WO2003028728A1 - 4-(piperazinyl-1yle substitue en 4)-butylcarboxamides utilises en tant que ligands selectifs du sous-type de la dopamine d3 - Google Patents

4-(piperazinyl-1yle substitue en 4)-butylcarboxamides utilises en tant que ligands selectifs du sous-type de la dopamine d3 Download PDF

Info

Publication number
WO2003028728A1
WO2003028728A1 PCT/HU2002/000095 HU0200095W WO03028728A1 WO 2003028728 A1 WO2003028728 A1 WO 2003028728A1 HU 0200095 W HU0200095 W HU 0200095W WO 03028728 A1 WO03028728 A1 WO 03028728A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
substituted
phenyl
compound
optionally substituted
Prior art date
Application number
PCT/HU2002/000095
Other languages
English (en)
Other versions
WO2003028728A8 (fr
Inventor
Katalin NÓGRÁDI
János Galambos
Tibor ÁCS
István BORZA
Attila Bielik
György DOMÁNY
Béla Kiss
István Gyertyán
István Laszlovszky
Attila HORVÁTH
Original Assignee
Richter Gedeon Vegyészeti Gyár Rt.
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 Richter Gedeon Vegyészeti Gyár Rt. filed Critical Richter Gedeon Vegyészeti Gyár Rt.
Publication of WO2003028728A1 publication Critical patent/WO2003028728A1/fr
Publication of WO2003028728A8 publication Critical patent/WO2003028728A8/fr

Links

Classifications

    • 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
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile 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
    • C07D213/24—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
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D295/06—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 halogen atoms or nitro radicals
    • C07D295/073—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 halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D295/096—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D295/12—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 or doubly bound nitrogen atoms
    • C07D295/125—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to new D 3 dopamine receptor subtype selective ligands of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, to the processes for producing the same, to pharmacological compositions containing the same and to their use in therapy and/or prevention of a condition which requires modulation of dopamine receptors.
  • the new carboxamide derivatives of formula (I) of the present invention have high affinity at dopamine D 3 receptors and high selectivity over other receptors, especially dopamine D 2 receptors. Due to this high selectivity the undesired side effects of the compounds are much less pronounced.
  • the invention relates to new carboxamide derivatives of formula (I):
  • R 3 is in the position 4 of the piperazinylphenyl moiety
  • Q represents an optionally substituted Ci-ealkyl, Ci- ⁇ alkenyl, phenyl or heteroaryl group; and/or geometric isomers and/or stereoisomers and/or diastereomers and/or the salts and/or hydrates and/or solvates thereof, to the processes for producing the same.to pharmacological compositions containing the same and to their use in therapy and/or prevention of psychoses (e.g. schizophrenia, schizo-affective disorders, etc.), drug (e.g. alcohol, cocaine and nicotine, opioids, etc.) abuse, cognitive impairment accompanying schizophrenia, mild-to-moderate cognitive deficits, amnesia, eating disorders (e.g.
  • psychoses e.g. schizophrenia, schizo-affective disorders, etc.
  • drug e.g. alcohol, cocaine and nicotine, opioids, etc.
  • cognitive impairment accompanying schizophrenia mild-to-moderate cognitive deficits, amnesia, eating disorders (e.
  • bulimia nervosa etc.
  • attention deficit disorders hyperactivity disorders in children, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders (e.g. Parkinson's disease, neuroleptic induced parkinsonism, tardive dyskinesias) anxiety, sexual dysfunction, sleep disorders, emesis, aggression, autism, pain, ophthalmological diseases (e.g. glaucoma, etc.).
  • dyskinetic disorders e.g. Parkinson's disease, neuroleptic induced parkinsonism, tardive dyskinesias
  • anxiety sexual dysfunction
  • sleep disorders emesis
  • aggression aggression
  • autism pain
  • ophthalmological diseases e.g. glaucoma, etc.
  • the invention relates to new carboxamide derivatives of formula (I):
  • R 3 Ci-e alkoxy in the position 2 or
  • R 3 is in the position 4 of the piperazinylphenyl moiety
  • Q represents an optionally substituted Ci- ⁇ alkyl, C ⁇ . ⁇ alkenyl, phenyl or heteroaryl group; and/or geometric isomers and/or stereoisomers and/or diastereomers and/or the salts and/or hydrates and/or solvates thereof.
  • a heteroaryl ring in the meaning of Q may be monocyclic, bicyclic or tricyclic ring.
  • the monocyclic heteroaryl ring may be an optionally substituted 5- or 6- membered aromatic heterocyclic group.
  • the 5- and 6-membered heterocyclic group is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl and pyrazolyl, preferably pyridyl, thienyl, pyrimidinyl and pyrazinyl.
  • the bicyclic heteroaromatic group is indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[1 ,5-a]pyrimidyl, pyrrolo[3,2-b]pyridyl, thieno[3,2-b]thiophenyl, 1 ,2-dihydro- 2-oxo-quinolinyl, 2,3-dihydro-3-oxo-4H-benoxazinyl, 1 ,2-dihydro-2-oxo-3H-indolyl, preferably quinolinyl, benzofuranyl, benzothiophenyl, benzthiazolyl,
  • the tricyclic heteroaromatic group is ⁇ -carbolinyl.
  • Ri, R 2 and R 3 may be the same or different.
  • R 3 trifluoromethyl in the position 3 of the piperazinylphenyl moiety.
  • the substituents of C ⁇ -6alkanoyloxy in the meaning of Ri are selected from hydrogen or halogen.
  • amino, aminoalkyl, aminocarbonyl, N-hydroxycarbamimidoyl, carbamimidoyl, hydroxycarbamoyl, thiocarbamoyl and sulfamoyl groups in the meaning of R 1 t R 2 and R 3 may optionally be substituted on the N atom.
  • the mono or bicyclic heterocyclic group in the meaning of Ri, R 2 and R 3 may be saturated or unsaturated containing 1 to 4-heteroatoms selected from O, N or S.
  • alkanoyl, alkanoylamino, alkanoyloxy groups may be straight or branched included methyl, ethyl, n-propyl, n-butyl, n-pentyl- n-hexyl and branched isomers thereof, such as isopropyl, t-butyl, sec-butyl, and the like.
  • the alkenyl moiety in the meaning of heteroalkenyl in Q may have 1 to 6 carbon atoms and 1 to 3 double bonds.
  • the halogen substituent(s) in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine, preferably fluorine, bromine and chlorine.
  • the invention relates also to the salts of compounds of formula (I) formed with acids.
  • Both organic and inorganic acids can be used for the formation of acid addition salts.
  • Suitable inorganic acids can be for example hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
  • Representatives of monovalent organic acids can be for example formic acid, acetic acid, propionic acid, and different butyric acids, valeric acids and capric acids.
  • Representatives of bivalent organic acids can be for example oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid.
  • organic acids can also be used, such as hydroxy acids for example citric acid, tartaric acid, or aromatic carboxylic acids for example benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids for example methanesulfonic acid, naphtalenesulfonic acid and p-toluenesulfonic acid.
  • hydroxy acids for example citric acid, tartaric acid, or aromatic carboxylic acids for example benzoic acid or salicylic acid
  • aliphatic and aromatic sulfonic acids for example methanesulfonic acid, naphtalenesulfonic acid and p-toluenesulfonic acid.
  • acid addition salts are pharmaceutically acceptable acid addition salts.
  • Certain compounds of formula (I) can exist in the form of cis- and/or trans- isomers and/or stereoisomers and/or diastereomers. These are likewise within the scope of the present invention including all such isomers and the mixtures thereof.
  • the invention relates also to the salts of compounds of formula (I) formed with acids, especially the salts formed with pharmaceutically acceptable acids, the meaning of compound of formula (I) is either the free base or the salt even if it is not referred separately.
  • Preferred compounds of the invention are those compounds of formula (I) wherein
  • R 3 represents halogen, C ⁇ - 6 alkyl, cyano, hydroxy, trifluoromethyl,
  • C ⁇ - 6 alkanoyloxy optionally substituted amino, carboxy, aminocarbonyl, N-hydroxycarbamimidoyl, carbamimidoyl, hydroxycarbamoyl, thiocarbamoyl, sulfamoyl, optionally substituted phenyl or naphthyl, optionally substituted mono or bicyclic heterocyclic group in the 2 or 3 position of the piperazinylphenyl moiety, or
  • R ⁇ H
  • R 2 and R 3 independently represent halogen, Ci-ealkyl, Ci- ⁇ alkoxy, cyano, hydroxy, trifluoromethyl, C ⁇ - 6 alkylsulfonyloxy, trifluoromethanesulfonyloxy, optionally substituted Ci- ⁇ alkanoyloxy, optionally substituted amino, carboxy, aminocarbonyl, N-hydroxycarbamimidoyl, carbamimidoyl, hydroxycarbamoyl, thiocarbamoyl, sulfamoyl, optionally substituted phenyl or naphthyl, optionally substituted mono or bicyclic heterocyclic groups in the 2,3-, 2,4- or 3,5 positions of the piperazinylphenyl moiety, whereby two adjacent groups of R 2 and R 3 may combine to form an optionally substituted fused mono or bicyclic heterocyclic group; or
  • R 1( R 2 and R 3 independently represent halogen, C ⁇ - 6 alkyl, C ⁇ -6alkoxy, cyano, hydroxy, trifluoromethyl, optionally substituted amino, aminocarbonyl or optionally substituted phenyl or naphthyl groups in the
  • Q represents optionally substituted thienyl, pyridyl, pyrimidyl, pyrazinyl, quinolinyl, benzofuranyl, benzothiophenyl, benzthiazolyi, benzimidazolyl, indolyl, ⁇ -carbolinyl; Ci-ealkyl substituted by an optionally substituted aryl or heteroaryl group; Ci- ⁇ alkenyl substituted by an optionally substituted aryl or heteroaryl group; phenyl substituted by bromine, Ci-
  • the invention also relates to the pharmaceutical compositions containing the compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or the salts and/or hydrates and/or solvates thereof as active ingredient.
  • the present invention also provides a process for preparing compounds of formula (I) by forming an amide bond between a carboxylic acid of formula (II):
  • the amide bond formation may be carried out by known methods, preferably by preparing an active derivative from a carboxylic acid of formula (II) and this active derivative is reacted with an amine of formula (III) in the presence of a base.
  • the transformation of a carboxylic acid into an active derivative may be carried out in situ during the amide bond formation in a suitable solvent (for example dimethylformamide, acetonitrile, tetrahydrofurane, chlorinated hydrocarbons or hydrocarbons).
  • a suitable solvent for example dimethylformamide, acetonitrile, tetrahydrofurane, chlorinated hydrocarbons or hydrocarbons.
  • the active derivatives can be acid chlorides (prepared for example from carboxylic acid with thionyl chloride), mixed anhydrides (prepared for example from carboxylic acid with isobutyl chloroformate in the presence of a base, e.g. triethylamine), active esters (prepared for example from carboxylic acid with hydroxybenztriazole and dicyclohexyl carbodiimide in the presence of a base e.g. triethylamine).
  • the active derivatives can be prepared advantageously between -10°C and the reflux temperature of the solvent used.
  • an appropriate amine of formula (III) is added in a form of base or of a salt formed with organic or inorganic acid.
  • the condensation reactions are followed by thin layer chromatography.
  • the necessary reaction time is about 6-20 h.
  • the work-up of the reaction mixture can be carried out by different methods.
  • the products can be purified by known methods, for example by crystallization or by column chromatography.
  • the structures of the products are determined by IR, NMR and mass spectroscopy. Where they are not commercially available, the carboxylic acids of formula (II) may be prepared by procedures described in literature (e.g.
  • the amines of formula (III) may be prepared by alkylation of compounds of formula (IV):
  • compound (IV) may be reacted with N-(4- bromobutyl)phthalimide followed by the removal of the phthaloyl group to give compound (III) or, where Ri, R 2 and R 3 are indifferent towards reducing agents, by alkylation with 4-bromobutyronitrile followed by reduction of the cyano group.
  • the piperazines of formula (IV) may be prepared by known methods.
  • a properly substituted aniline may be reacted with bis-(2-hydroxy-ethyl)amine and aquaeous hydrobromic acid (e.g. USP 2 830 056), with bis-(2-chloro-ethyl)amine hydrochloride (e.g. J. Med. Chem. 1997, 40, 2674) or with bis-(2-bromo-ethyl)amine (e.g. Collect. Czech. Chem. Comm ⁇ n. 1934, 211).
  • An other procedure may be the reaction of a properly substituted arylhalogenide with piperazine (e.g. J. Med. Chem. 1989, 32, 1052; Tetrahedron Lett. 1999, 40, 5661).
  • Ri and R 2 are the same or different and represent hydrogen, halogen, Ci- ealkyl, Ci- ⁇ alkoxy, cyano, hydroxy, trifluoromethyl, C ⁇ - 6 alkylsulfonyloxy, trifluoromethanesulfonyloxy, optionally substituted Ci- ⁇ alkanoyloxy, amino, aminoalkyl, carboxy, aminocarbonyl, N-hydroxycarbamimidoyl, carbamimidoyl; hydroxycarbamoyl, thiocarbamoyl, sulfamoyl, optionally substituted phenyl or naphthyl, optionally substituted mono or bicyclic heterocyclic group, two adjacent groups of Ri and R 2 may combine to form an optionally substituted fused mono or bicyclic heterocyclic group, and R 3 is optionally substituted phenyl, excluding when
  • the new piperazine derivatives of formula (IV), wherein R 1 ( R 2 and R 3 have the same meaning as defined above, and/or salts and/or hydrates and/or solvates thereof may be prepared by various methods known in the art. One of them is as follows: protecting the secondary amine of a piperazin derivative of formula (IV):
  • Ri and R 2 are as defined above, and
  • R 3 is halogen
  • R' and R" are the same or different and represent hydrogen, halogen, trifluoromethyl, C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy, C ⁇ - 6 alkanoyloxy, amino or alkyl amino; in the presence of a catalyst applied usually in Suzuki coupling and a base; and finally by deprotecting the piperazine derivative obtained; and thereafter optionally forming a salt and/or hydrate and/or solvate of formula (IV), wherein Ri, R 2 and R 3 are as defined above.
  • the process for producing new piperazine derivatives of formula (IV) are also included within the scope of the present invention.
  • the piperazines of formula (IV) are key intermediates for producing acid amide derivatives exhibiting selective dopamine D 3 receptor activity.
  • the use of piperazines of formula (IV) as intermediates for producing acid amide derivatives exhibiting selective dopamine D 3 receptor activity is also included within the scope of the present invention.
  • the compounds of formula (I) can also be obtained by the reaction of a compound of formula (IV) or derivatives thereof with a compound of formula (V):
  • the reaction may be carried out in an inert solvent, for example, acetone, dimethylformamide and acetonitrile in the presence of a base (e.g. sodium hydrogencarbonate or potassium carbonate).
  • a base e.g. sodium hydrogencarbonate or potassium carbonate.
  • the reaction temperature is usually between room temperature and the reflux temperature of the solvent used, and the reaction time varies from a few hours to approximately 20 hours.
  • the compounds of formula (I) may also be obtained by the reaction of a compound of formula (IV) or derivatives thereof with a compound of formula (VI):
  • reaction may be carried out in an inert solvent (e.g. chlorinated hydrocarbons, alkanols or ethers) in the presence of a reductive agent, for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a reductive agent for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the reaction temperature is usually between 0°C and room temperature.
  • the necessary reaction time is about 2-24 h.
  • the obtained carboxamide derivatives of formula (I) - independently from the method of preparation - in a given case can be transformed into an other compound of formula (I) by introducing further substituent(s) and/or modifying and/or removing the existing one(s), and/or formation of salts with acids and/or liberating the carboxylic acid amide derivative of formula (I) from the obtained acid addition salts by treatment with a base.
  • a base for example cleaving the methyl group from a methoxy group leads to phenol derivatives.
  • the cleavage of methyl group can be carried out, e.g. with boron tribromide in dichloromethane solution.
  • the compounds of formula (I) containing free phenolic hydroxy group can be transformed into acyloxy or sulfonyloxy derivatives thereof with different acylating or sulfonylating agents.
  • the reactions may be carried out at room temperature in chlorinated hydrocarbons using acid chloride or acid anhydride as acylating agent in the presence of a base (e.g. triethylamine or sodium carbonate).
  • a base e.g. triethylamine or sodium carbonate.
  • the compounds of formula (I) containing cyano groups can be, e.g. transformed to amides by hydrolysis with hydrogenperoxide in dimethylsulfoxide, or to amidines via forming iminoester with gaseous hydrochloric acid in ether, followed by treatment with ammonia, etc.
  • the carboxamide derivatives of formula (I) can also be prepared on solid support in the following way.
  • a protected 4-aminobutanol derivative e.g. triisopropylsilanyloxy-butylamine is attached to a polystyrene resin e.g. 4-formyl-3-methoxy-phenoxy polystyrene by reductive amination, e.g. with NaB(OAc) 3 H or NaBH 3 CN (i), followed by acylation the amino group with a carboxylic acid of formula (II):
  • the compounds of formula (I) of the present invention have been found to exhibit high affinity and selectivity for D 3 receptors, and are expected to be useful in the treatment and/or prevention of disease states in which the dopamine D 3 receptors are involved in disease pathology and thus their modulation is required.
  • the compounds of formula (I) have also been found to have greater affinity for dopamine D 3 than for D 2 receptors.
  • the compounds of formula (I) may therefore advantageously be used as modulators of D 3 receptors being selective over D 2 receptors.
  • Dysfunction of the dopaminergic neurotransmitter system is involved in the pathology of several neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and drug abuse.
  • the effect of dopamine is mediated via at least five distinct dopamine receptors belonging to the D (D ⁇ , D 5 ) or the D 2 - (D 2 , D 3) D 4 ) families.
  • D 3 receptors have been shown to have characteristic distribution in the cerebral dopaminergic systems. Namely, high densities were found in certain limbic structures such as nucleus accumbens and islands of Calleja.
  • D 3 receptors may be a promising approach for more selective modulation of dopaminergic functions and consequently for successful therapeutic intervention in several abnormalities such as schizophrenia, emotional or cognitive dysfunctions (Sokoloff, P. et al.: Nature 1990, 347, 146; Schwartz, J.C. et al.: Clin. Neuropharmacol. 1993, 16, 295; Levant, B.: Pharmacol. Rev. 1997, 49, 231), addiction (Pilla, C. et al.: Nature 1999, 400, 371) and Parkinson's disease (Levant, B. et al.: CNS Drugs 1999, 12, 391) or pain (Levant, B. et al.: Neurosci. Lett. 2001, 303, 9).
  • Dopamine D 3 receptors are implicated in regulation of intraocular pressure and agonists at these receptor are capable of decreasing the intraocular pressure (Chu, E. et al: J. Pharmacol. Exp. Ther. 2000, 292, 710), thus D 3 receptor agonists can be useful for the treatment of glaucoma.
  • This invention provides novel compounds of formula (I) which are D 3 dopamine receptor subtype selective ligands. Certain compounds of formula (I) have been found to be dopamine D 3 receptor antagonist, others may be full or partial agonists. Thus, the invention provides compounds of formula (I) useful in the treatment and/or prevention of neuropsychological disorders including, but not limited to psychoses (e.g.
  • schizophrenia, schizo-affective disorders, etc. drugs (e.g. alcohol, cocaine and nicotine, opioids, etc.) abuse, cognitive impairment accompanying schizophrenia, mild-to-moderate cognitive deficits, amnesia, eating disorders (e.g. bulimia nervosa, etc.), attention deficit hyperactivity disorder in children, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders (e.g. Parkinson's disease, neuroleptic induced parkinsonism, tardive dyskinesias) anxiety, sexual disorders, sleep disorders, emesis, aggression, autism, pain, ophthalmological diseases (e.g. glaucoma, etc.).
  • drug e.g. alcohol, cocaine and nicotine, opioids, etc.
  • cognitive impairment accompanying schizophrenia mild-to-moderate cognitive deficits, amnesia, eating disorders (e.g. bulimia nervosa, etc.)
  • attention deficit hyperactivity disorder in children psychotic depression, mania, paranoid and delusional disorders
  • the invention also provides the use of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or the physiologically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment and/or prevention of conditions which require modulation of dopamine D 3 receptors.
  • D 3 antagonists are in the treatment of schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders such as Parkinson's disease, neuroleptic induced parkinsonism, depression, anxiety, memory disorders, sexual dysfunction.drug abuse and pain.
  • D 3 agonists or partial agonists according to the present invention is in the treatment of drug abuse (such as cocaine abuse etc.) and eye diseases (such as glaucoma).
  • the compounds of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof of the present invention are usually administered as a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a new compound of formula (I), and or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof and a physiologically acceptable carrier.
  • the compounds of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof of the present invention may be administered by any convenient method, for example by oral, parental, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof of the present invention which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation of the compounds of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof of the present invention generally consists of a suspension or solution of the compound of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the solid form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose, cellulose, etc.
  • a composition in the solid form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof of the present invention in a steril aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration containing a compound of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in a single or multidose quantities in steril form is a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • the aerosol dosages form can also take the form af a pump-atomiser.
  • Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional supposiory base, such as cocoa butter.
  • Compositions for transdermal administration include ointments, gels and patches.
  • the composition containing a compound of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof of the present invention is preferably in the unit dose form such as tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1-25 mg) of a compound of formula (I) and/or geometric isomer and/or stereoisomer and/or diastereomer and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof calculated as a free base.
  • the physiologically acceptable compounds of the present invention may normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose between 1 mg and 500 mg, preferably between 10 mg and 400 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g.
  • the compounds of the present invention can be administered 1 to 4 times per day.
  • the compounds of the present invention will suitably be administered for a period of continous therapy, for example for a week or more.
  • Binding study was carried out on rat recombinant D 3 receptors expressed in Sf9 cells using [ 3 H]-spiperone (0.4 nM) as ligand and haloperidol (10 ⁇ M) for determination of non-specific binding.
  • the assay was performed according to Research Biochemical International assay protocol for D 3 receptor (Cat. No. D- 181 ). 2. D 2 receptor binding
  • Binding of [ 3 H]-spiperone (0.5 nM) to rat striatal tissue was measured according to the method of Seeman (J. Neurochem. 1984, 43, 221). The nonspecific binding was determined in the presence of ( ⁇ )-sulpiride (10 ⁇ M).
  • D 3 and D 2 receptor binding data of selected compounds of the invention are listed in the Table hereinbelow.
  • the former one is the result of blockade of D 2 receptors in the basal ganglia whereas the latter is the consequence of antagonism of alpha-1 receptors.
  • Compounds in the above table are potent ligands at D 3 receptors (IC-50 values are between 0.2-5.5 nM) and show 47-to 1200-fold selectivity over D 2 receptors.
  • the compounds have beneficial profile in terms of potency on D 3 receptors and selectivity towards D 2 receptors than the known D 3 receptor ligands described in the literatute. It is therefore anticipated that no or greatly diminished adverse effects related to D 2 receptors will occur in the course of therapeutical application of compounds of the present invention.
  • the solution was decolorized with 5g of carbon and the pH was adjusted to 4.5 with 5N aqueous hydrochloric acid.
  • the suspension was cooled to 10°C and filtered.
  • the solid was washed with ice water (2 x 50 ml) and dried in vacuo at 140°C overnight to give the title compound, 16.7g (72% ) melting at 312-315°C.
  • the resin was filtered, and washed twice with 400-400ml,, of the following solvents in sequence: dichloromethane, methanol, 10 % triethylamine in dimethylformamide, methanol, dimethylformamide, tetrahydrofuran.
  • the resin was dried in vacuo to give 12.9g of the title material.
  • the resin was filtered, washed in sequence with 2x4ml of dimethylformamide, 2 x 4ml of methanol, 2 x 4ml of tetrahyrofuran, 2 x 4ml of methanol and 2 x 4 ml of tetrahydrofuran.
  • the resin was filtered, washed in sequence with 2 x 4ml of tetrahydrofuran, 2 x 4ml of methanol, 2 x 4ml of dichloromethane, 2 x 4ml of methanol, 2 x 4 ml of tetrahydrofuran, 2 x 4ml of methanol and 2 x 4ml of dichloromethane.
  • the resin was filtered, washed in sequence with 2 x 4ml of dimethylformamide, 2 x 4ml of methanol, 2 x 4ml of dichloromethane, 2 x 4ml of dimethylformamide and 3 x 2ml of dichloromethane.
  • LC/MS analysis was performed using an HP1100 binary gradient system, controlled by ChemStation software.
  • Analytical chromatographic experiments were made on Discovery Ci 6 -Amide, 5cm X 4.6mm X 5 ⁇ m column with a flow rate of 1 ml/min for qualification (purity, capacity factor). All experiments were performed using HP MSD single quadruple mass spectrometer equipped with an electrospray ionisation source to determine the structure.
  • Buffer suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent typically water but may also include cyclodextrins (1 -100 mg) and co-solvents, such as propylene glycol, polyethylene glycol and alcohol.
  • Disintegrant may also include cyclodextrins 5-50 mg Lubricant 1-5 mg
  • Diluent e.g. mycrocrystalline cellulose, lactose starch.
  • Binder e.g. polyvinylpyrrolidone, hydroxypropylmethylcellulose.
  • Disintegrant e.g. sodium starch glycolate, crospovidone.
  • Lubricant e.g. magnesium stearate, sodium stearyl fumarate
  • Suspending agent e.g. xanthan gum, mycrocrystalline cellulose.
  • Diluent e.g. sorbitol solution, tipically water.
  • Preservative e.g. sodium benzoate.
  • Buffer e.g. citrate.
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin.

Abstract

L'invention concerne des nouveaux ligands sélectifs du sous-type du récepteur de la dopamine D3 de formule (I), dans laquelle R1, R2 et R3 représentent indépendamment des substituants choisis parmi hydrogène, halogène, alkyle C1-6, alcoxy C1-6, cyano, hydroxy, trifluorométhyle, alkylsulfonyloxy C1-6, trifluorométhanesulfonyloxy, alcanoyloxy C1-C6 éventuellement substitué, amino, aminoalkyle, carboxy, aminocarbonyle, N-hydroxycarbamimidoyle, carbamimidoyle, hydroxycarbamoyle, thiocarbamoyle, sulfamoyle, naphtyle ou phényle éventuellement substitué, groupe mono ou bicyclique hétérocyclique fusionné éventuellement substitué, deux groupes adjacents de R1, R2 et R3 peuvent se combiner pour former un groupe hétérocyclique mono ou bicyclique, à l'exception de composés dans lesquels a) R1=R2=R3=H, b) R1=R2=H et R3= alcoxy C1-6 en position 2 ou R3 en position 4 du fragment pipérazinylphényle ; c) R1=H et R2=R3=alcoxy C1-6 ; Q représente un groupe hétéroaryle, phényle, alcényle C1-6, ou alkyle C1-6 éventuellement substitué.
PCT/HU2002/000095 2001-09-28 2002-09-25 4-(piperazinyl-1yle substitue en 4)-butylcarboxamides utilises en tant que ligands selectifs du sous-type de la dopamine d3 WO2003028728A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0103987 2001-09-28
HU0103987A HUP0103987A3 (en) 2001-09-28 2001-09-28 Phenylpiperazinylalkyl carboxylic acid amid derivatives, process for their preparation, pharmaceutical compositions containing them and their intermediates

Publications (2)

Publication Number Publication Date
WO2003028728A1 true WO2003028728A1 (fr) 2003-04-10
WO2003028728A8 WO2003028728A8 (fr) 2005-04-07

Family

ID=89979731

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2002/000095 WO2003028728A1 (fr) 2001-09-28 2002-09-25 4-(piperazinyl-1yle substitue en 4)-butylcarboxamides utilises en tant que ligands selectifs du sous-type de la dopamine d3

Country Status (2)

Country Link
HU (1) HUP0103987A3 (fr)
WO (1) WO2003028728A1 (fr)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004004729A1 (fr) * 2002-07-04 2004-01-15 Schwarz Pharma Ag Heteroarene-carboxamides utilises comme ligands de la dopamine d3 pour traiter des maladies du snc
WO2006008133A2 (fr) * 2004-07-20 2006-01-26 Siena Biotech S.P.A. Modulateurs des recepteurs nicotiniques d'acetylcholine alpha7 et leurs utilisations therapeutiques
WO2004112729A3 (fr) * 2003-06-19 2006-02-16 Psychiatric Genomics Inc Composes a fonction duale et leurs utilisations
WO2006015737A1 (fr) * 2004-08-02 2006-02-16 Schwarz Pharma Ag Carboxamides d'indolizine et leurs aza- et diaza-derives
WO2006050976A1 (fr) * 2004-11-12 2006-05-18 Schwarz Pharma Ag Carboxamides d'azaindole
DE102004063797A1 (de) * 2004-12-30 2006-07-13 Schwarz Pharma Ag Sauerstoffhaltige annelierte Phenylpiperazin- und Phenyldiazepancarboxamide
EP1683790A1 (fr) * 2005-01-24 2006-07-26 Institut National De La Sante Et De La Recherche Medicale (Inserm) Dérivés de 3,4-dihydro-2-naphtamide comme ligands selectifs de la dopamine D3
WO2006082456A1 (fr) 2005-02-03 2006-08-10 Richter Gedeon Vegyészeti Gyár Rt. Cyclohexylamides servant d'antagonistes de la dopamine d3 , d2 et de 5ht1a
EP1733727A1 (fr) * 2002-07-04 2006-12-20 Schwarz Pharma Ag Dérivés ferrocenecarboxamide utiles comme des ligands dopamine D3 pour traiter des troubles du système nerveux central
WO2007099828A1 (fr) * 2006-02-23 2007-09-07 Shionogi & Co., Ltd. Derives heterocycliques azotes substitues par des groupes cycliques
WO2008009741A1 (fr) * 2006-07-21 2008-01-24 Pierre Fabre Medicament Nouveaux dérivés de type carboxamide de chromène et de thiochromène, leurs méthodes de synthèse et leurs applications thérapeutiques
US7345178B2 (en) 2005-08-04 2008-03-18 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
WO2008043839A1 (fr) * 2006-10-13 2008-04-17 Università Degli Studi Di Siena Dérivés d'arylpipérazine utiles pour le traitement de troubles neuropsychiatriques
JP2008526715A (ja) * 2005-01-03 2008-07-24 ユニベルシタ デグリ ストゥディ ディ シエナ 神経精神障害の治療のためのアリールピペラジン誘導体
WO2009112568A1 (fr) * 2008-03-14 2009-09-17 Neurosearch A/S Nouveaux dérivés de quinolinylamide utiles comme modulateurs des récepteurs de la dopamine et de la sérotonine
CN1948298B (zh) * 2006-11-09 2010-09-01 东南大学 一种多巴胺d3受体部分激动剂及其应用
US7829556B2 (en) 2007-06-20 2010-11-09 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US20110178091A1 (en) * 2008-10-02 2011-07-21 Green Cross Corporation Arylpiperazine-containing pyrrole 3-carboxamide derivatives for treating depressive disorders
JP2012505165A (ja) * 2008-10-10 2012-03-01 インスティチュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 新規なドーパミンｄ３受容体リガンド、その調製及び使用
US8163729B2 (en) 2007-01-16 2012-04-24 Wyeth Modulators of α7 nicotinic acetylcholine receptors and therapeutic uses thereof
WO2014059265A1 (fr) 2012-10-11 2014-04-17 Southern Research Institute Dérivés urée et amide d'aminoalkylpipérazines et leur utilisation
WO2015007615A1 (fr) * 2013-07-18 2015-01-22 Fondazione Istituto Italiano Di Tecnologia Phenyl carbamates et leur utilisation comme inhibiteurs de l'enzyme hydrolase d'amides d'acides gras (faah) et modulateurs du récepteur d3 de la dopamine (d3dr)
CN104672135A (zh) * 2014-12-22 2015-06-03 中国人民解放军成都军区总医院 新型喹啉-4-甲酰胺衍生物、其制备方法以及含该衍生物的药物组合物及其医药用途
US9227944B2 (en) 2008-10-10 2016-01-05 Institute Of Pharmacology And Toxicology Academy Of Military Science P.L.A. China Dopamine D3 receptor ligands and preparation and medical uses of the same
CN106966953A (zh) * 2017-03-07 2017-07-21 深圳市老年医学研究所 一种新型多巴胺d3受体选择性配体的制备方法及其应用
WO2017160552A1 (fr) * 2016-03-14 2017-09-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antagonistes/agonistes partiels sélectifs du récepteur d3 de la dopamine ; procédé de préparation ; et utilisation associée
US20180078548A1 (en) * 2016-09-22 2018-03-22 The National Institute for Biotechnology in the Negev Ltd. Methods for Treating Central Nervous System Disorders Using VDAC Inhibitors
CN108290889A (zh) * 2015-09-14 2018-07-17 内盖夫国家生物技术研究所 新的哌嗪和哌啶衍生物、它们的合成及其在抑制vdac寡聚化、细胞凋亡和线粒体功能障碍中的用途
WO2018153297A1 (fr) * 2017-02-24 2018-08-30 深圳市灵兰生物医药科技有限公司 Nouveau ligand sélectif pour le récepteur dopaminergique d3, procédé de préparation correspondant et application pharmaceutique correspondante
US10392378B2 (en) * 2014-12-23 2019-08-27 Proteostasis Therapeutics, Inc. Derivatives of 5-phenyl- or 5-heteroarylathiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10787423B2 (en) 2015-09-14 2020-09-29 The National Institute For Biotechnolgy In The Negev Ltd. Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction
US11299476B2 (en) 2016-03-14 2022-04-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Dopamine D3 receptor selective antagonists/partial agonists; method of making; and use thereof
US11337971B2 (en) 2018-09-11 2022-05-24 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Dopamine D3 receptor selective antagonists/partial agonists and uses thereof

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2261756A1 (en) * 1974-02-27 1975-09-19 Roussel Uclaf 2-Thiazole-N-(Piperazino or piperidino) alkyl carboxamides - as hypotensive and anti-hypertensive agents of low toxicity
EP0210782A2 (fr) * 1985-07-19 1987-02-04 Dainippon Pharmaceutical Co., Ltd. Composés de pyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0434561A2 (fr) * 1989-12-20 1991-06-26 Adir Et Compagnie Dérivés de la napht-1-yl pipérazine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO1993021179A1 (fr) * 1992-04-09 1993-10-28 Aktiebolaget Astra Nouvelle piperazine d'aminoalkyle et d'iminoalkyle
WO1996002249A1 (fr) * 1994-07-15 1996-02-01 Basf Aktiengesellschaft Utilisation de composes de thiazole et de thiadiazole comme ligands du recepteur de la dopamine d3
WO1996002246A1 (fr) * 1994-07-15 1996-02-01 Basf Aktiengesellschaft Utilisation de composes heterocycliques comme ligands de la dopamine-d¿3?
WO1997010229A1 (fr) * 1995-09-13 1997-03-20 Neurogen Corporation Nouveaux n-aminoalkylfluorenecarboxamides; nouvelle classe de ligands specifiques de sous-types de recepteurs dopaminergiques
WO1997034889A1 (fr) * 1996-03-21 1997-09-25 Neurogen Corporation N-aminoalkyldibenzothiophene carboxamides; ligands specifiques d'un sous-type de recepteur de la dopamine
WO1997038990A1 (fr) * 1996-04-15 1997-10-23 Neurogen Corporation Nouveaux n-aminoalkyl-1-biphenylenyl-2-carboxamides; nouveaux ligands specifiques de sous-types de recepteurs de la dopamine
WO1997038989A1 (fr) * 1996-04-18 1997-10-23 Neurogen Corporation N-aminoalkyl-2-anthraquinonecarboxamides; nouveaux ligands specifiques de sous-types de recepteurs de la dopamine
WO1999002503A1 (fr) * 1997-07-07 1999-01-21 Basf Aktiengesellschaft Composes de triazole et leur utilisation comme ligands de la dopamine d¿3?
WO1999003833A1 (fr) * 1997-07-15 1999-01-28 Sankyo Company, Limited Derives de piperazine
US5872119A (en) * 1995-12-11 1999-02-16 Institut National De La Sante et De La Recherche Medicale--INSERM 2-Naphthamide derivatives and their therapeutic applications
DE19756236A1 (de) * 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue piperazinylsubstituierte Pyridylalkan-, alken- und -alkincarbonsäureamide
WO2000067847A2 (fr) * 1999-05-07 2000-11-16 Basf Aktiengesellschaft Utilisation de ligands du recepteur de la dopamine d3 pour la production de medicaments servant au traitement de dysfonctionnements renaux
WO2002055496A1 (fr) * 2001-01-15 2002-07-18 Glaxo Group Limited Derives aryle de piperidine et de piperazine comme inducteurs de l'expression du recepteur ldl

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2261756A1 (en) * 1974-02-27 1975-09-19 Roussel Uclaf 2-Thiazole-N-(Piperazino or piperidino) alkyl carboxamides - as hypotensive and anti-hypertensive agents of low toxicity
EP0210782A2 (fr) * 1985-07-19 1987-02-04 Dainippon Pharmaceutical Co., Ltd. Composés de pyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0434561A2 (fr) * 1989-12-20 1991-06-26 Adir Et Compagnie Dérivés de la napht-1-yl pipérazine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO1993021179A1 (fr) * 1992-04-09 1993-10-28 Aktiebolaget Astra Nouvelle piperazine d'aminoalkyle et d'iminoalkyle
WO1996002249A1 (fr) * 1994-07-15 1996-02-01 Basf Aktiengesellschaft Utilisation de composes de thiazole et de thiadiazole comme ligands du recepteur de la dopamine d3
WO1996002246A1 (fr) * 1994-07-15 1996-02-01 Basf Aktiengesellschaft Utilisation de composes heterocycliques comme ligands de la dopamine-d¿3?
WO1997010229A1 (fr) * 1995-09-13 1997-03-20 Neurogen Corporation Nouveaux n-aminoalkylfluorenecarboxamides; nouvelle classe de ligands specifiques de sous-types de recepteurs dopaminergiques
US5872119A (en) * 1995-12-11 1999-02-16 Institut National De La Sante et De La Recherche Medicale--INSERM 2-Naphthamide derivatives and their therapeutic applications
WO1997034889A1 (fr) * 1996-03-21 1997-09-25 Neurogen Corporation N-aminoalkyldibenzothiophene carboxamides; ligands specifiques d'un sous-type de recepteur de la dopamine
WO1997038990A1 (fr) * 1996-04-15 1997-10-23 Neurogen Corporation Nouveaux n-aminoalkyl-1-biphenylenyl-2-carboxamides; nouveaux ligands specifiques de sous-types de recepteurs de la dopamine
WO1997038989A1 (fr) * 1996-04-18 1997-10-23 Neurogen Corporation N-aminoalkyl-2-anthraquinonecarboxamides; nouveaux ligands specifiques de sous-types de recepteurs de la dopamine
WO1999002503A1 (fr) * 1997-07-07 1999-01-21 Basf Aktiengesellschaft Composes de triazole et leur utilisation comme ligands de la dopamine d¿3?
WO1999003833A1 (fr) * 1997-07-15 1999-01-28 Sankyo Company, Limited Derives de piperazine
DE19756236A1 (de) * 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue piperazinylsubstituierte Pyridylalkan-, alken- und -alkincarbonsäureamide
WO2000067847A2 (fr) * 1999-05-07 2000-11-16 Basf Aktiengesellschaft Utilisation de ligands du recepteur de la dopamine d3 pour la production de medicaments servant au traitement de dysfonctionnements renaux
WO2002055496A1 (fr) * 2001-01-15 2002-07-18 Glaxo Group Limited Derives aryle de piperidine et de piperazine comme inducteurs de l'expression du recepteur ldl

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOYFIELD I ET AL: "N-(substituted-phenyl) piperazines: antagonists with high binding and functional selectivity for dopamine D4 receptors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 6, no. 11, 4 June 1996 (1996-06-04), pages 1227 - 1232, XP004134859, ISSN: 0960-894X *
MURRAY P J ET AL: "A novel series of arylpiperazines with high affinity and selectivity for the dopamine D3 receptor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 5, no. 3, 2 February 1995 (1995-02-02), pages 219 - 222, XP004135762, ISSN: 0960-894X *

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1733727A1 (fr) * 2002-07-04 2006-12-20 Schwarz Pharma Ag Dérivés ferrocenecarboxamide utiles comme des ligands dopamine D3 pour traiter des troubles du système nerveux central
JP2005538974A (ja) * 2002-07-04 2005-12-22 シュバルツ　ファルマ　アクチェンゲゼルシャフト 中枢神経系の病気を治療するドーパミン−ｄ３リガンドとして使用するためのヘテロアレーンカルボキサミド
WO2004004729A1 (fr) * 2002-07-04 2004-01-15 Schwarz Pharma Ag Heteroarene-carboxamides utilises comme ligands de la dopamine d3 pour traiter des maladies du snc
WO2004112729A3 (fr) * 2003-06-19 2006-02-16 Psychiatric Genomics Inc Composes a fonction duale et leurs utilisations
WO2006008133A2 (fr) * 2004-07-20 2006-01-26 Siena Biotech S.P.A. Modulateurs des recepteurs nicotiniques d'acetylcholine alpha7 et leurs utilisations therapeutiques
WO2006008133A3 (fr) * 2004-07-20 2006-03-23 Siena Biotech Spa Modulateurs des recepteurs nicotiniques d'acetylcholine alpha7 et leurs utilisations therapeutiques
WO2006015737A1 (fr) * 2004-08-02 2006-02-16 Schwarz Pharma Ag Carboxamides d'indolizine et leurs aza- et diaza-derives
WO2006050976A1 (fr) * 2004-11-12 2006-05-18 Schwarz Pharma Ag Carboxamides d'azaindole
DE102004054634A1 (de) * 2004-11-12 2006-05-18 Schwarz Pharma Ag Azaindolcarboxamide
DE102004063797A1 (de) * 2004-12-30 2006-07-13 Schwarz Pharma Ag Sauerstoffhaltige annelierte Phenylpiperazin- und Phenyldiazepancarboxamide
JP2008526715A (ja) * 2005-01-03 2008-07-24 ユニベルシタ デグリ ストゥディ ディ シエナ 神経精神障害の治療のためのアリールピペラジン誘導体
EP1683790A1 (fr) * 2005-01-24 2006-07-26 Institut National De La Sante Et De La Recherche Medicale (Inserm) Dérivés de 3,4-dihydro-2-naphtamide comme ligands selectifs de la dopamine D3
WO2006077487A1 (fr) * 2005-01-24 2006-07-27 Institut National De La Sante Et De La Recherche Medicale (Inserm) Derives de 3,4-dihydro-2-naphthamide et leurs applications therapeutiques
US7875617B2 (en) 2005-01-24 2011-01-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) 3,4-dihydro-2-naphthamide derivatives as selective dopamine D3 ligands
WO2006082456A1 (fr) 2005-02-03 2006-08-10 Richter Gedeon Vegyészeti Gyár Rt. Cyclohexylamides servant d'antagonistes de la dopamine d3 , d2 et de 5ht1a
US7345178B2 (en) 2005-08-04 2008-03-18 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8044198B2 (en) 2005-08-04 2011-10-25 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8163908B2 (en) 2005-08-04 2012-04-24 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
JPWO2007099828A1 (ja) * 2006-02-23 2009-07-16 塩野義製薬株式会社 環式基で置換された含窒素複素環誘導体
WO2007099828A1 (fr) * 2006-02-23 2007-09-07 Shionogi & Co., Ltd. Derives heterocycliques azotes substitues par des groupes cycliques
US7935706B2 (en) 2006-02-23 2011-05-03 Shionogi & Co., Ltd. Nitrogen-containing heterocycle derivatives substituted with cyclic group
FR2903986A1 (fr) * 2006-07-21 2008-01-25 Pierre Fabre Medicament Sa Nouveaux derives chromenes ou thiochromenes carboxamides, leur procede de preparation et leurs applications en therapeutique
WO2008009741A1 (fr) * 2006-07-21 2008-01-24 Pierre Fabre Medicament Nouveaux dérivés de type carboxamide de chromène et de thiochromène, leurs méthodes de synthèse et leurs applications thérapeutiques
WO2008043839A1 (fr) * 2006-10-13 2008-04-17 Università Degli Studi Di Siena Dérivés d'arylpipérazine utiles pour le traitement de troubles neuropsychiatriques
CN1948298B (zh) * 2006-11-09 2010-09-01 东南大学 一种多巴胺d3受体部分激动剂及其应用
US8163729B2 (en) 2007-01-16 2012-04-24 Wyeth Modulators of α7 nicotinic acetylcholine receptors and therapeutic uses thereof
US7829556B2 (en) 2007-06-20 2010-11-09 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8247565B2 (en) 2007-06-20 2012-08-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
WO2009112568A1 (fr) * 2008-03-14 2009-09-17 Neurosearch A/S Nouveaux dérivés de quinolinylamide utiles comme modulateurs des récepteurs de la dopamine et de la sérotonine
US20110178091A1 (en) * 2008-10-02 2011-07-21 Green Cross Corporation Arylpiperazine-containing pyrrole 3-carboxamide derivatives for treating depressive disorders
US8895558B2 (en) * 2008-10-02 2014-11-25 Green Cross Corporation Arylpiperazine-containing pyrrole 3-carboxamide derivatives for treating depressive disorders
US9227944B2 (en) 2008-10-10 2016-01-05 Institute Of Pharmacology And Toxicology Academy Of Military Science P.L.A. China Dopamine D3 receptor ligands and preparation and medical uses of the same
JP2012505165A (ja) * 2008-10-10 2012-03-01 インスティチュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 新規なドーパミンｄ３受容体リガンド、その調製及び使用
US8829001B2 (en) 2008-10-10 2014-09-09 The Institute of Pharmacology and Toxicology Academy of Military Medical Science P.L.A. China Dopamine D3 receptor ligands and preparation and medical uses of the same
WO2014059265A1 (fr) 2012-10-11 2014-04-17 Southern Research Institute Dérivés urée et amide d'aminoalkylpipérazines et leur utilisation
WO2015007615A1 (fr) * 2013-07-18 2015-01-22 Fondazione Istituto Italiano Di Tecnologia Phenyl carbamates et leur utilisation comme inhibiteurs de l'enzyme hydrolase d'amides d'acides gras (faah) et modulateurs du récepteur d3 de la dopamine (d3dr)
US9828352B2 (en) 2013-07-18 2017-11-28 Fondazione Istituto Italiano Di Tecnologia Phenyl carbamates and their use as inhibitors of the fatty acid amide hydrolase (FAAH) enzyme and modulators of the D3 dopamine receptor (D3DR)
RU2693457C2 (ru) * 2013-07-18 2019-07-03 Фондацьоне Иституто Итальяно Ди Текнолоджия Фенилкарбаматы и их применения в качестве ингибиторов фермента гидролазы амидов жирных кислот (faah) и модуляторов d3 допаминового рецептора (d3dr)
CN104672135A (zh) * 2014-12-22 2015-06-03 中国人民解放军成都军区总医院 新型喹啉-4-甲酰胺衍生物、其制备方法以及含该衍生物的药物组合物及其医药用途
US10392378B2 (en) * 2014-12-23 2019-08-27 Proteostasis Therapeutics, Inc. Derivatives of 5-phenyl- or 5-heteroarylathiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US11472777B2 (en) 2015-09-14 2022-10-18 The National Institute for Biotechnology in the Negev Ltd. Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction
CN108290889B (zh) * 2015-09-14 2021-08-10 内盖夫国家生物技术研究所 新的哌嗪和哌啶衍生物、它们的合成及其在抑制vdac寡聚化、细胞凋亡和线粒体功能障碍中的用途
US10946013B2 (en) 2015-09-14 2021-03-16 The National Institute for Biotechnology in the Negev Ltd. Methods for treating central nervous system disorders using vdac inhibitors
CN108290889A (zh) * 2015-09-14 2018-07-17 内盖夫国家生物技术研究所 新的哌嗪和哌啶衍生物、它们的合成及其在抑制vdac寡聚化、细胞凋亡和线粒体功能障碍中的用途
US10787423B2 (en) 2015-09-14 2020-09-29 The National Institute For Biotechnolgy In The Negev Ltd. Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction
AU2016325108B2 (en) * 2015-09-14 2020-10-22 The National Institute for Biotechnology in the Negev Ltd. Novel piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction
US10508091B2 (en) 2015-09-14 2019-12-17 The National Institute for Biotechnology in the Negev Ltd. Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction
AU2017233716B2 (en) * 2016-03-14 2020-10-29 The United States Of America, As Represented By The Secretary Department Of Health And Human Services Dopamine D3 receptor selective antagonists/partial agonists; method of making; and use thereof
EP3848351A1 (fr) * 2016-03-14 2021-07-14 The United States of America, as represented by The Secretary, Department of Health and Human Services Antagonistes/agonistes partiels sélectifs du récepteur d3 de la dopamine, procédé de préparation et utilisation associée
WO2017160552A1 (fr) * 2016-03-14 2017-09-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antagonistes/agonistes partiels sélectifs du récepteur d3 de la dopamine ; procédé de préparation ; et utilisation associée
US11299476B2 (en) 2016-03-14 2022-04-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Dopamine D3 receptor selective antagonists/partial agonists; method of making; and use thereof
US10434099B2 (en) * 2016-09-22 2019-10-08 The National Institute for Biotechnology in the Negev Ltd. Methods for treating central nervous system disorders using VDAC inhibitors
US20180078548A1 (en) * 2016-09-22 2018-03-22 The National Institute for Biotechnology in the Negev Ltd. Methods for Treating Central Nervous System Disorders Using VDAC Inhibitors
JP2020509088A (ja) * 2017-02-24 2020-03-26 深▲チェン▼市霊蘭生物医薬科技有限公司Ｓｈｅｎｚｈｅｎ Ｌｉｎｇｌａｎ Ｂｉｏ−Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ 新規なドーパミンｄ３受容体選択的リガンド及びびその調製方法並びに医薬使用
WO2018153297A1 (fr) * 2017-02-24 2018-08-30 深圳市灵兰生物医药科技有限公司 Nouveau ligand sélectif pour le récepteur dopaminergique d3, procédé de préparation correspondant et application pharmaceutique correspondante
JP7017797B2 (ja) 2017-02-24 2022-02-09 深▲チェン▼市霊蘭生物医薬科技有限公司 新規なドーパミンｄ３受容体選択的リガンド及びびその調製方法並びに医薬使用
CN106966953A (zh) * 2017-03-07 2017-07-21 深圳市老年医学研究所 一种新型多巴胺d3受体选择性配体的制备方法及其应用
US11337971B2 (en) 2018-09-11 2022-05-24 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Dopamine D3 receptor selective antagonists/partial agonists and uses thereof

Also Published As

Publication number Publication date
HUP0103987A3 (en) 2004-11-29
HUP0103987A2 (en) 2003-05-28
HU0103987D0 (en) 2001-11-28
WO2003028728A8 (fr) 2005-04-07

Similar Documents

Publication Publication Date Title
WO2003028728A1 (fr) 4-(piperazinyl-1yle substitue en 4)-butylcarboxamides utilises en tant que ligands selectifs du sous-type de la dopamine d3
EP1438302B1 (fr) Derives de sulfonamide tenant lieu de ligands vis-a-vis du recepteur d3 de la dopamine
US6291464B1 (en) Aminopiperazine derivatives
KR101020399B1 (ko) 퀴놀린 유도체 및 5-ｈｔ6 리간드로서의 그의 용도
KR101221864B1 (ko) 4-［［(7ｒ)-8-사이클로펜틸-7-에틸-5,6,7,8-테트라하이드로-5-메틸-6-옥소-2-프테리디닐］아미노］-3-메톡시-ｎ-(1-메틸-4-피페리디닐)벤즈아미드의 수화물 및 다형체, 이들의 제조방법, 및 약제로서의 이들의 용도
JP2003505373A (ja) ビフェニル誘導体、その製法及び薬剤としての使用
EP1991528A2 (fr) Modulateurs de la sous-unité alpha 7 du récepteur nicotinique de l'acétylcholine et leurs applications thérapeutiques
US8263598B2 (en) Substituted sulfonamide compounds
ZA200303638B (en) Piperidine MCH antagonists and their use in the treatment of obesity.
US20050090496A1 (en) Sulphonyl compounds with 5-ht6 receptor affinity
EP1778658A2 (fr) Modulateurs des recepteurs nicotiniques d'acetylcholine alpha7 et leurs utilisations therapeutiques
TW200418857A (en) Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
KR20030068547A (ko) 신경계 질환의 치료에 유용한 신규한 아미도알킬-피페리딘및 아미도알킬-피페라진 유도체
JPH09502177A (ja) ５ｈｔ１ｄレセプター拮抗薬用インドールおよびインドリン誘導体
WO2003028725A1 (fr) 4-(1-piperidiny)-butylcarboxamide utiles comme ligands selectifs du sous-type du recepteur d3 de la dopamine
KR20070063008A (ko) 피리딘 유도체 및 이의 제조법 및 치료학적 용도
JP5467044B2 (ja) Ｔｓｈ受容体拮抗性のテトラヒドロキノリン化合物
TWI824050B (zh) 化合物、製備化合物的方法、化合物的用途、藥物組合物、用作藥物的化合物及用作治療疼痛的藥物的化合物
US6395905B1 (en) Tetrahydroindazole derivatives as ligands for GABA-A α 5 receptors
EP1527075B1 (fr) Derives de diazabicyclononane et de -decane et leur utilisation comme ligands des recepteurs opioides
JP2009523747A (ja) α７ニコチン性アセチルコリン受容体のモジュレーターおよびその治療上の使用
KR20140085470A (ko) 바닐로이드 수용체 리간드로서의 아민 치환된 메탄설폰아미드 유도체
US20040067959A1 (en) Morphinoid derivatives as delta-opioid agonists and antagonists
US20100016288A1 (en) Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof
JP2013536812A (ja) 置換テトラヒドロピロロピラジン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i

Free format text: IN PCT GAZETTE 15/2003 ADD "DECLARATION UNDER RULE 4.17: - AS TO APPLICANT S ENTITLEMENT TO APPLY FOR AND BE GRANTED A PATENT (RULE 4.17(II))."

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP