US3532702A - 2-(o-aminophenoxy or phenylthio) phenyl-1-substituted (piperidyl or pyrrolidinyl) ketones - Google Patents

2-(o-aminophenoxy or phenylthio) phenyl-1-substituted (piperidyl or pyrrolidinyl) ketones Download PDF

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US3532702A
US3532702A US3532702DA US3532702A US 3532702 A US3532702 A US 3532702A US 3532702D A US3532702D A US 3532702DA US 3532702 A US3532702 A US 3532702A
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Paul Ramirez
Robert Allis Hardy Jr
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic 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
    • C07D211/08Heterocyclic 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
    • C07D211/18Heterocyclic 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
    • C07D211/30Heterocyclic 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
    • C07D211/32Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic 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
    • C07D211/36Heterocyclic 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
    • C07D211/60Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62Carbon 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
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/906Muscle relaxant

Description

United States Patent 3,532,702 Z-(o-AMINOPHENOXY OR PHENYLTHIO) PHENYL- I-SUBSTITUTED (PIPERIDYL OR PYRROLIDIN- YL) KETONES Charles Frederick Howell, Upper Saddle River, N.J., Paul Ramirez, Spring Valley, N.Y., and Robert Allis Hardy, Jr., Ridgewood, NJ., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Continuation-impart of application Ser. No. 677,012, Oct. 23, 1967, which is a continuation-in-part of application Ser. No. 542,738, Apr. 15, 1966. This application Oct. 11, 1968, Ser. No. 766,988

Int. Cl. C07d 29/28, 29/36 US. Cl. 260293.4 3 Claims ABSTRACT OF THE DISCLOSURE The preparation of 2-(o-aminophenoxy)phenyl l-substituted-piperidyl or pyrrolidinyl ketones and 2-(o-aminophenylthio)phenyl l-substituted-piperidyl or pyrrolidinyl ketones by reduction of the coresponding 2-(o-nitrophenoxy) or 2-(o-nitrophenylthio) compounds is described. Other methods are also described for the preparation of the above compounds. These compounds have a physiological effect on the central nervous system thereby making them useful as tranquilizers, hypnotics or anti-depressants.

wherein R is selected from the group consisting of hydrogen, lower alkyl and, hydroxy 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, trifluoromethyl, nitro, di(lower alkyl)sulfamoyl and lower alkanoyl; 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.

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. The compounds have been tested pharmacologically and found to have the above properties which show a desirable wide ice 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, are indicated by several procedures. For example, a test which indicates hypnotic and/or muscle relaxant type activity is represented by the following rod walking test. Groups of 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 efiective dose, rod Walking dose RW-D) 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 2250 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 (2250 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. Osterberg and C. E. Rauh, Archives Internationales et de Therapie, vol. 134, p. 198 (1961) and by W. J. Kinnard and C. J. Carr, Journal of Pharmacology and Experimental Therapeutics, vol. 121, p. 354 (1957).

When tested by the above procedures, the following compounds of this invention and conversion products therefrom show the activity indicated in Table I.

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 the intraperitoneal doses indicated, the following compounds of this invention and conversion products therefrom show anti-depresant activity as described in Table II:

TABLE -II Tetrabenazine reversal Example mg./kg. intraperitoneally 2 (o aminophenoxy)phenyl 4 piperidyl ketone dihydrochloride 3 TABLE IIContinued Tetrabenazine reversal Example mg./kg. intraperitoneally 2 aminophenylthio) chlorophenyl 4 piv 1 3.1 orally.

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 mineral acids at room temperature.

They form substantially insoluble acid addition salts such as the hydrochloride, sulfate, phosphate, and the like. 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. For oral administration 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.

The new compounds such as the 2-(o-aminophenoxy) phenyl l-substituted-piperidyl or pyrrolidinyl ketones and 2-(o-aminophenylthio)phenyl l-substituted-piperidyl or pyrrolidinyl ketones of this invention may be prepared by several methods which are described hereinafter. One method may be illustrated as follows:

1 W} Y 1 R1 O=C '+I-IA R N i oox R HX i 3 B1 i/ NO2 N R2 Y W -A i R1 NO 2 Rs n. I

lReduction wherein R, R R R X and Y are as hereinbefore described and A is a halogen of atomic weight less than 80. The requisite 2-(o-aminophenoxy)phenyl l-substituted-piperidyl or pyrrolidinyl ketones and 2-(o-aminophenylthio)phenyl l-substituted piperidyl or pyrrolidinyl ketones (I) are products of the reduction of nitroketones II), obtained by condensing o-nitrohalobenzenes with Z-hydroxyor Z-mercapto-S-substituted-phenyl 1- substituted 4 piperidyl or pyrrolidinyl ketones (III) which, in turn, are preparable from p-substituted phenols or thiophenols (IV) and isonipecotoyl halide hydrohalides (V) in the presence of Friedel-Crafts catalysts such as zinc chloride, aluminum chloride, hydrogen fluoride and the like.

A preferred method for obtaining the novel compounds of this invention is illustrated by their interconversion with the corresponding 11 substituted-dibenz[b,f][1,4] oxazepines and -thiazepines. This is illustrated by the following scheme:

If I {1 (VIa) wherein R, R and X are as previously described. The ketones Ia) and the dibenz[b,f] [1,4]oxazepines and -thiazepines (VIa) are interconverted in the presence of approximately 0.1 N hydrochloric acid. Isolation of either one or both components from mixtures containing (Ia) and (VIa) is dependent upon the individual properties of the equilibrium pair. Physical properties such as differential solubilities of the bases and/or acid addition salts may thus determine which of these components is more readily isolated from a given mixture. The proportions of each component will also vary in the equilibrium mixtures; which also influences the ease of isolation of the desired compound. Standard methods of separation and purification well known to those skilled in the art are used for isolation of the desired products; these include extraction, fractional crystallization, chromatographic separation and purification, and the like.

As shown in the above equilibrium scheme, the 2-(0- aminophenoxy)phenyl l-substituted-piperidyl ketones and 2- (o-aminophenylthio )phenyl l-substituted-piperidyl ketones (Ia) of this invention may be obtained together with the dibenz[b,f] [1,4]oxazepines and -thiaz'epines (VIa), or in some instances may be the sole product isolated, when a suitably substituted 2-aryloxyor 2'-arylthio substituted anilide (VIIa) is cyclized to the corresponding dibenz[b,f] [1,4]oxazepine or -thiazepine (VIa) followed by treatment with aqueous acid as shown with the following preferred embodiment:

wherein R, R and X are as hereinbefore defined.

Using the above method, appropriately substituted isonipecotanilides are treated with acidic condensing agents such as phosphorus oxychloridef; phosphorus pentachloride, polyphosphoric acid, zince chloride, aluminum chloride and the like either alone or in combination or in the presence of an inert solvent such as benzene, xylene, odichlorobenzene 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 nipecotanilides, pipecolinanilides, etc. are readily prepared by acylation of known o-aryloxyanilines and o-arylthioanilines with the desired substituted acid halide hydrohalide. This reaction is generally efiected in an inert solvent suchas acteone, benzene, dimethyltormamide and the like in the presence of an alkaline reagent such as triethylamine, pyridine, dimethylaniline, and the like.

Cyclization of the 2-(o-aminophenoxy)phenyl l-substituted-4-piperidyl or pyrrolidinyl ketones and 2-(0- aminophenylthio)phenyl 1-substituted-4-piperidyl or pyrrolidinyl ketones (Ia) of this invention to the corresponding 1l-substituted-dibenz[b,f] [1,4]oxazepines and -thiazepines (VIa) may also be carried out under anhydrous conditions in an inert solvent such as benzene, toluene, xylene and the like. Reagents such as zinc chloride, sulfuric acid, p-toluenesulfonic acid, phosphorus pentachloride, phosphorus pentoxide and the like are suitable for this purpose. The temperature range for carrying out this reaction is from about 80 C. to 150 C. The cyclized dibenz[b,f] [1,4]oxazepines and -thiazepines obtained therefrom are also valuable pharmaceutical products. In general, the individual ketone products (Ia) of this invention and the corresponding 11-piperidyl-dibenz[b,f] [1,4]- oxazepine (or -thiazepine) cyclization product (VIa) both show similar activities; i.e. both show antidepressant activity of a similar order, or both show CNS depressant properties. Thus, a further advantage of the compounds of this invention is their conversion into other products which also show excellent pharmaceutical properties.

DETAILED DESCRIPTION The following examples illustrate in detail the various methods of preparing 2-(o-aminophenoxy)phenyl l-substituted-piperidyl or pyrrolidinyl ketones and 2-(o-aminophenylthio)phenyl l-substituted-piperidyl or pyrrolidinyl ketones of the present invention.

EXAMPLE 1 Preparation of 2-(o-aminophenylthio)-5-chlorophenyl 4-piperidyl ketone The crude hydrobromide salt of 2'-(p-chlorophenylthio)isonipecotanilide, prepared from 2.4 g. of benzyl 4- [o (p chlorophenylthio)phenyl]carbamoylpiperidinel-carboxylate stirred for 15 minutes with 15 ml. of 48% hydrogen bromide in glacial acetic acid and concentrated, is cyclized with polyphosphoric acid as described in Example 2.

The above reaction solution is stirred and quenched with ice (exothermic reaction at the ice-phosphoric acid solution interface), made basic with concentrated potassium hydroxide, and the resulting aqueous-solid mixture is extracted with ether. The ether extract is dried and concentrated to give 0.65 g. (27%) of the anilino-ketone. Two recrystallizations from ether give pure 2-(o-aminophenylthio)-5-chlorophenyl 4-piperidyl ketone, M.P. 149- 152 C., UV 345 m 6 3300), 310 III/l. (e 4700), 270 m (e 8700), 235 ma (6 26,000), LR. (KBr) 2.93 and 304,44 (NH 5.96;]. (ketone C=O); NMR (CDCl ca. 6 1.8-2.1 (m., 4, C(CH ca. 6 2.0-2.15 (m., l, (:JH)

5 2.4 (s., 3, N-CH ca. 6 2.8-3.2 (m., 4, N(CH 5 2.25 (s., 2, NH ca. 5 6.7-7.7 (m., 7, aromatic).

Aanalysis.-Calcd. for C H ClN OS (percent): C, 62.3; H, 5.5; Cl, 10.2; N, 8.1; S, 9.2. Found (percent): C, 61.4; H, 5.5; CI, 10.3; N, 8.0; S, 9.0.

EXAMPLE 2 Preparation of 2-(o-aminophenylthio)-5-chlorophenyl 4-piperidyl ketone The hydrochloride salt of 3.5 g. (0.01 mole) of 2-(pchlorophenylthio)isonipecotanilide in 130 g. of polyphosphoric acid is heated for 7 hours at 163 C. The reaction is cooled and placed in a water saturated atmosphere overnight (initial quenching). Ice is added to the reaction solution while externally cooling with an acetone-ice bath. The resulting mixture (600 ml.) is treated with activated charcoal and 10% potassium hydroxide solution is added to the filtrate (to pH 9; 15) which precipitates a semisolid. This suspension is extracted with ether and evaporation of the ether extract gives 0.45 g. (14%) of the desired cyclized product, M.P. 157-162 C. (as the base). Recrystallization from ethyl acetate gives 200 mg. of 2- chloro-l1-(4-piperidyl)dibenzo[b,f] [1,4] thiazepine, M.P. 167-1 69 C., LR. (KBr) 6.14, (anil C=N).

The above aqueous suspension, after extraction with ether, is re-extracted with methylene chloride to give 2.7 g. of a semi-solid residue. A portion of the crude product (2.4 g.) is stirred in a mixture of ether and 10% sodium hydroxide (three phase system) for 3 hours during which all of the solid dissolves. The phase are separated and the ether phase is concentrated to dryness to give an additional 1.2 g. of 2-chloro-11-(4-piperidyl)dibenzo[b,f]- [l,4]thiazepine, M.P. 157-162 C. This is combined with the recrystallized base isolated from the ether extract (0.2 g., M.P. 167169 C.), dissolved in a minimum amount of hot ethanol, and treated with one equivalent of ethanolic hydrogen chloride. After 4 days of refrigeration (0-5 C.) the precipitate is filtered and dried to give 0.8 g. (22%, overall yield) of 2-chloro-11-(4-piperidyl)dibenzo[b,f] [1,4]thiazepine hydrochloride UV (MeOH) 340 ma (6 1300), 303 II'l/J. (e 2200); (KBr) 6.14 4 (anil C=N).

A mg. portion of the original 2.7 g. semi-solid residue is dissolved in 0.1 N hydrochloric acid and filtered. The filtrate is Washed with ether and made alkaline with 7 30% potassium hydroxide. The oily precipitate which forms is extracted into ether and concentrated to dryness. The residue, 39 mg., has an IR. spectrum (5.96 ketone C=O) identical to that of purified 2-(o-amin0phenylthio)-5-chlorophenyl 4piperidyl ketone.

EXAMPLE 3 Preparation of 2-(o-aminophenylthio)-5-chlorophenyl 1-methyl-4-piperidyl ketone EXAMPLE 4 Preparation of 2-(o-aminophenoxy)phenyl 4-piperidyl ketone 2'-phenoxyisonipecotanilide (6.7 g.) is converted to the oily hydrochloride with ethanolic hydrogen chloride and heated at 178 C. for 7 hours with 210 g. of polyphosphoric acid. The mixture is cooled, stored at O-5 C. I overnight in a water-saturated atmosphere and poured onto 700 g. of ice with stirring. The resulting mixture is filtered, treated with methylene chloride and then kept cold (-15 C.) while adjusting the pH to 9-10 with 20% potassium hydroxide. The mixture is stirred Overnight,

the methylene chloride layer is separated and dried over potassium carbonate. Concentration yields 5.4 g. of a mixture of the desired product together with 11-(4-piperidyl)dibenz[b,f] [1,4]oxazepine. This mixture in methylene chloride is treated with hydrogen chloride to yield the less soluble 2-(o-aminophenoxy)phenyl 4-piperidyl ketone as the dihydrochloride, M.P. 268-272 C.; IR. (KBr) 3.5-4.5 (-NH and NH 5.95 (C=O), 6.25 2; UV A (MeOH) 293 mp. (e 3700); NMR [(eD SO]69.6, 8.7 (two broad peaks, H total, NH and NH differential thermal analysis, endotherm at ca. 150 C. (9.5% loss in weight, loss of HCl), melting point ca. 250 C. (Weight loss, decomposition); mass spectrum (70 ev.) m/e 296, 278 (probe 122), m/e 278 (probe 265).

The more soluble 11-(4-piperidyl)dibenz[b,f] [1,4]- oxazepine hydrochloride is isolated by cooling the filtrate for several days and collecting the precipitated product; melting point 260-261 C. 1 LR. (KBr) 3.4-4.6

93 NH2), 6.2 r (acid C=N); UV Am... (MeOHgB 322 my (6 3,200); NMR ((CD SO)5 9.6 (ca. 2H, NH

differential thermal analysis, melting point ca. 230 C. (wt. loss, decomposition).

EXAMPLE 5 Preparation of 2-(o-aminopheny1thio)phenyl 1-methyl-4-piperidyl ketone A solution of 20 mg. of 11-(1-methyl-4-piperidyl)-dibenzo [b,f] [1,4]thiazepine in ml. of 0.1 N hydrochloric acid is prepared and, after 30 minutes for equilibration, is added to 1 ml. of 30% potassium hydroxide. The mixture of anilino ketone and acid is extracted with ether and dried over potassium carbonate. The ether is removed and the residue chromatographed on fluorescent silica gel using the upper phase of a 1:2:2 mixture of benzene:acetonezwater containing 5% triethylamine. Elution of the less polar UV-absorbing spot with 5% concentrated ammonium hydroxide in methanol and concentration gives recovered 11- (1-methy1-4-piperidyl) dibenzo [b,f] [1,4] thiazepine.

Similar elution of the more polar spot yields 2-(0- aminophenylthio)phenyl 1 methyl 4 piperidyl ketone, which has infrared absorption at 6.0 and 3.15m.

EXAMPLE 6 Preparation of 5-chloro-2- (o-aminophenylthio) phenyl 4-piperidyl ketone A solution of mg. of Z-chloro-l1-(4-piperidyl)dibenzo[b,f] [1,4]thiazepine hydrochloride in 10 m1. of 0.1 N hydrochloric acid is prepared and, after minutes for equilibration, is added to 1 ml. of 30% potassium hydroxide. The mixture of anilino ketone and acid is extracted with ether and dried over potassium carbonate. The ether is removed and the residue chromatographed on fluorescent silica gel using the upper phase benzenezacetone1water system containing triethylamine. Elution of the less polar UV-absorbing spot with 5% concentrated ammonium hydroxide in methanol and concentration gives recovered 2 chloro 11 (4-piperidy1) dibenzo[b,f]- [l,4]thazepine with infrared absorption at 6.1 1. Similar elution of the more polar spot yields 5-chloro-2- (o-aminophenylthio)phenyl 4-piperidyl ketone which has infrared absorption at 6.0 and 3.1;.

EXAMPLE 7 Preparation of 2-(o-aminophenoxy)phenyl l-methyl- 4-piperidyl ketone A solution of 20 mg. of 11-(1-methyl-4-piperidyl)- dibenz[b,f][1,4]oxazepine in 10 ml. of 0.1 N hydrochloric acid is prepared and, after 30 minutes for equilibration, is added to 1 ml. of 30% potassium hydroxide. The mixture of anilino ketone and acid is extracted with ether and dried over potassium carbonate. The ether is removed and the residue chromatographed on fluorescent silica gel using the upper phase benzene:acetone:water system contaning triethylamine. Elution of the benzene polar UV-absorbing spot with 5% concentrated ammonium hydroxide in methanol and concentration gives recovered 11 (1-methyl-4-piperidyl)dibenz[b,f] [1,4]- oxazepine with infrared absorption at 6.2 Similar elution of the more polar spot yields 2-(o-aminophenoxy)- phenyl 1-methyl-4-piperidyl ketone, which has infrared absorption at 6.0 and 3.211.

EXAMPLE 8 Preparation of 2-chloro-11-(4-piperidyl)dibenzoi] [1,4] thiazepine Thirty-nine milligrams of 2-(o-aminophenylthio)-5- chlorophenyl 4-piperidyl ketone (Example 1) in a suspension of phosphorus pentoxide in benzene is heated to reflux. After four days the suspension is cooled, the solvent decanted and methylene chloride is added to the residue followed by quenching with ice. The mixture is adjusted to an alkaline pH with 10% sodium hydroxide. The phases are separated and concentration of the organic phase gives an oil which crystallizes (ca. 20 mg), melting point 157-162 C., with the same IR. spectrum as 2- chloro 11 (4-piperidyl)dibenzo [b,f][1,4]thiazepine (base).

EXAMPLE 9 Preparation of 11-(4-piperidyl)dibenz[b,f] [1,4]- oxazepine sulfate A solution of 3.1 mg. of 2-(o-aminophenoxy)phenyl- 4-piperidyl ketone dihydrochloride (Example 4) in 0.2 ml. of water is treated with 48 mg. of sodium sulfate and warmed to ca. C. for 15 minutes. Cooling gives crystalline 11-(4-piperidyl) dibenz[b,f][l,4]oxazepine sulfate which has infrared absorption at 3.6, 4.0, 6.2 and 8.9;!

9 EXAMPLE 10 Preparation of 2- (o-aminophenylthio) -5-chloropheny1 1-methyl-4-piperidyl ketone p-Chlorothiophenol and l-methylisonipecotoyl chloride hydrochloride are condensed in the presence of aluminum chloride to give Z-mercapto-S-chlorophenyl 1-methyl-4- piperidyl ketone. This intermediate is treated With o-chloronitrobenzene and 2-(o-nitrophenylthio)-5chlorophenyl 1-methyl-4-piperidyl kctone is obtained. Reduction with zinc and aqueous ethanolic ammonium chloride then gives the desired product, 2 (o-aminophenylthio)-5-chlorophenyl 1-methyl-4-piperidyl ketone.

EXAMPLE 11 Preparation of 2-(o-aminophenoxy)phenyl 1-methyl-4 piperidyl ketone Dibenz[b, I][1,4]oxazepine (or thiazepine) Ketone 2-chloro-11-(1-methyl-4-piperidyl) 2-(o-aminophenoxy)-5-chlorodibenz[b,f][1,4]oxazepine.

phenyl l-methyl--piperidyl ketone. 2-chl0r0-11-(1-methyl-4piperidyl) 2-(o-aminophenylthio):5-chloro dibenzo[b,f][1,41thiazepine. ghienyl l-m ethyll-plperidyl e one.

2-(N,N-dimethylsuliamoyl)-11-(1- methyl-4-piperidyl) dibenz [1),f] [1,4]oxazepine.

3-ncetyl-11-(l-methyli piperidyl) dibez[b,f][1,410xazep1ne.

2-mcthoxy-1l-(l-methyli-piperidyl) dibenz[b,f][1,410xazepine.

2(0-aminophenoxy)-5'chlorohenyl 4-piperidyl ketone. 2 o-aminophenylthio)phenyl-4- piperidyl ketone. 2-(o-aminophenoxy)-5-ehl0r0- phenyl 1-(2-hyroxyethyD-4- piperidyl ketone. 2-(o-aminophenylthio)phenyl 1- methyl-4-piperidyl ketone. 2-(o-aminophenoxy)-5-trifiuoromethylphenyl l-methyl-ipiperidyl ketone. 2-(o-aminophenylthio)chromophenyl 1-methyl-4-piperidyl ketone. 2-(o-aminophenylthio)-5-fluorophenyl l-methyll-piperidyl ketone. 2-(0-aminophenoxy)-5(N,N-dimethylsulfamoyDphenyl 1- methyl-4-piperidyl ketone. 2-(o-amin0phenoxy)-5-acetylphenyl 1-methyl-4piperidyl ketone. 2-(o-aminophenoxy)-5-methoxyphenyl 1-methyl-4-piperidy1 ketone.

2-cl1loro-8-methyl-11-(l-methyl-t piperidyl) dibeuzo[b,f][1,4] thiazepine. 8-methyl-1l-(l-methylkpiperidyl) dibenzolb f][l,4]thiazepine. 2'chloro-1l-(l-methylkpropylk piperidyl) dibenzo[b,f] [1,4] thrazepine. 2-eh1oro 11-(1-methyl-3-pyrrolidinyl) dibenz[b,i][1,4]xazep1ne.

2-chloro-11-(l-methyl-Z-piperidyl) dibenzolbfl[1,4]thiazepine.

11-(6-rnethyl-3-piperidyl) dibenz[b,f]

[1,4]oxazepine.

11-(1-methy1-4piperidy1)-2-n1trodibenz[b,f][1,4]oxazepine.

2-(o-aminophenoxy) -5-methylthiophenyl l-methyl--piperidyl ketoue. 2-(3-amino-p-tolylthio)-5-chl01'o phenyl l-mcthyl-et-piperidyl ketone. 2-(3-amino-p-tolylthio)phenyl 1- methyl-4piperidyl ketone. 2-(o-aminophenylthio)-5-chl0rophenyl 1-methyl-4-propyl-4 piperidyl ketone. 2-(0-aminophenoxy)-5-ehlorophenyl 1-methyl-3-pyrrolidinyl ketone. 2-(o-aminophenylthio)-5-chl0rophenyl l-methyl-B-piperidyl ketone. 2-(o-aminophenylthio)-5-chlorophenyl l-methyl-Z-pipen'dyl ketone. 2-(o aminophenoxy)phenyl-6- methyl-3-piperidyl ketone. 2-(o-aminophenoxy)-5-nitrophenyl 1-methy1-4-piperidyl ketone.

EXAMPLE 13 Preparation of 2-chloro 11-(1-methyl-4-piperidyl) dibenz[b,f] [1,4]oxazepine A slurry of l-methylisonipecotoyl chloride hydrochloride is prepared by the reaction of thionyl chloride (25 ml.) and 9.7 g. of l-methylisonipecotic acid, hydrochloride at 25 C. After the evolution of gas ceases, the excess thionyl chloride is removed by distillation under reduced pressure. The crystalline residue is triturated with 250 ml. of anhydrous hexane. The resulting suspension is concentrated to dryness under reduced pressure (thereby removing solvent and residual thionyl chloride). This residue is then taken up in 200 ml. of anhydrous acetone. To this slurry is added 10.4 g. of 2-(p-chlorophenoxy)- aniline in 50 ml. of acetone. After 20 minutes, 10 g. of triethylamine is added with the immediate formation of a heavy slurry. After stirring for 2 hours at room temperature, the reaction mixture is filtered and the filtrate is concentrated to dryness. The residue is dissolved in a benzene-water mixture and the aqueous phase is made basic with potassium carbonate. The product is extracted into benzene and the benzene layer is dried over potassium carbonate and concentrated under reduced pressure. Recrystallization from hexane then gives 2'- (p-chlorophenoxy)-1-methylisonipecotanilide, melting point 141- 143 C.

The hydrochloride salt of 2'-'(p-chlorophenoxy)-1-methylisonipectoanilide is prepared by dissolving 0.7 g. of the base in ethanol containing an excess of hydrochloric acid. The resulting solution is concentrated to dryness. To the residue is added 1.4 g. of phosphorus pentoxide and 5 ml. of phosphorus oxychloride. The mixture is refluxed for 48 hours, after which it is quenched With ice and made alkaline with potassium hydroxide. 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 11 (1 methyl-4-piperidyl)dibenz[b,f] [1,4] oxazepine as a clear, colorless oil. The ultraviolet absorption spectrum of this material shows CHaOH maX.

300, 325 m (e=5200, 5500, respectively) Preparation of 2-chloro-1 1-(1-methyl-4-piperidyl)dibenzo [b,f] [l,4]thiazepine hydrochloride To a suspension of l-methylisonipecotoyl chloride hydrochloride, prepared by the procedure used in Example 13, in acetone is added 2-(p-chlorophenylthio)aniline. After 20 minutes, two equivalent of dimethylaniline is added with the immediate formation of a heavy precipitate. After stirring overnight the dimethylaniline hydrochloride is removed by filtration. The filtrate is concentrated to dryness and the residue is recrystallized from hexane to give 2'-(p-chlorophenylthio)-l-methylisonipecotanilide, melting point 126l28 C.

The hydrochloride salt of 2-(p-chlorophenylthio)-1 methylisonipecotanilide is prepared with ethanolic hydrochloric acid. This compound is treated wtih polyphosphoric at C. for 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 hydrochloride acid and the addi- 11 tion of ether precipitates 2-chloro-11-(l-methyl-4-piperidyl)dibenzo[b,f] [1,4]thiazepine hydrochloride, melting point 234237 C.

EXAMPLE 15 Preparation of 11-(1-methyl-4-piperidyl)dibenz i] [1,4]oxazepine The compound o-phenoxyaniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 14 to give 1-methyl-2-phenoxyisonipecotanilide.

This compound is cyclized with phosphorus pentoxide and phosphorus oxylchloride according to the procedure of Example 1 to give 1l-(1-methyl-4-piperidyl)dibenz- [b,f][1,4]oxazepine. Hydrogenolysis of 2-chloro-11-(1- methyl-4-piperidyl)dibenz[b,f][1,4]oxazepine with palladium in ethanol gives 1l-(1-methyl-4-piperidyl)dibenz- [b,f][l,4]oxazepine hydrochloride, melting point 230- 35 C.

EXAMPLE 16 Preparation of 11-(1-methyl-4-piperidyl)dibenzo- [b,f] [1,4] thiazepine The compound o-phenylthioaniline is reacted with l-methylisonipecotoyl chloride hydrochloride as in Example 14 to give 1-methyl-2-(phenylthio)isonipecotanilide.

The latter compound is cyclized with polyphosphoric acid according to the procedure of Example 14 to give 11-(1-methyl-4-piperidyl)dibenzo[b,f] [1,4] thiazepine.

EXAMPLE 17 Preparation of 2-chloro-11-(4-piperidyl)dibenzi] [1,4]oxazepine EXAMPLE 18 Preparation of 11-(4-piperidyl)dibenzo [b,f] [1,4] thiazepine l-carbo'benzyloxy 2 (phenylthio)isonipecotanilide is prepared by treating a solution of l-carbobenzyloxyisonipectic acid in tetrahydrofuran with carbonyldiimidazole at 10 C. followed by the addition of o-(phenylthio) aniline. The mixture is refluxed for 1 hour and the product is isolated.

This compound is cyclized with polyphosphoric acid according to the procedure of Example 14 to give 11-(4- piperidyl dibenzo [b,f [1,4] thiazepine.

EXAMPLE 19 Preparation of 2-chloro-1 1-[ 1-(2-hydroxyethyl 4-piperidy1] dibenz[b,f] [1,4] oxazepine 2-(p-chlorophenoxy)aniline is treated with the a-lactone of a-hydroxy-ot-(2-hydroxyethyl)butyric acid to give 2'-(p chlorophenoxy) 4 hydroxy-2-(Z-hydroxyethyl) butyranilide. This compound is refluxed with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 13 to give 2-chloro-11-[bis- (2 chloroethyl)methyl]dibenz[b,f][1,4]oxazepine hydrochloride. Treatment of 2-chloro-11-[bis(2-chloroethyl)methyl] dibenz[b,f] [1,4]oxazepine hydrochloride with aminoethanol yields the desired compound 2-chloro-1l- 12 [1 (2 hydroxyethyl) 4 piperidyl]dibenz[b,f] [1,4]oxazepine.

Treatment of 2-chloro 11 (4-piperidyl)dibenz[b,f]- [1,4]oxazepine with ethylene oxide gives the same compound, 2-chloro 11 [1-(2-hydroxyethyl)-4-piperidyl]dibenz [b,f] [1,4] oxazepine.

EXAMPLE 2 0 Preparation of 11-(1-methyl-4-piperidyl)-2-trifluo1'omethyl-dibenz [b,f] [1,4] oxazepine 2 (a,mot-trim]oro-p-tolyloxy)aniline is treated with 1- methylisonipecotyl chloride hydrochloride by the procedure of Example 14 to give 1-methyl-2-(a,a,a-trifluorop-tolyloxy)isonipecotanilide. This compound is treated with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 13 to give 11-(1- methyl-4-piperidyl) 2 trifluoromethyldizenz[b,f][1,4] oxazepine.

EXAMPLE 21 Preparation of 2-bromo-l l-(1-methyl-4-piperidyl) dibenzo [b,f [1,4] thiazepine The methods of Example 14 are repeated. Thus, 2-(pbromophenylthio) aniline is acylated with l-methylisonipecotoyl chloride hydrochloride to give 2(p-bromophenylthio)-1-methyl-isonipecotanilide as in Example 14. This compound is cyclized in hot polyphosphoric acid, as in Example 14, to give 2-bromo-11-(1-methyl-4-piperidyl) dibenzo [b,f] [1,4] thiazepine.

EXAMPLE 22 Preparation of 2-fluoro-11-(1-methyl-4-piperidyl) dizenzo [b,f] [1,4] thiazepine The methods of Example 14 are repeated. Thus, 2-pfluorophenylthio)aniline is acylated with l-methylisonipecotoyl chloride hydrochloride to give 2'-(p-fluorophenylthio)-1-methylisonipecotanilide, as in Example 14. This compound is cyclized in hot polyphosphoric acid, as in Example 14, to give 2-fluoro-11-(1-methyl-4-piperidyl) dibenzo[b,f] [1,4] thiazepine. I

EXAMPLE 23 Preparation of 2- (N,N-dimethylsulfamoyl)-1 l-( l-methyl- 4-piperidyl)dibenz [b,f] [1,4] oxazepine o [p (N,N dimethylsulfamoyl)phenoxy]aniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 13 to give 2-[p-(N,N-dimethylsulfamoyl)phenoxy] 1 rnethylisonipecotanilide. The hydrochloride has melting point 255-260 C. This compound is cyclized lWl'Eh phosphorus oxychloride according to the procedure of Example 13 to yield 2- (N-N- dimethylsulfamoyl) -1 1-(1-methyl-4-piperidyl)dibenz[b,f] [1,4]oxazepine. The hydrochloride has melting point 260-264 C. (decomposition).

EXAMPLE 24 Preparation of 3-acetyl-11-(1-methy1-4-piperidyl) dibenz[b,f] [1,4] oxazepine The compound o-(m-acetylphenoxy)aniline is treated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 14 to give 2'-(m-acetylphenoxy)-1- methylisonipecotanilide. This compound is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 13 to yield 3-acetyl-11- 1-methyl-4-piperidyl)dizenz[b,f] [1,4] oxazepine.

EXAMPLE 25 Preparation of 2-methoxy-11-(1-methyl-4-piperidy1) dibenz [b,f] [1,4] oxazepine Hydroquinone monomethyl other is acylated with 1- methylisonipecotic acid under Friedel-Crafts conditions in the presence of anhydrous hydrogen fluoride. The resulting Z-hydroxy-5-methoxyphenyl-4-piperidyl ketone is condensed with o-chloronitrobenzene in the presence of potassium carbonate and copper powder, and the resulting nitro compound is hydrogenated over palladium on charcoal in ethanol to give 2-(oaminophenoxy)-5-methoxyphenyl-1-methyl-4-piperidyl ketone. This compound is heated in xylene in the presence of zinc chloride to give 2-methoxy-11-(1-methyl 4 piperidyl)dibenz[b,f][1,4] oxazepine.

The same compound is obtained when o-(p-methoxyphenoxy)aniline is heated with l-methylisonipecotoyl chloride hydrochloride by the procedure of Example 14 to give 2'-(p-methoxyphenoxy) 1 methylisonipecotanilide which is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 13 to yield 2-methoxy-1l-(1-methyl-4-piperidyl)dibenz[b,f] [1,4]oxazepine.

EXAMPLE 26 Preparation of l 1-( 1-methyl-4-piperidyl) -2-methylthiodibenz[b,f] [1,4] oxazepine o (p Methylthiophenoxy)aniline is treated with 1- methylisonipecotoyl chloride hydrochloride by the procedure of Example 14 to give 2'-(p methylthiophenoxy)- 1-methylisonipecotanilide. This compound is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 13 to yield 11-(1-methyl- 4-piperidyl -2methylthiodibenz [-b,f] [1,4]oxazepine.

EXAMPLE 27 Preparation of 2-chloro-8-methyl-1l-( 1-methyl-4- piperidyl) dibenzo [b,f] 1,4]thiazepine The methods of Example 14 are repeated. Thus, 4-(pchlorophenylthio)-m-toluidine is acylated with l-methylisonipecotoyl chloride hydrochloride to give 4'-(p-chlorophenylthio)-1-methyl-m-isonipecotoluidide as in Example 14. This compound is cyclized in hot polyphosphoric acid as in Example 14 to give 2-chloro-8-methyl-1l-(l-methyl- 4-piperidyl dibenzo [b,f 1 [1,4] thiazepine.

EXAMPLE 28 Preparation of 8-rnethyl-l1( l-methylA-piperidyl) dibenzo [b,f] [1,41thiazepine 2-chloro 8-methyl-l1-(1-methyl 4 piperidyDdibenzo [b,f][1,4]thiazepine, prepared as in Example 27, is dissolved in ether and adder to a suspension of magnesium in ether previously activated by treatment with a little ethylene dibromide. The resulting Grignard reagent is decomposed by cautious addition of water to yield S-methyl- 1 1-( l-methyl-4-piperidyl) dibenzo [b,f] [1,4] thiazepine.

EXAMPLE 29 Preparation of 2-chloro-1 l- 1-methy1-4-propyl-4- piperidyl dibenzo [b,f] 1,4] thiazepine 1-methyl-4-propyl-4-cyanopiperidine is prepared and hydrolyzed to give 1-methyl-4-propylisonipecotic acid. This compound is converted to the acid chloride hydrochloride by the procedure described in Example 13, and condensed with 2-(p-chlorophenylthio)aniline to give 2'- (p-chlorophenylthio)-l-methyl-4 propylisonipecotanilide. This material is cyclized in hot polyphosphoric acid by the method of Example 14, to yield 2-chloro-11-(1- methyl-4-propyl-4 piperidyl) dibenzo [b,f] 1,4] thiazepine.

EXAMPLE 30 Preparation of 2-chloro-11-( l-methyl-3-pyrrolidinyl) dibenz [b,f] [1,4] oxazepine The methods described in Example 13 are used, and 2 (pchlorophenoxy)aniline is treated with l-methyl-3-pyrrolidinecarbonyl chloride hydrochloride, by the procedure of Example 13, to give 2'-(p-chlorophenoxy)-1-methyl-3- pyrrolidine-carboxanilide. This compound is cyclized with phosphorus pentoxide in phosphorus oxychloride to give 2-chloro-l 1- l-methyl 3 pyrrolidinyl) dibenz[b,f] [1,4]

oxa'zepine.

14 EXAMPLE 31 Preparation of 2-chloro-1 1- 1-methyl-3-piperidyl) dibenzo [b,f]-[1,4]thiazepine The methods of Example 14 are repeated. Thus, 2- (p-chlorophenylthio)aniline is acylated with l-methylnipecotoyl chloride hydrochloride to give 2-(p-chlorophenylthio)-1-rnethylnipecotanilide as in Example 14. This compound is cyclized in hot polyphosphoric acid, as in Example 14, to give 2-chloro-1l-(1-methyl-3-piperidyl) dibenzo [b,f] [1,4] thiazepine.

EXAMPLE 32 Preparation of 2-chloro-1 1-( I-methyl-Z-piperidyl) dibenzo [b,f] 1,4] thiazepine The methods of Example 14 are repeated. Thus, 2- (p-chlorophenylthio)aniline is acylated with l-methylpipecolyl chloride hydrochloride to give 2'-[p-ch1orophenylthio)-l-methyl-pipecoanilide as in Example 14. This compound is cyclized in hot polyphosphoric acid as in Example 14 to give 2-chloro-ll-(lmethyl-Z-piperidyl) dibenzo[b,f] [1,41thiazepine.

EXAMPLE 33 Preparation of 1 1-(6-methy1-3-piperidyl) dibenz [b,f]

[1,4] oxazepine EXAMPLE 34 Preparation of 1l-(l-rnethyl-4-piperidyl)-2-nitrodibenz [b,f] [1,4]-oxazepine The compound o-(p-nitrophenoxy)aniline is treated with l-methylisopecotoyl chloride hydrochloride by the procedure of Example 14 to give 1-methyl-2-(p-nitrophenoxy) isonipectanilide.

This compound is cyclized with phosphorus pentoxide and phosphorus oxychloride according to the procedure of Example 13 to give 11-(1-methyl-4-piperidyl)-2-nitrodibenz[b,f] 1,4] -oxazepine.

EXAMPLE 35 Preparation of benzyl 4-[o-(p-chlorophenylthio)phenyl] carbamoylpiperidine-l-carboxylate A solution of 4.0 g. of l,4-piperidinedicarboxylic acid l-benzyl ester in 25 ml. of thionylchloride is warmed (45 C.) until the evolution of gas ceases. The solution is concentrated to dryness, suspended in 200 ml. of hexane, and reconcentrated to dryness. The acid chloride is then dissolved in ml. of dry acetone.

The above solution is added dropwise to a solution of o-(p-chlorophenylthio)aniline base (prepared by dissolving 4.6 g. of the hydrochloride in a 10% aqueous potassium carbonate methylene chloride mixture, separating the phases, and evaporating the methylene chloride phase) in 100 ml. of dry acetone, and 2.4 g. of dimethylaniline is added After stirring overnight, the solution is concentrated to dryness and the oily residue is triturated with a 10% potassium carbonate-methylene chloride mixture. The phases are separated and the organic fraction is washed with three 25-ml. portions of 6 N hydrochloric acid. The methylene chloride solution is dried (potassium carbonate) and concentrated to dryness to give an oil.

The oil is reprecipitated from aqueous acetone followed by crystallization from hexane to give pure benzyl 4-[0 (p chlorophenylthio)phenyl carbamoyl]piperidine-l-carboxylate, melting point Ill-113 C.

15 16 7 EXAMPLE 36 2. The compound, 2 (o-aminophenylthio)-5-chlorophenyl 1-methyl-4-piperidyl ketone. Preparatron of N (o phenoxy)1son1pectotan1l1de 3. The compound 2 aminophenoxwphenyl The procedure described in Example 35 is repeated piperidylketone, and benzyl-4-(o-phen0xy)phenylcarbamoylpiperidine 1- carboxylate is prepared from 1,4-piperidinedicarboxylic 5 References Cited acid l-benzyl ester and o-phenoxyaniline. It is obtained UNITED STATES PATENTS as an 011; LR. 2.9 (amide NH), 5-85/L (broad, carbamate 3,159,683 12/1964 Renz et a1. 26O 293 4 and amide C O), ca. 8.08.3/L (CO).

Tbis oil is stirred with 48% hydrogen bromide in glacial 10 HENRY LES, Primary Examiner acetlc acid and concentrated to give N-(o-phenoxy)1sonipecotanflide S. D. WINTERS, Assistant Examiner What is claimed is:

1. The compound, 2 (o-aminophenylthio)-5chlorophenyl 4-piperidyl ketone. 15 260294.7, 326.5, 294, 326.3; 424-267, 274

US3532702D 1966-04-15 1968-10-11 2-(o-aminophenoxy or phenylthio) phenyl-1-substituted (piperidyl or pyrrolidinyl) ketones Expired - Lifetime US3532702A (en)

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US4045445A (en) * 1975-12-14 1977-08-30 American Cyanamid Company 11-(4-Piperidyl)dibenzo-diazepines
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
US20070105836A1 (en) * 2005-10-31 2007-05-10 Lars Pettersson Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders
EP1945208A2 (en) * 2005-10-06 2008-07-23 University of Massachusetts Composition and synthesis of new reagents for inhibition of hiv replication

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GB2094790B (en) * 1981-03-13 1985-10-09 Spofa Vereinigte Pharma Werke Tricycle compounds
IE912239A1 (en) * 1990-07-24 1992-01-29 Akzo Nv Tetrahydropyridinyldibenzazepine derivatives
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
AU2005257768A1 (en) * 2004-04-01 2006-01-05 Acadia Pharmaceuticals Inc. Method of synthesis and isolation of solid N-desmethylclozapine and crystalline forms thereof

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

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

Cited By (13)

* 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
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
US20050250767A1 (en) * 2003-01-23 2005-11-10 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
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
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
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
EP1945208A2 (en) * 2005-10-06 2008-07-23 University of Massachusetts Composition and synthesis of new reagents for inhibition of hiv replication
EP1945208A4 (en) * 2005-10-06 2011-08-03 Univ Massachusetts Composition and synthesis of new reagents for inhibition of hiv replication
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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