[go: up one dir, main page]

WO2015069110A1 - Multiples a(nta)gonistes de d2/antagonistes de h3 pour le traitement de troubles associés au snc - Google Patents

Multiples a(nta)gonistes de d2/antagonistes de h3 pour le traitement de troubles associés au snc Download PDF

Info

Publication number
WO2015069110A1
WO2015069110A1 PCT/NL2014/050772 NL2014050772W WO2015069110A1 WO 2015069110 A1 WO2015069110 A1 WO 2015069110A1 NL 2014050772 W NL2014050772 W NL 2014050772W WO 2015069110 A1 WO2015069110 A1 WO 2015069110A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
mixture
added
dihydrobenzo
concentrated
Prior art date
Application number
PCT/NL2014/050772
Other languages
English (en)
Inventor
André Heeres
Sandra WILLIGERS - Hogg
Marcus Leonardus Gerardus BORST
Melloney Joyce DRÖGE
Original Assignee
Aapa B.V.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Aapa B.V. filed Critical Aapa B.V.
Publication of WO2015069110A1 publication Critical patent/WO2015069110A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2

Definitions

  • the present invention relates to phenyl amine compounds having D 2 receptor antagonist/(partial) agonist activity and 3 ⁇ 4 antagonistic activity and to a method of preparing these phenyl amine compounds.
  • the present invention also relates to pharmaceutical compositions comprising these phenyl amine compounds.
  • the present invention further relates to methods for the prophylaxis or treatment of CNS-related disorders in a mammal in need thereof.
  • Bromocriptine ((5 'a)-2-bromo- 12'-hydroxy-5 '-(2-methylpropyl)-3 ',6', 18-trioxo- 2'-(propan-2-yl)ergotaman) is a D2 agonist. It is disclosed in US 3.752.814, incorporated by reference.
  • Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-l-piperidyl]-l-(4-fluorophenyl)- butan-l-one) is a D2 antagonist. It is disclosed in US 3.438.991, incorporated by reference.
  • H 3 receptors The predominant function of H 3 receptors is to act as pre-synaptic heteroreceptors modulating the release of pro-cognitive neurotransmitters such as acetylcholine (ACh) [Fink et al (1990) Naunyn Schmiedebergs Arch Pharmacol 342(5):513-9.; Schlicker et al (1989) Naunyn Schmiedebergs Arch Pharmacol 340(6) .633-8].
  • ACh acetylcholine
  • H 3 receptor antagonists have been shown to improve performance in a variety of animal models of cognitive function, including avoidance tasks and spatial, social and novel object recognition (NOR) memory models [Fox et al (2003) Journal Pharmacol Experimental Therapeutics 305: 897-908 ; Komater et al (2003) Psychopharmacol (Berl) 167:363-72; Chen (2000) Acta Pharmacol Sin 21:905-10; Fox et al (2005) Journal Pharmacol Experimental Therapeutics 313: 176-90; Ligneau et al (2007) Biochem Pharmacol 73:1215-24.].
  • NOR object recognition
  • Such pharmaceutically active compounds would, without being bound by theory, be suitable for the treatment of CNS-related disorders such as schizophrenia and Parkinson's disease.
  • the present invention relates to phenyl amine compounds having D 2 receptor antagonist/(partial) agonist activity and H 3 antagonistic activity.
  • the present invention also relates to methods of preparing these phenyl amine compounds.
  • the present invention further relates to pharmaceutical compositions comprising these phenyl amine compounds.
  • the present invention further relates to methods for the prophylaxis or treatment of CNS-related disorders in a mammal in need thereof.
  • the present invention relates to compounds according to Formula (I) or Formula (II):
  • P and S are independently O or NR 4 ;
  • Q and R are independently C(R 4 ) 2 or C(O), provided that not both Q and R are C(O), or Q is absent and R is C(R 4 ) 2 or C(O);
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, Ci - Ci2 alkyl, C2 - C12 alkenyl, C2 - C12 alkynyl, Ci - C12 alkoxy, C2 - C12 alkenoxy, C2
  • p 0, 1 or 2;
  • T is N or CR 4a , wherein R 4a is H or Ci - C 12 alkyl;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • U is selected from the group consisting of [C(R 5 ) 2 ] friendship, O, N(R 5 ) and C(O), or U and R 9 and the carbon atoms to which they are attached form a five-membered or six- membered ring, and when U is [C(R 5 )2] n , [C(R 5 )2] n may contain a carbon-carbon double bond or a carbon-carbon triple bond;
  • V is CHR 10 R U or NR 10 R U , wherein R 10 and R 1 1 are independently selected from the group consisting of H, Ci - C 12 alkyl, C 6 - C 24 aryl and C3 - C 24 heteroaryl, or wherein R 10 and R 11 represent together the group [C(R 5 ) 2 ] m ;
  • n 3, 4, 5 or 6;
  • the compounds disclosed in this document may comprise one or more asymmetric centres, and different diastereomers and/or enantiomers may exist of the compounds.
  • the compounds disclosed in this document are meant to include all diastereomers, and mixtures thereof, unless stated otherwise.
  • the compounds disclosed in this document are meant to include both the individual enantiomers, as well as any mixture, racemic or otherwise, of the enantiomers, unless stated otherwise.
  • the structure of a compound is depicted as a specific enantiomer, it is to be understood that the invention of the present application is not limited to that specific enantiomer.
  • the compounds disclosed in this document may occur as cis and trans isomers and/or as Z- and i somers. Unless stated otherwise, the compounds disclosed in this document are meant to include both the individual cis and the individual trans isomer and/or the individual Z-isomer and i -isomer of a compound, as well as any mixture thereof. Accordingly, when the structure of a compound is depicted as a cis isomer, it is to be understood that the corresponding trans isomer or any mixture of the cis and trans isomer are not excluded from the invention of the present application.
  • the compounds disclosed in this document may be in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts of the compounds according to Formula (I) and Formula (II) may be acid addition salts or base addition salts.
  • the Ci - Ci 2 alkyl group may be linear or branched.
  • the alkyl group may further comprise one or more heteroatoms, preferably one, two or three heteroatoms, selected from the group consisting of O, N and S.
  • the alkyl group may further be substituted by one or more substituents, preferably one, two or three substituents.
  • the C 2 - Co alkenyl group may be linear or branched.
  • the alkenyl group may further comprise one or more heteroatoms, preferably one, two or three heteroatoms, selected from the group consisting of O, N and S.
  • the alkenyl group may further be substituted by one or more substituents preferably one, two or three substituents.
  • the alkenyl group is preferably a Ci - C-6 alkenyl group. When the alkenyl group is a C5 - Ci 2 alkenyl group, preferably a C5 - C 6 alkenyl group, the alkenyl group may be cyclic.
  • the C 2 - C12 alkynyl group may be linear or branched.
  • the alkynyl group may further comprise one or more heteroatoms, preferably one, two or three heteroatoms, selected from the group consisting of O, N and S.
  • the alkynyl group may further be substituted by one or more substituents, preferably one, two or three substituents.
  • the alkynyl group is preferably a Ci - C 6 alkynyl group. When the alkynyl group is a C 8 - C 12 alkenyl group, the alkynyl group may be cyclic.
  • the Ce - C 2 4 aryl group includes monocyclic and bicyclic structures, wherein in the bicyclic structure one ring moiety may be (partly) saturated.
  • the aryl group may be substituted by one or more substituents, preferably one, two, three, four or five substituents.
  • the C 6 - C24 aryl group is preferably a C 6 - C 12 aryl group.
  • the aryl group is selected from the group consisting of phenyl, indenyl (1-, 2-, 3-, 4-, 5-, 6- or 7-), indanyl (1-, 2-, 3-, 4-, 5-, 6- or 7-), naphtyl (1-, 2-, 3- or 4-), 1,2- dihydronaphtyl (1 -, 2-, 3-, 4-, 5-, 6-, 7- or 8-) and 1 ,2,3,4-tetrahydronaphtyl (1 -, 2-, 3-, 4-, 5-, 6-, 7- or 8-).
  • the C3 - C24 heteroaryl group comprises at least one heteroatom, preferably one, two, three to four heteroatoms, selected from the group consisting of O, N and S and includes monocyclic and bicyclic structures, wherein one or two ring moieties may be (partly) saturated.
  • the heteroaryl group may be substituted by one or more substituents, preferably one, two, three, four or five substituents.
  • the heteroaryl group is selected from the group consisting of 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, triazolyl (this term includes the radical derived from 1,2,3-triazole and of 1,2,4-triazole, i.e.
  • triazolyl may be 1- triazolyl, 2-triazolyl, 3-triazolyl, 4-triazolyl or 5-triazolyl), 2-pyridinyl, 3-pyridinyl, 4- pyridinyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4- pyridazinyl, triazinyl, indolyl (1-, 2-, 3-, 4-, 5-, 6- or 7-), 3-H-indolyl (2-, 3-, 4-, 5-, 6-, 7-), isoindolyl (1-, 2-, 4- or 5-), indolizinyl (1-, 2-, 3-, 5-, 6-, 7- or 8-), indazolyl (1-, 3-, 4-, 5-, 6- or 7-), purinyl (2-, 6-, 8-or 9-), benzo[b]furanyl (2-, 3-, 4-, 5-, 6- or 7-), benzo[
  • Preferred substituents for the Ce - C 24 aryl group and the C3 - C24 heteroaryl group include independently halogen, hydroxy, Ci - Ce alkyl, Ci - Ce alkoxy, Ci - C alkylthio, NH 2 , NH(Ci - C 4 alkyl) and N(Ci - C 4 alkyl) 2 .
  • the group of halogens include fluorine, chlorine, bromine and iodine.
  • [C(R 5 ) 2 ] n may contain a carbon-carbon double bond or a carbon-carbon triple bond.
  • two groups R 5 on two adjoining carbon atoms may form with said adjoining carbon atoms a carbon-carbon double bond and four groups R 5 on two adjoining carbon atoms may form with said adjoining carbon atoms a carbon-carbon triple bond.
  • the compounds are according to Formula (I).
  • P is NR 4 , Q is absent, R is C(O) and S is O. More preferably, this group of compounds is according to Formula (I).
  • P and S are O and Q and R are C(R 4 ) 2 .
  • this group of compounds is according to Formula (I).
  • P is NR 4
  • S is O
  • Q and R are C(R 4 ) 2 . More preferably, this group of compounds is according to Formula (I).
  • R , R , R , R , R , R and R are independently selected from the group consisting of H, Ci - C 6 alkyl, Ci - C 6 alkoxy, Ci - C 6 alkylthio, OH, halogen, N(R 4 ) 2 , N0 2 , CN, S(0) p R 4 , S(0) 2 N(R 4 ) 2 , C(0)R 4 , C(0)OR 4 , C(0)N(R 4 ) 2 and N(R 4 )- C(0)R 4 .
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, Ci - C 6 alkyl, Ci - C 6 alkoxy, OH, halogen, N(R 4 ) 2 , C(0)R 4 , C(0)OR 4 and C(0)N(R 4 ) 2 .
  • R 4 is independently selected from the group consisting of H and Ci - Ci2 alkyl.
  • R 4a is H.
  • n 0, 1, 2, 3 or 4.
  • U and R 9 and the carbon atoms to which they are attached may form a five- membered or a six-membered ring, and said five-membered or six-membered ring may form a spiro compound with another five-membered or six-membered ring formed by V, when R 10 and R 11 represent a group [C(R 3 )2] m This is further illustrated below by the compounds according to Formula (VI).
  • a first preferred group of compounds according to the present invention is according to Formula (III):
  • a second preferred group of compounds according to the present invention is according to Formula (IV):
  • a third preferred group of compounds according to the present invention is according to Formula (V):
  • n, m, p, R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , R 8 , R y , T and V are as defined above and wherein U is O, NR 5 or C(O).
  • a fourth preferred group of compounds according to the present invention is according to Formula (VI):
  • this fourth preferred group of compounds according to the present invention is according to Formula (VI), it is preferred that W is O.
  • a fifth preferred group of compounds according to the present invention is according to Formula (VII):
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to Formula (I) or Formula (II) and a pharmaceutically acceptable carrier.
  • a pharmaceutically effective amount of a compound according to Formula (I) or Formula (II) is combined with a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • the pharmaceutical composition is desirably in unitary dosage form and may be suitable for administration by the oral, nasal, rectal, sublingual, transdermal, percutaneous or parenteral route.
  • the pharmaceutical composition in oral dosage form may a solid dosage form or a liquid dosage form.
  • Suitable solid oral dosage forms include tablets and capsules and these are very advantageous oral dosage forms because of their ease in administration.
  • Suitable liquid oral dosage forms include suspensions, syrups, elixirs and solutions.
  • compositions according to the present invention are suitable for preventing and treating CNS-disorders, preferably selected from the group consisting of depression, major depressive disorder, generalised anxiety disorder, major anxiety disorder and panic disorder.
  • the present invention also relates to a method for preventing or treating a CNS- disorder in a subject in need thereof, wherein a therapeutically effective amount of a compound according to the present invention or a pharmaceutical composition comprising said compound according to the present invention is administered to said subject.
  • the subject is a mammal and more preferably, the subject
  • the compounds aimed for were prepared by alkylation of 7-(piperazin-l- yl)benzo[d]oxazol-2(3H)-one with the appropriate bromine.
  • 4-(4-Iodophenoxy)piperidine hydrochloride (580 mg, 1.71 mmol) was mixed with methanol (9 mL). Et 3 N (0.24 mL, 1.7 mmol) was added and almost all solid dissolved. Subsequently, AcOH (0.29 mL, 5.1 mmol) was added and the mixture was cooled in ice. Cyclobutanone (0.64 mL, 8.6 mmol) was added, followed by portion-wise addition of NaBH 3 CN. The mixture was stirred at 0°C for 5 min, allowed to reach RT afterwards and stirred overnight. The mixture was poured in sat. NaHC0 3 (15 mL) and DCM (15 mL).
  • Boc-piperazine (1.86 g; 10.0 mmol) was dissolved in dichloroethane (35 mL). Acetic acid (0.57 mL; 0.60 g; 10.0 mmol) and NaBH(OAc) 3 (3.00 g; 14.2 mmol) were added. Cyclobutanone (0.71 g; 10.0 mmol) was added to the reaction mixture. After stirring overnight NaOH solution (IN, 60 mL) was added, followed by additional H 2 0 (50 mL). The aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were dried over Na 2 SC>4, filtered and evaporated to dryness to yield a slightly yellow oil (2.22 g, 9.24 mmol, 92% ).
  • HATU 124 mg, 0.325 mmol
  • lithium 6-((4-(2-oxo-2,3- dihydrobenzo[d]oxazol-7-yl)piperazin-l-yl)methyl)nicotinate 182 mg, max 0.27 mmol
  • isopropylpiperidine 52 mg, 0.41 mmol
  • DIPEA 0.2 mL, 1 mmol
  • DMF 5 mL
  • Boc-protection of 3-fluoroaniline afforded tert-butyl (3-fluorophenyl)carbamate.
  • Ortho- lithation with fert-butyllithium and reaction with benzyl piperidone furnished the alcohol 7-(l-benzyl-4-hydroxypiperidin-4-yl)benzo[d]oxazol-2(3H)-one in moderate yield.
  • Acidic aqueous reflux resulted in elimination of H 2 0 and subsequent treatment with H 2 in the presence of Pd(OH) 2 catalyst yielded 7-(piperidin-4-yl)benzo[d]oxazol- 2(3H)-one.
  • the compounds aimed for were prepared by alkylation of 7-(piperidin yl)benzo[d]oxazol-2(3H)-one with the appropriate bromine (see example la2).
  • Example 2d Synthesis of 7-(4-((6-((l-alkylpiperidin-4-yl)oxy)pyridin-3- yl)methyl)piperazin-l-yl)benzo[d]oxazol-2(3H)-ones
  • Example 3b Synthesis of l-(4-(3-(4-(2,3-dihydrobenzo[b][l,4]dioxin-5-yl)piperazin-l- yl)alkoxy)phenyl)-N-alkylmethanamines
  • the compounds aimed for were prepared by alkylation of l-(2,3- dihydrobenzo[b][l,4]dioxin-5-yl)piperazine with the appropriate bromine (see example la2).
  • Example 3d Synthesis of 3-(4-((4-(2,3-dihydrobenzo[b][l,4]dioxin-5-yl)piperazin-l- yl)methyl)phenoxy)-N-alkylpropan- 1 -amines HEME S
  • a pressure tube was charged with 4-(4-((4-(2,3-dihydrobenzo[b][l,4]dioxin-5- yl)piperazin-l-yl)methyl)phenyl)but-3-yn-l-yl-4-methylbenzenesulfonate (90 mg, 0.17 mmol), piperidine (0.04 mL, 0.34 mmol), Na 2 C0 3 (56 mg, 0.37 mmol) and DMF (10 - 20 mL). The reaction mixture was heated to 80°C for 2 h in a sand bath. The reaction mixture was cooled to RT, concentrated, diluted with H 2 0 (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried, filtered and concentrated. Purification by column chromatography (ISCO) furnished a colourless oil (16 mg, 0.035 mmol, 22%).
  • Example 4a Synthesis of 4-(4-(3-(4-(6-chloro-2,3-dihydrobenzo[b][l,4]d yl)piperazin- 1 -yl)propoxy)benzyl)morpholine (AG-0441 ) .
  • 2,3-Dihydrobenzo[b][l,4]dioxin-5-amine (3.8 g, 25.1 mmol; see example 3a) was dissolved in CHCI 3 (75 mL) and the mixture was cooled in an ice-bath. N- Chlorosuccinimide (3.4 g, 25.1 mmol) was added portion-wise and the mixture was stirred overnight at RT. The purple suspension was filtered over Celite and the filtrate was concentrated. The concentrate was dissolved in DCM and purified over a short plug of Silica. The filtrate was concentrated and the residue was purified by column column chromatography (ISCO, silicagel).
  • H 2 SO 4 (4 mL) was added to a solution of 35% wt. H 2 O 2 (16.3 mL, 190 mmol) in dioxane (69 mL) and the mixture was heated at 40°C for 1 h.
  • l-(5-Chloro-2- hydroxy-3-nitrophenyl)ethanone (5.00 g, 23.2 mmol) was added in one portion (endothermic) and the mixture was heated at 40°C for 15 min.
  • H 3 BO 3 (11.76 g, 190 mmol) was added (endothermic) and the mixture was heated at 80°C for 8 h. After cooling to RT the mixture was concentrated in vacuo.
  • Example 4c Synthesis of 8-(4-(3-(4-(morpholinomethyl)phenoxy)propyl)piperazin-l- yl)-2,3-dihydrobenzo[b][l,4]dioxine-6-carbonitrile (AG-0445)
  • the crude material was purified by automated column chromatography (ISCO slicagel) and the compound aimed for was obtained as a yellow oil (130 mg, 0.27 mmol, 19% from 8-amino-2,3- dihydrobenzo[b][l,4]dioxine-6-carbonitrile).
  • Example 4d Synthesis of 4-(4-(3-(4-(7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)piperazin- 1 -yl)propoxy)benzyl)morpholine (AG-0446)
  • H 2 0 2 (35%, 45 mL, 521 mmol) was diluted with dioxane (190 mL).
  • H 2 S0 4 (10.8 mL) was added carefully, the temperature rose to 40°C and kept 1 h at this temperature.
  • 1- (5-Fluoro-2-hydroxy-3-nitrophenyl)ethanone (12.5 g, 62.8 mmol) was added in one portion.
  • boric acid 32 g, 521 mmol
  • the reaction mixture was heated at 80°C for 8 h and cooled to RT overnight. After concentration in vacuo, FLO (250 mL) was added and the formed solids were removed by filtration. The filter cake was rinsed with TBME.
  • Methanesulfonic anhydride (946 mg, 5.4 mmol) was dissolved in MeCN (6 mL), under a N 2 atmosphere. The solution was cooled to -5°C with an ice/water/salt bath. A solution of N-benzyl-bis(2-hydroxyethyl)amine (482 mg, 2.5 mmol) in MeCN (2 mL) was added followed by the addition of Et 3 N (1.0 mL, 7.5 mmol), methanesulfonic acid (385 iL, 5.9 mmol) and a solution of 7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-amine (334 mg, 2.0 mmol) in MeCN (4 mL) respectively.
  • Example 4e Synthesis of 4-(4-(3-(4-(8-chloro-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)piperazin- 1 -yl)propoxy)benzyl)morpholine (AG-0443 ) .
  • HN0 3 (65%, 43 mL) and HN0 3 (90%, 11 mL) were cooled to 10°C with an ice/H 2 0 bath.
  • N-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)acetamide (5 g, 25.9 mmol) was added portion-wise. The temperature was kept below 10°C during addition. A red paste was formed.
  • H 2 0 (54 mL) was added and the mixture was cooled to RT. The solids were isolated by filtration. The filter cake was rinsed with H 2 0. The solids were stirred in acetone (80 mL), isolated by filtration and stripped with toluene (3.1 g, 10.8 mmol, 42%).
  • N-(7,8-Dinitro-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)acetamide (3.06 g, 10.8 mmol) was suspended in EtOH (20 mL).
  • HC1 (37%, 1.1 mL) was added and the solution was heated at reflux temperature for 4 h.
  • the mixture was cooled to RT and the solids were isolated by filtration.
  • the filter cake was rinsed with EtOH. According to MR only -25% product was present.
  • the mother liquor and the isolated solids were added together and HC1 (37%, 3 mL) was added.
  • the mixture was heated at reflux temperature for 7 h.
  • the mixture was cooled to RT and the solids were isolated by filtration.
  • the solids were rinsed with EtOH affording an orange solid (1.5 g, 6.4 mmol, 59%).
  • Methane sulfonic anhydride (416 mg, 2.4 mmol) was dissolved in MeCN (6 mL), under a N 2 atmosphere. The solution was cooled to -5°C with an ice/water/salt bath. A solution of N-benzyl-£ s-(2-hydoxyethoxy)amine (212 mg, 1.1 mmol) in MeCN (2 mL) was added followed by the addition of Et 3 N (0.46 mL, 3.3 mmol), methanesulfonic acid (169 ⁇ , 2.6 mmol) and a solution of 6-methoxy-2,3-dihydrobenzo[b][l,4]dioxin-5- amine (157 mg, 0.87 mmol) in MeCN ( ⁇ 5 mL).
  • the target was prepared by alkylation of 2,4-dimethyl-8-(piperazin-l-yl)-2H- benzo[b][l,4]oxazin-3(4H)-one with l-(4-(3-bromopropoxy)benzyl)piperidine.
  • 2,4-Dimethyl-8-(4-(3-(piperidin-l-ylmethyl)phenoxy)propyl)piperazin-l-yl)-2H- benzo[b][l,4]oxazin -3(4H)-one AG-0198
  • R D 2 (ICso) D 2 (ECso) H 3 antagonist Agonist (nM) (nM) (nM)
  • a functional assay (measurement of intracellular calcium by the aequorin calcium assay) was performed for the dopamine receptor D2.
  • D2L receptor commercially available frozen irradiated cells expressing the human recombinant long isoform of the receptor (i.e. the D2L receptor) were used.
  • a functional assay (measurement of intracellular cAMP by the LANCE ® Ultra cAMP assay) was performed for the histamine receptor H3.
  • LANCE ® Ultra cAMP assay commercially available frozen irradiated cells expressing the human recombinant receptor were used.
  • the development of an AequoScreen ® calcium assay for the dopamine D2L receptor was guided by an article of Brini et al (J. Biol. Chem. 1995; 270: 9896-9903).
  • the AequoScreen ® assay is a cellular aequorin-based assay in which cells are loaded with the apoaequorin cofactor coelenterazine.
  • Aequorin is a photoprotein originating from the jellyfish Aequorea Victoria.
  • the apo-enzyme (apoaequorin) is a 21 kD protein that needs a hydrophobic prosthetic group, coelenterazine, to be converted to aequorin, the active form of the enzyme.
  • This enzyme possesses three calcium binding sites which control its activity.
  • aequorin oxidizes coelenterazine into coelenteramide with production of C0 2 and emission of light.
  • the consumption of aequorin is proportional to the calcium concentration and the measurement of light (luminescence) emitted upon oxidation of coelenterazine is therefore a reliable tool for measurement of intracellular calcium flux resulting from the activation of the D2L receptor by a compound.
  • the compounds were analyzed in duplicate at 6 concentrations (ranging from 0.01 - 1000 nM).
  • the agonistic response of a compound was expressed as % of the control (i.e. the maximal response of the agonist bromocriptine was defined as 100%).
  • the E niax values were determined and EC5 0 values were fitted.
  • the compounds were screened in duplicate at 4 concentrations (ranging from 0.1 - 100 nM) allowing an estimation of their IC50 values.
  • the compounds were incubated for 2 or 15 minutes and bromocriptine was used as reference agonist.
  • the results were expressed as % of the control response (i.e. the response of bromocriptine at its ECgo value was set as 100%) and the IC5 0 values were calculated.
  • Eticlopride was used as reference inhibitor in each experiment (full concentration response curve 0.01 - 10 nM) for the determination of its IC5 0 value.
  • the LANCE ® Ultra cAMP assay is a homogenous TR-FRET immunoassay designed to measure cAMP produced upon modulation of adenylyl cyclase by GPCRs.
  • the assay is based on the competition between an europium (Eu)-chelate labeled cAMP tracer and sample cAMP for binding sites on cAMP-specific monoclonal antibodies labeled with the XJLighfTM dye.
  • Eu-chelate labeled cAMP tracer an europium (Eu)-chelate labeled cAMP tracer and sample cAMP for binding sites on cAMP-specific monoclonal antibodies labeled with the XJLighfTM dye.
  • the energy emitted by the Eu-chelate is transferred by FRET to XJLighfTM molecules on the antibodies, which in turn emit light at 665 nm. Residual energy from the Eu-chelate will produce light at 615 nm. In the absence of free cAMP, maximal TR-FRET signal is achieved. Free cAMP produced by stimulated cells competes with the Eu-cAMP tracer for binding to the XJLighfTM antibodies, causing a decrease in TR-FRET signal.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés répondant à la formule (III), et leurs sels, hydrates et solvats pharmaceutiquement acceptables. Les composés ont des effets antagonistes/agonistes (partiels) du récepteur D2 et des effets antagonistes de H3. L'invention concerne des compositions pharmaceutiques de ces composés et des procédés pour les utiliser pour une application dans la prophylaxie ou le traitement de troubles du SNC.
PCT/NL2014/050772 2013-11-07 2014-11-07 Multiples a(nta)gonistes de d2/antagonistes de h3 pour le traitement de troubles associés au snc WO2015069110A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP13191917.7 2013-11-07
EP13191917 2013-11-07

Publications (1)

Publication Number Publication Date
WO2015069110A1 true WO2015069110A1 (fr) 2015-05-14

Family

ID=49518865

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL2014/050772 WO2015069110A1 (fr) 2013-11-07 2014-11-07 Multiples a(nta)gonistes de d2/antagonistes de h3 pour le traitement de troubles associés au snc

Country Status (1)

Country Link
WO (1) WO2015069110A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004035556A1 (fr) * 2002-10-16 2004-04-29 Glaxo Group Limited Piperazines, (1,4) diazepines, et 2,5-diazabicyclo (2.2.1) heptanes substitues en tant qu'antagonistes de l'histamine h1 et/ou h3 ou antagonistes inverses de l'histamine h3
WO2012003418A2 (fr) * 2010-07-02 2012-01-05 The University Of North Carolina At Chapel Hill Ligands fonctionnellement sélectifs des récepteurs d2 de dopamine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004035556A1 (fr) * 2002-10-16 2004-04-29 Glaxo Group Limited Piperazines, (1,4) diazepines, et 2,5-diazabicyclo (2.2.1) heptanes substitues en tant qu'antagonistes de l'histamine h1 et/ou h3 ou antagonistes inverses de l'histamine h3
WO2012003418A2 (fr) * 2010-07-02 2012-01-05 The University Of North Carolina At Chapel Hill Ligands fonctionnellement sélectifs des récepteurs d2 de dopamine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAN Y ET AL: "Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 20, no. 9, 1 May 2010 (2010-05-01), pages 2983 - 2986, XP027012878, ISSN: 0960-894X, [retrieved on 20100303] *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11274095B2 (en) 2018-04-18 2022-03-15 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof

Similar Documents

Publication Publication Date Title
KR102438302B1 (ko) 리신 특이적 데메틸라제-1의 억제제
US9776974B2 (en) Inhibitors of lysine specific demethylase-1
KR102012057B1 (ko) Lrrk2 조절제로서 아미노피리미딘 유도체
EP1928236B1 (fr) Composes et compositions contenant de la diarylamine, et utilisation en tant que modulateurs de recepteurs de c-kit
CA2710234C (fr) Triazoles substitues par heteroaryle polycyclique utiles comme inhibiteurs de axl
AU2009287621B2 (en) Tri-substituted pyrimidine compounds and their use as PDE10 inhibitors
KR20210040368A (ko) 사이클린 의존성 키나제의 억제제
KR101663635B1 (ko) 크로몬 유도체, 그 제조방법 및 그들의 치료 분야
AU2013363957A1 (en) Histone demethylase inhibitors
AU2011260323A1 (en) Aminopyrimidine derivatives as LRRK2 modulators
US20150166523A1 (en) Branched chain alkyl heteroaromatic ring derivative
CA2785284A1 (fr) Nouveau derive aryl-uree
US8835436B2 (en) Arylpiperazine-containing imidazole 4-carboxamide derivatives and pharmaceutical composition comprising same
JPWO2004110986A1 (ja) ベンズアミド誘導体又はその塩
AU2006275568A1 (en) Dipiperazinyl ketones and related analogues
KR20120112618A (ko) 치환된 이소퀴놀리논 및 퀴나졸리논
WO2015152367A1 (fr) Dérivé cyclique oxo-hétérocyclique
CA3158079A1 (fr) Agonistes de trpml1 heterocycliques
WO2015069110A1 (fr) Multiples a(nta)gonistes de d2/antagonistes de h3 pour le traitement de troubles associés au snc
CN110770214B (zh) 杂环p2x7拮抗剂
JP2014141480A (ja) メチルピペリジン誘導体を含有する医薬
JP2015131802A (ja) 分岐鎖アルキルヘテロ芳香環誘導体を含有する医薬
CA2929742C (fr) Quinazolines substituees par une sulfoximine destinees a des compositions pharmaceutiques
EP2167498B1 (fr) Composés et compositions en tant qu'inhibiteurs de l'itpkb
WO2015087993A1 (fr) Oxazolidine et dérivés d'oxazinane

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14800166

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14800166

Country of ref document: EP

Kind code of ref document: A1