WO2014079504A1 - Ligands polycycliques du récepteur 5-ht7 et leur utilisation - Google Patents

Ligands polycycliques du récepteur 5-ht7 et leur utilisation Download PDF

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WO2014079504A1
WO2014079504A1 PCT/EP2012/073412 EP2012073412W WO2014079504A1 WO 2014079504 A1 WO2014079504 A1 WO 2014079504A1 EP 2012073412 W EP2012073412 W EP 2012073412W WO 2014079504 A1 WO2014079504 A1 WO 2014079504A1
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ethoxy
propanamide
piperazin
biphenyl
phenyl
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PCT/EP2012/073412
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English (en)
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Marcello Leopoldo
Enza Lacivita
Nicola Antonio Colabufo
Paola DE GIORGIO
Francesco Berardi
Roberto Perrone
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Biofordrug S.R.L.
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Priority to PCT/EP2012/073412 priority Critical patent/WO2014079504A1/fr
Publication of WO2014079504A1 publication Critical patent/WO2014079504A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • 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
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic 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
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the invention relates to a new class of compounds able to bind with high affinity and selectivity the 5-HT7 receptor.
  • the invention also relates to the utilization of such compounds as medicaments useful in the treatment and prevention of 5-HT7 receptor relating disorders of the central nervous system.
  • the invention also relates to the isotopically labeled compounds for use in vivo diagnosis or imaging of a 5-HT7 condition.
  • Serotonin (5-hydroxytryptamine, 5-HT) elicits a multitude of physiological effects through the interaction with at least fourteen receptors that have been grouped on the basis of molecular, pharmacological, and functional criteria into seven discrete families (5- HT1-7) [1] .
  • the 5-HT7 receptor was identified starting from 1993 by the application of targeted molecular biology techniques. It has been described in various species and remains the last 5-HT receptor to be discovered.
  • the 5-HT7 receptor has been localized in discrete areas of the brain and in the periphery. Within the central nervous system this receptor has been detected in high levels in the thalamus, hippocampus, and hypothalamus (especially within the suprachiasmatic nucleus, SCN) [2] .
  • the international application WO2008146064A1 disclosed some benzofuran compounds that bind 5-hydroxy triptamine- 7 receptor for use in the treatment or prevention of disorders of central nervous system and/or cardiovascular disorders .
  • PCT/EP2011/058419 filed by the present inventors, describes some 1-arylpiperazinic ligands of 5-HT7 receptor and used thereof.
  • the present invention relates to new compounds that present high affinity and selectivity for 5-HT7 receptors as well as good pharmacokinetic properties.
  • 5-HT7 ligands reported in literature have not been characterized regarding their metabolic liability or, when these data are available, they demonstrated a very short half-life time that limit their in vivo use.
  • plasma and brain concentration of LP-44 [12] became undetectable after 20 minutes following i.p injection.
  • the compounds of the present invention exhibit chemical features (i.e.: electron-withdrawing groups) that make them less metabolically liable.
  • the compounds of the present invention possess optimal lipophilicity (2 ⁇ logP > 3.5) for both in vivo use and for the development of a brain PET tracer. It is well- known that high lipophilicity reflects in high metabolic liability when administered in vivo and in low image resolution in PET imaging.
  • the compounds described in the present invention present structural features that allow easy radiolabelling with positron emitter radioisotopes.
  • object of the present invention is a family of compounds having the general formula as indicated in claim 1.
  • a second object of the invention are compounds selected from the above-indicated families isotopically radiolabeled .
  • a third object of the invention are compounds selected from the above-indicated families for use as medicaments, advantageously for use in the treatment of any condition susceptible of being improved or prevented by selective occupation of the 5-HT7 receptor.
  • a fourth object of the invention are compounds isotopically radiolabeled selected from the above- indicated families for use in vivo diagnosis or imaging of a 5-HT7 condition.
  • a further object of the invention are a pharmaceutical composition comprising the compounds of the invention and a pharmacologically acceptable excipient.
  • the invention relates to a family of novel compounds having the following general formula I:
  • A, B, D, E are independently CH or N with at most two of A, B, D, E being N;
  • Ri is selected from the group consisting of hydrogen, halogen, (C1-C2) alkyl, optionally further substituted with 1 to 5 fluorine substituents , (C1-C2 ) alkoxy, optionally further substituted with 1 to 5 fluorine substituents, cyano, (C1-C2) alkyl-S (0) 2-
  • X and Y are two linking chains, which may either independently be a (C1-C2 ) alkylen group or be absent, provided that at least one of X and Y is present; provided that when either X or Y is absent, R 2 is hydrogen or (C1-C2 ) alkyl ;
  • W is selected from: -C (0) - (CH2 ) n- , -S02- (CH2) n-, -C (0) - (CH2) 2-0- (CH2) 2-, wherein n is from 2 to 5;
  • Z is selected from:
  • K, J, L, M are independently CH or N with at most one of A, B, D, E being N;
  • Q is substituted or unsubstituted alkyl or alkoxy; substituted or unsubstituted cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted heterocyclyl .
  • Z is the compound is selected from the group consisting of:
  • Q is aromatic substituted with halogen, (Cl-C2)alkyl optionally further substitued with 1 to 5 fluoro substituents , (C1-C2 ) alkoxy optionally further substitued with 1 to 5 fluoro substituents, cyano .
  • ]3 ⁇ 4 is hydrogen and W is -C (0) - (CH2 ) n- wherein n is 2, 3, 4 or 5.
  • W is -C (0) - (CH2) 2-0- (CH2) 2- .
  • R 2 is hydrogen
  • W is -C (0) - (CH2 ) n- wherein n is 2, 3, 4 or 5.
  • Z is:
  • the present invention also encompasses isotopically radiolabeled compounds which are identical to the compounds of formula I or intermediates thereof but for the fact that one or more atoms are replaced by an atom having atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the intermediates or compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 3 H, X1 C, 14 C, 13 N, 15 0, 18 F, respectively.
  • the compounds of formula I of the present invention can be prepared according the procedures of the following Schemes. Suitable reaction conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art.
  • the synthetic intermediates may be isolated and/or purified by various well known techniques .
  • Reaction Scheme I illustrates the methods employed in the synthesis of the compounds of formula I when W is -C (0) - (CH2 ) 2-0- (CH2 ) 2- . All substituent are as defined above unless indicated otherwise.
  • Reaction Scheme II illustrates the synthesis of the compounds of formula I when W is -C (0) - (CH2 ) 5- . All substituent are as defined above unless indicated otherwise .
  • A 6-bromohexanoylchloride, NaOH; B: amine
  • radioactive fluorine atom into the compounds of formula (I) may be performed using techniques known in the art, for example by reaction of a suitable precursor, bearing a leaving groups, such as mesylate, triflate, nitro, tosylate, bromine, with a nucleophilic radioactive fluorinating reagent, such as K [ 18 F] /Kriptofix®222 or tetralkyl ammonium salts incorporating radioactive fluoride.
  • the reaction is carried out in an inert solvent such as, dimethylformamide, stirring the reaction mixture at a suitable temperature, typically at 100 °C, using conventionally heating or under microwave irradiation, for the required time to achieve completion of the reaction.
  • radioactive 11-Carbon atom into the compounds of formula (I) may be performed, for example by reaction of a suitable precursors bearing a phenolic hydroxyl group with radioactive methylating reagent, such as [ ⁇ C l Cfm , [ ⁇ CJCHSOTf.
  • the reaction is performed in an inert solvent such as dimethylformamide, in the presence of a strong base, such as NaOH, stirring the reaction mixture at a suitable temperature until complete achievement of the reaction.
  • a strong base such as NaOH
  • a further object of the present invention is a compound selected from the above-indicated families for use as medicament .
  • the compounds of the invention able to inhibit with high affinity and selectivity the 5-HT7 receptor activity find therapeutic applications in the treatment of any condition susceptible of being improved or prevented by selective occupation of the 5-HT7 receptor.
  • HT7 receptor activity comprise migraine, anxiety, persistent pain, inflammatory pain, neuropathic pain, depression, anxiety.
  • Compounds of the invention isotopically labeled for use in vivo diagnosis or imaging.
  • Isotopically labeled compounds of the present invention are useful in vivo diagnosis or imaging of a 5-HT7 condition.
  • compounds labeled with positron emitting isotopes such as 11 C, 13 N, 15 0, 18 F are useful for Positron Emission Tomography (PET) analysis.
  • PET Positron Emission Tomography
  • Radiotracers of the present invention are useful for assessing 5-HT7 receptors using PET, particularly in patient populations and preferably in subjects having or being diagnosed disorders as described herein. Further, radiotracers of the present invention are useful in drug development and drug discovery, for example, in neuroscience to assess interaction of drugs with 5-HT7 receptors or substrate occupancy.
  • a further object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds selected from the above-indicated families and a pharmacologically acceptable excipient and/or carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl ⁇ pyrrolidone or gelatin.
  • the term "pharmaceutically acceptable salt(s)” refers to salts derived from treating a compound of formula 1 with an organic or inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, or similarly
  • the pharmaceutical compositions of the invention are useful in the treatment and prevention of 5-HT7 receptor relating disorders of the central nervous system, in particular for use in the treatment of migraine, anxiety, persistent pain, inflammatory pain, neuropathic pain, depression, anxiety.
  • a further object of the invention is a diagnostic imaging composition
  • a diagnostic imaging composition comprising as imaging agent the compounds selected from the above-indicated families isotopically labeled and a carrier.
  • the radiolabeled compounds according to Formula I, II, III or IV may be administered in a single unit injectable dose.
  • Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier (s) or diluent (s) .
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with the liquid carrier.
  • the unit dose to be administered for a diagnostic agent has a sufficient radioactivity when they are, for example, 150 MBq. Higher or lower radioactivity may be used according to the circumstances.
  • imaging of the organ in vivo can take place in a matter of a few minutes. However, imaging takes place, if desired, in hours or even longer, after injecting into patients. In most instances, a sufficient amount of the administered dose will accumulate in the area to be imaged within about 1 hour to permit the taking of diagnostic images.
  • Any conventional method of imaging for diagnostic purposes can be utilized in accordance with this invention as positron emission tomography (PET) or Single photon emission computed tomography (SPECT) .
  • PET positron emission tomography
  • SPECT Single photon emission computed tomography
  • the diagnostic imaging compositions of the invention are useful for use in vivo diagnosis or imaging of a 5-HT7 condition.
  • a mammal requiring such treatment preferably a human
  • an effective amount of a compound of the families described above selected from migraine, anxiety, persistent pain, inflammatory pain, neuropathic pain, depression, anxiety.
  • the effective amount administered and frequency of administration of the compounds of the present invention will depend on the particular condition to be treated, the severity of the condition to be treated, age, weight and the overall physical condition of the particular patient as well as on other medicaments the patient is taking, as it is well known to the experts in the field.
  • the effective amount of the compounds of the invention to be administered daily or per dosage is within a range of from 0.1 ng to 100 mg per kg body weight, preferably within a range of from 1 ng to 10 mg per kg body weight.
  • It is a further object of the invention an in vivo method for diagnosis of a 5-HT7 condition comprising: administering to a mammal, preferably a human, an effective amount of a isotopically labeled compound of the families described above;
  • the imaging technique may be for example Positron emission tomography (PET) or Single positron emission computerized tomography (SPECT) .
  • PET Positron emission tomography
  • SPECT Single positron emission computerized tomography
  • the effective amount administered of the isotopically labelled compounds of the present invention will depend on the particular condition to be diagnosed, the age, weight and the overall physical condition of the particular patient as it is well known to the experts in the field.
  • the diagnostically effective amount of the labeled or unlabeled compounds of the present invention to be administered before conducting the in vivo diagnosis is within a range from 0.1 ng to 100 mg per kg body weight, preferably within a range of from 1 ng to 10 mg per kg body weight.
  • Example 1A To a cooled suspension of NaH (0.07 g; 3.0 mmol) in anhydrous THF (5 mL) was added, dropwise and under nitrogen, a solution of Example 1A (0.85 g; 3.0 mmol) in the same solvent (10 mL) . The reaction mixture was stirred at room temperature for 8-10 h until alcohol disappeared. Then, a solution of t-butyl acrylate (0.4 mL; 2.71 mmol) in anhydrous THF was added dropwise and the reaction mixture was stirred at room temperature for 20 h. Then, the solvent was removed under reduced pressure and the residue was cautiuosly taken up with cooled H20 and extracted with AcOEt (2 x 30 mL) .
  • Example IB To a solution of Example IB (1.14 mmol) in dioxane (5 mL) was added aqueous 3N HC1 (5 mL) . The reaction mixture was stirred at room temperature for 48 h, then dioxane was evaporated in vacuo. The acidic solution was neutralized with diluted NH40H and extracted with AcOEt (3 x 20 mL) . The combined organic layers were washed with brine, dried over Na2S04 and evaporated under reduced pressure to yield the desired compound that was used without further purification.
  • Example 1C A mixture of Example 1C (0.12 g; 0.32 mmol) and 1,1'- carbonyldiimidazole (0.06 g; 0.38 mmol) in 10 mL of anhydrous THF was stirred for 8 h.
  • the reaction mixture was partitioned between AcOEt (20 mL) and H20 (20 mL) . The separated organic layer was washed with a saturated aqueous solution of Na2C03 (20 mL) , dried (Na2S04) and concentrated in vacuo.
  • Example 5 1- (3 , 4-dihydro-lH-isoquinolin-2-yl) -3- [2- [4- (2-biphenyl) piperazin-l-yl] ethoxy] propan-l-one .
  • Example IB The compound was prepared as described for Example IB starting from Example 4A and t-butyl acrylate (0.9 g; 40% yield) .
  • Example 4B The compound was prepared from Example 4B as described for Example 1C (60% yield) .
  • Example IB The compound was prepared as described for Example IB starting from Example 5A and t-butyl acrylate (0.4 g; 33% yield) .
  • Example 5B The compound was prepared from Example 5B as described for Example 1C (60% yield) .
  • Example IB The compound was prepared as described for Example IB starting from Example 6A and t-butyl acrylate (0.9 g; 40% yield) .
  • Example 6B The compound was prepared from Example 6B as described for Example 1C (60% yield).
  • Example 8A A stirred mixture of Example 8A (0.2 g; 0.7 mmol), l-[2- (4-methoxyphenyl) phenyl] piperazine (0.16 g; 0.6 mmol) and K2C03 (0.7 mmol) in acetonitrile was refluxed overnight. After cooling, the mixture was evaporated to dryness and H20 (20 mL) was added to the residue. The aqueous phase was extracted with AcOEt (2 ⁇ 30 mL) . The collected organic layers were dried over Na2S04 and evaporated under reduced pressure. The crude residue was chromatographed (CHC13/MeOH, 19:1, as eluent) to afford pure compound as a thick yellow oil (0.23 g; 80% yield) .
  • Example 13B The compound was prepared as described for Example 13B starting from N- ( 6-Bromo-l-oxohexyl ) -1 , 2 , 3 , 4- tetrahydroisoquinoline (J. Med. Chem. 2008, 51, 5813) and 1- (2-biphenyl) piperazine . 48% Yield.
  • Example 20 N- [ (4-Cyanophenyl) methyl] -3- [ [1- (2-biphenyl) - 4-piperidyl] methylamino] propanamide .
  • Example 21 l-Isoindolin-2-yl-3- [ [1- (2-biphenyl) -4- piperidyl] methylamino] propan-l-one .
  • Radioligand binding assay at human cloned 5-HT 7 receptors Radioligand binding assay at human cloned 5-HT 7 receptors .
  • the incubation was stopped by rapid filtration on Whatman GF/C glass microfiber filters (pre-soaked in 0.3% polyethylenimine for 30 min) .
  • the filters were washed with 3 x 1 mL of ice-cold buffer (50 mM Tris-HCl, pH 7.4) .
  • Nonspecific binding was determined in the presence of 10 ⁇ 5-CT. Approximately 90% of specific binding was determined under these conditions.
  • Radioligand binding assay at human cloned 5-HTi A receptor Radioligand binding assay at human cloned 5-HTi A receptor .
  • liver S9 fractions are subcellular fractions that contain drug-metabolizing enzymes such as cytochromes P450, flavin monooxygenases , and UDP glucuronyl transferases.
  • the incubation was performed in 100 mM phosphate buffer (pH 7.4) containing 1.3 mM of NADP+ , 3.3 mM glucose 6- phosphate and 0.4 U/ml glucose 6-phosphate dehydrogenase, 3.3 mM MgC12 in a total volume of 1 mL .
  • Incubations were commenced with the addition of glucose 6-phosphate dehygrogenase and carried out for 30 min. at 37 °C.
  • the reaction was stopped by adding 1 mL of cooled acetonitrile .
  • the samples were centrifuged at 4600 rpm for 10 min at 4 °C.
  • the supernatant was separated and the acetonitrile phase was analyzed by using a reversed-phase HPLC equipped with a Perkin-Elmer series 200 LC pump and a Perkin-Elmer 785A UV/VIS detector. UV signals were monitored and obtained peaks integrated using a personal computer running Perkin-Elmer Turbochrom Software.
  • the column used was a Phenomenex Gemini C-18 (250 x 4.6 mm, 5 ⁇ particle size) .
  • the samples were eluted with ammonium formate (20 mM; pH 6.7) and acetonitrile 80:20 v/v at a flow rate of 1 mL/min and at the appropriate UV wavelength.
  • the sample injection volume was 20 ⁇ , . This assay provides information on the xenobiotic metabolism of the tested compounds; the results obtained are reported in table 1.
  • the compounds were active at 5-HT7 receptors because they showed Ki values lower than 100 nM in the radioligand binding assay.

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Abstract

L'invention concerne une nouvelle classe de composés capables de lier le récepteur 5-HT7 avec une affinité et une sélectivité élevées. L'invention concerne également l'utilisation de ces composés comme médicaments utiles dans le traitement et la prévention de troubles du système nerveux central associés au récepteur 5-HT7. L'invention concerne également les composés marqués par un isotope destinés à être utilisés dans le diagnostic ou l'imagerie in vivo d'un état pathologique associé au 5-HT7.
PCT/EP2012/073412 2012-11-22 2012-11-22 Ligands polycycliques du récepteur 5-ht7 et leur utilisation WO2014079504A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115433116A (zh) * 2022-09-20 2022-12-06 徐州医科大学 一种酰化吲哚啉类衍生物、组合物及其应用
CN115433116B (zh) * 2022-09-20 2023-07-14 徐州医科大学 一种酰化吲哚啉类衍生物、组合物及其应用

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