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(12) Patent Application Publication (10) Pub. No.: US 2017/0119913 A1 Osterkamp Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0119913 A1 Osterkamp Et Al US 201701 1991.3A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0119913 A1 Osterkamp et al. (43) Pub. Date: May 4, 2017 (54) CONJUGATE COMPRISINGA the first targeting moiety is capable of binding to a first NEUROTENSIN RECEPTOR LIGAND AND target, AD1 is a first adapter moiety or is absent, LM is a USE THEREOF linker moiety or is absent, AD2 is a second adapter moiety or is absent, and TM2 is a second targeting moiety, wherein (71) Applicant: 3B PHARMACEUTICALS GMBH, the second targeting moiety is capable of binding to a second target; wherein the first targeting moiety and/or the second Berlin (DE) targeting moiety is a compound of formula (2): wherein R' (72) Inventors: Frank Osterkamp, Berlin (DE); is selected from the group consisting of hydrogen, methyl Christian Haase, Berlin (DE); Ulrich and cyclopropylmethyl: AA-COOH is an amino acid Reineke, Berlin (DE); Christiane selected from the group consisting of 2-amino-2 adamantane Smerling, Berlin (DE); Matthias carboxylic acid, cyclohexylglycine and 9-amino-bicyclo3. Paschke, Berlin (DE); Jan Ungewi?, 3.1 nonane-9 carboxylic acid; R is selected from the group Berlin (DE) consisting of (C-C)alkyl, (C-C)cycloalkyl, (CCs)cy cloalkylmethyl, halogen, nitro and trifluoromethyl: ALK" is (21) Appl. No.: 15/317,598 (C-Cs)alkylidene, R, R and R are each and indepen dently selected from the group consisting of hydrogen and (22) PCT Filed: Jun. 10, 2015 (C-C)alkyl under the proviso that one of R, R and R is of the following formula (3) wherein ALK" is (C-Cs) (86). PCT No.: PCT/EP201S/OO1166 alkylidene; R is selected from the (2) group consisting of S 371 (c)(1), hydrogen and (C-C)alkyl; and R is a bond; or a pharma (2) Date: Dec. 9, 2016 cologically acceptable salt, Solvate or hydrate thereof. (30) Foreign Application Priority Data (2) Jun. 10, 2014 (EP) .................................. 14001992.8 Jun. 11, 2014 (EP) .................................. 140O2OO2.5 AA-COOH Publication Classification (51) Int. Cl. A6 IK 5L/04 (2006.01) A6 IK 49/00 (2006.01) A6 IK3I/337 (2006.01) (52) U.S. Cl. CPC. A61 K5I/0482 (2013.01); A61K 47/48061 (2013.01); A61 K3I/337 (2013.01); A61 K 47/48.184 (2013.01); A61K 49/0043 (2013.01); A61K 47/48146 (2013.01); A61K 47/48369 (2013.01) (3) (57) ABSTRACT The present invention is related to a conjugate comprising a structure of general formula (1) ITM1-AD1-LM-IAD2 ITM2 (1), wherein TM1 is a first targeting moiety, wherein Patent Application Publication May 4, 2017. Sheet 1 of 15 US 2017/01 19913 A1 Patent Application Publication May 4, 2017. Sheet 2 of 15 US 2017/01 19913 A1 CO s o <HOH g P s w 2 en v O () . s fa s 3. o E O U v s C s 8 que8 In) uoles Cou +2e) Patent Application Publication May 4, 2017. Sheet 3 of 15 US 2017/01 19913 A1 g C ce te ve O C. uu Oz9Co-uu Ostoo Patent Application Publication May 4, 2017. Sheet 4 of 15 US 2017/01 19913 A1 C e v Oz9CO lulu OStoo Patent Application Publication „N|ox=Tound tuoudAWO Patent Application Publication May 4, 2017. Sheet 6 of 15 US 2017/01 19913 A1 Patent Application Publication May 4, 2017. Sheet 7 of 15 US 2017/01 19913 A1 Patent Application Publication May 4, 2017. Sheet 8 of 15 US 2017/01 19913 A1 Patent Application Publication May 4, 2017. Sheet 9 of 15 US 2017/01 19913 A1 Q GN GN vm * 2 Patent Application Publication May 4, 2017. Sheet 10 of 15 US 2017/01 19913 A1 i CN vm Patent Application Publication May 4, 2017. Sheet 11 of 15 US 2017/01 19913 A1 Patent Application Publication May 4, 2017. Sheet 12 of 15 US 2017/01 19913 A1 ZI?!H Patent Application Publication May 4, 2017. Sheet 13 of 15 US 2017/01 19913 A1 Patent Application Publication May 4, 2017. Sheet 14 of 15 US 2017/01 19913 A1 i Patent Application Publication May 4, 2017. Sheet 15 of 15 US 2017/0119913 A1 CC on O C) O Ha 1. s a 6 S % s & s 3. o 6 E 9 g A i to (6/G) woe loun i US 2017/01 19913 A1 May 4, 2017 CONUGATE COMPRISING A protein coupled. NTR3 has a single transmembrane domain NEUROTENSIN RECEPTOR LIGAND AND and is encoded by the SORT1 gene. USE THEREOF 0005. The neurotensin receptor 1 (NTR1) was cloned in 0001. The present invention is related to a conjugate; a 1990 from rat brain and found to act as a high affinity, composition comprising the conjugate; the conjugate and levocabastine insensitive receptor for neurotensin (Tanaka et composition, respectively, for use in a method for the al., Neuron, 1990, 4, 847-854). The affinity of neurotensin diagnosis of a disease; the conjugate and composition, for the receptor could be decreased by both sodium ions and respectively, for use in a method for the treatment of a guanosine triphosphate (GTP) (Vincent et al., Trends Phar disease; the conjugate and composition, respectively, for use macol. Sci., 1999, 20, 302-309). NTR1 is expressed pre in a method of diagnosis and treatment of a disease which is also referred to as “thera(g)nosis” or “thera(g)nostics': the dominantly in the central nervous system and intestine conjugate and composition, respectively, for use in a method (Smooth muscle, mucosa and nerve cells). In the central for the identification of a subject, wherein the subject is nervous system, expression has been found in the diagonal likely to respond or likely not to respond to a treatment of band of Broca, medial septal nucleus, nucleus basalis mag a disease; the conjugate and composition, respectively, for nocellularis, Suprachiasmatic nucleus, Supramammillary use in a method for the selection of a Subject from a group area, Substantia nigra and Ventral tegmental area. The recep of subjects, wherein the subject is likely to respond or likely tor is also expressed in the dorsal root ganglion neurones of not to respond to a treatment of a disease; the conjugate and the spinal cord. The predominant response upon activation composition, respectively, for use in a method for the of the receptor by neurotensin is activation of phospholipase stratification of a group of Subjects into Subjects which are C, causing an increase in intracellular calcium levels. The likely to respond to a treatment of a disease, and into receptor can also stimulate cAMP formation, MAP kinase Subjects which are not likely to respond to a treatment of a activation and the induction of growth related genes. Such as disease; the conjugate and the composition, respectively, for kroX-24 (Vincent et al., Trends Pharmacol. Sci., 1999, 20, use in a method for delivering an effector to a neurotensin 302-309). receptor expressing tissue; a method for the diagnosis of a disease using the conjugate and the composition, respec 0006 Neurotensin receptor 2 (NTR2) is a protein that in tively; a method for the treatment of a disease using the humans is encoded by the NTSR2 gene (Vincent et al., conjugate and the composition, respectively; a method for Trends Pharmacol. Sci., 1999, 20, 302-309; Mazella et al., the diagnosis and treatment of a disease which is also J. Neurosci., 1996, 16, 5613-5620; Ramez et al., J. Invest. referred to as “thera(g)nosis' or “thera(g)nostics, using the Dermatol., 2001, 117,687-693). The protein encoded by this conjugate and the composition, respectively; a method for gene belongs to the G protein-coupled receptor family that the delivery of an effector to a neurotensin receptor express activates a phosphatidylinositol-calcium second messenger ing tissue using the conjugate and the composition, respec system. Binding and pharmacological studies demonstrate tively; and a kit comprising the compound and composition, that this receptor binds neurotensin as well as several other respectively. ligands already described for NTR1. However, unlike 0002 Neurotensin NT is a 13 amino acid neuropeptide NTR1, NTR2 recognizes, with high affinity, levocabastine, (pyroGlu'-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg a histamine H1 receptor antagonist previously shown to Pro'-Tyr-Ile-Leu-OH) (SEQID NO: 1) that is impli compete with neurotensin for low-affinity binding sites in cated in the regulation of luteinizing hormone and prolactin the central nervous system. These activities Suggest that this release and has significant interaction with the dopaminergic receptor may be of physiological importance and that a system. Neurotensin was first isolated from extracts of natural agonist for the receptor may exist. bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthe 0007 Neurotensin receptor 3 (NTR3) is a non-G-protein tized rats (Carraway et al., J. Biol. Chem., 1973, 248, coupled receptor. The cDNA encodes an 833-amino acid 6854-6861). protein 100% identical to the recently cloned gp95/sortilin 0003) Neurotensin is distributed throughout the central and was then designated NTR3/gp95/sortilin (Mazella, Cell nervous system, with highest levels in the hypothalamus, Signal., 2001, 13, 1-6; Vincent et al., Trends Pharmacol. amygdala and nucleus accumbens. It induces a variety of Sci., 1999, 20, 302-309). NTR3 is a sorting protein involved effects, including analgesia, hypothermia and increased in cellular trafficking and neuropeptide signalling. The locomotor activity. It is also involved in regulation of physiological and cellular roles of sortilin/NTR3 are puta dopamine pathways. In the periphery, neurotensin is found tive in many aspects and still under discussion.
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