WO1993016073A1 - Derives de piperazine et de piperidine, et leur utilisation comme neuroleptiques - Google Patents
Derives de piperazine et de piperidine, et leur utilisation comme neuroleptiques Download PDFInfo
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- WO1993016073A1 WO1993016073A1 PCT/GB1993/000285 GB9300285W WO9316073A1 WO 1993016073 A1 WO1993016073 A1 WO 1993016073A1 GB 9300285 W GB9300285 W GB 9300285W WO 9316073 A1 WO9316073 A1 WO 9316073A1
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- piperazinyl
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- butyl
- benzisothiazol
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- 0 C(CNCC1)*1*1N=C1 Chemical compound C(CNCC1)*1*1N=C1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
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- 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
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- 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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
-
- 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
- C07D417/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a group of piperazine and piperidine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular in the treatment of psychotic disorders.
- Receptors for the chemical messenger dopamine are known to be located in the striatum and the limbic brain area and such receptors have been classified as D 1 and D 2 based on receptor binding studies and on the presence or absence of a positive coupling between the receptor and adenylate cyclase activity.
- Activation of the D 1 -receptor is associated with stimulation of adenylate cyclase, whereas the D 2 -receptor mediates dopaminergic effects that do not involve direct stimulation of this enzyme (see Kebabian & Calne, Nature, 1979, 227, 93 and Harrold et al, J. Med. Chem., 1987, 30, 1631).
- D 2 -receptor antagonism and antipsychotic activity (see Seeman, Pharmacol. Rev., 1981, 32, 229, Sfeman et al, Biochem Pharmacol., 1985, 34, 151, Creese et al, Science, 1976, 192, 481 and Leysen in Clinical Pharmacology in Psychiatry: Neuroleptic and Antidepressant Research: Eds Usdin, Dahl, Gram and Lingjaerde, Macmillan: Basingstoke, 1982; pp35-52).
- 5-hydroxy tryptamine occurs widely in the central nervous system and is known to be involved in the control of behavior.
- 5-HT receptors and receptor sub-types have been identified.
- 5-HT 2 receptor antagonism is also desirable in an antipsychotic agent (see Janssen et al, J . Pharm. and Exper. Ther., 1988, 244(2), 685).
- blockade of central dopamine D 2 -receptors may control the positive symptoms of schizophrenia (e.g.
- blockade of 5-HT 2 receptors may assist in the amelioration of the negative symptoms of schizophrenia (e.g. apathy and social withdrawal). It has also been suggested that blockade of the 5-HT 2 receptor results in a reduction of the extrapyramidal side effects which are known to occur in the case of neuroleptic maintenance therapy with many known antipsychotic agents.
- a group of piperazine and piperidine derivatives has been discovered that are potent antagonists of dopamine D 2 receptors and/or 5-HT 2 receptors and are therefore useful in the treatment of psychotic disorders.
- the present invention provides a compound of formula (I), a physiologically acceptable salt thereof, a physiologically acceptable solvace thereof, and a physiologically functional derivative thereof
- Y represents a group of the formula (a), (b) or (c)
- R 1 represents one or more ring subscituencs comprising hydrogen, halogen, C 1-6 alkyl optionally substituted with one or more halogens, C 1-6 alkoxy optionally subsituted with one or more halogens, hydroxy, -N(R 4 ) 2 , nitro, S(O) n R 4 where n is 0, 1 or 2, C ⁇ N, CON(R 4 ) 2 ,
- R 3 represents hydrogen, C 1-6 alkyl, or C 1-6 alkoxycarbonyl
- R 4 represents hydrogen or C 1-6 alkyl
- R 5 represents -N-C- or -C-N-;
- R 6 represents hydrogen or C 1-6 alkyl
- R 7 ,R 8 , R 9 , R 10 and R 11 which are the same or different, each represent hydrogen, halogen, nitro, C 1-6 alkyl optionally substituted with one or more halogens, C. -alkoxy optionally substituted with one or more halogens, hydroxy, S(O) n R 4 where n is 0, 1 or 2, C ⁇ N,
- R 7 and R 8 or R 8 and R 9 or R 9 and R 10 or R 10 and R 11 represent
- V represents 0 or S
- Z represents C 4-8 alkylene, optionally interrupted by -S(O) n - where n is 0, 1 or 2, C 4-8 -alkenylene or C 4-8 -alkynylene;
- X represents N or C
- W represents a group of formula (d)
- A represents CR 4 or N
- B represents oxygen, NR 4 or S(O) n
- n and R 4 are as defined herein and R 12 represents hydrogen or halogen.
- alkyl as a group or a part of a group may be a straight or branched chain alkyl group, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl or 2-methylprop-2-yl.
- Alkyl groups are most preferably methyl or ethyl.
- aryl refers to phenyl, naphthalenyl, thienyl, pyridinyl, furanyl or pyrrolyl optionally substituted by one or more halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio, amino, mono- and di-alkyl amino or alkanoyl.
- alkenylene refers to a straight, branched or cyclic alkenyl group having from 4 to 8 carbon atoms, such as, for example, butenylene, pentenylene, hexenylene and the like.
- alkynylene refers to a straight or branched alkynyl group having from 4 to 8 carbon atoms, such as, for example, butynylene, pentynylene, hexynylene and the like.
- halo refers to fluoro, chloro, bromo and iodo.
- physiologically functional derivative means any physiologically acceptable ester, or salt of such ester, of a compound of formula (I) or a compound which upon administration to the recipient is capable of providing (directly or indirectly) such a compound or an active metabolite or residue thereof.
- the present invention includes all optical isomers of compounds of formula (I) and mixtures thereof including racemic mixtures.
- the invention also includes all geometric isomers of compounds of formula (I) including mixtures thereof.
- the invention further provides compounds of formula (I) and salts, solvates and derivatives thereof in which the nitrogen atom shown in formula (I) in the position adjacent to Z is in its oxidised form as N-oxide.
- the present invention includes compounds of formula (I) in the form of physiologically acceptable salts thereof.
- Suitable salts are, in particular, acid addition salts including those formed with both organic and inorganic acids.
- Such acids will normally be physiologically acceptable although salts of non-physiologically acceptable acids may be of utility in the preparation and purification of the compound in question.
- salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, trifluoroacetic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids.
- Salts of compounds of formula (I) can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
- ⁇ represents a double bond in each case;
- R is H or Cl, most preferably H;
- R 2 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -,
- R 3 is -CO 2 Et or H, most preferably H;
- R 4 is H or Me, most preferably H.
- R 1 is preferably H, Cl, F, Me, OH,
- R 6 is H or Me, most preferably H
- R 7 is H, NH 2 NHMe, OH, OMe or NHAc, more preferably NH 2 , OMe, NHAc or NHMe, most preferably NH 2 or NHMe
- R 8 is H, Cl, NHCO 2 t-Bu, Br or NH 2 , more preferably H or Br, most preferably H
- R is H, OMe, CF 3 t-Bu,
- -N N-Ph, NHAc, NHCO 2 t-Bu, NH 2 or Br, more preferably H or Br, most preferably Br;
- R 10 is H, NO 2 , Br or Cl, more preferably H or Br, most preferably H and
- R 11 is H, OMe or OH, more preferably OMe or OH, most preferably OH.
- V is O or S, preferably O;
- Z is C 4-6 alkylene, preferably C, alkylene;
- B is -S-, NH or -O- more preferably -S- or -O- , most preferably -S-;
- A is CH or N, preferably N and R 12 is H or F, preferably H.
- Preferred compounds of formula (I) include:-
- More preferred compounds of formula (I) include:-
- the compounds of formula (I) show an advantageous profile of pharmacological activity and are useful in the treatment of a number of conditions.
- the compounds show, for example anxiolytic, centrally-acting muscle relaxant, and antidepressant activity. They may also be useful in the treatment of aggression associated with senile dementia, borderline personality disorders and as a broad-spectrum antiemetic. In particular the compounds are useful in the treatment of psychotic disorders such as schizophrenia.
- Potential antipsychotic activity can be assessed by the ability of a compound to block apomorphine-induced climbing in the mouse (see Ogren et al, Eur. J . Pharmacol., 1984, 12, 459, Iversen, Science, 1975, 188, 1084 and Gudelsky & Moore, J. Neural Transm., 1976, 38, 95).
- the tendency of a compound to induce catalepsy and its ability to block apomorphine induced stereotypes are behavioural measures which indicate the potential of a compound to induce extrapyramidal side effects.
- the compounds of formula (I) are, in general, potent antagonists at dopamine D 2 receptors and at 5-HT 2 receptors suggesting potential utility as antipsychotics. This profile of activity has been confirmed by the potency of compounds of formula (I) in the mouse-climbing assay and by good ratios of the dose required for potency in this assay to the dose required for the induction of catalepsy.
- Certain compounds of formula (I) are also potent agonists at the 5HT 1A receptor. This activity has been associated with anti-depressant and anxiolytic effects as well as with a reduction of extrapyramidal side-effects.
- the combination of potent dopamine D 2 receptor antagonism and 5-HT 2 receptor antagonism with 5-HT 1A receptor agonism which is to be found in preferred compounds of formula (I) is a particularly advantageous profile of activity for an anti-psychotic agent and, in particular, for a drug for use in the treatment of schizophrenia.
- the present invention also provides a method for the treatment or prophylaxis in a mammal of a disorder selected from the following: anxiety, muscle spasm, depression, aggression associated with senile dementia, borderline personality disorders, emesis and psychosis which comprises administering to the mammal an effective treatment amount of a compound of formula (I) or a physiologically acceptable salt, or solvate or physiologically functional derivative or N-oxide thereof.
- a disorder selected from the following: anxiety, muscle spasm, depression, aggression associated with senile dementia, borderline personality disorders, emesis and psychosis which comprises administering to the mammal an effective treatment amount of a compound of formula (I) or a physiologically acceptable salt, or solvate or physiologically functional derivative or N-oxide thereof.
- the invention provides a method for the treatment or prophylaxis in a mammal of a psychotic disorder which comprises administering to the mammal an anti-psychotic effective treatment amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically functional derivative or N-oxide thereof.
- the invention provides such a method wherein the psychotic disorder is schizophrenia.
- the present invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically functional deriative or N-oxide thereof for use in therapy, in particular the therapy or prophylaxis of a psychotic disorder such as schizophrenia.
- the invention also provides the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prophylaxis of a psychotic disorder such as schizophrenia.
- the present invention provides a pharmaceutical formulation comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically functional derivative or N-oxide thereof together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients.
- the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the formulations include those suitable for oral, parenteral (including subcutaneous, transdermal, intradermal, intramuscular and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the present invention as herein defined or a pharmacologically acceptable salt or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
- active ingredient a pharmacologically acceptable salt or solvate thereof
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
- Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water-for-injection, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Formulations for transdermal administration may be delivered by passive diffusion or by electrically assisted transport, for example, iontopheresis (see, for example, Pharmaceutical Research 3 (6), 318 (1986)) and typically take the form of an optionally buffered aqueous solution of a compound of formula (I) or a salt or acid derivative thereof.
- Suitable formulations comprise citrate or bis/tris buffer (pH6) or ethanol/water.
- Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
- Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
- Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
- the compounds of the invention are preferably used to treat psychotic disorders such as schizophrenia by oral administration or injection (intraparenteral or subcutaneous).
- the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also the route of administration may vary depending on the condition and its severity.
- the compounds of the invention may typically be administered orally or via injection at a dose of from 0.02 to 50.0 mg/kg per day.
- the dose range for adult humans is generally from 1.4 to 3500mg/day and preferably 2.8. to 1750mg/day, more preferably 7 to 700mg/day.
- the present invention also provides processes for the preparation of compounds of formula (I) and physiologically acceptable salts and solvates and N-oxides thereof and physiologically functional derivatives thereof.
- the compounds of formula (I) can be prepared by any process known in the prior art for the preparation of analogous compounds.
- the groups Y, Z, X, W, V, A, B, and R 1 to R 12 have the meanings ascribed to them in formula (I) unless otherwise stated.
- compounds of formula (I) can be prepared by reaction of a compound of formula (II)
- L is a leaving group, for example, a halogen such as bromine, chlorine or iodine, an alkyl or arylsulfonyloxy such as methane-sulfonvloxy or p-toluenesulfonyloxy, in the presence of an appropriate solvent and base.
- a halogen such as bromine, chlorine or iodine
- an alkyl or arylsulfonyloxy such as methane-sulfonvloxy or p-toluenesulfonyloxy
- Suitable solvents include N,N-dimethylformamide, acetonitrile, benzene, toluene, xylene etc. and appropriate bases may be chosen from organic bases such as criethyl amine, pyridine etc., alkali metal carbonates or bicarbonates such as sodium carbonate, potassiuim carbonate, sodium bicarbonate, potassium bicarbonate etc., or alkali metal hydrides such as sodium hydride, potassium hydride etc.
- A- is a suitable anion, such as a halogen, for example, bromine or chlorine, sulphonic acid esters such as mesylate or tosylate and R 13 is -(CH 2 ) 4 - or -(CH 2 ) 5 , more particularly -(CH 2 ) 4 .
- the conditions of reaction may be the same as those described for general process (A) above.
- a complexing agent such as 1,4,7,10,13,16-Hexaoxacyclooctatecane may be included.
- compovmds of formula (I) can be prepared by reaction of a compound of formula (V) Y—Z—L (V)
- the process may be carried out as described for general process (A) above.
- the process may be carried out as described for general process (A) above.
- R 17 is R 7 , -S-L 2 or CH 2 -L 2
- L 1 is e.g. Cl, Br, OMe or OH
- L 2 is e.g. Cl, Br, OMs or OTs with a compound of formula (XI)
- compounds of formula (I) where Y represents a group of formula (c) and R 7 represents -N(R 4 ) 2 can be prepared by the treatment of a compound of formula X , where L 1 represents hydroxy, V represents oxygen and R 16 represents -N(R 4 ) 2 , with a compound of formula (XI) in the presence of silicon tetrachloride in a refluxing solvent such as anhydrous pyridine .
- a refluxing solvent such as anhydrous pyridine
- a poisoned catalyst such as Lindlar catalyst.
- Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and R 1 , R 7 , R 8 , R 9 , R 10 , or R 11 is N(R 4 ) 2 or NR 4 N(R 4 ) 2 can be prepared by hydrolysis of the corresponding alkoxycarbonylamino derivatives by known methods, for example, by treatment of a (tert-butoxycarbonyl)-amino derivative with an acid such as trifluroacetic acid, and a t-butyl cation scavenger such as anisole or thiophenol in a solvent such as chloroform at room temperature (Lundt, B.F. Int. J. Prept. Protein Res. 12, 258(1978).
- an acid chloride such as acetyl chloride or ethyl chloroformate and an organic base such as triethylamine in a solvent such as dichloromethane.
- Compounds of formula (I) where Y is a group of formula (c), where V represents sulphur may be prepared by treatment of compounds of formula (I) where Y is a group of formula (c), where V represents oxygen, with a sulfonating reagent such as Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in a solvent such as toluene at an elevated temperature.
- a sulfonating reagent such as Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in a solvent such as toluene at an elevated temperature.
- Suitable reducing agents include Sn/HCl in acetic acid at elevated temperature, e.g. 100 to 130oC.
- Other suitable reducing agents include Zn/acetic acid (J. Chem. Soc. 2038 (1977)) and CuCr 2 O 4 /dioxane/H 2 (Helv. Chim. Acta, 1650 (1977)).
- ethylchloroformate for example in the presence of a base such a triethylamine in a suitable solvent such as dichloromethane, e.g. at 0oC, to produce the ethyl carbamate of formula (XIII) which can then be cyclised, for example, by treatment with polyphosphoric acid at elevated temperature, e.g. 140 to 160°C.
- the dihydrobenzpyran is converted to the dihydrobenzopyranone by reaction with pyridinium chlorochromate in a suitable solvent such as dichloranethane at elevated temperature.
- a suitable solvent such as dichloranethane at elevated temperature.
- 2,2'-dithiosalicylic acid is treated with thionyl chloride and dimethylformamide in refluxing toluene to give 2,2'-dithiobisbenzoyl chloride.
- the acid chloride is converted to 1,2-benzisothiazol-3(2H)-one by cleaving the disulphide bond with chlorine gas in dichloromethane. Reaction of the resulting dichloride with ammonium hydroxide yields the benzisothiazolone (IIE).
- R 18 is alkyl (e.g. Me, Et, etc.) with hydrazine hydrate (see J. Org. Chem., 32, 1921 (1967)).
- Compounds of formula (III) can be prepared by alkylation of a compound of formula (VI) with a compound of formula (XXII) L —Z—L (XXII) where L is a leaving group such as for example a halogen such as bromine chlorine or iodine, an alkyl or an arylsulfonyloxy such as methane-sulfonyloxy or p-toluenesulfonyloxy.
- L is a leaving group such as for example a halogen such as bromine chlorine or iodine, an alkyl or an arylsulfonyloxy such as methane-sulfonyloxy or p-toluenesulfonyloxy.
- the compound of formula (XXIII) may in turn be prepared by condensation of a compound of formula (X) or (X 1 ) with an amino alcohol of formula (XXIV)
- the process may be carried out either at room temperature or at elevated temperature such as 60°C to 140°C.
- Suitable solvents include N,N-dimechylformamide, acetonitrile, benzene, toluene, xylene etc. and appropriate bases may be chosen from organic bases such as triethyl amine, pyridine etc., alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc., or alkali metal hydrides such as sodium hydride, potassium hydride etc.
- X C
- the requisite aminobenzofb] thiophenes can be prepared by treatment of appropriately substituted 2-fluorobenzonitrile with the anion of methyl thioglycolate followed by decarbomethoxylation of the resulting benzo[b]thiophene.
- X N
- X C
- X C
- X C
- L is Cl
- reaction may be carried out in a suitable solvent such as ethanol , for example at room temperature .
- isatoic anhydrides of formula (XE) can be prepared by the treatment of the appropriately substitute anthranilic acids with phosgene or a phosgene substitute (i.e. trichloromethyl chloroformate) in an appropriate solvent such as benzene or dioxane (J.Het.Chem. 12, 565 (1975); J. Amer. Chem. Soc., 72, 4887, (1950); J. Org .Chem. 41, 2070, (1976)).
- Isatoic anhydrides of formula (XE) where V represents oxygen can also be prepared by treatment of the appropriately substituted phthalic anhydrides of formula (XB) with azidotrimethylsilane in an appropriate solvent such as chloroform.
- Thioisatoic anhydrides of the formula (XE) where V represents sulphur can be prepared by treatment of the appropriately substituted isatoic anhydrides with phosphorus pentasulfide in refluxing xylenes.
- L 1 is methoxy and L 2 is Br
- L 1 is methoxy and L 2 is Br
- P is a protecting group, for example trifluoroacetate, by removal of the protecting group by known methods, for example aqueous potassium carbonate.
- a further embodiment of the present invention comprises the following compounds;
- Further embodiments of the present invention comprise the following: the use of one of the following compounds and salt, solvates, N-oxides and derivatives thereof in therapy; the use of one of the following compounds and salts, solvates, N-oxides and derivatives thereof in the preparation of a medicament for use in the treatment of any of the hereinbefore described disorders; a method for the treatment or prophylaxis in a mammal of any of the disorders hereinbefore described which comprises administering to the mammal a therapeutically effective treatment amount of one of the following compounds or a salt, solvate, N-oxide or derivative thereof; a pharmaceutical composition comprising one of the following compounds and salt, solvate, N-oxides and derivatives thereof; a process for the preparation of one of the following compounds or a salt, solvate,
- Antagonism of apomorphine (5mg/kg S.C.) - induced climbing in the mouse is a measure of dopamine receptor antagonism in the mesolimbic brain region and in turn reflects potential antipsychotic activity.
- test compound was administered orally. Cisplatin was then given i.v. (10-15mg/kg), 30 minutes later via jugular catheter. At 60 minutes a second dose of the test compound was administered. Onset of emesis and the number of emetic episodes was recorded over a 3 hr. period. Vehicle treated animals exhibited 3-5 episodes of emesis whereas animals given 3 mg/kg of the compound of Example 36 exhibited no episodes of emesis.
- the active ingredient was mixed with the lactose and starch and granulated with a solution of the polyvinylpyrrolidone in water.
- the resultant granules were dried, mixed with magnesium stearate and compressed to give tablets.
- the salt of a compound according to the invention was dissolved in sterile water for injection.
- Formulation I may be prepared by admixing the ingredients and filling two-part hard gelatin capsules with the resulting mixture.
- Capsules may be prepared by melting the Macrogel 4000 BP, dispersing the active ingredient in the melt, and filling two-part hard gelatin capsules therewith.
- Capsule Formulation III (Controlled release capsule) mg/capsule
- the controlled-release capsule formulation may be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with ethyl cellulose (d) as a controlled-release membrane and filled into two-part hard gelatin capsules.
- the sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added.
- the active ingredient is added and dissolved.
- the resulting solution is mixed with the glycerol and then made up to the required volume with the purified water.
- the active ingredient is used as a powder wherein at least 90% of the particles are of 63 ⁇ m diameter or less.
- Witepsol H15 is meleted in a steam-jacketed pan at 45°C maximum.
- the active ingredient is sifted through a 200 ⁇ m sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mix.
- the entire suspension is then passed through a 250 ⁇ m stainless steel screen and, with continuous stirring, allowed to cool to 40°C. At a temperature of 38-40°C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature.
- compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
- patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved in an adhesive or 3) dispersed in a polymer.
- a suitable concentration of the active compound is about 1% to 20%, preferably about 3% to 15%.
- the active compound must be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318(1986).
- N-(4-Bromobutyl)phthalimide (Aldrich Chemical Company) (15.6 g, 0.056 mL), glacial acetic acid (100 mL), tin metal (15.83, 0.133 mol, 2.4 eq) and hydrobromic acid (20.0 mL) was added to a 250-mL, round-bottomed flask. The resulting light yellow reaction mixture was placed under N 2 and heated at reflux for 6 h. The solution was filtered and the tin was washed with acetic acid. Most of the acetic acid was removed with a rotary evaporator and the resulting creamy residue was taken up in dichloromethane and washed with water.
- the solution was allowed to cool and was transferred to a separating funnel with the aid of ethyl acetate.
- the organics were washed with saturated K 2 CO 3 , dried over MgSO 4 , filtered and concentrated to give 7.31 g of a dark orange oil which solidified upon standing.
- the crude solids were recrystallized from acetonitrile to give 4.38 g of free amine.
- the hydrochloride salt was prepared via the addition of HCl (10.8 mL, 1.0 eq of a 1 N solution in ether) to a solution of the free amine in ethanol.
- 6-Chloro-1(3H)-isobenzofuranone (9.15 g, 0.0543 mol), ethanol amine (Aldrich Chemical Company) (3.32 g, 1.0 eq) and toluene (10.0 mL) was added to a 100-mL, round-bottomed flask equipped with a magnetic stirring bar and a 10-mL Dean-Stark trap. The solution was heated with an oil bath. The toluene which was collected in the Dean-Stark trap was not allowed to return to the reaction pot. The resulting orange melt was heated at 210°C for 22 h. Upon cooling, the material solidified to give 11.75 g of a brown solid. The crude material was used without further purification.
- This compound was prepared by the method analogous to that used in Example 1(b).
- the crude material obtained in this reaction was purified by flash chromatography to give 5.42 g (39% based on 6-chloro-1(3H)-isobenzofuranone) of an orange solid, mp: 71-72oC.
- 2-bromomethyl benzoyl bromide was obtained by bromination of o-toluoyl chloride.
- the 2-bromomethyl benzoyl bromide (0.184 mol) was taken up in dichloromethane (40 mL) and the solution was cooled in an ice-water bath. Absolute methanol (15 mL) was added and the reaction mixture was allowed to warm to room temperature and stir for 0.5 h. The solution was washed with saturated K 2 CO 3 and extracted with ethyl acetate.
- N-(2-(2-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)ethoxy)ethyl)- phthalimide 7.45 g, 0.017 mol
- methanol 20.0 mL
- hydrazine hydrate 1.49 g of an 85% solution in water, 0.025 mol, 1.5 eq
- the reaction mixture was allowed to cool to room temperature and 1 N HCl (50.0 mL) was added.
- the resulting precipitant was filtered and washed with distilled water.
- Methyl 2-bromomethyl benzoate (30.00 g, 0.131 mol) (Example 8(a)), trans-4-amino cyclohexanol hydrochloride (Aldrich Chemical Company) (20.85 g, 0.137 mol, 1.05 eq), potassium carbonate (27.15 g, 0.196 mol, 1.5 eq), toluene (110 mL) and water (20 mL) were added to a 500-mL, round-bottomed flask equipped with a magnetic stirring bar and a Dean-Stark trap. The two-phase mixture was heated at reflux for 19 h. The toluene-water azeotrope was collected and the water was not allowed to re-enter the reaction pot.
- Trans-4-(oxo-2-isoindolinyl)-1-cyclohexyl methanesulfonate (5.27 g, 0.017 mL), 3-(1-piperazinyl)-1,2-benzisothiazole (3.92 g, 0.079 mol, 1.05 eq), triethylamine (2.85 mL, 2.07 g, 0.020 mol, 1.2 eq), triethylamine (2.85 mL, 2.07 g, 0.020 mol, 1.2 eq) and acetonitrile (20 mL) were combined, placed under N 2 and heated at reflux for 2.5 d. The mixture was allowed to cool to room temperature and washed with saturated K 2 CO 3 .
- hydrochloride salt of this free base was formed, recrystallized from ethanol, and dried in a vacuum oven to give 0.120 g (2%, based on trans-2-(4-hydroxy-1- cyclohexyl)-1-isoindolinone) of (+/-)-cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-1-cyclohexyl)-1-isoindolinone hydrochloride monohydrate as light peach crystals, mp: 231-232oC.
- Example 8(b) This compound was prepared according to the method described for Example 8(b). From N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-2-butynyl)phthalimide, Example 25, (12.54 g, 0.630 mol), hydrazine hydrate (2.66 g of an 85% aqueous solution) and methanol (30 mL), 6.23 g (72.3%) of 3-(4-(4-amino-2-butynyl)-1- piperazinyl)-1,2-benzisothiazole was obtained as a crude orange oil. This material was used without further purification.
- Phthalimide (Aldrich Chemical Company ) (30.0 g, 0.204 mol) was placed in a 500-mL, round-bottomed flask with glacial acetic acid (150.0 mL), concentrated HCl (75.0 mL) and tin metal (Fisher Scientific) (58.08 g, 0.489 mL, 2.4 eq).
- the creamy slurry was heated in an oil bath at reflux. As the solution was heated the phthalimide dissolved, resulting in a light yellow solution.
- the reaction mixture was allowed to heat at reflux for 2 h, the solution was filtered hot, and the tin shavings were washed with fresh acetic acid.
- Sodium hydride (1.54 g of an 80% oil dispersion, 1.25 eq) was placed under N 2 in an oven-dried, 500-mL, round-bottomed flask. The sodium hydride was washed with hexanes (2X), and the waste hexanes were pipetted off of the solids. Anhydrous dimethylformamide (DMF) (100 mL) was added to the washed sodium hydride. To this grey suspension was added a solution of 1-isoindolinone (5.47 g, 0.041 mol) in dry DMF (50.0 mL).
- DMF dimethylformamide
- trans-1,4-dichloro-2-butene (Aldrich Chemical Company) (13.51. g, 0.103 mol, 2.5 eq) and dry DMF ( 100.0 mL).
- This solution was cooled in an ice-water bath and the 1-isoindolinone solution was slowly added via a cannula. After the addition was complete the reaction mixture was allowed to warm to room temperature and stir for 0.5 h. The majority of the DMF was removed with a rotary evaporator and the residue was taken up in dichloromethane and washed several times with water.
- This compound was prepared by an analogous method to that used in Example 1(c).
- a mixture of (E)-2-(4-chloro-2-butenyl)-1-isoindolinone (3.00 g, 0.014 mol), 3-(1-piperzinyl)-1,2-benzisothiazole (2.97 g, 0.014 mol, 1.0 eq), and triethylamine (2.26 mL) in acetonitrile (20.0mL) was heated under N, at reflux for 1 h.
- the crude material obtained was purified by flash chromatography with ethyl acetate as eluant to give 3.47 g of the free base as a light yellow solid.
- N-(4-Bromobutyl)phthalimide (Aldrich Chemical Company ) (3.50 g, 0.0124 mol), 3-(1-piperazinyl)-l,2-benzisothiazole (Yevich J.P. et al J.Med.Chem. 1986, 29, 359-369) (2.72 g, 0.0124 mol, 1.0 eq), triethylamine (2.24 mL, 0.0161 mol, 1.3 eq) and acetonitrile (15.0 mL) was added to a 100-mL, round-bottomed flask. The cloudy orange solution was heated under N, at reflux for 17 h.
- hydrochloride salt was prepared by the addition of 1N HCl in ether and recrystallized from 95% ethanol to give 4.53 g (82%) of 2-(4-(4-(1,2-benzisothiazol-3- yl)-1-piperazinyl)butyl) phthalmide hydrochloride as an off-white powder, mp: 258-260oC (dec).
- Example 14 to 20 and 22 were prepared from their corresponding substituted phthalic anhydride precursors by the method described in Example 13 (c).
- the phthalic anhydrides employed were obtained from commercial suppliers or prepared by known literature methods as indicated. The analytical data for these phthalimides are shown below.
- This compound was prepared according to the method described in Example 13(a). From an 80:20 mixture of N-(4-chlorobutyl)-4'- chloropthalimide and N-(4-bromobutyl)-4'-chloropthalimide (2.50 g, 0.0029 mol) and 3-(1-piperazinyl)-1,2-benziosothiazole (1.95 g, 0.0089 mol) was obtained 2.30 g of the target compound as the free base. The hydrochoride salt was prepared, recrystallized from 95% ethanol and dried in a vacuum oven to give 1.79 g (41%) of the title compound as light yellow crystals, mp: 253-255°C.
- LAH Lithium aluminum hydride
- (+/-)-Trans-1,2-cyclopropanedimethanol (4.0 g, 0.039 mol), tosylchloride (TsCl) (8.96 g, 0.047 mol, 1.2 eq), dimethylamino pyridine (DMAP) 5.30 g and anhydrous dichloromethane (75.0 mL) was added to an oven-dried, 500-mL, round-bottomed flask. The reaction mixture was placed under N, and allowed to stir at room temperature for 24 h. Additional portions of the reagents were added, TsCl (2.24 g), DMAP (1.0 g), and dichloromethane (1.0 mL). The solution was allowed to stir at room temperature for an additional 6 d.
- TsCl tosylchloride
- DMAP dimethylamino pyridine
- Triethylamine (5.43 mL, 3.95 g, 0.039 mol, 1.0 eq) was added and the solution was allowed to stir for 24 h. The reaction was still not complete. The mixture was heated at reflux for 1.5 h and the solvent was removed with a rotary evaporator to give a sticky tan solid.
- This crude material was purified by flash chromatography with hexanes/ethyl acetate 1:1, followed by ethyl acetate/methanol 19:1 as eluant to give 1.85 g of (+/-)-trans-2-(chloromethyl)-1-cyclopropane methanol. A portion of the starting diol (0.87 g) was recovered unchanged.
- (+/-)-Trans-N-((2-(hydroxymethyl)cyclopropyl)methyl)-phthalimide (1.04 g, 4.50 mmol), freshly distilled (over CaH,) triethylamine (0.94 mL, 0.68 g, 6.75 mmol, 1.5 eq) and anhydrous dichloromethane (14.0 mL) was added to a 50-mL, round-bottomed flask. The solution was placed under a N 2 atmosphere and cooled with an ice-water bath. To this cooled mixture was added a solution of mesyl chloride (0.52 mL, 0.77 g, 6.75 mmol, 1.5 eq) in dichloromethane (2.0 mL).
- (+/-)-Trans-(2-(phthalimidomethyl)-1-cyclopropyl)methyl methanesulfonate (1.17 g, 3,78 mmol)
- 3-(1-piperazinyl)-1,2-benzisothiazole (0.912 g, 4.16 mmol, 1.1 eq)
- triethylamine (0.633 mL, 0.459 g, 4.54 mmol, 1.2 eq)
- acetonitrite (10.0 mL) were added to a 100-mL, round-bottomed flask.
- the cloudy solution was placed tinder N 2 and heated at reflux for 3.5 h.
- This compound was prepared according to the method described in Example 24(a) from potassium phthalimide (Aldrich Chemical Company) (13.0 g, 0.0702 mol) and 1,4-dichloro-2-butyne (Aldrich Chemical Company) (25.9 g, 0.212 mol, 3.0 eq). After flush chromatography with 4:1 hexanes/ethyl acetate as eluant, 10.64 g (65%) of a light yellow solid was obtained. Analytically pure, colorless, diamond-like crystals formed by crystallization from a hexanes/ethyl acetate solution, mp: 112-115oC.
- This compound was prepared according to the method described in Example 13 (a). From N-(4-chloro-2-butynyl) phthalimide (10.64 g, 0.0455 mol) and 3- (1-piperazinyl) -1,2-benzisothiazole (9.98 g, 0.0455 mol, 1.0 eq) was obtained 14.14 g (74%) of the free amine.
- the hydrochloride salt was prepared from 4.49 g of the amine to give 3.17 g of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-2-butynyl)phthalimide hydrochloride as light yellow flakes after recrystallization from ethanol/ether.
- This compound was prepared by a method analogous to that described in Example 24(a). Potassium phthalimide (Aldrich Chemical Company) (8.35 g, 0.0451 mol), trans-1,4-dibromo-2-butene (Aldrich Chemical Company) (24.1 g, 0.1127 mol, 2.5 eq) and dimethylformamide (400.0 mL) were heated under N 2 at 125°C for 3.5 h.
- This compound was prepared according to the method described in Example 13(a). From a 90:10 mixture of (Z)-and (E)-N-(4-chloro-2-butenyl)phtalimide (9.86 g, 0.0418 mol) and 3-(1-piperazinyl)-1,2-benzisothiazole (9.17 g, 0.0418 mol, 1.0 eq) was obtained 18.93 g of a dark orange viscous oil. The crude material was purified by flush chromatography with 1:1 hexanes/ethyl acetate as eluant to give 14.35 g (82%) of an orange oil which solidified upon standing.
- This compound was prepared by a method analogous to that described in Example 13(a). From 2-(2-chloroethyl)-1,2-benzisothiazol- 3(2H)-one (3.54 g, 0.0165 mol), and 3-(1-piperazinyl)-1,2-benzisothiazole (4.00 g, 0.0182 mol, 1.1 eq) was obtained 6.94 g of crude product. This material was purified by flash chromatography with 1:1 hexanes/ethyl acetate as eluant to give 4.00 g of the free amine.
- hydrochloride salt was prepared and recrystallized from 95% ethanol to give 1.76 g (25%) of 2-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-1,2-benzisothiazol-3(2H)-one hydrochloride as a white crystalline solid, mp: 250-252'C.
- This compound was prepared according to the methods described in Example 28 (a)-(c). From 2-(3-chloropropyl)-1,2-benzisothiazol- 3(2H)-one (5.29 g, 0.0232 mol), and 3-(1-piperazinyl)-1,2-benzi sothiazole (5.09 g, 0.0232 mol, 1.0 eq) was obtained 4.40 g of the corresponding product after flash chromatography with ethyl acetate as eluant.
- hydrochloride salt was prepared and recrystallized from 95% ethanol to give 3.45 g (32%) of 2-(3-(4- (1,2-benzisothiazol-3-yl)-1-piperazinyl)propyl)-1,2-benzisothiazol-3(2H)-one hydrochloride as an off-white powder. mp: 185-187oC.
- This compound was prepared according to the methods described in Example 28 (a)-(c). From 2-(4-chlorobutyl)-1,2-benzisothiazole-3(2H)-one (6.61 g, 0.0273 mol), and 3-(1-piperazinyl)-1,2-benzisothiazole (6.78 g, 0.0309 mol, 1.13 eq) was obtained 14.16 g of a dark orange oil. This crude material was purified by flash chromatography with 4:1 ethyl acetate/dichloromethane as eluant, followed by recrystallization of the free amine from 95% ethanol to yield 3.68 g of an off-white powder.
- hydrochloride salt was prepared, recrystallized from 95% ethanol, and dried in a vacuum oven to give 2.81 g (22%) of 2-(4-(4-(1,2-benzisothiazole-3-yl)-1-piperazinyl)butyl)-1,2-benzisothiazole-3(2H)-one hydrochloride as an off-white powder, mp: 215-216oC.
- Sodium hydride (2.56 g, 0.0855 mol, 1.25 eq of an 80% 0.1 dispersion) was placed under N 2 in a 250-mL, round-bottomed flask. The sodium hydride was washed twice with hexanes and the waste hexanes were removed. Anhydrous dimethylformamide (DMF) (100.0 mL) was added. To this grey suspension a solution of 1-(2H)-phthalazinone (10.0 g, 0.0684 mol) anhydrous DMF (50.0 mL) was added and the resulting solution was allowed to stir at room temperature for 0.5 h.
- DMF dimethylformamide
- This anion solution was added, via cannula, to a 500-mL, round-bottomed flask containing a solution of 1-bromo-4-chlorobutane (8.67 mL, 12.91 g, 0.0753 mol, 1.1 eq) in anhydrous DMF (100.0 mL).
- the reaction mixture was allowed to stir at room temperature for 4 h. As the reaction proceeded, the mixture became a clear orange solution.
- Distilled water (10.0 mL) was added and most of the solvent was removed with a rotary evaporator. The residue was taken up in dichloromethane and washed with water (2 ⁇ 50 ml). The organics were dried over MgSO 4 , filtered and concentrated to provide 16.49 g of crude material.
- the product was purified by flash chromatography with
- This compound was prepared according to a method analogous to that described in Example 13(a). From 3-(1-piperazinyl)-1,2-benzisothiazole (3.93 g, 0.0179 mol, 1.1 eq) and an 80:20 mixture of 2-(4-chlorobutyl)-1(2H)-phthalazinone and 2-(4-bromobutyl)-1(2H)-phthalazinone (4.00 g, 0.163 mol), was obtained 7.75 g of crude material which was purified by flash chromatography with 3:1 ethyl acetate/hexanes as eluant.
- the hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 4.09 g (55%) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl-1(2H)-phthalazinone hydrochloride as a white crystalline solid, mp: 252-253oC.
- This compound was prepared by a method analogous to that described in Example 31(a). From 4-methyl-1(2H)phthalazinone (50.0 g, 0.31 mol), and 1,4-dibromobutane (80.33 g, 0.37 mol) was obtained 31.05 g (34%) of 2-(4-bromobutyl)-4-methyl-1(2H)-phthalazinone as orange crystals, mp: 166-172oC.
- This compound was prepared according to the method outlined in Example 13(a).
- the crude product obtained from the reaction of 2-(4- bromobutyl)-4-methyl-1(2H)-phthalazinone (2.48 g, 8.4 mmol) and 3-(1-piperazinyl)-1,2-benzisothiazole (1.93 g, 8.80 mmol, 1.05 eq) was purified by recrystallization from acetonitrile to give 2.89 g of the free base as a light orange solid.
- the hydrochloride salt was prepared, recrystallized from 95% ethanol, and dried in a vacuum oven to give 2.71 g (68%) of 2-(4-(4-(1,2- benisothiazole-3-yl)-1-piperazinyl)butyl)-4-methyl-1(2H)-phthalazinone hydrochloride hydrate as an off-white powder. mp: 228-230oC.
- N-(4-Bromobutyl)-phthalimide (Aldrich Chemical Company) (0.956 g, 3.39 mmol), 3-(4-piperidinyl)-1,2-benzisothiazole (0.740 g, 3.39 mmol, 1.0 eq), triethylamine (0.57 mL, 0.412 g, 4.07 mmol, 1.2 eq) and acetonitrile (5.0 mL) was added to a round-bottomed flask. The resulting mixture was placed under N 2 and heated at reflux overnight. The dark orange solution was allowed to cool to room temperature and transferred to a separatory funnel with the aid of dichloromethane. The reaction mixture was washed with saturated potassium carbonate.
- Phenethylamine (Aldrich Chemical Company) (31.1 mL, 30.0 g, 0.248 mol), triethylamine (34.6 mL, 25.1 g, 0.248 mol, 1.0 eq) and anhydrous dichloromethane (300.0 mL) were added to a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, addition funnel and a nitrogen inlet. The solution was cooled in an ice-water bath and a solution of ethyl chloroformate (Aldrich Chemical Company) (23.7 mL, 26.9 g, 0.248 mol, 1.0 eq) in dichloromethane (25 mL) was added dropwise.
- ethyl chloroformate Aldrich Chemical Company
- Sodium hydride as an 80% oil dispersion (0.945 g, 31.5 mmol, 2.5 eq) was added to a flame-dried, 100-mL, round-bottomed flask equipped with a magnetic stirring bar and nitrogen inlet.
- the sodium hydride was washed with hexanes (3X), and the waste hexanes were removed each time with a pipet.
- To the washed sodium hydride was added anhydrous N,N-dimethylformamide (20.0 mL) and the resulting suspension was cooled in an ice-water bath.
- the crude material was purified by flash chromatography with ethyl acetate/0.1% triethylamine as eluant to give 2.26 g of an orange oil.
- the free base was taken up in ethyl acetate and HCl (5.37 mL of a 1N solution in ether, 1.0 eq) was added.
- the resulting salt was recrystallized from ethanol to give 2.0 g (55%) of a light orange solid, mp: 229-231oC.
- the reaction mixture was heated at reflux for 1 h, allowed to cool to room temperature, and concentrated to give an orange oil.
- the oil was dissolved in a solution of ethyl acetate and dichloromethane and the organics were washed with saturated potassium carbonate. The organics were dried over MgSO 4 , filtered and concentrated to give 1.41 g of a tan solid.
- the crude material was purified by flash chromatography with 24:1 dichloromethane/methanol as eluant to give 1.02 g of a white solid.
- To a solution of the free base in ethyl acetate was added HCl (2.43 mL of a 1N solution in ether, 1.0 eq).
- Example 13(b) Isatoic anhydride (Aldrich Chemical Company) (0.894 g, 5.48 mmol), ethanol (15.0 mL) and 3-(4-(4-aminobutyl)-1-piperazinyl)- 1,2-benzisothiazole (1.59 g, 5.48 mmol, 1.0 eq) (Example 13(b)) were added to a round-bottom flask equipped with a magnetic stirring bar and nitrogen inlet. The reaction mixture was stirred at room temperature for 22 h. The solvent was removed in vacuo to give 2.35 g of a brown oil.
- the reaction mixture was stirred for 2 h and treated with 1.2 mL of 10 N sodium hydroxide. After 1 h, the pH was adjusted to 6-7 by the addition of acetic acid and subsequently to a pH of 10 with 10 N sodium hydroxide. The organics were extracted with ethyl acetate, dried over MgSO 4 , filtered and concentrated to give 0.900 g of an orange oil. The crude material was purified by flash chromatography with 2:1 ethyl acetate/hexanes to give 0.630 g of a white solid. The free base was dissolved in ethyl acetate and to this solution was added HCl (1.5 mL of a 1N solution in ether, 1.0 eq).
- hydrochloride salt was recrystallized from ethanol/water to give 0.490 g (46%) of 3-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,2,3 benzotriazin-4(3H)-one hydrochloride as a white solid. mp: 242-243.5°C.
- the crude oil was purified by flash chromatography with 3:1 hexanes/ethyl acetate as eluant to give 2.00 g of Ethyl 2-(4-chlorobutyl)-2,3-dihydro-3-oxo-1H-indazole 1-carboxylate and Ethyl 2-(4-bromobutyl)-2,3-dihydro-3-oxo-1H-indazole-1-carboxylate as a 60:40 mixture of the chloride and bromide.
- the chloride/bromide ratio was determined by integration of their corresponding methylene triplets at 3.39 and 3.52 ppm, respectively. This material was used as a mixture without further isolation of each halide.
- hydrochloride salt was recrystallized from ethanol/ether to give 0.36 g (20%) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,2-dihydro-3H-indazol-3-one hydrochloride hydrate as a white solid. mp: 80-90°C (softens, shrinks), 125-145°C (effervesces).
- This compound was prepared according to the method described in Example 36, by employing 5-chloroisatoic anhydride (Aldrich Chemical Company) (1.02 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1- piperazinyl)-1,2-benzisothiazole (1.5 g, 5.17 mmol, 1.0 eq. (Example 13(b)).
- the free base was purified by flash chromatography with 1:1 ethyl acetate/hexanes as eluant.
- hydrochloride salt was prepared and recrystallized from ethanol/water to give 1.61 g (65%) of 2-amino-N-(4-(4-(1,2-benzi sothiazol-3-yl)-1-piperazinyl)butyl)-5-chlorobenzamide
- the compound was prepared according to the method described in Example 36, by employing 5-nitroisatoic anhydride (Trans World Chemicals) (1.08 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.5 g, 5.17 mmol, 1.0 eq) (Example 13(b)).
- the free base was purified by flash chromatography with ethyl acetate as eluant.
- hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 1.10 g (43%) of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)- 1-piperazinyl)butyl)-5-nitrobenzamide hydrochloride as a yellow solid, mp: 224-230oC (dec).
- This compound was prepared according to the method described in Example 36, by employing N-methylisatoic anhydride (Aldrich Chemical Company) (0.92 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1- piperazinyl)-1,2-benzisothiazole (1.5 g, 5.17 mmol, 1.0 eq) (Example 13(b)).
- N-methylisatoic anhydride Aldrich Chemical Company
- 3-(4-(4-aminobutyl)-1- piperazinyl)-1,2-benzisothiazole 1.5 g, 5.17 mmol, 1.0 eq
- the hydrochloride salt was prepared, recrystallized from ethanol/ether, and dried in a vacuum oven to give 1.22 g (51%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-(methylamino)benzamide hydrochloride as a pale beige solid. mp: 169-173oC.
- (+/-)-cis-2-(Methoxycarbonyl)-1-cyclohexanecarboxylic acid (11.7 g, 63.0 mmol) and anhydrous tetrahydrofuran (35.0 mL) was added to a flame-dried, 250-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, septum and nitrogen inlet. The reaction mixture was cooled with an ice-water bath containing rock salt.
- (+/-)-cis-Methyl 2-(hydroxymethyl)-1-cyclohexanecarboxylate (7.20 g, 41.8 mmol), anhydrous dimethylsulfoxide (42.0 mL), anhydrous dichloromethane (200.0 mL) and triethylamine (29.1 mL, 21.2 g, 209 mmol, 5 eq) was added to a flame-dried, 1-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, thermometer and nitrogen inlet.
- (+/-)-cis-4A 5 6, 7, 8, 8A-hexahydro-1(2H)- phthalazinone and (+/-)-trans-4A, 5, 6, 7, 8, 8A-Hexahydro- 1(2H)-phthalazinone
- (+/-)-cis-Methyl 2-formylbenzoate (11.9 g, 69.8 mmol), 95% ethanol (120 mL) and hydrazine hydrate (Fisher Scientific) (9.0 g, 154 mmol, 2.2 eq) as an 85% aqueous solution was added to a round -bottomed flask equipped with a magnetic stirring bar, reflux condenser, and nitrogen inlet. The reaction mixture was refluxed for 0.5 h, cooled to room temperature, and concentrated in vacuo. The residue was partitioned between distilled water (100.0 mL) and ethyl acetate (300.0 mL). The organics were dried over MgSO 4 , filtered and concentrated to give 7.79 g (74%) of a pale yellow oil. The crude material was used without further purification.
- (+/-)-cis-2-(4-chlorobutyl)-4A Preparation of (+/-)-cis-2-(4-chlorobutyl)-4A, 5, 6, 7, 8, 8A- hexahydro-1(2H)-phthalazinone and (+/-)-trans-2-(4-chlorobutyl)- 4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-phthalazinone
- (+/-)-cis-2-(4-Chlorobutyl)-4A 5, 6, 7, 8, 8A-hexahydro-1(2H)- phthalazinone (1.05 g, 4.33 mmol)
- 3-(1-piperazinyl)-1,2-benziso thiazole (1.04 g, 4.76 mmol, 1.1 eq)
- triethylamine (0.725 mL, 0.526 g, 5.20 mmol, 1.2 eq) and acetonitrile (10.0 mL) were added to a round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and nitrogen inlet. The reaction mixture was allowed to reflux for 6 h.
- Homophthalic anhydride (Aldrich Chemical Company) (15 g, 92.5 mmol) and 4-amino-1-butanol (Aldrich Chemical Company) (8.54 mL, 8.26 g, 92.5 mmol, leq) were added to a three-necked, round-bottomed flask equipped with a reflux condenser and addition funnel.
- the reaction mixture was heated with an oil bath at 150oC for 2 h.
- the green solution was cooled to room temperature and phosphorous tribromide (6.0 mL, 17.1 g, 63 mmol) was added dropwise.
- the reaction mixture was heated slowly to 170oC and maintained at that temperature for 45 min.
- the hot reaction mixture was poured onto crushed ice (150 g).
- This compound was prepared according to a modified procedure of F. Bonadies and R. Di Fabio (J. Org. Chem. 1984, 49, 1647). 3,4-Dihydro-1H-2-benzopyran (Aldrich Chemical Company) (32.8 ml, 35.0 g, 0.261 mol), pyridinium chlorochromate (Aldrich Chemical Company) (56.3 g,0.261 mol, 1 eq) and anhydrous dichloromethane (100.0 mL) were added to a flame-dried, 1-L, round-bottomed flask equipped with a condenser, magnetic stirring bar and nitrogen inlet. The reaction mixture was heated with an oil bath at 60-70oC.
- hydrochloride salt was prepared, recrystallized from ethanol, and dried in a vacuum oven to give 227 mg (30%) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2,3,4,5- tetrahydro-1H-2-benzazepin-1-one hydrochloride as a beige solid, m.p.: 215-217 oC (dec).
- Example 33 Methanol (40.0 mL) and N-(4-(4-(1,2-benzisothiazol-3-yl) piperidino)butyl)phthalimide (6.77 g, 16.1 mmol) (Example 33) was added to a three-necked, 250-mL, round-bottomed flask equipped with a magnetic stirring bar, addition funnel, nitrogen inlet and reflux condenser. The reaction mixture was heated to reflux and hydrazine hydrate (Aldrich Chemical Company) (1.41 g of a 55 % aqueous solution, 24.2 mmol, 1.5 eq) was added dropwise. The solution was refluxed for 3 h after the addition of hydrazine hydrate was complete.
- hydrazine hydrate Aldrich Chemical Company
- reaction mixture was allowed to cool to room temperature and acidified (pH - 2) with 1N HCL.
- the suspension was filtered and the filtrate was cooled in an ice-water bath.
- the pH of the cooled filtrate was adjusted to 10 by the addition of 50% NaOH.
- the organics were extracted with dichloromethane, dried with MgSO 4 , filtered and concentrated to give 4.22 g (91%) of 3-(1-(4-aminobutyl)-4-piperidinyl)-1,2-benzisothiazole as an orange oil.
- This compound was prepared according to the method described in Example 36. Alkylation of isatoic anhydride (Aldrich Chemical Company) (0.68 g, 4.15 mmol) with 3-(1-(4-aminobutyl)-4-piperidinyl)-1,2-benzisothiazole (1.2 g, 4.15 mmol, 1.0 eq) gave 1.38 g of the free base which was purified by flash chromatography with 2:1 ethyl acetate/hexanes/0.1% triethylamine as eluant.
- Alkylation of isatoic anhydride Aldrich Chemical Company
- 3-(1-(4-aminobutyl)-4-piperidinyl)-1,2-benzisothiazole 1.2 g, 4.15 mmol, 1.0 eq
- hydrochloride salt was prepared and recrystallized from ethanol/water to give 1.09 g (59%) of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)piperidino)butyl)benzamide hydrochloride as a beige solid, mp: 239-240 oC.
- the reaction mixture was cooled in an ice-water bath and a solution of acetylsalicyloyl chloride (Aldrich Chemical Company) (2.06 g, 10.4 mmol, 1.0 eq) in dichloromethane (20 mL) was added dropwise.
- the reaction mixture was allowed to warm to room temperature and stirred for 15 min.
- the reaction mixture was washed with cold saturated sodium bicarbonate.
- the organics were dried over MgSO 4 , filtered and concentrated to give 5.8 g of the crude material as an orange oil.
- the crude reaction mixture was purified by flash chromatography with 95:5 dichloromethane/methanol as eluant.
- the product (2.93 g) was obtained as a mixture of ((4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)carbamoyl)- phenyl acetate and N-(4-(-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-hydroxybenzamide.
- the crude reaction mixture was purified by flash chromatography with ethyl acetate/0.1% triethylamine as eluant to give 0.99 g of the free base as a white solid.
- the free base was dissolved in ethyl acetate and dichloromethane, and 2.31 mL of 1N ethereal HCl (1.0 eq) was added.
- This compound was prepared according to the method described in Example 53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2- benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and 3,4-dichlorobenzoyl chloride (Aldrich Chemical Company) (0.723 g, 3.45 mmol, 1.0 eq). The crude reaction mixture was purified by flash chromatography with ethyl acetate/0.1% triethylamine as eluant to give the free base (1.52 g) as a white solid.
- the hydrochloride salt was prepared, recrystallized from ethanol/water and dried in a vacuum oven to give 0.88 g (51%) of N-(4-(4-(1,2-benzisothiazol-3-yl)- 1-piperazinyl)butyl)-3,4-dichlorobenzamide hydrochloride as a pale beige solid, mp: 208-210 oC (dec).
- Example 53 by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2- benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine
- This compound was prepared according to the method described in Example 53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2- benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and 4-(trifluoromethyl) benzoyl chloride (Aldrich Chemical Company) (0.513 mL, 0.720 g, 3.45 mmol, 1.0 eq). After the 4-(trifluoromethyl) benzoyl chloride was added, the ice-water bath was removed and the reaction mixture was stirred for 1.5 h.
- the crude reaction mixture was purified by flash chromatography with 1:1 ethyl acetate/hexanes with 0.1% triethylamine as eluant followed by ethyl acetate/0.1% triethylamine to give 0,57 g of the free base as a solid.
- the hydrochloride salt was prepared and recrystallized from ethanol to give 0.26 g (15%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-(trifluoromethyl)benzamide hydrochloride as a tan solid: mp: 205-207 °C (dec).
- This compound was prepared according to the method described in Example 56, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2- benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.0 eq) and tert-butylbenzoyl chloride (Aldrich Chemical Company) (0.674 mL, 0.679 g, 3.45 mmol, 1.0 eq).
- the hydrochloride salt was prepared from the free base (0.560 g) and recrystallized from ethanol to give 0.251 g (15%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)- 4-tert-butylbenzamide hydrochloride as a tan solid. mp: 220.5-222 °C (dec).
- This compound was prepared according to the method described in Example 53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2- benzisothiazole (1.24 g, 4.27 mmol) (Example 13(b)), triethylamine (0.893 mL, 0.648 g, 6.41 mmol, 1.5 eq) and p-phenylazobenzoyl chloride (Kodak) (1.05 g, 4.27 mmol, 1.0 eq). The reaction mixture was allowed to stir for 1 h following the addition of p-phenylazobenzoyl chloride.
- the free base was purified by flash chromatography with 3:1 ethyl acetate/hexanes with 0.1% triethylamine followed by ethyl acetate/0.1% triethylamine and finally ethyl acetate/0.2% triethylamine as eluant to give the
- reaction mixture was transferred to a separatory funnel with the aid of dichloromethane and washed with saturated K 2 CO 3 .
- the organics were filtered, dried with MgSO 4 , filtered and concentrated to give a yellow oil (1.70 g) .
- the crude reaction mixture was purified by flash chromatography with 9:1 dichloromethane/methanol to give 0.74 g of the free base as a white foam.
- This compound was prepared according to the method described in Example 59, by employing 4-((tert-Butoxycarbonyl)amino)benzoic acid (2.05g, 8.65 mmol), triethylamine (1.45 mL, 1.05 g, 10.4 mmol, 1.2 eq), isobutylchloroformate (Aldrich Chemical Company) (1.12 mL, 1.18 g, 8.65 mmol, 1,0 eq) and 3-(4-(4-aminobutyl)-1- perazinyl)-1,2-benzisothiazole (2.51 g, 8.65 mmol, 1.0 eq) (Example 13(b)).
- the crude reaction mixture was purified by flash chromatography with ethyl acetate/0.1% triethylamine as eluant to give 0.78 g of the free base as a white solid. Impure fractions were combined and purified by flash chromatography with 9:1 dichloromethane/methanol as eluant to give 0.40 g of the free base as a white solid.
- the free base obtained from each column was combined and dissolved in ethanol and chloroform. To a solution of the free base was added 1N ethereal HCl (2.41 mL, 1.0 eq).
- This compound was prepared according to the method described in Example 60(a), by employing 3-aminobenzoic acid (Aldrich Chemical Company) (5.0 g, 36.5 mmol), 5% Na 2 CO 3 (25 mL) and di-tert-butyl dicarbonate (Fluka) (19.9 g, 91.1 mmol, 2.5 eq). After 65 h, the reaction mixture was worked up to give 7.48 g (86%) of 3-((tert-butoxycarbonyl)amino)benzoic acid as a white solid.
- This compound was prepared according to the method described in Example 59, by employing 3-((tert-butoxycarbonyl)amino)benzoic acid (2.45 g, 10.3 mmol), triethylamine (1.72 mL, 1,25 g, 12.4 mmol, 1.2 eq), isobutylchloroformate (Aldrich Chemical Company) (1.34 mL, 1.41 g, 10.3 mmol, 1.0 eq) and 3-(4-(4-aminobutyl)-1- piperazinyl)-1,2-benzisothiazole (3.0 g, 10.3 mmol, 1.0 eq) (Example 13(b)).
- the crude oil was dissolved in ethyl acetate, washed with saturated K 2 CO 3 , dried over MgSO 4 , filtered, and concentrated to give a yellow solid.
- the crude amine was purified by flash chromatography with ethyl acetate/0.2% triethylamine to give 0.37 g of the amine as an oil.
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Abstract
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93903266A EP0625978A1 (fr) | 1992-02-12 | 1993-02-11 | Derives de piperazine et de piperidine, et leur utilisation comme neuroleptiques |
JP5513907A JPH07503723A (ja) | 1992-02-12 | 1993-02-11 | ピペラジン及びピペリジン誘導体,並びに抗精神薬としてのこれらの使用 |
SK964-94A SK96494A3 (en) | 1992-02-12 | 1993-02-11 | Piperazine and piperidine derivatives, and their use as antipsychotic |
NO942977A NO942977L (no) | 1992-02-12 | 1994-08-11 | Piperazin og piperidinderivater og anvendelse derav som antipsykotiske midler |
FI943718A FI943718A (fi) | 1992-02-12 | 1994-08-11 | Piperatsiini- ja piperadiinijohdannaisia ja niiden käyttö antipsykoottisina aineina |
KR1019940702790A KR950700290A (ko) | 1992-02-12 | 1994-08-12 | 피페라진 및 피레리딘 유도체, 및 이들의 항정신병제로서의 용도(piperazine and piperidine derivatives, and their use as antipsychotics) |
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GB929202915A GB9202915D0 (en) | 1992-02-12 | 1992-02-12 | Chemical compounds |
GB9202915.6 | 1992-02-12 |
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WO1993016073A1 true WO1993016073A1 (fr) | 1993-08-19 |
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PCT/GB1993/000285 WO1993016073A1 (fr) | 1992-02-12 | 1993-02-11 | Derives de piperazine et de piperidine, et leur utilisation comme neuroleptiques |
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EP (1) | EP0625978A1 (fr) |
JP (1) | JPH07503723A (fr) |
KR (1) | KR950700290A (fr) |
AU (1) | AU3460393A (fr) |
CA (1) | CA2117434A1 (fr) |
CZ (1) | CZ194994A3 (fr) |
FI (1) | FI943718A (fr) |
GB (1) | GB9202915D0 (fr) |
HU (1) | HUT72309A (fr) |
IL (1) | IL104690A0 (fr) |
MX (1) | MX9300786A (fr) |
NO (1) | NO942977L (fr) |
RU (1) | RU94038064A (fr) |
SK (1) | SK96494A3 (fr) |
WO (1) | WO1993016073A1 (fr) |
ZA (1) | ZA93958B (fr) |
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WO1996014297A1 (fr) * | 1994-11-04 | 1996-05-17 | Sumitomo Pharmaceuticals Company, Limited | Nouveaux derives de lactame |
EP0732332A1 (fr) * | 1995-03-17 | 1996-09-18 | Hoechst Marion Roussel, Inc. | Benzothiénylpipérazines substituées, leur utilisation comme médicaments et procédés pour leur préparation |
EP0749967A1 (fr) * | 1995-06-22 | 1996-12-27 | Suntory Limited | Dérivé de benzothiazine substitué |
US5637710A (en) * | 1989-05-19 | 1997-06-10 | Hoechst Marion Roussel, Inc. | Intermediate compounds in the synthesis of heteroarylpiperidines and piperazines |
US5658911A (en) * | 1989-05-19 | 1997-08-19 | Hoechst Marion Roussel, Inc. | Heteroarylpiperidines, and their use as antipsychotics and analgetics |
US5874429A (en) * | 1993-12-24 | 1999-02-23 | Suntory Limited | Benzothiazine derivative |
US6001827A (en) * | 1993-12-24 | 1999-12-14 | Suntory Limited | Benzothiazine derivative |
US6087364A (en) * | 1998-01-29 | 2000-07-11 | Warner-Lambert Company | Dopamine D4 receptor antagonists |
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US8835438B2 (en) | 2004-02-20 | 2014-09-16 | Sumitomo Dainippon Pharma Co., Ltd. | Method of treating memory/learning dysfunctions caused by schizophrenia with lurasidone |
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Also Published As
Publication number | Publication date |
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ZA93958B (en) | 1994-08-11 |
CZ194994A3 (en) | 1995-09-13 |
AU3460393A (en) | 1993-09-03 |
HUT72309A (en) | 1996-04-29 |
CA2117434A1 (fr) | 1993-08-19 |
SK96494A3 (en) | 1995-07-11 |
FI943718A0 (fi) | 1994-08-11 |
JPH07503723A (ja) | 1995-04-20 |
GB9202915D0 (en) | 1992-03-25 |
NO942977D0 (no) | 1994-08-11 |
MX9300786A (es) | 1994-03-31 |
EP0625978A1 (fr) | 1994-11-30 |
KR950700290A (ko) | 1995-01-16 |
IL104690A0 (en) | 1993-06-10 |
FI943718A (fi) | 1994-08-11 |
NO942977L (no) | 1994-10-10 |
RU94038064A (ru) | 1997-05-27 |
HU9402343D0 (en) | 1994-10-28 |
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