US3014911A - Derivatives of dibenzo[a, e]cycloheptatriene - Google Patents

Derivatives of dibenzo[a, e]cycloheptatriene Download PDF

Info

Publication number
US3014911A
US3014911A US826493A US82649359A US3014911A US 3014911 A US3014911 A US 3014911A US 826493 A US826493 A US 826493A US 82649359 A US82649359 A US 82649359A US 3014911 A US3014911 A US 3014911A
Authority
US
United States
Prior art keywords
dibenzo
piperidine
ml
solution
example
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US826493A
Inventor
Edward L Engelhardt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
Priority to US76380958A priority Critical
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to US826493A priority patent/US3014911A/en
Application granted granted Critical
Publication of US3014911A publication Critical patent/US3014911A/en
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27117345&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US3014911(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Anticipated expiration legal-status Critical
Application status is Expired - Lifetime legal-status Critical

Links

Classifications

    • 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
    • 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
    • C07D211/10Heterocyclic 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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12Heterocyclic 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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • 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
    • C07D211/20Heterocyclic 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 singly bound oxygen or sulfur atoms
    • C07D211/22Heterocyclic 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 singly bound oxygen or sulfur atoms 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
    • C07D211/68Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/70Sulfur atoms

Description

a United States Patent Ghice This invention relates to derivatives of dibenzo'[a,e]- cycloheptatriene and particularly to those having the structure:

Compound I..- alkyH-(S hydroxy 5 dibeuzo[a,e]cyclhcptatrienyl)- pipcrdine (when there is a double bond between 10 and 11 Cs) (when R is alkyl) and Compound II.1 alkyl 4 (5 dibenzoiae] eycloheptatrienylidene) piperidine (when there is a double bond between and 11 Gs) (when R is alkyl) in which R is-hydrogen or lower alkyl or alkenyl containing up to 4 carbon atoms and which may be straight or branched chained.

The alkyl radical may be substituted, for example, with a hydroxy, a mesyloxy or an amino group. The presence of either a single bond or a double bond between the 10 and 11 carbon atoms is indicated by the dotted line. The numbering of the dibenzocycloheptatriene ring system conforms to the Ring Index, number 2077.

The radicals X and X may be hydrogen or a halogen which particularly is chlorine, bromine or fluorine, but X and X may as well be radicals such as trifluoromethyl, lower alkyl having up to four carbon atoms, lower alkoxy having up to four carbon atoms, or a mononuclear aryl radical such as phenyl. The radicals X and X may be similar or may be dissimilar and each benzene ring may have one or two of the aforementioned radicals attached to it.

One or more of the hydrogens in positions 2, 3, 5, and 6 of the piperidine ring may be replaced by alkyl groups so long as the total number of carbon atoms in all such substituent alkyl groups does not exceed four. The invention also contemplates the N-oxides of compound I, which may be prepared from the bases by known methods.

The compounds represented by the structure I are useful as intermediates and may be sold commercially for making the compounds of structure II. The compounds of structure II possess antiserotonin and antihistamine activity. They may be administered to persons in any of the usual pharmaceutical oral forms such as powders, capsules, tablets, elixirs and aqueous suspensions, in the amount of from l to 250 milligrams per dose taken 2 to 4 times a day. For sterile solutions, for injection, from 0.1 to 50 milligrams would be injected per dose 2 to 4 times a day. The compound II may most easily be administered as a salt and any convenient, nontoxic acidsuch as hydrochloric acid may be used for this purpose and these salts are considered to be equivalent to the bases.

To prepare the compounds of the invention, theknown compound dibenzo[a,e]cycloheptatrien-S-one and its 10,11-dihydro derivative are used as starting materials and they are hereinafter referred to generically as dibenzo[a,e]cycloheptatrien-S-ones. They may be prepared by using the process described by -A. C. Cope et al., entitled Cyclic Polyolefins, [XV. 1-methylene- 2,3,6,7-dibenzo-cycloheptatriene, appearing in I. Am.

Chem. Soc. 73, 1673-1678 (1951)]. Or the starting compounds and particularly those having sub'stituents on the benzene rings may be made by following the teachings of T. W. Campbell et al., in an article entitled Synthesis of 2'-acetamido-2,326-,7-dibenzotropilidene and Z-acetamido-19,9-dimethylfluorene, appearing in Helv. Chim. Acta 36, 1489-1499 (1953). The preparation of specific starting materials is referred to in the subsequent examples.

The selected dibenzo[a,e]cycloheptatrien-S one (III) is condensed with a 1-alkyl-4-piperidylmagnesium halide (IV) employing tetrahydrofuran as the solvent, the precautions usually taken to exclude air and moisture from the apparatus during Grignard reactions being observed. (See Step B hereinafter.) This 1-alkyl-4- piperidylmagnesium halide may be either the bromide or the chloride but is preferably the chloride.

The Grignard reagent may be prepared as follows: The selected 1-alkyl-4-piperidone is reduced to the carbinol by the method described by S. M. McElvain and K. Rorig, J. Am. Chem. Soc. 70, 1826 (1948). The l-alkyl-4-piperidinol then may be converted to the l-alkyl- 4-chloropiperidine as described by these authors or to the 1-alkyl-4-bromopiperidine by the method employed by A. Einhorn, Ber. der Deutschen Chemischen Gesellschaft 23, 2891 (1890) for the conversion of tropine to 3-bromotropane. The Grignard reagent is then prepared by combining the -1-alkyl-4-halopiperidine with magnesium, preferably using tetrahydrofuran as the solvent. The usual maintenance of dry conditions should be observed. This may be represented as follows:

R IV

Step A The Grignard reagent and the dibenzo[a,e]cycloheptratrien-S-one are combined according to the following equation:

I 1 R Step B The condensation reaction of StepB is preferably initially carried out at low temperature for example cooling by means of an ice bath and finally may, continue at room temperature. It has been found that tetrahydrofuran is an. excellent solvent for carrying out the reaction of Step B and the source of this may be the solution obtained in Step- A. The dibenzo[a,e]cycloheptatrien-S-one can be added directly to the reaction mixture in which the Grignard reagent IV was prepared. However, any inert solvent for the reactants of Step B may be employed.

After the reaction of Step'B is completed the bulk of the solvent is removed by vacuum distillation, the Grignard adduct dissolved in benzene and hydrolyzed by the addition of water or ammonium chloride soiution with cooling. Compound I is recovered from the benzene solution. p

Compound I is dehydrated to produce Compound 11, as is represented by the following:

CQ .0 H X Step Compound IH2O-) Compound 11 The dehydration of compo-und l may be effected by means of such commonly used dehydrating agents as acetyl chloride or acetic anhydride but alternatively o-sulfobenzoic anhydride may be used. The alcohol may be dehydrated directly or may be first converted to a salt such as the hydrochloride, hydrob rornide or sulfate. Conversion to a salt prior to dehydration is preferable in some cases. The reactionmay be carried out in an excess of dehydrating agent as so-lvent, or employing a solvent such as chloroformpi: glacial acetic acid. Thesolvent then is removed by vacuum distillation and the compound II in the form of a salt is crystallized from a suitable 501-.

vent.

The following examples will further illustrate the invention:

4 EXAMPLE 1 1 ritethyl-4-(5-dibenzo[a,e]cycloheptatrienyliden)-piperidine hydrochloride and I-mefhyl-4 -(5-dibenzo[a,e]- cycloheptatrieny lidene -piperidine STEP A.PREPARATION OF l-METHYL -IIPERIDYL- MAGNESIUM CHLORIDE Magnesium turnings (5.45 g., 0.22 g. atom) were placed in a 500 ml. S-necked flask provided with a condenser, Hershberg stirrer and dropping funnel and protected with a drying tube. An atmosphere of dry nitro gen was maintained in the apparatus throughout the reaction. The magnesium was covered with 20 ml. of dry tetrahydr'ofuran. A crystal of iodine and 1.2 g. of ethyl bromide were added and after the reaction had subsided (formation of ethylmagnesium bromide) a solution of 29.4 g. (0.22 mole) of 4-chloro-1-methyl-piperidine in dry tetra-hydrofuran (total volume, 103 ml.) was added dropwise at such a rate that gentle reflux was maintained. The solution of 4-chloro-l-methyl-piperidine in tetrahydrofuran was dried over calcium hydride at icebath temperature prior to use. When the addition of the halide was complete the reaction mixture was refluxed with stirring for 1 hour. in some subsequent experiments this period of refluxing was omitted with no deleterious result.

STEP B.PREPARATION on l-METHYL- l-(S-HYDROXY- 5 DIBENZO[A,E]CYCLOHEPTATRIENYL) PIPERI- DINE The solution of the Grignard reagent prepared in step A was cooled to 5 to 10 C. and stirred while 22.7 g. (0.11 mole) of dibenzo[n.e]cycloheptatrien-5one was added in portions. After stirring for 1 hour during which time the reaction mixture was allowed to warm up to room temperature, the bulk of the tetrahydrofuran was distilled at 4050 C. under reduced pressure. Benzene, 150 ml., was added and the reaction mixture stirred and cooled in an iee-bath while water, ml., was added gradually. The benzene layer was separated by decantation and the gelatinous residue extracted three times with 75 ml. portions of boiling benzene. The solvent was evaporated from the combined benzene extracts to give 33 .4 g. of a clear light brown resin. Crystallization from an alcohol-water mixture gave 19.5 g. of 1-methyl-4-(5- hydroxy 5 dibenzo[a,e]cycloheptatrienyl)-piperidine, M.P. 156-157 C. Two reci'yst-aliizations from alcoholwater mixtures followed by two recrystallizations from benzene-hexane mixtures gave analytically pure product, M.P., 166.7l67.7 C.

Analysis-Calculated for C21HZ'3NOZ C, 82.59; H, 7.59; N, 4.59. Found: C, 82.39; H, 7.67; N, 4.58.

STEP C.PREPARATION OF I-METI-lYL Q-(RDIBENZO [A,E] CYCLOHEP'IATRIENYLIDENE -PIPERIDINE HY- DROCHLORIDE 1 methyl 4-(5 hydroxy-S-diben'zo[a,e]cycloheptatrienyl)-piperidine (3.05 g., 0.01 mole) was dissolved in glacial acetic acid, 15 ml. The solution was saturated with dry hydrogen chloride with external cooling. A white solid separated. Acetic anhydride (3.07 g., 0.03 mole) was added and the mixture heated on the steam-bath for 1 hour. The solid dissolved in the first 5 minutes of the heating period. The reaction mixture was poured into 25 ml.of water and the mixture made strongly basic with 10 N sodium hydroxide solution. The mixture was extracted three times with 50 ml. portions of benzene, the combined extracts washed with water and concentrated to a volume of approximately 50 ml. The solution was saturated with dry hydrogen chloride and the while crystalline product collected and dried. The yield of product, M.P. 251.6242.6C. (dec.) was 2.5 g. Recrystallization from a mixture of absolute alcohol and absolute ether gave a product, M.P. 252.6253.6 C. A sample was analyzed after drying for 7 hours at over phosphorus pentoxide in vacuo. i

Analysis.-Calculated for C H N-HCl: C, 77.88; H, 6.85; N, 4.33. Found: C, 77.60; H, 6.80; N, 4.31. STEP D.PREPARATION OF l-METHYL-l-(5-DIBENZO [A,E] CY CLO HEPTATRIENYLIDENE -PIPERIDINE The hydrochloride salt, 4.3 g., was suspended in 100 ml. of warm water and the mixture made strongly alkaline by the addition of 15 ml. of 5% sodium hydroxide. The mixture was extracted with four 50 ml. portions of henzene and the extracts dried over sodium sulfate. Evaporation of the benzene on the steam-bath at reduced pres sure left 3.7 g. (97%) of the base, M.P., 110.3-lll.3 C. Recrystallization from a mixture of alcohol and water gave product, M.P., 112.3113.3 C.

Analysis-Calculated for C H N: C, 87.76; H, 7.37; N, 4.88. Found: C, 87.77; H, 7.47; N, 4.87.

EXAMPLE la 1 methy l-4- 5 -di benzo {a,e*] cycloh eptaltrierzy Z id cne -p iperidine hydrochloride hydrate 1 methyl-4-(5-dibenzo[a,e] cycloheptatrienylidene) -piperidine (0.400 g., 0.00139 mole) as obtained in Example I, was dissolved in 55 ml. of 1 N hydrochloric acid at the boiling point. The solution was allowed to cool to room temperature and to stand for 24 hours. The crystalline product was collected and dried in a vacuum desiccator over concentrated sulfuric acid and soda lime for 6 hours. The product then was pulverized and dried over calcium chloride and soda lime at 0.1 mm. for approximately 65 hours. The yield of dried product was 0.420 g. In a melting point determination, this substance sintered at 190 C. and melted at 214216 C. when heated at a rate of 6 per minute from 180 C.

Anaylsis.Calculated for C H N-HCl-H O: C, 73.76; H, 7.08; N, 4.10; C1, 10.37. Found: C, 73.69; H, 7.31; N, 4.19; C1, 10.36.

EXAMPLE lb 1 -mefhyl-4-(5-dib enzo [at,e]cyclh epta rrienylidene) piperidine hydrogen m'aleate l methyl 4 dibenzo[a,e]cycloheptatrienylidene)- piperidine (0.400 g., 0.00139 mole) as obtained in Example I, was dissolved in 8 ml. of absolute alcohol. A solution of 0.170 g. (0.00147 mole) of maleic acid in 4 ml. of absolute alcohol was added and the resulting solution diluted to incipient crystallization with absolute ether. The product melted at 187-188 C. It was recrystallized from a mixture of isopropyl alochol and ether with no change in melting point.

Analysis.Calculated for C H N-C H O C, 74.41; H, 6.25; N, 3.47. Found: C, 74.17; H, 6.31; N, 3.64.

EXAMPLE II 1-is0pr0pyl-4-(5-dibenz0[a,e] cycloheptatrienylidene)piperidine STEP A.PREPARATION 0F 1-ISOPROPYL 4- PIPERIDYLMAGNESIUM CHLORIDE By substituting an equimolecular quantity of 4-chlorol-isopropylpiperidine for the 4-chloro-l-meth-yl-piperidine of Example I, Step A, and following substantially the pro cedure of Example I, Step A, a solution of l-isopropyl- 4-piperidylmagnesium chloride in tetrahydrofuran is obtained.

STEP B.PREPARATION OF 1ISOPROPYL-4-(5-HY- DROXY 5 DIBENZO[A,E]CYCLOHEPTATRIENYL-PI- PERIDINE Dibenzo[a,e]cycloheptatrien-5-one is added to the solution of the Grignard reagent obtained in Step A, and

the product isolated as described in Example I, Step B.

STEP C.PREPARATION 0F 1-ISOPROPYL-4-(5-DIBEN- Z0 [A,E] CYCLOHEPTATRIENYLIDENE -PIPERIDINE The 1-isopropyl-4-(5-hydroxy-5-dibenzo[a,e] cycloheptatrienyl)-piperidine obtained in Step B is dehydrated as 6 described in Example I, Step C, to give 1-isopropyl-4- (S-dibenzo[a,e]cycloheptatrienylidene)-piperidine that is isolated in the form of the hydrochloride salt.

EXAMPLE III I -butyl-4- (5 -dibe'nzo [me] cycloh epzatrienylidene piperidine STEP A'.PREPARATION OF 1-BUTYL-4PIPERIDYL- MAGNESIUM CHLORIDE By substituting an equimolecular quantity of 4-chloro-1- butylpiperidine for the 4-chloro-l-methylpiperidine of Example I, Step A and following substantially the procedure of Example I, Step A, a solution of l-butyl-4- piperidylmagnesium chloride in tetrahydrofuran is obtained.

STEP B.PREPARATION OF 1-BU'1YL-4-(5-HYDROXY-5- DIBENZO [A,E] -CYCLOHEPTA'TRIENYL -P IPERIDINE Dibenzo[a,e]cycloheptatrien-S-one is added to the solution of the Grignard reagent obtained in Step A and the product isolated as described in Example I, Step B.

STEP C.-PREPARATION 0F l-BUTYL4-(5-DIBENZO [A,E CYCLOHEPTATRIENYLIDENE -PIPER IDINE The 1-butyl-4- S-hydroxy-S -dibenzo [a,e] cycloheptatrienyl)-piperidine obtained in Step B is dehydrated as described in Example I, Step C to give 1-butyl-4-(5- dibenzo[a,e] cycloheptatrienylidene)-piperidine that is isolated in the form of the hydrochloride salt.

EXAMPLE IV 1-mezhyl-4-(5-dibenzo[ma] cyclo-heptazrienylidene) piperidine N-o xide A solution of 3.0 g. (0.0104 mole) of 1-methyl-4-(5- dibenzo[a,e]cycloheptatrienylidene)-piperidine in 30 ml. of absolute methanol was stirred and cooled in an ice-bath while 3.5 g. of 30% hydrogen peroxide was added dropwise over a 5 minute period. A colorless solid separated while the mixture was being stirred in the cold. After 15 minutes the ice-bath was removed and stirring was continued for 3 hours at room temperature. During this period the solid dissolved to give a clear pale yellow solution. After 22 hours the solution was cooled in an icebath and treated with an aqueous suspension of platinum black. After stirring for 1 hour at room temperature a test for peroxide was negative and the mixture was filtered through a mat of diatomaceous earth. The solvent then was evaporated under reduced pressure keeping the temperature below 35 C. The residue, a glass-like resin, was pulverized. It became partially crystalline on further drying. After additional drying over phosphorus pentoxide at 0.1 mm. pressure, the product gave elementary analyses agreeing well with the values calculated for the hernihydrate.

Analyser-Calculated for c ,n ,No- /2H,o: C, 80.71; H, 7.10; N, 4.48. Found: C, 80.77; H, 7.36; N, 4.58.

A sample from another experiment that was subjected to further drying gave the following analyses:

Armlysis.-Calculated for C H NO: C, 83.00; H, 6.97; N, 4.61. Found: C, 82.58; H, 7.37; N, 4.59.

EXAMPLE V 1-mcthyl-4( I 0,11-dihydr0-5-dibenz0[nae] cycloheptatrienylidene) -piperidine hydrochloride STEP A.-PREPARATION OF 1-\'IETHYL-4PIPERIDYL- MAGNESIUM CHLORIDE The Grignard reagent was prepared from 227 g. (0.0921 g. atom) of magnesium and 12.3 g. (0.0921 mole) of 1-methyl-4-piperidyl chloride in approximately ml. of tetrahydrofuran, following the procedure of Example I, Step A.

7 STEP B.PREPARATION OF LMETHYLA-(IOJl-DIHY- DRO HYDROXY-zS-DIBENZO[A,E]CYCLOHEPTA- TRIENYL)-PIPERIDINE 10,1 l-dihydrodibenzo [a,e] cycloheptatriene-5one (9 .5 8 g., 0.046 mole) was added to the Grignard solution of StepA and the product was isolated substantially as described in Example I, Step B. The l-methyl-4-(10,11- dihydro 5 hydroxy 5 dibenzo[a,e] cycloheptatrienyl)- piperidine, M.P. 179-l81 C. weighed 8.3 g. (59%) after recrystallization from a mixture of alcohol and water. A further recrystallization gave product, M.P. 180- 181 C.

Analysis.Calculated for C H NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 81.79; H, 7.93; N, 4.64. STEP C.PREPARATION OF 1-METHYL-4-(10,11-DIHY- DRO-5-DIBENZO {A,E] CYCLOHEPTATRIENYLIDENE) PIPERIDINE HYDROCHLORIDE 1 methyl 4 (10,11 dihydro S hydroxy 5 dibenzo[a,e]cycloheptatrienyl)-piperidine (6.3 g., 0.0205 mole) was dehydrated following substantially the procedure of Example 1, Step C. The hydrochloride of 1- methyl 4 (10,11 dihydro 5 dibenzo[a,e]cycloheptatrienylidene)-piperidine was obtained in a yield of 5.89 g. (99%), M.P. 273-274 C. (with decomposition). Recrystallization from a mixture of isopropyl alcohol and ether did not change the M.P.

Anaiysis.Calculated for C H N-HCl: C, 77.40; H, 7.42; N, 4.29; Cl, 10.88. Found: C, 77.23; H, 7.46; N, 4.4-5; Cl, 10.7 6.

EXAMPLE VT 1 -mathy[-4-(3-chl0r0-5-dibenz0 [a,e] cycloheptatrienylidene)-piperidine hydrogen malcate STEP A.-PREPARATION OF l-METHYL--PIPERID "L- MAGNESIUM CHLORIDE The Girgnard reagent was prepared from 2.43 g. (0.1)

g. atom), of magnesium and 13.36 g. (0.1 mole) of 1-methyl-4-chloropiperidine in approximately 90 ml. of

tetrahydrofuran, following the procedure of Example 1,

Step A and omitting the final period of heating.

STEP B.-PREPARATION OF 1METHYL-'4-(3-CHLORO- 5 HYDROXY 5 DIBENZO[A,E] CYCLOHEPTATRI- ENYL)-PIPERIDINE The solution of the Grignard reagent prepared in step A was cooled to 510 C. and stirred at this temperature while 3-chlorodibenzo[a,e]oycloheptatrien-S-one (12.03

g., 0.05 mole) was added. The product was isolated essentially as described in Example I, step B. The yield of product, M.P., 94.595.5 C. was 9.6 g. (54%). Recrystallization from a mixture of alcohol and Water raised the M.P. to 9597 C. After a second recrystallization the M.P. was increased to 199-200 C. The yield of this material was 5.4 g. (32% A further recrystallization from a mixture of alcohol and Water followed by a recrystallization from benzene and hexane did not change the M.P.

Analysis-Calculated for C H C1NO: C, 74.21; H,

6.53; N, 4.12. Found: C, 73.90; H, 6.39; N, 4.01.

The 3 chlorodibenzo[a,e]cycloheptatrien 5 one employed in step B was prepared by the following sequence.

3-(p-chlorobenzylidene)-phthalidewas prepared from pchlorophenylacetic acid and phthalic anhydride following essentially the method for the preparation of benzalpthalide described in Organic Syntheses Collective Volume II, page 61 (John Wiley and Sons, 1948). The 3-(pchlorobenzylidene)-phthalide was reduced to 2-(p-chlorophenethyl)-benzoic acid with phosphorus and hydriodic acid, essentially as described by A. C. Cope and S. W.

Fenton [1. Am. Chem. Soc. 73, 1673 (1951)] for the reduction of benzalphthalide. The cyclization of 2-(pchlorophenethyD-benzoic acid to 3-chloro-10,11-dihydrodibenzocycloheptatrien-S-one was accomplished by heating with polyphosphoric acid substantially as described by T. W. Campbell, R. Ginsig and H. Schmid, Helv. Chim.

Acta 36 1489 (1953). he 3-chloro-10,ll-dihydrodienzocycloheptatrien-S-one was brominated with N- bromosuccinimide and converted to 3-chlorodibenzo[a,e]

cycloheptatrien-S-one essentially as described by Cope and Fenton [1. Am. Chem. Soc. 73, 1673 (1951)].

STEP C.PREPARATION OF 1-METHYL-4-(aCHLORo- 5 DIBENZO[A,E]CYCLOHEPTATRIENYLIDENE) PI- PERIDENE HYDROGEN MALEATE 1-methyl-4-(3-chloro-5-hydroxy 5 dibenzo[a,e]cycloheptatrienyl)-piperidine (0.65 g., 0.00192 mole) and osulfobenzoic anhydride (3.68 g., 0.02 mole) were mixed and heated to 135-140 C. for minutes. The solid that formed on cooling was ground up and mixed with water. The m xture was made strongly alkaline and extracted with benzene. After washing with water the benzene was evaporated on the steam-bath under reduced pressure. The residue, a clear brown gum, was dissolved in benzene and the solution diluted with hexane. A

small quantity of an insoluble solid was separated by filtration and the solvent evaporated. The clear light yellow residue weighed 0.16 g. It was dissolved in 15 ml. of absolute ether and treated with a solution of 0.064 g. of maleic acid in 3 ml. of absolute alcohol. The

white crystalline product, M.P., 197l98 C. Weighed 0.08 g. Recrystallization from a mixture of alcohol and ether did not change the M.P.

Analysis.Calculated for C H ClN-C H O C, 68.57; H, 5.52; N, 3.20; Cl, 8.10. Found: C, 68.39; H, 5.47; N, 3.27; Cl, 7.91.

EXAMPLE VII 4-(5-dibenz0 [a,e,] cycloheptatrienylidene) -piperidine STEP A.PREPARATION OF l-CYANOd-(zS-DIBENZO 11,13] -CYCLOHEPTATRIENYLIDENE) -PIPERIDINE A solution of 1-methyl-4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidene (8.9 g., 0.031 mole) in 20 ml.

of dry benzene was added dropwise to a stirred solution of cyanogen bromide (3.6 g., 0.034 mole) in 15 ml. of benzene at room temperature. When approximately half of the solution had been added a white solid began to separate. When the addition was complete, 15 ml. of benzene was added to facilitate stirring and the mixture stirred for 75 minutes, then allowed to stand overnight.

After the addition of 50 ml. of absolute ether the product was'collected and recrystallized from a mixture of acetone and absolute alcohol. The yield of product, M.P., 203- 205 C. was 6.18-g. (67%).

An analytical sample, prepared by recrystallizing the roduct from a similar experiment from acetone and subsequently from ethyl acetate, melted at 203.5-

Analysis.Calculated for C H N C, 84.53; H, 6.08;

N, 9.39. Found: C, 84.62; H, 6.30; N, 9.58.

STEP B.PREPARATION 0F '4-(5-DIBENZO[A,E]CYCLO- HEPTATRIENYLIDENE) PIPERIDINE HYDROCHLO- RIDE 1-cyano-4- S-dibenzo [a,e] cycloheptatrienylidene) -piperidine (6.18 g., 0.0206 mole) was heated to refluxing in a mixture of 150 ml. of glacial acetic acid, ml. of

water and 15 ml. of concentrated hydrochloric acid for 16 hours. The solution was concentrated until solid began to separate (volume approximately ml.) and diluted with 100 ml. of water. The White crystalline product was collected and dried at 65 C. The yield of product, M.P., 290292 C. (with decomposition) was 5.8 g. (91%).

Y Analysis.-Calculated for C HlgN'HCIZ C, 77.53; H,

6.51; N, 4.52.- Found: C, 77.46; H, 6.51; N, 4.54.

STEP C,--PREPARATION OF 4-(5-DIBENZO[A,E]CYCLO- HEPTATRIENYLIDENE) -PIPERIDINE The hydrochloride of 4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidine was converted to the base by suspending it in water addingbenzene and an excess of sodium hydroxide and shaking the mixture till the solid dissolved. Evaporation. of the benzene left the crystalline base that was purified by recrystallization from a mixture of alcohol and Water, followed by recrystallization from a mixture of benzene and hexane.

Analysis.--Calculated for C I-I -N: C, 87.87; H, 7.01; N, 5.12. Found: C, 88.13; H, 7.05; N, 5.09.

EXAMPLE VIII 1 -eIhyl-4-(5-dibenz0 [cw] cycloheptatrienylidene) -piperidine hydrogen maleate 4 (5 dibenzo[a,e]cycloheptatrienylidene) piperidine (1.093 g., 0.004 mole) was dissolved in 25 ml. of dry t-butyl alcohol. Potassium t-butoxide (4.5 m1. of a 0.97 molar solution in t-butyl alcohol) was added followed by 0.624 g. (0.004 mole) of ethyl iodide. The solution was allowed to stand at room temperature for 20 hours then heated on the steam-bath for 2 hours. In order to remove unreacted starting material, ethyl chlorocarbonate (0.5 ml.) and pyridine (0.5 ml.) were added to the cooled solution which then was stirred 30 minutes at room temperature, heated on the steam-bath for 15 minutes, cooled and treated with 10 ml. of water followed by 10 ml. of 1.25 N sodium hydroxide solution. Benzene was added and the benzene extract separated and washed with Water. The basic material was extracted into 200 ml. of 0.05 molar citric acid solution. The acidic extract then was made basic and the basic material extracted into benzene. Evaporation of the benzene and drying the residue on the steam-bath under reduced pressure gave 048 g. of a viscous yellow oil that was dissolved in 95% ethanol and added to a solution of 0.203 g. of maleic acid in 95% ethanol. The solution was concentrated and diluted with ether. The white crystalline product, M.P., 202.5203.5 C. weighed 0.57 g. Further recrystallization from mixtures of alcohol and ether gave material melting at 203.5204.5 C.

Ana!ysis.Calculated for C H N-C H O C, 74.80; H, 6.52; N, 3.36. Found: C, 74.59; H, 6.54; N, 3.44.

EXAMPLE IX 1 propyl 4 (5 dibenz[a,e]cycl0heptatrienylidene)- piperidine hydrogen maleate 4 dibenzo[a,e] cycloheptatrienylidene)-piperidine (5.47 g., 0.02 mole) and sodamide (0.78 g., 0.02 mole) were heated to refluxing in 50 ml. of toluene for 15 hours. The light brown turbid solution was cooled to room temperature and n-propyl iodide (3.40 g., 0.02 mole) was added. The mixture was stirred at room temperature for 1 hour during which time a fiocculent light brown precipitate separated. The mixture then was heated on the steam-bath for 1 hour and finally at reflux for 30 minutes. After cooling to room temperature, 50 ml. of water was added to the reaction mixture which then was diluted with 200 ml. of hexane. The aqueous layer was separated and the organic layer washed with additional portions of water. After standing for days at room temperature the solution had deposited some prismatic crystals that were separated by filtration. The solution then was concentrated to a volume of approximately 25 ml. In order to remove unreacted starting material, maleic anhydride (4.70 g., 0.05 mole) in 35 ml. of benzene was added and the solution refluxed for 20 minutes. Methanol, 5 1111., then was added to destroy the excess maleic anhydride and the solution was concentrated to a volume of approximately 25 ml., and transferred to a separator-y funnel. Hexane, 200 ml., water, 200 ml. and triethanolamine (14.9 g., 0.1 mole) were added and the mixture shaken. After the separation was complete the clear yellow organic layer was separated and washed with water. Evaporation of the solvent and drying the residue on the steam-bath under reduced pressure gave 4.42 g. of a clear light brown residue. This material was dissolved in absolute alcohol and treated with a solution of 1.79 g. (0.0154 mole) of maleic acid in absolute alcohol. The hydrogen maleate of 1-propyl-4-(5- dibenzo[a,e]cycloheptatrienylidene) piperidine, M.P. 214-215 C. weighed 5.42 g. Recrystallization from npropyl alcohol gave product M.P. 214216 C. (sintered at 213 C.).

Analysis.Calculated for C H N'C H O 'C, 75.15; H, 6.77; N, 3.25. Found: C, 75.34; H, 6.86; N, 3.23.

EXAMPLE X 1 allyl 4 (5 dibenz0[a,e]cycl0hap-tatrienylidene)- piperidine hydrogen maleate The procedure of Example IX was followed, substituting 2.42 g. (0.02 mole) of allyl bromide for the n-propyl iodide. The product was isolated by substantially the same procedure. The product melted at 175177 C. after recrystallization from a mixture of alcohol and ether followed by recrystallization from n-propyl alcohol.

Analysis.Calculated for C H N'C H O C, 75.50; H, 6.34; N, 3.26. Found: C, 75.21; H, 6.42; N, 3.28.

EXAMPPLE XI 1 (Z-hydroxyethyl) 4 (5 dibenz0[a,e]cycloheptatri enylidene) -piperidine 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperidine (5.47 g., 0.02 mole) was dissolved in 109 ml. of ethanol. The solution was cooled to 0 C. and ethylene oxide was passed in until the gain in weight was 1.76 g. The container then was stoppered and heated to 65-70 C. in an autoclave for 1 hour. The solvent then was distilled and the last traces of alcohol and water removed by azeotropic distillation with benzene. The crystalline residue was extracted with boiling hexane and recrystallized from a mixture of benzene and hexane. Further recrystallization from mixtures of alcohol and water gave product, MP. 158-159 C.

Analysis.Calculated for C H NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 83.00; H, 7.29; N, 4.38.

EXAMPLE XII 1 (2 methane snlfonyloxyethyl) 4 (5 dibenzo[a,e]- cycloheptatrienylidene)-piperidine hydrochloride 1 (2 hydroxyethyl) 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperdine (2.10 g., 0.00662 mole) was dissolved in ml. of. dry acetonitrile. A solution of methanesulfo-nic anhydride (1.22 g., 0.007 mole) in 4 ml. of acetonitrile was added and the solution allowed to stand at room temperature for 48 hours. Some crystals that had been deposited were separated by decantation and approximately 50 m1. of acetonitrile was distilled at 35-45 C. under reduced pressure. After 3 days in the refrigerator the solution was filtered to remove the solid that had separated and the solvent evaporated at 2535 C. under reduced pressure. The syrupy residue, the methanesulfonic acid salt of the product, weighed 3.32 g. It was dissolved in 13 ml. of absolute alcohol and treated with 0.84 ml. of an 8.9 N solution of dry hydrogen chloride in absolute alcohol. Absolute ether was added portionwise to precipitate the hydrochloride. The product was recrystallized by dissolving it in absolute methanol, warming the solution in a bath at 30 C. and cautiously adding ether to incipient turbidity. The product melted at 130.5 134 C. with eifervescence.

Analysis.Calculated for C H O NS-HCl: C, 63.95; H, 6.07; Cl, 8.21; N, 3.24; S, 7.42. Found: C, 64.47; H, 6.22; Cl, 8.02; N, 3.24; S, 7.35.

EXAMPLE H11 1 (,6 dimethylaminoethyl) 4 (5 dibenz0[a,e]cycloheptatrienylidene)-piperidine dihydrogen dimaleate 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperidine (5.47 g., 0.02 mole) and sodarnide (1.64 g., 0.042 mole) were heated to refluxing in 50 ml. of toluene for 3 hours. ,B-Dimethylaminoethyl chloride hydrochloride (3.17 g., 0.022 mole) was added to the warm solution. Stirring and refluxing then were resumed and were continued for 12 hours. The reaction mixture then was filtered and the solvent evaporated on the steam-bath under reduced pressure. The residue contained a white crystalline solid. It was taken up in ether and shaken with water till the solid dissolved. The ether layer then was separated, washed with water and evaporated. The residue, a clear dark brown resin, weighed 6.31 g. It was dissolved in benzene, 25 m1. and treated with a solution of 4.70 g. (0.05 mole) of maleic anhydride in 50 ml. of benzene. The dark brown solution was refluxed on the steam-bath for 20 minutes. The Warm mixture then was treated with ml. of absolute methanol. The dark brown solution was decanted from a black tarry solid that had separated. The solid was shaken with a solution of 6 g. (0.15 mole) of sodium hydroxide in 100 ml. of water. Nearly all the black solid dissolved. This solution was added to the benzene layer. A heavy emulsion resulted. Water, 100 ml. and benzene, 100 ml. were added without effecting a separation. Ether, 100ml was added. A clear yellow organic phase separated and a tan precipitate collected in the water layer. The organic layer was separated and the aqueous layer filtered. The precipitate dissolved readily in water. This solution was extracted with ether and the extract combined with the organic layer. The combined organic layers then were washed with water. Evaporation of the solvent and drying the residue on the steam-bath under reduced pressure left 3.35 g. of residue. The residue was dissolved in absolute alcohol and treated with a solution of 2.48 g. (0.021 mole) of maleic acid in absolute alcohol. The product separated as a white crystalilne solid, M.P. 192193 C. (sintered at 190 C.) in a yield of 4.29 g. Recrystallization from absolute alcohol raised the MP. to 193-1945" C.

Analysis-Calculated for C H N -2C H O C, 66.65; H, 6.29; N, 4.86. Found: C, 66.51; H,f6.26; N, 4.80.

EXAMPLE XIV 1-metIzyl-4-(3-methoxy-5-dibenzo [a,e]cyclolzepiatrienylidene) -piperidine hydrogen maleate By substituting 3-methoxydibenzo[a,e]cycloheptatrien- 5-one for the 3-chlorodibenzo[a,e]cycloheptatrien-S-one of Example VI and following substantially the method of Example Vl, 1-methyl-4-(S-methoxy-S-dibenzo[a,e]cycloheptatrienylidene)-piperidine hydrogen maleate is obtained.

The 3-methoxydibenzo[a,e]cycloheptatrien-S-one is obtained by the sequence employed for the preparation of 3- chlorodibenzo[a,e]cycloheptatrien-5-one except that 3 (p methoxybenzylidene)-phthalide is reduced to 2-(p-methoxyphenethyl)-benzoic acid by the three step method of W. Treibs and H. Klinkhammer [Chemische Berichte, 84,671 (1951)] instead of employing the hydriodic acid method. 1

EXAMPLE'XV 1-methyl-4-(3-flu0r0-5-a'ibenzo [a,e] cyclohepratrienylid ene -pi peridine hydrogen maleate 1 2 EXAMPLE XVI 1-methyl-4-(1 -bromo-5-dibenz0 [a,e] cycloheptatrierzylidene) -piperidine hydrogen maleate EXAMPLE XVII 1 -methyl (3,7-dichl0r0-5-dibenzo [a,e] cycloheptatrieny liderze) -piperidine By substituting 3,7-dichlorodibenzo[a,e]-cycloheptatrien-S-one for the 3-chlorodibenzo[a,e]cycloheptatrien-5- one of Example VI and following substantially the method of Example VI, l-methyl(3,7-dichloro-5-dibenzo[a,e]- cycloheptatrienylidene)piperidine is obtained.

The 3,7 dichlorodibenzo{a,e]cycloheptatrien-S-one is prepared from 3,7-dinitrodibenzo[a,e]cycloheptatrien-5- one by reducing the nitro groups to amino and replacing the amino groups by chlorine, employing the Sandmeyer reaction. The dinitrodibenzocycloheptatrienone is prepared by the method of T. W. Campbell, R. Ginsig and H. Schmid, Helv. Acta 36, 1489 (1953).

EXAMPLE XVIII 1 -methyl-4- (4-methyl-10,1 1 -dzhydr0-5-dibenzo [me] -cycloheptatrienylidene) -piperidine hydrogen maleate By substituting 4-methyl-10,11-dihydrodibenzo[a,e]- cyclOheptatrien-S-one for the 10,11-dihydrodibenzo[a,e]- cycloheptatrien-S-oneof Example V and following substantially the procedure of Example V, 1-methyl-4-(4- methyl 10,11 dihydro S dibenzo[a,e]cycloheptatrienylidene)-piperidine is obtained. The product is isolated as the hydrogen maleate salt.

The 4 methyl 10,11 dihydro 5 dibenzo[a,e]- cyclohept-atrien-5one is prepared by the cyclization of 2-methyl-6-phenethylbenzoic acid with polyphosphoric acid under the conditions for the cyclization of Z-phenethylbenzoic acid described by T. W. Campbell, R. Ginsig and H. Schmid, Helv. Chim. Acta 36, 1489 (1953).

EXAMPLE XIX 1 methyl 4 (10,11 dihydro 2,3 dimethyl 7 isopropyl 5 dibenzo[a,e]cycloheptatrienylidene) piperidiize hydrochloride By substituting 10,11-dihydro-2,3-dimethyl-7-isopropyldibenzo[a,e]cycloheptatrien-S-one for the 10,11-dihydrodibenzo[a,e] cycloheptatrien-S-one of Example V and following substantially the procedure of Example V, 1- methyl 4 (10,11 dihydro 2,3 dimethyl 7 isopropyl 5 dibenzo [a,e]cycloheptatrienylidene)-piperidine hydrochloride is obtained.

The 10,11 dihydro 2,3 dimethyl 7 isopropyl-dibenzoIa,e]cycloheptatrien-S-one is prepared by the following sequence. 4,5-dimethylphthalic anhydride is condensed with p-isopropylphenylacetic acid to give 3-(p-isopropylbenzylidene)-phthalide. Reduction with phosphorus and hydriodic acid gives 2- (p-isopropylphenethyl)-4,5- dimethylbenzoic acid. The acid is cyclized to the desired ketone by the action of polyphosphoric acid as described by T. W. Campbell, R. Ginzig and H. Schmid, Helv. Chim. Acta 36, 1489 (1953).

13 EXAMPLE XX 1 methyl 4 (10,11 dihydro 2,3 dichloro 7- methyl 5 dibenz[a,e]cyclohepmtrienylidene) piperidiize hydrochloride By substituting 10,11-dihydr0-2,3-dich1oro-7-methyl-dibenzo[a,e]cycloheptatrien-S-one for the 10,11-dihydr0dibenzo[a,e]cycloheptatrien-S-one of Example V and following substantially the procedure of Example V, 1- methyl 4 (10,11 dihydro 2,3 dichloro 7 methyl- 5 dibenzo[a,e]cycloheptatrienylidene) piperidine hydrochloride is obtained.

The 10,11 dihydro 2,3 dichloro 7 methyldibenzo[a,e]cycloheptatrien-S-one is prepared by the sequence of reactions employed for the preparation of 10, 11 dihydro 2,3 dimethyl 7 isopropyldibenzo[a,e]- cycloheptatrien-S-one, described in Example XIX, employing 4,5-dichlorophtha1ic anhydride and p-methylphenylacetic acid as starting materials.

This application is a contination-in-part of my copending US. patent application, Serial No. 763,809, now abandoned, filed September 29, 1958.

What is claimed is:

1. A compound selected from the group consisting of:

ii if? m 1} X piperidine.

4. 1 methyl 4 (10,11-dihydro-5-dibenzo[a,e]cycloheptatrienylidene -piperidine.

5. 1 methyl 4 (3-chloro-5-dibenzo[a,e]c-ycloheptatrienylidene) -piperidine.

6. 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperidine.

7. 1 (2 hydroxyethyl)-4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidine.

8. The compound 1 methyl-4-(5-dibenzo[a,e]-cycloheptatrienylidene) -piperidine.

9. The compound 1-me-thyl-4-(5-dibenzo[a,e]-cyclo-' heptatrienylidene)-piperidine hydrochloride hydrate.

References Cited in the file of this patent UNITED STATES PATENTS 2,498,431 Lee Feb. 21, 1950 2,599,364 Berger et al. June 3, 1952 2,739,968 Sperber et al. Mar. 27, 1956 2,985,660 Judd et a1. May 23, 1961 FOREIGN PATENTS 535,142 Canada Jan. 1, 1957 925,468 Germany Mar. 21, 1955

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF:
US826493A 1958-09-29 1959-07-13 Derivatives of dibenzo[a, e]cycloheptatriene Expired - Lifetime US3014911A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US76380958A true 1958-09-29 1958-09-29
US826493A US3014911A (en) 1958-09-29 1959-07-13 Derivatives of dibenzo[a, e]cycloheptatriene

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US826493A US3014911A (en) 1958-09-29 1959-07-13 Derivatives of dibenzo[a, e]cycloheptatriene
GB2949059A GB931555A (en) 1958-09-29 1959-08-28 Dibenzocycloheptatriene derivatives
GB730863A GB931556A (en) 1958-09-29 1959-08-28 Dibenzocycloheptatriene derivatives
BE582220A BE582220A (en) 1958-09-29 1959-09-01 steroid compounds and their preparation
DE19591420072 DE1420072C3 (en) 1958-09-29 1959-09-03
CH7878959A CH387037A (en) 1958-09-29 1959-09-29 A process for the manufacture of dibenzo (a, e) cycloheptatrien derivatives
OA51101A OA998A (en) 1958-09-29 1964-12-29 Process for producing derivatives of bibenzo (a, e) cycloheptatriene
MY6400051A MY6400051A (en) 1958-09-29 1964-12-30 Dibenxocyclohepatriene derivatives

Publications (1)

Publication Number Publication Date
US3014911A true US3014911A (en) 1961-12-26

Family

ID=27117345

Family Applications (1)

Application Number Title Priority Date Filing Date
US826493A Expired - Lifetime US3014911A (en) 1958-09-29 1959-07-13 Derivatives of dibenzo[a, e]cycloheptatriene

Country Status (7)

Country Link
US (1) US3014911A (en)
BE (1) BE582220A (en)
CH (1) CH387037A (en)
DE (1) DE1420072C3 (en)
GB (2) GB931555A (en)
MY (1) MY6400051A (en)
OA (1) OA998A (en)

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3133935A (en) * 1962-01-08 1964-05-19 American Home Prod Dibenzo [a, d] [1, 4] cyclooctadienes
US3152135A (en) * 1962-11-02 1964-10-06 Warner Lambert Pharmaceutical Heterocyclic substituted indazole compounds and process therefor
US3188347A (en) * 1961-12-18 1965-06-08 Schering Corp 5(4-dimethylaminocyclohexy)-dibenzo [a, d] cyclohepta[1, 4]diene and salts thereof
US3227716A (en) * 1959-04-01 1966-01-04 Koninklijke Pharma Fab Nv Therapeutically-active dibenzocycloheptane derivatives
US3231468A (en) * 1962-07-02 1966-01-25 Merck & Co Inc Dexamethasone-cyproheptadine oral antiflammatory compositions
US3272826A (en) * 1962-08-31 1966-09-13 Sandoz Ltd Substituted 4[piperidylidene(4')]-9, 10-dihydro-4h-benzo [4, 5] cyclohepta [1, 2-b] thiophene and the 4 piperidyl 4 ol compounds
US3275640A (en) * 1961-09-29 1966-09-27 Merck & Co Inc Substituted 1-hydrocarbyl-4-(10-thiaxanthylidene) piperidines
US3324138A (en) * 1963-12-03 1967-06-06 Koninklijke Pharma Fab Nv Quinuclidin-3-yl-ester of 10, 11-dihydro-5h-dibenzo[a, d]cyclohepten-5-yl-acetic acid
US3326924A (en) * 1963-04-24 1967-06-20 Schering Corp Novel aza-dibenzo[a, d]-cycloheptene derivatives
US3352869A (en) * 1965-05-18 1967-11-14 Merck & Co Inc Substituted and unsubstituted 4-(5h-dibenzo[a, d] cyclohepten-5-ylidene)-1-(amino ornitroso) piperidines
US3357982A (en) * 1964-08-18 1967-12-12 Koninklijke Pharma Fab Nv 1-(5h-dibenzo [a, d] cyclohepten-5-yl)-4-alkylpiperazines
US3391143A (en) * 1966-05-16 1968-07-02 Smith Kline French Lab 9-piperidyl and 9-piperidylidene derivatives of acridan
US3419565A (en) * 1963-04-24 1968-12-31 Schering Corp Aza-dibenzocycloheptenes
US3420848A (en) * 1964-05-18 1969-01-07 Sandoz Ag Dibenzocycloheptane derivatives
US3458522A (en) * 1967-05-17 1969-07-29 Sandoz Ag 4-piperidine substituted benzocycloheptaoxazoles and benzocycloheptathiazoles
US3475438A (en) * 1967-08-24 1969-10-28 Merck & Co Inc Piperidine derivatives of dibenzobicyclo(5.1.0)octane
US3484520A (en) * 1965-05-17 1969-12-16 Merck & Co Inc Compositions and methods for treating helminthiasis comprising combinations of organo-phosphates and certain dibenzocycloheptenes
US3487078A (en) * 1960-11-09 1969-12-30 Sandoz Ag Improvements in or relating to dibenzocycloheptane compounds
US3491103A (en) * 1963-12-19 1970-01-20 Sandoz Ag Certain 4h-benzo(4,5)cyclohepta-(1,2-b) thiophenes
DE1952206A1 (en) * 1968-10-22 1970-04-23 Soc Ind Fab Antibiotiques Sifa New derivatives of Tropans, their salts and processes for preparing
US3524000A (en) * 1965-03-15 1970-08-11 Merck & Co Inc Anthelmintic compositions and method of using same
US3919321A (en) * 1966-11-08 1975-11-11 Hoffmann La Roche Halo-substituted-5H-dibenzo{8 a,d{9 cyclohepten-5-ones
US3960872A (en) * 1970-02-05 1976-06-01 Merck & Co., Inc. 1 Alkyl-4-(10:oxo or hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine compounds
US3968115A (en) * 1970-02-05 1976-07-06 Merck & Co., Inc. 1-Alkyl-4-(10 and/or 11)-bromo-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ylidene piperidine compounds
US3974285A (en) * 1974-04-10 1976-08-10 Merck & Co., Inc. 10,11-Furo-derivatives of cyproheptadine
US3979513A (en) * 1974-02-04 1976-09-07 Imperial Chemical Industries Limited 1'-Substituted-9,10-dihydroanthracene-9-spiro-4'-piperidine derivatives
US3981876A (en) * 1970-02-05 1976-09-21 Merck & Co., Inc. 1-Alkyl-4-(10[1-piperidyl]-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine compounds
US3981877A (en) * 1972-08-14 1976-09-21 Merck & Co., Inc. Piperidylidene derivatives of carboxy-5H-dibenzo[a,d]cycloheptene
US3988461A (en) * 1974-06-13 1976-10-26 Egyt Gyogyszervegyeszeti Gyar Pharmaceutical composition for the treatment of Parkinson's disease
US3988342A (en) * 1972-08-14 1976-10-26 Merck & Co., Inc. Piperidylidene derivatives of cyano-5H-dibenzo[a,d]cycloheptene
US3992547A (en) * 1974-11-20 1976-11-16 Merck & Co., Inc. 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine-N-oxide isomer
US4022902A (en) * 1975-08-29 1977-05-10 Merck & Co., Inc. 10,11-Dihydro-3-carboxycyproheptadien-N-oxide
US4044143A (en) * 1975-01-30 1977-08-23 Merck & Co., Inc. 10,11-Bis-(hydroxyalkyl) derivatives of cyproheptadine
US4072756A (en) * 1973-05-17 1978-02-07 Sandoz Ltd. Tricyclo piperidino ketones and soporific compositions thereof
DE2736259A1 (en) * 1976-08-12 1978-02-16 Merck & Co Inc Low 3-alkoxycyproheptadine
US4089864A (en) * 1974-03-25 1978-05-16 Merck & Co., Inc. 4-(10,11-Dihydro-cis and trans-10,11-dihydroxy-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidines
US4112112A (en) * 1976-06-29 1978-09-05 Merck & Co., Inc. Pyrrolo[2,1-b] [3]benzazepines useful for producing a skeletal muscle relaxing or tranquilizing effect
US4132796A (en) * 1977-12-01 1979-01-02 Merck & Co., Inc. Antipsychotic 3-trifluoromethylsulfinyl analogs of cyproheptadine
EP0000716A2 (en) * 1977-07-28 1979-02-21 Merck & Co., Inc. Pyrrolo(2,1-b)(3)benzazepine derivatives, process for their preparation and pharmaceutical compositions containing them
US4160031A (en) * 1975-03-28 1979-07-03 Merck & Co., Inc. Antihistaminic and appetite stimulating 10,11-dihydro-3-carboxycyproheptadine
US4195091A (en) * 1978-11-15 1980-03-25 Merck & Co., Inc. Appetite stimulating pyrrolo[2,1-b][3]benzazepines
EP0012988A1 (en) * 1979-01-02 1980-07-09 Merck & Co., Inc. Levorotatory or dextrorotatory enantiomers of 3-halocyproheptadines, process for their preparation and pharmaceutical composition thereof
US4212871A (en) * 1979-03-02 1980-07-15 Merck & Co., Inc. Appetite stimulating and antihistaminic 3-hydroxymethylcyproheptadine and analogs
US4220651A (en) * 1979-05-21 1980-09-02 Merck & Co., Inc. Antipsychotic levorotatory enantiomers of 3-halocyproheptadines, analogs and derivatives
EP0019797A1 (en) * 1979-05-21 1980-12-10 Merck & Co., Inc. Levorotatory and dextrorotatory enantiomers of 3-methoxycyproheptadine and analogs thereof, process for their preparation and antipsychotic pharmaceutical compositions
US4275070A (en) * 1979-05-21 1981-06-23 Merck & Co., Inc. Antipsychotic pharmaceutical compositions of the levorotatory enantiomers of 3-methoxycyproheptadine and an analog thereof
US4356184A (en) * 1980-06-04 1982-10-26 G. D. Searle & Co. Anti-allergic or antihypertensive 1-piperidinylmethyl benzenamines
US4412999A (en) * 1982-04-14 1983-11-01 Merck & Co., Inc. Anti-emetic esters of cyproheptadine-3-carboxylic acid and structurally related compounds
US4590202A (en) * 1984-01-19 1986-05-20 Merck & Co., Inc. N-(2-imidazolidinylidene)-5H-dibenzo[a,d]cyclohepten-5-amine compounds and α2 -adrenergic antagonistic uses thereof
US4626542A (en) * 1984-04-05 1986-12-02 Merck & Co., Inc. 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds, pharmaceutical compositions and methods
US4758577A (en) * 1984-04-05 1988-07-19 Merck & Co., Inc. 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds for treating cardiovascular disorders
FR2618151A1 (en) * 1987-07-16 1989-01-20 Synthelabo Piperidine derivatives, their preparation and their application in therapeutics
EP0347123A2 (en) * 1988-06-17 1989-12-20 Fisons Corporation Dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
US4912222A (en) * 1988-06-17 1990-03-27 Fisons Corporation Antihistamines related to cyproheptadine
EP0371805A2 (en) * 1988-11-30 1990-06-06 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
US5021426A (en) * 1990-02-26 1991-06-04 Merck & Co., Inc. Method of traeting malaria with cyproheptadine derivatives
US5250681A (en) * 1988-06-02 1993-10-05 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
US6214837B1 (en) 1997-03-06 2001-04-10 Blomqvist Goeran Pharmaceutical composition for the treatment of so-called restless legs

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2498431A (en) * 1945-06-13 1950-02-21 Hoffmann La Roche 2-and 4-homocyclyl substituted piperidines
US2599364A (en) * 1949-01-26 1952-06-03 Hoffmann La Roche 1-alkyl-3-benzohydryl piperidines
DE925468C (en) * 1941-08-13 1955-03-21 Hoechst Ag A process for preparing ª †, † ª diaryl-propyl-amines
US2739968A (en) * 1950-12-05 1956-03-27 Schering Corp Substituted piperidines
CA535142A (en) * 1957-01-01 W. Weston Arthur Pipecolyl carbinol compounds
US2985660A (en) * 1960-04-29 1961-05-23 Lakeside Lab Inc 5-heterocyclic-5h-dibenzo [a, d] cycloheptenes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA535142A (en) * 1957-01-01 W. Weston Arthur Pipecolyl carbinol compounds
DE925468C (en) * 1941-08-13 1955-03-21 Hoechst Ag A process for preparing ª †, † ª diaryl-propyl-amines
US2498431A (en) * 1945-06-13 1950-02-21 Hoffmann La Roche 2-and 4-homocyclyl substituted piperidines
US2599364A (en) * 1949-01-26 1952-06-03 Hoffmann La Roche 1-alkyl-3-benzohydryl piperidines
US2739968A (en) * 1950-12-05 1956-03-27 Schering Corp Substituted piperidines
US2985660A (en) * 1960-04-29 1961-05-23 Lakeside Lab Inc 5-heterocyclic-5h-dibenzo [a, d] cycloheptenes

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3227716A (en) * 1959-04-01 1966-01-04 Koninklijke Pharma Fab Nv Therapeutically-active dibenzocycloheptane derivatives
US3487078A (en) * 1960-11-09 1969-12-30 Sandoz Ag Improvements in or relating to dibenzocycloheptane compounds
US3275640A (en) * 1961-09-29 1966-09-27 Merck & Co Inc Substituted 1-hydrocarbyl-4-(10-thiaxanthylidene) piperidines
US3188347A (en) * 1961-12-18 1965-06-08 Schering Corp 5(4-dimethylaminocyclohexy)-dibenzo [a, d] cyclohepta[1, 4]diene and salts thereof
US3133935A (en) * 1962-01-08 1964-05-19 American Home Prod Dibenzo [a, d] [1, 4] cyclooctadienes
US3231468A (en) * 1962-07-02 1966-01-25 Merck & Co Inc Dexamethasone-cyproheptadine oral antiflammatory compositions
US3272826A (en) * 1962-08-31 1966-09-13 Sandoz Ltd Substituted 4[piperidylidene(4')]-9, 10-dihydro-4h-benzo [4, 5] cyclohepta [1, 2-b] thiophene and the 4 piperidyl 4 ol compounds
US3152135A (en) * 1962-11-02 1964-10-06 Warner Lambert Pharmaceutical Heterocyclic substituted indazole compounds and process therefor
US3357986A (en) * 1963-04-24 1967-12-12 Schering Corp 1, 2, 3 or 4, aza,-[5-piperdyl or hydrocarbyl amino]-10, 11 dihydro-5h-dibenzo-[a, d]-cycloheptene
US3419565A (en) * 1963-04-24 1968-12-31 Schering Corp Aza-dibenzocycloheptenes
US3326924A (en) * 1963-04-24 1967-06-20 Schering Corp Novel aza-dibenzo[a, d]-cycloheptene derivatives
US3324138A (en) * 1963-12-03 1967-06-06 Koninklijke Pharma Fab Nv Quinuclidin-3-yl-ester of 10, 11-dihydro-5h-dibenzo[a, d]cyclohepten-5-yl-acetic acid
US3491103A (en) * 1963-12-19 1970-01-20 Sandoz Ag Certain 4h-benzo(4,5)cyclohepta-(1,2-b) thiophenes
US3420848A (en) * 1964-05-18 1969-01-07 Sandoz Ag Dibenzocycloheptane derivatives
US3357982A (en) * 1964-08-18 1967-12-12 Koninklijke Pharma Fab Nv 1-(5h-dibenzo [a, d] cyclohepten-5-yl)-4-alkylpiperazines
US3524000A (en) * 1965-03-15 1970-08-11 Merck & Co Inc Anthelmintic compositions and method of using same
US3484520A (en) * 1965-05-17 1969-12-16 Merck & Co Inc Compositions and methods for treating helminthiasis comprising combinations of organo-phosphates and certain dibenzocycloheptenes
US3352869A (en) * 1965-05-18 1967-11-14 Merck & Co Inc Substituted and unsubstituted 4-(5h-dibenzo[a, d] cyclohepten-5-ylidene)-1-(amino ornitroso) piperidines
US3391143A (en) * 1966-05-16 1968-07-02 Smith Kline French Lab 9-piperidyl and 9-piperidylidene derivatives of acridan
US3919321A (en) * 1966-11-08 1975-11-11 Hoffmann La Roche Halo-substituted-5H-dibenzo{8 a,d{9 cyclohepten-5-ones
US3458522A (en) * 1967-05-17 1969-07-29 Sandoz Ag 4-piperidine substituted benzocycloheptaoxazoles and benzocycloheptathiazoles
US3475438A (en) * 1967-08-24 1969-10-28 Merck & Co Inc Piperidine derivatives of dibenzobicyclo(5.1.0)octane
DE1952206A1 (en) * 1968-10-22 1970-04-23 Soc Ind Fab Antibiotiques Sifa New derivatives of Tropans, their salts and processes for preparing
US3725415A (en) * 1968-10-22 1973-04-03 Ind Pour La Fab Antibiotiques 3-tropanylidine derivatives of tricyclic compounds, their salts, and process of preparation
US3960872A (en) * 1970-02-05 1976-06-01 Merck & Co., Inc. 1 Alkyl-4-(10:oxo or hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine compounds
US3968115A (en) * 1970-02-05 1976-07-06 Merck & Co., Inc. 1-Alkyl-4-(10 and/or 11)-bromo-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ylidene piperidine compounds
US3981876A (en) * 1970-02-05 1976-09-21 Merck & Co., Inc. 1-Alkyl-4-(10[1-piperidyl]-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine compounds
US3981877A (en) * 1972-08-14 1976-09-21 Merck & Co., Inc. Piperidylidene derivatives of carboxy-5H-dibenzo[a,d]cycloheptene
US3988342A (en) * 1972-08-14 1976-10-26 Merck & Co., Inc. Piperidylidene derivatives of cyano-5H-dibenzo[a,d]cycloheptene
US4072756A (en) * 1973-05-17 1978-02-07 Sandoz Ltd. Tricyclo piperidino ketones and soporific compositions thereof
US3979513A (en) * 1974-02-04 1976-09-07 Imperial Chemical Industries Limited 1'-Substituted-9,10-dihydroanthracene-9-spiro-4'-piperidine derivatives
US4089864A (en) * 1974-03-25 1978-05-16 Merck & Co., Inc. 4-(10,11-Dihydro-cis and trans-10,11-dihydroxy-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidines
US3974285A (en) * 1974-04-10 1976-08-10 Merck & Co., Inc. 10,11-Furo-derivatives of cyproheptadine
US3988461A (en) * 1974-06-13 1976-10-26 Egyt Gyogyszervegyeszeti Gyar Pharmaceutical composition for the treatment of Parkinson's disease
US3992547A (en) * 1974-11-20 1976-11-16 Merck & Co., Inc. 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine-N-oxide isomer
US4044143A (en) * 1975-01-30 1977-08-23 Merck & Co., Inc. 10,11-Bis-(hydroxyalkyl) derivatives of cyproheptadine
US4160031A (en) * 1975-03-28 1979-07-03 Merck & Co., Inc. Antihistaminic and appetite stimulating 10,11-dihydro-3-carboxycyproheptadine
US4022902A (en) * 1975-08-29 1977-05-10 Merck & Co., Inc. 10,11-Dihydro-3-carboxycyproheptadien-N-oxide
US4112112A (en) * 1976-06-29 1978-09-05 Merck & Co., Inc. Pyrrolo[2,1-b] [3]benzazepines useful for producing a skeletal muscle relaxing or tranquilizing effect
DE2736259A1 (en) * 1976-08-12 1978-02-16 Merck & Co Inc Low 3-alkoxycyproheptadine
US4104398A (en) * 1976-08-12 1978-08-01 Merck & Co., Inc. 3-Lower alkoxycyproheptadines as serotonin inhibitors
EP0000716A2 (en) * 1977-07-28 1979-02-21 Merck & Co., Inc. Pyrrolo(2,1-b)(3)benzazepine derivatives, process for their preparation and pharmaceutical compositions containing them
US4148903A (en) * 1977-07-28 1979-04-10 Merck & Co., Inc. Antipsychotic, antiserotonin and antihistaminic pyrrolo[2,1-b][3]benzazepines
EP0000716B1 (en) * 1977-07-28 1983-03-09 Merck & Co., Inc. Pyrrolo(2,1-b)(3)benzazepine derivatives, process for their preparation and pharmaceutical compositions containing them
US4132796A (en) * 1977-12-01 1979-01-02 Merck & Co., Inc. Antipsychotic 3-trifluoromethylsulfinyl analogs of cyproheptadine
US4195091A (en) * 1978-11-15 1980-03-25 Merck & Co., Inc. Appetite stimulating pyrrolo[2,1-b][3]benzazepines
EP0012988A1 (en) * 1979-01-02 1980-07-09 Merck & Co., Inc. Levorotatory or dextrorotatory enantiomers of 3-halocyproheptadines, process for their preparation and pharmaceutical composition thereof
US4212871A (en) * 1979-03-02 1980-07-15 Merck & Co., Inc. Appetite stimulating and antihistaminic 3-hydroxymethylcyproheptadine and analogs
US4220651A (en) * 1979-05-21 1980-09-02 Merck & Co., Inc. Antipsychotic levorotatory enantiomers of 3-halocyproheptadines, analogs and derivatives
EP0019797A1 (en) * 1979-05-21 1980-12-10 Merck & Co., Inc. Levorotatory and dextrorotatory enantiomers of 3-methoxycyproheptadine and analogs thereof, process for their preparation and antipsychotic pharmaceutical compositions
US4275070A (en) * 1979-05-21 1981-06-23 Merck & Co., Inc. Antipsychotic pharmaceutical compositions of the levorotatory enantiomers of 3-methoxycyproheptadine and an analog thereof
US4356184A (en) * 1980-06-04 1982-10-26 G. D. Searle & Co. Anti-allergic or antihypertensive 1-piperidinylmethyl benzenamines
US4412999A (en) * 1982-04-14 1983-11-01 Merck & Co., Inc. Anti-emetic esters of cyproheptadine-3-carboxylic acid and structurally related compounds
US4590202A (en) * 1984-01-19 1986-05-20 Merck & Co., Inc. N-(2-imidazolidinylidene)-5H-dibenzo[a,d]cyclohepten-5-amine compounds and α2 -adrenergic antagonistic uses thereof
US4626542A (en) * 1984-04-05 1986-12-02 Merck & Co., Inc. 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds, pharmaceutical compositions and methods
US4758577A (en) * 1984-04-05 1988-07-19 Merck & Co., Inc. 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds for treating cardiovascular disorders
FR2618151A1 (en) * 1987-07-16 1989-01-20 Synthelabo Piperidine derivatives, their preparation and their application in therapeutics
US5250681A (en) * 1988-06-02 1993-10-05 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
WO1989012443A1 (en) * 1988-06-17 1989-12-28 Fisons Corporation Novel dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
EP0347123A3 (en) * 1988-06-17 1991-07-03 Fisons Corporation Dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
US4912222A (en) * 1988-06-17 1990-03-27 Fisons Corporation Antihistamines related to cyproheptadine
EP0347123A2 (en) * 1988-06-17 1989-12-20 Fisons Corporation Dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
EP0371805A2 (en) * 1988-11-30 1990-06-06 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
EP0371805A3 (en) * 1988-11-30 1991-07-31 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
US5021426A (en) * 1990-02-26 1991-06-04 Merck & Co., Inc. Method of traeting malaria with cyproheptadine derivatives
US6214837B1 (en) 1997-03-06 2001-04-10 Blomqvist Goeran Pharmaceutical composition for the treatment of so-called restless legs

Also Published As

Publication number Publication date
BE582220A (en) 1960-03-01
BE582220A1 (en)
DE1420072C3 (en) 1974-08-08
MY6400051A (en) 1964-12-31
CH387037A (en) 1965-01-31
DE1420072B2 (en) 1974-01-03
GB931555A (en) 1963-07-17
DE1420072A1 (en) 1968-10-03
GB931556A (en) 1963-07-17
OA998A (en) 1968-08-07

Similar Documents

Publication Publication Date Title
Krapcho et al. Substituted 2, 3-Dihydro-1, 5-benzothiazepin-4 (5H)-one and Related Compounds. II. A New Class of Antidepressants1
US6797824B2 (en) Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; new classes of dopamine receptor subtype specific ligands
CA2205998C (en) Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; new classes of dopamine receptor subtype specific ligands
CA1341044C (en) Benzopyrido piperidine, piperidylidene and peperazine compounds, compositions, methods of manufacture and methods of use
US4207324A (en) 1,2-Di-Substituted-4-haloimidazole-5-acetic acid derivatives and their use
US3491093A (en) Derivatives of 5 aminomethyl-4,5,6,7-tetrahydro-4-oxoindoles
CA1125749A (en) 5h-2,3-benzodiazepine derivatives and a process for the preparation thereof
CA1119601A (en) Tetrahydropyridine and piperidine derivatives and their acid addition salts, processes for their preparation and pharmaceutical preparations containing such compounds
EP0339978B1 (en) Fused polycyclic compounds, compositions, methods of manufacture, and their use as PAF antagonists, antihistamines and/or antiinflammatory agents
US4066654A (en) 1-triarylalkyl-4-phenyl-4-piperidine carboxylic acids and derivatives
US5292761A (en) Piperidine, tetrahydropyridine and pyrrolidine compounds
JP2656189B2 (en) Benzisothiazole and benzisoxazole-3-carboxamide, their preparation and their more composed antipsychotics
US3183234A (en) Octahydroindoloquinolines
JP2660407B2 (en) The novel imide derivatives
US4500525A (en) Pharmacologically active pyrazolo/4,3-c/pyridines
Engelhardt et al. Structure-activity relationships in the cyproheptadine series
US3420851A (en) Novel dibenzoxepines
DK160314B (en) Analogifremgangsmaade for the preparation of bicyclic pyrimidin-5-one derivatives and pharmaceutically acceptable salts thereof
US3822258A (en) 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production
US5134147A (en) 1,2-benzisoxazole compounds
US4022791A (en) 2-Aminomethyl-3,4-dihydronaphthalenes
HU211895A9 (en) Cyclic amide derivatives
BG98815A (en) Derivatives of isatin, method for their preparation and pharmaceutical compositions containing them
US5294619A (en) Arylpiperidine derivatives
US5104876A (en) Benzopyrido piperidine, piperidylidene and piperazine compounds, compositions, methods of manufacture and methods of use