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WO1998007711A1 - Piperazines de troponyle en tant que ligands selectifs du recepteur d4 de dopamine - Google Patents

Piperazines de troponyle en tant que ligands selectifs du recepteur d4 de dopamine Download PDF

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Publication number
WO1998007711A1
WO1998007711A1 PCT/US1997/013264 US9713264W WO9807711A1 WO 1998007711 A1 WO1998007711 A1 WO 1998007711A1 US 9713264 W US9713264 W US 9713264W WO 9807711 A1 WO9807711 A1 WO 9807711A1
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Prior art keywords
cycloheptatriene
piperazinyl
phenyl
compound
compound according
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PCT/US1997/013264
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English (en)
Inventor
Jian-Min Fu
Xin Wang
Adi M. Treasurywala
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Hoechst Marion Roussel, Inc.
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Publication date
Application filed by Hoechst Marion Roussel, Inc. filed Critical Hoechst Marion Roussel, Inc.
Priority to BR9711965A priority Critical patent/BR9711965A/pt
Priority to IL12862997A priority patent/IL128629A0/xx
Priority to NZ333519A priority patent/NZ333519A/en
Priority to HU9903913A priority patent/HUP9903913A3/hu
Priority to AU38171/97A priority patent/AU3817197A/en
Priority to JP10510754A priority patent/JP2000516629A/ja
Priority to EP97935166A priority patent/EP0929537A1/fr
Publication of WO1998007711A1 publication Critical patent/WO1998007711A1/fr
Priority to NO990796A priority patent/NO990796L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—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 doubly bound oxygen or sulphur 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
    • C07D295/10—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 doubly bound oxygen or sulphur atoms
    • C07D295/112—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 doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic 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
    • 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 or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered 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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
    • 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

Definitions

  • This invention relates to compounds that bind to the dopamine D4 receptor, to their preparation and their use for therapeutic and drug screening purposes.
  • Neuronal cell receptors that bind the neurotransmitter dopamine constitute a group of at least five structurally distinct proteins that can now be produced using recombinant DNA techniques. These techniques have been applied to construct cell lines that incorporate the dopamine receptor in their membranes, to provide regenerable and homogeneous substrates with which chemical libraries can be screened to identify potential CNS-active drugs.
  • D4 dopamine receptor classified as D4 in the etiology of schizophrenia. It has been suggested that compounds capable of interfering with the function of this receptor, which is present in schizophrenics at levels that are six times normal, would be useful in the treatment of this disease (Seeman et al, Nature, 1993, 365:441). Some drugs currently on the market in fact exhibit the desired antagonism of D4 receptor activity, and bind with relative strong affinity to the receptor. Yet because of their structure, these drugs interact also with related dopamine receptors, particularly the D2 receptor type, which results in significant side effects that include altered motor function and tachycardia. It would be desirable to provide compounds that exhibit not only a high degree of affinity for the D4 receptor, but also a relatively low degree of affinity for the D2 receptor. In this specification, this desired combination of receptor binding properties is referred to as D4 selectivity.
  • Products currently marketed to treat indications in which the D4 receptor function is implicated include the dibenzodiazepine, clozapine, and the dibenzoxazepine, isoloxapine. Analysis of their dopamine receptor binding properties has shown that the preference for binding the D4 receptor relative to the D2 receptor is about 10 fold, for both products. Similarly, both bind the D4 receptor with about the same affinity (Ki value approximately 20 nM). Other products, recently published in the scientific literature, have shown similar D4 to D2 selectivity profile and D4 affinity values.
  • It is a further object of the present invention to provide a pharmaceutical composition comprising a compound of the present invention, as active ingredient.
  • Ri is H, halo, aryl or aryl substituted with one or two groups independently selected from halo, nitro, tnfluoromethyl, trifluoromethoxy or cyano;
  • R 2 is C 4 . 9 alkyl; phenyl or phenyl substituted with one or two groups selected independently from OH, cyano, halo, C- ⁇ alkoxy, d ⁇ alkyl, tnfluoromethyl, trifluoromethoxy, nitro or phenyl; naphthyl; phenyl fused to a 5 or 6-membered heterocycle; the coumarin moiety
  • R 3 and R 4 are selected independently from H, or 1 ,2-methylenedioxy phenyl; with the proviso that R 2 is not phenyl or 3,4-dimethoxyphenyl when R 1 is H.
  • a pharmaceutical composition comprising a compound of Formula I and II in an amount effective to antagonize D4 receptor stimulation and a pharmaceutically acceptable carrier;
  • Ri is selected independently from H, halo, aryl and aryl substituted with one or two groups independently selected from H, halo, d. alkyl, nitro, tnfluoromethyl, trifluoromethoxy and cyano.
  • R 5 is selected independently from C 4 . 9 alkyl; phenyl or phenyl substituted with one or two groups selected independently from OH, cyano, halo, tnfluoromethyl, trifluoromethoxy, nitro or phenyl; naphthyl; phenyl fused to a 5 or
  • R 3 and R 4 are selected independently from H, and C alkoxy; or 1 ,2-methylenedioxy phenyl.
  • This is essentially Formula I without the provisio.
  • Formula II is to be used as a pharmaceutical composition.
  • the invention provides the use of compounds of Formulas I and II as D4 receptor antagonists for the treatment of medical conditions mediated by inhibition of D4 receptor antagonism, and use in treating schizophrenia and anxiety.
  • C h alky as used herein means straight alkyl radicals containing from four to nine carbon atoms and branched chain alkyl radicals containing six to eight carbon atoms and includes pentyl, hexyl, 1 -methylhexyl and the like.
  • C h alky as used herein means straight alkyl radicals containing from one to four carbon atoms and branched chain alkyl radicals containing three or four carbon atoms and includes methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl and the like. 1 -Methylethyl and 1 -methylpropyl are also known as isopropyl and sec-butyl respectively.
  • Ci »alkoxy means straight chain alkoxy radicals containing from one to four carbon atoms and branched chain alkoxy radicals containing three to four carbon atoms and includes methoxy, ethoxy, 1 -methylethoxy, propyloxy, butoxy and the like.
  • halo as used herein means halide and includes fluoro, chloro, bromo and iodo.
  • heterocycle means a five or six membered saturated or unsaturated ring wherein the heterocycle contains one to three heteroatoms independently selected from nitrogen, oxygen and sulfur and includes 1 ,3-dioxole, thiophene, furan, pyrrole, imidazole, pyrazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, morpholine, and the like.
  • phenyl fused to a 5 or 6 membered heterocycle are benzothiophene, isobenzofuran, chromene, indole, isoindole, indazole, isoquinoline, quinoline, phtalazine, quinoxaline, quinazoline, cinnoline, isochroman, chroman, indoline, isoindoline, and the like.
  • aryl as used herein means afive or six membered carbocylic unsaturated ring system which is either an aromatic (such as phenyl) or heteroaromatic ring which contains one or two nitrogen atoms, one or two oxygen atoms, one nitrogen and one oxygen atom, one nitrogen and one sulfur atom, or one sulfur atom, and includes, but is not limited to, thiophene, furan, pyrrole, pyran, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, pyrazoline, and pyrazine.
  • aryls may be substituted as is appropriate to their chemical structure with one or two groups independently selected from halo, C ⁇ - 4 alkyl, alkoxy, nitro, trifluoromethyl, trifluoromethoxy and cyano.
  • aryl is phenyl substituted at the meta or para position thereof with one substitutent.
  • pharmaceutically acceptable salts means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients for the intended use.
  • “Pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p- toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2- hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • “Pharmaceutically acceptable basic addition salts” means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of its intermediates. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline.
  • alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides
  • ammonia and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline.
  • the selection of the appropriate salt may be important so that the ester is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
  • Solvate means a compound of Formula I or the pharmaceutically acceptable salt of Formula I wherein molecules of a suitable solvent are incorporated in a crystal lattice.
  • a suitable solvent is not substantially toxic at the dosage administered as the solvate to achieve the desired effect. Examples of suitable solvents are ethanol and the like.
  • stereoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • patient means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
  • treat or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • terapéuticaally effective amount means an amount of the compound which is effective in treating the named disorder or condition.
  • pharmaceutically acceptable carrier is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient
  • a pharmaceutical composition i.e., a dosage form capable of administration to the patient
  • a pharmaceutically acceptable oil typically used for parenteral administration.
  • schizophrenia means schizophrenia, schizophreniform disorder, schizoaffective disorder and psychotic disorder wherein the term “psychotic” refers to delusions, prominent hallucinations, disorganized speech or disorganized or catatonic behavior. See Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington D.C.
  • the invention relates to compounds that bind the dopamine D4 receptor in a selective manner, relative to the dopamine D2 receptor.
  • compounds of Formula I and II include those in which Ri is H and R 2 is d-galkyl.
  • a compound of Formula I and II has Ri equal to H and R 2 equal to n-pentyl.
  • compounds of Formula I and II include those in which Ri is H and R 2 is selected from naphthyl, phenyl, phenyl substituted with one or two groups selected from methyl, methoxy, nitro, bromo, chloro, fluoro, trifluoromethoxy, tnfluoromethyl, phenyl and cyano and phenyl fused to a 5 or 6- membered heterocycle.
  • compounds of Formula I and II include those in which Ri is H and R 2 is the following:
  • compounds of Formula I and II are those in which Ri is H and Rjris the coumarin moiety shown below, and R 3 and R 4 are selected from H and d ⁇ alkoxy.
  • a specific embodiment of the invention includes compounds of Formula I and II where Ri is H and R 2 is 1-(6,7-dimethoxycoumarin) and 1-(7-methoxycoumarin).
  • compounds of Formula I and II include those in which Ri is selected from halo, aryl and aryl substituted with one or two groups independently selected from H, halo, C ⁇ -4alkyl, nitro, tnfluoromethyl, trifluoromethoxy and cyano and R is selected from C 4 - 9 alkyl, naphthyl, phenyl, phenyl substituted with one or two groups selected from methyl, methoxy, nitro, bromo, chloro, fluoro, trifluoromethoxy, tnfluoromethyl, cyano and phenyl, phenyl fused to a 5 or 6- membered heterocycle and the coumarin moiety shown below, wherein R 3 and R 4 are selected from H and
  • compounds Formula I and II include those in which R 1 is selected from halo and aryl attached at carbon 7 of the 7- membered ring and R 2 is phenyl substituted with one or two groups selected from methyl, methoxy, nitro, bromo, chloro, fluoro, trifluoromethoxy, tnfluoromethyl, cyano and phenyl; or R 2 is naphthyl or a phenyl fused to a 5 or 6-membered heterocycle.
  • compounds Formula I and II include those in which R 1 is selected from bromo and thienyl attached at carbon 7 of the 7-membered ring and R 2 is selected from 1 ,2-methylenedioxyphenyl and phenyl substituted with chloro.
  • the compounds of Formula I and II include:
  • Particularly preferred compounds of Formula I and Formula II include:
  • Acid addition salts of the compound of Formula I and II are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.
  • Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • solvates and hydrates of the invention are also included within the scope of the invention.
  • the conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution of the given salt is treated with a solution of base e.g. sodium carbonate or potassium hydroxide, to liberate the free base which is then extracted into an appropriate solvent, such as ether.
  • the free base is then separated from the aqueous portion, dried, and treated with the requisite acid to give the desired salt.
  • base e.g. sodium carbonate or potassium hydroxide
  • the compounds of the present invention can be prepared by processes analogous to those known in the art.
  • the present invention therefore provides, in a further aspect, a process for the preparation of a compound of Formula I and II wherein Ri is H or halo or a salt, solvate or hydrate thereof, which comprises one of two possible processes.
  • the first comprises coupling a reagent of Formula A:
  • R 2 in refluxing methanol as described in EP 034,894 and can be used when the corresponding reagent of Formula B is available by synthesis or commercial means.
  • Reagent (A), wherein Ri is H or halo can be synthesized using established techniques where the appropriate tropolone is treated with a methylating reagent (see Pietra, F. Chem. Rev. 1973, 73:293 when R 1 is H and Takeshita, H.; Mori, A. Synthesis, 1986, 578 when R 1 is halo). For example, treating tropolone with dimethyl sulfate and potassium carbonate in acetone.
  • a compound of Formula I and II may also be prepared by coupling a reagent of Formula C:
  • Reagent C compounds wherein V ⁇ ⁇ is H or halo are synthesized using established techniques, for example by treating reagent A with piperazine according to the procedure described by Bagli (J. Med. Chem. 1984, 27:875).
  • Ri is aryl or aryl substituted with one or two groups independently selected from H, halo, nitro, trifluoromethyl, trifluoromethoxy and cyano
  • Ri is halo using standard palladium catalysed cross coupling techniques in reactions with a metallo-aryl compound R r M, wherein Ri is as defined above and M is an optionally substituted metal substituent, attached at any carbon node of the aryl group, suitable for cross-coupling reactions.
  • M groups examples include (alkyl) 3 Sn-, (alkyl) 2 B-, (HO) 2 B-, (alkoxy) 2 B-, Li, Cu, chloroZn or haloMg.
  • the most preferred M group is chloroZn.
  • the reaction takes place in an inert solvent, and optionally in the presence of base, lithium chloride and a suitable catalyst.
  • Suitable catalysts included palladium (II) and palladium (0) species such as palladium (II) acetate, palladium (II) chloride and tetrakis(triphenylphosphine) palladium (0).
  • the preferred catalyst is tetrakis(triphenylphosphine) palladium (0).
  • Suitable inert solvents include acetonitrile. N,N-dimethylformamide and tetrahydrofuran, with tetrahydrofuran being preferred.
  • the reaction takes place at a temperature of from 25-100°C, preferably 50-100°C.
  • Compounds of formula RrM can be prepared from reagents of R ⁇ -Y, wherein Y is halo or triflate, by standard metallation reactions either independently or in situ.
  • the compound R M wherein M is chloro-Zn can be prepared, in an in situ fashion prior to the cross coupling reaction, by treating R Br with n-butyl lithium and zinc chloride In tetrahydrofuran at -78°C.
  • the clozapine-like binding profile of the present compounds indicates their utility as pharmaceuticals that may be useful as a neuroleptic for the treatment of various conditions in which D4 receptor stimulation is implicated, such as for the treatment of anxiety and schizophrenia. Accordingly, in another of its aspects, the present invention provides pharmaceutical compositions useful to treat D4-related medical conditions, in which a compound of Formula II is present in an amount effective to antagonize D4 receptor stimulation, together with a pharmaceutically acceptable carrier.
  • Compounds of Formula II are those compounds embraced by Formula I, but further include the compounds in which R 2 is phenyl or 3,4-dimethoxyphenyl.
  • the invention provides a method for treating medical conditions for which a D4 antagonist is indicated, which comprising the step of administering to the patient an amount of a compound of Formula II effective to antagonize D4 receptor stimulation, and a pharmaceutically acceptable carrier therefor.
  • the compounds of the present invention can be administered in a standard pharmaceutical composition.
  • the present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a Formula II compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to antagonize D4 receptor stimulation.
  • the compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Compounds of Formula I and II and their stereoisomers, solvates, hydrate, or pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, or as solid forms such as tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the 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 hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
  • a suitable pharmaceutical carrier for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in 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 after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as flurochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • Suitable unit doses i.e. therapeutically effective amounts; can be determined during clinical trials designed appropriately for each of the conditions for which administration of a chosen compound is indicated and will of course vary depending on the desired clinical endpoint. It is anticipated that dosage sizes appropriate for administering the compounds of the examples will be roughly equivalent to, or slightly less than, those used currently for clozapine. Accordingly, each dosage unit for oral administration may contain from 1 to about 500 mgs, and will be administered in a frequency appropriate for initial and maintenance treatments.
  • the present compounds can be stored in packaged form for reconstitution and use.
  • the present compounds can be used to distinguish dopamine receptors from other receptor types, for example glutamate and opioid receptors, within a population of receptors and in particular to distinguish between the D4 and D2 receptors.
  • the latter can be achieved by incubating preparations of the D4 receptor and of the D2 receptor with a D4 selective compound of the invention and then incubating the resulting preparation with a radiolabelled dopamine receptor ligand, such as 3 H-spiperone.
  • the D2 and D4 receptors are then distinguished by determining the difference in membrane-bound radioactivity, with the D4 receptor exhibiting lesser radioactivity, i.e., lesser 3 H-spiperone binding.
  • the compound in another embodiment, is provided in labelled form, such as radiolabelled form e.g. labelled by incorporation within its structure of 3 H or 14 C or by conjugation to 125 l or 123 l.
  • radiolabelled forms can be used directly to distinguish between dopamine D4 and dopamine D2 receptors.
  • radiolabelled forms of the present compounds can be exploited to screen for more potent dopamine D4 ligands, by determining the ability of the test ligand to displace the radiolabelled compound of the present invention.
  • This compound was prepared from 2-methoxytropone and piperazine according to the procedure of Bagli, J. et al., J. Med. Chem. 1984, 27:875.
  • the maleic acid salts of the following additional compounds were prepared: b) 2-[4-(4-trifluoromethoxybenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one (example 3f); m.p. 170-172°C; HRMS (FAB): MH + for (free base), Calc'd 365.1523, Found 365.1477.
  • D2 and D4 receptor-binding affinities of the compounds of examples 1 and 2 were evaluated according to their ability to reduce binding of 3 H-spiperone as compared to the reference compound clozapine.
  • the potency of the test compound to reduce 3 H- spiperone binding directly correlated to its binding affinity for the receptor.
  • HEK 298 human embryonic kidney cells stably transfected with human D4 receptor (D4.2 sub-type) were grown in NUNC cell factories for 5 days (75% confluency) without a media change and removed with versene (approximately 19 mg of cells per cell factory tray). The cells were then centrifuged in a Sorval centrifuge for 10 min, 5000 ⁇ m (GS3 rotor) and the pellets quickly frozen in liquid nitrogen and stored at -80°C until used in binding assay.
  • D2 Receptor Preparation GH 4 C 1 (rat pituitary) cells stably transfected with the human D2 receptor (short isoform) were grown in HAM'S F10 media in NUNC cell factories for 5 days. 100 ⁇ M ZnS0 4 was added to the cells (the D2 promoter being zinc inducible). After 16 hours, fresh media was added to allow the cells to recover for 24 hours. The cells were harvested using versine and then centrifuged in a Sorval centrifuge for 10 minutes, at 5000 rpm (GS3 rotor). Pellets were quickly frozen in liquid nitrogen and stored at -80°C until used in the binding assays. When used in the assay, cells were thawed on ice for 20 minutes.
  • Each cell factory produced approximately 72 mg of protein. 10 ml of incubation buffer was added to the pellets which were then vortexed, resuspended and homogenized with a Kinematica CH-6010 Kriens-LU homogenizer for 15 seconds at setting 7. The receptor protein concentration was determined using the Pierce BCA assay.
  • the incubation was started by the addition of 100 ⁇ l (50 ⁇ g protein) membrane homogenate to a solution of 300 ⁇ l incubation buffer and 100 ⁇ l (0.25 nM final cone.) 3 H-spiperone (90 Ci/mmol Amersham diluted in borosilicate glass vial) in 96-well polypropylene plates (1 mL per well). The plates were vortexed and incubated at room temperature for 90 minutes. The binding reaction was stopped by filtering using a Packard Harvester. The samples were filtered under vacuum over glass fibre filter plates (Whatman GF/B) presoaked for 2 hours in 0.3% polyethylenimine (PEI) in 50 mM Tris buffer (pH 7.4).
  • PEI polyethylenimine
  • the filters were then washed 6 times with 7 ml ice cold 50 mM Tris buffer (pH 7.4). The filter plates were dried overnight and 35 ⁇ l of Microscint- O (Packard) was added. The plates were sealed and counted in the Packard Top Count (3 minutes per well).
  • Non-Specific Binding Assay for D4 The incubation was started by the addition of 100 ⁇ l (50 ⁇ g protein) membrane homogenate to a solution of 200 ⁇ l incubation buffer, 100 ⁇ l 3 H-spiperone (90 Ci/mmol Amersham diluted in borosilicate glass vial to 0.25 nM final cone.) and 100 ⁇ l (30 ⁇ M final cone.) of fresh dopamine (Research Biochemicals Inc., light protected and dissolved in incubation buffer) in 96-well polypropylene plates (1 mL per well). The plates were vortexed and incubated at room temperature for 90 minutes at which time the binding reaction was stopped by filtering. The filters were washed and counted using the same procedure as in the total binding assay described above to give the non-specific binding value (NSB).
  • NBS non-specific binding value
  • This assay employed the same procedures as the non-specific binding assay for D4 with the exception that 2 ⁇ M (final cone.) of (-) sulpiride (Research Chemicals Inc.) was used in place of dopamine.
  • the incubation was started by the addition, in 96-well polypropylene plates (1 mL per well), of 100 ⁇ l (50 ⁇ g protein) membrane homogenate to a solution of 200 ⁇ l incubation buffer, 100 ⁇ l (0.25 final cone.) 3 H-spiperone (90 Ci/mmol, Amersham, diluted in borosilicate glass vial) and 100 ⁇ l of test compound that was prepared from 1 mM stock dissolved in DMSO and stored at -20°C in polypropylene cryogenic storage vials until dilution in incubation buffer in 96-well polypropylene plates. The plates were vortexed and incubated at room temperature for 90 minutes at which time the binding reaction was stopped by filtering. The filters were washed and counted using the same procedure as in the total binding assay described above to give the displacement binding value (B D ).
  • test compounds were initially assayed at 1 and 0.1 ⁇ M and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of 3 H-spiperone binding.
  • Specific binding in the absence of test compound (B 0 ) was the difference of total binding (B ⁇ ) minus non-specific binding (NSB) and similarly specific binding (in the presence of test compound) (B) was the difference of displacement binding (Bo) minus non-specific binding (NSB).
  • IC 5 o was determined from an inhibition response curve, logit-log plot of %B/B 0 vs concentration of test compound.
  • the D4 receptor responds to dopamine and other agonists by reducing adenyl cyclase mediated production of cyclic AMP.
  • Particular test compounds were assayed for their ability to reverse dopamine inhibition of adenyl cyclase by the following procedure. Forskolin was used to elevate the basal adenyl cyclase activity.
  • CHO Pro 5 cells stably expressing human D4.2 receptors were plated in 6 well plates in DMEM (Dulbecco's Modified Eagle Medium)/F12(Nutrient Mixture F12
  • SFM+IBMX media was removed and fresh SFM+IBMX media was added to wells separately with one of a) forskolin (10 ⁇ M final cone); b) dopamine and forskolin (both 10 ⁇ M final cone); and c) test compound (10 "4 to 10 *6 M), and dopamine and forskolin (both 10 ⁇ M final cone). Basal adenyl cyclase activity was determined from wells with only SFM+IBMX media added.
  • the cells were then incubated at 37°C for 30 minutes in a C0 2 incubator. Following incubation the media was removed from each well and then washed once with 1 mL of PBS (phosphate buffered saline). Each well was then treated with 1 mL cold 95% ethanol:5 mM EDTA (2:1) at 4°C for 1 hr. The cells from each well were then scraped and transferred into individual Eppendorf tubes. The tubes were centrifuged for 5 min at 4°C, and the supematants were transferred to new Eppendorf tubes. The pellets were discarded and the supernatants stored at 4°C until assayed for cAMP concentration. cAMP content measured in fmoles/well for each extract was determined by EIA (enzyme-immunoassay) using Amersham Biotrak cAMP EIA kit (Amersham RPN 225).
  • EIA enzyme-immunoassay
  • Total inhibition (l 0 ) of forskolin-stimulated adenyl cyclase activity by dopamine was determined as the difference in concentration of cAMP in the forskolin-treated cells (C f ) and dopamine-forskolin treated cells (Cd).
  • lo Cf - Cd Net inhibition (I) of forskolin-stimulated adenyl cyclase activity by dopamine in the presence of an antagonist was determined as the difference in concentration of cAMP in the forskolin-treated cells (C f ) and test compound, dopamine and forskolin treated cells (C).
  • I C f - C The ability of the test compounds to reverse the dopamine inhibition (% reversal,
  • %R (1 - l/lo) X 100
  • test compound stably expressing CHO cells prepared as previously described were added test compound and forskolin (10 ⁇ M final concentration). The cells were incubated, extracted and measured for cAMP concentration as above. Agonist activity of a test compound would result in a decrease in cAMP concentration compared to cells treated with forskolin (Cf) only. No decrease was observed, therefore the test compounds exhibited no dopamine agonist activity. It is predicted based on structural and biological functional similarities that the remaining compounds of the invention would also exhibit dopamine antagonist activity.

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Abstract

L'invention concerne des composés représentés par la formule générale: ou un de leurs stéréoisomères, solvates ou sels acceptables sur le plan pharmaceutique, dans laquelle R1 représente H, halo, aryle ou aryle substitué par un ou deux groupes indépendamment sélectionnés dans halo, alkyle C1-C4, alkoxy C1-C4, nitro, trifluorométhyle, trifluorométhoxy ou cyano; R2 représente alkyle C4-C9, phényle ou phényle substitué par un ou deux groupes sélectionnés indépendamment dans OH, cyano, halo, alkoxy C1-C4, alkyle C1-C4, trifluorométhyle, trifluorométhoxy, nitro ou phényle; naphtyle; phényle fusionné à un hétérocycle à 5 ou 6 éléments; la fraction de coumarine (a): dans laquelle R3 et R4 sont sélectionnés indépendamment dans H, alkyle C1-C4 et alkoxy C1-C4; ou 1,2-méthylènedioxyphényle; à condition que R2 ne représente pas phényle ou 3,4-diméthoxyphényle quand R1 représente H. Elle concerne également leur utilisation en tant que produits pharmaceutiques afin de traiter des cas impliquant le récepteur D4 de dopamine, tels que la schizophrénie et l'anxiété.
PCT/US1997/013264 1996-08-22 1997-07-30 Piperazines de troponyle en tant que ligands selectifs du recepteur d4 de dopamine WO1998007711A1 (fr)

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BR9711965A BR9711965A (pt) 1996-08-22 1997-07-30 Troponil piperazinas como ligantes receptores d4 seletivos de dopamina
IL12862997A IL128629A0 (en) 1996-08-22 1997-07-30 Troponyl piperazines as selective dopamine D4 receptor ligands
NZ333519A NZ333519A (en) 1996-08-22 1997-07-30 Troponyl piperazines as selective dopamine d4 receptor ligands
HU9903913A HUP9903913A3 (en) 1996-08-22 1997-07-30 Troponyl piperazines as selective dopamine d4 receptor ligands, process for producing them, pharmaceutical compositions containing them and their use
AU38171/97A AU3817197A (en) 1996-08-22 1997-07-30 Troponyl piperazines as selective dopamine d4 receptor ligands
JP10510754A JP2000516629A (ja) 1996-08-22 1997-07-30 選択的ドーパミンｄ４受容体リガンドとしてのトロポニルピペラジン
EP97935166A EP0929537A1 (fr) 1996-08-22 1997-07-30 Piperazines de troponyle en tant que ligands selectifs du recepteur d4 de dopamine
NO990796A NO990796L (no) 1996-08-22 1999-02-19 Troponylpiperaziner som selektive dopamin D4-receptorligander

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KR100394083B1 (ko) * 2000-12-04 2003-08-06 학교법인 성신학원 도파민 ｄ3 및 ｄ4 수용체의 선택적 활성을 지닌 신규4,5-디히드로이소옥사졸릴알킬피페라진 유도체와, 이의제조방법
KR100394086B1 (ko) * 2000-12-04 2003-08-06 한국과학기술연구원 도파민 ｄ3 및 ｄ4 수용체의 선택적 활성을 지닌 신규이소옥사졸릴알킬피페라진 유도체와, 이의 제조방법

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WO1992004338A1 (fr) * 1990-08-29 1992-03-19 The Upjohn Company Derives de tropolone et composition pharmaceutique a base desdits derives pour la prevention et le traitement de maladies ischemiques
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BAGLI,J. ET AL.: "TROPONOIDS. 7. CHEMISTRY AND DOPAMINE AGONIST ACTIVITY OF CILADOPA AND RELATED ARALKYLTROPONYLPIPERAZINES", J.MED.CHEM., vol. 29, no. 2, 1986, WASHINGTON, pages 186 - 193, XP002046685 *
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Publication number Priority date Publication date Assignee Title
US6890919B2 (en) 2001-06-26 2005-05-10 Shitij Kapur Atypical antipsychotic agents having low affinity for the D2 receptor

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BR9711965A (pt) 1999-08-24
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