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

Derivatives of dibenzo[a, e]cycloheptatriene Download PDF

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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
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dibenzo
piperidine
solution
methyl
cycloheptatrienylidene
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US826493A
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Edward L Engelhardt
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Merck and Co Inc
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Merck and Co Inc
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Priority to US826493A priority Critical patent/US3014911A/en
Priority to GB29490/59A priority patent/GB931555A/en
Priority to GB7308/63A priority patent/GB931556A/en
Priority to BE582220A priority patent/BE582220A/fr
Priority to DE1420072A priority patent/DE1420072C3/de
Priority to CH7878959A priority patent/CH387037A/de
Priority to FR837257A priority patent/FR490M/fr
Publication of US3014911A publication Critical patent/US3014911A/en
Application granted granted Critical
Priority to OA51101A priority patent/OA00998A/xx
Priority to MY51/64A priority patent/MY6400051A/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms

Definitions

  • 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.
  • 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.
  • 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 Chemischenmaschine 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:
  • StepB 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.
  • Compound I is dehydrated to produce Compound 11, as is represented by the following:
  • EXAMPLE la 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.
  • this substance sintered at 190 C. and melted at 214216 C. when heated at a rate of 6 per minute from 180 C.
  • Step A and omitting the final period of heating.
  • the 3 chlorodibenzo[a,e]cycloheptatrien 5 one employed in step B was prepared by the following sequence.
  • 3-(p-chlorobenzylidene)-phthalide was 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.Deutschs and H. Klinkhammer [Chemische Berichte, 84,671 (1951)] instead of employing the hydriodic acid method. 1
  • 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).
  • 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).
  • 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).
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
US826493A 1958-09-29 1959-07-13 Derivatives of dibenzo[a, e]cycloheptatriene Expired - Lifetime US3014911A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US826493A US3014911A (en) 1958-09-29 1959-07-13 Derivatives of dibenzo[a, e]cycloheptatriene
GB29490/59A GB931555A (en) 1958-09-29 1959-08-28 Dibenzocycloheptatriene derivatives
GB7308/63A GB931556A (en) 1958-09-29 1959-08-28 Dibenzocycloheptatriene derivatives
BE582220A BE582220A (fr) 1958-09-29 1959-09-01 Composés steroides et leur préparation
DE1420072A DE1420072C3 (de) 1958-09-29 1959-09-03 (5'-Dibenzo- eckige Klammer auf a,e eckige Klammer zu -cycloheptatrienyliden)-piperidine, Verfahren zu ihrer Herstellung und Arzneimittel
CH7878959A CH387037A (de) 1958-09-29 1959-09-29 Verfahren zur Herstellung von Dibenzo(a,e)cycloheptatrien-Derivaten
FR837257A FR490M (cs) 1958-09-29 1960-08-30
OA51101A OA00998A (fr) 1958-09-29 1964-12-29 Procédé de fabrication de dérivés du bibenzo (a,e) cycloheptatriène.
MY51/64A MY6400051A (en) 1958-09-29 1964-12-30 Dibenxocyclohepatriene derivatives

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US76380958A 1958-09-29 1958-09-29
US826493A US3014911A (en) 1958-09-29 1959-07-13 Derivatives of dibenzo[a, e]cycloheptatriene

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CH (1) CH387037A (cs)
DE (1) DE1420072C3 (cs)
FR (1) FR490M (cs)
GB (2) GB931556A (cs)
MY (1) MY6400051A (cs)
OA (1) OA00998A (cs)

Cited By (60)

* 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 (de) * 1968-10-22 1970-04-23 Fabrication Des Antibiotiques Neue Derivate des Tropans,deren Salze und Verfahren zur Herstellung
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
US3981877A (en) * 1972-08-14 1976-09-21 Merck & Co., Inc. Piperidylidene derivatives of carboxy-5H-dibenzo[a,d]cycloheptene
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
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 (de) * 1976-08-12 1978-02-16 Merck & Co Inc Niedere 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
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FR2618151A1 (fr) * 1987-07-16 1989-01-20 Synthelabo Derives de piperidine, leur preparation et leur application en therapeutique
WO1989012443A1 (en) * 1988-06-17 1989-12-28 Fisons Corporation Novel dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
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US5021426A (en) * 1990-02-26 1991-06-04 Merck & Co., Inc. Method of traeting malaria with cyproheptadine derivatives
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US6214837B1 (en) 1997-03-06 2001-04-10 Blomqvist Goeran Pharmaceutical composition for the treatment of so-called restless legs
US10398687B2 (en) 2010-09-14 2019-09-03 David Reed Helton Use of cyproheptadine to treat organophosphate exposure
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DE2736259A1 (de) * 1976-08-12 1978-02-16 Merck & Co Inc Niedere 3-alkoxycyproheptadine
US4104398A (en) * 1976-08-12 1978-08-01 Merck & Co., Inc. 3-Lower alkoxycyproheptadines as serotonin inhibitors
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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 (fr) * 1987-07-16 1989-01-20 Synthelabo Derives de piperidine, leur preparation et leur application en therapeutique
US5250681A (en) * 1988-06-02 1993-10-05 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
US4912222A (en) * 1988-06-17 1990-03-27 Fisons Corporation Antihistamines related to cyproheptadine
EP0347123A3 (en) * 1988-06-17 1991-07-03 Fisons Corporation Dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
WO1989012443A1 (en) * 1988-06-17 1989-12-28 Fisons Corporation Novel dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
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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
US10398687B2 (en) 2010-09-14 2019-09-03 David Reed Helton Use of cyproheptadine to treat organophosphate exposure
CN110407737A (zh) * 2019-07-30 2019-11-05 广州普星药业有限公司 一种盐酸赛庚啶的制备方法

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MY6400051A (en) 1964-12-31
GB931556A (en) 1963-07-17
OA00998A (fr) 1968-08-07
DE1420072B2 (de) 1974-01-03
BE582220A (fr) 1960-03-01
GB931555A (en) 1963-07-17
CH387037A (de) 1965-01-31
FR490M (cs) 1961-05-08
DE1420072C3 (de) 1974-08-08
DE1420072A1 (de) 1968-10-03

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