CA1055945A - Pharmaceutical compositions and method of producing antipsychotic activity without extrapyramidal symptoms - Google Patents
Pharmaceutical compositions and method of producing antipsychotic activity without extrapyramidal symptomsInfo
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- CA1055945A CA1055945A CA238,781A CA238781A CA1055945A CA 1055945 A CA1055945 A CA 1055945A CA 238781 A CA238781 A CA 238781A CA 1055945 A CA1055945 A CA 1055945A
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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- Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Pharmaceutical compositions and a method of producing antipsychotic activity without extrapyramidial symptoms by administering internally a nontoxic effective quantity of a tricyclic piperidylidene derivative to an animal host. The active ingredients are prepared from an appropriately substitu-ted xanthone, thioxanthone or dibenxoxepinons by reaction with an N-substituted piperidyl magnesium halide. Certain of the piperidylidene derivatives are novel compounds per se.
Pharmaceutical compositions and a method of producing antipsychotic activity without extrapyramidial symptoms by administering internally a nontoxic effective quantity of a tricyclic piperidylidene derivative to an animal host. The active ingredients are prepared from an appropriately substitu-ted xanthone, thioxanthone or dibenxoxepinons by reaction with an N-substituted piperidyl magnesium halide. Certain of the piperidylidene derivatives are novel compounds per se.
Description
105S9~5 1 This invention relates to novel pharmaceutical compositions containing as an active ingredient compounds which produce antipsychotic activity without extrapyramidal symptoms and to a method of producing antipsychotic activity without extrapyramidal symptoms which comprises administer~ing nontoxic effective quantities of said active ingredients to an animal. Extrapyxamidal symptoms (EPS) are some of the most undesirable and common side-effects produced by antipsychotic or neuroleptic drugs. The compounds which are the active ingredients used in the compositions and methods of this invention have a neuropharmacological profile indicative of potent antipsychotic activity but essentially no liability to produce EPS.
The active ingredients used in the compositions and methods of this invention are piperidylidene derivatives of xanthene J thioxanthene and dibenzozepin of the following general formulas:
Z_~Y\~ CH20~/~,(~) -~ W, ~X Z~C~
25FORM~LA I FORMULA II
wherein, for formula I:
when Y represents oxygen7 X is 2-chloro9 2-fluoro,
The active ingredients used in the compositions and methods of this invention are piperidylidene derivatives of xanthene J thioxanthene and dibenzozepin of the following general formulas:
Z_~Y\~ CH20~/~,(~) -~ W, ~X Z~C~
25FORM~LA I FORMULA II
wherein, for formula I:
when Y represents oxygen7 X is 2-chloro9 2-fluoro,
2-trifluoromethyl~ 2-thiomethyl, 2-bromo or 2-cyano, Z is hydrogen and R is methyl, 1 when Y represents oxygen, X is 2-chloroy Z is hydrogen and R is hydrogen, ethyl, ~-hydroxyethylg n-propyl, 3-hydroxypropyl or cyclobutylmethyl, when Y represents oxygen, X is 2-bromo9 Z is hydrogen and R is hydrogen9 ~-hydroxyethyl or n-butyl~
when Y represents oxygen9 X is 2-trifluoromethyl9 Z is hydrogen and R is n-butyl, when Y represents sulfur9 X is 2-or 3-chloro9 2-thiomethyl9 2-or 3-fluoro9 2-bromo or 2-cyano9 Z is hydrogen and R is methyl, when Y represents sulfur, X is 2-chloro9 Z is hydrogen and R is ~-hydroxyethyl, ethyl9 n-butyl or cyclo-butylmethyl; and when Y represents oxygen, X is 2-fluoro9 Z is lS 6-chloro and R is methyl;
when Y represents sulfur, X is 2-fluoro9 Z is 6-chloro or 6-fluoro and R is methyl, and for formula II:
when X is 2-or 3-chloro, Z is hydrogen~ and when X is hydrogen9 Z is 9-chloroO
Preferred o~pounds for use as active ingredients are those of formula I wherein Y is oxygen9 X is 2-chloro9 Z is hydrogen and R is methyl, and of formula II wherein - X is hydrogen and Z is 9-chloro.
Certain of the compounds of formulas I and II
are novel compounds and as such form a part of this inven-tion. These compounds are as follows:
in formula I, when Y represents oxygen9 X is 2-chlorog 2-fluoro 2-bromo9 2-thiomethyl or 2-cyano, Z is hydrogen and R is methyl;
~0 S S9 4 5 1when Y represents oxygen, X is 2-fluoro, Z is 6-chloro and R is methyl, when Y represents oxygen, X is 2-chloro, Z is hydrogen and R is hydrogen9 ethyl9 ~-hydroxyethyl~ n-propyl 5or 3-hydroxypropyl, when Y represents oxygen, X is 20bromo9 ~ is hydrogen and R is hydrogen, ~-hydroxyethyl or n-butyl, when Y represents oxygen9 X is 2-trifluoromethyl9 Z is hydrogen and R is n-butyl;
10when Y represents sulfur 9 X iS 2-cyano 9 Z iS
hydrogen and R is methyl, and in formula II:
when X is hydrogeng Z is 9-chloro.
The nontoxic pharmaceutically acceptable acid addition salts of the compounds of formulas I and II are similarly useful in the compositions and methods of this invention. Such salt~ are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible ~-solvent 9 such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
Exemplary of such organic salts are those with maleic9 fumaric, benzoic, ascorbic9 pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, scetic9propionic, tartaric, salicylic, citric9 gluconic9 lactic9 malic, mandelic, cinnamic9 citraconic, aspartic, stearic9 palmitic, itaconic, glycolic9 p-aminobenzoic 3 glutamic, benzenesulfonic and theophylline acetic acids as well l as with 8-halotheophyllines 7 for example 8-bromotheo-phylline. Exemplary of such inorganic salts are those with hydrochloricl hydrobromic, sulfuric, cyclohexylsul-famic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts which is well known to the art.
The compounds of formulas I and II where R is methyl are generally prepared from an appropriately substi-tuted xanthone, thioxanthone or dibenzoxepinone by reaction with an N-methylpiperidyl magnesium halide in an inert organic solvent such as ether, for example ethyl ether 9 dioxane or tetrahydrofuran9 at from room temperature to the reflux temperature of the solvent, for from 30 minutes to 4 hours. The tricyclic carbinol intermediate is dehy-drated to the olefin under acid or thermal conditions.
To prepare the compounds of formula I where R
is other than methyl 3 the N-methylpiperidylidene derivative is treated with cyanogen bromide to give the N-cyanamide ~ which is treated with acid to obtain the N-unsubstituted derivatives. The latt~r are N-alkylated by one of the following methods:
a) direct alkylation with the appropriate alkyl bromide;
b) acylation with the appropriate acyl ch~oride to the corresponding amides followed by lithium aluminun hydride reduction, or c) reaction with ethylene oxide.
UOS. Patents 3,275,640 and 3,055,903 disclose piperidylidene thioxanthenes; South African Patent 67/04371 l discloses piperidylidene dibenzoxepin ~ and U~SO Patent 394709188 discloses piperidylidene xanthenes and thioxan-thenes9 however~ none of these or equivalent prior art dis~
close the unique feature of the compounds of formula I, namely antipsychotic activity with no EPS~ Belgian Patent 8089347 describes di~nuclear substituted thioxanthenes having a heterocyclic propyl or propylidene side chain as neuroleptics with reduced extrapyramidal symptoms.
There is evidence that antipsychotic drugs cause EPS by interfering with neurotransmission in a nigrostriatal dopaminergic pathwayO It is thought that they block dopamine receptors in the neostriatum. Thereforeg the ability of a drug to block striatal dopamine receptors is a measure of its EPS liability.
To assess the potency of drugs in blocking striatal dopamine receptors a procedure was used which was developed by Ungerstedt [Ungerstedt and Arbuthnott9 Brain ResO 24 485 (1970)~ Ungerstedt9 Acta physiolO scand.~
Suppl. 3679 49 (1971)] using rats with unilateral lesions of the substantia nigra induced by inJection of 6-hydroxy-dopamine. This treatment causes degeneration of the nigr~striatal dopaminergic pathway accompanied by a marked decrease in the dopamine content of the neostriatum on the side of the lesion. Animals with this lesion develop postural and motor asymmetries which are altered ~y drugs which affect dopaminergic activity. Amphetamine9 which releases dopamine and norepinephrine from catecholaminergic 1~)5S945 1 neurons9 causes these rats to rotate unidirectionally toward the side of the lesion. Since there is a much larger amount of dopamine to be released by amphetamine from the intact nigrostriatal neurons on the non~lesioned side than from those remaining on the lesioned side9 the rotational behavior is apparently due to a preponderance of activation of striatal dopamine receptors on the intact side. The ability of a drug to antagonize the rotational behavior is therefore a measure of its ability to block striatal dopamine receptors and is indicative of its potential to produce EPS.
To predict the potential ability of a drug to cause EPS9 the ratio of its ED50 (i~po) for antagonism of amphetamine-induced rotation to its ED50 (i.p.~ for blockade of shock avoidance acquisition in the rat9 a procedure for assessing antipsychotic activity, (R/A ratio~ is calculated.
The ED50 values of some clinically established antipsychotics in the avoiclance and rotational tests and the R/A ratios are presented in Table I. Chlorpromazine has a R/A ratio ?0 of 103. Antipsychotics that have a considerably greater propensity to cause EPS than chlorpromazine9 e.g.g tri~
fluoperazine9 haloperidol and pimozide~ have ratios of 0.3 to 0.5. The two antipsychotics known to produce EPS
to a lesser extent than chlorpromazine~ i.e~ thioridazine and clozapine9 have ratios of 2.7 and 3.89 respectively.
Therefore a high R/A ratio predicts that a drug will have a low potential to produce EPS.
when Y represents oxygen9 X is 2-trifluoromethyl9 Z is hydrogen and R is n-butyl, when Y represents sulfur9 X is 2-or 3-chloro9 2-thiomethyl9 2-or 3-fluoro9 2-bromo or 2-cyano9 Z is hydrogen and R is methyl, when Y represents sulfur, X is 2-chloro9 Z is hydrogen and R is ~-hydroxyethyl, ethyl9 n-butyl or cyclo-butylmethyl; and when Y represents oxygen, X is 2-fluoro9 Z is lS 6-chloro and R is methyl;
when Y represents sulfur, X is 2-fluoro9 Z is 6-chloro or 6-fluoro and R is methyl, and for formula II:
when X is 2-or 3-chloro, Z is hydrogen~ and when X is hydrogen9 Z is 9-chloroO
Preferred o~pounds for use as active ingredients are those of formula I wherein Y is oxygen9 X is 2-chloro9 Z is hydrogen and R is methyl, and of formula II wherein - X is hydrogen and Z is 9-chloro.
Certain of the compounds of formulas I and II
are novel compounds and as such form a part of this inven-tion. These compounds are as follows:
in formula I, when Y represents oxygen9 X is 2-chlorog 2-fluoro 2-bromo9 2-thiomethyl or 2-cyano, Z is hydrogen and R is methyl;
~0 S S9 4 5 1when Y represents oxygen, X is 2-fluoro, Z is 6-chloro and R is methyl, when Y represents oxygen, X is 2-chloro, Z is hydrogen and R is hydrogen9 ethyl9 ~-hydroxyethyl~ n-propyl 5or 3-hydroxypropyl, when Y represents oxygen, X is 20bromo9 ~ is hydrogen and R is hydrogen, ~-hydroxyethyl or n-butyl, when Y represents oxygen9 X is 2-trifluoromethyl9 Z is hydrogen and R is n-butyl;
10when Y represents sulfur 9 X iS 2-cyano 9 Z iS
hydrogen and R is methyl, and in formula II:
when X is hydrogeng Z is 9-chloro.
The nontoxic pharmaceutically acceptable acid addition salts of the compounds of formulas I and II are similarly useful in the compositions and methods of this invention. Such salt~ are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible ~-solvent 9 such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
Exemplary of such organic salts are those with maleic9 fumaric, benzoic, ascorbic9 pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, scetic9propionic, tartaric, salicylic, citric9 gluconic9 lactic9 malic, mandelic, cinnamic9 citraconic, aspartic, stearic9 palmitic, itaconic, glycolic9 p-aminobenzoic 3 glutamic, benzenesulfonic and theophylline acetic acids as well l as with 8-halotheophyllines 7 for example 8-bromotheo-phylline. Exemplary of such inorganic salts are those with hydrochloricl hydrobromic, sulfuric, cyclohexylsul-famic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts which is well known to the art.
The compounds of formulas I and II where R is methyl are generally prepared from an appropriately substi-tuted xanthone, thioxanthone or dibenzoxepinone by reaction with an N-methylpiperidyl magnesium halide in an inert organic solvent such as ether, for example ethyl ether 9 dioxane or tetrahydrofuran9 at from room temperature to the reflux temperature of the solvent, for from 30 minutes to 4 hours. The tricyclic carbinol intermediate is dehy-drated to the olefin under acid or thermal conditions.
To prepare the compounds of formula I where R
is other than methyl 3 the N-methylpiperidylidene derivative is treated with cyanogen bromide to give the N-cyanamide ~ which is treated with acid to obtain the N-unsubstituted derivatives. The latt~r are N-alkylated by one of the following methods:
a) direct alkylation with the appropriate alkyl bromide;
b) acylation with the appropriate acyl ch~oride to the corresponding amides followed by lithium aluminun hydride reduction, or c) reaction with ethylene oxide.
UOS. Patents 3,275,640 and 3,055,903 disclose piperidylidene thioxanthenes; South African Patent 67/04371 l discloses piperidylidene dibenzoxepin ~ and U~SO Patent 394709188 discloses piperidylidene xanthenes and thioxan-thenes9 however~ none of these or equivalent prior art dis~
close the unique feature of the compounds of formula I, namely antipsychotic activity with no EPS~ Belgian Patent 8089347 describes di~nuclear substituted thioxanthenes having a heterocyclic propyl or propylidene side chain as neuroleptics with reduced extrapyramidal symptoms.
There is evidence that antipsychotic drugs cause EPS by interfering with neurotransmission in a nigrostriatal dopaminergic pathwayO It is thought that they block dopamine receptors in the neostriatum. Thereforeg the ability of a drug to block striatal dopamine receptors is a measure of its EPS liability.
To assess the potency of drugs in blocking striatal dopamine receptors a procedure was used which was developed by Ungerstedt [Ungerstedt and Arbuthnott9 Brain ResO 24 485 (1970)~ Ungerstedt9 Acta physiolO scand.~
Suppl. 3679 49 (1971)] using rats with unilateral lesions of the substantia nigra induced by inJection of 6-hydroxy-dopamine. This treatment causes degeneration of the nigr~striatal dopaminergic pathway accompanied by a marked decrease in the dopamine content of the neostriatum on the side of the lesion. Animals with this lesion develop postural and motor asymmetries which are altered ~y drugs which affect dopaminergic activity. Amphetamine9 which releases dopamine and norepinephrine from catecholaminergic 1~)5S945 1 neurons9 causes these rats to rotate unidirectionally toward the side of the lesion. Since there is a much larger amount of dopamine to be released by amphetamine from the intact nigrostriatal neurons on the non~lesioned side than from those remaining on the lesioned side9 the rotational behavior is apparently due to a preponderance of activation of striatal dopamine receptors on the intact side. The ability of a drug to antagonize the rotational behavior is therefore a measure of its ability to block striatal dopamine receptors and is indicative of its potential to produce EPS.
To predict the potential ability of a drug to cause EPS9 the ratio of its ED50 (i~po) for antagonism of amphetamine-induced rotation to its ED50 (i.p.~ for blockade of shock avoidance acquisition in the rat9 a procedure for assessing antipsychotic activity, (R/A ratio~ is calculated.
The ED50 values of some clinically established antipsychotics in the avoiclance and rotational tests and the R/A ratios are presented in Table I. Chlorpromazine has a R/A ratio ?0 of 103. Antipsychotics that have a considerably greater propensity to cause EPS than chlorpromazine9 e.g.g tri~
fluoperazine9 haloperidol and pimozide~ have ratios of 0.3 to 0.5. The two antipsychotics known to produce EPS
to a lesser extent than chlorpromazine~ i.e~ thioridazine and clozapine9 have ratios of 2.7 and 3.89 respectively.
Therefore a high R/A ratio predicts that a drug will have a low potential to produce EPS.
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l The specific piperidylidene derivatives of formulas I and II having a large R/A ratio and therefore should be essentially free of EPS liability are listed below.
S I. 4-(2-chloro-9-thioxanthenylidene)-1-methylpiperi-dine IIo l-methyl-4-(2-methylthio-9-thioxanthenylidene~-piperidine III. 4-(3-chloro-9-thioxanthenylidene)-1-methylpiperi-dine IV~ 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine V. l-methyl-4-(2-methylthio-9-xanthenylidene)piperi-dine VI. l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)-lS piperidine VII. 4-(2-chloro-11(6H)-dibenz[b,e]oxepinylidene~
methylpiperidine VIII. 4-(2-fluoro-9-xanthenylidene)-1-methylpiperidine IX. 4-(2-chloro-9-thioxanthenylidene)-1-(~-hydroxy-~-0 ethyl)piperidine.
X. 4-(2-bromo~-xanthenylidene)-1-methylpiperidine XI. 4-(2-cyano-9-xanthenylidene)-1-methylpiperidine XII. 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperi-dine XIII. 4-(3-fluoro-9-thioxanthenylidene)-1-methylpiperi-dine XIV. 4-(2-bromo-9-thioxanthenylidene)-1-methylpiperidine XV. 4-(6-chloro-2-fluoro-9-thioxanthenylidene)-1-methylpiperidine XVI. 4-(6-chloro-2-fluoro-9-xanthenylidene)-1-methyl~
piperidine 1XVII. 4-(2-chloro-9-thioxanthenylidene)-1-ethylpiperidine XVIII. 4-(2-chloro-9-thioxanthenylidene)-1-n-butglpiperi-dine XIX. 4-~2~chloro-9-thioxanthenylidene)-1-cyclobutylmethyl-5piperidine XX. 4-(2-chloro-9-xanthenylidene~-piperidine XXIo 4~ (2-chloro-9-xanthenylidene)-1-ethylpiperidine XXII. 4-(2~chloro-9-xanthenylidene)-1-(~-hydroxyethyl~-piperidine 10XXIII. 4-(2-chloro 9-xanthenylidene)-1-n-propylpiperidine XXIV. 4-(2-chloro-9-xanthenylidene)-1-cyclobutylmethyl-piperidine XXV. 4-(2-bromo-9-xanthenylidene)-piperidine XXVIo 4-(2-bromo-9-xanthenylidene)-1-(~-hydroxyethyl)-15piperidine XXVII. 4-(9-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-methylpiperidine XXVIII. 4-~2-cyano-9-thioxanthenylidene)-1-methylpiperidine XXIX. 4-(296-difluoro-9-thioxanthenylidene)-l-methyl-~-0piperidine XXXO 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl~
piperidine XXXI. 4-(2-trifluoromethyl-9-xanthenylidene)-1-n-butyl piperidine 25XXXII. 4-(2-bromo-9-xanthenylidene)-1-n-butylpiperidine XXXIII~ 4-(3-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-methylpiperidine.
The ED50 values of these compounds in the a~oidance acquisi-tion and rotational tests and their R/A ratios are presented 30in Table IIo ~ U~ o~ ~ o ,~
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~0559~5 1 The compositions of this invention are prepared in conventional dosage unit forms by incorporating a compound of formulas I or II or a pharmaceutically acceptable salt thereof, in a nontoxic amount sufficient to produce anti psychotic activity without extrapyramidal symptoms in an animal9 with a nontoxic pharmaceutical carrier according ~o accepted proceduresO Preferably the compositions will con-tain the active ingredient in an active but nontoxic amount selected from about 1 mg. to about 300 mg.~ advantageously from about 5 mg. to about 200 mg.~ of active ingredient per dosage unit.
The pharmaceutical carrier employed may be9 for example, either a solid or liquid, giving rise to a wide variety of pharmaceutical forms. If a solid pharmaceutical carrier is used, such as lactose9 magnesium stearate9 terra alba9 sucrose9 talc9 stearic acid9 gelatin9 agar9 pectin9 acacia and the like9 the composition can be tableted9 used as a pharmaceutical powder~ placed in a hard gelatin capsule or in the form of a troche or lozenge. The amount of solid ?0 carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid pharmaceutical carrier is used, such as syrup9 peanut oil, olive oil~ sesame oil9 water and the like9 the composition will be in the form of a soft gelatin capsule9 syrup, emulsion or a liquid suspen-sion~ Similarly the carrier or diluent may include a timedelay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.
Parenteral dosage forms such as for intramuscular administration are obtained by dissolving a water soluble 3~ salt of the active medicament in water or saline solution 1 in a concentration such that 1 ccO of the solution contains from about 2 mgO to about 50 mgO of active ingredient. The solution can then be filled into single ampuls or multiple dose vialsO
In accordance with the method of this invention a compound of formula I or II or a nontoxic acid addition salt thereof is administered internally to an animal in need of antipsychotic activity9 preferably with a pharmaceutical carrier9 in a nontoxic amount sufficient to produce anti psychotic activity without extrapyramidal symptoms, The active medicament9 preferably in a dosage unit9 is adminis-tered orally or intramuscularly in an active3 nontoxic quantity selected from about 1 mg. to about 300 mgO of the parent chemical of formula I or II. Advantageously equal doses will be administered until a desired effect is ob-tained9 such as two or three times a day~ The daily dosage is selected from about 2 mg. to about 900 mg. of active medicament9 advantageously from about 10 mg. to about 600 mg. When the method described above is carried out9 ~0 antipsychotic activity is obtained with minimal EPSo The followi~g examples illustrate specific pharma-ceutical compositions and their use in accordance with the method of this invention and as such are not to be con-sidered as limitations thereo.
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l The specific piperidylidene derivatives of formulas I and II having a large R/A ratio and therefore should be essentially free of EPS liability are listed below.
S I. 4-(2-chloro-9-thioxanthenylidene)-1-methylpiperi-dine IIo l-methyl-4-(2-methylthio-9-thioxanthenylidene~-piperidine III. 4-(3-chloro-9-thioxanthenylidene)-1-methylpiperi-dine IV~ 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine V. l-methyl-4-(2-methylthio-9-xanthenylidene)piperi-dine VI. l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)-lS piperidine VII. 4-(2-chloro-11(6H)-dibenz[b,e]oxepinylidene~
methylpiperidine VIII. 4-(2-fluoro-9-xanthenylidene)-1-methylpiperidine IX. 4-(2-chloro-9-thioxanthenylidene)-1-(~-hydroxy-~-0 ethyl)piperidine.
X. 4-(2-bromo~-xanthenylidene)-1-methylpiperidine XI. 4-(2-cyano-9-xanthenylidene)-1-methylpiperidine XII. 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperi-dine XIII. 4-(3-fluoro-9-thioxanthenylidene)-1-methylpiperi-dine XIV. 4-(2-bromo-9-thioxanthenylidene)-1-methylpiperidine XV. 4-(6-chloro-2-fluoro-9-thioxanthenylidene)-1-methylpiperidine XVI. 4-(6-chloro-2-fluoro-9-xanthenylidene)-1-methyl~
piperidine 1XVII. 4-(2-chloro-9-thioxanthenylidene)-1-ethylpiperidine XVIII. 4-(2-chloro-9-thioxanthenylidene)-1-n-butglpiperi-dine XIX. 4-~2~chloro-9-thioxanthenylidene)-1-cyclobutylmethyl-5piperidine XX. 4-(2-chloro-9-xanthenylidene~-piperidine XXIo 4~ (2-chloro-9-xanthenylidene)-1-ethylpiperidine XXII. 4-(2~chloro-9-xanthenylidene)-1-(~-hydroxyethyl~-piperidine 10XXIII. 4-(2-chloro 9-xanthenylidene)-1-n-propylpiperidine XXIV. 4-(2-chloro-9-xanthenylidene)-1-cyclobutylmethyl-piperidine XXV. 4-(2-bromo-9-xanthenylidene)-piperidine XXVIo 4-(2-bromo-9-xanthenylidene)-1-(~-hydroxyethyl)-15piperidine XXVII. 4-(9-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-methylpiperidine XXVIII. 4-~2-cyano-9-thioxanthenylidene)-1-methylpiperidine XXIX. 4-(296-difluoro-9-thioxanthenylidene)-l-methyl-~-0piperidine XXXO 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl~
piperidine XXXI. 4-(2-trifluoromethyl-9-xanthenylidene)-1-n-butyl piperidine 25XXXII. 4-(2-bromo-9-xanthenylidene)-1-n-butylpiperidine XXXIII~ 4-(3-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-methylpiperidine.
The ED50 values of these compounds in the a~oidance acquisi-tion and rotational tests and their R/A ratios are presented 30in Table IIo ~ U~ o~ ~ o ,~
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~0559~5 1 The compositions of this invention are prepared in conventional dosage unit forms by incorporating a compound of formulas I or II or a pharmaceutically acceptable salt thereof, in a nontoxic amount sufficient to produce anti psychotic activity without extrapyramidal symptoms in an animal9 with a nontoxic pharmaceutical carrier according ~o accepted proceduresO Preferably the compositions will con-tain the active ingredient in an active but nontoxic amount selected from about 1 mg. to about 300 mg.~ advantageously from about 5 mg. to about 200 mg.~ of active ingredient per dosage unit.
The pharmaceutical carrier employed may be9 for example, either a solid or liquid, giving rise to a wide variety of pharmaceutical forms. If a solid pharmaceutical carrier is used, such as lactose9 magnesium stearate9 terra alba9 sucrose9 talc9 stearic acid9 gelatin9 agar9 pectin9 acacia and the like9 the composition can be tableted9 used as a pharmaceutical powder~ placed in a hard gelatin capsule or in the form of a troche or lozenge. The amount of solid ?0 carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid pharmaceutical carrier is used, such as syrup9 peanut oil, olive oil~ sesame oil9 water and the like9 the composition will be in the form of a soft gelatin capsule9 syrup, emulsion or a liquid suspen-sion~ Similarly the carrier or diluent may include a timedelay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.
Parenteral dosage forms such as for intramuscular administration are obtained by dissolving a water soluble 3~ salt of the active medicament in water or saline solution 1 in a concentration such that 1 ccO of the solution contains from about 2 mgO to about 50 mgO of active ingredient. The solution can then be filled into single ampuls or multiple dose vialsO
In accordance with the method of this invention a compound of formula I or II or a nontoxic acid addition salt thereof is administered internally to an animal in need of antipsychotic activity9 preferably with a pharmaceutical carrier9 in a nontoxic amount sufficient to produce anti psychotic activity without extrapyramidal symptoms, The active medicament9 preferably in a dosage unit9 is adminis-tered orally or intramuscularly in an active3 nontoxic quantity selected from about 1 mg. to about 300 mgO of the parent chemical of formula I or II. Advantageously equal doses will be administered until a desired effect is ob-tained9 such as two or three times a day~ The daily dosage is selected from about 2 mg. to about 900 mg. of active medicament9 advantageously from about 10 mg. to about 600 mg. When the method described above is carried out9 ~0 antipsychotic activity is obtained with minimal EPSo The followi~g examples illustrate specific pharma-ceutical compositions and their use in accordance with the method of this invention and as such are not to be con-sidered as limitations thereo.
Ii~E~ . per capsule
4-(2-chloro-9-thioxanthenyli-50 (free base) dene-l-methylpiperidine (as an acid addition salt) Magnesium stearate 2 Lactose 200 l The above ingredients are mixed~ passed through a #40 me~h screen9 remixed and filled into #2 capsules.
In~redients W/V Percenta,~es 4-(2-chloro-9-xanthenylidene)- Equivalent to 20 mg~ of l-methylpiperidine (as a water free base per ml.
soluble acid addition salt) ~odium tartrate Tartaric acid 0,7 Water for parenterals, q.s. 100 The above ingredients are dissolved in an amount of the water equal to approximately 95% of the final volume9 mixed9 heated a~ required~ cooled to room temperature and the re-mainder of water is added. The solution is ~iltered and filled in ampuls.
The capsules or solution prepared as in Examples 1 or 2 are administered internally to an animal requiring antipsychotic activity within the dose ranges set forth hereinabove. Similarly other compounds of formulas I or II
can be formulated in the same manner to give pharmaceutical ?0 compositions useful in the methods of this invention.
To 4.3 g. (0.175 m.) of magnesium turnings just covered with dry tetrahydrofuran at gentle reflux under nitrogen is added l ml. of a tetrahydrofuran solution of the base derived from 29.8 g. (0.175 m.) of 4-chloro-N-methylpiperidine hydrochloride (base in about 50 ml. of tetrahydrofuran). (The base was previously liberated by use of ether, potassium hydroxide pellets9 l ml. of water;
triturating9 extracting with ether and evaporating in vacu-the dried ether solution.) A small amount of ethereal 1 methyl magnesium bromide is added and when the reaction starts the remainder of the base is diluted with about 150 ml. of tetrahydrofuran while stirring. This solution is added dropwise over one-half hour while maintaining low heat and the resulting mixture is refluxed and stirred for one hour. At low reflux 27.0 g. (0.117 m.) of 2-chloro-xanthone is added portionwise with stirring. The reaction mixture is stirred and refluxed for one hour and then quenched on a mixture of ice-water-ammonium chloride to give an oil which solidified. Recrystallization from ethyl acetate gives 2-chloro-9-(1-methyl-4-piperidyl)-xanthene-9-ol, m.p. 206-208C.
A mixture of 12.5 g. (0.038 m.) of the xanthene-9-ol, 14.0 g. (0.76 m.) of o-sulfobenzoic anhydride and 380 ml.
lS of propionic acid is refluxed for three hours. The reaction mixture is heated in vacuo at 100C. and the resulting syrup is dissolved in water, made strongly basic with 40% sodium hydroxide solution, extracted with ether9 and the dried extract is evaporated. The residual free base is dissolved in ethyl acetate and maleic acid (4.4 g.) is added to yield 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine maleate, m.p. 206-207C.
The Grignard reagent from 68 g. (0.4 m.) of 4-chloro-N-methylpiperidine hydrochloride and 9.7 g.
(0.4 m.) of magnesium turnings in a total volume of 250 ml.
of tetrahydrofuran is obtained following the procedure of Example 3. After all the halide is added, 75.6 g. (0.287 m.) of 2-trifluoromethylxanthone is added portionwise and refluxing/stirring are continued for one hour under nitrogen.
1055~45 1 The reaction mixture is quenched on ice-water-ammonium chloride to give 9~ methyl~4-piperidyl) 2-trifluoro-methylxanthene-9-019 m.p~ 179-183CD
Dehydration of the xanthene-9 ol (88.2 gO 9 0.24 mO~ is accompli~hed by refluxing with 88~1 g. (0048 mO7 of sulfobenzoic anhydride and 1O2 lo of propionic acid for two hoursO The reaction mixture is heated in vacuo at 100Co and the residual syrup is dissolved in water and made strongly basic with 40% sodium hydroxide solution.
Extraction with ether gives l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)-piperidine, m.p. 82-83C.
EXAMPLh 5 Following the procedure of Example 39 the Grignard reagent formed from 2O4 gO (0~1 m.) of magnesium and 1303 gD
(0 01 mO) of 4-chloro-N-methylpiperidine is reacted with 1201 g. (0O05 mO) of 2~thiomethylxanthone to give 9-(1-methyl-4-piperidyl)-2~thiomethylxanthene-9-ol9 m.p. 169Co The xanthene-9-ol (10.8 g,9 0~032 m.) thus pre-pared is dehydrated by refluxing with 11.6 gO (00064 mc) of ?0 sulfobenzoic anhydride and 258 mlO of propionic acid.
After work~up of the ~eaction mixture9 extraction with methylene chloride followed by addition of ether precipi~
tates unreacted xanthene-9-ol which is removed by filtra-tion. The filtrate is concentrated to give an oil which is converted in ether to the maleate salt of 1-methyl-4-(2 methylthio-9-xanthenylidene)-piperidine9 mOp. 172-180Co The Grignard reagent prepared from 0O53 g.
(0.0216 mO) of magnesium and 2.9 g. (0.0216 m.) of 4-chloro-N-methylpiperidine is reacted with 2.3 g. (0O0108 mO) 1 of ~-fluoroxanthone as described in Example 3. The reac-tion mixture is heated for four hours and then decomposed with saturated ammonium chloride solution to yield 2-fluoro-9-(l-methyl-4-piperidyl)-xanthene-9-ol9 m.p. 193-200C.
A mixture of 0.58 g. (0.002 m.) of the above pre-pared xanthene-9-ol9 0.34 g. (0.004 m.~ of sulfobenzoic anhydride and 20 mlO of propionic acid is refluxed for about 15 minutes and then stirred without heating until cooled.
The reaction mixture is evaporated in vacuo and the residue is taken up in methylene chloride. The product is treated with maleic acid to afford the maleate salt of 4-(2-fluoro-9-xanthenylidene)-l-methylpiperidine9 m.p. 189-193C.
To a solution of 13.2 g. (0.0318 m.) of 4-(2-chloro-9-thioxanthenylidene)-piperidine in 50 ml. of methan-ol at 50C~ is added a solution of 2.2 g. (0.0383 m.) of ethylene oxide in 30 ml. of methanol over ten minutes and the mixture is refluxed for one and one-half hours. After standing overnight at room temperature9 the reaction mixture is filtered to yield 4-(2-chloro-9-thioxanthenylidene)-1-(~-hydroxyethyl)-piperidine9 m.p. 178-180C.
To a stirred suspension of 2.43 g. (0.1 gO~atom~
of magnesium turnings in 5 ml. of tetrahydrofuran under nitrogen is added several drops of ethyl bromide. After the reaction is started9 13.4 g. (0.1 mole) of 4-chloro-1-methylpiper;dine in 50 ml. of tetrahydrofuran is added at a rate sufficient to cause reflux. The mixture is stirred and refluxed for one hour 9 then it is cooled to 0C~ and 2006 g. (0O075 mole) of 2-bromoxanthone is added in portions~
1055~45 1 The stirred mixture is refluxed for four hours and then it is poured into a solution of 26.5 g. (0.5 mole) of ammonium chloride in 500 ml. of ice-water. The crystalline alcohol 9 2-bromo-9-(1-methyl-4-piperidyl)-xanthene-9-ol~ m.p.
201-2029 is filtered.
The above alcohol 20.0 g~ (0.05~ mole) is dis~
solved in 200 ml. of propionic acid and 20O0 g. (OoOll mole~
of sulfobenzoic anhydrideO The solution is refluxed for one hour, concentrated in vacuo, and then the residue is diluted with waterO The mixture is made alkaline with 2~5 N sodium hydroxide and extracted with ether~ The ether extracts are dried and concentrated to give 4-(2-bromo-9-xanthenylidene)-l-methylpiperidine9 which identified as its maleate salt9 m.p. 206C. ~dec.)O
.. ..
To a stirred solution of 7.0 g. (0.065 mole~ of cyanogen bromide in 150 ml. of benzene at 50-55C. is added 19.5 gO (0.055 mole) of 4-(2-bromo-9-xant~enylidene)-1-methylpiperidine in 150 ml. of benzene. The solution is ~0 heated for 2.5 hours) then it is concentrated in vacuo~
The residue is dissolved in methylene chloride and the solu-tion is washed with lN hydrochloric acid~ water and a saturated aqueous solution of sodium chloride. The organic solution is concentrated to give a semi-crystalline residue which is refluxed for 16 hours with a solution of 225 mlO
of acetic acid and 25 ml. of 12N hydrochloric acid in 125 mlO of water. The solution is concentrated and the residue is dissolved in water. After the solution is made alkaline with sodium hydroxide, the mixture is extracted with ethyl acetateO The extracts are concentrated and a solution of 1 the crystalline residue in acetonitrile is treated with methanesulfonic acid in acetonitrile-ether .o give color-less crystals 9 mOp ~ 257.5-258.5C.9 of 4-(2-bromo-9-xan-thenylidene)piperidine methanesulfonate.
To 102 g. (0O05 mol) of magnesium turnings cover-ed by tetrahydrofuran in an Argon atmosphere is added about 0.5 g. of 4-chloro-N-.nethylpiperidine (from 8.5 g. 9 0~025 mol of the hydrochloride salt) and a small amount of ethyl bromide. The mixture is heated until the reaction is ini-tiated9 the remainder of the chloro compound in about 20 ml.
of tetrahydrofuran is added and the mixture is refluxed for four hours. 2-~romothioxanthone (7.3 g., 0.025 mol) is added and the mixture is refluxed for five hours 3 and then stirred at room temperature three days. The reaction mix-ture is poured into aqueous ammonium chloride and filtered to give 2-bromo-9~ methyl-4-piperidyl)thioxanthene-9-ol 3 m.p. 225.5-226C.
A solution of 4.0 g. (0.0103 mol) of 2-bromo-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol in 20 ml. of con-centrated hydrochloric acid is refluxed for 1.5 hours~ The reaction mixture is evaporated to dryness and redissolved in water. The aqueous solution is washed with ether, basi-fied and extracted with ether. The dried extract is evap-orated and the residue in acetonitrile is treated with methanesulfonic acid to yield 4-(2-bromo-9-thioxanthenyli-dene)-l-methylpiperidine methanesulfonate, m.p. 210-212C.
(dec.~.
To a solution of 4-(2-bromo-9-xanthenylidine)-piperidine (205 g~, 0.0073 mol) in 50 ml. of ethanol9 10555~45 1 cooled to ca 0C. is added excess ethylene oxide (1.1 ml~, 0.022 mol.)O The reaction mixture is kept at 0C. After 30 minutes the ice-bath is removed and after an additional 205 hours9 a thick white precipitate is formed which is filtered to give 4-(2-bromo-9 xanthenylidene)-l-(~-hydroxy-ethyl~piperidine9 m.pO 142-146Co 9 methanesulfonate salt9 mOp. 247-248C.
To a stirred solution of 5.4 g, (0.051 mol) of cyanogen bromide in 30 ml. of benzene at 50C. is added gradually a solution of 14.7 g. (0.0426 mol) of 4-(2-chloro-9-thioxanthenylidene)-1-methylpiperidine in 70 ml. of ben-zene. The solution is heated at 50C. and stirring con-tinued for 1O5 hours. Excess water is added and the solu-tion is extracted with dilute hydrochloric acid. The ben-zene is evaporated in vacuo and the crude cyanamide (14.9 g) is refluxed with 12.4 g. (0.22 mol) of potassium hydroxide in 125 ml. of 70% aqueous ethanol for 24 hours. The reac-tion mixture is evaporated in vacuo, water is added and ?0 extracted with ether. Etheral hydrogen chlorlde is added to form a hydrochloride salt which is then treated with base to liberate 4-(2-chloro-9-thioxanthenylidene)piperi-dine.
A solution of 0.~ g. (0.01 mol) of acetyl chloride in 10 ml. of benzene is added to 6.3 g. (0.02 mol) of the above-prepared piperidine in 30 ml. of benzene and the mix-ture refluxed for one hour. The cooled reaction mixture is extracted with waterg then dilute acetic acid. The organic layer is washed with dilute sodium bicarbonate until neutral and then ~vaporated in vacuo~ The oil residue (intermediate 1055~45 l amide) is dissolved in ether, dried and gradually added to a suspension of 105 g. (0.04 mol) of lithium aluminum hydride in 50 ml~ of etherl The mixture is stirred at room temperature for 24 hours 9 treated cautiously with 2.1 mlO
of water and filtered. The filtrate is treated with ethereal lydrogen chloride to give 4-(2-chloro-9-thioxan-thenylidene)-l-ethylpiperidine hydrochloride9 m.p~ 253C, (dec.)O
Similarly~ 6~3 gO (0.02 mol) of 4-(2-chloro-9-thioxanthenylidene)piperidine in 30 ml. of benzene is treated with a solution of 1.2 g. (0.01 mol) of cyclobutyl-carboxylic acid chloride in 10 ml. of benzene. Following the above workup procedureg the intermediate amide is reduced with 1.5 g. (0.04 mol) of lithium aluminum hydride in 50 ml, of ether. After isolation of the amine productg the ether is evaporated in vacuo and a hexamate salt formed of 4-(2-chloro-9~thioxanthenylidene)-1-cyclobutylmethyl-piperidine, mOp. 180-182Co Following the procedures as described above9 ?0 4-(chloro-9-thioxanthenylidene)piperidine (6~3 g.9 OrO2 mol) in 30 ml. of benzene is reacted with 1.0 g. (0.01 mol) of butyryl chloride in 10 ml. of benzene, followed by reduction of the intermediate amide with 1.5 g. (0.04 mol) of lithium aluminum hydride to yield as a final product, 4-(2-chloro-9 thioxanthenylidene)-l-butylpiperidine hydrochloride9 m.p. 259Co (dec.).
Sodium hydride (1.0 mol) is suspended in about 300 ml. of dimethylformamide and phenol (1.0 mol) in about 200 ml. of dimethylormamide is added dropwise9 keeping ~ 23 ~
lOS5945 1 the reaction temperature around 25C. The mixture is stirred until hydrogen evolution is completed. 6-Chloro-phthalide (1.0 mol) in about 250 ml. of dimethylformamide is then added slowly. The resulting mixture is refluxed for 2 hours and allowed to stand at room temperature overnight.
The reaction mixture is diluted with ice/water and extracted several times with ether. The aqueous fraction is acidified with dilute hydrochloric acid and extracted with etherO
The ether is dried and concentrated to a gummy solid which is recrystalliæed from a minimum volume of alcohol to give 2-phenoxymethyl-5-chlorobenzoic acid9 m~p. 149-155Co A mixture of 1.0 mol. of the above prepared ben-zoic acid~ supercel (570 g.) and xylene (about 2200 ml.) is stirred and about 300 ml. of xylene is distilled off.
After cooling9 570 g. of phosphorus pentoxide is added along with sufficient dry xylene to facilitate stirring. This mixture is stirred at reflux for 17 hours, cooled and fil-teredO The filter cake is washed well with xylene 9 then with ether. The filtrates are combined and concentrated .0 to an oil which crystallizes on trituration with hexane yielding 9-chloro-ll-keto-6911-dihydrodibenzo[bJe]oxepine9 m.p~ 82-83C.
To the Grignard reagent obtained from 4-chloro-N-methylpiperidine (0.70 mol) and magnesium (0,54 mol) in tetrahydrofuran is added 0.38 mol of the above oxepinone in 750 ml~ of tetrahydrofuran at a rate sufficient to main-tain a gentle reflux~ The mixture is refluxed for about 90 minutes and stirred at room temperature overnight. The reaction mixture is poured over ice, treated with ammonium chloride and extracted several times with ether. The lQ5~5~45 l combined ether fractions are dried and concentrated to give 9 chloro~ methyl-4-piperidyl)-6~11-dihydrodibenzo-[b9e]oxepine-11~019 hydrochloride salt9 m.p. 150-160C, The above oxepinol (0.5 mol) is stirred with o~sulfobenzoic anhydride (1O15 mol) and propionic acid ~3400 ml.~O The mixture is heated on a ste~m bath for one hourg cooled9 basified and extracted with methylene chloride. The organic extract i5 dried and concentrated in vacuo to an oil which is chromatographed on silica gel eluted with chloroform. The collected oil crystallizes when triturated with petroleum ether to yield 4-(9-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-methylpiperidine9 mqpO
145-146C.~ hydrochloride salt9 m.p. 289C~ (dec.)O
A solution of cyanogen bromide (14.1 g.g 0.133 mol) in benzene (200 ml) at 35C~ is treated with a solu-tion of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine (31~2 g.9 OolO mol) in benzene (250 mlO) over 15 minutesO
The solution is heated to 55C. for four hours. The sol--~7~ vent is evaporated and the residue is recrystallized from ethanol to give 4-(2-chloro-9-xanthenylidene)-1-cyanopiperi-dine9 mqp~ 148-150C. A solution of the latter (27.2 gO 9 0O084 mol) in glacial acetic acid (450 ml.)9 water (250 ml.) and concentrated hydrochloric acid is refluxed for 18 hours9 and the major portion of the solvent is evapo ated. The residue is basified and extracted with ethylacetate. The extracts are washed with water and the solvent evaporated.
The residue is triturated with ethanol~ filtered and the filtrate is evaporated to leave 4-(2-chloro-9-xanthenyli-dene)piperidine, The free base is dissolved in acetonitrile ~055945 l and treated with one equivalent of methanesulfonic acid to yield 4-(2-chloro-9-xanthenylidene)piperidine methane-sulfonate9 m.pO 256-260Co .
A solution of 4-(2-chloro-9-xanthenylidene)piperi-dine (1.5 gO 9 5 mmol) in 50 ml. of methanol at 0C. is treated with ethylene oxide (5 mlO~. The solution is allowed to come to 23Co 9 then heated to 40C. for one hour and the solvent evaporatedO The residue is dissolved in acetonitrile and treated with one equivalent of methane-sulfonic acid to give 4-(2-chloro-9-xanth~nylidene)-1-(~-hydroxyethyl)-piperidine methanesulfonate9 m.p. 242-244C~
A solution of 4-(2-chloro-4-xanthenylidene)-lS piperidine (3.8 g., 12.8 mmol) and 2 ml. of triethylamine in 75 ml. of benzene is treated with a solution of cyclo-butylcarboxylic acid chloride (1.9 g., 16 mmol) in benzene (25 mlO)O After two hours at 23C. the mixture is washed with water, lN hydrochloric acid and 5% potassium carbonateO
?0 The organic solution is dried and evaporated to leave the intermediate amideO A solution of the amide (4.95 g.) in 75 mlO of ether is added to a stirred slurry of lithium aluminum hydride (3.0 g.) in ether (30 mlO)O ~he mixture is refluxed for six hours and stirred at 23Co for two days~
Excess hydride is decomposed by the cautious addition of 6 ml. of water and 4.8 ml. of 10% sodium hydroxide and the solid is filtered. The filtrate is treated with ethereal hydrogen chloride and the precipitated salt is dissolved in a mixture of water and benzene. The water is separated 9 washed with ether, basifiedg and extracted with ether.
1 The dried extract is evaporated and the residue is chroma-tographed on an alumina column, eluting with ether. The first fraction is evaporated to give 4-(2-chloro-9-xanthen-ylidene)-l-cyclobutylmethylpiperidine. A solution of the free base in acetonitrile is treated with one equivalent of methanesulfonic acid to obtain the methanesulfonate salt9 m.p. 196-l97C.
A mixture of 4-(2-bromo-9-xanthenylidene)-1-methyl-piperidine (7.0 g. 9 19.7 mmol), cuprous cyanide (3.5 g.)~
cupric sulfate pentahydrate (50 mg.) and sodium cyanide (50 mg.) in 60 ml. of dimethylformamide is refluxed for 18 hours. The reaction mixture is poured into 10% aqueous sodium cyanide (500 ml.) and extracted with ether. The extract is washed with 10% aqueous sodium cyanide, water, dried and the solvent is evaporated. The residue is chromatographed on an alumina column, eluting with ether.
The second fraction gives the product as an oil which is dissolved in ethanol and treated with one equivalent of fumaric acid, yielding 4-(2-cyano-9-xanthenylidene) 1-methylpiperidine ~umarate, m.p. 238-241C. (dec.).
A solution of 4-(2-chloro-9-xanthenylidene)piperidine (2.0 g.9 6.75 mmol) in 5 ml. of acetic anhydride is heated on a steam ba~h for 2.5 hours Acetone (30 ml.) and 50 ml.
of 20% aqueous potassium carbonate is added to the cooled solution and the mixture stirred for one hour. Additional water is added and the mixture is extracted with ether.
The extract is washed with lN hydrochloric acid, water and dried. The solvent is evaporated to give the crude amide, 2.2 g. (recrystallized amide m.p. 165-166C.). The amide is dissolved in 500 ml. of ether and added to a 1 stirred suspension of 2.0 g. of lithium aluminum hydride in 200 ml. of ether. After two hours at 23C. excess hydride is decomposed with water (4 ml.) and 10% sodium hydrixode (3.2 ml.). The mixture is filtered and the fil-trate is evaporatedO The residue is dissolved in a mixture of methanol and ether and treated with one equivalent of methanesulfonic acid~ The precipitated salt is filtered and recrystallized from methanol/ether to give 4-(2-chloro-9-xanthenylidene)- l-ethylpiperidine methanesulfonate, m.pO 249-252~C.
A solution of 4-~2-chloro-9-xantherYlidene)-piperidine (3~2 g., 10.8 mmol) and propyliodide (5 ml.) in dimethylformamide (25 ml.) is stirred at 23C. for three hours and at 100C. for one hour. The reaction mixture is diluted with water and extracted with ether. The extract is washed with water, dried and the solvent evaporated.
The residue is chromatographed on an alumina column9 using ether as the eluent. The first fraction gives the product which is con~rerted to the hydrochloride salt: 4-(2-chloro-9-xanthe~ylidene) - l-propylpiperidine hydrochloride, m.pO
238-240~.
A mixture of 4.4 g. of 4-fluoroanthranilic acid in 35 mlO of water and 7 ml. of hydrochloric acid is diazotized with 2.0 g. of sodium nitrite in 6 ml. of water at 0-5C. The resulting cold solution is added dropwise to a mixture of 7.1 g. of potassium iodide, 2 ml. of sul-furic acid and 10 ml. of water. The mixture is heated for two hours to 100C. and steam distilled. The cooled 1055~45 1 residue gives 4-fluoro-~-iodobenzoic acid, m.p. 140-147 C.
A mixture of 4.7 g. of the above prepared benzoic acid9 1.93 g. of thiophenol, 3.62 g. of potassium carbonate and a catalytic amount of copper powder is stirred for one hour with 50 ml. of nitrobenzene at 160-165C. The cooled reaction mixture is poured into 100 mlO of water, strongly acidified9 and extracted with chloroform. The extract is washed with water, decolorized with charcoal and filtered.
The filtrate is extracted with 5% sodium bicarbonate solu-tion. Acidification of the aqueous solution, followed by extraction with ether and subsequent evaporation of the dried extract yields 4-fluoro-2-(phenylthio)benzoic acid9 m.p. 193-200C.
This benzoic acid (3 g.) is heated for one hour on a steam bath with 45 g. of sulfuric acid. The solution is poured onto ice, filtered and the solid is washed with water, then stirred with 5% sodium bicarbonate solution.
The solid is filtered, washed with water and dissolved in chloroform. Evaporation of the dried chloroform solution furnishes 3-fluoro-9-thioxanthone, m.p. 168C.
The Grignard reagent prepared from 0.62 g. of magnesium turnings and 3.5 g. of 4-chloro-N-methylpiperi-dine in tetrahydrofuran is treated with a solution of 3-fluoro-9-thioxanthone (3.0 g.) in 50 ml. of tetrahydro-furan. The mixture is refluxed for four hours, cooled~
treated with saturated ammonium chloride solution and ex-tracted with ether. The ethex extract is washed with water, dried and concentrated to give 3-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 120-130C.
105S9~5 1 The thioxanthene-9-ol (3.2 g.) is dehydrated by refluxing for one hour with 3.68 g. of o-sulfobenzoic anhydride and 60 ml. of propionic acid. The cooled reaction mixture is poured into a mixture of ice and 40% sodium hydroxide solution, then extracted with ether. The dried extract is decolorized with charcoal, concentrated and the residue9 dissolved-in ether, is treated with maleic acid to yield 4-(3-fluoro-9-thioxanthenylidene)-1-methylpiperi-dine maleate, m.p. 162-164C.
Similarly, 2-fluoro-9-thioxanthone (5.0 g.) is reacted with the Grignard reagent derived from 1.06 g. of magnesium turnings and 5.85 g. of 4-chloro-N-methylpiperi-dine in tetrahydrofuran as described above to give the corresponding 2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 189-190C. The latter is dehydrated by the same procedure to obtain 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperidine as the maleate salt, m.p. 175-179C.
To a solution of 1.28 g. (0.01 mol) of p-fluoro-~- thiophenol and 2.82 g. (0.01 mol) of 2-iodo-4-chlorobenzoic acid in 20 ml. of pyridine is added 1.3 g. (0.01 mol) of potassium carbonate, ~ith stirring. Additional pyridine is adde~ until solution is clear and then 0.3 g. of cuprous chloride is introduced. The resulting mixture is refluxed overnight, poured into ice-water, stirred and filtered.
The aqueous solution is acidified and filtered. The solid is dissolved in 5% sodium bicarbonate solution and this solution is extracted with ether. The aqueous solution is acidified, extracted with ether and the washed, dried extract is concentrated to give 4-chloro-2-(4-fluorophenyl-lO5SS~45 1 thio~benzoic acid, m.p. 204-213C. The latter (6.5 g., 0.023 mol) is heated for one hour with 105 g. of sulfuric acid to obtain 2-fluoro-6-chloro-9-thioxanthone, m.p. 222-224C.
The Grignard reagent prepared from 5.9 gO (0.044 mol) of 4-chloro-N-methylpiperidine and l.l g. (0.044 mol) of magnesium turnings in tetrahydrofuran is treated with
In~redients W/V Percenta,~es 4-(2-chloro-9-xanthenylidene)- Equivalent to 20 mg~ of l-methylpiperidine (as a water free base per ml.
soluble acid addition salt) ~odium tartrate Tartaric acid 0,7 Water for parenterals, q.s. 100 The above ingredients are dissolved in an amount of the water equal to approximately 95% of the final volume9 mixed9 heated a~ required~ cooled to room temperature and the re-mainder of water is added. The solution is ~iltered and filled in ampuls.
The capsules or solution prepared as in Examples 1 or 2 are administered internally to an animal requiring antipsychotic activity within the dose ranges set forth hereinabove. Similarly other compounds of formulas I or II
can be formulated in the same manner to give pharmaceutical ?0 compositions useful in the methods of this invention.
To 4.3 g. (0.175 m.) of magnesium turnings just covered with dry tetrahydrofuran at gentle reflux under nitrogen is added l ml. of a tetrahydrofuran solution of the base derived from 29.8 g. (0.175 m.) of 4-chloro-N-methylpiperidine hydrochloride (base in about 50 ml. of tetrahydrofuran). (The base was previously liberated by use of ether, potassium hydroxide pellets9 l ml. of water;
triturating9 extracting with ether and evaporating in vacu-the dried ether solution.) A small amount of ethereal 1 methyl magnesium bromide is added and when the reaction starts the remainder of the base is diluted with about 150 ml. of tetrahydrofuran while stirring. This solution is added dropwise over one-half hour while maintaining low heat and the resulting mixture is refluxed and stirred for one hour. At low reflux 27.0 g. (0.117 m.) of 2-chloro-xanthone is added portionwise with stirring. The reaction mixture is stirred and refluxed for one hour and then quenched on a mixture of ice-water-ammonium chloride to give an oil which solidified. Recrystallization from ethyl acetate gives 2-chloro-9-(1-methyl-4-piperidyl)-xanthene-9-ol, m.p. 206-208C.
A mixture of 12.5 g. (0.038 m.) of the xanthene-9-ol, 14.0 g. (0.76 m.) of o-sulfobenzoic anhydride and 380 ml.
lS of propionic acid is refluxed for three hours. The reaction mixture is heated in vacuo at 100C. and the resulting syrup is dissolved in water, made strongly basic with 40% sodium hydroxide solution, extracted with ether9 and the dried extract is evaporated. The residual free base is dissolved in ethyl acetate and maleic acid (4.4 g.) is added to yield 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine maleate, m.p. 206-207C.
The Grignard reagent from 68 g. (0.4 m.) of 4-chloro-N-methylpiperidine hydrochloride and 9.7 g.
(0.4 m.) of magnesium turnings in a total volume of 250 ml.
of tetrahydrofuran is obtained following the procedure of Example 3. After all the halide is added, 75.6 g. (0.287 m.) of 2-trifluoromethylxanthone is added portionwise and refluxing/stirring are continued for one hour under nitrogen.
1055~45 1 The reaction mixture is quenched on ice-water-ammonium chloride to give 9~ methyl~4-piperidyl) 2-trifluoro-methylxanthene-9-019 m.p~ 179-183CD
Dehydration of the xanthene-9 ol (88.2 gO 9 0.24 mO~ is accompli~hed by refluxing with 88~1 g. (0048 mO7 of sulfobenzoic anhydride and 1O2 lo of propionic acid for two hoursO The reaction mixture is heated in vacuo at 100Co and the residual syrup is dissolved in water and made strongly basic with 40% sodium hydroxide solution.
Extraction with ether gives l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)-piperidine, m.p. 82-83C.
EXAMPLh 5 Following the procedure of Example 39 the Grignard reagent formed from 2O4 gO (0~1 m.) of magnesium and 1303 gD
(0 01 mO) of 4-chloro-N-methylpiperidine is reacted with 1201 g. (0O05 mO) of 2~thiomethylxanthone to give 9-(1-methyl-4-piperidyl)-2~thiomethylxanthene-9-ol9 m.p. 169Co The xanthene-9-ol (10.8 g,9 0~032 m.) thus pre-pared is dehydrated by refluxing with 11.6 gO (00064 mc) of ?0 sulfobenzoic anhydride and 258 mlO of propionic acid.
After work~up of the ~eaction mixture9 extraction with methylene chloride followed by addition of ether precipi~
tates unreacted xanthene-9-ol which is removed by filtra-tion. The filtrate is concentrated to give an oil which is converted in ether to the maleate salt of 1-methyl-4-(2 methylthio-9-xanthenylidene)-piperidine9 mOp. 172-180Co The Grignard reagent prepared from 0O53 g.
(0.0216 mO) of magnesium and 2.9 g. (0.0216 m.) of 4-chloro-N-methylpiperidine is reacted with 2.3 g. (0O0108 mO) 1 of ~-fluoroxanthone as described in Example 3. The reac-tion mixture is heated for four hours and then decomposed with saturated ammonium chloride solution to yield 2-fluoro-9-(l-methyl-4-piperidyl)-xanthene-9-ol9 m.p. 193-200C.
A mixture of 0.58 g. (0.002 m.) of the above pre-pared xanthene-9-ol9 0.34 g. (0.004 m.~ of sulfobenzoic anhydride and 20 mlO of propionic acid is refluxed for about 15 minutes and then stirred without heating until cooled.
The reaction mixture is evaporated in vacuo and the residue is taken up in methylene chloride. The product is treated with maleic acid to afford the maleate salt of 4-(2-fluoro-9-xanthenylidene)-l-methylpiperidine9 m.p. 189-193C.
To a solution of 13.2 g. (0.0318 m.) of 4-(2-chloro-9-thioxanthenylidene)-piperidine in 50 ml. of methan-ol at 50C~ is added a solution of 2.2 g. (0.0383 m.) of ethylene oxide in 30 ml. of methanol over ten minutes and the mixture is refluxed for one and one-half hours. After standing overnight at room temperature9 the reaction mixture is filtered to yield 4-(2-chloro-9-thioxanthenylidene)-1-(~-hydroxyethyl)-piperidine9 m.p. 178-180C.
To a stirred suspension of 2.43 g. (0.1 gO~atom~
of magnesium turnings in 5 ml. of tetrahydrofuran under nitrogen is added several drops of ethyl bromide. After the reaction is started9 13.4 g. (0.1 mole) of 4-chloro-1-methylpiper;dine in 50 ml. of tetrahydrofuran is added at a rate sufficient to cause reflux. The mixture is stirred and refluxed for one hour 9 then it is cooled to 0C~ and 2006 g. (0O075 mole) of 2-bromoxanthone is added in portions~
1055~45 1 The stirred mixture is refluxed for four hours and then it is poured into a solution of 26.5 g. (0.5 mole) of ammonium chloride in 500 ml. of ice-water. The crystalline alcohol 9 2-bromo-9-(1-methyl-4-piperidyl)-xanthene-9-ol~ m.p.
201-2029 is filtered.
The above alcohol 20.0 g~ (0.05~ mole) is dis~
solved in 200 ml. of propionic acid and 20O0 g. (OoOll mole~
of sulfobenzoic anhydrideO The solution is refluxed for one hour, concentrated in vacuo, and then the residue is diluted with waterO The mixture is made alkaline with 2~5 N sodium hydroxide and extracted with ether~ The ether extracts are dried and concentrated to give 4-(2-bromo-9-xanthenylidene)-l-methylpiperidine9 which identified as its maleate salt9 m.p. 206C. ~dec.)O
.. ..
To a stirred solution of 7.0 g. (0.065 mole~ of cyanogen bromide in 150 ml. of benzene at 50-55C. is added 19.5 gO (0.055 mole) of 4-(2-bromo-9-xant~enylidene)-1-methylpiperidine in 150 ml. of benzene. The solution is ~0 heated for 2.5 hours) then it is concentrated in vacuo~
The residue is dissolved in methylene chloride and the solu-tion is washed with lN hydrochloric acid~ water and a saturated aqueous solution of sodium chloride. The organic solution is concentrated to give a semi-crystalline residue which is refluxed for 16 hours with a solution of 225 mlO
of acetic acid and 25 ml. of 12N hydrochloric acid in 125 mlO of water. The solution is concentrated and the residue is dissolved in water. After the solution is made alkaline with sodium hydroxide, the mixture is extracted with ethyl acetateO The extracts are concentrated and a solution of 1 the crystalline residue in acetonitrile is treated with methanesulfonic acid in acetonitrile-ether .o give color-less crystals 9 mOp ~ 257.5-258.5C.9 of 4-(2-bromo-9-xan-thenylidene)piperidine methanesulfonate.
To 102 g. (0O05 mol) of magnesium turnings cover-ed by tetrahydrofuran in an Argon atmosphere is added about 0.5 g. of 4-chloro-N-.nethylpiperidine (from 8.5 g. 9 0~025 mol of the hydrochloride salt) and a small amount of ethyl bromide. The mixture is heated until the reaction is ini-tiated9 the remainder of the chloro compound in about 20 ml.
of tetrahydrofuran is added and the mixture is refluxed for four hours. 2-~romothioxanthone (7.3 g., 0.025 mol) is added and the mixture is refluxed for five hours 3 and then stirred at room temperature three days. The reaction mix-ture is poured into aqueous ammonium chloride and filtered to give 2-bromo-9~ methyl-4-piperidyl)thioxanthene-9-ol 3 m.p. 225.5-226C.
A solution of 4.0 g. (0.0103 mol) of 2-bromo-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol in 20 ml. of con-centrated hydrochloric acid is refluxed for 1.5 hours~ The reaction mixture is evaporated to dryness and redissolved in water. The aqueous solution is washed with ether, basi-fied and extracted with ether. The dried extract is evap-orated and the residue in acetonitrile is treated with methanesulfonic acid to yield 4-(2-bromo-9-thioxanthenyli-dene)-l-methylpiperidine methanesulfonate, m.p. 210-212C.
(dec.~.
To a solution of 4-(2-bromo-9-xanthenylidine)-piperidine (205 g~, 0.0073 mol) in 50 ml. of ethanol9 10555~45 1 cooled to ca 0C. is added excess ethylene oxide (1.1 ml~, 0.022 mol.)O The reaction mixture is kept at 0C. After 30 minutes the ice-bath is removed and after an additional 205 hours9 a thick white precipitate is formed which is filtered to give 4-(2-bromo-9 xanthenylidene)-l-(~-hydroxy-ethyl~piperidine9 m.pO 142-146Co 9 methanesulfonate salt9 mOp. 247-248C.
To a stirred solution of 5.4 g, (0.051 mol) of cyanogen bromide in 30 ml. of benzene at 50C. is added gradually a solution of 14.7 g. (0.0426 mol) of 4-(2-chloro-9-thioxanthenylidene)-1-methylpiperidine in 70 ml. of ben-zene. The solution is heated at 50C. and stirring con-tinued for 1O5 hours. Excess water is added and the solu-tion is extracted with dilute hydrochloric acid. The ben-zene is evaporated in vacuo and the crude cyanamide (14.9 g) is refluxed with 12.4 g. (0.22 mol) of potassium hydroxide in 125 ml. of 70% aqueous ethanol for 24 hours. The reac-tion mixture is evaporated in vacuo, water is added and ?0 extracted with ether. Etheral hydrogen chlorlde is added to form a hydrochloride salt which is then treated with base to liberate 4-(2-chloro-9-thioxanthenylidene)piperi-dine.
A solution of 0.~ g. (0.01 mol) of acetyl chloride in 10 ml. of benzene is added to 6.3 g. (0.02 mol) of the above-prepared piperidine in 30 ml. of benzene and the mix-ture refluxed for one hour. The cooled reaction mixture is extracted with waterg then dilute acetic acid. The organic layer is washed with dilute sodium bicarbonate until neutral and then ~vaporated in vacuo~ The oil residue (intermediate 1055~45 l amide) is dissolved in ether, dried and gradually added to a suspension of 105 g. (0.04 mol) of lithium aluminum hydride in 50 ml~ of etherl The mixture is stirred at room temperature for 24 hours 9 treated cautiously with 2.1 mlO
of water and filtered. The filtrate is treated with ethereal lydrogen chloride to give 4-(2-chloro-9-thioxan-thenylidene)-l-ethylpiperidine hydrochloride9 m.p~ 253C, (dec.)O
Similarly~ 6~3 gO (0.02 mol) of 4-(2-chloro-9-thioxanthenylidene)piperidine in 30 ml. of benzene is treated with a solution of 1.2 g. (0.01 mol) of cyclobutyl-carboxylic acid chloride in 10 ml. of benzene. Following the above workup procedureg the intermediate amide is reduced with 1.5 g. (0.04 mol) of lithium aluminum hydride in 50 ml, of ether. After isolation of the amine productg the ether is evaporated in vacuo and a hexamate salt formed of 4-(2-chloro-9~thioxanthenylidene)-1-cyclobutylmethyl-piperidine, mOp. 180-182Co Following the procedures as described above9 ?0 4-(chloro-9-thioxanthenylidene)piperidine (6~3 g.9 OrO2 mol) in 30 ml. of benzene is reacted with 1.0 g. (0.01 mol) of butyryl chloride in 10 ml. of benzene, followed by reduction of the intermediate amide with 1.5 g. (0.04 mol) of lithium aluminum hydride to yield as a final product, 4-(2-chloro-9 thioxanthenylidene)-l-butylpiperidine hydrochloride9 m.p. 259Co (dec.).
Sodium hydride (1.0 mol) is suspended in about 300 ml. of dimethylformamide and phenol (1.0 mol) in about 200 ml. of dimethylormamide is added dropwise9 keeping ~ 23 ~
lOS5945 1 the reaction temperature around 25C. The mixture is stirred until hydrogen evolution is completed. 6-Chloro-phthalide (1.0 mol) in about 250 ml. of dimethylformamide is then added slowly. The resulting mixture is refluxed for 2 hours and allowed to stand at room temperature overnight.
The reaction mixture is diluted with ice/water and extracted several times with ether. The aqueous fraction is acidified with dilute hydrochloric acid and extracted with etherO
The ether is dried and concentrated to a gummy solid which is recrystalliæed from a minimum volume of alcohol to give 2-phenoxymethyl-5-chlorobenzoic acid9 m~p. 149-155Co A mixture of 1.0 mol. of the above prepared ben-zoic acid~ supercel (570 g.) and xylene (about 2200 ml.) is stirred and about 300 ml. of xylene is distilled off.
After cooling9 570 g. of phosphorus pentoxide is added along with sufficient dry xylene to facilitate stirring. This mixture is stirred at reflux for 17 hours, cooled and fil-teredO The filter cake is washed well with xylene 9 then with ether. The filtrates are combined and concentrated .0 to an oil which crystallizes on trituration with hexane yielding 9-chloro-ll-keto-6911-dihydrodibenzo[bJe]oxepine9 m.p~ 82-83C.
To the Grignard reagent obtained from 4-chloro-N-methylpiperidine (0.70 mol) and magnesium (0,54 mol) in tetrahydrofuran is added 0.38 mol of the above oxepinone in 750 ml~ of tetrahydrofuran at a rate sufficient to main-tain a gentle reflux~ The mixture is refluxed for about 90 minutes and stirred at room temperature overnight. The reaction mixture is poured over ice, treated with ammonium chloride and extracted several times with ether. The lQ5~5~45 l combined ether fractions are dried and concentrated to give 9 chloro~ methyl-4-piperidyl)-6~11-dihydrodibenzo-[b9e]oxepine-11~019 hydrochloride salt9 m.p. 150-160C, The above oxepinol (0.5 mol) is stirred with o~sulfobenzoic anhydride (1O15 mol) and propionic acid ~3400 ml.~O The mixture is heated on a ste~m bath for one hourg cooled9 basified and extracted with methylene chloride. The organic extract i5 dried and concentrated in vacuo to an oil which is chromatographed on silica gel eluted with chloroform. The collected oil crystallizes when triturated with petroleum ether to yield 4-(9-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-methylpiperidine9 mqpO
145-146C.~ hydrochloride salt9 m.p. 289C~ (dec.)O
A solution of cyanogen bromide (14.1 g.g 0.133 mol) in benzene (200 ml) at 35C~ is treated with a solu-tion of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine (31~2 g.9 OolO mol) in benzene (250 mlO) over 15 minutesO
The solution is heated to 55C. for four hours. The sol--~7~ vent is evaporated and the residue is recrystallized from ethanol to give 4-(2-chloro-9-xanthenylidene)-1-cyanopiperi-dine9 mqp~ 148-150C. A solution of the latter (27.2 gO 9 0O084 mol) in glacial acetic acid (450 ml.)9 water (250 ml.) and concentrated hydrochloric acid is refluxed for 18 hours9 and the major portion of the solvent is evapo ated. The residue is basified and extracted with ethylacetate. The extracts are washed with water and the solvent evaporated.
The residue is triturated with ethanol~ filtered and the filtrate is evaporated to leave 4-(2-chloro-9-xanthenyli-dene)piperidine, The free base is dissolved in acetonitrile ~055945 l and treated with one equivalent of methanesulfonic acid to yield 4-(2-chloro-9-xanthenylidene)piperidine methane-sulfonate9 m.pO 256-260Co .
A solution of 4-(2-chloro-9-xanthenylidene)piperi-dine (1.5 gO 9 5 mmol) in 50 ml. of methanol at 0C. is treated with ethylene oxide (5 mlO~. The solution is allowed to come to 23Co 9 then heated to 40C. for one hour and the solvent evaporatedO The residue is dissolved in acetonitrile and treated with one equivalent of methane-sulfonic acid to give 4-(2-chloro-9-xanth~nylidene)-1-(~-hydroxyethyl)-piperidine methanesulfonate9 m.p. 242-244C~
A solution of 4-(2-chloro-4-xanthenylidene)-lS piperidine (3.8 g., 12.8 mmol) and 2 ml. of triethylamine in 75 ml. of benzene is treated with a solution of cyclo-butylcarboxylic acid chloride (1.9 g., 16 mmol) in benzene (25 mlO)O After two hours at 23C. the mixture is washed with water, lN hydrochloric acid and 5% potassium carbonateO
?0 The organic solution is dried and evaporated to leave the intermediate amideO A solution of the amide (4.95 g.) in 75 mlO of ether is added to a stirred slurry of lithium aluminum hydride (3.0 g.) in ether (30 mlO)O ~he mixture is refluxed for six hours and stirred at 23Co for two days~
Excess hydride is decomposed by the cautious addition of 6 ml. of water and 4.8 ml. of 10% sodium hydroxide and the solid is filtered. The filtrate is treated with ethereal hydrogen chloride and the precipitated salt is dissolved in a mixture of water and benzene. The water is separated 9 washed with ether, basifiedg and extracted with ether.
1 The dried extract is evaporated and the residue is chroma-tographed on an alumina column, eluting with ether. The first fraction is evaporated to give 4-(2-chloro-9-xanthen-ylidene)-l-cyclobutylmethylpiperidine. A solution of the free base in acetonitrile is treated with one equivalent of methanesulfonic acid to obtain the methanesulfonate salt9 m.p. 196-l97C.
A mixture of 4-(2-bromo-9-xanthenylidene)-1-methyl-piperidine (7.0 g. 9 19.7 mmol), cuprous cyanide (3.5 g.)~
cupric sulfate pentahydrate (50 mg.) and sodium cyanide (50 mg.) in 60 ml. of dimethylformamide is refluxed for 18 hours. The reaction mixture is poured into 10% aqueous sodium cyanide (500 ml.) and extracted with ether. The extract is washed with 10% aqueous sodium cyanide, water, dried and the solvent is evaporated. The residue is chromatographed on an alumina column, eluting with ether.
The second fraction gives the product as an oil which is dissolved in ethanol and treated with one equivalent of fumaric acid, yielding 4-(2-cyano-9-xanthenylidene) 1-methylpiperidine ~umarate, m.p. 238-241C. (dec.).
A solution of 4-(2-chloro-9-xanthenylidene)piperidine (2.0 g.9 6.75 mmol) in 5 ml. of acetic anhydride is heated on a steam ba~h for 2.5 hours Acetone (30 ml.) and 50 ml.
of 20% aqueous potassium carbonate is added to the cooled solution and the mixture stirred for one hour. Additional water is added and the mixture is extracted with ether.
The extract is washed with lN hydrochloric acid, water and dried. The solvent is evaporated to give the crude amide, 2.2 g. (recrystallized amide m.p. 165-166C.). The amide is dissolved in 500 ml. of ether and added to a 1 stirred suspension of 2.0 g. of lithium aluminum hydride in 200 ml. of ether. After two hours at 23C. excess hydride is decomposed with water (4 ml.) and 10% sodium hydrixode (3.2 ml.). The mixture is filtered and the fil-trate is evaporatedO The residue is dissolved in a mixture of methanol and ether and treated with one equivalent of methanesulfonic acid~ The precipitated salt is filtered and recrystallized from methanol/ether to give 4-(2-chloro-9-xanthenylidene)- l-ethylpiperidine methanesulfonate, m.pO 249-252~C.
A solution of 4-~2-chloro-9-xantherYlidene)-piperidine (3~2 g., 10.8 mmol) and propyliodide (5 ml.) in dimethylformamide (25 ml.) is stirred at 23C. for three hours and at 100C. for one hour. The reaction mixture is diluted with water and extracted with ether. The extract is washed with water, dried and the solvent evaporated.
The residue is chromatographed on an alumina column9 using ether as the eluent. The first fraction gives the product which is con~rerted to the hydrochloride salt: 4-(2-chloro-9-xanthe~ylidene) - l-propylpiperidine hydrochloride, m.pO
238-240~.
A mixture of 4.4 g. of 4-fluoroanthranilic acid in 35 mlO of water and 7 ml. of hydrochloric acid is diazotized with 2.0 g. of sodium nitrite in 6 ml. of water at 0-5C. The resulting cold solution is added dropwise to a mixture of 7.1 g. of potassium iodide, 2 ml. of sul-furic acid and 10 ml. of water. The mixture is heated for two hours to 100C. and steam distilled. The cooled 1055~45 1 residue gives 4-fluoro-~-iodobenzoic acid, m.p. 140-147 C.
A mixture of 4.7 g. of the above prepared benzoic acid9 1.93 g. of thiophenol, 3.62 g. of potassium carbonate and a catalytic amount of copper powder is stirred for one hour with 50 ml. of nitrobenzene at 160-165C. The cooled reaction mixture is poured into 100 mlO of water, strongly acidified9 and extracted with chloroform. The extract is washed with water, decolorized with charcoal and filtered.
The filtrate is extracted with 5% sodium bicarbonate solu-tion. Acidification of the aqueous solution, followed by extraction with ether and subsequent evaporation of the dried extract yields 4-fluoro-2-(phenylthio)benzoic acid9 m.p. 193-200C.
This benzoic acid (3 g.) is heated for one hour on a steam bath with 45 g. of sulfuric acid. The solution is poured onto ice, filtered and the solid is washed with water, then stirred with 5% sodium bicarbonate solution.
The solid is filtered, washed with water and dissolved in chloroform. Evaporation of the dried chloroform solution furnishes 3-fluoro-9-thioxanthone, m.p. 168C.
The Grignard reagent prepared from 0.62 g. of magnesium turnings and 3.5 g. of 4-chloro-N-methylpiperi-dine in tetrahydrofuran is treated with a solution of 3-fluoro-9-thioxanthone (3.0 g.) in 50 ml. of tetrahydro-furan. The mixture is refluxed for four hours, cooled~
treated with saturated ammonium chloride solution and ex-tracted with ether. The ethex extract is washed with water, dried and concentrated to give 3-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 120-130C.
105S9~5 1 The thioxanthene-9-ol (3.2 g.) is dehydrated by refluxing for one hour with 3.68 g. of o-sulfobenzoic anhydride and 60 ml. of propionic acid. The cooled reaction mixture is poured into a mixture of ice and 40% sodium hydroxide solution, then extracted with ether. The dried extract is decolorized with charcoal, concentrated and the residue9 dissolved-in ether, is treated with maleic acid to yield 4-(3-fluoro-9-thioxanthenylidene)-1-methylpiperi-dine maleate, m.p. 162-164C.
Similarly, 2-fluoro-9-thioxanthone (5.0 g.) is reacted with the Grignard reagent derived from 1.06 g. of magnesium turnings and 5.85 g. of 4-chloro-N-methylpiperi-dine in tetrahydrofuran as described above to give the corresponding 2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 189-190C. The latter is dehydrated by the same procedure to obtain 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperidine as the maleate salt, m.p. 175-179C.
To a solution of 1.28 g. (0.01 mol) of p-fluoro-~- thiophenol and 2.82 g. (0.01 mol) of 2-iodo-4-chlorobenzoic acid in 20 ml. of pyridine is added 1.3 g. (0.01 mol) of potassium carbonate, ~ith stirring. Additional pyridine is adde~ until solution is clear and then 0.3 g. of cuprous chloride is introduced. The resulting mixture is refluxed overnight, poured into ice-water, stirred and filtered.
The aqueous solution is acidified and filtered. The solid is dissolved in 5% sodium bicarbonate solution and this solution is extracted with ether. The aqueous solution is acidified, extracted with ether and the washed, dried extract is concentrated to give 4-chloro-2-(4-fluorophenyl-lO5SS~45 1 thio~benzoic acid, m.p. 204-213C. The latter (6.5 g., 0.023 mol) is heated for one hour with 105 g. of sulfuric acid to obtain 2-fluoro-6-chloro-9-thioxanthone, m.p. 222-224C.
The Grignard reagent prepared from 5.9 gO (0.044 mol) of 4-chloro-N-methylpiperidine and l.l g. (0.044 mol) of magnesium turnings in tetrahydrofuran is treated with
5.8 g. tO.022 mol) of the above-prepared thioxanthone. The mixture is refluxed for four hours and worked up by the usual procedure to yield 6-chloro-2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 133-142C.
Dehydration is accomplished by heating 6.4 g.
(0.018 mol) of the above thioxanthene-9-ol for one hour with 6.5 g. (0.035 mol) of o-sulfobenzoic anhydride in 100 ml. of propionic acid. Workup of the reaction mixture affords 4-(6-chloro-2-fluoro-9-thioxanthenylidene~ l-methyl-piperidine, isolated as the hydrochloride salt, m.p. 264-265C.
~ Following the procedures outlined in Example 21, 10.7 g. (0.038 mol) of 2-iodo-4-chlorbenzoic acidg 4~3 g.
(0.038 mol) of 4-fluorophenol 5.25 g. (0.038 mol) of potassium carbonate and 1.14 g. of cuprous chloride in 180 ml. of pyridine are heated under reflux overnight to give upon workup 4-chloro-2-(4-fluorophenoxy)-benzoic acid9 154-173C. Heating the acid (5.0 g., 0.019 mol) for one hour with 75 g. of sulfuric acid yields the corresponding 2-fluoro-6-chloro-9-xanthone, m.p. 210C.
Reaction of the xanthone (4.9 g. J 0.0197 mol) with the Grignard reagent derived from 5.3 g. (0.039 mol) 1 Of 4-chloro-N-methylpiperidine and 0.95 g. (0.039 mol)Mg in tetrahydrofuran furnishes upon workup 6-chloro-2-fluoro-9-(1-methyl-4-piperidyl)-xanthene-9-ol, m.p. 107-127C.
The xanthene-9-ol (1.7 g., 0.0049 mol) is dehy-drated by heating for one hour with o-sulfobenzoic anhy-dride (1.8 g. 9 0.0098 mol) in 35 mlO of propionic acid.
The product is isolated as its hydrochloride sal~9 4-(6-chloro-2-fluoro-9-xanthenylidene)-1-methylpiperidine hydro-chloride, m.pO 235~.
To a solution of 3.28 g. (0.0256 mol) of p-fluoro thiophenol and 6.8 g. (0.0256 mol) of 2-iodo-4-fluoroben-zoic acid in 40 ml. of pyridine is added 3.54 g. (0.0256 mol) of potassium carbonate at room temperature with stirring. Additional pyridine is added to dissolve the precipitate and then 1.54 g. of cuprous chloride is added.
The mixture is refluxed overnight, cooled, poured into ice-water, stirred and filtered. The aqueous solution is acidified, filtered and the solid dissolved in 5% sodium bicarbonate solution, then extracted with ether. The aqueous solution is acidified, extracted with ether 9 and the dried extract is concentrated to give 4-fluoro-2-(4-fluorophenylthio)benzoic acid, m.p. 209-218C. The latter (3.0 g., 0O0113 mol) is cyclized by heating for one hour with 45 g. of concentrated sulfuric acid to obtain 2,6-difluorothioxanthone, m.p. 205-210C.
The Grignard reagent prepared from 2.7 g. (0.02 mol) of 4-chloro-N-methylpiperidine and 0.5 g. (0.02 mol) of magnesium turnings in tetrahydrofuran is treated with 2.5 g. (0.01 mol) of 2,6-difluorothioxanthone at a rate ~O5 ~ 45 1 to maintain slow reflux. The mixture is refluxed for 8iX
hours, hydrolyzed with saturated ammonium chloride solution and extracted with ether to yield 2,6-difluoro-9~ methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 207-209C~
The thioxanthene-9-ol (2.6 g.g 0.0075 mol) pre-pared as above is heated with 2.8 g. (0.015 mol) of o-sulfo-benzoic anhydride in 80 mlO of propionic acid. The product is isolated by the usual procedure to give 4-(2,6-difluoro-9-thioxanthenylidene)-1-methylpiperidine, m.p. 120-123C.
Sodium hydride (0.1 mol) is suspended in 60 ml.
of dry dimethylformamide and 0.1 mol of 3-chlorophenol in about 60 ml. of dimethylformamide is added dropwise main-taining the temperature at 25C. When hydrogen evolution is completed, 0.1 mol of phthalide in about 60 ml. of dimethylformamide is added slowly at 25C. The mixture is refluxed for two hours, stirred at room temperature over-night, poured into ice-water and extracted with ether. The aqueous fraction is acidified with concentrated hydrochloric acid and extracted with ether. The combined ether fraction is dried and concentrated to give 2-(3-chlorophenoxymethyl) benzoic acid, m.p. 154-155C.
Following the procedure of Example 13, the above prepared benzoic acid is cyclized with phosphorus pentoxide in xylene to furnish 3-chloro-11-keto-6,11-dihydrodibenz-[bge]oxepine, m.p. 105-106C.
To the Grignard reagent prepared from 0.54 mol of magnesium and 0.7 mol of 4-chloro-N-methylpiperidine in tetrahydrofuran is added 0.38 mol of the ll-keto dibenzo-xepine prepared above in tetrahydrofuran. The mixture is ~5~.~45 1 refluxed three hours, stirred at room temperature over-nightJ poured into ice-water, treated with ammonium chloride and extracted with ether. The ether extract is dried and concentrated in vacuo to yield 3-chloro~ (1-r,lethyl-4-piperidyl)-6911-dihydrodibenz[b9e]oxepine-ll-ol 9 m~p~ 199-200C.
A mixture of 0.1 mol of the above oxepinol and 0.2 mol of o-sulfobenzoic anhydride in about 1200 ml. of propionic acid is stirred on a steambath for about 45 min-utes. Thè cooled reaction mixture is poured over ice~
basified with 30% sodium hydroxide solution and extracted with chloroform. The dried extract is concentrated to give 4-(3-chloro-11(6H)-dibenz[b,e]oxepinylidene)-l-methylpiperi-dine, m.p. 113-116C.
EXAMPLÆ 25 A mixture of 5.0 g. (13.5 mmol) of 4-(2-bromo-9-thioxanthenylidene)-l-methylpiperidine (prepared as in Example 10) and 2.42 g. (27 mmol) of cuprous cyanide in 30 ml. of dimethylformamide is refluxed with stirring for 18 hours. The reaction mixture is poured into 10% aqueous sodium cyànide and extracted with ether. The extract is washed with water, dried and the solvent evaporated. The residue is chromatographed over an alumina column using ether as the eluent. The first fraction is evaporated9 the residue is dissolved in ethanol and the solution is treated with one equivalent of fumaric acid to precipitate 4-(2-cyano-9-thioxanthenylidene)-1-methylpiperidine fumarate salt, m.p. 211-215C.
A solution of 3.5 g. (11.8 mmol) of 4-(2-chloro-9-xanthenylidene)piperidine (prepar~d as in Example 14) 9 ~05~945 l 2.0 g. (13.4 mmol) of 3-bromo-1-propanol and 50 mg. of potassium iodide in 50 ml. of dimethylformamide is stirred at 23C. for 18 hours and 100C. for 12 hours. The reaction mixture is poured into water, basified and extracted with a mixture of ether and ethyl acetate. The extract is washed with water~ dried and the solvent evaporated. The residue is chromatographed on an alumina column using ethyl acetate-ether 1:1 as the eluent. The first fraction yields the product which is treated with ethereal hydrogen chloride to give 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl)-piperidine hydrochloride, m.p. 255-258C.
A mixture of 2.0g. (0.0058 mol) of 4-(2-bromo-9-xanthenylidene)piperidine (prepared as in Example 9), 0.89 g. (0.70 ml., 0.0065`mol) of n-butyl bromide and a few crystals of potassium iodide in 15 ml. of dimethylform-amide is heated at 90-95C. for 2.5 hours under argon. The reaction mixture is poured into water, basified with sodium carbonate and extracted with ether. The extract is washed ~0 with water, dried and evaporated to an oil which is chromatographed ovei alumina with chloroform to give an oil which is converted to a methanesulfonic acid salt of the product 4-(2-bromo-9-xanthenylidene)-1-n-butylpiperi-dine, m.p. l99-200C.
To a solution of 18.6 g. (0.176 mol) of cyanogen bromide in 200 ml. of dry benzene at 50C. is added gradu-ally over four hours a solution of 57.9 g. (0.168 mol) of l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)piperidine.
The reaction mixture is heated and stirred for 1.5 hours, ~ OS 59 4 S
1 excess water is added and the benzene solution is extracted with excess dilute acetic acid. The acetic acid extract is washed with water and the benzene solution is evaporated to give the l-cyano intermediate. The latter (20 g. 9 0.0561 mol) is refluxed for 18 hours with a solution of 420 ml. of acetic acid9 280 ml. of water and 42 ml. of concentrated hydrochloric acid.- The reaction mixture is concentrated in vacuo to about 125 ml., diluted with 400 ml. of water and extracted with ether. The aqueous layer is basified with excess sodium hydroxide solution and the mixture is ex-tracted with ether. Concentration of the ether extract yields 4-(2-trifluoromethyl-9-xanthenylidene)piperidine.
A mixture of 4.0 g. (0.0121 mol) of the above prepared piperidine and 15 ml. of butyric anhydride is re-fluxed 2-3 hours. The reaction mixture is cooled, washed and stirred with an excess of 20% aqueous potassium car-bonate-acetone for three hours. This mixture is extracted with ether and azeotroped with toluene. The crude amide (5.0 g.) is dissolved in 30 ml. of ether and gradually added to 0.9 g. (0.025 mol) of lithium aluminum hydride in 100 ml. of ether, with stirring. The mixture is stirred at room temperature over~ight, decomposed with 1.8 ml. of water added slowly and filtered. The solid is treated with ethereal hydrogen chloride to give l-n-butyl-4-(2-trifluoro-methyl-9-xanthenylidene)piperidine hydrochlorideJ
m.p. 251-252C.
A solution of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine in acetonitrile is treated with one equivalent of methanesulfonic acid to give the corresponding methanesulfonate salt, m.p. 225-228C.
Dehydration is accomplished by heating 6.4 g.
(0.018 mol) of the above thioxanthene-9-ol for one hour with 6.5 g. (0.035 mol) of o-sulfobenzoic anhydride in 100 ml. of propionic acid. Workup of the reaction mixture affords 4-(6-chloro-2-fluoro-9-thioxanthenylidene~ l-methyl-piperidine, isolated as the hydrochloride salt, m.p. 264-265C.
~ Following the procedures outlined in Example 21, 10.7 g. (0.038 mol) of 2-iodo-4-chlorbenzoic acidg 4~3 g.
(0.038 mol) of 4-fluorophenol 5.25 g. (0.038 mol) of potassium carbonate and 1.14 g. of cuprous chloride in 180 ml. of pyridine are heated under reflux overnight to give upon workup 4-chloro-2-(4-fluorophenoxy)-benzoic acid9 154-173C. Heating the acid (5.0 g., 0.019 mol) for one hour with 75 g. of sulfuric acid yields the corresponding 2-fluoro-6-chloro-9-xanthone, m.p. 210C.
Reaction of the xanthone (4.9 g. J 0.0197 mol) with the Grignard reagent derived from 5.3 g. (0.039 mol) 1 Of 4-chloro-N-methylpiperidine and 0.95 g. (0.039 mol)Mg in tetrahydrofuran furnishes upon workup 6-chloro-2-fluoro-9-(1-methyl-4-piperidyl)-xanthene-9-ol, m.p. 107-127C.
The xanthene-9-ol (1.7 g., 0.0049 mol) is dehy-drated by heating for one hour with o-sulfobenzoic anhy-dride (1.8 g. 9 0.0098 mol) in 35 mlO of propionic acid.
The product is isolated as its hydrochloride sal~9 4-(6-chloro-2-fluoro-9-xanthenylidene)-1-methylpiperidine hydro-chloride, m.pO 235~.
To a solution of 3.28 g. (0.0256 mol) of p-fluoro thiophenol and 6.8 g. (0.0256 mol) of 2-iodo-4-fluoroben-zoic acid in 40 ml. of pyridine is added 3.54 g. (0.0256 mol) of potassium carbonate at room temperature with stirring. Additional pyridine is added to dissolve the precipitate and then 1.54 g. of cuprous chloride is added.
The mixture is refluxed overnight, cooled, poured into ice-water, stirred and filtered. The aqueous solution is acidified, filtered and the solid dissolved in 5% sodium bicarbonate solution, then extracted with ether. The aqueous solution is acidified, extracted with ether 9 and the dried extract is concentrated to give 4-fluoro-2-(4-fluorophenylthio)benzoic acid, m.p. 209-218C. The latter (3.0 g., 0O0113 mol) is cyclized by heating for one hour with 45 g. of concentrated sulfuric acid to obtain 2,6-difluorothioxanthone, m.p. 205-210C.
The Grignard reagent prepared from 2.7 g. (0.02 mol) of 4-chloro-N-methylpiperidine and 0.5 g. (0.02 mol) of magnesium turnings in tetrahydrofuran is treated with 2.5 g. (0.01 mol) of 2,6-difluorothioxanthone at a rate ~O5 ~ 45 1 to maintain slow reflux. The mixture is refluxed for 8iX
hours, hydrolyzed with saturated ammonium chloride solution and extracted with ether to yield 2,6-difluoro-9~ methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 207-209C~
The thioxanthene-9-ol (2.6 g.g 0.0075 mol) pre-pared as above is heated with 2.8 g. (0.015 mol) of o-sulfo-benzoic anhydride in 80 mlO of propionic acid. The product is isolated by the usual procedure to give 4-(2,6-difluoro-9-thioxanthenylidene)-1-methylpiperidine, m.p. 120-123C.
Sodium hydride (0.1 mol) is suspended in 60 ml.
of dry dimethylformamide and 0.1 mol of 3-chlorophenol in about 60 ml. of dimethylformamide is added dropwise main-taining the temperature at 25C. When hydrogen evolution is completed, 0.1 mol of phthalide in about 60 ml. of dimethylformamide is added slowly at 25C. The mixture is refluxed for two hours, stirred at room temperature over-night, poured into ice-water and extracted with ether. The aqueous fraction is acidified with concentrated hydrochloric acid and extracted with ether. The combined ether fraction is dried and concentrated to give 2-(3-chlorophenoxymethyl) benzoic acid, m.p. 154-155C.
Following the procedure of Example 13, the above prepared benzoic acid is cyclized with phosphorus pentoxide in xylene to furnish 3-chloro-11-keto-6,11-dihydrodibenz-[bge]oxepine, m.p. 105-106C.
To the Grignard reagent prepared from 0.54 mol of magnesium and 0.7 mol of 4-chloro-N-methylpiperidine in tetrahydrofuran is added 0.38 mol of the ll-keto dibenzo-xepine prepared above in tetrahydrofuran. The mixture is ~5~.~45 1 refluxed three hours, stirred at room temperature over-nightJ poured into ice-water, treated with ammonium chloride and extracted with ether. The ether extract is dried and concentrated in vacuo to yield 3-chloro~ (1-r,lethyl-4-piperidyl)-6911-dihydrodibenz[b9e]oxepine-ll-ol 9 m~p~ 199-200C.
A mixture of 0.1 mol of the above oxepinol and 0.2 mol of o-sulfobenzoic anhydride in about 1200 ml. of propionic acid is stirred on a steambath for about 45 min-utes. Thè cooled reaction mixture is poured over ice~
basified with 30% sodium hydroxide solution and extracted with chloroform. The dried extract is concentrated to give 4-(3-chloro-11(6H)-dibenz[b,e]oxepinylidene)-l-methylpiperi-dine, m.p. 113-116C.
EXAMPLÆ 25 A mixture of 5.0 g. (13.5 mmol) of 4-(2-bromo-9-thioxanthenylidene)-l-methylpiperidine (prepared as in Example 10) and 2.42 g. (27 mmol) of cuprous cyanide in 30 ml. of dimethylformamide is refluxed with stirring for 18 hours. The reaction mixture is poured into 10% aqueous sodium cyànide and extracted with ether. The extract is washed with water, dried and the solvent evaporated. The residue is chromatographed over an alumina column using ether as the eluent. The first fraction is evaporated9 the residue is dissolved in ethanol and the solution is treated with one equivalent of fumaric acid to precipitate 4-(2-cyano-9-thioxanthenylidene)-1-methylpiperidine fumarate salt, m.p. 211-215C.
A solution of 3.5 g. (11.8 mmol) of 4-(2-chloro-9-xanthenylidene)piperidine (prepar~d as in Example 14) 9 ~05~945 l 2.0 g. (13.4 mmol) of 3-bromo-1-propanol and 50 mg. of potassium iodide in 50 ml. of dimethylformamide is stirred at 23C. for 18 hours and 100C. for 12 hours. The reaction mixture is poured into water, basified and extracted with a mixture of ether and ethyl acetate. The extract is washed with water~ dried and the solvent evaporated. The residue is chromatographed on an alumina column using ethyl acetate-ether 1:1 as the eluent. The first fraction yields the product which is treated with ethereal hydrogen chloride to give 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl)-piperidine hydrochloride, m.p. 255-258C.
A mixture of 2.0g. (0.0058 mol) of 4-(2-bromo-9-xanthenylidene)piperidine (prepared as in Example 9), 0.89 g. (0.70 ml., 0.0065`mol) of n-butyl bromide and a few crystals of potassium iodide in 15 ml. of dimethylform-amide is heated at 90-95C. for 2.5 hours under argon. The reaction mixture is poured into water, basified with sodium carbonate and extracted with ether. The extract is washed ~0 with water, dried and evaporated to an oil which is chromatographed ovei alumina with chloroform to give an oil which is converted to a methanesulfonic acid salt of the product 4-(2-bromo-9-xanthenylidene)-1-n-butylpiperi-dine, m.p. l99-200C.
To a solution of 18.6 g. (0.176 mol) of cyanogen bromide in 200 ml. of dry benzene at 50C. is added gradu-ally over four hours a solution of 57.9 g. (0.168 mol) of l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)piperidine.
The reaction mixture is heated and stirred for 1.5 hours, ~ OS 59 4 S
1 excess water is added and the benzene solution is extracted with excess dilute acetic acid. The acetic acid extract is washed with water and the benzene solution is evaporated to give the l-cyano intermediate. The latter (20 g. 9 0.0561 mol) is refluxed for 18 hours with a solution of 420 ml. of acetic acid9 280 ml. of water and 42 ml. of concentrated hydrochloric acid.- The reaction mixture is concentrated in vacuo to about 125 ml., diluted with 400 ml. of water and extracted with ether. The aqueous layer is basified with excess sodium hydroxide solution and the mixture is ex-tracted with ether. Concentration of the ether extract yields 4-(2-trifluoromethyl-9-xanthenylidene)piperidine.
A mixture of 4.0 g. (0.0121 mol) of the above prepared piperidine and 15 ml. of butyric anhydride is re-fluxed 2-3 hours. The reaction mixture is cooled, washed and stirred with an excess of 20% aqueous potassium car-bonate-acetone for three hours. This mixture is extracted with ether and azeotroped with toluene. The crude amide (5.0 g.) is dissolved in 30 ml. of ether and gradually added to 0.9 g. (0.025 mol) of lithium aluminum hydride in 100 ml. of ether, with stirring. The mixture is stirred at room temperature over~ight, decomposed with 1.8 ml. of water added slowly and filtered. The solid is treated with ethereal hydrogen chloride to give l-n-butyl-4-(2-trifluoro-methyl-9-xanthenylidene)piperidine hydrochlorideJ
m.p. 251-252C.
A solution of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine in acetonitrile is treated with one equivalent of methanesulfonic acid to give the corresponding methanesulfonate salt, m.p. 225-228C.
Claims (9)
1. A process for the preparation of a compound represented by one of the formulas:
FORMULA I FORMULA II
wherein, for formula I:
when Y represents oxygen, X is 2-chloro, 2-fluoro, 2-bromo, 2-thiomethyl or 2-cyano, Z is hydrogen and R is methyl;
when Y represents oxygen, X is 2-fluoro, Z is 6-chloro and R is methyl;
when Y represents oxygen, X is 2-chloro, Z is hydrogen and R is hydrogen, ethyl, .beta.-hydroxyethyl, n-propyl or 3-hydroxypropyl;
when Y represents oxygen, X is 2-bromo, Z is hydrogen and R is hydrogen, .beta.-hydroxyethyl or n-butyl, when Y represents oxygen, X is 2-trifluoromethyl, Z is hydrogen and R is n-butyl;
when Y represents sulfur, X is 2-cyano, Z is hydrogen and R is methyl; and for formula II:
when X is hydrogen, Z is 9-chloro, which com-prises reacting a substituted 9-xanthone, 9-thioxanthone or dibenzoxepin-11-one with an N-methylpiperidyl magnesium halide and dehydrating the carbinol intermediate formed, and to prepare the compounds of formula I where R is other than methyl, reacting the N-methylpiperidylidene derivative with cyanogen bromide, treating the N-cyanamide with acid to give the N-unsubsti-tuted derivative and N-alkylating with:
a) an alkyl bromide;
b) an acyl chloride followed by reduction of the amide; or c) ethylene oxide.
FORMULA I FORMULA II
wherein, for formula I:
when Y represents oxygen, X is 2-chloro, 2-fluoro, 2-bromo, 2-thiomethyl or 2-cyano, Z is hydrogen and R is methyl;
when Y represents oxygen, X is 2-fluoro, Z is 6-chloro and R is methyl;
when Y represents oxygen, X is 2-chloro, Z is hydrogen and R is hydrogen, ethyl, .beta.-hydroxyethyl, n-propyl or 3-hydroxypropyl;
when Y represents oxygen, X is 2-bromo, Z is hydrogen and R is hydrogen, .beta.-hydroxyethyl or n-butyl, when Y represents oxygen, X is 2-trifluoromethyl, Z is hydrogen and R is n-butyl;
when Y represents sulfur, X is 2-cyano, Z is hydrogen and R is methyl; and for formula II:
when X is hydrogen, Z is 9-chloro, which com-prises reacting a substituted 9-xanthone, 9-thioxanthone or dibenzoxepin-11-one with an N-methylpiperidyl magnesium halide and dehydrating the carbinol intermediate formed, and to prepare the compounds of formula I where R is other than methyl, reacting the N-methylpiperidylidene derivative with cyanogen bromide, treating the N-cyanamide with acid to give the N-unsubsti-tuted derivative and N-alkylating with:
a) an alkyl bromide;
b) an acyl chloride followed by reduction of the amide; or c) ethylene oxide.
2. The process according to claim 1 in which the reaction with an N-methylpiperidyl magnesium halide is carried out in an inert organic solvent at from room temperature to the reflux temperature of the solvent for from 30 minutes to 4 hours.
3. The process according to claim 1 in which the carbinol intermediate is dehydrated under acid or thermal conditions.
4. The process according to claim 1 in which the products are converted to a nontoxic pharmaceutically acceptable acid addition salt.
5. The process for the preparation of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine which comprises reacting 2-chloro-9-xanthone with N-methylpiperidyl mag-nesium chloride and dehydrating the intermediate 2-chloro-9-(1-methyl-4-piperidyl)-xanthene-9-ol by heating with o-sulfobenzoic anhydride and propionic acid.
6. The process according to claim 5 in which the product is treated with methanesulfonic acid to give the corresponding methanesulfonate salt.
7. A compound represented by one of the for-mulas:
FORMULA I FORMULA II
wherein, for formula I:
when Y represents oxygen, X is 2-chloro, 2-fluoro, 2-bromo, 2-thiomethyl or 2-cyano, Z is hydrogen and R is methyl;
when Y represents oxygen, X is 2-fluoro, Z is 6-chloro and R is methyl;
when Y represents oxygen, X is 2-chloro, Z is hydrogen and R is hydrogen, ethyl, .beta.-hydroxyethyl, n-propyl or 3-hydroxypropyl;
when Y represents oxygen, X is 2-bromo, Z is hydrogen and R is hydrogen, .beta.-hydroxyethyl or n-butyl;
when Y represents oxygen, X is 2-trifluoromethyl, Z is hydrogen and R is n-butyl;
when Y represents sulfur, X is 2-cyano, Z is hydrogen and R is methyl; and for formula II:
when X is hydrogen, Z is 9-chloro, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
FORMULA I FORMULA II
wherein, for formula I:
when Y represents oxygen, X is 2-chloro, 2-fluoro, 2-bromo, 2-thiomethyl or 2-cyano, Z is hydrogen and R is methyl;
when Y represents oxygen, X is 2-fluoro, Z is 6-chloro and R is methyl;
when Y represents oxygen, X is 2-chloro, Z is hydrogen and R is hydrogen, ethyl, .beta.-hydroxyethyl, n-propyl or 3-hydroxypropyl;
when Y represents oxygen, X is 2-bromo, Z is hydrogen and R is hydrogen, .beta.-hydroxyethyl or n-butyl;
when Y represents oxygen, X is 2-trifluoromethyl, Z is hydrogen and R is n-butyl;
when Y represents sulfur, X is 2-cyano, Z is hydrogen and R is methyl; and for formula II:
when X is hydrogen, Z is 9-chloro, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
8. The compound 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine, whenever prepared by the process of claim 5 or an obvious chemical equivalent thereof.
9. The compound 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine methanesulfonate, whenever prepared by the process of claim 6 or an obvious chemical equivalent thereof.
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| FR2357251A1 (en) * | 1976-07-09 | 1978-02-03 | Merck & Co Inc | Carboxy-thioxanthenylidene-piperidine - useful as appetite stimulants and antiallergics |
| US4073912A (en) * | 1976-10-12 | 1978-02-14 | Smithkline Corporation | Piperidylidene derivatives of benzo-fused xanthenes, thioxanthenes and dibenzoxepins and antipsychotic use thereof |
| US4089961A (en) * | 1976-11-08 | 1978-05-16 | Smithkline Corporation | Antipsychotically useful quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins |
| NZ189108A (en) * | 1977-12-29 | 1982-02-23 | Kefalas As | 2-methylthio-6-fluoro-9-(1-methyl-4-piperidylidene)-thioxanthene and pharmaceutical compositions intermediate 2-methylthio-6-fluoro-9-(1-methyl-4-piperidyl)-thioxanthen-9-ol |
| US4777177A (en) * | 1984-10-19 | 1988-10-11 | Ciba-Geigy Corporation | Pesticidal thioxanthen-9-ylidenepiperidines |
| US5250681A (en) * | 1988-06-02 | 1993-10-05 | Ajinomoto Co., Inc. | Piperidine derivatives and hypotensives containing the same |
| CA2004211A1 (en) * | 1988-11-30 | 1990-05-31 | Masataka Syoji | Piperidine derivatives and hyportensives containing the same |
| EP1306376A1 (en) * | 2001-10-25 | 2003-05-02 | Biofrontera Pharmaceuticals AG | Derivatives of 4-(thio- or selenoxanthene-9-ylidene)-piperidine or acridine and its use as a selective 5-HT2B receptor antagonist |
| US7060711B2 (en) | 2001-10-25 | 2006-06-13 | Biofrontera Bioscience Gmbh | Derivatives of 4-(thio- or selenoxanthene-9-ylidene)-piperidine or acridine and its use as a selective 5-HT2B receptor antagonist |
| JP4810423B2 (en) * | 2003-06-27 | 2011-11-09 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Tricyclic delta opioid regulator |
| WO2007030089A1 (en) | 2004-08-05 | 2007-03-15 | Janssen Pharmaceutica N.V. | Tricyclic delta- opioid modulators |
| BRPI0519201A2 (en) | 2004-12-22 | 2008-12-30 | Janssen Pharmaceutica Nv | tricyclic delta-opioid modulators |
| WO2006069276A2 (en) | 2004-12-22 | 2006-06-29 | Janssen Pharmaceutica N.V. | TRICYCLIC ō-OPIOID MODULATORS |
| EP1836196A1 (en) * | 2004-12-22 | 2007-09-26 | Janssen Pharmaceutica N.V. | Tricyclic delta-opioid modulators |
| JP2008526878A (en) | 2005-01-06 | 2008-07-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Tricyclic δ-opioid regulator |
| DE602006018604D1 (en) | 2005-06-16 | 2011-01-13 | Janssen Pharmaceutica Nv | TRICYCLIC OPIOID MODULATORS |
| AU2007301145B2 (en) * | 2006-09-29 | 2012-12-13 | Nippon Zoki Pharmaceutical Co., Ltd. | Oxepin derivative |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL260070A (en) * | 1960-02-25 | |||
| NL283292A (en) * | 1961-09-29 | |||
| DE1670118A1 (en) * | 1966-07-22 | 1970-11-05 | Boehringer Mannheim Gmbh | Process for the preparation of new derivatives of 6,11-dihydro-dibenz [b, e] oxepins and their salts |
| US3470188A (en) * | 1967-01-05 | 1969-09-30 | Smithkline Corp | 9-cycloalkyl-lower alkyl-piperidylidene derivatives of xanthenes and thioxanthenes |
| JPS5018478A (en) * | 1973-05-17 | 1975-02-26 |
-
1975
- 1975-10-16 ZA ZA00756550A patent/ZA756550B/en unknown
- 1975-10-31 AU AU86247/75A patent/AU498298B2/en not_active Expired
- 1975-10-31 CA CA238,781A patent/CA1055945A/en not_active Expired
- 1975-11-02 IL IL48400A patent/IL48400A/en unknown
- 1975-11-03 NZ NZ179139A patent/NZ179139A/en unknown
- 1975-11-03 HU HU75SI1494A patent/HU174639B/en not_active IP Right Cessation
- 1975-11-03 PH PH17733A patent/PH12158A/en unknown
- 1975-11-04 DK DK495775AA patent/DK139429B/en not_active IP Right Cessation
- 1975-11-04 IE IE2398/75A patent/IE42137B1/en unknown
- 1975-11-04 LU LU73714A patent/LU73714A1/xx unknown
- 1975-11-04 BE BE161500A patent/BE835224A/en not_active IP Right Cessation
- 1975-11-04 FR FR7533631A patent/FR2290202A1/en active Granted
- 1975-11-05 ES ES442357A patent/ES442357A1/en not_active Expired
- 1975-11-05 NL NL7512974A patent/NL7512974A/en not_active Application Discontinuation
- 1975-11-05 CH CH1432175A patent/CH624403A5/en not_active IP Right Cessation
- 1975-11-05 JP JP50133564A patent/JPS5826754B2/en not_active Expired
- 1975-11-06 DE DE19752549841 patent/DE2549841A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DK495775A (en) | 1976-05-07 |
| FR2290202A1 (en) | 1976-06-04 |
| AU498298B2 (en) | 1979-03-01 |
| IE42137B1 (en) | 1980-06-04 |
| DE2549841C2 (en) | 1988-07-07 |
| AU8624775A (en) | 1977-05-05 |
| IL48400A0 (en) | 1976-01-30 |
| HU174639B (en) | 1980-02-28 |
| FR2290202B1 (en) | 1980-05-23 |
| NZ179139A (en) | 1978-04-28 |
| NL7512974A (en) | 1976-05-10 |
| DK139429C (en) | 1979-08-06 |
| BE835224A (en) | 1976-05-04 |
| ES442357A1 (en) | 1977-04-01 |
| IL48400A (en) | 1979-01-31 |
| JPS5170768A (en) | 1976-06-18 |
| JPS5826754B2 (en) | 1983-06-04 |
| IE42137L (en) | 1976-05-06 |
| CH624403A5 (en) | 1981-07-31 |
| PH12158A (en) | 1978-11-10 |
| LU73714A1 (en) | 1976-06-11 |
| ZA756550B (en) | 1976-09-29 |
| DK139429B (en) | 1979-02-19 |
| DE2549841A1 (en) | 1976-05-13 |
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