EP0000716B1 - Pyrrolo(2,1-b)(3)benzazepinderivate, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Präparate - Google Patents

Pyrrolo(2,1-b)(3)benzazepinderivate, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Präparate Download PDF

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Publication number
EP0000716B1
EP0000716B1 EP78100454A EP78100454A EP0000716B1 EP 0000716 B1 EP0000716 B1 EP 0000716B1 EP 78100454 A EP78100454 A EP 78100454A EP 78100454 A EP78100454 A EP 78100454A EP 0000716 B1 EP0000716 B1 EP 0000716B1
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EP
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Prior art keywords
pharmaceutically acceptable
acid addition
compound
acceptable acid
addition salt
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EP78100454A
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English (en)
French (fr)
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EP0000716A3 (en
EP0000716A2 (de
Inventor
Joseph George Atkinson
Clarence Stanley Rooney
Patrice C. Belanger
David Caroll Remy
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention is concerned with novel pyrrolo-[2,1 b][3]benzazepines with a piperidinylidene group in the 11-position which are active as antipsychotic, antiserotonin, and antihistaminic agents.
  • Cyproheptadine and several derivatives are _known tricyclic compounds with antiserotonin and antihistamine activity as described in U.S. Patent 3,014,911. It is also known that the cyano- and trifluoromethylthio-derivatives of cyproheptadine, as described in U.S. Patent 3,988,342 and 4,031,222, are antipsychotic agents.
  • the French Patent 2,315,935 discloses compounds having a pyrollobenzazepine nucleus. In said compounds however an aminopropylidene group is bonded to the carbon atom 11 of the structure, while in contrary to this in the inventive compounds a piperidylidene group is bonded to the carbon atom 11 of the structure.
  • an object of this invention to provide certain pyrrolo[2,1 b][3]benzazepines with a piperidinylidene group in the 11-position and non-toxic pharmaceutically acceptable acid addition salts thereof. Another object is to provide novel processes for the synthesis of the novel compounds. Another object is to provide pharmaceutical formulations comprising the novel compounds. Said formulations are suitable for treating psychoses and disease states with which are associated abnormally high levels of serotonin and/or histamine activity.
  • the compounds of the present invention have the following structural formula: or pharmaceutically acceptable acid addition salts thereof, wherein the dotted line represents saturation or unsaturation; X and Y are independently
  • a preferred embodiment of the novel compounds of this invention is the compound of structural formula: or pharmaceutically acceptable acid addition salts thereof, wherein X, Y, and R are as defined above.
  • a still more preferred embodiment is where one of X and Y is hydrogen, and the other is hydrogen, chloro, cyano or trifluoromethylthio.
  • compositions prepared by conventional means, include the hydrochloride, maleate, sulfate, phosphate, citrate, tartrate, succinate, and the like.
  • novel processes of this invention comprise treatment of a pyrrolobenzazepin-11-one, II, with a 1R-piperidin-4-yl-magnesium chloride, followed by dehydration of the resulting carbinol compound, III, to the final product, I, as illustrated below.
  • the ketone starting material (II) is treated with the Grignard reagent in a solvent such as tetrahydrofuran, ether, or the like at a temperature of from about -10°C. to reflux for from about 10 minutes to about 10 hours to provide the 11-hydroxy intermediate, (III), which species is then dehydrated by treatment with an acid such as hydrochloric, oxalic, trifluoroacetic, formic, acetic, trifluoroacetic anhydride, trichloroacetic acid, phosphorous oxychloride with a tertiary amine, or the like at a temperature of from about 0 to about 100°C.
  • a solvent such as tetrahydrofuran, ether, or the like
  • an acid such as hydrochloric, oxalic, trifluoroacetic, formic, acetic, trifluoroacetic anhydride, trichloroacetic acid, phosphorous oxychloride with a ter
  • novel compounds of this invention of structure I or a pharmaceutically acceptable acid addition salt thereof possess antipsychotic, antiserotonin and antihistaminic activity and may be administered to patients requiring antipsychotic, antiserotonin and/or antihistamine treatment in any of the usual pharmaceutical forms such as powders, capsules, tablets, elixirs, and aqueous suspension, in the amount of from about 1 to about 750 mgms per day, preferably in divided doses taken 2 to 4 times daily. Sterile solutions for injection purposes would be administered in amounts of from 0.1 to 150 mgms per day.
  • 6,11-Dihydro-5H-pyrrolo[2,1-b] f3]benzazepin-11-one (7 g., 35.6 mmol) is dissolved in 100 ml. of tetrahydrofuran and to it is added with stirring 200 ml. of tetrahydrofuran containing 0.425 mmoles/ml. of 1-methyl-piperidin-4-ylmagnesium chloride. After a few minutes of stirring, 40 ml. of water is added and after another few minutes the mixture is diluted with methylene chloride. The organic phase is separated, dried over magnesium sulfate, filtered, and concentrated to dryness.
  • Step B there may be substituted for the oxalic acid in ethanol dehydration system (1) used therein, trifluoroacetic anhydride chloroform (2), trifluoroacetic acid (3), hydrogen chloride in chloroform (4), phosphorus oxychloride-pyridine (5), trichloroacetic acid- ethanol (6), acetic acid (7), or formic acid (8).
  • aqueous phase is extracted two times with benzene, once with ether and the combined-benzene-ether extracts are washed successively with dilute sodium cyanide, water, dilute ammonium hydroxide, and water. Upon drying over sodium sulfate the solvents are evaporated in vacuo to give 1-methyl-4-[9-cyano-11 H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine as an oil (5.0 g., 94%). Trituration with acetonitrile gives a solid (3.6 g., m.p. 156-159°C.). An analytical sample is obtained after one recrystallization from acetonitrile, m.p. 158-1610C.
  • a typical tablet containing 10 mg. 1-methyl-4-[9-cyano-11 H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine per tablet is prepared by mixing together with the active ingredient calcium phosphate, lactose and starch in the amounts shown in the tables below. After these ingredients are thoroughly mixed, the dry mixture is blended for an additional three minutes. This mixture is then compressed into tablets weighing approximately 134 mg. each.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (9)

1. Verbindung mit der Strukturformel
Figure imgb0015
oder ein pharmazeutisch brauchbares Säureadditionssalz davon, worin X und Y unabhängig Wasserstoff, Halogen, Trifluoromethyl, Niedrigalkyl, Niedrigalkoxy, Cyano, Trifluormethylthio oder Trifluoromethylsulfonyl sind, R Niedrigalkyl oder Cyclopropylmethyl ist und die unterbrochene Linie Sättigung oder Unsättigung anzeigt.
2. Verbindung nach Anspruch 1 mit der Strukturformel
Figure imgb0016
oder ein pharmazeutisch brauchbares Säureadditionssalz davon, worin X, Y, R und die unterbrochene Linie wie in Anspruch 1 definiert sind.
3. Verbindung nach Anspruch 2 oder ein pharmazeutisch brauchbares Säureadditionssalz davon, worin eines von X und Y Wasserstoff ist und das andere Wasserstoff, Chlor, Cyano oder Trifluormethylthio ist.
4. Verfahren zur Herstellung einer Verbindung mit der Strukturformel
Figure imgb0017
oder eines pharmazeutisch brauchbaren Säureadditionssalzes davon, worin X und Y unabhängig Wasserstoff, Halogen, Trifluoromethyl, Niedrigalkyl; Niedrigalkoxy, Cyano, Trifluoromethylthio oder Trifluormethylsulfonyl sind, R Niedrigalkyl oder Cyclopropylmethyl ist und die unterbrochene Linie Sättigung oder Unsättigung anzeigt, dadurch gekennzeichnet, dass eine Verbindung mit der Strukturformel
Figure imgb0018
mit einem Dehydratisierungsmittel behandelt wird.
5. Verfahren nach Anspruch 4 zur Herstellung der Verbindungen mit der Strukturformel
Figure imgb0019
oder eines pharmazeutisch brauchbaren Säureadditionssalzes davon, worin, X, Y, R und die unterbrochene Linie wie in Anspruch 4 definiert sind.
6. Verfahren nach Anspruch 5 zur Herstellung der Verbindung oder eines pharmazeutisch brauchbaren Säureadditionssalzes davon, worin eines von X und Y Wasserstoff und das andere Wasserstoff, Chlor, Cyano oder Trifluormethyl bedeuten.
7. Pharmazeutische Zusammensetzung zur Behandlung von Psychosen oder einem Erkrankungszustand, der mit abnormal hohen Serotoninspiegeln oder Histaminaktivität einhergeht, enthaltend einen pharmazeutischen Träger und eine wirksame Menge einer Verbindung mit der Strukturformel
Figure imgb0020
oder eines pharmazeutisch brauchbaren Säureadditions-salzes davon, worin X und Y unabhängig Wasserstoff, Halogen, Trifluormethyl, Niedrigalkyl, Niedrigalkoxy, Cyano, Trifluormethylthio oder Trifluormethylsulfonyl sind, R Niedrigalkyl oder Cyclopropylmethyl ist und die unterbrochene Linie Sättigung oder Unsättigung anzeigt.
8. Pharmazeutische Zusammensetzung nach Anspruch 7, worin die Verbindung die Strukturformel
Figure imgb0021
aufweist, oder ein pharmazeutisch brauchbares Säureadditionssalz davon, worin X, Y, R und die unterbrochene Linie wie in Anspruch 7 definiert sind.
9. Pharmazeutische Zusammensetzung nach Anspruch 8, worin in der Verbindung oder einem pharmazeutisch brauchbaren Säureadditionssalz davon eines von X und Y Wasserstoff und das andere Wasserstoff, Chlor, Cyano oder Trifluormethylthio ist.
EP78100454A 1977-07-28 1978-07-20 Pyrrolo(2,1-b)(3)benzazepinderivate, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Präparate Expired EP0000716B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US05/819,739 US4148903A (en) 1977-07-28 1977-07-28 Antipsychotic, antiserotonin and antihistaminic pyrrolo[2,1-b][3]benzazepines
US819739 1977-07-28

Publications (3)

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EP0000716A2 EP0000716A2 (de) 1979-02-21
EP0000716A3 EP0000716A3 (en) 1979-05-16
EP0000716B1 true EP0000716B1 (de) 1983-03-09

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Country Status (7)

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US (1) US4148903A (de)
EP (1) EP0000716B1 (de)
JP (1) JPS5427597A (de)
DE (1) DE2862196D1 (de)
DK (1) DK328478A (de)
IE (1) IE47146B1 (de)
IT (1) IT1107463B (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4242349A (en) * 1979-10-01 1980-12-30 Merck & Co., Inc. Orexigenic use of pyrrolo[2,1-b][3]benzazepines
WO1992006981A1 (en) * 1990-10-10 1992-04-30 Schering Corporation Substituted imidazobenzazepines and imidazopyridoazepines
IL101851A (en) * 1991-06-13 1996-05-14 Janssen Pharmaceutica Nv 10-(4-piperidinyl- and piperidinylidene)-imidazo [1,2-a] (pyrrolo thieno or furano) [2,3] azepine derivatives their preparation and pharmaceutical compositions containing them and certain novel intermediates therefor
IL101850A (en) * 1991-06-13 1996-01-31 Janssen Pharmaceutica Nv 11-(4-Piperidinyl)-imidazo (2,1-b) (3) benzazepine derivatives their preparation and pharmaceutical compositions containing them
ITRM20040178A1 (it) * 2004-04-07 2004-07-07 Sigma Tau Ind Farmaceuti Composti ad attivita' antipsicotica atipica.
EA016221B1 (ru) 2006-03-31 2012-03-30 ВИСТЭКОН ФАРМАСЬЮТИКАЛС, ЭлЭлСи Офтальмические композиции и способ лечения аллергических заболеваний глаз
WO2025186833A1 (en) * 2024-03-07 2025-09-12 Council Of Scientific And Industrial Research Dihydrobenzo[b,e]pyrroloazepines hybrids and a process for the preparation thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3014911A (en) * 1958-09-29 1961-12-26 Merck & Co Inc Derivatives of dibenzo[a, e]cycloheptatriene
US3988342A (en) * 1972-08-14 1976-10-26 Merck & Co., Inc. Piperidylidene derivatives of cyano-5H-dibenzo[a,d]cycloheptene
US4031222A (en) * 1975-12-22 1977-06-21 Merck & Co., Inc. Trifluoromethylthio (and sulfonyl) derivatives of cyproheptadine analogs

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA746508A (en) * 1966-11-15 D. Marcus Arnold Dibenzocycloheptenes
US3458522A (en) * 1967-05-17 1969-07-29 Sandoz Ag 4-piperidine substituted benzocycloheptaoxazoles and benzocycloheptathiazoles
PT65295B (en) * 1975-07-02 1978-05-10 Merck & Co Inc Process for the preparation of pyrrolo (2,1-b) (3) benzazepines
US4056536A (en) * 1976-06-29 1977-11-01 Merck & Co., Inc. Pyrrolo[2,1-b][3]benzazepines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3014911A (en) * 1958-09-29 1961-12-26 Merck & Co Inc Derivatives of dibenzo[a, e]cycloheptatriene
US3988342A (en) * 1972-08-14 1976-10-26 Merck & Co., Inc. Piperidylidene derivatives of cyano-5H-dibenzo[a,d]cycloheptene
US4031222A (en) * 1975-12-22 1977-06-21 Merck & Co., Inc. Trifluoromethylthio (and sulfonyl) derivatives of cyproheptadine analogs

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Publication number Publication date
EP0000716A3 (en) 1979-05-16
IE47146B1 (en) 1983-12-28
JPS5427597A (en) 1979-03-01
EP0000716A2 (de) 1979-02-21
IE781517L (en) 1979-01-28
DK328478A (da) 1979-01-29
IT1107463B (it) 1985-11-25
IT7850403A0 (it) 1978-07-20
DE2862196D1 (en) 1983-04-14
US4148903A (en) 1979-04-10

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