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WO1996039403A1 - 1(-n'-(arylalkylaminoalkyle)) aminoisoindoles utilises en tant que ligands de recepteurs de dopamine - Google Patents

1(-n'-(arylalkylaminoalkyle)) aminoisoindoles utilises en tant que ligands de recepteurs de dopamine Download PDF

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Publication number
WO1996039403A1
WO1996039403A1 PCT/US1996/008836 US9608836W WO9639403A1 WO 1996039403 A1 WO1996039403 A1 WO 1996039403A1 US 9608836 W US9608836 W US 9608836W WO 9639403 A1 WO9639403 A1 WO 9639403A1
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Prior art keywords
lower alkyl
hydrogen
hydroxy
halogen
carbon
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PCT/US1996/008836
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English (en)
Inventor
Xiao-Shu He
Brian Decosta
Jan W. F. Wasley
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Neurogen Corporation
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Publication date
Priority claimed from US08/463,430 external-priority patent/US5744472A/en
Priority claimed from US08/463,037 external-priority patent/US5656632A/en
Priority claimed from US08/464,336 external-priority patent/US5602168A/en
Application filed by Neurogen Corporation filed Critical Neurogen Corporation
Priority to AU59826/96A priority Critical patent/AU5982696A/en
Publication of WO1996039403A1 publication Critical patent/WO1996039403A1/fr

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    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to aminoisoindole derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to l-(N'-(arylalkylaminoalkyl)) aminoisoindoles and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating various neuropsychochological disorders. Description of the Related Art
  • 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 (disordered thought, hallucinations and delusions) and negative symptoms (social withdrawal and unresponsiveness). 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 institutionalization. Within the United States of America, approximately 40% of all hospitalized psychiatric patients suffer from schizophrenia.
  • neuroleptics This classification of antipsychotic medication was based largely on the activating (neuroleptic) properties of the nervous system by these drugs.
  • neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain. This finding suggested that altered neuronal firing of the dopamine system contributed in some way to the aberrant behavior observed in schizophrenic patients. 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 neurotransmitter dopamine was involved in schizophrenia.
  • dopamine receptors One of the major actions of antipsychotic medication is the blockade of dopamine receptors in brain.
  • Several 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 on the basis of their ability to bind various dopaminergic ligands.
  • the butyrophenones are a class of drugs containing many potent antipsychotic drugs. Perhaps the most prominent member of this class of compounds is the antipsychotic drug haloperidol (chemical name). Haloperidol binds relatively weakly at the major dopamine receptor subtype which activates adenylate cyclase (commonly classified as the Di dopamine receptor). In contrast, haloperidol displayed binding affinity at a dopamine receptor subtype which suppressed the activity of adenylate cyclase (commonly classified as D2 receptors) in the subnanomolar range.
  • D3, D4, and D5 dopamine receptor subtypes
  • D3 and D4 subtypes are pharmacologically related to the D2 receptor via their ability to suppress the activity of adenylate cyclase.
  • D5 receptor is classified as a "Di-like" dopamine subtype through its ability to stimulate cyclase activity.
  • EPS extrapyramidal side effects
  • D2 Mockers do not possess a similar profile, hypotheses underlying the differences have been investigated. Major differences have been detected in the anticholinergic actions of these drugs. It has also been suggested that the dopamine receptors in motor areas may differ from those in the limbic areas which are thought to mediate the antipsychotic responses. The existence of the D3, D4 and D5 and other as yet undiscovered dopamine receptors may contribute to this profile.
  • This invention provides novel compounds of Formula 1 which interact with dopamine receptor subtypes.
  • the invention provides pharmaceutical compositions comprising compounds of Formula 1.
  • 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 are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. Since particularly dopamine D3 and D4 receptor subtypes are concentrated in the limbic system (Taubes, Science 265 (1994) 1034), which controls cognition and emotion, compounds which interact with these receptors are useful 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.
  • Other disorders involving memory impairment or attention deficit disorders can also be treated with some of the compounds of this invention that interact specifically with dopamine D3 and/or D4 receptor subtypes. Accordingly, a broad embodiment of the invention is directed to a compounds of Formula 1
  • the 6-membered A ring may be optionally substituted with up to four groups independently selected from halogen, hydroxy, lower alkyl, or lower alkoxy;
  • Ar represents optionally substituted aryl or heteroaryl
  • Z represents carbon or nitrogen provided that where Z is carbon, Rn represents hydrogen, halogen, hydroxy, lower alkyl. or lower alkoxy, or phenyl optionally substituted with one or two groups selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and where Z is nitrogen, Ri i represents an electron pair;
  • R5 is hydrogen or lower alkyl;
  • L is an integer of from 1-4;
  • m is an integer of from 2-5;
  • n is 0, or an integer of from 1-4;
  • Rl2 and R13 independently represent lower alkyl; or together may represent (CR ⁇ Ry)s where s is an integer of from 1-6 and R x and Ry independently represent hydrogen or lower alkyl;
  • CR'R" represents a methylene group optionally substituted with lower alkyl; and k is 0 or an integer of from 1 to 3.
  • the compounds of Formula 1 can be used in the treatment of various neuropsychochological disorders including, for example, schizophrenia, dementia, depression, anxiety, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.
  • Rl, R2, R3, R4 and R7, R8 and R9 are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
  • X represents carbon or nitrogen provided that where X carbon, R ⁇ represents hydrogen, halogen, hydroxy, lower alkyl having 1-6 carbon atoms, or lower alkoxy; and where X is nitrogen, R6 represents an electron pair,
  • Y represents carbon or nitrogen provided that where Y is carbon, Rio represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and where Y is nitrogen, Rio represents an electron pair;
  • Z represents carbon or nitrogen provided that where Z is carbon, Rn represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, or phenyl optionally substituted with one or two groups selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and when Z is nitrogen, Rl 1 represents an electron pair,
  • R5 is hydrogen or lower alkyl
  • Rl2 and R13 taken together may represent (CR x R y ) s where s is an integer of from 1-6 and R x and Ry independendy represent hydrogen or lower alkyl;
  • R7 and Rg together may represent a benzo ring optionally substituted with up to four substitutents selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and Rl4, R15, Ri6 and R17 are the same or different and represent hydrogen or lower alkyl.
  • Preferred compounds of Formula ia are those where s is an integer of from 1-4, and most preferably from 2-3.
  • the present invention also encompasses compounds of Formula 2-
  • Rl, R2, R3, R4 and R7, R8 and R9 are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
  • X represents carbon or nitrogen provided that where X carbon, R6 represents hydrogen, halogen, hydroxy, lower alkyl having 1-6 carbon atoms, or lower alkoxy; and where X is nitrogen, R6 represents an electron pair,
  • Y represents carbon or nitrogen provided that where Y is carbon, Rio represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and where Y is nitrogen, Rio represents an electron pair;
  • Z represents carbon or nitrogen provided that where Z is carbon, Rn represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, or phenyl optionally substituted with one or two groups selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and when Z is nitrogen, Rl l represents an electron pair, R5 is hydrogen or lower alkyl;
  • Rl2 and R13 taken together represent (CH2)s where s is an integer of from 1-6; R7 and R8 together may represent a benzo ring optionally substituted with up to four substitutents selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy.
  • Preferred compounds of Formula 2 are those where s is an integer of from 1-4, and most preferably from 2-3.
  • the present invention further encompasses compounds of Formula 3_:
  • Rl, R2, R3, R4 and R7, Rg and R9 are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
  • Rl6 represents hydrogen or lower alkyl;
  • X represents carbon or nitrogen provided that where X carbon, R6 represents hydrogen, halogen, hydroxy, lower alkyl having 1-6 carbon atoms, or lower alkoxy; and where X is nitrogen, R represents an electron pair;
  • Y represents carbon or nitrogen provided that where Y is carbon, Rio represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and where Y is nitrogen, Rio represents an electron pair; m is an integer of from 2-5;
  • R7 and Rg together optionally represent a benzo ring optionally substituted with up to four substitutents selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy.
  • Preferred compounds of formula 2 are those where m is 2, 3 or 4. Particularly preferred compounds of Formula are those where m is 2 or 3; Ri, R2, R3, R4 are hydrogen; R7 and R9 are hydrogen and Rg is hydrogen, hydroxy, halogen or alkoxy. More particularly preferred compounds of Formula 2 are those where m is 2 or 3; Ri , R2, R3, R4 are hydrogen; Ri6 is hydrogen or methyl; R7 and R9 are hydrogen; and Rg is hydrogen, hydroxy or methoxy.
  • Still other preferred compounds of formula 2 are those where m is 2 or 3; X and Y independently represent methylene optionally substituted with lower alkyl, preferably methyl; Ri, R2, R3, R4 are hydrogen; Rl6 is hydrogen or methyl; R7 and R9 are hydrogen and Rg is hydrogen, hydroxy or methoxy.
  • the present invention also encompasses compounds of Formula 4:
  • Rl, R2, R3, R4 and R7, Rg and R9 are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
  • Y represents carbon or nitrogen provided that where Y is carbon, Rio represents* hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and where Y is nitrogen, Rio represents an electron pair;
  • m is an integer of from 2-5; and
  • R7 and Rg together may represent a benzo ring optionally substituted with up to four substitutents selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy.
  • Preferred compounds of formula 4 are those where m is 2, 3 or 4. Particularly preferred compounds of Formula 4 are those where m is 2 or 3; and Ri, R2, R3, R4 are hydrogen; R7 and
  • R9 are hydrogen; and Rg is hydrogen, hydroxy, halogen or alkoxy. More particularly preferred compounds of Formula 4 are those where m is 2 or 3; and Ri, R2, R3, R4 are hydrogen; R7 and
  • R9 are hydrogen; and Rg is hydrogen, hydroxy or methoxy.
  • the present invention also encompasses compounds of Formula 5:
  • Rl, R2, R3, R4 and R7, Rg and R9 are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
  • X represents carbon or nitrogen provided that where X carbon, R ⁇ represents hydrogen, halogen, hydroxy, lower alkyl having 1-6 carbon atoms, or lower alkoxy; and where X is nitrogen, R6 represents an electron pair,
  • Y represents carbon or nitrogen provided that where Y is carbon, Rio represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and where Y is nitrogen, Rio represents an electron pair; Z represents CH2 or nitrogen; m is an integer of from 2-5; n is 0, or an integer of from 1-4; Rl2 represents hydrogen or lower alkyl; and
  • R7 and Rg together optionally represent a benzo ring optionally substituted with up to four substitutents selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy.
  • Preferred compounds of formula 5_ are those where m is 2, 3 or 4 and n is 0.
  • Particularly preferred compounds of Formula 5 are those where R12 is hydrogen or alkyl; m is 2, n is 0; Z is CH2; Rl , R2- R3, 4 are hydrogen; R7 and R9 are hydrogen; and Rs is hydrogen, hydroxy, halogen or alkoxy.
  • More particularly preferred compounds of Formula 2 are those where R12 is hydrogen or methyl; m is 2; n is 0; Z is CH2; and Rl, R2, R3, R4 are hydrogen; R7 and R9 are hydrogen; and Rg is hydrogen, hydroxy or methoxy.
  • Rl, R2, R3, R4 and Rg are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
  • R6 and Rio independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy
  • Z represents CH2 or nitrogen; m is an integer of from 2-5; R5 represents hydrogen or lower alkyl; n is 0, or an integer of from 1-4; and
  • Rl2 represents lower alkyl.
  • Preferred compounds of formula 6, are those where m is 2, 3 or 4 and n is 0.
  • Particularly preferred compounds of Formula 6, are those where R12 is hydrogen or alkyl; m is 2, n is 0; Z is CH2; Rl, R2 > R3, R4 are hydrogen; and Rg is hydrogen, hydroxy, halogen or alkoxy.
  • More particularly preferred compounds of Formula 6 are those where R12 is hydrogen or methyl; R ⁇ is hydrogen; Rio is hydrogen or lower alkoxy, preferably methoxy; m is 2; n is 0; Z is CH2; and Ri.
  • R2, R3, R4 are hydrogen; and Rg is hydrogen, hydroxy or methoxy.
  • Preferred X ' m Ri 12 o R "1 3 * 'n ⁇ groups of formula I above include the following:
  • OR represents hydroxy or alkoxy
  • Representative compounds of the present invention include, but are not limited to the compounds shown below in Table 1 and their pharmaceutically acceptable salts.
  • Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic, hydroiodic, acetic and the 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 and “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, trifiuoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
  • aromatic e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl
  • 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 the 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 with e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifiuoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
  • halogen fluorine, chlorine, bromine and iodine.
  • alkylsulfonyl is meant a sulf onyl group substituted with a lower alkyl group.
  • arylalkylsulfonyl is meant a sulf onyl group substituted with an arylalkyl group.
  • aminosulfonyl is meant a sulfonyl group substituted with an amino group.
  • alkylaminosulfonyl is meant a sulfonyl group substituted with a lower alkylamino, or di-lower alkylamino group.
  • Pellets of COS cells containing recombinantly produced D2 or D3 receptors from African Green monkey were used for the assays.
  • the sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl 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 the final tissue sample is frozen until use.
  • the tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl. Incubations are carried out at 48°C and contain 0.4 ml of tissue sample, 0.5 nM - ⁇ H-YM
  • Nonspecific binding is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is less than 20% of total binding.
  • the binding characteristics of examples of this patent for the D2 and D3 receptor subtypes are shown in Table 2 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 MgCl2- 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.
  • the remaining homogenate is centrifuged as above, the supernatant removed and the pellet stored at 4° C until needed at which time it is resuspended to a final concentration of 625 mg/ml (250 mg per sample) with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use. Incubations were carried out for 60 minutes at 25° C in the presence of 0.1 nM [ 3 H] YM-09151-2. The incubation was terminated by rapid filtration through Whatman GF/C filters and rinsed with 2 x 4 ml washes of chilled 50 mM Tris (pH 7.4) and 120 mM NaCl.
  • Non-specific binding was determined with 1 mM spiperone and radioactivity determined by counting in an LKB beta counter. Binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constant Ki could be calculated for each test compound.
  • the binding characteristics of some examples of this invention are shown in Table 3 for the dopamine D4 binding assay. In general, compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for the displacement of [3H]YM-09151-2 from the human dopamine D4 receptor subtype of below 500 nM. Some specific data is indicated in Table 3.
  • Compounds 1 and 2 are particularly preferred embodiments of the present invention because of their profile in binding to dopamine receptor subtypes.
  • the compounds of general Formulas 1 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 1 and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula 1 may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of general Formula 1 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 art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the 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 with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn 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 with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • 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, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
  • the 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.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • 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 those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anu-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • compositions of the invention may also be in the 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 tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or pa ⁇ ial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said pa ⁇ ial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, 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 those 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 synthetic mono or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general Formula 1 may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with 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 the 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 the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Compounds of general Formula 1 may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the 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 that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the pa ⁇ icular mode of administration.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient
  • the specific dose level for any pa ⁇ icular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the pa ⁇ icular disease undergoing therapy.
  • the compounds of the invention may be prepared by the reactions shown below in Scheme 1. Those having skill in the an will recognize that the sta ⁇ ing materials may be varied and additional steps employed to produce other compounds encompassed by the present invention.
  • Example 3 The following compounds are prepared essentially according to the procedures set forth above in Examples 1 and 2.

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Abstract

Composés de formule (1), ou sels pharmaceutiquement acceptables desdits composés. Dans cette formule, le cycle A à 6 chaînons peut être éventuellement substitué par quatre groupes au maximum indépendamment choisis parmi halogène, hydroxy, alkyle inférieur ou alcoxy inférieur; Ar représente aryle ou hétéroaryle éventuellement substitués; Z représente carbone ou azote à condition que, lorsque Z est carbone, R11 représente hydrogène, halogène, hydroxy, alkyle inférieur ou alcoxy inférieur, ou phényle éventuellement substitué par deux groupes choisis parmi hydrogène, halogène, hydroxy, alkyle inférieur ou alcoxy inférieur, et, lorsque Z est azote, R11 représente une paire d'électrons; R5 est hydrogène ou alkyle inférieur; L et m représentent des nombres entiers; n est 0 ou un nombre entier; R12 et R13 représentent indépendamment alkyle inférieur, ou peuvent former ensemble un cycle éventuellement substitué possédant de 5 à 11 chaînons avec les atomes d'azote auxquels ils sont liés; CR'R' représente un groupe méthylène éventuellement substitué par alkyle inférieur et k est un nombre entier de 1 à 3. Lesdits composés sont utiles pour traiter divers troubles neuropsychologiques dont, par exemple, la schizophrénie, la démence, la dépression, l'anxiété, les troubles moteurs de type Parkinson et les troubles de la motricité liés à l'utilisation de neuroleptiques.
PCT/US1996/008836 1995-06-05 1996-06-04 1(-n'-(arylalkylaminoalkyle)) aminoisoindoles utilises en tant que ligands de recepteurs de dopamine WO1996039403A1 (fr)

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US08/463,037 1995-06-05
US08/463,430 1995-06-05
US08/464,336 US5602168A (en) 1995-07-10 1995-07-10 1-(N'-(arylalkylaminoalkyl)) aminoisoindoles; dopamine receptor subtype specific ligands
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WO1998056786A1 (fr) * 1997-06-13 1998-12-17 Neurogen Corporation 2-aminoalkylaminoquinoleines utilisees comme ligands de la dopamine d¿4?
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WO1998029410A1 (fr) * 1995-06-05 1998-07-09 Neurogen Corporation 1-(n'-(arylalkylaminoalkyl)) aminoisoindoles, et ligands specifiques d'un sous-type de recepteur de la dopamine
WO1998056786A1 (fr) * 1997-06-13 1998-12-17 Neurogen Corporation 2-aminoalkylaminoquinoleines utilisees comme ligands de la dopamine d¿4?
US5972945A (en) * 1997-06-13 1999-10-26 Neurogen Corporation 2-aminoalkylaminoquinolines; dopamine receptor subtype specific ligands
US6313141B1 (en) 1997-06-13 2001-11-06 Neurogen Corporation 2-aminoalkylaminoquinolines as dopamine D4 ligands
WO1999021848A3 (fr) * 1997-10-27 1999-07-15 Neurogen Corp Nouveau 1-(n'-(arylalkylaminoalkyl)aminoisoquinolines; nouvelle classe de ligands specifiques de sous-type de recepteur de dopamine
US6441175B1 (en) 1997-10-27 2002-08-27 Neurogen Corporation 1-(N'-arylalkylaminoalkyl)aminoisoquinolines: a new class of dopamine receptor subtype
WO2000018767A3 (fr) * 1998-09-30 2000-07-27 Neurogen Corp Derives de 2-piperazino -alkyl- aminobenzoazole: ligands specifiques du sous-type du recepteur de la dopamine
US6284759B1 (en) 1998-09-30 2001-09-04 Neurogen Corporation 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands
US6432958B1 (en) 1998-09-30 2002-08-13 Neurogen Corporation 2-piperazinoalkylaminobenzoazole derivatives: dopamine receptor subtype specific ligands
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US7294634B2 (en) 1999-10-27 2007-11-13 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7589098B2 (en) 1999-10-27 2009-09-15 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7105668B1 (en) 1999-10-27 2006-09-12 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US6613901B2 (en) 2000-03-08 2003-09-02 Neurogen Corporation 2-aminoalkylaminoquinolines as dopamine D4 ligands
US7161002B2 (en) 2002-02-15 2007-01-09 Cytokinetics, Inc. Syntheses of quinazolinones
US7009049B2 (en) 2002-02-15 2006-03-07 Cytokinetics, Inc. Syntheses of quinazolinones
US7166595B2 (en) 2002-05-09 2007-01-23 Cytokinetics, Inc. Compounds, methods and compositions
US7214800B2 (en) 2002-05-09 2007-05-08 Cytokinetics, Inc. Compounds, compositions, and methods
US7528137B2 (en) 2002-05-09 2009-05-05 Cytokinetics, Inc. Compounds, compositions, and methods
US7332498B2 (en) 2002-05-23 2008-02-19 Cytokinetics, Inc. Modulation of KSP kinesin activity with heterocyclic-fused pyrimidinone derivatives
US7038048B2 (en) 2002-05-23 2006-05-02 Cytokinetics, Inc. 3H-pyridopyrimidin-4-one compounds, compositions, and methods of their use
US7041676B2 (en) 2002-06-14 2006-05-09 Cytokinetics, Inc. Compounds, compositions, and methods
US7211580B2 (en) 2002-07-23 2007-05-01 Cytokinetics, Incorporated Compounds, compositions, and methods
US7557115B2 (en) 2002-09-30 2009-07-07 Cytokinetics, Inc. Compounds, compositions, and methods
US7439254B2 (en) 2003-12-08 2008-10-21 Cytokinetics, Inc. Compounds, compositions, and methods

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WO1998029410A1 (fr) 1998-07-09
AU5982696A (en) 1996-12-24

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