EP0793662A1 - Composes aminomethyle aryle, ligands selectifs d'un sous-type de recepteur de dopamine - Google Patents

Composes aminomethyle aryle, ligands selectifs d'un sous-type de recepteur de dopamine

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Publication number
EP0793662A1
EP0793662A1 EP95943057A EP95943057A EP0793662A1 EP 0793662 A1 EP0793662 A1 EP 0793662A1 EP 95943057 A EP95943057 A EP 95943057A EP 95943057 A EP95943057 A EP 95943057A EP 0793662 A1 EP0793662 A1 EP 0793662A1
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EP
European Patent Office
Prior art keywords
straight
carbon atoms
branched chain
chain lower
lower alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP95943057A
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German (de)
English (en)
Inventor
Jun Yuan
Andrew Thurkauf
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Neurogen Corp
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Neurogen Corp
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Priority claimed from US08/344,497 external-priority patent/US5594141A/en
Application filed by Neurogen Corp filed Critical Neurogen Corp
Publication of EP0793662A1 publication Critical patent/EP0793662A1/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • 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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • This invention relates to certain aminomethyl biphenyl. phenylpyridines and phenylpyrimidine derivatives which selectively bind to brain dopamine receptor subtypes.
  • This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Par insonism.
  • Schizophrenia or psychosis is a term used to describe a group of illnesses of unknown origin which affect approximately 2.5 million people in the United States. These disorders of the brain are characterized by a variety of symptoms which are classified as positive symptoms
  • disorders disordered thought, hallucinations and delusions
  • negative symptoms social withdrawal and u ⁇ responsiveness
  • These disorders have an age of onset in adolescence or early adulthood and persist for many years. The disorders tend to become more severe during the patient's lifetime and can result in prolonged institutionalizarion. In the United States today, approximately 40% of all hospitalized psychiatric patients suffer from schizophrenia.
  • neuroleptics this classification of antipsychoric medication was based largely on die activating ⁇ ,neuroleptic) properties of the nervous system by these drugs. Subsequently, neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain suggesting altered neuronal firing of the dopamine system. Additional evidence indicated that dopamine could increase the activity of adenylate cyclase in the corpus striatum, an effect reversed by neuroleptic agents. Thus, cumulative evidence from these and later experiments strongly suggested that the neurotransmi ⁇ er dopamine was involved in schizophrenia.
  • One of the major actions of antipsychotic medication is the blockade of dopamine receptors in brain.
  • dopamine systems appear to exist in the brain and at least five classes of dopamine receptors appear to mediate the actions of this transmitter. These dopamine receptors differ in their pharmacological specificity and were originally classified upon these differences in the pharmacology of different chemical series.
  • the butyrophenones a class of compounds containing many potent antipsychotic drugs, were quite weak at the dopamine receptor that activated adenylate cyclase (now known as a Dl dopamine receptor).
  • D2 receptors dopamine receptors
  • D3 a third type
  • D5 which is somewhat similar to the Dl receptor subtype, and D4 which is closely related to D3 and D2 receptor types.
  • the phenothiazines which include chlorpromazine, possess nanomolar affinity for all three types of dopamine receptors.
  • Other drugs have been developed with great specificity for the Dl receptor subtype and for the D2 receptor subtype.
  • a group of drugs (such as sulpiride and clozapine) have been developed which display a lesser incidence of extrapyramidal side effects than classical neuroleptics. In addition, there is some indication that these drugs may be more beneficial in treating negative symptoms in some patients. Since all D2 blockers do not possess a similar profile, certain hypotheses underlying the differences have been investigated. One of the major differences among these various classes of antipsychotics has been in the anticholinergic actions of these drugs. The possibility also exists that the various dopamine receptor subtypes may be differentially distributed between the limbic areas, thought to mediate antipsychotic responses, and the motor areas of the brain. The existence of the D3, D4 and D5 and other as yet undiscovered dopamine receptors may contribute to this profile.
  • Atypical antipsychotics have loosely been defined as those compounds which impart antipsychotic action without the concurrent motor impairment.
  • Some of the atypical compounds G and K are the same or different and represent N or CR' where R' is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched lower alkoxy having 1-6 carbon atoms: R is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; Ri, X, Y. Z and T are the same or different and represent hydrogen, halogen, cyano.
  • R4 is straight or branched chain lower alkyl having 1-6 carbon atoms or where R4 is NH2 or NHCH3;
  • R2 and R3 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl, arylalkyl; or
  • NR2R3 together represent 2-(l,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR2R3 represents:
  • R5 is phenyl, either unsubstituted or mono or disubstituted by either halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or
  • NR2 3 represents
  • W is N or CH
  • R6 is phenyl, benzyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl
  • This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes.
  • the invention provides pharmaceutical compositions comprising compounds of Formula I.
  • the invention also provides compounds useful in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.
  • compounds of this invention may be useful in treating the extrapyramidyl side effects associated with the use of conventional neuroleptic agents. Since dopamine D3 and D4 receptor subtypes are concentrated in the limbic system (Taubes, Science (1994) 265. 1034) which controls cognition and emotion, compounds which interact with these receptors may have utility in the treatment of cognitive disorders.
  • Such disorders may be the cognitive deficits which are a significant component of the negative symptoms (social withdrawal, and unresponsiveness) of schizophrenia.
  • a broad embodiment of the invention is directed to a compound of
  • R4 is straight or branched chain lower alkyl having 1-6 carbon atoms or where R4 is NH2 or NHCH3;
  • R2 and R3 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl, arylalkyl; or
  • NR2R3 together represent 2-(l,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR2R3 represents:
  • R5 is phenyl, either unsubstituted or mono or disubstituted by either halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or NR2R3 represents
  • W is N or CH
  • R6 is phenyl, benzyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and n is 1, 2 or 3.
  • aminomethyl biphenyl, aminomethyl phenylpyridi ⁇ es and aminomethyl phenylpyrimidine derivatives of the invention results in the pharmacological activities of these compounds.
  • These compounds are highly selective partial agonists or antagonists at brain dopamine receptor subtypes or prodrugs thereof and are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.
  • compounds of this invention are useful in treating the extrapyramidyl side effects associated with the use of conventional neurolep ⁇ c agents.
  • the invention encompasses methods for the treatment of neuropsychological disorders comprising administering to a patient having a neuropsychological disorder an amount of a compound according to Formula I effective to treat the neuropsychological disorder.
  • Ri, X, Y. Z and T represent hydrogen or alkyl and R9 represents hydrogen or alkyl.
  • Preferred compounds according to Formula III are those where Ri, X, Y, Z and T are hydrogen; R9 represents hydrogen; and Ar represents benzyl or phenyl.
  • Other preferred compounds of Formula III are those where Ri, X. Y, Z and T are hydrogen; Ro represents hydrogen; and Ar represents 2-pyridyl or pyrimidinyl.
  • the invention further encompasses compounds of Formula IV:
  • Ri, X. Y. Z and T represent hydrogen or alkyl; and Rio and Rl 1 independently represent hydrogen or alkyl.
  • Preferred compounds according to Formula IV are those where Rl, X, Y, Z and T are hydrogen; Ar represents phenyl; and Rio and Ri 1 independendy represent alkyl.
  • Other preferred compounds of Formula IV are those where Rl, X, Y, Z and T are hydrogen; Rio and Ri 1 independendy represent methyl; and Ar represents phenyl.
  • the invention further encompasses compounds of Formula V:
  • R 1 , X. Y. Z and T represent hydrogen or alkyl; R7 and Rg independently represent hydrogen or alkoxy; R ⁇ is hydrogen or alkyl; and W represents nitrogen or CH.
  • Preferred compounds of Formula I include ti ose where W is N or CH; and R7 is phenyl, pyridyl or pyrimidinyl, each of which is optionally mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.
  • Preferred compounds according to Formula II are those where Ri, X, Y, Z and T are hydrogen: R7 and Rg are different and represent hydrogen or alkoxy; W is CH: and Ar represents benzyl or phenyl.
  • Other preferred compounds of Formula II are those where Rj, X, Y. Z and T are hydrogen; R7 and R% are different and represent hydrogen or alkoxy; W is nitrogen; and Ar represents 2-pyridyl or pyrimidinyl.
  • the invention further encompasses compounds of Formula IH:
  • Ri, X, Y, Z and T represent hydrogen or alkyl; R9 is hydrogen or alkyl; Rifj represents hydrogen or alkyl: and R12 represents alkoxy.
  • Preferred compounds according to Formula V are those where Rl , X, Y, Z and.T are hydrogen; R9 is hydrogen; Rio represents alkyl and R 12 is an alkoxy group in die 2-position of die phenyl ring.
  • the invention further encompasses compounds of Formula VI:
  • Rl, X, Y, Z and T represent hydrogen or alkyl; and R is a group of the formula:
  • W is N or CH; R represents alkyl; and R ⁇ j represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted with halogen, alkyl or alkoxy.
  • Preferred compounds according to Formula VI are those where Ri, X. Y. Z and T are hydrogen; Ar is optionally substituted phenyl and Re is a 4-substituted pipcrazin- 1 -yl or piperidin-
  • Particularly preferred compounds of Formula VI are those where the 4-substituted piperazin- 1-yl or piperidin-1-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.
  • the invention further provides compounds of Formula VII:
  • Ri , X, Y, Z and T represent hydrogen or alkyl; and R is a group of the formula:
  • W is N or CH
  • R represents alkyl: and R ⁇ represents pyridyl, pyrimidinyl. phenylalkyl, or phenyl optionally substituted wirJi halogen, alkyl or alkoxy.
  • Preferred compounds according to Formula VII are those where Rl, X. Y. Z and T are hydrogen; and Re is a 4-substituted piperazin-1-yl or piperidin-l-yl group.
  • Particularly preferred compounds of Formula VII are those where the 4-substituted piperazin- 1-yl or piperidin-l-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.
  • the invention further provides compounds of Formula VIE:
  • W is N or CH: R represents alkyl; and R represents pyridyl. pyrimidinyl, phenylalkyl, or phenyl optionally substituted widi halogen. alkyl or alkoxy.
  • Preferred compounds according to Formula VIII are those where Ri, X, Y. Z and T are hydrogen: and Re is a 4-substituted piperazin-1-yl or piperidin-l-yl group.
  • Particularly preferred compounds of Formula VIII are those where the 4-substituted piperazin-1-yl or piperidin-l-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.
  • the invention further provides compounds of Formula DC:
  • W is N or CH; R represents alkyl; and Rd represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionally substituted widi halogen, alkyl or alkoxy.
  • Preferred compounds according to Formula IX are those where Rj, X, Y. Z and T are hydrogen; and Re is a 4-substiruted piperazin- 1-yl or piperidin-l-yl group.
  • Particularly preferred compounds of Formula IX are those where the 4-substituted piperazin- 1 -yl or piperidin-l-yl groups are substituted with optionally substituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.
  • Still other preferred compounds of Formula IX are those where Re is N-benzyl-N- methylamino.
  • Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric. phosphoric, hydrobromic. sulfuric, sulfinic, formic, toluene sulfonic. hydroiodic. acetic and die like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
  • the present invention also encompasses the acylated prodrugs of the compounds of
  • aryl or “Ar” is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2.3,4-tetrahydronaphthyl. naphthyl. anthryl. or phenanthryl), which can optionally be unsubstituted or substituted with e.g., halogen, lower alkyl. lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
  • alkyl and lower alkyl is meant straight and branched chain alkyl groups having from 1-6 carbon atoms.
  • lower alkoxy and alkoxy is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.
  • heteroaryl is meant 5. 6. or 7 membered aromatic ring systems having at least one hetero atom selected from die group consisting of nitrogen, oxygen and sulfur.
  • heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionally be unsubstituted or substituted widi e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio. trifluoromethyl, lower acyloxy. aryl, heteroaryl, and hydroxy.
  • halogen is meant fluorine, chlorine, bromine and iodine.
  • arylalkyl and aralkyl is meant the group -R-Ar where Ar is an aryl group and R is a straight or branched chain aliphatic group.
  • Arylalkyl groups may optionally be substituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, and hydroxy.
  • Preferred arylalkyl groups in the above formulas where W is CH and R8 represents arylalkyl are phenylalkyl groups where die alkyl portion is lower alkyl.
  • a particularly preferred phenylalkyl group is benzyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.
  • cycloalkyl cyclic hydrocarbons having from 3-8 carbon atoms. These cyclic hydrocarbon groups may be substituted with up to three substituents independendy selected from hydrogen, halogen, trifluoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy. straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2R9 where R9 is H2 or
  • Striatial tissue is dissected from adult male Sprague Dawley rats or BHK 293 cells are harvested containing recombinandy produced D2 or D3 receptors.
  • the sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HC1 buffer at 4°C and pH 7.4.
  • the sample is then centrifuged at 30,000 x g and resuspended and rehomogenized.
  • the sample is then centrifuged as described and die final tissue sample is frozen until use.
  • the tissue is resuspended 1:20 (wt vol) in 0.05 M Tris HC1 buffer containing 100 mM NaCl.
  • Incubations are carried out at 48°C and contain 0.5 ml of tissue sample, 0.5 nM -1H- raclopride and the compound of interest in a total incubation of 1.0 ml.
  • Nonspecific binding is defined as that binding found in die presence of 10" 4 M dopamine; without further additions. nonspecific binding is less than 20% of total binding.
  • the binding characteristics of examples of this patent are shown in Table 1 for rat striatal homogenates.
  • Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and the cells centrifuged and the pellets stored at -80°C until used in the binding assay.
  • the pellets were resuspended and the cells lysed at 4° C in 50 mM Tris pH 7.4 buffer containing 120 mM NaCl, 1 mM EDTA and 5 mM MgC-2-
  • the homogenate is centrifuged at 48000 x g for 10 minutes at 4°C.
  • the resulting pellet is resuspended in fresh buffer and centrifuged again. After resuspension of the pellet in fresh buffer a 100 ml aliquot is removed for protein determination.
  • Compounds 1, 3, 4 and 9 are particularly preferred embodiments of die present invention because of their potency in binding to dopamine receptor subtypes.
  • the compounds of die invention including those represented by general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula I may be present in association
  • compositions containing compounds of general formula I may be in a form suitable for oral use. for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the an for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from die group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture widi non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inen diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents, for example, com starch, or alginic acid: binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed wid an inen solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein die active ingredient is mixed wid water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inen solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • die active ingredient is mixed wid water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose. sodium alginate. polyvinylpynolidone. gum tragacandi and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene
  • aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate. one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil. olive oil, sesame oil or coconut oil. or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as diose set fonh above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anri-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by die addition of water provide the active ingredient in admixture widi a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients. for example sweetening, flavoring and coloring agents, may also be present.
  • Pharmaceutical compositions of the invention may also be in d e form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacantii. naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol , anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters widi ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • -21- Syrups and elixirs may be formulated with sweetening agents, for example giycerol. propylene glycol. sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known an using tiiose suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1.3-butanediol.
  • Suitable vehicles and solvents that may be employed are water. Ringer ' s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including syndietic mono or diglycerides.
  • fatty acids such as oieic acid find use in die preparation of injectables.
  • the compounds of general formula I may also be administered in the form of suppositories for rectal acLministration of the drug.
  • These compositions can be prepared by mixing the drug widi a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release die drug.
  • suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release die drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Compounds of general formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can eidier be suspended or dissolved in die vehicle.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above- indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of active ingredient diat may be combined with die carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient-
  • Example IV The following compounds were prepared essentially according to the procedure described in Example IH.
  • Example VI The following compound was prepared essentially according to the procedure described in
  • Example V (a) 2-Phenyl-6-[(4-benzyi-piperidin-l-yl)med ⁇ yl]-pyridine (Compound 10), mp 81-83°C.
  • Example VTH The following compound was prepared essentially according to die procedure described in Example VII.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I) et ceux de leurs sels qui sont acceptables du point de vue pharmaceutique. Dans cette formule, S et V sont divers agents de substitution organiques ou inorganiques; G et K sont semblables ou différents et représentent N ou CR', R' étant un agent de substitution organique ou inorganique; R est hydrogène ou un groupe alkyle; R1, X, Y, Z et T sont des agents de substitution organiques ou inorganiques; et R2 et R3 représentent hydrogène ou des agents de substitution organiques; ou bien l'ensemble NR2R3 représente un système à noyau hétérocyclique. Ces composés sont, au niveau des sous-types de récepteurs de la dopamine cérébrale, des agonistes partiels ou des antagonistes hautement sélectifs, et sont donc utiles dans le diagnostic et le traitement des troubles affectifs tels que la schizophrénie et la dépression ainsi que de certains troubles moteurs tels que le parkinsonisme.
EP95943057A 1994-11-23 1995-11-22 Composes aminomethyle aryle, ligands selectifs d'un sous-type de recepteur de dopamine Ceased EP0793662A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US08/344,497 US5594141A (en) 1994-11-23 1994-11-23 Certain aminomethyl biphenyl, aminomethyl phenyl pyridine and aminomethyl phenyl pyrimidine derivatives; novel dopamine receptor subtype selective ligands
US344497 1994-11-23
US457633 1995-06-01
US08/457,409 US6281359B1 (en) 1994-11-23 1995-06-01 Aminomethyl phenyl pyridine derivatives
US457409 1995-06-01
US08/457,633 US5677454A (en) 1994-11-23 1995-06-01 Certain methylpiperazinyl and methylpiperidinyl substituted biphenyl derivatives; novel dopamine receptor subtype selective ligands
PCT/US1995/016040 WO1996016058A1 (fr) 1994-11-23 1995-11-22 Composes aminomethyle aryle, ligands selectifs d'un sous-type de recepteur de dopamine

Publications (1)

Publication Number Publication Date
EP0793662A1 true EP0793662A1 (fr) 1997-09-10

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EP95943057A Ceased EP0793662A1 (fr) 1994-11-23 1995-11-22 Composes aminomethyle aryle, ligands selectifs d'un sous-type de recepteur de dopamine

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EP (1) EP0793662A1 (fr)
JP (1) JP2918002B2 (fr)
AU (1) AU4420296A (fr)
CA (1) CA2205969A1 (fr)
MX (1) MX9703671A (fr)
WO (1) WO1996016058A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594141A (en) 1994-11-23 1997-01-14 Neurogen Corporation Certain aminomethyl biphenyl, aminomethyl phenyl pyridine and aminomethyl phenyl pyrimidine derivatives; novel dopamine receptor subtype selective ligands
SK285198B6 (sk) 1997-10-27 2006-08-03 Neurosearch A/S Homopiperazínový derivát, farmaceutická kompozícia obsahujúca tento derivát a jeho použitie
CO5011067A1 (es) * 1997-11-03 2001-02-28 Novartis Ag Derivados de bifenilo como productos farmaceuticos, su pre- paracion y composiciones farmaceuticas que los contienen
EP2222639A1 (fr) * 2007-11-21 2010-09-01 Decode Genetics EHF Inhibiteurs de biaryle pde4 pour le traitement de troubles pulmonaires et cardiovasculaires
WO2009067600A2 (fr) * 2007-11-21 2009-05-28 Decode Genetics Ehf Inhibiteurs de pde4 biaryle pour traiter une inflammation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727073A (en) * 1984-10-01 1988-02-23 Fujisawa Pharmaceutical Co., Ltd. Pyrimidine derivatives and composition of the same
DE3609142A1 (de) * 1986-03-19 1987-09-24 Merck Patent Gmbh Pyridinderivate
DE3609598A1 (de) * 1986-03-21 1987-10-01 Hoechst Ag 2-azolylmethyl-2-aryl-1,3-dioxolane und deren salze, verfahren zu ihrer herstellung, sie enthaltende mittel und ihre verwendung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9616058A1 *

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MX9703671A (es) 1997-12-31
WO1996016058A1 (fr) 1996-05-30
JPH10503214A (ja) 1998-03-24
CA2205969A1 (fr) 1996-05-30
AU4420296A (en) 1996-06-17
JP2918002B2 (ja) 1999-07-12

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