WO2003028725A1 - 4-(1-piperidiny)-butylcarboxamide utiles comme ligands selectifs du sous-type du recepteur d3 de la dopamine - Google Patents

4-(1-piperidiny)-butylcarboxamide utiles comme ligands selectifs du sous-type du recepteur d3 de la dopamine Download PDF

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WO2003028725A1
WO2003028725A1 PCT/HU2002/000094 HU0200094W WO03028725A1 WO 2003028725 A1 WO2003028725 A1 WO 2003028725A1 HU 0200094 W HU0200094 W HU 0200094W WO 03028725 A1 WO03028725 A1 WO 03028725A1
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formula
compound
diastereomers
solvates
hydrates
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PCT/HU2002/000094
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Tibor ÁCS
Éva ÁGAINÉ CSONGOR
Gizella BARTÁNÉ SZALAI
Ildikó MAGDÓ
Gábor TÁRKÁNYI
György DOMÁNY
Béla Kiss
István Gyertyán
István Laszlovszky
Krisztina GÁL
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Richter Gedeon Vegyészeti Gyár Rt.
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Publication of WO2003028725A1 publication Critical patent/WO2003028725A1/fr

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • 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.
  • Fused imidazo-pyridine derivatives are described in patent applications WO 9740051 and WO 9720632 having antihyperglycemic activity.
  • Dihyd ropy rid ine derivatives for the treatment of benign prostatic hyperplasia are disclosed in patent US 5 767 131.
  • Ri and R 2 represent independently a substituent selected from hydrogen, halogen, C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy, cyano, hydroxy, trifluoromethyl, C ⁇ - 6 alkylsulfonyloxy, trifluoromethanesulfonyloxy, optionally substituted C ⁇ - 6 alkanoyloxy, amino, aminoalkyl, carboxy, aminocarbonyl, N- hydroxycarbamimidoyl, carbamimidoyl, hydroxycarbamoyl, thiocarbamoyl, sulfamoyl or mono or bicyclic heterocyclic group;
  • Y represents an oxygen atom or NH or CH2 or OCH 2 group
  • Q represents an optionally substituted C ⁇ - 6 alkyl, aryl, heteroaryl, heteroaralkyl or heteroaralkenyl group, 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 psychoses (e.g. schizophrenia, schizo-affective disorders, etc.), drug (e.g.
  • psychoses e.g. schizophrenia, schizo-affective disorders, etc.
  • drug e.g.
  • the invention relates to new piperidinyl compounds having carboxylic acid amide structures of formula (I):
  • Ri and R 2 represent independently a substituent selected from hydrogen, halogen, d- ⁇ alkyl, C ⁇ -6 alkoxy, cyano, hydroxy, trifluoromethyl, C 1 - 6 alkylsulfonyloxy, trifluoromethanesulfonyloxy, optionally substituted C 1 -6 alkanoyloxy, amino, aminoalkyl, carboxy, aminocarbonyl, N- hydroxycarbamimidoyl, carbamimidoyl, hydroxycarbamoyl, thiocarbamoyl, sulfamoyl or mono or bicyclic heterocyclic group;
  • Y represents an oxygen atom or NH or CH 2 or OCH 2 group
  • Q represents an optionally substituted C ⁇ - 6 alkyl, aryl, heteroaryl, heteroaralkyl or heteroaralkenyl group, and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.
  • the aryl moiety may be selected from an optionally substituted mono-, bi- or tricyclic aryl such as phenyl, naphthyl, fluorenonyl, or antraquinonyl group.
  • 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 containing 1 to 4 heteroatoms selected from O, N or S.
  • Examples of 5- and 6-membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl and pyrazolyl, preferably pyridyl and thienyl.
  • bicyclic heteroaromatic groups include indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, preferably quinolinyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzimidazolyl and indolyl group.
  • Example of a tricyclic heteroaromatic group include beta-carboline.
  • the substituents of aryl, heteroaryl, heteroaralkyl or heteroaralkenyl group in the meaning of Q are selected from hydrogen, halogen, hydroxy, cyano, amino, trifluoromethyl, C ⁇ -6 alkyl, C ⁇ . 6 alkoxy, C ⁇ - 6 alkanoyl, methylenedioxy, C ⁇ . 6 alkylamino, C ⁇ - 6 alkanoylamino, optionally substituted aroyl, aryloxy, aminosulfonyl, arylsulfonylamido, optionally substituted mono or bicyclic aromatic or heteroaromatic ring, wherein the aryl has the same meaning as mentioned above.
  • the substituents of C ⁇ - 6 alkanoyloxy in the meaning of Ri and R 2 are selected from hydrogen or halogen.
  • amino, aminoalkyl, aminocarbonyl, N-hydroxycarbamimidoyl, carbamimidoyl, hydroxycarbamoyl, thiocarbamoyl and sulfamoyl groups in the meaning of Ri and R 2 may optionally be substituted on the N atom.
  • the mono or bicyclic heterocyclic group in the meaning of Ri and R 2 may be saturated or unsaturated containing 1 to 4 heteroatoms selected from O, N or S.
  • the substituents Ri and R 2 may be the same or different.
  • an alkyl group or moiety in alkoxy, 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.
  • 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.
  • the reason why acid addition salts, which do not belong to the pharmaceutically acceptable acid addition salts belong to the present invention is, that in given case they can be advantageous in the purification and isolation of the desired compounds.
  • Ci- ⁇ alkenyl group when the compound contains Ci- ⁇ alkenyl group can exist in the form of cis- and/or trans- isomers. These are likewise within the scope of the present invention including all such isomers and the mixtures thereof.
  • Certain compounds of formula (I) can exist as stereoisomers and diastereomers. These and the mixtures thereof are likewise within the scope of the present invention.
  • 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 Ri and R 2 represent independently halogen or trifluoromethyl, cyano, alkoxy, alkyl, hydroxy, alkansulfonyloxy, aminocarbonyl;
  • Q represents optionally substituted alkyl, phenyl, biphenylyl, naphthyl, pyridyl, indolyl, indolylethenyl, carbolinyl, benzothiophen-yl, benzofuranyl or quinolinyl;
  • Y represents an oxygen atom or NH or CH 2 or OCH 2 group; and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.
  • Especially preferred compounds of the invention are those compounds of formula (I) wherein Ri and R 2 represent independently halogen or trifluoromethyl;
  • Q represents 4-methylphenyl, 4-bromophenyl, 4-chlorophenyl, 2-naphthyl,
  • the invention also relates to the pharmaceutical compositions containing the compounds of formula (I) as active ingredient. Further subject of the present invention is the pharmaceutical manufacture of medicaments containing compounds of formula (I), as well as the process of treatments and/or prevention with these compounds, which means administering to a mammal to be treated - including human - effective amounl/amounts of compounds of formula (I) of the present invention as such or as medicament.
  • 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 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).
  • 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 room temperature.
  • an appropriate amine of formula (III) is added in a form of base or of 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, e.g. by crystallization or by column chromatography.
  • the carboxylic acids of formula (II) are either commercially available or can be synthesized by different known methods (e.g. 6-methoxybenzofuran-2- carboxylic acid: J.Chem.Soc, 1940, 787; 6-methoxybenzothiazole-2-carboxylic acid: J.Am.Chem.Soc, 1963, 85, 337; 5-methoxybenzothiophene-2-carboxylic acid: J.Org.Chem., 1961 , 26, 1326; 4-imidazo[1 ,2-a]pyridin-2-yl-benzoic acid: WO 9534540; (4-pyrimidin-4-yl)-benzoic acid: WO 99571 13; 9H- ⁇ -carboline-3- carboxylic acid: Heterocycles 1998, 48, 993).
  • the syntheses of some commercially not available carboxylic acids of formula (II) are described in the Examples. Following these procedures the other commercially not available carboxylic acids of formula (II)
  • the amines of formula (III) may be prepared by alkylation of compounds of formula (IV):
  • the piperidines of formula (IV) may be prepared by known methods (e.g. where Y stands for NH group: Synlett, 1961, 537; where Y stands for oxygen: J.Med.Chem., 1974, 17, 1000; where Y stands for CH 2 group: US 3,632,767; WO 97/23216; FR 2,534,580).
  • the obtained carboxylic acid amide derivatives of formula (I) - independently from the method of preparation - can be transformed into an other compound of formula (I) in given case by introducing further substituent(s) and/or modifying and/or removing the existing one(s).
  • cleaving the methyl group(s) from methoxy group(s) which stand for R 1 and/or R 2 leads to phenol derivatives.
  • the cleavage of methyl group(s) can be carried out, e.g. with boron tribromide in dichloromethane solution.
  • the compounds of formula (I) containing free phenolic hydroxy group(s) can be transformed into acyloxy or sulfonyloxy derivatives thereof with different acylating or sulfonylating agents.
  • the reactions are carried out at room temperature in chlorinated hydrocarbons using acid chloride or acid anhydride as acylating agent in the presence of a base (for example triethylamine or sodium carbonate).
  • the compounds of formula (I) containing cyano group(s) e.g. can be transformed to amides by hydrolysing them with hydrogenperoxide in dimethylsulfoxide, or to amidines by reacting them first with gaseous hydrogenchloride in ether, then by reacting the iminoester obtained with ammonia, etc.
  • the obtained carboxylic acid amide derivatives of formula (I) can be transformed into the salts thereof with acids and/or liberated the carboxylic acid amide derivative of formula (I) from the obtained acid addition salts by treatment with a base, and/or can be separated the cis- and/or fra ⁇ s-isomers and/or the stereoisomers and/or diastereomers and/or can be transformed into hydrates and/or solvates thereof.
  • the carboxamide derivatives of formula (I) can also be prepared on solid support, e.g. 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 affinity for dopamine receptors, in particular the D 3 receptors, and are expected to be useful in the treatment of disease states and/or prevention the same in which 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 afffinity for dopamine D 3 than for D 2 receptors. The compounds of formula (I) may therefore advantageously be used as selective modulators of D 3 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 1( D5) 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 and addiction (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.
  • 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 receptors agonists can be useful for the treatment of glaucoma.
  • the invention provides novel compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof which are D 3 dopamine receptor subtype selective ligands.
  • a further aspect of the present invention provides a method of treating conditions which require modulation of dopamine D 3 receptors, for example psychoses (e.g. schizophrenia, schizo-affective disorders), psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders such as schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders such as schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders such as
  • Parkinson's disease neuroleptic induced parkinsonism, eating disorders (e.g. bulimia nervosa), depression, anxiety, memory disorders, sexual dysfunction and drug abuse, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.
  • the invention also provides the use of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment 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, pain.
  • a preferred use for D 3 agonists or partial agonists according to the present invention is in the treatment of drug abuse (such as cocaine abuse etc.), eye diseases (such as glaucoma).
  • drug abuse such as cocaine abuse etc.
  • eye diseases such as glaucoma
  • the compounds of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof 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 isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof and physiologically acceptable carriers.
  • the compounds of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof 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) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof 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) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof generally consists of a suspension or solution of the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates 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 suspesion of the compound of formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof 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 of the present invention for nasal administration containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates 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 isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates 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 of the present invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof 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 etc.
  • compositions of the present invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for rectal administration are conveniently in the form of suppositories containing a conventional supposiory base, such as cocoa butter.
  • compositions of the present invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for transdermal administration include ointments, gels and patches.
  • compositions of the present invention containing a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof are preferably in the unit dose form, such as tablet, capsule or ampoule.
  • Each dosage unit of the present invention for oral administration contains preferably from 1 to 250mg of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
  • Each dosage unit of the present invention for parenteral administration contains preferably from 0.1 to 25mg of a compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
  • physiologically acceptable compounds formula (I) of the present invention and/or geometric isomers and/or stereoisomers and/or diastereomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof can 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 100mg, 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 can 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).
  • Binding of [ 3 H]-spiperone (0.5 nM) to rat striatal tissue was measured according to the method of Seeman (J. Neurochem. 1984, 43, 221-235 ). 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.
  • One of the most prominent side effects of the first generation antipsychotic compounds e.g. chlorpromazine and haloperidol
  • preferential blockade at dopamine D 2 , and alpha-1 receptors are the tardive dyskinesia and orthostatic hypotension.
  • 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 0.7 and 10.3 nM) and show 40 to >666 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 which are described in the literature. 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.
  • 4-methoxybenzoic acid (0.55g; 3.6 mmol) was dissolved in dimethylformamide (20ml), 1-hydroxybenztriazole (0.46g; 3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6g; 3.6 mmol), the mixture was stirred for 10 minutes at room temperature and N-[4- ([3,4-difluoro-phenylamino)-1-piperidinyl]-butylamine (1.02g; 3.6 mmol) in dimethylformamide (5ml) was added and stirred overnight at room temperature. The precipitate was filtered and the solution evaporated in vacuo.
  • 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.
  • 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.
  • Diluent7Filter may also include cyclodextrins 50-250 mg
  • Disintegrant may also include cyclodextrins 5-50 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
  • Colourant 0.001-0.1 mg Suspending agen 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.

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Abstract

L'invention concerne de nouveaux ligands sélectifs du sous-type du récepteur D3 de la dopamine de formule (I), dans laquelle R1 et R2 représentent de manière indépendante un substituant sélectionné parmi un hydrogène, un halogène, un alkyle en C1-6, un alcoxy en C1-6 , un cyano, un hydroxy, un trifluorométhyle, un alkylsulfonyloxy en C1-6, un trifluoroméhanesulfonyloxy, un alkanoyloxy en C1-6 éventuellement substitué, un amino, un aminoalkyle, un carboxy, un aminocarbonyle, un N-hydroxycarbamimidoyle, un carbamimidoyle, un hydroxycarbamoyle, un thiocarbamoyle, un sulfamoyle ou un groupe hétérocyclique mono ou bicyclique; Y désigne un atome d'oxygène ou groupe NH ou CH2 ou OCH2; Q représente un groupe alkyle en C1-6, un aryle, un hétéroaryle, hétéroaralkyle ou hétéroaralcènyle éventuellement substitué, et/ou des isomères géométriques et/ou des stéréoisomères et/ou des diastéréomères et/ou des sels et/ou des hydrates et/ou des solvates de ceux-ci. L'invention concerne également un procédé de préparation de ceux-ci, des compositions pharmaceutiques renfermant ceux-ci et l'utilisation de ceux-ci dans une thérapie et/ou pour la prévention de psychoses (par exemple, la schizophrénie, des troubles schizo-affectifs, etc.), de l'abus de drogue (par exemple, l'alcool, la cocaïne et la nicotine, des opioïdes, etc.), d'une déficience cognitive liée à la schizophrénie, de déficits cognitifs légers-à-moyens, de l'amnésie, de troubles de l'alimentation (par exemple, la boulimie, etc.), de troubles liés à une déficience de l'attention/hyperactivité chez des enfants, de dépression psychotique, de manie, de troubles paranoïaques et délirants, de troubles dyskinétiques (par exemple, la maladie de Parkinson, le parkinsonisme induit par les neuroleptiques, une dyskinésie tardive) de l'anxiété, de troubles sexuels, de troubles du sommeil, de vomissement, d'agression, d'autisme, de douleurs, de maladies ophtalmologiques (par exemple, le glaucome, etc.).
PCT/HU2002/000094 2001-09-28 2002-09-25 4-(1-piperidiny)-butylcarboxamide utiles comme ligands selectifs du sous-type du recepteur d3 de la dopamine WO2003028725A1 (fr)

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