EP0000716B1 - Dérivés de la pyrrolo(2,1-b)(3)benzazépine, procédé pour leur préparation et compositions pharmaceutiques les contenant - Google Patents

Dérivés de la pyrrolo(2,1-b)(3)benzazépine, procédé pour leur préparation et compositions pharmaceutiques les contenant 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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Prior art keywords
pharmaceutically acceptable
acid addition
compound
acceptable acid
addition salt
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EP78100454A
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German (de)
English (en)
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EP0000716A2 (fr
EP0000716A3 (en
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. Composé de formule développée:
Figure imgb0022
ou un sel d'addition d'acide pharmaceutiquement acceptable d'un tel composé, où X et Y sont choisis indépendamment parmi l'hydrogène, les halogènes et les groupes trifluorométhyle, alcoyle inférieur, alcoxy inférieur, cyano, trifluorométhylthio et trifluorométhylsulfonyle, R est un groupe alcoyle inférieur ou cyclopropylméthyle et la ligne formée de tirets représente une saturation ou une insaturation.
2. Composé selon la revendication 1, caractérisé en ce qu'il est de la formule développée:
Figure imgb0023
ou est un sel d'addition d'acide pharmaceutiquement acceptable d'un tel composé, où X, Y, R et la ligne formée de tirets sont tels que définis dans la revendication 1.
3. Composé selon la revendication 2 ou un sel d'addition d'acide pharmaceutiquement acceptable d'un tel composé caractérisé en ce que l'un des substituants X et Y est de l'hydrogène et l'autre est de l'hydrogène, du chlore ou un groupe cyano ou trifluorométhylthio.
4. Procédé pour la préparation d'un composé de formule développée:
Figure imgb0024
ou d'un sel d'addition d'acide pharmaceutiquement acceptable d'un tel composé, où X et Y sont choisis indépendamment parmi l'hydrogène, les halogènes et les groupes trifluorométhyle, alcoyle inférieur, alcoxy inférieur, cyano, trifluorométhylthio et trifluorométhylsulfonyle, R est un groupe alcoyle inférieur ou cyclopropylméthyle et la ligne formée de tirets représente une saturation ou une insaturation, caractérisé en ce qu'un composé de formule développée:
Figure imgb0025
est traité par un agent déshydratant.
5. Procédé selon la revendication 4, caractérisé en ce qu'il est utilisé pour la préparation de composés de la formule développée:
Figure imgb0026
ou d'un sel d'addition d'acide pharmaceutiquement acceptable d'un tel composé, où X, Y, R et la ligne formée de tirets sont tels que définis dans la revendication 4.
6. Procédé selon la revendication 5, caractérisé en ce qu'il est utilisé pour la préparation d'un composé, ou d'un sel d'addition d'acide pharmaceutiquement acceptable d'un composé dans lequel l'un des substituants X et Y est de l'hydrogène et l'autre est de l'hydrogène, du chlore ou un groupe cyano ou trifluorométhyle.
7. Composition pharmaceutique pour le traitement de psychoses ou d'un état maladif associé è des niveaux anormalement élevés d'activité de sérotonine ou d'histamine, caractérisée en ce qu'elle comprend un véhicule pharmaceutique et une quantité efficace d'un composé de formule développée:
Figure imgb0027
ou d'un sel d'addition d'acide pharmaceutiquement acceptable d'un tel composé, où X et Y sont choisis indépendamment parmi l'hydrogène, les halogènes et les groupes trifluorométhyle, alcoyle inférieur, alcoxy inférieur, cyano, trifluorométhylthio ou trifluorométhylsulfonyle, R est un groupe alcoyle inférieur ou cyclopropylméthyle et la ligne formée de tirets représente une saturation ou une insaturation.
8. Composition pharmaceutique selon la revendication 7, caractérisée en ce que le composé a la formule développée:
Figure imgb0028
ou est un sel d'addition d'acide pharmaceutiquement acceptable d'un tel composé, où X, Y, R et la ligne formée de tirets sont tels que définis dans la revendication 7.
9. Composition pharmaceutique selon la revendication 8, caractérisée en ce que dans le composé ou dans un sel d'addition d'acide pharmaceutiquement acceptable du composé, 1'un'des substituants X et Y est de l'hydrogène et l'autre est de l'hydrogène, du chlore ou un groupe cyano ou trifluorométhylthio.
EP78100454A 1977-07-28 1978-07-20 Dérivés de la pyrrolo(2,1-b)(3)benzazépine, procédé pour leur préparation et compositions pharmaceutiques les contenant Expired EP0000716B1 (fr)

Applications Claiming Priority (2)

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

Publications (3)

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

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Country Status (7)

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

Families Citing this family (6)

* 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
AU8902591A (en) * 1990-10-10 1992-05-20 Schering Corporation Substituted imidazobenzazepines and imidazopyridoazepines
IL101850A (en) * 1991-06-13 1996-01-31 Janssen Pharmaceutica Nv History 11-) 4-Pipridinyl (-Imidazo] B-1, 2 [] 3 [Benzazepine, their preparation and pharmaceutical preparations containing them
IL101851A (en) * 1991-06-13 1996-05-14 Janssen Pharmaceutica Nv History 01 -) 4 - Pipridinyl - and Pipridinylidene (- Imidazo] A-1,2 [Pirolo, Thiano or Purano (] 3,2 [Azpin, their preparation and pharmaceutical preparations containing them and composition
ITRM20040178A1 (it) * 2004-04-07 2004-07-07 Sigma Tau Ind Farmaceuti Composti ad attivita' antipsicotica atipica.
ES2752823T3 (es) 2006-03-31 2020-04-06 Vistakon Pharmaceuticals Llc Tratamiento de alergias oculares

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

Also Published As

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

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