NO752346L - - Google Patents

Description

Analogy method in the preparation of therapeutically active cyproheptadine derivatives.

The present invention relates to the preparation of ( + )-1-methyl-4-(3-cyano-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine (hereinafter referred to as "(+)-3- cyanocyproheptadine") with pharmaceutical utility as a peripheral and central anticholinergic agent, and (-)-1-methyl-4-(3-cyano-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine (hereafter designated as "(-)-3-cyanocyproheptadine") with pharmaceutical use as a major psychosedative. Furthermore, the invention relates to a method for splitting racemic 3-cyanocyproheptadine into (-)-3-cyanocyproheptadine and (+)-3-cyanocyproheptadine, pharmaceutical preparations comprising one of these isomers essentially free of the other, pharmaceutical preparations containing preferred ratios of the (+)- and (-)-isomers, and methods of treatment including administration of such compounds and preparations.

The symbols "( + )" and "(-)">as used above, denote that under the measurement conditions described here, i.e. frequency, temperature and solvent, these compounds rotate the plane of polarized light to the right, respectively. on the left, considered according to the established convention. For the purposes of the invention, the term "substantially free" when it comes to the state of purity of an isomer with respect to its enantiomer, is defined to be a contamination of the pure isomer from about 0.1 to about. 5.0% by weight of its enantiomer.

The racemic 3-cyanocyproheptadine (Formula I below) is disclosed in US Patent Application No. 476,630, filed June 5, 1974, which application is a continuation-in-part of Application No. 280,685, filed August 14, 1972. , which is again a "continuation-in-part" of US application No. 9,049, filed on February 5, 1970, which is again a "continuation-in-part" of US application No. 4-123. filed on January 19, 1970. For purposes of describing the synthesis of the racemic 3-cyanocyproheptadine, these applications are hereby incorporated by reference.

However, there is no indication in the above-mentioned US patent applications that the cleavage of the racemic 3-cyanocyproheptadine also causes a separation of pharmacological activity. Thus, while racemic 3-cyanocycproheptadine is a strong main psychosedative, • it also has strong anticholinergic activity which can cause unwanted side effects. However, the (+)-isomer has no psychosedative activity, but is a strong peripheral and central anticholinergic agent and can. is used as an anticholinergic agent for treating the extraparametric effects of haloperidol and similar agents, while the (-)-isomer has no central or peripheral anticholinergic activity, but is a major psychosedative. The unexpected separation of pharmacological activity by optical resolution of the racemic 3-cyanoc3'proheptadine into its enantiomers is of considerable value as it is now possible to obtain either psychosedative effects, anticholinergic effects or a desired combination of such effects by administering one isomer substantially free of its enantiomers, or by administering a combination of the isomers in preferred ratios.

It is thus an aim of the present invention to provide ( + )-3-cyanocyproheptadine therein. substantially free of the corresponding (-)-enantiomer, (~)-3-cyanocyproheptadine substantially free of the corresponding (+)-enantiomer, and preferred ratios of the two isomers. It is also an aim of the present invention to provide a method for producing (resolving) such optical isomers from the racemic mixture.

A further aim of the invention is to provide pharmaceutical preparations which comprise therapeutically effective amounts of such isomers essentially free of the corresponding enantiomer, and preparations which are included. therapeutically effective amounts of preferred mixtures of such isomers. Furthermore, it is an aim of the present invention to provide methods of treatment comprising the administration of such compounds and preparations when the effects of a main psychosedative, anticholinergic agent, or a combination of such effects are indicated.

Finally, it is an aim of the present invention to provide pharmaceutically acceptable acid addition salts of the compounds described above.

The racemic 3-cyanocyproheptadine can be conveniently prepared from the corresponding 3-bromocyproheptadine disclosed in US patent 3.OI4.9H5 according to the following reaction:

where 3-bromocyproheptadine is treated with a metal cyanide (MCN) such as cuprocyanide or the like, in an inert dissolution medium such as N,N-dimethylformamide, N-methylpyrrolidone and the like, at a temperature from approx. 80° to approx. 180°C.

The preferred purification method for the racemic 3-cyanocyproheptadine to obtain (-)-3-cyanocyproheptadine substantially free of the (~)-enantiomer and (+)-3-cyanocyproheptadine substantially free of the (-)-enantiomer , involves forming diastereomeric salts of racemic 3-cyanocyproheptadine with optically active acids such as di-p-toluoyl-d-tartaric acid, di-p-toluoyl-l-tartaric acid, 1-malic acid, and the like, in a suitable solvent such as methanol, ethanol, 2-propanol, benzene, acetonitrile, nitromethane, acetone and the like. 1 principle, the diastereomeric salts formed from solution differ in physico-chemical properties so that one salt can be distinguished from the other, i.e. differences in solubility. Repeated recrystallizations give an essentially pure diastereomer, as when treated with a base such as sodium bicarbonate, sodium bicarbonate. sodium hydroxide and the like, extraction in a non-polar or semi-polar solvent such as ether, benzene, chloroform and the like, followed by evaporation of the solvent and recrystallization gives one enantiomer essentially free of the other. Ideally, the second enantiomer is obtained from the above solution after the removal of the first precipitated diastereomer in comparable purity by evaporation, transfer to the free base form and recrystallization.

In the method of treatment and pharmaceutical preparations according to the invention, it is to be noted that the specific unit dosage form and the dosage mirror depend on the medical history of the individual being treated, and are consequently left to the doctor's decision. In general, however, the method compounds and preferred combinations thereof may be administered to subjects in any of the usual pharmaceutical oral forms such as tablets, elixirs and aqueous suspensions in an amount from about 0.05 to approx. 500 mg per dose for two to four times daily. Sterile solutions for injection containing from approx. 0.025 to approx. 250 mg per dose is injected two to four times daily. Furthermore, the process compounds can be readily administered as a salt, and any convenient non-toxic acid addition salt prepared in a conventional manner can be used. Examples of such salts include: the hydrochloride, the sulfate, the phosphate, the acetate, the propionate, the citrate. the tartrate and the succinate. These salts are generally equivalent in strength to the base from which they are formed considering the stoichiometric amounts used.

The following examples illustrate the product, the preparation, cleavage methods and methods of treatment according to the inventor.

Example 1

Cleavage of (t)-1-methyl-4-(3~cyano-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)- pipe eridine

To a solution of 4.37 g (0.014 mol) (t)-1-methyl-4-(3-cyano-5H-dibenzo-[α,dJ-cyclohepten-5-ylidene)-piperidine in 20 ml of ethanol at 25 °C, 5.40 g (0.014 mol) of di-p-toluoyl-d-tartaric acid are added. The crystalline precipitate that forms on cooling is removed by filtration, washed with cold ethanol and dried at 100°C in vacuum, which gives 6.75 g of material, denoted by A. The clear ethanol filtrate and the washings are denoted by B.

The 6.75 g of A is recrystallized from absolute ethanol six times to obtain a product which has a constant rotation, m.p. 169.5 -171.5°C, [a]<2>|9-142°, [ af5758~150°, [a]^. _i80°,

[a]^6<=>~^3^°'(c =°>010 g/ml pyridine) . The material is dissolved in the minimal amount of water, and 1.0 M aqueous sodium bicarbonate solution is added dropwise to complete the fining. The precipitate formed is extracted in chloroform, washed with water and dried over magnesium sulphate. After filtration, the chloroform is evaporated. The residue is triturated with acetonitrile, collected by filtration and dried at 100°C in vacuum, thereby obtaining (-)-1-methyl-4-(3-cyano-5l-1-dibenzo-[a ,d]-cycloheptene~5 -ylidene)-piperidine, m.p. 176 - 178°C;

[ af5589 -191°, [a]^8 = -202°, [a]<g>6 -248°, [a]^6 -671°,

(C = 0.010 g/ml CHCl 2 ).

Elemental analysis for C^2H20N2:

Calculated: C 84.58; H 6.45; N 8.97.

Found: C 84.32; H 6.52; N 9.00.

The ethanol filtrate and the washings, B, are prepared at room temperature. perature for 7 days. The supernatant liquid is decanted from a small amount of crystalline material. This remaining liquid is allowed to stand for 7 days at room temperature, after which it is decanted again. Et ha no len. removed by evaporation. The residue is dissolved in the minimal amount of water and treated with an aqueous solution of sodium bicarbonate to obtain an alkaline pH. The precipitate formed is extracted in chloroform, washed with water and dried over magnesium sulphate. After filtration, the chloroform is evaporated. The residue is recrystallized three times from acetonitrile, collected and dried at 100°C in vacuum, whereby (+)-1-methyl-4-(3-cyano-5H-dibenzo-[a,d]-cyclo-heptene-5) is obtained -ylidene, mp 177.5 - 179.5°C; I>]||o = +191°, .. [a]^8 = +205°, [a]^6 = +250°, [a ]^6 = +675 , (C = 0.010 g/ml CHCl 2 ).

Elemental analysis for C22^20N<2:>

Calculated: C 84.58; H 6.45; N 8.97-

Found: C 84.50; H 6.62; N 8.74-

Example 2

Pharmaceutical preparations

A typical tablet containing 1 mg (+)-1-methyl-4-(3-cyano-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine per tablet is prepared by mixing with the active ingredient calcium phosphate, lactose and starch in the amounts shown in the table below. After these ingredients are thoroughly mixed, the appropriate amount of magnesium stearate is added and the dry mixture is mixed for an additional 3 minutes. This mixture is then pressed into tablets weighing approx. 124 ra 9 each.

TABLET COMPOSITION

In a similar manner, tablets containing methyl-4-(3-cyano-5H-dibenzo-[a,d]-cyanohepten-5-ylidene)-piperidine are prepared by the method of Example 2 when (+)-3-cyanocyproheptadine is replaced by an equivalent amount of (-)-3-cyanocyproheptadine. In a similar manner, tablets are prepared containing a preferred mixture for a particular purpose of the optical isomers (+)- and (-)-3-cyanocyproheptadine, and the following tablet composition illustrates such mixtures:

T TABLET COMPOSITION

Claims (2)

1. 1. Process for the production of -1-methyl-4-(3~cyar>°~ 5H-dibenzo-[a ,dj -cyclohepten-5-ylidene)-piperidine and ( + )-1-methyl-4 -( 3-cyano-5l-1-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine both in essentially pure. form, characterized in that the (t)-racemate is reacted with an optically active acid to form the diastereomeric salts, and that the (■-)-form is separated essentially free of the (+)-form by crystallization. 2. Method according to claim 1, characterized in that di-p-toluoy.I-d-tartaric acid is used as an optically active acid.