CA1113091A - Pyrrolo [2,1-b][3] benzazepines with piperidinylidene group in the 11-position - Google Patents

Abstract

Abstract o the Disclosure Pyrrolo[2,1-b][3]benzazepines with a piperidinylidene group in the 11-position have utility as antipsychotic agents. They also demonstrate antiserotonin and antihistaminic activity. They are prepared by reaction of a pyrrolo [2,1-b][3]benzàzepin-11-one with a pipèridinyl magnesium halide followed by dehydration.

Description

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Background of the Invention This invention is concerned with novel pyrrolo[2,1b]~3]benæazepines with a piperidinylidene group in the ll-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 ~lso knc~-n that the cyano-and trifluoromethylthio- derivatives of cypro-heptadine, as described in U.S. Patents 3,988,342 . .
and 4,031,222 are antipsycho~ic agents.
Now with this invention there are provided related hetero-tricyclic compounds with somewhat analogous utilitie~. Accordingly, it is an object of this invention to provide cextain pyrrolo12,1-b][3]benzazepines with a piperidinylidene group in the ll-position and non-toxic pharmaceutically acceptable salts thereof. Another object is to provide a method of treating psychoses, and disease states with which are associated abnormally high levels of serotonin and/or histamine activity with the novel compounds. Another object is to provide pharmaceutical ~ormulations comprising the novel compounds~ A fourth object is to provide novel processes for the synthe is of the novel compounds.

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Detailed Description_of the Invention The compounds of the present invention have the following structural formula:

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or pharmaceutically acceptable salt thereof, ~
5 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 Cl_4alkyl, or (S) lower alkoxy, especially Cl_4 alkoxy, ~ :
(6) cyano, (7) tri1uoromethylthio, or (8) trifluoromethylsulfonyl; and R is (1~ lower alkyl, especially Cl_4 ~:
alkyl, or (2) cyclopropylmethyl.
A preferred embodiment of the novel : ; compounds of this invention is the compound of structural ormula~

: ~ ' ~X

~: . R ~ ~ ;
Ia ~' :

. ..- ~ , or pharmaceutically acceptable salt 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 pyrrolobenzazepinllone, II, with a lRpiperidin4ylmagnesium chloride, followed by dehydration of the resulting carbinol compound, III, to the final produc~, I, as illustrated bel~ ~ y ~ X

II III ~

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~X

I R

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-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 -10C. to reflux for from about 10 minutes to about 10 hours to provide the ll-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 ~he like at a temperature of from about 0 to about 100C. for from about 5 minutes to about 24 hours to provide the final product pyrrolobenzazepines. The Grignard reaction and 15 the subsequent dehydration described above are j:
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 important intermediate ll-hydroxy compounds of Structure I}I form another embodiment of this invention wherein the symbols X, Y, and R, are as previously defined or the compounds of Structure I.
The novel compounds of this invention of s~ructure I or a pharmaceutically acceptable salt thereof, possess antipsychotic, antiserotonin and antihistaminic activity and may be administered to patients requiring antipsychotic, antiserotonin and/or an~ihistamine treatment in any of the usual ,~

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- 5 - 15856 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 proaesses 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]
benzazep.~n-ll-ylidene]piperidine 5te~ A: Preparation of ll-hydroxy-ll-(l-methyl piperidin-4-yl)-6,11-dihydro-5H-pyrrolo t2,1-b][3]benzazepine

6,11-Dihydro-5H-pyrrolol2,1-b][3]benza-zepin-ll-one (7 g., 35.6 mmol) is dissolved in 100 ml. of tetrahydrofuran and to it is added with stirring 200 ml. of tetrahydrofuran containin~
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 ew 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 drynes~

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gives 7.3 g. of ll-hydroxy-ll-(l-methyl-piperidin-4-yl)-6,11-dihydro-5H-pyrrolol2,1-b][3]benzazepine, m.p. 175-177C.
Step B- Preparation of l-methyl-4-[6,11-dihydro-SH-pyrrolo[2,1-b][3]benzazepin-11-ylidenelpiperidine 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 l-methyl-4-[6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-ylidene]piperidine, m.p.
239C. (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 anhydridechloroform (2), trifluoro-cetic acid (3), hydrogen chloride in chloroform (4), phosphorus oxychloride-pyridine (5), trichloro-acetic acid-ethanol (6), acetic acid (7~, or formic acid ~8).
Employing the procedure substantially as described in Example 1, Steps A and B, but sub-stituting for the 6,11-dihydro-5H-pyrrolo[2,1-b]13]
benzazepin-ll-one and l-methyl-piperidin-4-yl ~; ~ magnesium chloride used in Step A, the substituted ketones and~l-R-piperidin-4-yl magnesium chlorides :::: : :

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- 7 - 15856 de~cribed in Tables 1 and II in the same relative molecular amounts, there are produced the respective ll-hydroxy-ll-piperidin-4-yl and ll-piperidinylidene compounds also described in Tables I and II, by the previously described novel process.

Y ,,~ X

R

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- 8 - 15856 Table I
~ehydration~ m.p.
R Y X System (C ) 5CH3 H 2-CN 2 208-209'tdec~

CH3 H 2-Br 4 CH3 H 2-C1 4 221-222(dec)a CH3 9~CH3 H
CH3 9-CH(CH3)2 H

15CH3 9-Cl H 4 CH3 9-SO2cF3 H 4 -CH2~ H 2-$2CF3 4 -CH2~ H 2-SCF3 4 -CH2~ H 2-C1 4 -CH2~ 9-SO2CF3 H 4 -CH2~ 9-SCF3 H 4 CH2 ~ 9 Cl H 4 ~ See paragraph following Example 1, Step B

a oxalate salt ~ :

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Table II
Dehydration~ m.p.
R Y X System (C.) _ CH3 H 2-CN 2 217-219(dec~a CH3 9-Cl H 4 : CH3 9-CN H 1 158-161 C~3 9-Br H 4 138-142 -CH2~ H 2-SCF3 4 -CH2a H 2-C1 4 -CH2~ H 2 S2CF3 4 ~ CH2 a 9-SCF3 H ~ 4 2~0 -CH2 ~ 9-Cl H 4 ~ See paragraph following Example 1, Step B
: ~: : a oxalate salt , .

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- 10 - 15856 Example 2 l-Methyl-4-[9-cyano-llH-pyrrolo[2,1-b][3]benzazepin-ll-ylidene]piperidine l-Methyl-4-[9-bromo-llH-pyrrolo[2,1-b]
5 [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 tr~ated 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-llH-pyrrolo~2,1-b]
[3]benzazepin-11-ylidene]piperidine as an oil ~5.0 g., 94%). Trituration with acetonitrile giVes a 801id (3.6 g., m.p. 156-159C.). An analytical ~ample $s obtained a~ter one recrystalliza-tion from acetonitrile, m.p. 158-161C.
Example 3 Pharmaceutical Compositions A typical tablet containing 10 mg.
l-methyl-4-[9-cyano-llH-pyrrolo[2,1-b]~3]benzazepin-ll-ylidene]piperidine per tablet is prepared by ~ mixing together with the active ingredient calaium ;~ 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 .;

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~ 15856 compressed into tablets weighing approximately 134 mg. each. Similarly prepared are tablets containing l-methyl-4-~llH-pyrrolo-[2,1-b][3~
benzazepin~ ylidene~piperidine, l-methyl-4-16,11-dihydro-2-methoxy-5H pyrrolo~2,1-b~[3]-benzazepin-ll-ylidene]piperidine, or any of the novel compounds of this invention of Structure I.
Tablet Formula .
Ingredient Mg. per Tablet 10 1-methyl-4-[9-cyano-llH-pyrrolo-[2,1-b][3]benzazepin-11-ylidene]piperidine 10 mg.

Calcium phosphate 52 mg.
Lactose 60 mg.
15 Starch 10 mg.
Magnesium stearate 1 mg.

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Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

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

or a pharmaceutically acceptable salt thereof, wherein X and Y are independently hydrogen, halogen, trifluoro-methylthio or cyano, and R is lower alkyl, characterized in that a compound of structural formula:

is treated with a dehydrating agent.

2. The process of Claim 1, wherein R is -CH3, X is -CN and Y is H.

3. The process of Claim 1, wherein R is -CH3, X is H and Y is -CN.

4. The process of Claim 1, wherein R is -CH3, X is H and Y is C1.

5. The process of Claim 1, wherein R is -CH3, X is SCF3 and Y is H.

6. The process of Claim 1, wherein R is -CH3, X is H and Y is SCF3.

7. A compound of the structural formula:

or a pharmaceutically acceptable salt thereof, wherein X and Y are independently hydrogen, halogen, trifluoro-methylthio or cyano, and R is lower alkyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

8. The compound of Claim 7, wherein R is -CH3, X is -CN and Y is H, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.

9. The compound of Claim 7, wherein R is -CH3, X is H and Y is -CN, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

10. The compound of Claim 7, wherein R is -CH3, X is H and Y is C1, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

11. The compound of Claim 7, wherein R is -CH3, X is SCF3 and Y is H, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

12. The compound of Claim 7, wherein R is -CH3, X is H and Y is SCF3, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.