CA1093560A - N, n-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)- allylamine dihydrochloride monohydrate - Google Patents

Abstract

Abstract of-the Disclosure The compound N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate, and a method for its preparation are described.
This compound exhibits the same pharmaceutical activity as the known anhydrous hydrochloride, but in contrast thereto is a non-hygroscopic free flowing powder.

Description

The present invention is related to a new, therapeutically active compound.
The object of the in~ention is to obtain a compound which has im-proved storage proper~ies and which may be produced in an advantageous manner as compared to similar, previously known com~ounds.
From Belgian Patent No. 781 105 compounds of the general formula Rl R _ ~ / CH3 C = CHCH2N~

N
are known, wherein Rl and R2 are selected rom the group of H, Cl and Br, ~Id wherein the pyridyl gTOUp is bound in 2, 3 or 4 position. Specifically mentioned is among other compounds the anhydrous di-hydrochloride o the compound Br ~ 2 \

having a therapeutical value in the treatment of depressive conditions.
According to the reference mentioned, the anhydrous compound is ob-tained rom the corresponding base in ether solution, by introduction of dry HCl. It has turned out, that in working up the compound by separation and drying, a considerable amount o the anhydrous compound is most unsuitable for preparation of pharmaceutical compositions. For similar compounds crystal-lisation of the dihydrochloride from ethanol is taught by the reference. By 2Q this procedure the ethanolate is obtained. It has, however, turned out that ` ~-on working up said compound by separation and drying a considerable amount of solvent is retained. To remove said solvent, drying for about 1 to 2 days at 335~

a temperature of round 90 to 100C is required. These conditions, being in-convenient per se, may further cause discolouration and decomposition of the product. The anhydrous cornpound is not suitable for preparation of pharma-ceutical preparations such as tablets, due to its hygroscopic properties. On storage the anhydrous compound absorbs moisture to the formation of hard cakes, which must be broken up before further processing.
The drawbacks of the previously known compound are successfully overcome by the present invention providingJ as a new compound, the dihydro-chloride monohydrate of the compound of formula II above i.e. N,N-dimethyl-3-~4-bromophenyl)-3-~3-pyridyl)-allylamine dihydrochloride monohydrate.
The compound of the invention exists in two stereoisomeric forms, i.e. in an E-form and a Z-form. The therapeutical properties of the com-pound reside mainly in one o said isomers, namely the Z-isomer. The pre-ferred embodiment of the present invention is thus Z-N, N- dimethyl-3-~-bromophenyl)-3-~3-pyridyl)-allylamine dihydrochloride monohydrate having the formula III.
Br ~

C = 2HCl . H20 . III

CH N~CH ) Pharmaceutical preparations of the new compound constitute a further advantageous aspect of the invention. The compound may thus be incorporated in different forms of solid pharmaceutical preparations such as tablets or granules. Suitably the compound is included in pharmaceutical preparations for oral application. Usually the active substance will constitute from 0,1 to 95% by weight of the preparation, more specifically from 2 to 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral applicationJ the selected com-:~' '. '; .

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pound may be mixed with a solid pulverulent carrier, e.g. lactose~ saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol waxes, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solu*ion which may contain e.g. gum arabic, gelatine, talcum or titanium dioxide, Alternatively, the tablet can be coated with a lacquer dissolved ln a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish be~ween tablets containing different active substances or different amounts of the active compound.
Dosage ~mits for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
The compound of the invention may be prepared in the following manner:
a) Reaction of the base of formula II N, N-dimethyl-3-~4-bromo-phenyl)-3-~3-pyridyl)-allylamine in solution with hydrous hydrogen chloride, followed by collection of the precipitated dihydrochloride monohydrate. The reaction is suitably carried out in an organic solvent, with cooling pre-ferably at about 0C. Suitable organic solvents are polar solvents such as acetone. The hydrous hydrogen chloride is suitably concentrated hydrochloric acid. Alternatively H20 may be added to a solution of the base whereafter ;
anhydrous HCl is added.
b) Hydratization of the anhydrous dihydrochloride of the compound of formula II.
Starting material for the reaction a) above may be obtained aa) by dehydration of a compound of the formula ~ ; ~
, 35~

Br ~
~H

\ / 3 ~ N J CH2CH2N \ CH3 V

The dehydration may be done by means of treatment with sulphuric acid and heating of the reaction mixture, by means of other types of acid catalysis or by catalysis with a solid dehydration catalyst at a temperature of 300 to 500C.
ab) by alkylation of dimethylamine with a compound of the formula ~L~,, wherein Y is a leaving group, to the formation of a compound of the formula I.
Illustrative examples of Y are halogens such as Cl, Br and I or sulphonates such as methanesulphonate, toluenesulphonate and benzene-sulphonate.

ac) by mono- or di-methylation of a compound of the formula 3~Br C ::`

wherein R is CH3 or H.
Starting material for the reaction b~ above may be obtained by treat-ing a compound obtained by any of the reactions aa), ab) or ac) with dry HCl.

An isomer pure produc e.g. the preferred isomer of formula III may be obtained by isomer separation or conversion of an isomer mixture of either the end product~ a starting material or an intermediate of any reaction step, provided that the double bond o~ the end product is present in said starting ~: , . . .

~33~

material or intermediate, and that said double bond is not broken up in a subsequent reaction step.
Example I
9Q g of N~ N-dimethyl-3-(~-bromophenyl)-3-(3-pyridyl)-allylamine was dissolved in acetone (900 ml) and 2 equivalents o~ concentrated hydro-chloric acid was added with cooling. After cooling at about 0C for 1 hour the precipitate was filtered off and washed with acetone. Recrystallisation was made from isopropanol (800 ml) and water (15 ml). (Z)-N, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate was ob-lQ tained after washing with isopropanol and drying at about 50C. M.p. 195-200C (decomposition). Karl Fisher analysis showed a water content of 4, 4%
by weight.
An IR spectrum was obtained with the KBr pe~let technique ~1 mg in 250 mg KBr). Region: 4000-650 cm . Instrument: Perkin-Elmer IR Spectrometer.
Marked absorption ~in general less than 50% transmittance) was re- ;
corded at the wave numbers given below with their presumed corresponding s~ructural elements.
Wave Number Structural Element cm-l . . . _ _ _ -- -- -- -- - --3300 OH in water 260Q - 2400 Ammonium 1650 Carbon double band ~transmittance ;~
~60%) 1490 and 1470 Aromatic double bands _ 820 _ _ _ Disubstituted benzene An NMR spectrum was obtained from a solution of 100 mg of the com-pound in 0,5 ml deuterium oxide. Tetramethylsilane ~TMS) was employed as an internal reference. Instrument: Varian T 60 (60 M~12) The chemical shifts are given as follows:

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Proton Chemical Shift (ppm) . _ . . ~
A 3,12 B 4,12 ~;
C 4,8 D 6,73 7,23 - 7,84 F 8,24 - 8,87 G 8,90 - 9,3Q

r : ~ ~
2HCl ' H20 H ~ ~2 C~
EX~mple 2 30~0 g of crude N, N-dimethyl-3-~4-bromophenyl~-3-(3-pyridyl)-ally-lamine was dissolved in 300 ml of ether and 95 ml of 2,6N HCl in ether was added. The crude anhydrous di-hydrochloride obtained was filtered off and vacuum dried. The anhydrous dihydrochloride was dissolved in 150 ml of : :
isopropanol and 4 ml of water (5 eqw) under heating and the product was allowed ~ ~-to crystallize. Yield 20 g of (Z) -N, N-dimethyl-3-~4-bromophenyl)-3-(3-py-ridyl)-allylamine dihydrochloride monohydrate. Karl Fisher analysis showed a water content of 4.5% by weight.
2Q Example-3: Preparation of-Intermediates Stage 1~ 4-bro_o~henyl)-3-dime_h-l_m no~ rop ne This compound was prepared by reacting 4-bromoacetophenone with para-formaldehyde and dimethylamine hydrochloride in a conventional Mannich reaction.

~ ~ "

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Stage 2: 1-(4-bromophenyl~-1-(3-pyridyl)-3-dimethylamino-1-_ _ _ _ _ ~pro~anol _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The intermediate 3-pyridyllithium, formed by treating 3-brompyridine with butyllithium in ether at a low temperaturej was treated with 1-(4-bromo-phenyl)-l-dimethylamino-l-propanone~ dissolved in e~her to yield 1-(4-bromo-phenyl)-1-(3-pyridyl)-3-dimethylamino-1-propanol.
; The reaction mixture was hydrolyzed with ice and water, the aqueous layer was extracted with methylene chloride at pH 4, followed by an ether extraction at pH 10. The residue after evaporation was triturated with petro-leum ether and ether. The crystalline product was recrystallized from iso- ;
propanol.
Stage 3: N, N-dimet~yl-3-(4-bromo~henyl)-3-(3~pyridyl)-allylamine _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~ _ _ _ _ _ _ .
The product from stage 2 was dehydrated with acetic acid anhydride and sulfuric acid. The reaction mixture was poured on ice and the aqueous phase extracted with ether at pH 10. Evaporation of the solvent yielded the base.
Example ~: Preparation of Pharmaccutical Preparàtions . _ .
Tablets of the following compositions were prepared A B

2~ ~Z)-N, N-dimethyl-3-~4-bromophenyl)-3-(3-pyridyl) ~allylamine dihydrochloride monohydrate 25 mg 50 mg Lactose 192 mg 140 mg Starch 30 mg 50 mg Polyvinylpyrrolidone 3 mg 5 mg Cellulose Avicel 18 mg 23 mg Magnesium Stearate 2 mg 2 mg A granulate of the active substance, lactose and starch was made with polyvinylpyrrolidone dissolved in ethanol. The granulate was dried and screened, and cellulose avicel and magnesium stearate were admixed. Tablets

3~
were compressed in a known manner.

,:

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Film coated tablets were obtained by applying methyl cellulose and ethyl cellulose to the tablets in an organic solvent.
Comparative Tests Stab_l_t_ at_C_n_tant Humidity_and Room Te_p_rature The compound of the invention was compared with the corresponding anhydrous dihydrochloride and dihydrochloride containing 1 eqw. of ethanol.

Table Weight Aftçr Storage at Different Relative Humidity , Relative Monohydrate Anhydrous Ethanolate Humidity 40% Unchanged ~1 week) Increased 4,6% Decreased 5%
(1 day) (4 days) 60% Unchanged ~1 week~ Increased 4,6% Decreased 4%
(1 day) ~5 days) 90% Increased 12% ~1 week) Increased 50% Unchanged (8 h~
~6 days) Increased 11%
Liquefied ~4 days) Result: The monohydrate is stable at 40 and 60% relative humidity room temperature at which conditions the anhydrous compound and the ethanolate `~
are not stable.
Stability on Vacuum Drying Ethanolate: Drying at 110C for about 24 h was required to decrease the amount of ethanol to the acceptable level of less than 0,5%. After dry-ing decomposition is indicated by increased turbidity, colour ~A405nm=0,165 and extra spots on TLC. -~
Monohydrate: Drying at 40C for about 2 to 4 hours was required to obtain a product suitable for preparing solid pharmaceutical preparation.
Decomposi~ion could not be detected by observing turbidity, colour or TLC.

After s-torage at 45C for 6 days A405 n was 0,05.

'

Claims (11)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the preparation of N, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate which comprises either:
a) reacting a solution of N, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine with hydrogen chloride in the presence of water and recovering the thus-formed monohydrate precipitate, or b) hydrating N, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-ally-lamine hydrochloride in solution.

2. Process according to claim 1 wherein Z-N, N-dimethyl-3-(4-bromophenyl) -3-(3-pyridyl) allylamine dihydrochloride monohydrate of formula III

? 2HCl ? H2O III

is obtained.

3. Process according to claim l(a) wherein a polar solvent is used.

4. Process according to claim 3 wherein the solvent is acetone.

5. Process according to claim l(a) wherein the reaction temperature is maintained at about 0°C.

6. Process according to claim l(a) wherein concentrated hydrochloric acid is used to provide both the hydrogen chloride and the water.

7. Process according to claim l(b) wherein the solvent isopropanol con-taining about 3% water, by weight.

8. N, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydro-chloride monohydrate, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

9. Z-N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylammmine dihydro-chloride monohydrate of formula III as defined in claim 2, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

10. Process according to claim 1 wherein a mixture of isomers is used.

11. Process according to claims 1 or 2 wherein only the Z-isomer is recovered.