EP0000716B1

EP0000716B1 - Pyrrolo(2,1-b)(3)benzazepine derivatives, process for their preparation and pharmaceutical compositions containing them

Info

Publication number: EP0000716B1
Application number: EP78100454A
Authority: EP
Inventors: Joseph George Atkinson; Clarence Stanley Rooney; Patrice C. Belanger; David Caroll Remy
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1977-07-28
Filing date: 1978-07-20
Publication date: 1983-03-09
Also published as: DK328478A; US4148903A; JPS5427597A; IT7850403A0; IT1107463B; EP0000716A2; DE2862196D1; IE47146B1; EP0000716A3; IE781517L

Description

Background of the Invention

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 chemical compounds described in said U.S.A. Patents are dibenzocycloheptenes with a piperidylidene appendage.
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.
Accordingly, it is 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.

Detailed Description of the Invention

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

(1) hydrogen,
(2) halogen such as chloro, bromo, fluoro, or iodo
(3) trifluoromethyl,
(4) lower alkyl, especially C_1-4 alkyl, or
(5) lower alkoxy, especially C_1-4 alkoxy,
(6) cyano,
(7) trifluoromethylthio, or
(8) trifluoromethylsulfonyl; and
R is (1) lower alkyl, especially C_1-4 alkyl, or
(2) cyclopropylmethyl.

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.
Also contemplated to be within the scope of the present invention are pharmaceutically acceptable acid addition salts. These salts, prepared by conventional means, include the hydrochloride, maleate, sulfate, phosphate, citrate, tartrate, succinate, and the like.
The 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. for from about 5 minutes to about 24 hours to provide the final product pyrrolobenzazepines. The Grignard reaction and the subsequent dehydration des-' cribed above are substantially identical to those disclosed in U.S. Patents 3,014,911 (issued December 26, 1961), 2,951,082 (issued August 30, 1960), 3,428,677 (issued February 18, 1969), 3,428,735 (issued February 18, 1969), 3,454,643 (issued July 8, 1969), and 3,499,037 (issued March 3, 1970), all to Edward L. Engelhardt or Edward L. Engelhardt et al.
The 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.
The following examples illustrate the novel processes of this invention used for the synthesis of the novel carbinol intermediates and products of this invention and are not meant to limit the invention to the particular process conditions used and products produced thereby.

Example 1

1-Methyl-4-[6,11-dihydro-5H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine

Step A: Preparation of 11-hydroxy-11-(1-methylpiperidin-4-yl)-6,11-dihydro-5H-pyrrolo[2,1-b] [3]benzazepine

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. The residue is chromatographed on a silica gel column (1.5 x 17 inches) by elution with 5% (v/v) methanol in chloroform. Combination of the appropriate fractions and evaporation to dryness gives 7.3 g. of 1 1-hydroxy-1 1-(1-methyl-piperidin-4-yl)-6,11-dihydro-5H-pyrrolo[2,1-b] [3]benzazepine, m.p. 175-177°C.

Step B: Preparation of 1-methyl-4-[6,11-dihydro-5H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine

The hydroxy compound from Step A (3.02 g., 10.2 mmole) and 950 mg. of oxalic acid in 100 ml. of absolute ethanol is refluxed 2 hours. Oxalic acid (50 mg.) is added and refluxing is continued for 15 minutes. Oxalic acid 100 mg. is added and refluxing is continued for 1/2 hour. The mixture is cooled to room temperature, then in an icebath and finally in a freezer overnight. The precipitate is collected, washed with ethanol, and dried under nitrogen to give 2.78 g. of the oxalic acid salt of 1-methyl-4-[6,11-dihydro-5H-pyrrolo-[2,1-b] [3]benzazepin-11-ylidene]piperidine, m.p. 239°C. (decomp.)
Following the procedure of Example I, 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).
Employing the procedure substantially as described in Example 1, Steps A and B, but substituting for the 6,11-dihydro-5H-pyrrolo[2,1-b] [3]benzazepin-11-one and 1-methyl-piperidin-4-yl magnesium chloride used in Step A, the substituted ketones and 1-R-piperidin-4-yl magnesium chlorides described in Tables I and II in the same relative molecular amounts, there are produced the respective 11-hydroxy-11-piperidin-4-yl and 11-piperidinylidene compounds also described in Tables and II, by the previously described novel process.

Example 2

1-Methy)-4-[9-cyano-11H-pyrro)o[2,1-b] [3]benzazepin-11-ylidene]piperidine

1 - Methyl - 4 - [9 - bromo - 11 H - pyrrolo[2,1-b] [3]benzazepin - 11 - ylidene]piperidine (6.3 g., 0.017 mole) and cuprous cyanide (3.2 g, 0.035 mole) in 25 ml. of dry dimethylformamide are refluxed under nitrogen for five hours. The mixture is cooled to an internal temperature of 50° and treated with 60 ml. each of benzene and aqueous saturated sodium cyanide solution. After stirring one hour the contents are transferred to a separatory funnel with the aid of additional benzene and water. The 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.

Example 3

Pharmaceutical Compositions

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. Similarly prepared are tablets containing 1-methyl-4-[11H-pyrrolo-[2,1-b] [3]benzazepin-11-ylidene]piperidene, 1-methyl-4-[6,11-dihydro-2-methoxy-5H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidene, or any of the novel compounds of this invention of Structure I.

Claims

1. A compound of structural formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein X and Y are independently hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, trifluoromethylthio, or trifluoromethylsulfonyl, R is lower alkyl or cyclopropylmethyl, and the dotted line represents saturation or unsaturation.

2. The compound of claim 1 with structural formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein X, Y, R and the dotted line are defined as in claim 1.

3. The compound of claim 2 or a pharmaceutically acceptable acid addition salt thereof, wherein one of X and Y is hydrogen, and the other is hydrogen, bromo, chloro, cyano or trifluoromethylthio.

4. A process for the preparation of a compound of structural formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein X and Y are independently hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, trifluoromethylthio or trifluoromethylsulfonyl, R is lower alkyl or cyclopropylmethyl, and the dotted line represents saturation or unsaturation, characterized in that a compound of structural formula:

is treated with a dehydrating agent.

5. The process of claim 4 for the preparation of the compounds of the structural formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein X, Y, R and the dotted line are defined as in claim 4.

6. The process of claim 5 for the preparation of the compound or a pharmaceutically acceptable acid addition salt thereof, wherein one of X and Y is hydrogen and the other is hydrogen, bromo, chloro, cyano or trifluoromethylthio.

7. A pharmaceutical composition for the treatment of psychoses or a disease state associated with abnormally high levels of serotinin or histamine activity comprising a pharmaceutical carrier and an effective amount of a compound of structural formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein X and Y are independently hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, trifluoromethylthio or trifluoromethylsulfonyl, R is lower alkyl or cyclopropylmethyl and the dotted line represents saturation or unsaturation.

8. The pharmaceutical composition of claim 7, wherein the compound has the structural formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein X, Y, R and the dotted line are as defined in claim 7.

9. The pharmaceutical composition of claim 8, wherein in the compound or a pharmaceutically acceptable acid addition salt thereof, one of X and Y is hydrogen and the other is hydrogen, bromo, chloro, cyano or trifluoromethylthio.