US3726897A - 1,2,3,8-tetrahydrodibenzo(3,4:6,7)cyclohepta(1,2-c)pyrroles as cns-depressants - Google Patents

1,2,3,8-tetrahydrodibenzo(3,4:6,7)cyclohepta(1,2-c)pyrroles as cns-depressants Download PDF

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US3726897A
US3726897A US00145010A US3726897DA US3726897A US 3726897 A US3726897 A US 3726897A US 00145010 A US00145010 A US 00145010A US 3726897D A US3726897D A US 3726897DA US 3726897 A US3726897 A US 3726897A
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acid
dibenzo
cyclohepta
mol
tetrahydrodibenzo
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L Gysin
W Schindler
J Gosteli
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/38—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • the present invention relates to new cycloheptene derivatives to processes for their production, to medicaments containing the new compounds and their use.
  • the present invention relates to compounds of Formula I wherein R represents hydrogen, an alkyl group having at most 4 carbon atoms, or the allyl group, and
  • X represents hydrogen, chlorine, the methyl or methoxy and the pharmaceutically acceptable acid addition salts thereof.
  • R as an alkyl group is e.g. the methyl, ethyl, propyl, isopropyl, butyl, sec. butyl or the isobutyl group.
  • Preferred members of this class are:
  • methanesulphonic acid salts are preferred also other pharmaceutically acceptable acid addition salts can be used.
  • the pharmacological properties of the compounds of the present invention render them suitable for the treatment of states of tension and agitation of psychic and muscular genesis.
  • R and X have the meaning given under Formula I, and, optionally, converting the obtained reaction prodnot with an inorganic or organic acid into an addition salt.
  • Suitable as reactive esters of compounds of the general Formula II are, e.g. the dichlorides, bis-sulphonic acid esters, e.g. bis-methanesulphonic acid esters, bis-oand bis-p-toluenesulphonic acid esters, and, in particular, the dibromides.
  • the reactive esters of compounds of the general Formula II are reacted with the free bases of the general Formula III preferably in the presence of a solvent.
  • Suitable solvents are such which are inert under the reaction conditions, e.g. hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as chloroform, lower alkanols such as methanol or ethanol, ethereal liquids such as ether or dioxane, lower alkanols such as acetone, methyl ethyl ketone, or diethyl ketone, as well as mixtures of such solvents.
  • the reaction is preferably performed at a temperature of ca. 10 to 100 C.
  • Preferably used for the binding of the acid eliminated in the reaction according to the invention is a fairly large excess of the base of the general Formula III.
  • the obtained intermediate, 10,1l-dimethyl-SI-I-dibenzo- [a,d] cycloheptene can be subsequently oxidised, e.g. with selenium dioxide, to give 5H-dibenzo[a,d]cycloheptene- 1-0,11-dicarboxaldehyde, which is reduced, e.g. by sodium borohydride, to SH-dibenzo[a,d]cycloheptene- 10,11-dimethanol.
  • the reduction product yields, e.g.
  • Ac is, in particular, the cyano or chlorocarbonyl group, an alkanoyl or arenecarbonyl group, or the radical of a monofunctional derivative of carbonic acid, thiocarbonic acid, or dithiocarbonic acid. Mentioned as examples are: for alkanoyl or arenecarbonyl groups: the acetyl or benzoyl group, for radicals of monofunctional derivatives of carbonic acid, of thiocarbonic acid, or of the dithiocarbonic acid: the methoxycarbonyl,
  • ethoxycarbonyl tert.butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, methylthiothiocarbonyl, or the ethylthiothiocarbonyl group.
  • hydrolysis of compounds of the general Formula IV is performed, e.g. by several hours heating of such compounds in an alkanolic or aqueous-alkanolic alkali hydroxide solution, e.g. by boiling in a mixture of potassium or sodium hydroxide with ethanol or methanol and a little water.
  • an alkanolic or aqueous-alkanolic alkali hydroxide solution e.g. by boiling in a mixture of potassium or sodium hydroxide with ethanol or methanol and a little water.
  • hydrolysis may be effected, especially of compounds of the general Formula IV wherein Ac is the cyano group, also by heating with a mineral acid in an organic-aqueous or aqueous medium, e.g. by several hours boiling in a mixture of phosphoric acid and formic acid, or by several hours heating in 48% hydrobromic acid to
  • R represents a lower alkyl group, the allyl group or benzyl group
  • X has the meaning given under the general Formula I by allowing to act on the stated compounds, at room temperature or at elevated temperatures, an organic acyl halide, e.g. a cyanogen halide, particularly cyanogen bromide, also phosgene, a chloroformic acid alkyl ester, e.g.
  • the chloroforrnic acid methyl ester or -ethyl ester also the chloroformic acid phenyl ester or -benzyl ester, the chloride or bromide of a lower alkanoic acid or of an arenecarbonic acid, especially acetyl chloride, acetyl bromide, or benzoyl chloride, whereby occurs, according to the Von Braun reaction, the desired acylation with liberation of an R -halide, e.g. an alkyl, allyl or benzyl halide.
  • the reaction is performed preferably in an inert organic solvent such as, e.g. chloroform or benzene, or, optionally, also in excess acyl halide.
  • the compounds of the general Formula I obtained by the process according to the invention can, optionally, be converted in the usual manner into their addition salts with inorganic and organic acids.
  • a solution of a compound of the general Formula I in an organic solvent is added the acid desired as the salt component, or a solution of the acid.
  • organic solvents in which the formed salt is difiiculty soluble are, e.g. methanol, acetone, methyl ethyl ketone, acetone/ethanol, methanol/ether, or ethanol/ether.
  • hydrochloric acid hydrobrornic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, ,B-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, man delic acid and embonic acid.
  • the new active substances are administered orally, rectally, or parenterally.
  • the dosage depends on the manner of administration, the species, the age, and on the individual condition.
  • the daily dosages of the free bases or of pharmaceutically acceptable salts thereof vary between 0.1 mg./kg. and 10 mg./kg. for Warm-blooded animals.
  • Suitable dosage units such as drages, tablets, suppositories or ampoules, preferably contain 2-150 mg. of an active substance according to the invention.
  • Dosage units for oral administration preferably con tain as active substance between 1 and 90% of a compound of the general Formula I, or of a pharmaceutically acceptable salt of such a compound. They are produced by combining the active substance, e.g. with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or drage cores. The drage cores are coated, e.g. with cone.
  • solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol
  • starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder
  • cellulose derivatives or gelatine optionally
  • sugar solutions which may also contain, e.g. gum arabic, talcum and/ or titanium dioxide; or they are coated with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents.
  • Dyestuffs may be added to these coatings, eg for identification of the varying dosages of active substance.
  • Further dosage units suitable for oral administration are hard gelatine capsules, as well as soft closed capsules made from gelatine and a softener such as glycerin.
  • the hard capsules contain the active substance preferably as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and, optionally, stabilisers such as sodium metabisulphite (Na S O or ascorbic acid.
  • the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby likewise stabilisers may be added.
  • Suitable dosage units for rectal administration are, e.g. suppositories consisting of a combination of an active substance with a fatty base. Also suitable are gelatine rectal capsules containing a combination of the active substance with polyethylene glycol.
  • Ampoules for parenteral administration especially intramuscular administration, preferably contain as active substance a water-soluble salt in a concentration of preferably O.55 optionally together with suitable stabilisers and buffer substances, in aqueous solution.
  • a granulate is produced from 250 g. of 2-methyl- 1,2,3,8 tetrahydrodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole-methanesulphate, 175.90 g. of lactose, and the alcoholic solution of 10 g. of stearic acid; after drying, the granulate is mixed with 56.60 g. of colloidal silicon dioxide, 165 g. of talcum, 20 g. of potato starch, and 2.50 g. of magnesium stearate; and the mixture is then pressed to form 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 502.28 g. of crystallised saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestuff, and 1.5 g. of titanium dioxide, and then dried. The obtained drages each weight mg, and each contain 25 mg. of active substance.
  • a suppository foundation substance is prepared from 2.5 g. of 2-methyl-1,2,3,8-tetrahydrodibenzo[3,4:6, 7]cyclohepta[1,2-c]pyrrole-methanesulphonate and 167.5 g. of adeps solidus; it is then used to fill 100 suppositories each containing 25 mg. of active substance.
  • EXAMPLE 1 (a) An amount of 18.9 g. (0.05 mol) of 10,11-bisbromomethyl-SH-dibenzo [a,d]cycloheptene is dissolved in 75 ml. of benzene. This solution is added dropwise at 40, within one hour, to a solution of 46.5 g. (1.5 mol) of methylamine in 270 m1. of methanol. The reaction mixture is stirred for a further one hour at 50, and the excess methylamine and the solvent are subsequently distilled oif. To the residue are added 50 ml. of water, and the formed emulsion is extracted with ether. The ethereal solution is washed with water, dried over potassium carbonate, and concentrated by evaporation. The residue, which is recrystallised from petroleum ether, yields 2- methyl 1,2,3,8 tetrahydrodibenzo[3,4:6,7]cyclohepta [1,2-c]pyrrole, M.P. 146148.
  • the starting material is produced as follows:
  • the reaction mixture is then further stirred at the following temperatures: for 30 minutes at 10; after addition of 1 ml. (0.128 mol) of methyl iodide, for one hour at 35-37"; and subsequently for 15 hours at room temperature.
  • the obtained suspension is filtered oif, the filtrate concentrated in vacuo to 85 g., and 120 g. of ice, 100 ml. of water, and 200 ml. of methylene chloride are added.
  • To the mixture are then added some drops of glacial acetic acid until a neutral reaction of the aqueous phase is obtained.
  • the organic phase is separated, Washed with water, dried over sodium sulphate, and concentrated in vacuo.
  • a sample of the obtained oil is dissolved in abs. benzene, and chromatographed on a column of 20fold the amount of silica gel (Merck, particle size 0.050.2 mm.) using the elution method.
  • the elution agent is used absolute benzene.
  • the benzene solution is concentrated in vacuo, the residue taken up in hexane, and the undissolved oil separated.
  • the hexane solution is concentrated by evaporation, whereupon pure (9-methy1-9,10-dihydroanthracen-9-yl)-methyl ketone, M.'P. 48-51", crystallises out.
  • the obtained compound is readily oxidisable; it should be stored under nitrogen in a refrigerator.
  • the methanolic extract is concentrated in vacuo until the weight is 103 g.
  • the obtained emulsion is diluted with 200 ml. of water and extracted with methylene chloride.
  • the methylene chloride solution is washed with water, dried over sodium sulphate, and concentrated in vacuo to obtain a,9-dimethyl-9,10-dihydro-9-anthracenemethanol, which is used as crude product.
  • This compound too is readily oxidisable; it must be stored under nitrogen in a refrigerator.
  • EXAMPLE 2 The following final products are produced analogously to Example 1(a): from 18.9 g. (0.05 mol) of 10,11-bisbromomethyl-5H-dibenzo[a,d] cycloheptene and 67.5 g. (1.5 mol) of ethylamine in 270 of methanol:
  • EXAMPLE 3 (a) 1.52 g. (0.005 mol) of 1,2,3,8-tetrahydrodibenzo- [3,4:6,7]cyclohepta[1,2-c]pyrrole-2-carboxylic acid ethyl ester and a mixture of 11.4 ml. of glacial acetic acid and 3.9 ml. (0.035 mol) of 48% hydrobromic acid are refluxed for 3 hours. The reaction mixture is afterwards poured on to water, and rendered, with cone. ammonia, phenolphthalein-alkaline. The obtained emulsion is extracted with ether, the ether solution washed with water, dried over potassium carbonate, and concentrated by evaporation.
  • the starting material is produced as follows:
  • reaction solution is washed with 2 N hydrochloric acid and then with water; it is then dried over sodium sulphate and concentrated in vacuo to a small volume, whereupon 1,2,3 ,8-tetrahydrodibenzo[3,4:6,7]cyclohepta[1,2 c] pyrrole-2-carboxylic acid ethyl ester, M.P. 145-147, crystallises out.
  • the 2-methoxy-l0,1 1-bisbromomethyl-SH-dibenzo [a,d] cycloheptene (M.P. -111) required as starting material is prepared analogously toExample 1(h) to 1(1) followed by the process analogously to Example 1(e) to 1( g) through the following intermediate compounds (b to (b (b from u-(p-methoxyphenyl)-o-tolyl-acetonitrile the u- (p-methoxyphenyl)-o-tolyl-cyanacetic acid ethylester, B.P. 160-16 /0.02 torr; the further intermediates are obtained therefrom:
  • Example 1(h) through 1(1) is prepared analogously to Example 1(h) through 1(1) followed by the process analogous 0t Example 1(e) through 1(g) through the intermediate compounds (b to (b (b from a-(p-tolyl)-o-toly1-acetonitrile the a-(p-tolyl)- o-tolyl-cyanacetic acid ethyl ester, crude product; the following intermediate compounds are prepared therefrom:
  • X is hydrogen, chlorine, the methyl or methoxy group, and the pharmaceutically acceptable acid addition salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Primary Cells (AREA)
  • Hybrid Cells (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US00145010A 1970-05-25 1971-05-19 1,2,3,8-tetrahydrodibenzo(3,4:6,7)cyclohepta(1,2-c)pyrroles as cns-depressants Expired - Lifetime US3726897A (en)

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CH767270A CH532038A (de) 1970-05-25 1970-05-25 Verfahren zur Herstellung von neuen Cycloheptenderivaten

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US00283010A Expired - Lifetime US3773940A (en) 1970-05-25 1972-08-23 1,2,3,8-tetrahydrodibenzo(3,4:6,7)cyclohepta(1,2-c)pyrroles as cns-depressants

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CA (1) CA953719A (enrdf_load_stackoverflow)
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Cited By (15)

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Publication number Priority date Publication date Assignee Title
US4064139A (en) * 1975-04-07 1977-12-20 Merck & Co., Inc. Substituted 9,10-dihydroanthracen-9,10-imines
US4076830A (en) * 1976-04-07 1978-02-28 E. I. Du Pont De Nemours And Company Alkylmethanodibenzocycloheptapyrroles
US4088772A (en) * 1975-01-30 1978-05-09 E. I. Du Pont De Nemours And Company Methanodibenzocycloheptapyrroles
US4154836A (en) * 1976-05-24 1979-05-15 Akzona Incorporated Tension reducing 1,2,3,4,4a,13b-hexahydro-dibenz[2,3;6,7]oxepino[4,5-c]pyridines
US4263315A (en) * 1978-07-07 1981-04-21 Ciba-Geigy Corporation Azatetracyclic carbonitriles
US4271178A (en) * 1976-05-24 1981-06-02 Akzona Incorporated 1,2,3,3a,8,12b-Hexahydro-dibenzo[b,f]pyrrolo[3,4-d]azepines and pharmaceutical use thereof
US4271179A (en) * 1976-05-24 1981-06-02 Akzona Incorporated 1,2,3,3a,8,12b-Hexahydro-dibenzo[1,2;5,6]cyclohepta[3,4-C]pyrroles and pharmaceutical use thereof
US4271177A (en) * 1976-05-24 1981-06-02 Akzona Incorporated 2,3,3a,12b-Tetrahydro-1H-dibenzo[2,3;6,7]thiepino[4,5-c]pyrroles and pharmaceutical use thereof
US4492691A (en) * 1979-12-10 1985-01-08 Ciba-Geigy Corporation Azatetracyclic carbonitriles
US4927640A (en) * 1985-10-11 1990-05-22 Aktiebolaget Hassle Controlled release beads having glass or silicon dioxide core
US4942040A (en) * 1987-10-08 1990-07-17 Aktiebolaget Hassle Pharmaceutical preparation and a process for its preparation
US4957745A (en) * 1985-10-11 1990-09-18 Aktiebolaget Hassle Pharmaceutical preparation
US5760246A (en) * 1996-12-17 1998-06-02 Biller; Scott A. Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
US20080027049A1 (en) * 2006-07-27 2008-01-31 Wyeth Benzofurans as potassium ion channel modulators
US20080027090A1 (en) * 2006-07-27 2008-01-31 Wyeth Tetracyclic indoles as potassium channel modulators

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HRP20020441A2 (en) * 2002-05-21 2003-12-31 Pliva D D 1-oxa-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof
HRP20020440B1 (en) * 2002-05-21 2008-02-29 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. 1-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof
HRP20020452A2 (en) * 2002-05-23 2004-02-29 Pliva D D 1,2-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof
HRP20030160A2 (en) * 2003-03-06 2005-04-30 Pliva-Istra�iva�ki institut d.o.o. 1-thiadibenzoazulene derivatives and biological action thereof
HRP20030956A2 (en) * 2003-11-21 2005-08-31 Pliva-Istra�iva�ki institut d.o.o. USE OF 1,2-DIAZA-DIBENZO[e,h]AZULENES FOR THE MANU
HRP20030954A2 (en) * 2003-11-21 2005-08-31 Pliva D.D. USE OF 1-AZA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISEASES AND DISORDERS
HRP20030955A2 (en) * 2003-11-21 2005-08-31 Pliva-Istra�iva�ki institut d.o.o. USE OF 1-OXADIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISEASES AND DISORDERS
HRP20040104A2 (en) * 2004-01-30 2005-10-31 Pliva-Istra�iva�ki institut d.o.o. Use of benzonaphthoazulenes for the manufacture of pharmaceutical formulations for the treatment and prevention of central nervous system diseases and disorders

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FR145F (enrdf_load_stackoverflow) * 1964-06-01
CH501007A (de) * 1968-11-27 1970-12-31 Ciba Geigy Ag Verfahren zur Herstellung von neuen Thiepin- und Oxepinderivaten
CH505826A (de) * 1968-12-19 1971-04-15 Ciba Geigy Ag Verfahren zur Herstellung von neuen Azepinderivaten

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4088772A (en) * 1975-01-30 1978-05-09 E. I. Du Pont De Nemours And Company Methanodibenzocycloheptapyrroles
US4064139A (en) * 1975-04-07 1977-12-20 Merck & Co., Inc. Substituted 9,10-dihydroanthracen-9,10-imines
US4076830A (en) * 1976-04-07 1978-02-28 E. I. Du Pont De Nemours And Company Alkylmethanodibenzocycloheptapyrroles
US4271177A (en) * 1976-05-24 1981-06-02 Akzona Incorporated 2,3,3a,12b-Tetrahydro-1H-dibenzo[2,3;6,7]thiepino[4,5-c]pyrroles and pharmaceutical use thereof
US4158058A (en) * 1976-05-24 1979-06-12 Akzona Incorporated Tension reducing 1,2,3,4,4a,13b-hexahydro-dibenzo[2,3;6,7]thiepino[4,5-c]pyridines
US4271178A (en) * 1976-05-24 1981-06-02 Akzona Incorporated 1,2,3,3a,8,12b-Hexahydro-dibenzo[b,f]pyrrolo[3,4-d]azepines and pharmaceutical use thereof
US4271179A (en) * 1976-05-24 1981-06-02 Akzona Incorporated 1,2,3,3a,8,12b-Hexahydro-dibenzo[1,2;5,6]cyclohepta[3,4-C]pyrroles and pharmaceutical use thereof
US4154836A (en) * 1976-05-24 1979-05-15 Akzona Incorporated Tension reducing 1,2,3,4,4a,13b-hexahydro-dibenz[2,3;6,7]oxepino[4,5-c]pyridines
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US4927640A (en) * 1985-10-11 1990-05-22 Aktiebolaget Hassle Controlled release beads having glass or silicon dioxide core
US4957745A (en) * 1985-10-11 1990-09-18 Aktiebolaget Hassle Pharmaceutical preparation
US4942040A (en) * 1987-10-08 1990-07-17 Aktiebolaget Hassle Pharmaceutical preparation and a process for its preparation
US5760246A (en) * 1996-12-17 1998-06-02 Biller; Scott A. Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
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US20080027049A1 (en) * 2006-07-27 2008-01-31 Wyeth Benzofurans as potassium ion channel modulators
US20080027090A1 (en) * 2006-07-27 2008-01-31 Wyeth Tetracyclic indoles as potassium channel modulators
US7601856B2 (en) 2006-07-27 2009-10-13 Wyeth Benzofurans as potassium ion channel modulators
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Also Published As

Publication number Publication date
IE35431B1 (en) 1976-02-18
NL7106827A (enrdf_load_stackoverflow) 1971-11-29
CA953719A (en) 1974-08-27
NO130587B (enrdf_load_stackoverflow) 1974-09-30
SU383288A3 (enrdf_load_stackoverflow) 1973-05-25
DK135585B (da) 1977-05-23
GB1335129A (en) 1973-10-24
NO130587C (enrdf_load_stackoverflow) 1975-01-08
CS177036B2 (enrdf_load_stackoverflow) 1977-07-29
FR2126967A1 (enrdf_load_stackoverflow) 1972-10-13
US3773940A (en) 1973-11-20
DK135585C (da) 1977-10-31
BE767597A (fr) 1971-11-25
ZA713317B (en) 1972-01-26
ES391497A1 (es) 1973-06-16
AT307398B (de) 1973-05-25
IL36903A0 (en) 1971-08-25
FR2126967B1 (enrdf_load_stackoverflow) 1974-11-15
DE2125634A1 (de) 1972-01-05
AT302287B (de) 1972-10-10
SU396020A3 (enrdf_load_stackoverflow) 1973-08-28
IE35431L (en) 1971-11-25
IL36903A (en) 1973-07-30
PL83825B1 (enrdf_load_stackoverflow) 1976-02-28
SE358390B (enrdf_load_stackoverflow) 1973-07-30
CH532038A (de) 1972-12-31

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