US3501483A - Novel 11-(4-piperidyl)dibenz(b,f)(1,4) oxazepines and thiazepines - Google Patents

Novel 11-(4-piperidyl)dibenz(b,f)(1,4) oxazepines and thiazepines Download PDF

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US3501483A
US3501483A US677012A US3501483DA US3501483A US 3501483 A US3501483 A US 3501483A US 677012 A US677012 A US 677012A US 3501483D A US3501483D A US 3501483DA US 3501483 A US3501483 A US 3501483A
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piperidyl
dibenz
methyl
oxazepine
give
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Charles Frederick Howell
Paul Ramirez
Robert Allis Hardy Jr
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Wyeth Holdings LLC
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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 to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

  • This invention relates to new organic compounds. More particularly, it relates to ll-substituted dibenz[b,f] [1,4]- oxazepines and thiazepines, intermediates, and methods of preparing the same.
  • novel compounds of the present invention may be illustrated by the formula:
  • R is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, carbo(lower)alkoxy, carbobenzyloxy and ar(lower alkyl);
  • R is selected from the group consisting of hydrogen and lower alkyl;
  • R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower alkylmercapto, halogen, trifiuoromethyl, nitro, di(lower alkyl) sulfamoyl and lower alkanoyl;
  • X is selected from the group consisting of oxygenand sulfur;
  • Y is selected from the group consisting of methylene and ethylene; and nontoxic acid addition salts.
  • the compounds of the present invention possess valuable central nervous system (CNS) properties at nontoxic doses. As such, they show one or more of the following CNS actions: tranquilizer, hypnotic and/ or muscle relaxant type actions, and anti-depressant activity.
  • CNS central nervous system
  • the compounds have been tested pharmacologically and found to have the above properties which show a desirable wide spread between doses producing depressant or sedative actions or anti-depressant actions and toxic symptoms such as paralysis or lethality. They are also analgesics.
  • the CNS depressant properties such as tranquilizer, hypnotic and muscle relaxant type activity
  • CNS depressant properties are indicated by several procedures.
  • a test which indicates hypnotic and/or muscle relaxant type activity is represented by the following rod walking test.
  • Groups of 3,501,483 Patented Mar. 17, 1970 6 mice each are tested for their ability to walk across a horizontal rod in a normal manner after receiving graded intraperitoneal doses of a test compound.
  • a median effective dose, rod walking dose (RWD) is estimated.
  • a test which indicates tranquilizing activity is represented by a measure of the reduction in motor activity.
  • One half of the rod walking dose (RWD); see above, is given to a group of 5 mice and a 5 minute count of motor activity is recorded (actophotometer).
  • Counts of 5250 are considered to indicate a specific reduction (more than two standard deviations) of activity at a dose causing only minimal impairment of neurological function as measured by "rod walking ability.
  • Compounds that appeared to reduce motor activity (5250 count) are administered to additional groups of 5 mice at graded doses and tested similarly.
  • the motor depressant dose (MDD) which causes a 50% reduction of motor activity (A count of 250) is estimated.
  • the use of reduced motor activity as a measure of tranquilizing activity has been described by W. D. Gray, A. C.
  • the anti-depressant properties of the compounds of the present invention are determined by measuring their ability to counteract a depression induced in animals by the administration of tetrabenazine hexamate.
  • Graded doses of the active compounds of this invention are administered to groups of 5 mice each, and this is followed by administering a dose of tetrabenazine which is known to markedly depress the exploratory behavior of normal mice.
  • the anti-depressant treated groups show normal exploratory behavior, while the control groups, and groups treated with an ineffective anti-depressant agent, do not show normal exploratory behavior, but show the well known profound depression induced by tetrabenazine. When tested by this procedure at an intraperitoneal dose of 1.6 mg./kg.
  • the compounds of this invention are, in general, oils or low melting solids only slightly soluble in water, but soluble in organic solvents such as methanol, ethanol and the like. They are basic substances which are usually soluble in aqueous minerals acids at room temperature. They form substantially insoluble acid addition salts such as the hydrochloride, sulfate, phosphate, citrate, tartrate, maleate, fumarate, etc.
  • the present compounds generally in the form of their salts, may be administered orally or parenterally and when so administered, are effective central nervous system agents.
  • the new compounds of this invention may be incorporated with the usual pharmaceutical excipients and used, for instance, in the form of tablets, capsules, dragees, liquids to be administered in drops, emulsions, suspensions and syrups, and in chocolate, candy, chewing gum and the like. They may also be administered in suppositories, and in aqueous solutions for parenteral injection.
  • isonipecotanilides are treated with acid condensing agents such as phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acid, zinc chloride, aluminum chloride and the like either alone or in combination or in the presence of an inert solvent such as benzene, Xylene, o-dichlorobenzene and the like.
  • acid condensing agents such as phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acid, zinc chloride, aluminum chloride and the like either alone or in combination or in the presence of an inert solvent such as benzene, Xylene, o-dichlorobenzene and the like.
  • This reaction is generally carried out at an elevated temperature but the temperature may range from about 90 C. to about 240 C.
  • the reaction is usually complete within several hours but may take as long as 2 to 4 days with mild reagents at low temperatures.
  • the required substituted isonipecotanilides nipecot
  • (H) are readily prepared by acylation of known o-aryloxyanilines and o-arylthioanilines with the desired substituted acid halide hydrohalide. This reaction is generally eifected in an inert solvent such as acetone, benzene, dimethylformamide and the like in the presence of an alkaline reagent such as triethylamine, pyridine, dimethylaniline, and the like.
  • an inert solvent such as acetone, benzene, dimethylformamide and the like
  • an alkaline reagent such as triethylamine, pyridine, dimethylaniline, and the like.
  • This cyclization is generally effected in an inert solvent such as benzene, toluene, xylene and the like in the presence of an acidic catalyst.
  • Reagents such as zinc chloride, sulphuric acid, p-toluene sulfonic acid, phosphorus pentachloride and the like are suitable for this purpose.
  • a suitable temperature range is from about to C.
  • a preferred embodiment of this method illustrates the synthesis of novel 2-substituted-11-(1-substituted-4-piperidyl)dibenz[b,f][1,4]oxazepines and thiazepines of this invention:
  • ketone (IIIa) are products of the reduction of nitroketones (IV), obtained by condensing o-nitrohalobenzenes with 2-hydroxyor 2-mercapto 5 substituted phenyl l-substituted 4 piperidyl ketone (V) which, in turn, are preparable from p-substituted phenols or thiophenols (VI) and isonipecotoyl halide hydrohalides (VII) in the presence of Friedel-Crafts catalysts such as zinc chloride, aluminum chloride, hydrogen fluoride and the like.
  • This sequence may be illustrated as follows:
  • R, R and X are as hereinbefore described and A represents a halogen atom of atomic weight less than 80.
  • R, R R R Y and X are as hereinbefore described, and W and Z are reactive groups including mercapto, hydroxyl, halogen, nitro and diazonium, one of which is hydroxyl or mercapto.
  • R, R R and X are as hereinbefore described and E is a suitably reactive group such as halogen or arylsulfonyloxy (such as tosyloxy), and the like.
  • substituents R may be transformed to other substituents R as defined hereinbefore. Illustrative of such sequences are the conversion of carbethoxy to hydrogen (by hydrolysis), or to methyl (by reduction) and the conversion of hydrogen to 2- hydroxyethyl (by reaction with ethylene oxide) or to acyloxy lower alkyl (by reaction with ot-acetoxypropyl chloride).
  • substituents on the aromatic rings such as amino, nitro, diazonium, and halogen groups may be converted to the R and R groups either directly or sequentially by methods well known to those skilled in the art.
  • the semi-solid product is collected, and is dried in a vacuum over phosphorus pentoxide.
  • This semi-solid product is purified by adsorption chromatography on an alumina column.
  • the purified product is eluted from the column using an ethyl acetatehexane solvent system. Removal of the solvent then gives 2 chloro ll (1-methyl-4-piperidyl)dibenz[b,f][1,4] oxazepine as a clear, colorless oil.
  • the ultraviolet absorption spectrum of this material shows xCHKOH 300, 325 my.
  • This compound is treated with polyphosphoric acid (30:1 by weight) and is heated to about C. for approximately 8 hours. After which it is quenched on ice and made alkaline. The product is extracted into ether, dried with potassium carbonate and concentrated to dryness. The oily residue is dissolved in ethanol containing an equivalent amount of hydrochloric acid and the addition of ether precipitates 2-chloro-11(1-methyl- 4 piperidyl)dibenzo[b,f] [1,4]thiazepine hydrochloride, melting point 234-237 C.
  • This compound is cyclized With phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to give ll-(l-methyl-4-piperidyl.)dibenz- [b,f][1,4]oxazepine.
  • Hydrogenolysis of Z-chloro-ll-(lmethyl-4-piperidyl)dibenz [b,f] [1,4] oxazepine with palladium in ethanol gives ll-(l-methyl-4-piperidyl)dibenz- [b,f][1,4]oxazepine hydrochloride, melting point 230- 35 C.
  • This compound is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to give 2-chloro-1l(4-piperidyl)dibenz- [b,f] [1,4] oxazepine.
  • 2-chloro 11 (4-piperidyl)dibenz- [b,f] [1,4]oxazepine is also prepared by cleavage of 11-(1- carbobenzyloxy-4-piperidyl) 2 chlorodibenz[b,f] [1,4]- oxazepine wtih' hydrobromic acid in glacial acetic acid.
  • the hydrochloride has melting point 2735 C.
  • EXAMPLE 8 Preparation of 11-(4-piperidyl)dibenzo[b,f] [1,4] thiazepine 1 carbobenzyloxy-2'-(phenylthio)isonipecotanilide is prepared by treating a solution of l-carbobenzyloxyisonipectic acid in tetrahydrofuran with carbonyldiimidazole at C. followed by the addition of o-(phenylthio) aniline. The mixture is refluxed for 1 hour and the product is isolated.
  • This compound is refluxed with phosphorus pentoxide and phosphous oxychloride according to the procedure of Example 1 to give 2-chloro-11-[bis(2-chloroethyl) methyl] dibenz [b,f] [1,4] oxazepine hydrochloride.
  • 2-chloro-1 1- bis (2-chloroethyl methyl] dibenz[b,f] [l,4]oxazepine hydrochloride with amino-ethanol yields the desired compound 2-chloro-ll-[1-(2-hydroxyethyl) -4-piperidyl] dibenz [b,f] 1,4] oxazepine.
  • EXAMPLE 11 Preparation of 1 1-[ 1-(2-hydr'oxyethy1)-4-piperidyl] dibenzo [b,f [1,4] thiazepine l1-(4-piperidyl)dibenzo[b,f] [1,4] thiazepine (Example 8 is treated with ethylene oxide in ethanol to give 11- l- 8 (Z-hydroxyethyl) 4 piperidyl] dibenzo [b,f] [l,4]thiazepine.
  • This compound is cyclized with phosporus pentoxide in phosphorus oxychloride according to the procedure of Example 1 to give 11-(4-piperidy1)dibenz[b,f] [1,4] oxazepine hydrochloride, melting point 259-262 C.
  • EXAMPLE 18 Preparation of 2-fluoro-1 1-( 1-methyl-4-piperidyl dibenzo i] [1,4] thiazepine
  • Z-(p-fluorophenylthio)aniline is acylated with l-methylisonipecotoyl chloride hydrochloride to give 2'-(p-fluorophenylthio)-1-methylisonipecotanilide, as in Example 4.
  • This compound is cyclized in hot polyphosphoric acid, as in Example 3, to give 2-fluoro-l1-(1-methyl-4-piperidyl) dibenzo [b,f] 1,4] thiazepine.
  • EXAMPLE 20 Preparation of 3-acetyl-l1-(l-methyl-4-piperidyl)dibenz i] 1,4] oxazepine
  • the compound o-(m-acetylphenoxy)aniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 4 to give 2'-(m-acetylphenoxy)-lmethylisonipecotanilide.
  • This compound is cyclized with phosphorus pentoxide and phosphorous oxychloride according to the procedure of Example 1 to yield 3-acetyl- 11-(1-methyl-4-piperidyl)dibenz[b,f] [1,4] oxazepine.
  • This compound is cyclized with phosphorus pentoxide in phosphorus oxychlo ride to give 2-chloro-l1-(1-methy1-3-pyrrolidiny1)dibenz- [b,f] [1,410xazepine.
  • EXAMPLE 27 Preparation of 2-chloro-11-(1-methyl-3-piperidy1) dibenzo [b,f] [1,4] thiazepine
  • Z-p-chlorophenylthio)aniline is acylated with l-methylnipecotoyl chloride hydrochloride to give 2'-(p-chlorophenylthio)-lmethylnipecotanilide as in Example 4.
  • This compound is cyclized in hot polyphosphoric acid, as in Example 3, to give 2-chloro-l1-(1-methyl-3-piperidyl) dibenzo [b,f] [1,4] thiazepine.
  • EXAMPLE 28 Preparation of 2-chloro-1 1-(1-methyl-2-piperidyl) dibenzo['b,f] [1,4] thiazepine
  • 2-(p-chlorophenylthio)aniline is acylated with l-methylpipecoloyl chloride hydrochloride to give 2'-(p-chlorophenylthio)-1-methylpipecolanilide as in Example 4.
  • This compound is cyclized in hot polyphosphoric acid as in Example 3 to give 2-chlor0-l1-(1-methyl-2-piperidyl) dibenzo[b,f] [1,4] thiazepine.
  • This compound is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 1 to give 11-(1-methyl-4-piperidy1)-2-nitrodibenz [b,f] [1,4]oxazepine.
  • R is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, carbo(lower)alkoxy, and carbobenzyloxy;
  • R is selected from the group consisting of hydrogen and lower alkyl;
  • R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, methylthio, halogen, trifluoromethyl, di(lower) alkylsulfamoyl, lower alkanoyl and nitro;
  • X is selected from the group consisting of oxygen and sulfur;
  • Y is selected from the group consisting of methylene and ethylene; and non-toxic acid addition salts.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Hydrogenated Pyridines (AREA)
US677012A 1966-04-15 1967-10-23 Novel 11-(4-piperidyl)dibenz(b,f)(1,4) oxazepines and thiazepines Expired - Lifetime US3501483A (en)

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US766988A Expired - Lifetime US3532702A (en) 1966-04-15 1968-10-11 2-(o-aminophenoxy or phenylthio) phenyl-1-substituted (piperidyl or pyrrolidinyl) ketones

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4431808A (en) * 1981-03-13 1984-02-14 Spofa, Spojene Podniky Pro Zdravotnickou Vyrobu Tricyclic compounds
EP0468562A1 (en) * 1990-07-24 1992-01-29 Akzo Nobel N.V. Tetrahydropyridinyl substituted tricyclic derivatives with dopamine antagonistic activity
US5286722A (en) * 1990-07-24 1994-02-15 Akzo N.V. Tetrahydropyridinyldibenzazepine derivatives
US5602121A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Alkyl-substituted compounds having dopamine receptor affinity
US20040224942A1 (en) * 2003-01-23 2004-11-11 Weiner David M. Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20050085463A1 (en) * 2003-01-23 2005-04-21 Weiner David M. Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20050192268A1 (en) * 2003-12-22 2005-09-01 Fredrik Ek Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20050250767A1 (en) * 2003-01-23 2005-11-10 Weiner David M Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20050282800A1 (en) * 2004-04-01 2005-12-22 Bo-Ragnar Tolf Method of synthesis and isolation of solid N-desmethylclozapine and crystalline forms thereof
US20070105836A1 (en) * 2005-10-31 2007-05-10 Lars Pettersson Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4045445A (en) * 1975-12-14 1977-08-30 American Cyanamid Company 11-(4-Piperidyl)dibenzo-diazepines
US7754773B2 (en) * 2005-10-06 2010-07-13 University Of Massachusetts Composition and synthesis of new reagents for inhibition of HIV replication

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3100207A (en) * 1959-07-08 1963-08-06 Smith Kline French Lab 10-aminoalkylbenzo[b,f]thiepin and -dibenz[b,f]oxepin derivatives

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US3159683A (en) * 1961-05-24 1964-12-01 Fidelity Union Trust Company Preparation of 3-nitro-4-bromothioanisole

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3100207A (en) * 1959-07-08 1963-08-06 Smith Kline French Lab 10-aminoalkylbenzo[b,f]thiepin and -dibenz[b,f]oxepin derivatives

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4431808A (en) * 1981-03-13 1984-02-14 Spofa, Spojene Podniky Pro Zdravotnickou Vyrobu Tricyclic compounds
EP0468562A1 (en) * 1990-07-24 1992-01-29 Akzo Nobel N.V. Tetrahydropyridinyl substituted tricyclic derivatives with dopamine antagonistic activity
US5286722A (en) * 1990-07-24 1994-02-15 Akzo N.V. Tetrahydropyridinyldibenzazepine derivatives
US5602121A (en) * 1994-12-12 1997-02-11 Allelix Biopharmaceuticals, Inc. Alkyl-substituted compounds having dopamine receptor affinity
US5834459A (en) * 1994-12-12 1998-11-10 Allelix Biopharmaceuticals Inc. Alkyl-substituted compounds having dopamine receptor affinity
US20050250767A1 (en) * 2003-01-23 2005-11-10 Weiner David M Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20050085463A1 (en) * 2003-01-23 2005-04-21 Weiner David M. Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20040224942A1 (en) * 2003-01-23 2004-11-11 Weiner David M. Use of N-desmethylclozapine to treat human neuropsychiatric disease
US20090018119A1 (en) * 2003-01-23 2009-01-15 Acadia Pharmaceuticals, Inc. Use of n-desmethylclozapine to treat human neuropsychiatric disease
US20050192268A1 (en) * 2003-12-22 2005-09-01 Fredrik Ek Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7491715B2 (en) 2003-12-22 2009-02-17 Acadia Pharmaceuticals, Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7517871B2 (en) 2003-12-22 2009-04-14 Acadia Pharmaceuticals, Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7550454B2 (en) 2003-12-22 2009-06-23 Acadia Pharmaceuticals, Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US7622461B2 (en) 2003-12-22 2009-11-24 Acadia Pharmaceuticals Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20050282800A1 (en) * 2004-04-01 2005-12-22 Bo-Ragnar Tolf Method of synthesis and isolation of solid N-desmethylclozapine and crystalline forms thereof
US20070105836A1 (en) * 2005-10-31 2007-05-10 Lars Pettersson Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders

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US3532702A (en) 1970-10-06
NL155830B (nl) 1978-02-15
BE697032A (oth) 1967-10-16
DE1645964A1 (de) 1970-06-04
NL6705298A (oth) 1967-10-16
GB1184251A (en) 1970-03-11
FR7194M (oth) 1969-08-18
CH496727A (de) 1970-09-30
FR1602883A (oth) 1971-02-08

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