EP1692099A1 - Composes actifs du sous-type 1 de recepteur de somatostatine (sstr1) et leur utilisation en therapie - Google Patents

Composes actifs du sous-type 1 de recepteur de somatostatine (sstr1) et leur utilisation en therapie

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Publication number
EP1692099A1
EP1692099A1 EP04805145A EP04805145A EP1692099A1 EP 1692099 A1 EP1692099 A1 EP 1692099A1 EP 04805145 A EP04805145 A EP 04805145A EP 04805145 A EP04805145 A EP 04805145A EP 1692099 A1 EP1692099 A1 EP 1692099A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
pyridin
ylethyl
naphthalen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04805145A
Other languages
German (de)
English (en)
Inventor
Pia Knuuttila
Harri Salo
Jussi Tomperi
Siegfried Wurster
Anna-Marja Hoffren
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Juvanita Pharma Ltd Oy
Original Assignee
Juvanita Pharma Ltd Oy
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Filing date
Publication date
Priority claimed from FI20031824A external-priority patent/FI20031824A0/fi
Application filed by Juvanita Pharma Ltd Oy filed Critical Juvanita Pharma Ltd Oy
Publication of EP1692099A1 publication Critical patent/EP1692099A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Somatostatin receptor subtype 1 SSTRl active compounds and their use in therapy.
  • This invention relates to a group of novel somatostatin receptor subtype 1 (SSTR1 ) active compounds and pharmaceutical compositions comprising said compounds. Furthermore, the invention concerns the use of said compounds for the treatment or prevention of diseases or conditions responding to selective SSTR1 active compounds. Moreover, the invention concerns methods of targeting a tissue bearing SSTRIs either for tissue imaging or as carriers for drugs to be transported to said tissue.
  • SSTR1 novel somatostatin receptor subtype 1
  • Somatostatin is a cyclic peptide found endogenously in two major forms made up of 14 (SRIF-14) or 28 (SRIF-28) amino acids.
  • the shorter SRIF-14 is identical in sequence to the C-terminal half of SRIF-28.
  • Somatostatin is produced widely in the body and acts both systemically and locally to inhibit the secretion of various hormones, growth factors and neurotransmitters.
  • the biological effects of somatostatin are mediated by a family of G protein-coupled receptors, of which five subtypes (SSTR1-5) have been cloned in humans (Reisine and Bell 1995; Patel 1999).
  • somatostatin The affinities of the two endogenous forms of somatostatin on the five subtypes are relatively similar, although SRIF-28 has been reported to have a moderate preference for the SSTR5.
  • the five subtypes are differentially expressed in different tissues and do also show some differences in their interaction with a number of signalling pathways.
  • the pleiotropic physiological responses mediated by somatostatin are a reflection of its widespread distribution and the existence of multiple receptor subtypes.
  • the five subtypes in the somatostatin receptor family form two receptor subfamilies: One made up of SSTR2, SSTR3 and SSTR5 and another subfamily made up of SSTR1 and SSTR4.
  • the former possesses high and the latter rather low affinity towards the aforementioned hexapeptide and octapeptide analogs (Hoyer et al. 1995).
  • SSTR1 and SSTR4 are less well understood, a number of findings about the role of these subtypes have been described in scientific publications and the patent literature.
  • US 6,124,256 reported that, given their localisation in the vascular wall and their time-related induction during the proliferative stage, SSTR1 and/or SSTR4 may be the optimal subtypes to prevent fibroproliferative vasculopathy via a somatostatin receptor based therapy.
  • Curtis et al. (2000) have described SSTR1 and SSTR4 to represent the predominant subtypes expressed in human blood vessels and have proposed the use of SSTR1- or SSTR4-selective agonists for the treatment of endothelial cell-mediated proliferative diseases.
  • SSTR1 -selective agonists may be useful for the treatment of SSTR1 bearing tumors.
  • SSTR1 receptors are expressed in prostate cancer (Sinisi et al. 1997; Reubi et al. 1997; Reubi et al. 2001 ) but not in normal prostate tissue.
  • any SSTR1 selective ligand may be useful for the diagnosis of prostate tumors or tumors in other tissues expressing the SSTR1 subtype.
  • Somatostatin has a very short biological half-life and is therefore unsuitable for therapeutic use.
  • WO 97/03054 and US 6,221 ,870 describe benzo[g]quinoline- derived (WO 97/03054) or ergoiine-derived (US 6,221 ,870) SSTR1 -selective antagonist as lowering aggressive behavior in mice and, based on this observation, suggest such compounds to be useful for the treatment of depression, anxiety, affective disorders and attention deficit hyperactivity disorder.
  • Non-peptide somatostatin receptor ligands for all five somatostatin receptor subtypes have also been identified by Rohrer et al. (1998) through a strategy that consisted in the pharmacophore filtering of an existing compound collection in order to retrieve a subset of compounds which possessed structural features perceived to be critical for proper receptor-ligand interactions.
  • the object of the present invention is to provide novel compounds, or more specifically, novel urea-based peptidomimetics possessing a high degree of selectivity towards the somatostatin receptor subtype 1 (SSTR1 ).
  • a particular object is to provide novel compounds, the binding interaction of which to the SSTR1 is independent of the presence or absence of a basic function at physiological pH values.
  • this invention concerns a novel compound of formula I as defined hereinafter or a pharmaceutically acceptable salt or ester thereof.
  • this invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a novel compound of formula I as defined hereinafter or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable carrier.
  • the invention concerns a compound of formula I as defined hereinafter or a pharmaceutically acceptable salt or ester thereof, for use in the manufacture of a pharmaceutical preparation for the treatment and/or prevention of a disease or condition responding to targeting with a selective SSTR1 compound.
  • the invention concerns the use of a compound of formula I as defined hereinafter or a pharmaceutically acceptable salt or ester thereof in combination with a detectable label, for targeting a tissue bearing SSTRIs for tissue imaging.
  • the invention concerns a compound of formula I as defined hereinafter or a pharmaceutically acceptable salt or ester thereof, for use as a carrier for another therapeutically active compound to be targeted to a tissue bearing SSTRIs.
  • the invention provides compounds of Formula
  • heteroaryl-(C C 6 )alkyl wherein aryl and heteroaryl can be optionally substituted with 1 to 3 substituents selected from R a ; and alkyl can be optionally substituted with Cy;
  • Cy is cycloalkyl, heterocyclyl, aryl or heteroaryl
  • R b is to be defined hereinafter; E is 1 ) CH 2 ,
  • Cy-(C C 3 )alkyl wherein Cy can be unsubstituted or substituted with a group selected from R a and alkyl, alkenyl and alkynyl can be unsubstituted or substituted with a group selected from R c ; R3 is 1) H or
  • R a is independently
  • R b is independently
  • R1 , R a and R c , R b and R b together with the atom to which they are attached can also form a 5 to 6 membered ring containing 1 to 2 heteroatoms selected from N, O and S; R c is independently 1 ) H,
  • alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
  • the size of the alkyl can further be specified by adding the number of carbons in front of the group, e.g. (CrC 6 )alkyl, (C C 3 )alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, ⁇ eo-pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • Alkenyl means carbon chains which contain at least one carbon- carbon double bond, and which may be linear or branched or combinations thereof.
  • the size of the alkenyl can further be specified by adding the number of carbons in front of the group, e.g. (C 2 -C 6 )alkenyl, (C 2 -C 8 )alkenyl.
  • alkenyl groups include, but are not limited to, vinyl, allyl, isopropenyl, 1- pentenyl, 2-pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, and the like.
  • Alkynyl means carbon chains which contain at least one carbon- carbon triple bond, and which may be linear or branched or combinations thereof.
  • the size of the alkynyl can further be specified by adding the number of carbons in front of the group, e.g. (C 2 -C 6 )alkynyl, (C 2 -C 8 )alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, 3-methyl-1- pentynyl, 2-heptenyl, and the like.
  • Alkoxy refers to an "alkyl", as defined above, which is appended to the parent molecular moiety via -O-, i.e. an ether bond.
  • the size of the alkyl in the alkoxy can further be specified by adding the number of carbons in front of the group, e.g. (CrC 6 )alkoxy.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like.
  • Cycloalkyl means mono- or bicyclic saturated carbocyclic rings, each of which having from 3 to 8 carbon atoms. The term also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. The size of the cycloalkyl can further be specified by adding the number of carbons in front of the group, e.g. (C 3 -C 7 )cycloalkyl, (C 5 - C ⁇ o)cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
  • Aryl means mono- or bicyclic aromatic rings containing only carbon atoms.
  • the term also includes aryl groups fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
  • the size of the aryl can further be specified by adding the number of carbons in front of the group, e.g. (C 6 -C 12 )aryl.
  • aryl groups include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydro-benzofuranyl, benzopyranyl, 1 ,4- benzodioxanyl, and the like.
  • Heteroaryl means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
  • the term also includes heteroaryl groups fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
  • heteroaryl groups include, but are not limited to, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • Heterocyclyl means mono- or bicyclic saturated rings containing at least one heteroatom selected from N, O, S, each of said ring having from 5 to 8 atoms in which the point of attachment may be carbon or nitrogen.
  • the term also includes monocyclic heterocycles fused to an aryl or a heteroaryl group in which the point of attachment is on the non-aromatic portion.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- and 4-pyridones attached through the nitrogen.
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, imidazolinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindanyl, and the like.
  • cycloalkyl-alkyl refers to a "cycloalkyl", as defined above, appended to the parent molecular moiety through an alkyl group, as defined above.
  • the size of the cycloalkyl and the alkyl can further be specified by adding the number of carbons in front of the group, e.g. (C 3 -C 7 )cycloalkyl(CrC 6 )alkyl, (C 3 -C 5 )cycloalkyl(CrC 2 )alkyl.
  • cycloalkyl-alkyl examples include, but are not limited to, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, and the like.
  • aryl-alkyl refers to an "aryl", as defined above, appended to the parent molecular moiety through a (C C 6 )alkyl group, as defined above.
  • the size of the aryl or alkyl can further be specified by adding the number of carbons in front of the group, e.g. aryl-(Cr C 6 )alkyl, (C 6 -C ⁇ 2 )aryl-(C ⁇ -C 3 )alkyl.
  • aryl-alkyl examples include, but are not limited to, 2-naphthylmethyl, 1-(2- indanyl)ethyl, 2- tetrahydronaphthylethyl, and the like.
  • heteroaryl-alkyl refers to a “heteroaryl”, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above.
  • the size of the alkyl can further be specified by adding the number of carbons in front of the group, e.g. heteroaryl-(CrC 6 )alkyl, heteroaryl-(CrC 2 )alkyl.
  • heteroaryl-alkyl include, but are not limited to, 2-(2-pyridyl)propyl, 2-benzothiophenylmethyl, 4- (2-quinolyl)butyl, and the like.
  • Cy-alkyl refers to a “Cy”, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above.
  • the size of the alkyl can further be specified by adding the number of carbons in front of the group, e.g. Cy-(C ⁇ -C 6 )alkyl, Cy-(d-C 3 )alkyl.
  • Cy-alkyl include, but are not limited to, benzyl, 1-(2- naphthyl)ethyl, 2-cyclohexylethyl, and the like.
  • alkoxy-alkyl refers to at least one
  • alkoxy as defined above, appended to the parent molecular moiety through an alkyl group, as defined above.
  • the size of the alkoxy and alkyl can further be specified by adding the number of carbons in front of the groups, e.g. (d- C 3 )alkoxy-(CrC 6 )alkyl.
  • alkoxy-alkyl include, but are not limited to, methoxymethyl, propoxyethyl, tert-butoxypentyl, 3,3-dimethoxypropyl, and the like.
  • amino-alkyl refers to at least one amino group (i.e.
  • alkyl group appended to the parent molecular moiety through an alkyl group, as defined above.
  • the size of the alkyl can further be specified by adding the number of carbons in front of the group, e.g. amino- (C ⁇ -Ce)alkyl.
  • Representative examples of amino-alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 1- methyl-1-aminoethyl, and the like.
  • halogen refers to chlorine, bromine, fluorine or iodine.
  • the compounds of formula I, as well as the pharmaceutically acceptable salts and esters thereof, are referred to below as the compounds of the invention, unless otherwise indicated.
  • the invention includes within its scope all possible stereoisomers of the compounds, including geometric isomers, e.g. Z and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers. Furthermore, the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting materials or they may be separated after the preparation of a mixture of isomers according to conventional separation methods, such as e.g. fractional crystallisation.
  • ketones can exist also in their enol form (keto-enol tautomerism).
  • the individual tautomers as well as mixtures thereof are encompassed within the compounds of the invention.
  • Pharmaceutically acceptable salts e.g. acid addition salts with both organic and inorganic acids are well known in the field of pharmaceuticals.
  • Non-limiting examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
  • Pharmaceutically acceptable esters when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form.
  • Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl esters.
  • the compounds of the present invention possess selectivity towards the somastotatin receptor subtype 1 (SSTR1 ) and are therefore valuable for the treatment and/or prevention of diseases or conditions, where SSTR1 agonists or antagonists are indicated to be useful.
  • SSTR1 somastotatin receptor subtype 1
  • the compounds of the current invention can be viewed as consisting of two different motifs constructed around an 'aromatic amino acid'.
  • the ⁇ /-alpha of the 'aromatic amino acid' is part of a urea function whereas the remaining half of the urea is formed with a 'secondary amine' (motif No 1).
  • the structure of the compounds of the invention is completed via amidation of the 'aromatic amino acid' with motif No 2.
  • the compounds of the invention are named as amides wherein the selection of the core amide depends on the structure of the motif No 2, i.e. the core amide is either the motif No 2 or the amidated 'aromatic amino acid'.
  • the naming is further exemplified with the following structures:
  • Another preferred embodiment of the compounds of formula I are those wherein Q is aryl-(CrC 6 )alkyl or heteroaryl-(CrC6)alkyl, and even more preferably an aryl-methyl or a heteroaryl-methyl.
  • a preferred aryl and heteroaryl is naphthyl and indoyl, which can be optionally substituted with 1 to 2 groups selected from (d-C ⁇ Jalkyl, (C ⁇ -C 6 )alkoxy, halogen and - CF 3 .
  • Another preferred embodiment of the compounds of formula I are those wherein the carbon to which the substituent Q is attached has the absolute configuration R.
  • R2 is as defined above or even more preferably, for this purpose R2 is (CrC 6 )alkyl substituted with a group selected from R c .
  • Yet another preferred embodiment of the compounds of the formula I are those wherein R2 is (CrC 6 )alkyl.
  • Yet another preferred embodiment of the compounds of the formula I are those wherein n is 0. Yet another preferred embodiment of the compounds of the formula
  • I are those wherein h is 0.
  • SSTR1 selective shall be understood to include compounds having a binding affinity constant Ki of at least 10 times better for the somatostatin receptor subtype 1 than for any of the other somatostatin receptor subtypes.
  • treatment shall be understood to include complete curing of a disease or condition, as well as amelioration or alleviation of said disease or condition.
  • prevention shall be understood to include complete prevention, prophylaxis, as well as lowering the individual's risk of falling ill with said disease or condition.
  • Determination whether a certain compound is an SSTR1 agonist or an SSTR1 antagonist can be carried out according to known methods, such as those described by Sato et al. (1995) and Jasper et al. (1998).
  • Typical diseases or conditions that can be treated or prevented by the use of the compounds of this invention are:
  • Indications relating to diseases or conditions of central nervous system such as anxiety, depression, schizophrenia, attention deficit hyperactive disorder and neurodegenerative diseases such as dementia, Alzheimer's disease and Parkinson's disease.
  • the affective disorders includes bipolar disorders, e.g. manic-depressive psychoses, extreme psychotic states e.g. mania and excessive mood swings for which a behavioural stabilization is being sought.
  • the anxiety states include generalized anxiety as well as social anxiety, agoraphobia and those behavioural states characterized by social withdrawal, e.g. negative symptoms;
  • anti-proliferative agents e.g. involving pathological vascular proliferation
  • angiogenesis e.g. involving pathological vascular proliferation
  • restenosis e.g. involving smooth muscle proliferation
  • endothelial cell proliferation e.g. vascular proliferation associated with surgical procedures, e.g. angioplasty and AV shunts.
  • Other possible indications are the treatments of arteriosclerosis, plaque neovascularization, hypertrophic cardiomyopathy, myocardial angiogenesis, valvular disease, myocardiac infarction, coronary collaterals, cerebral collaterals and ischemic limb angiogenesis; 3.
  • Pathological conditions in the retina and/or iris-ciliary body such as high intraocular pressure (IOP) and/or deep ocular infections.
  • IOP intraocular pressure
  • diseases may for instance be glaucoma, stromal keratitis, ulceris, retinitis, cataract and conjunctivitis.
  • Other diseases connected to the eye may be ocular and corneal angiogenic conditions, for example, corneal graft rejection, retrolental fibroplasia, Osier-Webber
  • Diabetic complications such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, Doan syndrome and orthostatic hypotension; 5. Cancers or excessive proliferation of normal or malignant tissue, such as the proliferation of adenoma cells, thyroid cancer, large bowel cancer, breast cancer, prostatic cancer, benign prostatic hyperplasia, small cell lung cancer, non-small cell cancer, pancreatic cancer, stomach cancer, Gl tumors, cholangiocarcinoma, hepatic cancer, vesical cancer, ovarian cancer, melanoma, osteosarcoma, chondrosarcoma, malignant pheochromocytoma, neuroblastoma, brain tumors, thymoma, paragangliomas, prostate carcinomas, sarcomas, gastroenteropancreatic tumors, gastric carcinomas, phaeochromocytomas, ependymomas, renal cancers, leukemia e.g., leukemia of basophilic leuk
  • the compounds according to this invention can also be used for targeting a tissue bearing SSTRIs in tissue imaging for diagnostic purposes in vitro or in vivo.
  • the compound shall be coupled to a detectable label.
  • labels are different isotopes, such as 123-1, 125-1, 111-ln, 11-C etc., or fluorescent labels.
  • the label can be coupled directly to the compound or to a suitable spacer, which in turn is coupled to the compound. Brain, vessels and tumors are examples of tissues and organs that possess SSTR1 receptors and which thus could be imaged with SSTR1 selective compounds according to this invention.
  • the compounds according to this invention can also, based on their high affinity for the SSTR1 receptor, be used as carrier for another therapeutically active compound to be targeted to tissues bearing SSTR1 receptors.
  • the other therapeutically active compound can be conjugated directly with the compound of this invention.
  • said therapeutically active compound may be conjugated to a suitable spacer, which in turn is conjugated with the compound of this invention. This would offer a useful means for transporting e.g. anti-cancer drugs to tissues bearing
  • Preferred diseases or conditions to be treated or prevented with the compounds of the invention are anxiety, depression, schizophrenia, attention deficit hyperactive disorder and neurodegenerative diseases such as dementia, Alzheimer's disease and Parkinson's disease; and even more preferably schizophrenia.
  • Another group of preferred diseases or conditions to be treated or prevented with the compounds of the invention are cancers or excessive proliferation of normal or malignant tissue, and even more preferably prostatic cancer, benign prostatic hyperplasia, pancreatic cancer, thyroid cancer, brain tumors and Gl tumors.
  • Another group of preferred diseases or conditions to be treated or prevented with the compounds of the invention are diabetic complications, and even more preferably diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
  • diseases or conditions to be treated or prevented with the compounds of the invention are those involving pathological vascular proliferation, and even more preferably said disease or condition is angiogenesis, restenosis, smooth muscle proliferation, endothelial cell proliferation, new blood vessel sprouting or neovascularization.
  • compositions of the compounds of the invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • Formulations may for instance enable oral, buccal, topical, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration or administration by inhalation or insufflation.
  • Compounds of the invention may also be formulated for sustained delivery.
  • compositions include but are not limited to tablets, chewable tablets and capsules. These may be prepared by conventional means with pharmaceutically acceptable excipients, such as binding agents (e.g. pregelatinized maize starch), disintegrants (e.g. potato starch), fillers (e.g. lactose) or lubricants (e.g. magnesium stearate).
  • pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinized maize starch), disintegrants (e.g. potato starch), fillers (e.g. lactose) or lubricants (e.g. magnesium stearate).
  • Tablets may be coated by methods well known in the art.
  • possible liquid preparations include but are not limited to solutions, syrups or suspensions, or they may exist as dry powder for constitution with water or other suitable vehicle prior to use.
  • These liquid preparations may be prepared by conventional means with pharmaceutically acceptable agents, such as suspending agents, non-aqueous vehicles, preservatives and emulsifiers.
  • a possible dose of the active compounds of the invention for oral, parenteral, buccal or topical dose to an adult human is between 0.1 and 500 mg of the active compound per unit dose, which may be administered, for instance, 1 to 4 times a day.
  • the precise dose, the route of administration and the dosing interval can be determined by those skilled in the art. It is also well recognized that these variables depend on multiple factors including but not restricted to the activity of the therapeutic compound, the formulation thereof, pharmacokinetic properties (such as absorption, distribution, metabolism and excretion) of the therapeutic compound, the nature and location of the target tissue or organ and the issues connected to the state of a disease or disorder in a patient in need of treatment. Additionally, when the compounds of the invention are administered with additional pharmaceutically active ingredients, one or more pharmaceutical compositions may be used for the delivery of all the agents, which may be administered together, or at different times, as determined by those skilled in the art. The invention will be illuminated by the following non-restrictive
  • TRIS tris(hydroxymethyl)aminomethane Compounds of the invention can be prepared using the following general synthetic schemes.
  • DIPEA, THF/DCM (3:1); v) urea formation by amine addition, DIPEA, DMF; vi) 3 % TFA/DCM. r 2-6.
  • Rink and Trityl resins were obtained from Advanced ChemTech, UK.
  • the amino acid derivatives were purchased from Novabiochem, Switzerland and PepTech Co., USA.
  • DIC, HOBt and piperidine were products of Acros Organics, Belgium.
  • DIPEA was from Fluka AG, Germany. All the other reagents or solvents were purchased from Aldrich or Merck, Germany, if not otherwise specified. The reagents were used as such and solvents were purified and dried according to the methods described in W.L.F. Armareggo and D.D. Perrin, "Purification of Laboratory Chemicals", 4 th ed. Butterworth- Heinemann, 1996, Bath, Great Britain. MS analysis
  • HPLC purity of the compounds was determined using a Waters 616 pump, controlled by a Waters 600 controller unit. The instrument was further equipped with a Waters 2487 UV detector (detection wavelengths 254 nm and 220 nm). A Waters Symmetry Shield 2.1 X 50 mm C ⁇ 8 column with a corresponding precolumn and a flow rate of 0.4 ml/min was used. A linear gradient starting with water (containing 0.01% HCOOH) (A) and ending with acetonitrile (containing 0.01% HCOOH) (B) over 17 minutes was applied, followed by maintaining solvent B for another minute.
  • Microwave reactions were done in sealed, temperature- controlled and pressure-monitored reaction vessels in a Smith Creator microwave synthesis instrument from Personal Chemistry, Sweden. The instrument regulates the microwave power output according to the temperature and pressure achieved in the reaction vessel. Typical reaction times were around 10 minutes in a temperature of 200 °C.
  • Rink amide resin (0.8 g, 0.7 mmol/g, 0.56 mmol) was washed with DMF prior to use. Washed resin was dissolved in 40 ml of 20 vol-% piperidine in DMF and the mixture was agitated for 30 minutes. The piperidine treatment was repeated with fresh solution. The resin was then washed twice with DMF, twice with DCM and twice with diethyl ether.
  • N ⁇ -Fmoc-N ⁇ -Boc-D-Omithine (762.4 mg, 454.5 g/mol, 1.7 mmol, 3 eq) and DIC (266.4 ⁇ l, 126.2 g/mol, 0.806 g/cm 3 , 1.7 mmol, 3 eq) were dissolved in dry THF/DCM (1 :1 , 32 ml) and after 10 minutes mixed with the resin. After 8 hours of agitation, the solvent was filtered out and a fresh solution of N ⁇ -Fmoc-N ⁇ -Boc-D-Ornithine and DIC in dry THF/DCM was introduced. After an additional 5 hours, the solvent was again filtered out.
  • Step III Possibly unreacted amino groups of the resin were acetylated with a solution consisting of acetic anhydride (8 ml, 102.09 g/mol, 1.087 g/cm 3 , 85.2 ⁇ mol) and pyridine (16 ml, 79.1 g/mol, 0.98 g/cm 3 , 0.20 mmol) in dry DCM (16 ml) for 30 minutes. The resin was then filtered and washed three times with DMF, three times with DCM, and three times with MeOH. Step IV
  • Phenethyl(2-pyridin-2-ylethyl)amine (example 16, 709.6 mg, 226.32 g/mol, 3.1 mmol, 5.6 eq) and DIPEA (336.0 ⁇ l, 129.3 g/mol, 0.755 g/ml, 1.96 mmol, 3.5 eq) were dissolved in dry DMF (32 ml) and mixed with the resin.
  • Fmoc-L-methionine was used instead of N ⁇ -Fmoc-N ⁇ -Boc-D-Ornithine and in step VIII bis(2-pyridin-2-ylethyl)amine (example 17) was used instead of phenethyl(2-pyridin-2-ylethyl)amine.
  • the product was purified using preparative RP-HPLC purification to obtain the title compound with 33 % yield.
  • step VIII (2-cyclohexylethyl)-(2-pyridin-2-ylethyl)amine (example 19) was used instead of phenethyl(2-pyridin-2-ylethyl)amine.
  • the product was purified using preparative RP-HPLC purification to obtain the title compound with 21 % yield.
  • step VIII 4-[2-(2-pyridin-2-yIethylamino)ethyl]phenylamine was used instead of phenethyl(2-pyridin-2-ylethyl)amine.
  • the product was purified using preparative RP-HPLC purification to obtain the title compound with 32 % yield. MS-ESr (m/z): 597 [M+H] + , 299 [M+2H] 2+
  • Trityl chloride resin (0.15 g, 1.5 mmol/g, 0.225 mmol) was washed with DCM prior use.
  • 1 ,4-Diaminobutane (0.226 ml, 88.15 g/mol, 0.877 g/ml, 2.25 mmol, 10 eq) in DCM (3 ml) was added to the resin and the mixture was agitated for 15 hours. The resin was then washed three times with DCM.
  • step V N ⁇ -Fmoc-N( in )-Boc-D-tryptophan was used instead of Fmoc-3-(1-naphthyl)-D-alanine and in step VIII (3-phenylpropyl)-(2- pyridin-2-ylethyl)amine (example 20) was used instead of phenethyl(2-pyridin- 2-ylethyl)amine.
  • step VIII the TFA-wash was not carried out and cleavage from the resin was achieved with 25 % TFA in DCM to remove the Boc- protection from the tryptophan at the same time.
  • the product was purified using preparative RP-HPLC purification to obtain the title compound with 31 % yield.
  • step V Fmoc-3-(2-naphthyl)-D-alanine was used instead of N ⁇ -Fmoc-N(i n )- Boc-D-tryptophan and in step VIM butyl(2-pyridin-2-ylethyl)amine (example 21 ) was used instead of (3-phenylpropyl)-(2-pyridin-2-ylethyl)amine.
  • Cleavage from the resin was done with 5 % TFA in DCM.
  • Fmoc-3-naphthalen-1-yl-D-alanine (200.0 mg, 437.5 g/mol, 0.46 mmol, 1 eq) and DIPEA ( 79 ⁇ l, 129.12 g/mol, 0.755 g/cm 3 , 0.46 mmol, 1 eq.) were dissolved in 1 ml of dry DCM.
  • phenethyl(2-pyridin-2-ylethyl)amine (example 16, 92 mg, 226.3 g/mol, 0.40 mmol, 2 eq.) dissolved in 1 ml of dry THF was added to the reaction mixture.
  • Step III (2R)-2-Amino-3-naphthalen-1 -yl- ⁇ /-(1 -phenylethyl)propionamide (58 mg, 318.4 g/mol, 0.18 mmol, 1 eq) was reacted with 4-nitrophenyl chloroformate (37 mg, 201.6 g/mol, 0.18 mmol, 1 eq.) and phenethyl(2-pyridin-
  • Fmoc-3-naphthalen-1-yl-D-alanine (200.0 mg, 437.5 g/mol, 0.46 mmol, 1 eq) and cyclohexylamine (52 ⁇ l, 99.2 g/mol, 0.867 g/cm 3 , 0.46 mmol, 1 eq) were coupled using the same coupling agents and procedure as described in step I of example 12. After workup, the crude (2R)-Fmoc-2-amino- ⁇ /-cyclohexyl-3naphthalen-1-ylpropionamide was used in the next step without purification.
  • Phenylacetic acid (1.04 g, 136.15 g/mol, 7.6 mmol) was dissolved in DCM (15 ml).
  • DCC (1.57 g, 206.33 g/mol, 7.6 mmol, 1 eq) was added and the mixture stirred for 30 min after which 2-(2-aminoethyl)pyridine (1.0 ml, 122.17 g/mol, 1.027 g/ml, 8.41 mmol, 1.1 eq) was added and the mixture stirred over night.
  • the formed precipitate was filtered and the filtrate washed with water and dried over Na 2 SO . After evaporation, the product was purified using flash chromatography. The yield was 54 %.
  • Step II The product from step I (0.93 g, 240.31 g/mol, 3.87 mmol) was dissolved in THF (20 ml) and BH 3 -THF -complex (1 M, 11.6 ml, 3 eq) was added to reduce the carbonyl group. The reaction mixture was refluxed for two hours and then quenched by adding water (11.6 ml). The mixture was made acidic with cone. HCI (11.6 ml) and stirred for 30 min. The mixture was then made alkaline with NaOH solution (5M) and the product was extracted with ethyl acetate. Drying and evaporation of the organic fractions gave the title compound with 71 % yield.
  • step I 2-(4-aminophenyl)ethylamine was used instead of 2-(2-aminoethyl)pyridine.
  • the yield for step I was 85 % and 88 % for step II.
  • step I ethyl cyclohexylacetate (2 eq) was used instead of ethyl-2-pyridyl acetate.
  • step II 3 eq of borane-THF -complex were used.
  • the yield for step I was 67 % and 31 % for step II.
  • step I 3-phenylpropionic acid was used instead of phenylacetic acid.
  • the yield for step I was 95 % and 64 % for step II.
  • step I butyric acid was used instead of phenylacetic acid.
  • the yield for step I was 87 % and 49 % for step II.
  • step I 2-dimethylamino ethylamine (1 eq) was used instead of 2-(2- aminoethyl)pyridine.
  • the yield for step I was 90 % and 57 % for step II.
  • the product was purified first with silica flash chromatography (gradient elution from 1% MeOH to 10% MeOH in DCM) and then with reversed phase flash chromatography (gradient elution from water to 50% aq ACN, column Supelco Discovery DSC- C18, 10g), which yielded 0.35 g (38 %) of (2S,2'R)-2- ⁇ 2-[3,3-bis(2-pyridin-2- ylethyl)ureido]-3'-naphthalen-1-ylpropionylamino ⁇ -3-methylbutyramide.
  • the affinity of the compounds of the invention for the five human somatostatin receptor subtypes was determined in competition binding assays with ( 125 l-Tyr)-[Leu 8 ,DTrp 22 ]- somatostatin-28 ( 125 l-LTT-SRIF-28).
  • the biological material for these experiments consisted of membranes from Chinese hamster ovary (CHO) cells stably transfected with one of the five human somatostatin receptor subtypes.
  • Membranes (3-20 ⁇ g of total protein per sample) and trace amount of 125 I-LTT- SRIF-28 were incubated in 10 mM Hepes, 1 mM EDTA, 5 mM MgCI 2 , 5 mg/ml of BSA and 30 ⁇ g/ml bacitracin, pH 7.6 with six concentrations of the compounds. Each concentration was run in duplicate. Non-specific binding was defined by 1 ⁇ M somatostatin-14 (SRIF-14) and corresponded to 5-25% of total binding.
  • SRIF-14 somatostatin-14

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Abstract

L'invention concerne un groupe de composés actifs du sous-type 1 de récepteur de somatostatine (SSTR1) et des compositions pharmaceutiques renfermant les composés en question. L'invention concerne également l'utilisation de ces composés pour le traitement ou la prévention des maladies qui réagissent aux composés actifs SSTR1 considérés. L'invention concerne également des procédés de ciblage de tissu porteur de SSTR1, soit pour l'imagerie de tissus soit pour le transport de médicaments vers les tissus.
EP04805145A 2003-12-12 2004-12-09 Composes actifs du sous-type 1 de recepteur de somatostatine (sstr1) et leur utilisation en therapie Withdrawn EP1692099A1 (fr)

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AU2009322164B2 (en) 2008-12-05 2014-12-18 Molecular Insight Pharmaceuticals, Inc. Technetium-and rhenium-bis(heteroaryl) complexes and methods of use thereof
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