EP1027347A2 - 3-aminoalkylamino- 2h-1,4-benzoxazines et 3-aminoalkylamino- 2h-1,4-benzothiazines constituant des ligands specifiques d'un sous-type de recepteur de la dopamine - Google Patents

3-aminoalkylamino- 2h-1,4-benzoxazines et 3-aminoalkylamino- 2h-1,4-benzothiazines constituant des ligands specifiques d'un sous-type de recepteur de la dopamine

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EP1027347A2
EP1027347A2 EP98956310A EP98956310A EP1027347A2 EP 1027347 A2 EP1027347 A2 EP 1027347A2 EP 98956310 A EP98956310 A EP 98956310A EP 98956310 A EP98956310 A EP 98956310A EP 1027347 A2 EP1027347 A2 EP 1027347A2
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Prior art keywords
alkyl
compound according
nitrogen
hydrogen
amino
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German (de)
English (en)
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Xiao-Shu He
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Neurogen Corp
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Neurogen Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain 3 -aminoalkylamino-2H- 1, 4-benzoxazines and 3-aminoalkylamino-2H-l , 4-benzothiazines and pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases .
  • neuroleptics The therapeutic effect of conventional antipsychotics, known as neuroleptics , is generally believed to be exerted through blockade of dopamine receptors.
  • neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain.
  • EPS extrapyramidal side effects
  • the dopamine D4 receptor subtype has recently been identified (Nature, 347 : 146, Sokoloff et al . , 1990; Nature, 350: 610, Van Tol et al . , 1991). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics indicates that the D 4 receptor plays a major role in the etiology of schizophrenia.
  • Selective D4 antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics .
  • Ar represents aryl or heteroaryl of the formula
  • Rl , R2 , R3 and R 4 are the same or different and represent hydrogen, halogen, Ci-C ⁇ alkyl, C1 . -C 4 alkoxy, cycloalkoxy, alkylthio, hydroxy, amino, mono- or dialkylamino where each alkyl is alkyl, cyano, nitro, trifluoromethyl or trifluoromethoxy; or R 3 and R 4 together represent a C ⁇ -C ⁇ alkylene dioxy group or a
  • R5 is hydrogen or C ⁇ -C6 alkyl
  • W represents CH or nitrogen
  • X is oxygen or sulfur
  • A represents an alkylene group of 2 to 5 carbon atoms, each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms .
  • Dopamine D 4 receptors are concentrated in the limbic system (Science, 265 : 1034 (Taubes, 1994)) which controls cognition and emotion. Therefore, compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders include those involving memory impairment or attention deficit disorders.
  • Compounds of the present invention demonstrate high affinity and selectivity in binding to the D4 receptor subtype.
  • Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D4
  • the invention provides methods for treatment and/or prevention of neuropsychochological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents.
  • neuropsychochological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents.
  • the compounds of the invention are useful in treatment of memory-impairment or Alzheimer's disease by modulation of D4 receptors which
  • the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
  • the invention provides pharmaceutical compositions comprising compounds of Formula I .
  • the compounds of Formula I can be used in in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia. Furthermore compounds of this invention can be used in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
  • the compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder.
  • the invention encompasses 3- aminoalkylamino-2H-l, 4-benzoxazines and 3-aminoalkylamino-2H- 1, 4-benzothiazines of Formula I.
  • Formula I are those where R x and R 2 are hydrogen, and A is alkylene of from 2-4 carbon atoms.
  • R l R 21 R 3 a d R4 independently represent CH or nitrogen;
  • R l R 21 R 3 a d R4 are the same or different and represent
  • R5 is hydrogen or C1-C6 alkyl
  • W represents CH or nitrogen
  • X is oxygen or sulfur
  • A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms .
  • Preferred compounds of Formula IA are those where Z and Y are both nitrogen. More preferably, , Y and Z are all nitrogen.
  • Other preferred compounds of Formula IA are those where R ⁇ and R 2 are hydrogen and R 5 is hydrogen, methyl, or ethyl .
  • the present invention also provides compounds of Formula
  • Y and Z independently represent CH or nitrogen
  • Rl , R2 , R3 and R4 are the same or different and represent
  • A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms .
  • Preferred compounds of Formula IB are those where Z and Y are both nitrogen. More preferred compounds of Formula IB are where W, Y and Z are nitrogen and R 5 is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula IB are where , Y and Z are nitrogen, R 5 is hydrogen, methyl, or ethyl , and R x and R 2 are both hydrogen .
  • the invention further provides compounds of Formula IC.
  • Y and Z independently represent CH or nitrogen; Ri , R2 R3 and R 4 are the same or different and represent
  • A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms.
  • Preferred compounds of Formula IC are those where Z and Y are both nitrogen. More preferred compounds of Formula IC are where , Y and Z are nitrogen and R 5 is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula IC are where , Y and Z are nitrogen, R 5 is hydrogen, methyl, or ethyl , and R x and R 2 are both hydrogen .
  • the invention further encompasses compounds of Formula II
  • Y and Z independently represent CH or nitrogen
  • Rl , R2 , R3 and R4 are the same or different and represent
  • R5 is hydrogen or Ci-C ⁇ alkyl
  • W represents CH or nitrogen; X is oxygen or sulfur; and A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms .
  • Preferred compounds of Formula II are those where Z and Y are both nitrogen. More preferred compounds of Formula II are where Y and Z are nitrogen and R 5 is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula II are where Y and Z are nitrogen, R s is hydrogen, methyl, or ethyl, R l r R 2 and R 4 are hydrogen.
  • Y and Z independently represent CH or nitrogen; Ri, R2 , R3 and R4 are the same or different and represent
  • A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms.
  • Preferred compounds of Formula IIA are those where Z and Y are both nitrogen. More preferred compounds of Formula IIA are where Y and Z are nitrogen and R 5 is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula IIA are where Y and Z are nitrogen, R 5 is hydrogen, methyl, or ethyl, R 1 , R 2 and R 4 are hydrogen .
  • Y and Z independently represent CH or nitrogen
  • R l , R2 , R3 and R4 are the same or different and represent
  • each alkyl is C- L -Cg alkyl, cyano, nitro, trifluoromethyl or trifluoromethoxy;
  • R5 is hydrogen or C1-C6 alkyl;
  • W represents CH or nitrogen; X is oxygen or sulfur; and A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms .
  • Preferred compounds of Formula III are those where Z and Y are both nitrogen. More preferred compounds of Formula III are where Y and Z are nitrogen and R 5 is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula III are where Y and Z are nitrogen, R 5 is hydrogen, methyl, or ethyl, R ⁇ , R 2 and R 4 are hydroge .
  • the invention further provides compounds of Formula IIIA:
  • Y and Z independently represent CH or nitrogen
  • Rl, R2, R3 and R4 are the same or different and represent
  • each alkyl is C- L -Cg alkyl, cyano, nitro, trifluoromethyl or trifluoromethoxy;
  • R5 is hydrogen or Ci-C ⁇ alkyl;
  • A represents an alkylene group of 2 to 5 carbon atoms each of which carbon atoms is optionally substituted with one or two alkyl groups having from 1 to 4 carbon atoms .
  • Preferred compounds of Formula IIIA are those where Z and Y are both nitrogen. More preferred compounds of Formula IIIA are where Y and Z are nitrogen and R 5 is hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula IIIA are where Y and Z are nitrogen, R 5 is hydrogen, methyl, or ethyl, R 17 R 2 and R 4 are hydrogen.
  • R a is halogen, alkyl, hydroxy, or alkoxy
  • R represents hydrogen or alkyl .
  • those substituents are the same or different.
  • Preferred Ar groups of formula I above include the followin :
  • Ar groups of formula I above include 5-fluoropyrimidin-2-yl and pyrimidin-2-yl .
  • the compounds of this invention I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
  • Representative compounds of the present invention include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
  • Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 )n-ACOOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 )n-ACOOH where n is 0-4, and the like.
  • the present invention also encompasses the acylated prodrugs of the compounds of Formula I .
  • acylated prodrugs of the compounds of Formula I Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I .
  • 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, trifluoromethyl , lower acyloxy, aryl, heteroaryl, and hydroxy.
  • heteroaryl in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups include, for example, thienyl, furanyl , thiazolyl, imidazolyl, (is) oxazolyl , pyridyl , pyrimidinyl, (iso) quinolinyl , naphthyridinyl , benzimidazolyl , and benzoxazolyl .
  • alkyl or “lower alkyl” in the present invention is meant alkyl, i.e., straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl , hexyl, 2-hexyl, 3- hexyl, and 3-methylpentyl .
  • alkoxy or “lower alkoxy” in the present invention is meant alkoxy, i . e ., straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3- hexoxy, and 3-methylpentoxy .
  • cycloalkoxy in the present invention is meant cycloalkylalkoxy groups having 3-7 carbon atoms where cycloalkyl is defined above.
  • C ⁇ ⁇ -C z alkylene dioxy group is meant a group of the formula:
  • n 1 or 2.
  • C- L -C J alkylene oxy group is meant a group of the formula :
  • n 1, 2 or 3.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • the compounds of the invention are useful in the treatment of neuropsychological disorders; the pharmaceutical utility of compounds of this invention is indicated by the assays for dopamine receptor subtype affinity described below in the Examples.
  • the interaction of the compounds of the invention with dopamine receptor subtypes results in the pharmacological activities of these compounds.
  • the compounds of 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, intrasternal 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 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 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 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 monostearate 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 anti-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. 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.
  • 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 partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol 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 art 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 .
  • the acceptable 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 I 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 I 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 anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0. Img to about 140mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5mg to about 7g 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 particular mode of administration. Dosage unit forms will generally contain between from about Img to about 500mg of an active ingredient. It will be understood, however, that the specific dose level for any particular 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 particular disease undergoing therapy.
  • a 2H-1, 4-benzoxazine or 2H-1 , 4-benzothiazine of general structure IV, possessing an appropriate leaving group at the 3 position may be reacted with a primary or secondary amine of general structure V in the presence of a base to afford a compound of Formula I as the desired product.
  • Example 1 demonstrates the preparation of a l-aryl-4- aminoalkylpiperazine.
  • Example 2 provides an example of the preparation of a 2H-1 , 4-benzoxazine .
  • Example 3 demonstrates the preparation of a 3-aminoalkylamino-2H-l , 4- benzoxazine.
  • Example 4 is an example of the preparation of 3- aminoalkylamino-2H-l, 4-benzothiazine .
  • 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 again centrifuged as described above 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.
  • tissue sample 0.5 nM 3 H-YM 09151-2 (Nemonapride, cis-5-Chloro- 2-methoxy-4- (methylamino) -N- (2 -methyl-2- (phenylmethyl) -3- pyrrolidinyl) benzamide) and the test compound in a total incubation of 1.0 ml.
  • 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. Binding characteristics of examples of the invention for the D2 and D4 receptor subtypes are shown in
  • the above compound numbers relate to compounds shown in Table 1.
  • the compounds tested are the compounds described in the above examples. In all cases, test compounds are acid addition salts.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la formule générale (I) ou certains de leurs sels d'addition acides pharmaceutiquement admis. En l'occurrence, Ar est aryle ou hétéroaryle. R1 et R2, qui sont identiques ou différents, sont des substituants organiques ou inorganiques. R5 est hydrogène ou C1-C6 alkyle. W est CH ou azote. X est oxygène ou soufre. Enfin, A est un groupe alkylène. Se liant sélectivement avec une affinité élevée au récepteur de sous-type D4 de la dopamine, ces composés conviennent particulièrement au traitement de divers troubles neurophychologiques.
EP98956310A 1997-10-31 1998-10-28 3-aminoalkylamino- 2h-1,4-benzoxazines et 3-aminoalkylamino- 2h-1,4-benzothiazines constituant des ligands specifiques d'un sous-type de recepteur de la dopamine Withdrawn EP1027347A2 (fr)

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US96202297A 1997-10-31 1997-10-31
US962022 1997-10-31
PCT/US1998/022936 WO1999023092A2 (fr) 1997-10-31 1998-10-28 3-aminoalkylamino- 2h-1,4-benzoxazines et 3-aminoalkylamino- 2h-1,4-benzothiazines constituant des ligands specifiques d'un sous-type de recepteur de la dopamine

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EP1027347A2 true EP1027347A2 (fr) 2000-08-16

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US6100255A (en) * 1998-10-28 2000-08-08 Neurogen Corporation 3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines: dopamine receptor subtype specific ligands
US6084098A (en) 1999-02-26 2000-07-04 Neurogen Corporation Benzylpiperazinyl and piperidinyl ethanone derivatives: dopamine receptor subtype specific ligands
HUP0100926A3 (en) * 1998-02-26 2003-03-28 Neurogen Corp Branford Benzylpiperazinyl- and benzylpiperidinyl ethanone derivatives, their preparation and their use as dopamine d4 receptor antagonists
US6284759B1 (en) 1998-09-30 2001-09-04 Neurogen Corporation 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands
AU6280199A (en) * 1998-09-30 2000-04-17 Neurogen Corporation 2-piperazino alkylamino benzoazole derivatives: dopamine receptor subtype specific ligands
DE19941115A1 (de) 1999-08-25 2001-03-01 Schering Ag Neue Benzoxazin- und Bezothiazin-Derivate und deren Verwendung in Arzneimitteln
EP1177792A3 (fr) 2000-07-27 2002-10-23 Pfizer Products Inc. Ligands dopamine d4 destines au traitement des troubles associees a la cherche de la nouveaute
US8411271B2 (en) 2005-12-28 2013-04-02 Nikon Corporation Pattern forming method, pattern forming apparatus, and device manufacturing method

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EP0186310A1 (fr) * 1984-11-28 1986-07-02 Takeda Chemical Industries, Ltd. Dérivés de 1,4-benzothiazine, leurs préparation et application

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CA2307905A1 (fr) 1999-05-14
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AU1286399A (en) 1999-05-24
WO1999023092A3 (fr) 1999-08-05

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