group, which may be linear or branched. Therefore, the "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. "C _1-6 alkyl" means an alkyl group having 1-6 carbon atoms. Preferred exemplary alkyl groups include methyl, ethyl, propyl (eg n-propyl or isopropyl) or butyl (eg n-butyl, isobutyl, sec-butyl or t-butyl).

As used herein, the term "alkylene" refers to an alkanediyl group, ie. divalent saturated acyclic hydrocarbon group, which may be linear or branched. "C _1-3 alkylene" means an alkylene group having 1-3 carbon atoms. Preferred exemplary alkylene groups include methylene (-CH ₂ -), ethylene (eg -CH ₂ -CH ₂ - or -CH(-CH ₃ )-), or propylene (eg -CH ₂ -CH ₂ -CH ₂ -, -CH(-CH ₂ -CH ₃ )-, -CH ₂ -CH(-CH ₃ )- or -CH(-CH ₃ )-CH ₂ -).

As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group, including monocyclic rings, as well as a bridged ring, a spiro ring, and/or fused ring systems (which may consist of, for example, two or three rings; such as, for example, a fused ring system , consisting of two or three condensed rings). "Cycloalkyl", for example, may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl.

"Halogen" means F, Cl, Br and I, more preferably F or Cl, even more preferably F.

The term "heteroarylene" refers to a divalent five- or six-membered aromatic ring where one or more carbon atoms in the ring is substituted by 1, 2, or 3 identical or different heteroatoms selected from N, O, and S. Examples of the heteroarylene group include furan, thiophene, pyridine , pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine, and the like.

As used herein, the terms "optional", "optional", and "may" mean that the specified feature may or may not be present. When the term "optional", "optional", or "maybe" is used, the present invention specifically refers to both probabilities, ie. the corresponding characteristic is present or, alternatively, that the corresponding characteristic is absent. For example, the expression "X is optionally substituted by Y" (or "X may be substituted by Y") means that X is either substituted by Y or not. Also, if a component of a composition is listed as "optional", the invention specifically refers to both probabilities, ie, that the corresponding component is present (contained in the composition), or that the corresponding component is not present in the composition.

When a compound or group is designated as "optionally substituted" it may in each instance include one or more of the indicated substituents, where the substituents may be the same or different.

The term "pharmaceutically acceptable salt" refers to a salt of a compound in accordance with this invention. Suitable pharmaceutically acceptable salts include acid addition salts which, for example, may be formed by mixing a solution of the compounds of this invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carboxylic acid or phosphoric acid. Moreover, if the compound has an acidic group, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (eg sodium or potassium salts); alkaline earth metal salts (eg calcium or magnesium salts); and salts with suitable organic ligands (eg, ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrite, alkylsulfonate, and arylsulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride. , citrate, clavulanate, cyclopentane propionate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hex ilresorcinate, hydrabamine, hydrobromide , hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, almond, mesylate, methanesulfonate, methyl sulfate, mukat, 2-naphthalenesulfonate, napsilate, nicotinate, nitrate, ammonium N-methylglucamine salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, undecanoate, valerate and the like (see, for example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sc., 66, pp. 1-19 (1977)).

Detailed description of the invention

This invention relates to a compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, ester of a polymorph, tautomer, racemate, enantiomer, diastereomer, or mixtures thereof.

In the compound of formula (I), R ¹ is selected from the group consisting of -hydrogen, -(C _1-6 alkyl), -(C _3-6 cycloalkyl) and -(C _1-3 alkylene-C _3-6 cycloalkyl), where C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkylene and C _3-6 cycloalkyl in (C _1-3 alkylene-C _3-6 cycloalkyl) may be substituted with one or more halogen atoms. R ¹ is preferably -(C _1-3 alkyl) or -CH ₂ -cyclopropyl. R ¹ is more preferably -(C _1-3 alkyl).

R ² is selected from -hydrogen, -halogen, nitro, -(C _1-6 alkyl), -(C _3-6 cycloalkyl) and -(C _1-3 alkylene-C _3-6 cycloalkyl), where C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkylene and C _3-6 cycloalkyl in (C _1-3 alkylene-C _3-6 cycloalkyl) may be substituted with one or more halogen atoms. R ² is preferably -halogen, nitro or -(C _1-6 alkyl), where C _1-6 alkyl is optionally substituted with one or more fluorine. R ² is more preferably -(C _1-6 alkyl).

R ³ is selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-aminobicyclo[3.3.1]nonane-9-carboxylic acid. R ³ is preferably a group having the following formula

Group Z

Z can be any group that contains a chelator. Preferably, Z in formula (I) does not contain a radionuclide as defined in this invention, unless otherwise indicated.

Z preferably contains a linker group and a chelator group. More preferably, Z is -(linker group)-(chelator group). The linker group and the chelator group are preferably as defined below.

.The Z group may also contain one or two or three groups from the following specific structure:

.

In these particular structures, the definitions of R ¹ , R ² and R ³ are independently as defined above for formula (I). If the Z group contains such substructures, the compound of formula (I) forms a multimeric structure that potentially exhibits improved avidity for the neurotensin receptor, probably due to the accumulated strength of multiple affinities of more than one non-covalent binding interaction with the receptor. The most important beneficial effects of such a multimeric structure may include improved uptake by the tumor in vivo, as well as significantly improved retention in the tumor and hence improved imaging and therapeutic properties compared to monomers.

Linker group

Linker groups, which are also generally referred to as spacers, are groups that separate two parts of a molecule. In the present invention, the linker group forms covalent bonds with both chelator groups and the part of the structure of formula (I) that is different from Z. The linker group can in principle be any chemical group that is capable of forming bonds with both chelator groups and the part of the structure of formula (I) , which is different from Z. Preferably, the linker group does not itself bind to the neurotensin receptor. Preferably, the linker group contains only atoms selected from H, B, C, N, O, F, Si, P, S, Cl, Br and I, which are preferably different from the radionuclides defined here.

Examples of linker groups that can be used in accordance with this invention contain one or more groups selected from -N(R ⁴ )-, -C _1-10 alkylene-, -C(O)-, -O-, -heteroarylene -, -phenylene-, -S-, -S(O)- and -S(O) ₂ -,

where each R ⁴ is independently selected from hydrogen and C _1-6 alkyl,

each C _1-10 alkylene is independently optionally substituted with one or more selected from halo, C(O)OH and OH,

each heteroarylene is independently a 4-6 membered heteroarylene containing 1-3 heteroatoms selected from N, O and S, and the heteroarylene is optionally substituted with one or more selected from halogen and C _1-6 alkyl, and

each phenylene is optionally substituted with one or more selected from halo and C _1-6 alkyl.

Moreover, the linker group may contain one or two or three side chains, which can be attached to the main chain of the linker group by replacing one or two or three hydrogen residues, preferably in the -C _1-10 alkylene group, in the main chain of the linker group with side chains. chains. Such side chains may contain 1-10, preferably 1-8 groups selected from -N(R ⁴ )-, -C _1-10 alkylene-, -C(O)-, -O-, -heteroarylene-, - phenylene-, -S-, -S(O)- and -S(O) ₂ -, and end in -H, where the definitions of R ⁴ and optional substituents of other groups are as defined for the main chain of the linker group.

The linker group preferably consists of one or more groups selected from -N(R ⁴ )-, -C _1-10 alkylene-, -C(O)-, -O-, -heteroarylene-, -phenylene-, -S- , -S(O)- and -S(O) ₂ -.

In the present invention, it is preferred that the linker group contains or consists of 3-15, more preferably 3-12, even more preferably 3-10, and most preferably 4-8 of the above groups.

Moreover, as will be apparent to one skilled in the art, the two adjacent groups in the linker group must be chosen to avoid direct bonding between the two groups, which can result in a substructure that is not stable, particularly in an aqueous environment at 25°C and pressure. 1 atm. From this point of view, combinations such as -N(R ⁴ )-N(R ⁴ )-, -C(O)-C(O)-, -OO-, -SS-, -S(O)-S (O)-, -S(O) ₂ -S(O) ₂ -, -N(R ⁴ )-O-, -ON(R ⁴ )-, -N(R ⁴ )-S-, -SN( R ⁴ )-, -N(R ⁴ )-S(O)-, -S(O)-N(R ⁴ )-, -C(O)-S-, -SC(O)-, -C( O)-S(O)-, -S(O)-C(O)-, -C(O)-S(O) ₂ -, -S(O) ₂ -C(O)-, -SO- , -OS-, -S(O)-O-, -OS(O)-, -S(O)-S-, -SS(O)-, -S(O) ₂ -S-, -SS( O) ₂ -, S(O) ₂ -S(O)- and -S(O)-S(O) ₂ - are preferably excluded.

Moreover, it is preferred that the combinations -C _1-10 alkylene-C _1-10 alkylene-, -heteroarylene-heteroarylene- and -phenylene-phenylene- are also excluded.

An example of a side chain of a linker group that is of particular interest in this invention is the following:

This group has been found to bind well to albumin and can be used to increase the plasma half-life and bioavailability of certain compounds (Angew. Chem., Int. Ed. 2008, 47(17) 3196-3201).

A more preferred class of linker groups is represented by -(X) _p - where p is an integer from 1 to 10. Preferably, p is an integer from 1 to 8, 1 to 6, 1 to 5, 1 to 4, or from 1 to 3.

Each X is preferably independently selected from

(a) -(N(R ⁴ )-C _1-10 alkylene),

(b) -(N(R ⁴ )-heteroarylene)-,

(c) -(N(R ⁴ )-C(O))-,

(d) -(OC _1-10 alkylene)-,

(e) -(O-heteroarylene)-,

(f) -(O-C(O))-,

(g) -(C _1-10 alkyleneheteroarylene)-,

(h) -(C _1-10 alkylene-C(O))-,

(i) -(C(O)-C _1-10 alkylene)-,

(j) -(C(O)-heteroarylene)-,

(k) -(heteroarylene-C _1-10 alkylene)-,

(l) -(heteroarylene-C(O))-, and

(m) -(C _1-10 alkylene)-.

In each X, C _1-10 alkylene is independently optionally substituted with one or more selected from halo, C(O)OH and OH.

In each X, heteroarylene is a 4-6 membered heteroarylene containing 1-3 heteroatoms selected from N, O and S, and the heteroarylene is optionally substituted with one or more selected from halogen and C _1-6 alkyl.

Each R ⁴ is independently selected from hydrogen and C _1-6 alkyl.

Particularly preferred linker groups are selected from

(i) -C _1-10 alkylene-N(R ⁴ )-C _1-10 alkylene-N(R ⁴ )-C(O)-C _1-10 alkylene-N(R ⁴ )-,

(ii) -C _1-10 alkylene-N(R ⁴ )-C _1-10 alkylene-heteroarylene-C _1-10 alkylene-C(O)-C _1-10 alkylene-N(R ⁴ )-, and

(iii) -C _1-10 alkylene-N(R ⁴ )-C _1-10 alkylene-N(R ⁴ )-.

In these preferred examples, each C _1-10 alkylene is independently optionally substituted with one or more selected from halo, C(O)OH and OH. Heteroarylene is a 4-6 membered heteroarylene containing 1-3 heteroatoms selected from N, O and S, and the heteroarylene is optionally substituted with one or more selected from halogen and C _1-6 alkyl. Each R ⁴ is independently selected from hydrogen and C _1-6 alkyl. Preferably, each R ⁴ is independently selected from H, methyl, ethyl, n-propyl, and iso-propyl.

Chelation group

A chelator group is a group capable of bonding with and/or complexing with a metal ion to form a heterocyclic ring containing the metal ion. The metal ion includes metal ions, which are defined as radionuclides. Preferably, the chelator group contains only atoms selected from H, B, C, N, O, F, Si, P, S, Cl, Br and I, which are preferably different from the radionuclides defined here.

Such chelators are known to the person skilled in the art. A variety of relevant chelators are available and summarized by Banerjee et al. (Banerjee et al., Nucl. Med. Biol., 2005, 32, 1-20 and references therein, Wadas et al., Chem. Rev., 2010, 110, 2858-2902 and references therein). Such chelators include, but are not limited to, linear, macrocyclic, tetrapyridine, N ₃ S, N ₂ S ₂ and N ₄ chelators as described in US 5,367,080 A, US 5,364,613 A, US 5,021,556 A, US 5,075,099 A and US 5,886,142 A .

Other examples of suitable chelators are described in US 5,720,934 and Doulias et al. (Doulias et al., Free Radio. Biol. Med., 2003, 35, 719-728).

The diagnostic and/or therapeutic use of some of the above chelators is described in the prior art. For example, 2-hydrazinonicotinamide (HYNIC) is widely used in the presence of a solvent to introduce ^99m Tc and ^186,188 Re (Schwartz et al., Bioconj. Chem., 1991, 2, 333-336; Babich et al., J. Nucl. Med. , 1993, 34, 1964-1970; Babich et al., Nucl. Med. Biol., 1995, 22, 25-30). DTPA is used in Octreoscan® (Covidien) to form complexes with ¹¹¹ In, and some modifications are described in the literature (Brechbiel et al., Bioconj. Chem., 1991, 2, 187-194; Li et al., Nucl Med. Biol, 2001, 28, 145-154). Chelators of the DOTA type are described for use in radiotherapy by Tweedle et al. (US 4,885,363). Certain polyazamacrocycles for chelation of trivalent metal isotopes are described in Maecke et al. (Maecke et al., Bioconj. Chem., 2002, 13, 530-541). N ₄ chelators such as ^{the 99m} Tc-N ₄ chelator are used for peptide labeling in the case of minigastrin to target CCK-2 receptors (Nock et al., J. Nucl Med., 2005, 46, 1727-1736) .

Metal chelators for trivalent metals or pentavalent metals and their closely related analogues are, for example, described in WO 2009/109332 A1. The use of the above chelators for divalent and tetravalent radionuclides is described (Dalton Transactions 44.11 (2015), 4845-4858; Journal of Labeled Compounds and Radiopharmaceuticals 57.4 (2014), 224-230; Nuclear Medicine and Biology 40.1 (2013 ), 3-14; and Chemical Society Reviews 43.1 (2014), 260-290).

N'-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide ( DFO) has been described as a particularly preferred chelator for Zr radionuclides (Nuclear Medicine and Biology 40.1 (2013), 3-14).

The chelating group is preferably - (a hydrocarbon group which contains 8-40 carbon atoms, 2-12 nitrogen atoms and optionally 1-10 oxygen atoms and/or optionally 1-5 sulfur atoms and/or optionally 1- 5 phosphorus atoms).

Preferred examples of chelating groups contain at least two groups selected from carboxylic acid, phosphinic acid, phosphonic acid and hydroxylamine.

Preferred examples of chelating groups are selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 2,2',2''-(1,4,7-triazonan-1, 4,7-triyl)triacetic acid (NOTA), 1,4,7-triazacyclononane-1,4-diacetic acid (NODA), N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine -N,N'-diacetic acid (HBED-CC), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA), diethylenetriaminepentaacetic acid (DTPA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl }amino)pentyl]-N-hydroxysuccinamide (DFO), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), ethylenediamine-N,N'-tetraacetic acid (EDTA), 1,4,7-triazacyclononane-N-glutaric acid-N',N"-diacetic acid (NODAGA), 1,4,7-triazacyclononan-1-succinic acid-4,7-diacetic acid (NODASA), 1, 4,7,10 tetraazacyclotridecane-1,4,7,10-tetraacetic acid (TRITA), trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA), 1-[2- (2-mercapto-2-methylpropylamino)ethylamino]-2-methylpropan-2-thiol (BAT), 6-hydrazinonicotinic acid (HYNIC), 1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphine acid]-7-[methylene(2-carboxyethyl)phosphinic acid] and 1,4,7-triazacyclononanephosphinic acid.

These chelator groups may be attached to the linker groups in any manner. For example, the chelator group may be attached to the linker group through a nitrogen atom in the heterocyclic ring or chain of the chelator group, or through a carboxylic acid in one of the side chains of the chelator group.

Certain chelating groups can be described by the following partial formula

where T is -[(CR ⁵ ₂ ) _m (NR ⁶ )] _q (CR ⁵ ₂ ) _m -.

Although the bond is depicted on the nitrogen atom in the ring, such chelating groups can also be linked to the remainder of the compound of formula (I) through other groups of the chelating group, for example, through side chains.

Each R ⁵ is independently selected from -hydrogen, -halogen, -OH, -C _1-6 alkyl, and -OC _1-6 alkyl. Preferably, each R ⁵ is -hydrogen.

Each R ⁶ is independently selected from -hydrogen, -C _1-6 alkyl, -(C _1-6 alkylene)-COOH, -(C _1-3 alkylene)-P(O)(OH)-(C _1-3 alkylene )-COOH and -(C _1-3 alkylene)-P(O)(OH)-(C _1-3 alkylene)-OH. Preferably, each R ⁶ is C _1-3 alkylene-COOH.

Each m is independently an integer from 1 to 4. Preferably, each m is 2 or 3.

q is an integer from 3 to 5. Preferably, q is 3.

Radionuclide

Radionuclides are isotopes of elements in the periodic table that are considered unstable. The core of such radionuclides typically emits electromagnetic radiation, such as γ-rays, or small particles, such as α- or β-radiation. In the present invention, radionuclides are preferably isotopes of elements of the periodic table that have a half-life of less than 10 ²² years, more preferably less than 10 ¹⁰ years, even more preferably less than 10 ⁵ years, even more preferably less than 100 years, most preferably less than 1 of the year. Some preferred radionuclides have a half-life of less than one week.

In the present invention, the radionuclide is preferably selected from F-18, P-32, P-33, Sc-44, Sc-47, Cr-51, Fe-52, Fe-59, Mn-51, Mn-52m, Co-55 , Co-57, Co-58, Cu-62, Cu-64, Cu-67, Ga-67, Ga-68, As-72, Se-75, As-77, Br-76, Br-75, Br -77, Br-80m, Br-82, Rb-82m, Sr-83, Sr-89, Y-86, Y-90, Zr-89, Mo-99, Tc-94m, Tc-99m, Ru-97 , Rh-103m, Rh-105, Pd-109, Pt-109, Ag-111, In-110, In-111, In-113m, In-114m, Sb-119, Sn-121, Te-127, I -120, I-123, I-124, I-125, I-129, I-131, Pr-142, Pr-143, Pm-149, Pm-151, Sm-153, Dy-152, Dy-166 , Gd-157, Gd-159, Ho-161, Tb-161, Ho-166, Er-169, Tm-172, Yb-169, Yb-175, Lu-177, Lu-177m, Re-186, Re -188, Re-189, Rd-188, Os-189m, Ir-192, Ir-194, Au-198, Au-199, Hg-197, Tl-201, Pb-203, Pb-211, Pb-212 , Bi-211, Bi-212, Bi-213, At-211, At-217, Po-215, Ra-223, Rn-219, Fr-221, Ac-225, Th-227 and Fm-255.

More preferably, the radionuclide is selected from P-32, P-33, Sc-44, Sc-47, Co-58, Fe-59, Cu-64, Cu-67, Ga-67, Ga-68, Se-75, As-77, Br-80m, Sr-89, Zr-89, Y-90, Mo-99, Rh-103m, Rh-105, Pd-109, Pt-109, Ag-111, In-111, Sb- 119, Sn-121, I-123, I-125, I-129, I-131, Te-127, Pr-142, Pr-143, Pm-149, Pm-151, Dy-152, Dy-166, Sm-153, Gd-159, Tb-161, Ho-161, Ho-166, Er-169, Tm-172, Yb-169, Yb-175, Lu-177, Lu-177m, Re-186, Re- 188, Rd-188, Re-189, Os-189m, Ir-192, Ir-194, Au-198, Au-199, At-211, Pb-211, Pb-212, Bi-211, Bi-212, Bi-213, Po-215, At-217, Rn-219, Ra-223, Fr-221, Ac-225, Th-227 and Fm-255.

Even more preferably, the radionuclide is selected from Lu-177, Y-90, Cu-64, Ga-67, Ga-68, Sc-44, Zr-89 and In-111.

In the present invention, the radionuclide is usually reacted with a compound of formula (I) in the form of a salt of the radionuclide. These salts include a radionuclide ion and at least one additional ion. If the radionuclide is a cation, one of the other ions is an anion which, for example, can be selected from acetate, bicarbonate, bromide, carbonate, chlorate, chloride, dihydrogen phosphate, fluoride, hydrogen phosphate, hydrogen sulfate, hydroxide, iodide, nitrate, nitride, nitrite, phosphate, sulfate, sulfide and sulfite. If the radionuclide is an anion, one of the other ions is a cation which, for example, can be selected from ammonium, lithium, sodium, magnesium, aluminium, potassium, calcium and gallium. Examples of such salts include Lu(NO ₃ ) ₃ , Y(NO ₃ ) ₃ , Cu(NO ₃ ) ₂ , Ga(NO ₃ ) ₃ , Zr(NO ₃ ) ₄ , In(NO ₃ ) ₃ , LuCl ₃ , YCl ₃ , CuCl ₂ , GaCl ₃ , ZrCl ₄ and InCl ₃ .

Methods for preparing compounds of formula (I) without radionuclide

Compounds according to the invention having structure C can be prepared by reacting compound A with an activated derivative of chelator B in the presence of a solvent and a base. Examples of activated derivatives of the carboxyl group in typical acylation reactions are described in the literature (for example, in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Activated esters can be prepared in situ, for example by adding HOBt (1-hydroxybenzotriazole) or N-hydroxysuccinimide.

Preferred solvents are selected from the group of dioxane, tetrahydrofuran, dimethylformamide and acetonitrile. The reaction is usually carried out under an inert atmosphere. Preferred bases are selected from triethylamine and diisopropylethylamine. The reaction may be carried out at 20°C to 90°C, preferably at 30°C, for 1 to 48 hours, preferably 24 hours. The group shown as "activated" may be O-succinimide, acid halide or acid anhydride . The variable n1 is from 1 to 10.

Compounds of structure F can be prepared by reacting compound D with an azide-derived chelator E in the presence of a solvent, a source of copper, and a reducing agent.

Preferred solvents are selected from the group of tetrahydrofuran, dimethylformamide and t-butanol with or without the addition of water. The reaction is usually carried out under an inert atmosphere and a copper source such as CuSO ₄ , CuI, copper on carbon or Cu(OAc) ₂ is added. The reaction is carried out in the presence or absence of a reducing agent, which is preferably ascorbic acid. The reaction temperatures range from 20°C to 90°C, preferably from 25°C to 35°C. A typical reaction time is 1-48 hours, preferably about 24 hours. The variables n2 and n3 are independently 1 to 10.

Compounds of structures D and E can be obtained by methods described in the literature (Efficient Synthesis of Heterocyclic Neurotensin receptor Ligands by Microwave Assisted Aminocarbonylation, Christopher Lang and Peter Gmeiner, Synthesis (2013); and "Click" chemistry towards bis (DOTA-derived) heterometallic complexes : potential bimodal MRI/PET (SPECT) molecular imaging probes." Suchý, Mojmír, Robert Bartha, and Robert HE Hudson, RSC Advances 3,10 (2013): 3249-3259; a recent review of CuAAC chemistry applied to metal chelating systems, see: H. Struthers, TL Mindt and R. Schibli, Dalton Trans. , 2010, 39 , 675).

Compounds of structure K can be prepared by reacting compound G with an azide-derived chelator H in the presence of a solvent, a source of copper, and a reducing agent.

Preferred solvents are selected from the group of tetrahydrofuran, dimethylformamide and t-butanol with or without the addition of water. The reaction is usually carried out under an inert atmosphere and a copper source such as CuSO ₄ , CuI, copper on carbon or Cu(OAc) ₂ is added. The reaction is carried out in the presence or absence of a reducing agent, which is preferably ascorbic acid. The reaction temperatures range from 20°C to 90°C, preferably from 25°C to 35°C. A typical reaction time is 1-48 hours, preferably 24 hours.

Other examples of reactions that can be used to prepare compounds of formula (G) are described in non-patent document 11 and in "Efficient Synthesis of Heterocyclic Neurotensin receptor Ligands by Microwave Assisted Aminocarbonylation" by Lang, C. and Gmeiner, P., Synthesis 2013, 45, 2474-2480).

The Sonogashira reaction is discussed in "A Booming Methodology in Synthetic organic Chemistry" by Chinchilla, R. and Najera, C. in Chem. Rev., 2007, 107(3), 874-922.

Methods for reacting compounds of formula (I) with a radionuclide

The invention also relates to a process comprising reacting a compound of formula (I) according to the invention with one or more diagnostically or therapeutically effective radionuclides to form a complex of a compound of formula (I) with one or more diagnostically or therapeutically effective radionuclides.

This reaction is preferably carried out in a solvent containing water, which may also contain a buffer. The buffer is preferably 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid or sodium acetate.

In the process according to the invention, the pH of the solution in which the reaction is carried out is preferably in the range of 2 to 7, more preferably 4 to 6, and most preferably 4.5 to 5.5. Moreover, the reaction is preferably carried out at a temperature in the range of 20°C to 100°C, more preferably 50°C to 98°C, and most preferably 85°C to 95°C.

The reaction is preferably carried out for 5 to 30 minutes, more preferably 7 to 15 minutes, most preferably 8 to 12 minutes.

This type of synthesis is described in the literature ("Syntheses, Receptor Bindings, in vitro and in vivo Stabilities and Biodistributions of DOTA-Neurotensin(8-13) Derivatives Containing Beta-Amino Acid Residues - A Lesson about the Importance of Animal Experiments" by Sparr, Christof; Purkayastha, Nirupam; Yoshinari, Tomohiro; Seebach, Dieter; Maschauer, Simone; Prante, Olaf; Hübner, Harald; Gmeiner, Peter; Kolesinska, Beata; Cescato, Renzo; Waser, Beatrice; and Claude Reubi, Jean; Biodiversity 2013 , 10, 2101-212; " ¹⁸ F- and ⁶⁸ Ga-labeled Neurotensin Peptides for PET Imaging of Neurotensin receptor 1" by Maschauer, Simone; Einsiedel, Juergen; Hübner, Harald; Gmeiner, Peter; and Prante. Olaf; J. Med. Chem. 2016, in press)

Moreover, such reactions are summarized in numerous reviews (Brasse, David, and Aline Nonat; "Radiometals: towards a new success story in nuclear imaging?"; Dalton Transactions 44.11 (2015): 4845-4858; Cai, Zhengxin, and Anderson, CJ; "Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals"; Journal of Labelled Compounds and Radiopharmaceuticals 57.4 (2014): 224-230; Deri, Melissa A., et al.; "PET imaging with ⁸⁹ Zr: from radiochemistry to the clinic"; Nuclear Medicine and Biology 40.1 (2013): 3-14; Price, Eric W., and Orvig, C.; "Matching chelators to radiometals for radiopharmaceuticals"; Chemical Society Reviews 43.1 (2014): 260-290).

Compositions, complexes and sets

The invention also relates to a complex obtainable by the process of the invention, optionally in the form of a pharmaceutically acceptable salt, solvate, ester, polymorph, tautomer, racemate, enantiomer or diastereomer, or a mixture thereof.

In complexes in accordance with this invention, at least one type of radionuclide is associated with and/or forms a complex with the compound of formula (I). Such binding and/or complexation is usually achieved by interaction between the chelator group and the radionuclide.

The invention also relates to a composition or complex containing a compound according to the invention, optionally in the form of a pharmaceutically acceptable salt, solvate, ester, polymorph, tautomer, racemate, enantiomer or diastereomer or salt thereof, and one or more diagnostically or therapeutically effective radionuclides.

This invention also relates to a pharmaceutical composition, where the composition contains (i) a compound, composition or complex in accordance with this invention and, optionally, (ii) a pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients for use in pharmaceutical compositions contain one or more bulking agents, carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility improvers. Preferred excipients are antioxidants and solubility improvers.

The diluent is preferably an injection buffer, which may be, for example, phosphate buffer. Moreover, the diluent may include saccharides, including monosaccharides, disaccharides, polysaccharides, and sugar alcohols such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, and derivatives thereof.

Injectable solutions of the compounds, compositions and complexes according to the invention may be formulated in saline or isotonic buffers, for example with a maximum ethanol content of 10%. A preferred example of a stabilizer is gentisic acid (2,5-dihydroxybenzoic acid). Sodium ascorbate is preferably added as an antioxidant.

The invention also provides kits containing a compound of formula (I) and one or more radionuclides. Examples of radionuclides are described above.

Disorders Which Can Be Treated, Diagnosed, or Prevented by the Compounds of the Invention

This invention also relates to the use of the compounds, compositions or complexes described herein in medicine, in particular for use in the diagnosis, treatment or prevention of a disorder.

A variety of disorders can be diagnosed, treated or prevented with the compounds of this invention, including tumors and hematological malignancies. Disorders involving the neurotensin receptor are preferred. More preferably, the disorder is a disorder involving the neurotensin 1 receptor.

Specific examples of cancer-related disorders include prostate cancer, lung cancer, thyroid cancer, pancreatic cancer, colon cancer, rectal cancer, pituitary cancer, and breast cancer.

When the compounds of this invention are in crystalline form, the structure may contain solvent molecules. Solvents are usually pharmaceutically acceptable solvents and include, among others, water (hydrates) or organic solvents. Examples of possible solvates include ethanolates and iso-propanolates.

Moreover, the scope of the invention covers compounds of formula (I) in any solvated form, including, for example, solvates with water, for example hydrates, or with organic solvents, such as, for example, methanol, ethanol or acetonitrile, i.e. in the form of methanolate, ethanolate or acetonitrile, respectively, or in the form of any polymorph. It is to be understood that such solvates of compounds of formula (I) also include solvates of pharmaceutically acceptable salts of compounds of formula (I).

Moreover, the compounds of formula (I) may exist in the form of various isomers, in particular stereoisomers (including, for example, geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds of formula (I) are considered to be part of this invention, either in admixture or in pure or substantially pure form. For stereoisomers, the invention encompasses the isolated optical isomers of the compounds of this invention, as well as any mixtures thereof (including, in particular, racemic mixtures/racemates). Racemates can be separated by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can also be obtained from racemates via salt formation with an optically active acid followed by crystallization. This invention also covers any tautomers of the compounds presented here.

The scope of the invention also covers compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention covers compounds of formula (I) in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (ie ² H; also referred to as "D").

The compounds provided herein may be administered as compounds per se or may be formulated as medicaments. Drugs/pharmaceutical compositions may optionally contain one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and/or solubility improvers.

Moreover, the compounds provided herein may be administered as a single dose or, preferably, as multiple doses.

In particular, pharmaceutical compositions may contain one or more solubility improvers such as, for example, poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range from about 200 to about 5000 Da, ethylene glycol, propylene glycol, non-ionic surfactants. active substances, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β -cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β -cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkylthioethers, hydroxypropylmethylcellulose, hydroxypropylcellulose , polyvinylpyrrolidone, vinyl acetate copolymers, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

Pharmaceutical compositions may be formulated by methods known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, ^22nd edition.

Compounds of formula (I) or pharmaceutical compositions as described above containing a compound of formula (I) may be administered to a subject by any convenient route of administration, systemically/peripherally or at the site of desired action. Parenteral administration is preferred. It includes, for example, the use of injection methods or infusion methods, and includes, for example, injection, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular , subarachnoid or intrasternal, most preferably intravenous injection.

When the compounds or pharmaceutical compositions are administered parenterally, the compounds are best administered in the form of a sterile aqueous solution which may contain other substances, such as sufficient salts or glucose, to render the solution isotonic with blood. Aqueous solutions should be suitably buffered (preferably to pH 3-9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard (radio)pharmaceutical techniques well known to those skilled in the art.

This description cites a variety of documents, including patent applications and scientific literature. The description of these documents, although not considered relevant to the patentability of this invention, is incorporated here by reference in its entirety. More specifically, all referenced documents are incorporated herein by reference to the same extent as if each individual document were specifically and individually identified for inclusion herein as a reference.

The present invention can be summarized in the following paragraphs 1-36:

(1) A compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, ester, polymorph, tautomer, racemate, enantiomer, diastereomer, or mixture thereof

Where

R ¹ is selected from the group consisting of -hydrogen, -(C _1-6 alkyl), -(C _3-6 cycloalkyl) and -(C _1-3 alkylene-C _3-6 cycloalkyl), where C _1-6 alkyl , C _3-6 cycloalkyl and C _1-3 alkylene and C _3-6 cycloalkyl in (C _1-3 alkylene-C _3-6 cycloalkyl) may be substituted with one or more halogen atoms,

R ² is selected from -hydrogen, -halogen, nitro, -(C _1-6 alkyl), -(C _3-6 cycloalkyl) and -(C _1-3 alkylene-C _3-6 cycloalkyl), where C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkylene and C _3-6 cycloalkyl in (C _1-3 alkylene-C _3-6 cycloalkyl) may be substituted with one or more halogen atoms,

R ³ is selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-aminobicyclo[3.3.1]nonane-9-carboxylic acid, and

Z contains a chelator group.

(2) The compound of formula (I) according to item 1, wherein R ¹ is -(C _1-3 alkyl).

(3) The compound of formula (I) according to item 1 or 2, where R ² is -(C _1-6 alkyl).

(4) The compound of formula (I) according to any one of paragraphs 1-3, where R ³ is

.

.

(5) The compound of formula (I) according to any one of 1-4, wherein the chelator group is -(hydrocarbon group which contains 8-40 carbon atoms, 2-12 nitrogen atoms, and optionally 1-10 oxygen atoms and/or , optionally 1-5 sulfur atoms and/or optionally 1-5 phosphorus atoms).

(6) The compound of formula (I) according to any one of 1 to 5, wherein the chelator group contains at least two groups selected from carboxylic acid, phosphinic acid, phosphonic acid, and hydroxylamine.

(7) The compound of formula (I) according to any one of items 1-6, where the group Z contains one or two or three groups of the following substructure,

where the definitions of R ¹ , R ² and R ³ are independently as defined in any of paragraphs 1-5.

(8) A compound of formula (I) according to any one of 1-7, wherein the chelating group is selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 2,2', 2''-(1,4,7-triazonan-1,4,7-triyl)triacetic acid (NOTA), 1,4,7-triazacyclononane-1,4-diacetic acid (NODA), N,N'- bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene-3,6,9,-triacetic acid (PCTA), diethylenetriaminepentaacetic acid (DTPA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4- [(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), 1,4,8,11-tetraazacyclododecan-1,4,8,11-tetraacetic acid (TETA ), ethylenediamine-N,N'-tetraacetic acid (EDTA), 1,4,7-triazacyclononan-N-glutaric acid-N',N'-diacetic acid (NODAGA), 1,4,7-triazacyclononan-1- succinic acid-4,7-diacetic acid (NODASA), 1,4,7,10 tetraazacyclotridecane-1,4,7,10-tetraacetic acid (TRITA), trans-1,2-diaminocyclohexane-N,N,N' ,N'-tetraacetic acid (CDTA), 1-[2-(2-mercapto-2-methylpropylamino)ethylamino]-2-methylpropane-2-thiol (BAT), 6-hydrazinonicotinic acid (HYNIC), 1.4, 7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid] and 1,4,7-triazacyclononanephosphinic acid.

(9) The compound of formula (I) according to any one of paragraphs 1-7, where

the chelating group is

where T is -[(CR ⁵ ₂ ) _m (NR ⁶ )] _q (CR ⁵ ₂ ) _m -

Where

each R ⁵ is independently selected from -hydrogen, -halogen, -OH, -C _1-6 alkyl and -OC _1-6 alkyl,

each R ⁶ is independently selected from -hydrogen, -C _1-6 alkyl, -(C _1-6 alkylene)-COOH, -(C _1-3 alkylene)-P(O)(OH)-(C _1-3 alkylene )-COOH, -(C _1-3 alkylene)-P(O)(OH)-(C _1-3 alkylene)-OH,

each m is independently an integer from 1 to 4, and

q is an integer from 3 to 5.

(10) The compound of formula (I) according to item 9, where each R ⁵ is -hydrogen.

***(11) The compound of formula (I) according to item 9 or 10, where each R ⁶ is C _1-3 alkyl - COOH.

(12) The compound of formula (I) according to any one of 9-11, wherein each m is 2 or 3.

(13) The compound of formula (I) according to any one of 9-12, wherein q is 3.

(14) The compound of formula (I) according to any one of items 1-13, where Z is -(linker group)-(chelator group) and

the linker group is -(X) _p -, where

p is an integer from 1 to 10, and

each X is independently chosen from

(a) -(N(R ⁴ )-C _1-10 alkylene)-,

(b) -(N(R ⁴ )-heteroarylene)-,

(c) -(N(R ⁴ )-C(O))-,

(d) -(OC _1-10 alkylene)-,

(e) -(O-heteroarylene)-,

(f) -(O-C(O))-,

(g) -(C _1-10 alkyleneheteroarylene)-,

(h) -(C _1-10 alkylene-C(O))-,

(i) -(C(O)-C _1-10 alkylene)-,

(j) -(C(O)-heteroarylene)-,

(k) -(heteroarylene-C _1-10 alkylene)-,

(l) -(heteroarylene-C(O))-, and

(m) -(C _1-10 alkylene)-,

where each C _1-10 alkylene is independently optionally substituted with one or more selected from halo, C(O)OH and OH,

where heteroarylene is a 4-6 membered heteroarylene containing 1-3 heteroatoms selected from N, O and S, and where heteroarylene is optionally substituted with one or more selected from halogen and C _1-6 alkyl; And

where each R ⁴ is independently selected from hydrogen and C _1-6 alkyl.

(15) The compound of formula (I) according to item 14, wherein p is an integer from 1 to 5.

(16) The compound of formula (I) according to item 14 or 15, where the linker group is selected from

(i) -C _1-10 alkylene-N(R ⁴ )-C _1-10 alkylene-N(R ⁴ )-C(O)-C _1-10 alkylene-N(R ⁴ )-,

(ii) -C _1-10 alkylene-N(R ⁴ )-C _1-10 alkyleneheteroarylene-C _1-10 alkylene-C(O)-C _1-10 alkylene-N(R ⁴ )-, and

(iii) -C _1-10 alkylene-N(R ⁴ )-C _1-10 alkylene -N(R ⁴ )-.

where each C _1-10 alkylene is independently optionally substituted with one or more selected from halo, C(O)OH and OH, and

where heteroarylene is a 4-6 membered heteroarylene containing 1-3 heteroatoms selected from N, O and S, and where heteroarylene is optionally substituted with one or more selected from halogen and C _1-6 alkyl, and

where each R ⁴ is independently selected from hydrogen and C _1-6 alkyl.

(17) The compound of formula (I) according to any one of items 14-16, wherein each R ⁴ is independently selected from H, methyl, ethyl, n-propyl, and iso-propyl.

(18) A composition or complex comprising a compound according to any one of 1-17, optionally in the form of a pharmaceutically acceptable salt, solvate, ester, polymorph, tautomer, racemate, enantiomer or diastereomer, or a mixture thereof, and one or more therapeutically effective radionuclides.

(19) The composition or complex of claim 18 wherein the radionuclide is selected from F-18, P-32, P-33, Sc-44, Sc-47, Cr-51, Fe-52, Fe-59, Mn-51, Mn-52m, Co-55, Co-57, Co-58, Cu-62, Cu-64, Cu-67, Ga-67, Ga-68, As-72, Se-75, As-77, Br- 76, Br-75, Br-77, Br-80m, Br-82, Rb-82m, Sr-83, Sr-89, Y-86, Y-90, Zr-89, Mo-99, Tc-94m, Tc-99m, Ru-97, Rh-103m, Rh-105, Pd-109, Pt-109, Ag-111, In-110, In-111, In-113m, In-114m, Sb-119, Sn- 121, Te-127, I-120, I-123, I-124, I-125, I-129, I-131, Pr-142, Pr-143, Pm-149, Pm-151, Sm-153, Dy-152, Dy-166, Gd-157, Gd-159, Ho-161, Tb-161, Ho-166, Er-169, Tm-172, Yb-169, Yb-175, Lu-177, Lu- 177m, Re-186, Re-188, Re-189, Rd-188, Os-189m, Ir-192, Ir-194, Au-198, Au-199, Hg-197, Tl-201, Pb-203, Pb-211, Pb-212, Bi-211, Bi-212, Bi-213, At-211, At-217, Po-215, Ra-223, Rn-219, Fr-221, Ac-225, Th- 227 and Fm-255.

(20) The composition or complex of claim 18 wherein the radionuclide is selected from P-32, P-33, Sc-44, Sc-47, Co-58, Fe-59, Cu-64, Cu-67, Ga-67, Ga-68, Se-75, As-77, Br-80m, Sr-89, Zr-89, Y-90, Mo-99, Rh-103m, Rh-105, Pd-109, Pt-109, Ag- 111, In-111, Sb-119, Sn-121, I-123, I-125, I-129, I-131, Te-127, Pr-142, Pr-143, Pm-149, Pm-151, Dy-152, Dy-166, Sm-153, Gd-159, Tb-161, Ho-161, Ho-166, Er-169, Tm-172, Yb-169, Yb-175, Lu-177, Lu- 177m, Re-186, Re-188, Rd-188, Re-189, Os-189m, Ir-192, Ir-194, Au-198, Au-199, At-211, Pb-211, Pb-212, Bi-211, Bi-212, Bi-213, Po-215, At-217, Rn-219, Ra-223, Fr-221, Ac-225, Th-227 and Fm-255.

(21) The composition or complex of claim 18 wherein the radionuclide is selected from Lu-177, Y-90, Cu-64, Ga-67, Ga-68, Sc-44, Zr-89 and In-111.

(22) A method comprising reacting a compound of formula (I) according to any one of 1 to 17 with one or more diagnostic or therapeutically effective radionuclides to form a complex of the compound of formula (I) with one or more diagnostic or therapeutically effective radionuclides.

(23) The method according to item 22, wherein the reaction is carried out in a solvent containing water.

(24) The method of claim 23, wherein the water also contains a buffer.

(25) The method of claim 24, wherein the buffer is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid or sodium citrate.

(26) The method according to any one of items 22 to 25, wherein the pH of the solution in which the reaction is carried out is in the range of 2 to 7, preferably 4 to 6, more preferably 4.5 to 5.5.

(27) The method according to any one of items 22 to 26, wherein the reaction is carried out at a temperature in the range of 20°C to 100°C, preferably 80 to 98°C, and more preferably 85 to 95°C.

(28) The method according to any one of items 22 to 27, wherein the reaction is carried out for 5 to 30 minutes, preferably 7 to 15 minutes, more preferably 8 to 12 minutes.

(29) The complex obtainable by the method of any one of paragraphs 22-28, optionally in the form of a pharmaceutically acceptable salt, solvate, ester, polymorph, tautomer, racemate, enantiomer or diastereomer, or a mixture thereof.

(30) A compound according to any one of items 1 to 17 or a composition or complex according to items 18 to 21 or a complex according to item 29 for use in medicine.

(31) A compound according to any one of items 1-17 or a composition or complex according to items 18-21 or a complex according to item 29 for use in diagnosing a disorder.

(32) A compound according to any one of items 1-17 or a composition or complex according to items 18-21 or a complex according to item 29 for use in the treatment or prevention of a disorder.

(33) The compound, composition or complex for use according to 31 or 32, wherein the disorder is a disorder involving the neurotensin receptor, preferably the disorder is a disorder involving the neurotensin 1 receptor.

(34) The compound, composition or complex for use according to item 31 or 32, wherein the disorder is selected from the group consisting of tumors and hemoblastoses.

(35) The compound, composition or complex for use according to item 31 or 32, wherein the disorder is selected from the group consisting of prostate cancer, lung cancer, thyroid cancer, pancreatic cancer, colon cancer, rectal cancer, pituitary cancer and cancer chest.

(36) A method for diagnosing a disorder, wherein a diagnostically effective amount of a compound according to any one of items 1 to 17 or a diagnostically effective amount of a composition or a diagnostically effective amount of a complex according to items 18 to 21 or a diagnostically effective amount of a complex according to item 29 is administered to a patient in need thereof.

(37) A method for treating or preventing a disorder, wherein a therapeutically effective amount of a compound according to any one of items 1 to 17 or a therapeutically effective amount of a composition or a therapeutically effective amount of a complex according to items 18 to 21 or a therapeutically effective amount of a complex according to item 29 is administered to a patient in need of such.

(38) The method of claim 36 or 37, wherein the disorder is a disorder involving the neurotensin receptor, preferably the disorder is a disorder involving the neurotensin 1 receptor.

(39) The method according to item 36 or 37, wherein the disorder is selected from the group consisting of tumors and hemoblastoses.

(40) The method of claim 36 or 37, wherein the disorder is selected from the group consisting of prostate cancer, lung cancer, thyroid cancer, pancreatic cancer, colon cancer, rectal cancer, pituitary cancer, and breast cancer.

(41) The use of a compound according to any one of items 1 to 17 or a composition or complex according to items 18 to 21 or a complex according to item 29 to obtain an agent for diagnosing a disorder.

(42) The use of a compound according to any one of items 1 to 17 or a composition or complex according to items 18 to 21 or a complex according to item 29 to obtain an agent for treating or preventing a disorder.

(43) Use according to 41 or 42, wherein the disorder is a disorder involving the neurotensin receptor, preferably the disorder is a disorder involving the neurotensin 1 receptor.

(44) Use according to item 41 or 42, wherein the disorder is selected from the group consisting of tumors and hemoblastoses.

(45) Use according to 41 or 42, wherein the disorder is selected from the group consisting of prostate cancer, lung cancer, thyroid cancer, pancreatic cancer, colon cancer, rectal cancer, pituitary cancer and breast cancer.

(46) A pharmaceutical composition, wherein the composition comprises (i) a compound of any one of items 1-17, or a composition or complex of items 18-21, or a complex of item 29, and optionally (ii) a pharmaceutically acceptable excipient.

(47) A kit containing a compound according to any one of paragraphs 1-17 and one or more radionuclides.

Various modifications and variations of the invention are obvious to a person skilled in the art without departing from the scope of the invention. While the invention has been described in terms of certain preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Moreover, various modifications of the described ways of carrying out the invention, which are obvious to experts in the relevant fields of technology, are covered by this invention.

The following examples are only illustrative of the present invention and should not be construed as limiting the scope of the invention as defined by the claims.

Examples

The following describes the synthesis of compounds in accordance with this invention, the introduction of radioactive label Lu-177 and subsequent use in radiotherapy of prostate tumors in a mouse model. The results are also shown in figures 1 and 2.

General methods

All reactions requiring anhydrous conditions are carried out under nitrogen and the solvents are suitably dried before use. All reactions are monitored by TLC using silica gel 60 F ₂₅₄ plates. The reaction components are visualized using UV fluorescence (254 nm) and KMnO ₄ staining. Chromatography on silica gel is carried out over Silicagel 60. The yield is shown after purification.

¹ H and ¹³ C NMR spectra were recorded in deuterated solvents and chemical shifts (δ) were quoted in parts per million (ppm) calibrated to TMS ( ¹ H and ¹³ C). Interaction constants ( J ) are measured in Hertz (Hz). The following abbreviations are used to describe multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, w=wide, m=multiplet.

Purity and identity are assessed by analytical RP-HPLC (Agilent 1100 analytical series, column: Zorbax Eclipse XDB-C8 analytical column, 4.6×150 mm, 5 µm, flow rate: 0.5 ml/min, detection wavelength: 254 nm ) coupled with a Bruker Esquire 2000 mass detector equipped with an ESI or CIAD trap. The purity of the products is evaluated from HPLC-MS.

System A: methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system 0-3 min: 10% methanol, 3-18 min: 10-100% methanol, 18-24 min: 100% methanol, 24-30 min: 100-10% methanol, flow rate: 0.5 ml/min.

System B: methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-11 min: 10-100% methanol, at 11-16 min: 100% methanol, 16-19 min: 100-10% methanol, flow rate: 0.5 ml/min.

System C: acetonitrile/H ₂ O 0.1% TFA as solvent system and using the following gradient system at 0-21 min: 10-100% acetonitrile, 21-24 min: 100% acetonitrile, 24-27 min 100- 10% acetonitrile.

System D: methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-21 min: 10-100% methanol, at 21-24 min: 100% methanol, 24-27 min: 100-10% methanol, flow rate: 0.5 ml/min.

System E: methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-12 min: 10-100% methanol, at 12-15 min: 100% methanol, 15-18 min: 100-10% methanol, flow rate: 0.5 ml/min.

Example 1

Product 14 of the following example is highly preferred over previously published counterparts such as those described in WO 2014/086499. Without wishing to be bound by theory, this is believed to be due to greatly improved selectivity for the NTS1 receptor with reduced affinity for dopamine receptors and due to an increased rate of tumor growth inhibition in vivo.

Methyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutyrate (1)

To a solution of 7 g (38.8 mmol) of 2,6-dimethoxyacetophenone in 120 ml of dry methanol was added 31.6 ml (232 mmol) of diethyl oxalate. The mixture is cooled to 0°C, treated with 1.78 g (77.6 mmol) of sodium and stirred for 18 h at 40°C. The pH is adjusted to moderately acidic with 2N-HCl and the mixture is extracted with diethyl ether/H ₂ O. The combined organic layers are dried, evaporated and the residue is stored for 2 h in the refrigerator. The resulting solid is separated from the liquid by filtration and washed with chilled ethanol. The filtrate is concentrated and treated as described above to give another product fraction. The solid is dissolved in methanol and stirred overnight. Evaporation of the solvent gave the desired compound as a yellow solid (7.9 g, 87%).

¹H-NMR (360 MHz, CDCl₃) δ (ppm): 3.82 (s, 6 H), 3.90 (s, 3 H), 6.58 (d, J=8.5 Hz, 2 H), 6.62 (s, 1 H), 7.34 (t, J=8.5 Hz, 1 H), 14.3 (brs, 1 H)

4-Bromo-2-isopropylaniline (2)

To a solution of 2-isopropylaniline (2.70 g, 2.83 ml, 20 mmol) and NH ₄ OAc (154 mg, 2 mmol) in acetonitrile (100 ml) was added N -bromosuccinimide (3.74 g, 21 mmol). The mixture is stirred at room temperature for 10 minutes followed by in vacuo concentration. After addition of H ₂ O and extraction with ethyl acetate, the organic layer is dried (MgSO ₄ ), evaporated and the residue is purified by flash column chromatography (cyclohexane/ethyl acetate 10:1) to give 2 (3.45 g, 81%) as a brown oil .

¹ H NMR (360 MHz, CDCl ₃ ): δ=1.17 (d, J =6.8 Hz, 6 H), 2.77 (hept, J =6.8 Hz, 1 H), 3.56 ( brs, 2 H), 6.48 (d, J = 8.4 Hz, 1 H), 7.03 (dd, J = 8.4, 2.3 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H).

MS (APCI): m/z 213.9 [M+H] ⁺ and 215.9 [M+H] ⁺ .

Methyl 1-(4-bromo-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1 H -pyrazole-3-carboxylate (3)

Concentrated aqueous hydrochloric acid (32 ml) is added to vigorously stirred 2 (4 g, 18.7 mmol) at 0°C. After 15 minutes, a solution of NaNO ₂ (1.27 g, 18.4 mmol) in H ₂ O (7.8 ml) was added over 15 minutes. This mixture was further stirred for 15 minutes after adding SnCl ₂ dihydrate (9.37 g, 41 mmol) in concentrated HCl (9.4 ml) and stirring for 30 minutes without cooling. 1 (4.97 g, 18.7 mmol) in ethanol (160 ml) was added to the reaction mixture and refluxed for 20 min. After neutralization with 50% aqueous NaOH, the mixture was concentrated in vacuo , treated with H ₂ O and extracted with ethyl acetate. The combined organic layers were dried (MgSO ₄ ), evaporated and the residue purified by flash column chromatography (cyclohexane/ethyl acetate 25:2) to give 3 (4.80 g, 56%) as a colorless solid.

So pl. 181°C

IR: (NaCl): 2965, 1723, 1605, 1589, 1475, 1253, 1230, 1111 cm^-1.

¹ H NMR (360 MHz, CDCl ₃ ): δ=0.95 (br, 6 H), 2.65 (hept, J =6.9 Hz, 1 H), 3.64 (s, 6 H), 3.94 (s, 3 H), 6.46 (d, J = 8.4 Hz, 2 H), 6.93 (s, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.25 (dd, J = 8.4, 2.2 Hz, 1 H), 7.25 (t, J = 8.4 Hz, 1 H), 7.31 (d, J = 2.2Hz, 1H).

¹³ C NMR (90 MHz, CDCl ₃ ): δ=23.8, 27.7, 51.9, 55.5, 103.5, 106.7, 111.2, 123.2, 128.4, 129 .1, 130.0, 131.4, 137.0, 138.9, 143.6, 148.2, 158.3, 163.1.

MS (APCI): m/z 459.1 [M+H] ⁺ and 461.0 [M+H] ⁺ .

Methyl 5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-((trimethylsilyl)ethynyl)phenyl)-1H-pyrazole-3-carboxylate (4)

A mixture of compound 3 (1 g, 2.2 mmol), trimethylsilylacetylene (0.9 ml, 6.5 mmol), bistriphenylphosphine palladium-(II)-dichloride, CuI (41 mg, 0.21 mmol), triethylamine (0.9 ml, 6.5 mmol) in 5 ml of toluene is heated in a sealed tube at 120° C. for 2 hours. It is then cooled to room temperature and the solvent is evaporated in vacuo . The product was then purified by flash chromatography 7:3 (hexane:ethyl acetate) to give compound 4 (0.566 g) in 55% yield.

¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) 0.24 (s, 9H), 0.95 (d, J =6.9 Hz, 6H), 2.66 (hept , J = 6.9 Hz, 1H), 3.63 (s, 6H), 3.94 (s, 3H), 6.43 (d, J = 8.4 Hz, 2H), 6.94 (s , 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H), 7.20-7.25 (m, 1H), 7 .29-7.31 (m, 1H).

¹³ C-NMR (150 MHz, CDCl ₃ ): δ (ppm) -1.9, 27.0, 27.5, 52.0, 55.5, 95.0, 103.6, 104 .8, 106.9, 111.4, 123.9, 128.5, 128.9, 129.9, 131.4, 138.1, 139.0, 143.6, 146.0, 158.4 , 163.3.

LC-MS-APCI : m/z Calc. for C ₂₇ H ₃₂ N ₂ O ₄ Si: 477.2, [M+H] ⁺ : m/z Found: 477.2 [M+H] ⁺

5-(2,6-Dimethoxyphenyl)-1-(4-ethynyl-2-isopropylphenyl)-1H-pyrazole-3-carboxylic acid (5)

Compound 4 (0.46 g, 0.96 mmol) was dissolved in 3 ml of methanol and K ₂ CO ₃ (0.5 g, 0.5 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The solvent is evaporated and the product is separated and purified by flash chromatography (ethyl acetate with 0.1% HCOOH) to give 0.23 g (61%) of compound 5 .

¹ H-NMR (360 MHz, CDCl ₃ ): δ (ppm) 0.98 (d, J =7.0 Hz, 6H), 2.69 (hept., J =7.0 Hz, 1H), 3.09 (s, 1H), 3.64 (s, 6H), 6.45 (d, J = 8.4 Hz, 2H), 6.98 (s, 1H), 7.24 ( t, J = 8.4 Hz, 1H), 7.25-7.26 (m, 2H), 7.35-7.37 (m, 1H).

¹³ C-NMR (90 MHz, CDCl ₃ ): δ (ppm) 23.7, 27.5, 56.0, 82.3, 83.3, 104.3, 106.4, 111, 3, 123.3, 128.6, 129.4, 130.0, 132.2, 138.2, 139.1, 144.5, 146.4, 158.5, 163.8.

LC-MS-APCI : m/z Calc. for C ₂₃ H ₂₂ N ₂ O ₄ : 391.2, [M+H] ⁺ : m/z Found: 391.1 [M+H] ⁺ ,

HPLC purity (Agilent 1100 analytical series, column: Zorbax Eclipse XDB-C8 analytical column, 4.6×150 mm, 5 µm, flow rate: 0.5 ml/min, detection wavelength: 254 nm, acetonitrile/H ₂ O 0.1% TFA as solvent system and using the following gradient system at 0-21 min: 10-100% acetonitrile, 21-24 min: 100% acetonitrile, 24-27 min 100-10% acetonitrile): 99% , t _R =12.5 min.

2-(5-(2,6-Dimethoxyphenyl)-1-(4-ethynyl-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (6)

Compound 5 (229 mg, 0.59 mmol) is dissolved in 5 ml of acetonitrile in a Schlenk flask under nitrogen atmosphere and trimethylamine (0.160 ml, 1.2 mmol) and isobutyl chloroformate (92 μl, 0.70 mmol) are added and the reaction mixture is stirred at room temperature for 30 minutes to obtain the first reaction mixture. 2-Aminoadamantane-2-carboxylic acid hydrochloride (172 mg, 0.89 mmol) was suspended in 5 ml of acetonitrile in a microwave tube and trimethylamine (0.24 ml, 1.8 mmol) and trimethylsilyl chloride (0.21 ml, 1 .8 mmol) and the mixture was stirred for 5 minutes at room temperature. The first reaction mixture is then added to this microwave tube and heated at 80° C. in a sealed tube for 16 hours. The mixture is then cooled and acidified with 2N HCl and extracted with dichloromethane, the organic phase is dried with Na ₂ SO ₄ and purified by preparative HPLC. Column ZORBAX ECLIPSE XDB-C8 (21.2×150 mm), 5 µm, flow rate 12 ml/min. Solvent methanol, water 0.1% HCOOH, gradient 40-95% methanol in 20 min, 95-95% in 24 min, 95-40% in 27 min, product peak appears at 23 min. Yield 250 mg, 75%.

¹ H-NMR (360 MHz, CDCl ₃ ): δ (ppm) 1.04 (d, J =7.0 Hz, 6H), 1.59-1.84 (m, 8H),1 .93-2.01 (m, 2H), 2.05-2.15 (m, 2H), 2.51-2.56 (m, 2H), 2.62 (hept., J =7.0 Hz, 1H), 3.64 (s, 6H), 4.24 (s, 1H), 6.61 (d, J = 8.4 Hz), 6.69 (s, 1H), 7.14 ( d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5 Hz, 1.9 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7 .35 (brs, 1H), 7.45 (d, J = 1.9 Hz, 1H).

¹³C-NMR (90 MHz, CDCl₃); δ (ppm) 23.3, 26.0, 26.3, 27.2, 31.9, 32.5, 33.3, 37.2, 55.6, 62.2, 81.7, 82.7, 103, 7, 106.0, 108.2, 122.7, 127.4, 128.9, 129.7, 131.6, 137.3, 138.9, 146.0, 146.3, 157.9, 160.0, 173.1.

Calc. for C ₃₄ H ₃₇ N ₃ O ₅ : 568.2, [M+H] ⁺ : m/z Found: 568.1 [M+H] ⁺ ,

HPLC purity (Agilent 1100 analytical series, column: Zorbax Eclipse XDB-C8 analytical column, 4.6×150 mm, 5 µm, flow rate: 0.5 ml/min, detection wavelength: 254 nm, methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-21 min: 10-100% methanol, at 21-24 min: 100% methanol, 24-27 min: 100-10% methanol, speed flow: 0.5 ml/min): 97%, t _R =16.0 min.

Tert-butyl (3-hydroxypropyl) carbamate (7)

3-Aminopropanol (100 mg, 1.3 mmol) is dissolved in 5 ml of tetrahydrofuran. Add 2 ml of 2N NaOH solution, then Boc anhydride (435 mg, 2 mmol) and the reaction mixture is stirred at room temperature for 16 hours. The product is then extracted with ethyl acetate and the organic layer is dried with Na ₂ SO ₄ . The product was purified by flash chromatography using hexane:ethyl acetate (6:3) to give 230 mg (98%) of the product as a colorless oil.

¹ H-NMR (600 MHz, CDCl ₃ ): δ (ppm) 1.45 (s, 9H), 1.64-1.68 (m, 2H), 2.94 (s, 1H) , 3.29 (q, J =6.2 Hz, 2H), 3.66 (q, J =5.7 Hz, 2H), 4.77 (s, 1H).

Tert-butyl (3-oxopropyl)carbamate (8)

Compound 7 (58 mg, 0.32 mmol) is dissolved in 1 ml of DMSO and 1 ml of dichloromethane and cooled to 0°C. NEt ₃ (0.07 ml, 0.5 mmol) and pyridine-sulfur trioxide complex (79 mg, 0.5 mmol) are added. The reaction mixture is then warmed to room temperature and stirred for 1 h. Then 3 ml of water are added and the organic layer is extracted three times with dichloromethane and dried with Na ₂ SO ₄ and concentrated in vacuo. The crude product is used in the next step.

Tert-butyl (3-((3-chloropropyl)(methyl)amino)propyl)carbamate (9)

Aldehyde 8 (57 mg, 0.329 mmol) is dissolved in 3 ml dichloromethane and cooled to 0°C. To this mixture is added chloro-N-methylpropylamine hydrochloride (53 mg, 0.49 mmol) followed by Na(OAc) ₃ BH (104 mg, 0.49 mmol) and the reaction mixture is stirred at 0°C for 1 h. The mixture was then warmed up to room temperature and stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted three times with dichloromethane. The combined organic phases are dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to obtain the crude product. The product was purified by flash chromatography (20% methanol in ethyl acetate and 0.1% NH ₃ ) to give 54 mg (62%) 10 as a colorless oil.

¹ H-NMR (600 MHz, CDCl ₃ ): δ (ppm) 1.44 (s, 9H), 1.66 (quint, J =6.5 Hz, 2H), 1.94 (quint , J =6.6Hz, 2H), 2.23(s, 3H), 2.45(t, J =6.5Hz, 2H), 2.51(t, J =6.5Hz, 2H ), 3.19 (kv, J= 6 Hz, 2H), 3.60 (t, J =6.6 Hz, 2H).

Tert-butyl (3-((3-azidopropyl)(methyl)amino)propyl)carbamate (10)

Compound 9 (17 mg, 64 µmol) is dissolved in a mixture of 5 ml of acetonitrile and 1 ml of water, and KI (32 mg, 0.2 mmol) and NaN ₃ (12 mg, 0.2 mmol) are added thereto and the reaction mixture is refluxed refrigerate for 16 hours. Quench the reaction with saturated aqueous NaHCO ₃ and extract three times with ethyl acetate. The combined organic phases are dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product which is used in the next step without further purification.

2-(1-(4-(1-(3-((3-((T-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)-1H-1,2,3-triazol-4-yl) -2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (11)

_{CuSO 4} 5H _{2 O (} 6 _mg , 26 µmol) and sodium ascorbate (5 mg, 26 µmol) and the mixture was stirred overnight at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by adding 0.1 M aqueous EDTA. The organic compounds are extracted with CH ₂ Cl ₂ (3 times), the organic phase is dried over Na ₂ SO ₄ and evaporated. The pure compound is isolated by HPLC. Nucleodur C18 HTec column, 32×250 mm, particles 5 µm, flow rate 32 ml/min, solvent acetonitrile, H ₂ O (0.1% TFA), 10-100% acetonitrile in 0-18 min. 80-100% acetonitrile in 20 min. 100-100% acetonitrile at 23 min, 100-10% acetonitrile at 24 min, 10-10% acetonitrile at 27 min. The peak of the product is observed at 15 min. Yield 14 mg (60%).

¹ H-NMR (600 MHz, CD ₃ OD): δ (ppm) 1.13 (d, J =6.4 Hz, 6H), 1.40 (s, 9H), 1.76- 1.90 (m, 10H), 2.14 (d, J = 13.3 Hz, 2H), 2.24 (d, J = 13.3 Hz, 2H), 2.43 (brs, 2H), 2.65 (s, 2H), 2.79 (hept, J =6.8 Hz, 1H), 2.89 (s, 3H), 3.12-3.29 (m, 6H), 3. 69 (s, 6H), 4.60 (t, J =6.4 Hz, 2H), 6.58 (d, J =8.5 Hz, 2H), 6.79 (s, 1H), 7. 28 (t, J = 8.7 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 7.62 (dd, J = 8.1 , 1.9 Hz, 1H), 7.83 (d, J =1.9 Hz, 1H), 8.41 (s, 1H).

Calc. for C ₄₆ H ₆₂ N ₈ O ₇ - Boc group: 739.6, [M+H-Boc] ⁺ : m/z Found: 739.6 [M+H-Boc] ⁺ ,

HPLC purity (Agilent 1100 analytical series, column: Zorbax Eclipse XDB-C8 analytical column, 4.6×150 mm, 5 µm, flow rate: 0.5 ml/min, detection wavelength: 254 nm, methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-12 min: 10-100% methanol, at 12-15 min: 100% methanol, 15-18 min: 100-10% methanol, speed flow: 0.5 ml/min): 97%, t _R =11.8 min.

2-(1-(4-(1-(3-((3-Aminopropyl)(methyl)amino)propyl)-1H-1,2,3-triazol-4-yl)-2-isopropylphenyl)-5- (2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (12)

Compound 11 (11 mg, 13 µmol) was dissolved in 2 ml ethyl acetate, a solution of 2M HCl in diethyl ether (0.5 ml, 1 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The organic compounds were extracted with ethyl acetate (3 times ), dried over Na ₂ SO ₄ and evaporated. The pure compound was isolated by HPLC using a Nucleodur C18 HTec column, 32×250 mm, particles 5 µm, flow rate 32 ml/min, solvent methanol, H ₂ O (0.1% HCOOH), 0-10% methanol in 0-2 minutes, 10-100% methanol in 0-12 minutes, 100-100% methanol in 12-15 minutes, 100-10% methanol in 15-16 minutes, 10-10% in 16-18 minutes. The peak of the product appears at 11 minutes. Yield 9 mg (92%).

¹ H-NMR (600 MHz, CD ₃ OD): δ (ppm) 1.13 (d, J =6.4 Hz, 6H), 1.74-1.85 (m, 8H), 2.09-2.14 (m, 4H), 2.24 (d, J = 13.3 Hz, 2H), 2.45 (quint, J = 7.3 Hz, 2H), 2.64 (br , 2H), 2.79 (hept, J = 6.8 Hz, 1H), 2.89 (s, 3H), 3.03 (t, J = 7.6 Hz, 2 H), 3.24- 3.27 (m, 3H), 3.69 (s, 6H), 4.60 (t, J = 6.4 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 6.79 (s, 1H), 7.28 (t, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 8 .1, 1.9 Hz, 1H), 7.83 (d, J =1.9 Hz, 1H), 8.41 (s, 1H).

¹³ C-NMR (150 MHz, CD ₃ OD); δ (ppm) 23.6, 25.8, 28.0, 28.2, 28.5, 29.0, 34.0, 34.1, 35.0, 37.9, 38, 9, 40.7, 48.4, 54.4, 54.8, 56.2, 64.7, 104.7, 107.9, 109.9, 123.3, 123.9, 124.4, 129.7, 132.8, 132.9, 138.8, 147.3, 148.2, 148.4, 159.9, 162.9, 163.1, 163.4, 175.7.

LC-MS-ESI : m/z Calc. for C ₄₁ H ₅₄ N ₈ O ₅ : 739.4, [M+H] ⁺ : m/z Found: 739.6 [M+H] ⁺ ,

HPLC purity (Agilent 1100 analytical series, column: Zorbax Eclipse XDB-C8 analytical column, 4.6×150 mm, 5 µm, flow rate: 0.5 ml/min, detection wavelength: 254 nm, methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-12 min: 10-100% methanol, at 12-15 min: 100% methanol, 15-18 min: 100-10% methanol, speed flow: 0.5 ml/min): 99%, t _R =10.6 min.

FAUC 468 (13)

Compound 12 (9 mg, 12 µmol) was dissolved in 2 ml dimethylformamide and trimethylamine (3 µl, 18 µmol) was added followed by DOTA-NHS ester (9 mg, 18 µmol) and the reaction mixture was stirred at room temperature for 16 h. The solvent is evaporated to dryness and the product is purified by HPLC ZORBAX Eclipse XDB C8 HTec column, 21.2×250 mm, particles 5 µm, flow rate 12 ml/min, solvent methanol, H ₂ O (0.1% HCOOH), 10-80 % methanol in 0-18 min. 80-100% methanol in 20 min. 100-10% methanol in 22 min, 10-10% methanol in 25 min. The peak of the product is observed at 20 min. Yield 11.5 mg (84%).

ESI MS : m/z calc. for C ₅₇ H ₈₀ N ₁₂ O ₁₂ : 563.5, [M+2H] ²⁺ : m/z found: 563.8 [M+2H] ²⁺ ,

HPLC purity (Agilent 1100 analytical series, column: Zorbax Eclipse XDB-C8 analytical column, 4.6×150 mm, 5 µm, flow rate: 0.5 ml/min, detection wavelength: 254 nm, methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-12 min: 10-100% methanol, at 12-15 min: 100% methanol, 15-18 min: 100-10% methanol, speed flow: 0.5 ml/min): 95%, t _R =12.0 min.

HRMS: C ₅₇ H ₈₁ N ₁₂ O ₁₂ : 1125.61067, found 1125.60914.

FAUC 469 (14)

Compound 13 (6.5 mg, 6 µmol) was dissolved in 2 ml HEPES buffer and the pH was adjusted to 5 with 0.2 N HCl solution and Lu(NO ₃ ) ₃ (6.57 mg, 17 µmol) was added and the reaction mixture was stirred at 98°C for 10 min. The product was purified by HPLC ZORBAX Eclipse XDB C8 HTec column, 21.2 x 250 mm, particles 5 µm, flow rate 12 ml/min, solvent methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system in 0-12 min: 10-100% methanol, at 12-15 min: 100% methanol, 15-18 min: 100-10% methanol, flow rate: 12 ml/min. The product peak is observed at 11.7 min. Yield 6 mg (80%).

MS-ESI: m/z Calc. for C ₅₇ H ₇₈ LuN ₁₂ O ₁₂ : 650.1, [M+2H] ²⁺ : m/z Found: 649.6 [M+2H] ²⁺ ,

HPLC purity (Agilent 1100 analytical series, column: Zorbax Eclipse XDB-C8 analytical column, 4.6×150 mm, 5 µm, flow rate: 0.5 ml/min, detection wavelength: 254 nm, methanol/H ₂ O 0.1% HCOOH as solvent system and using the following gradient system at 0-12 min: 10-100% methanol, at 12-15 min: 100% methanol, 15-18 min: 100-10% methanol, speed flow: 0.5 ml/min): 98%, t _R =11.3 min.

HRMS: C ₅₇ H ₇₈ LuN ₁₂ O ₁₂ : 1297.52524, found: 1297.52644.

Example 2

Tert-butyl (S)-(3-((3-chloropropyl)(methyl)amino)-2-hydroxypropyl)carbamate (15)

( S )-N-Boc-2,3-epoxypropylamine (50 mg, 0.3 mmol) is dissolved in 5 ml of acetonitrile. 3-Chloro-N-methylpropan-1-amine (46 mg, 0.43 mmol) and DIPEA (0.1 ml, 0.46 mmol) are added and the reaction mixture is stirred at room temperature for 16 h. The product is then extracted ethyl acetate, and the organic layer is dried with Na ₂ SO ₄ . The product was purified by flash chromatography using hexane:ethyl acetate (7:3) to give 43 mg (53%) of the product as a colorless oil.

¹ H-NMR (600 MHz, CDCl ₃ ): δ (ppm) 1.45 (s, 9H), 1.93 (n, J =6.4 Hz, 2H), 2.26 (s , 3H), 2.30-2.38 (m, 2H), 2.48-2.52 (m, 1H), 2.64-2.68 (m, 1H), 3.01-3.06 (m, 1H), 3.32-3.36 (m, 1H), 3.58 (t, J= 6.4 Hz, 2H), 3.73-3.76 (m, 1H), 4, 97 (shs, 1H).

LC-MS-ESI: m/z Calc. for C ₁₂ H ₂₅ ClN ₂ O ₃ : 281.1, [M+H] ⁺ : m/z Found: 281.0 [M+H] ⁺

Tert-butyl (S)-(3-((3-azidopropyl)(methyl)amino)-2-hydroxypropyl)carbamate (16)

Compound 15 (35 mg, 0.124 mmol) was dissolved in a mixture of 5 ml of acetonitrile and 1 ml of water, and KI (62 mg, 0.4 mmol) and NaN ₃ (24 mg, 0.4 mmol) were added thereto, and the reaction mixture was refluxed with reflux for 16 hours. The reaction is quenched with saturated NaHCO ₃ solution and extracted three times with ethyl acetate. The combined organic phases are dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product which is used in the next step without further purification.

(1R,3S,5R,7R)-2-(1-(4-(1-(3-((3-((T-butoxycarbonyl)amino)-2-hydroxypropyl)(methyl)amino)propyl)-1H -1,2,3-triazol-4-yl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (17)

_{CuSO 4} 5H _{2 O} ( _{2 mg} , 8.8 µmol) and sodium ascorbate (3.5 mg, 17 µmol) and the reaction mixture was stirred overnight at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by adding 0.1 M aqueous EDTA. The organic compounds are extracted with CH ₂ Cl ₂ (3 times), the organic phase is dried over Na ₂ SO ₄ and evaporated. The pure compound was isolated by HPLC using a Nucleodur C8 HTec column, 21.2×250 mm, particles 5 µm, flow rate 12 ml/min, solvent acetonitrile, H ₂ O (0.1% HCOOH), 10-100% acetonitrile in 0 -10 min., 100-100% acetonitrile in 10-12 minutes, 100-10% acetonitrile in 12-13 minutes, 10-10% acetonitrile in 13-15 minutes. The peak of the product is observed at 8 min. Yield 45 mg (60%).

¹ H-NMR (600 MHz, CDCl ₃ ): δ (ppm) 1.14 (d, J =6.4 Hz, 6H), 1.42 (s, 9H), 1.70-1 .88 (m, 8H), 2.07 (d, J =13.3 Hz, 2H), 2.23-2.28 (m, 4H), 2.50 (s, 3H), 2.57 ( d, J = 13.1 Hz, 1H), 2.67-2.81 (m, 6H), 3.05-3.09 (m, 1H), 3.32-3.35 (m, 1H) , 3.61 (s, 6H), 3.92-3.94 (m, 2H), 4.47 (t, J =6.7 Hz, 2H), 5.16 (s, 1H), 6, 43 (d, J =8.5 Hz, 2H), 6.86 (s, 1H), 7.11 (d, J =8.1 Hz, 1H), 7.21 (t, J =8.7 Hz, 1H), 7.33 (s, 1H), 7.38 (dd, J =8.1, 1.9 Hz, 1H), 7.83 (d, J =1.9 Hz, 1H), 7.85 (s, 1H).

¹³ C-NMR (150 MHz, CDCl ₃ ); δ (ppm) 24.9, 25.6, 26.7, 26.9, 27.9, 28.4, 32.5, 32.8, 33.8, 33.9, 37, 7, 41.8, 44.3, 47.6, 54.4, 55.5, 60.9, 64.9, 66.4, 79.5, 103.4, 106.9, 109.0, 120.4, 122.9, 123.6, 127.6, 131.3, 137.1, 139.7, 145.5, 146.5, 147.2, 156.5, 158.4, 163, 6, 174.0.

[α] ₅₈₉ =+6.6° (24°C, c=1.13, methanol).

MSWR: Calc. for C ₄₆ H ₆₂ N ₈ O ₈ : 855.0, [M+H-Boc] ⁺ : m/z Found: 855.4 [M+H-Boc] ⁺ ,

purity by HPLC (system E): 97%, t _R =11.8 min

(1R,3S,5R,7R)-2-(1-(4-(1-(3-(((S)-3-Amino-2-hydroxypropyl)(methyl)amino)propyl)-1H-1, 2,3-triazol-4-yl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (18)

Compound 17 (38 mg, 44 µmol) was dissolved in 2 ml ethyl acetate and a solution of 2M HCl in diethyl ether (0.5 ml, 1 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo and the residue dissolved in methanol and purified by HPLC (Nucleodur C8 HTec column, 32×250 mm, particles 5 µm, flow rate 32 ml/min, solvent acetonitrile, H ₂ O (0.1% TFA), 10-80% acetonitrile in 0- 20 minutes, 80-100% acetonitrile at 20-21 minutes, 100-100% acetonitrile at 21-24 minutes, 100-10% at 24-25 minutes, 10-10% acetonitrile at 25-27 minutes) 12.6 minutes. Yield 30 mg (89%).

¹ H-NMR (600 MHz, CD ₃ OD): δ (ppm) 1.12 (d, J =6.7 Hz, 6H), 1.74-1.85 (m, 8H), 2.13 (d, J = 13.1 Hz, 2H), 2.23 (d, J = 12.5 Hz, 2H), 2.39-2.58 (m, 2H), 2.64 (br , 2H), 2.79 (hept, J = 6.8 Hz, 1H), 2.92-2.94 (m, 1H), 2.95 (s, 3H), 3.13 (dd, J= 13.2, 3.2 Hz, 1H), 3.26-3.28 (m, 2H), 3.31 (n, J =1.7 Hz, 1H), 3.68 (s, 6H), 4.27-4.31 (m, 1H), 4.60 (t, J = 6.6 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 6.79 (s , 1H), 7.28 (t, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 8.1, 1, 9 Hz, 1H), 7.83 (d, J =1.9 Hz, 1H), 8.41 (s, 1H).

¹³ C-NMR (150 MHz, CD ₃ OD); δ (ppm) 24.0, 26.6, 26.8, 27.4, 32.4, 32.5, 33.4, 37.4, 42.1, 46.7, 46, 8, 48.2, 48.3, 54.6, 57.7, 62.0, 103.1, 108.3, 121.6, 122.3, 122.8, 128.0, 131.1, 131.3, 137.1, 146.6, 146.8, 158.3, 159.6, 161.3, 161.5, 161.7, 173.9.

[α] ₅₈₉ =+3.2° (24°C, c=1.6, methanol).

LC-MS-ESI : m/z Calc. for C ₄₁ H ₅₄ N ₈ O ₆ : 754.9, [M+H] ⁺ : m/z Found: 755.3 [M+H] ⁺ ,

purity by HPLC system E: 99%, t _R =10.6 min.

FAUC 550 (19)

Compound 18 (15 mg, 20 µmol) is dissolved in 2 ml dimethylformamide and trimethylamine (5 µl, 30 µmol) is added followed by DOTA-NHS ester (15 mg, 30 µmol) and the reaction mixture is stirred at room temperature for 16 h The reaction mixture was evaporated to dryness to remove the dimethylformamide, the residue was dissolved in methanol and the product was purified by HPLC (ZORBAX Eclipse XDB C8 HTec column, 21.2×250 mm, particles 5 µm, flow rate 10 ml/min, solvent acetonitrile, H ₂ O ( 0.1% HCOOH), 10-100% acetonitrile in 10 minutes, 100-100% acetonitrile in 12 minutes, 100-10% acetonitrile in 13 minutes, 10-10% acetonitrile in 15 minutes). The peak of the product is observed at 7.5 minutes. The yield is 11.5 mg (48%).

MS-ESI : m/z Calc. for C ₅₇ H ₈₀ N ₁₂ O ₁₃ : 570.5, [M+2H] ²⁺ : m/z Found: 570.2 [M+2H] ²⁺ ,

purity by HPLC system E: 95%, t _R =12.0 min.

HRMS: C ₅₇ H ₈₁ N ₁₂ O ₁₂ : 1125.61067 found 1125.60914.

FAUC 551 (20)

Compound 19 (5 mg, 4.1 µmol) was dissolved in 2 ml HEPES buffer and the pH was adjusted to 5 with 0.2 N HCl solution and Lu(NO ₃ ) ₃ (5 mg, 12 µmol) was added and the reaction mixture was stirred at 98 °C for 10 minutes. The product was purified by HPLC (Column ZORBAX Eclipse XDB C8 HTec, 21.2×250 mm, particles 5 μm, flow rate 10 ml/min, solvent acetonitrile, H ₂ O (0.1% TFA), 10-100% acetonitrile in 10 min, 100-100% acetonitrile in 12 minutes, 100-10% acetonitrile in 13 minutes, 10-10% acetonitrile in 15 minutes). The peak of the product is observed at 8.1 minutes. The yield is 3 mg (55%).

MS-ESI: m/z Calc. for C ₅₇ H ₇₈ LuN ₁₂ O ₁₃ : 658.1, [M+2H] ²⁺ : m/z Found: 657.4 [M+2H] ²⁺ ,

purity by HPLC system E: 98%, t _R = 11.3 min.

HRMS: C ₅₇ H ₇₈ LuN ₁₂ O ₁₂ : 1314.2888, found: 1314.2888.

Example 3:

Radiosynthesis ¹⁷⁷ Lu-14 (FAUC Lu469)

To solution 13 (2 nmol in 2 µl of water) was added 200 µl of 0.5 M HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) and 20 µl (200 MBq) of nca ¹⁷⁷ LuCl ₃ (in 0.04 M HCl). This mixture is allowed to react in a heating block at 98°C. After 10 min, the radiochemical yield ^{of 177} Lu-14 is >99% determined by radio-HPLC: Chromolith RP-18e, 10-100% acetonitrile in water (0.1% TFA) in a linear gradient over 5 min; t _R \u003d 2.35 min.

K-values _i

Affinities for NTS1 and NTS2, as well as for dopaminergic and serotonergic receptors, were determined in comparative radioligand binding assays as shown in Table 1. The results are presented in the following table. Affinities for human NTS1 are high (0.19 nM and 1.4 nM) with high selectivity over dopamine D2 receptors.

Table 1. _Ki values for FAUC 468, FAUC 469, FAUC 550 and FAUC 551 K _i values [nM] 13 (FAUC 468 ) 14 (FAUC 469 ) 19 (FAUC 550 ) 20 (FAUC 551 ) Reference connection 1 Reference connection 2 hNTS1 ([ ³ H]NT; CHO) 1.9 0.19 1.6 1.4 0.46 0.18 hNTS2 ([ ³ H]NT(8-13); HEK) 100 13 59 27 25 7.7 hD1 ([ ^3H ]SCH 23990) But. >50000 But. But. But. >50000 hD5 ([ ^3H ]SCH 23990) But. >50000 But. But. But. But. hD2 _long ([ ³ H]spiperone) But. >50000 But. But. But. 2600 hD2 _short ([ ³ H]spiperone) But. >50000 But. But. But. 1700 hD3 ([ ³ H]spiperone) But. >50000 But. But. But. >50000 hD4.4 ([ ³ H]spiperone) But. >50000 But. But. But. >50000 p5-HT _1A ([ ^3H ]WAY600135) But. >50000 But. But. But. But. h5-HT ₂ ([ ³ H]ketanserin) But. >50000 But. But. But. But. pα1 ([ ³ H]prazosin) But. >50000 But. But. But. But.

Reference connections 1 and 2 have the following structure:

where in reference compound 1: X=Ga

and in reference compound 2: X=Lu.

Stability in human plasma

An aliquot of ¹⁷⁷ Lu-14 ( FAUC Lu469 ) in PGFB (50 µl) was added to human plasma (200 µl) and incubated at 37°C. Aliquots (25 μl) were taken at different time intervals (1 h, 4 h, 24 h, 96 h, 7 days) and quenched with acetonitrile/0.1% TFA (1:1, 100 μl). Samples are centrifuged and supernatants analyzed by radio-HPLC. No degradation products are observed after 1 week.

Determination of the distribution coefficient (logD _7.4 )

The lipophilicity of ¹⁷⁷ Lu-14 ( FAUC Lu469 ) was assessed by determining the water-octanol partition coefficient. 1-Octanol (0.5 ml) was added to a solution of approximately 25 kBq of ¹⁷⁷ Lu-14 in PBS (0.5 ml, pH 7.4) and the layers were vigorously stirred for 3 minutes at room temperature. The tubes are centrifuged (14,000 rpm, 1 min) and three samples of 100 µl of each layer are counted in a γ-counter (Wallac Wizard). The distribution coefficient is determined by calculating the ratio imp./min. (octanol)/imp./min. (FRBF) and expressed as logD _7.4 ) log(imp./min. _octanol /imp./min. _buffer ). Experiments are carried out three times. A logD value of _7.4 is defined as -1.8±0.1 (mean±standard deviation, n=6).

Animal models

Nude mice (nu/nu) were obtained from Harlan Winkelmann GmbH (Borchen, Germany) at 4 weeks of age and kept under standard conditions (12 h light/dark) with free access to food and water. AsPC-1, PC-3 or HT29 cells are harvested and suspended in sterile BGF at a concentration of 2×10 ⁷ cells/ml. Viable cells (2×10 ⁶ ) in FGFB (100 μl) are injected subcutaneously into the back. Two weeks after inoculation (tumor weight: 400-800 mg), mice (about 10-12 weeks old and about 40 g body weight) were used for biodistribution studies.

Biodistribution studies

Xenotransplanted mice are injected with ¹⁷⁷ Lu-14 ( FAUC Lu469 , 1 MBq/mouse) intravenously into the tail vein. Mice are sacrificed by cervical dislocation 24 hours and 48 hours after injection (p.i.). Tumors and other tissues (blood, lungs, liver, kidneys, heart, muscles and intestines) are taken out and weighed. The radioactivity of the excised tissues is determined using a γ-counter. The results are expressed as percentage of administered dose per gram of tissue (% ID/g) and the tumor to organ ratio is calculated. The results are presented as percentage of administered dose per gram (% ID/g) in Table 2 and Figure 1.

Table 2 Absorption expressed as % VD/g of ¹⁷⁷ Lu-14 ( FAUC Lu469 ) in various tumors and normal tissues at 24 h and 48 s p.i. Biodistribution 24 h p.i. Biodistribution 48 h p.i. organ average SO N average SO N blood 0.36 0.08 8 0.14 0.05 8 lung 4.15 4.80 8 1.23 0.42 8 liver 11.61 4.68 8 5.45 0.73 8 kidneys 4.54 0.43 4 2.48 0.66 7 heart 1.05 0.58 8 0.56 0.17 8 spleen 2.40 1.00 8 1.60 0.27 8 brain 0.06 0.02 8 0.04 0.01 8 muscles 0.29 0.04 8 0.19 0.06 8 femur 0.89 0.21 8 0.75 0.19 8 HT29 18.64 nd 1 16.34 1.23 2 PC3 15.57 2.42 2 10.85 0.98 2 intestines 1.40 0.18 8 0.77 0.17 8 AsPC1 22.36 3.33 2 14.41 4.19 2

In comparison, biodistribution studies are performed with reference compound 2 showing tumor uptake of AsPC1 of 34.2±2.5% ID/g (2) at 24 h p.i., together with low uptake by the kidneys (0.9±0.5 % ID/g) and liver (1.5±0.5% ID/g). However, the retention of reference compound 2 in the AsPC1 tumor (4.6±2.2% ID/g on day 7 p.i., n=2) was significantly lower than the retention in the AsPC1 FAUC Lu469 tumor (13.2±2 .1% ID/g on day 7 p.i., n=2), indicating a favorable dosimetry of FAUC Lu469 radiation for radiotherapy.

Single Dose Therapeutic Trial of PC3 Tumors

Nude mice with PC3 tumors on the back are used for therapeutic research. One week after PC3 cell inoculation, ¹⁷⁷ Lu-14 ( FAUC Lu469 ) was injected into four mice at a dose of 30±9 MBq/animal. An additional eight animals are injected with saline as controls. Body weights and tumor diameter are measured every three days. The result of tumor growth over time after the start of treatment is shown in Figure 2. Animals were injected with ¹⁷⁷ Lu-14 ( FAUC Lu469 ), which showed significant inhibition of tumor growth and reduction in tumor size compared to untreated control animals. The tumor growth inhibition ratio is 64% after 49 days. Therefore, treated animals showed significantly longer survival than untreated control animals (figure 2).

Therapeutic Study of AsPC-1 Tumors Using Single Dose and Double Dose

Nude mice bearing AsPC-1 tumors (human pancreatic adenocarcinoma) on the back were used for therapeutic study. One week after inoculation of AsPC-1 cells, six mice are injected with a single dose of ¹⁷⁷ Lu-14(FAUC Lu469) (28±6 MBq/animal, group B, single dose) on day 0, and another six mice are injected with a double dose ¹⁷⁷ Lu-14(FAUC Lu469) (2×29±4 MBq/animal, group C, double dose) consisting of the first dose (29 MBq/animal) on the day of initiation of radiotherapy (day 0) and the second dose (29 MBq/animal) on day 10 after start of treatment. An additional six mice are injected with saline as controls (Group A). Body weights and tumor diameter are measured five times a week. The result of tumor growth over time after the start of treatment is shown in Figure 3. Animals are injected with a single dose of ¹⁷⁷ Lu-14(FAUC Lu469), which shows a significant inhibition of tumor growth and reduction in tumor size between 11 and 21 days after the start of therapy compared with untreated control animals (adjusted p=0.049, n=6). Animals that received ¹⁷⁷ Lu-14(FAUC Lu469) double dose (group C) show significantly longer survival (+209%) than untreated control animals (figure 3).

As shown in the examples above, the present invention provides radiopharmaceutical agents that exhibit low binding to dopamine receptors and improved selectivity for NTS1. This increased selectivity improves the quality of data obtained in the diagnosis and imaging of NTS1-positive tumors and, therefore, opens up new possibilities for the early detection of NTS1-positive tumors. Moreover, the increased selectivity, together with the superior activity of the compounds of this invention, is expected to provide new therapeutic possibilities, in particular for the treatment of cancer.

Claims (21)

1. A compound of formula (I), optionally in the form of a pharmaceutically acceptable salt thereof

Where R ¹ is selected from -(C _1-6 alkyl), R ² is selected from -(C _1-6 alkyl), R ³ is selected from 2-amino-2-adamantanecarboxylic acid, and Z is -(linker group)-(chelator group), where the linker group is -C _1-6 alkylene-N(R ⁴ )-C _1-6 alkylene-N(R ⁴ )-, where each R ⁴ is independently selected from hydrogen and C _1-6 alkyl, and each C _1-6 alkylene is independently optionally substituted with one substituent selected from OH, where the chelating group is selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 6-hydrazinonicotinic acid (HYNIC) and 2-amino-3-(1-(2-carboxyethyl )-1H-1,2,3-triazol-4-yl)propanoic acid. 2. The compound of formula (I) according to claim 1, where R ³ is

. 3. The compound of formula (I) according to claim 1 or 2, wherein the chelating group is selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 6-hydrazinonicotinic acid (HYNIC) . 4. Complex connection according to any one of paragraphs. 1-3 with one or more diagnostically or therapeutically effective radionuclides, containing a compound according to any one of paragraphs. 1-3, optionally in the form of a pharmaceutically acceptable salt thereof, and one or more diagnostically or therapeutically effective radionuclides selected from Cu-62, Cu-64, Cu-67, Tc-99m, Lu-177, and Ac-225. 5. The method of obtaining a complex compounds according to any one of paragraphs. 1-3 with one or more diagnostically or therapeutically effective radionuclides, including the interaction of the compound according to any one of paragraphs. 1-3 with one or more diagnostically or therapeutically effective radionuclides selected from Cu-62, Cu-64, Cu-67, Tc-99m, Lu-177 and Ac-225, to obtain a compound complex according to any one of paragraphs. 1-3 with one or more diagnostically or therapeutically effective radionuclides. 6. Process according to claim 5, wherein the reaction is carried out in a solvent containing water and optionally a buffer, and/or where the reaction is carried out at a temperature in the range of 20 to 100°C. 7. Complex connection according to any one of paragraphs. 1-3 with one or more diagnostically or therapeutically effective radionuclides selected from Cu-62, Cu-64, Cu-67, Tc-99m, Lu-177 and Ac-225 obtained by the method of claim 5 or 6, optionally, in the form of a pharmaceutically acceptable salt. 8. Use of the complex of claim 4 or the complex of claim 7 for the diagnosis and/or treatment of a disorder involving the neurotensin 1 receptor. 9. The use of claim 8 wherein the disorder involving the neurotensin 1 receptor is selected from the group consisting of tumors selected from prostate cancer, pancreatic cancer, colon cancer, lung cancer, rectal cancer and breast cancer. 10. Pharmaceutical composition with activity on the neurotensin 1 receptor, where the composition contains (i) a therapeutically effective amount of a compound according to any one of paragraphs. 1-3, or a complex according to p. 4, or a complex according to p. 7 and (ii) a pharmaceutically acceptable excipient. 11. A kit for diagnosing a disorder involving the neurotensin 1 receptor, containing a diagnostically effective amount of a compound according to any one of paragraphs. 1-3 and one or more radionuclides selected from Cu-62, Cu-64, Cu-67, Tc-99m, Lu-177 and Ac-225.

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