BE639873A - - Google Patents

Description

       

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  New amines.
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  The present invention relates to the for tf DOL-P? had t 2-phenyl-3-methyl-butyl-anine- (3) from tor = u1.
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 their salts with phys1olofically effective acids.
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 procedures for preparing these compounds,
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 It is known that pbnyl..iaapropyam3, e and some of its derivatives methylated on the carbon atom close to the JH2 group have good anorectic properties.

   Based on comparative pharmacological research by HOLM et al., Acta pharmaool. and tox100., lzi-136 (I960), the most interesting compound of this class is 1- (P-chlorophenyl) .. 2-methyl-propyl.amine- (2j which.

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 anorectic activity and a less pronounced central nervous system stimulation activity than phenylisopropylamine,
It has now been found that the D, L, D and L forms of 2-phenyl-3-methyl-butylamine- (3) are superior to 1- (p-chlorophenyl) - 2-methyl-propylamine- ( 2) with regard to toxicity, anorectic activity and the absence of side effects. At room temperature, amines are oily and difficult to make into tablets and other therapeutic preparations.

   Do the salts of these amines with physiologically compatible acids offer important advantages? on amines; in fact, at the ordinal temperature, they are solid compounds which are easy to transform into tablets and possess interesting pharmacological properties. Thus, the acid tartrate of 2-phenyl-3-methyl-butylamine- (3) (called in the suite F 394) is not very toxic and has a strong anorectic activity.



   Table I below shows the amount of food absorbed by rats to which F 360 and F 394 were orally administered and also, by way of comparison, some known appetite moderators. Table II indicates the side effects, by measuring the mobility quotient, (oscillating cap method, according to WA BERENDT, R. DEININGER and HO HILLERS, Int. J. Neuropharmacol., 1 (1962) p. 125) and of the quotient pupillary (according to P.PULEWKA, Naunyn-Schmiedebergs Arche exp, Path. u.



  Pharmacol., 168, (1932) p. 307) and Table III gives the values of acute toxicity.

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  BOARD
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<tb> Compose <SEP> Dose <SEP> Quantity <SEP> of <SEP> food <SEP> absorbed
<tb>
<tb>
<tb>
<tb> mg / kg <SEP> after <SEP> the <SEP> treatment, <SEP> expressed <SEP> in
<tb>
<tb>
<tb>
<tb> administered <SEP>% <SEP> of <SEP> the <SEP> quantity <SEP> absorbed <SEP> by <SEP> the
<tb>
<tb>
<tb>
<tb> by <SEP> channel <SEP> conducted <SEP> animals <SEP> not <SEP> treated *
<tb>
<tb>
<tb> oral <SEP> 2 <SEP> hours <SEP> a. <SEP> a <SEP> 8 <SEP> hours <SEP> * water
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> Phenylisopropylamine <SEP> 1.25 <SEP> 30 <SEP>. <SEP> 89
<tb>
<tb>
<tb>
<tb> 2.5 <SEP> 26 <SEP> 89
<tb>
<tb>
<tb>
<tb> 5.0 <SEP> 19 <SEP> 68
<tb>
 
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 2-phenyl-3-methyl.

   5.0 67 orphan 7.5 93
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<tb> 10.0 <SEP> 86
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 20.0 <SEP> 36 <SEP> 94 <SEP> -mimes
<tb>
 
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 1-p-chlorophenyl-2-5.0 86 93 methyl-propy1-runint '! - (2) 7.5 54 88
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<tb> 11.3 <SEP> 64
<tb>
<tb>
<tb> 22.5 <SEP> 10 <SEP> 44
<tb>
<tb>
<tb> 45.0 <SEP> 14 <SEP> 25
<tb>
 
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   360 .. 5.0 90 81 360 7.1 45 71
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<tb> 14.2 <SEP> 9 <SEP> 46
<tb>
<tb> 28.4 <SEP> 0 <SEP> 31
<tb>
<tb>
<tb>
<tb> 39 '<SEP> 5.0 <SEP> 76 <SEP> 89
<tb>
<tb>
<tb> 394 <SEP> 10.0 <SEP> 12 <SEP> 65
<tb>
<tb>
<tb> 20.0 <SEP> 5 <SEP> 64
<tb>
<tb> 40.0 <SEP> 2 <SEP> 12
<tb>
 
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 --i ## - i i i Il..LI.

   inu m I #lui '## - # irT * i "' l '" l "" "" * # * - = after administration
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 ## * Zph snyl3-mthy.but hydrochloride, yl-aaiâ

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   TABLE II
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 Compose "IbpTion # -writing motility quotient ns Dose ***) Value
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<tb> DEM2 <SEP> hours <SEP> *) <SEP> hours *) <SEP> mg <SEP> kg <SEP> total <SEP> lively <SEP> mg / kg <SEP> maximum
<tb>
 
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 ndkg mg / kg - #######, #####,.,., i '' '".' 11 lp-chlorophenyl-2-0.0 bzz3 le5o 5 1.93 methyl-propylamine a 20jO phenyl-isopropyjamine ls3 5, g 5 11.42 I, S6 5 23 Y 360 7to 145 5 3s, 03 leo6 2., 22 ¯ wu |,, ############### ##### "*) Doses in mg kg which, when administered orally to rats, reduce the amount of food absorbed to half the normal amount.



  **) Doses in mg / kg, administered subcutaneously to rats.



  ***) Doses in mg / kg, administered intraperitoneally to mice.

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 TABLE III
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 Compound LD50 ...) cheè the rat DI <-0 ***) dear the
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<tb> me / kg <SEP> mouse <SEP> mg / kg
<tb>
<tb> in <SEP> administration <SEP> by <SEP> in <SEP> administration
<tb> oral <SEP> route <SEP> by intraperitoneal <SEP> <SEP> route.
<tb>
 
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  F '94 241 132 y 360 180 71 lp-ehlorophenyl-2-230 *) U4 *) m thyl-propyl-amine- (2) 1BO) Ph <! Ny] - 'i)'! Opï'opyl-M) ine 55 71.5 ''
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<tb>
<tb>
 *) According to the instructions given by the manufacturer
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 ##) Following HOLM and collaborator, Acta phannaool. and toûool ..



  120 121 (I960).



  ***) The toxicity has been calculated according to MILLER and TAIMTEB. your phnyl-i! opropylAmine is the compound which most strongly affects the amount of food to be absorbed but it is not suitable as an appetite suppressant due to its side effects! clinically undesirable.

   Table II
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 shows that phdnyl-1sopropylam1n. causes a strong excitation of the central nervous system and a great modification of the contractions of the pupil (a motility quotient> 1 means excitation, a pupillary quotient> 1 means pupil dilation) *
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 The l.p-ehlorophenyl-2 methyl-propylaaine (2) and the F 394 have a lower anoretic activity but xeandder effects! much lower and 1-p-chlorophenyl-2-Nethyl "propylemine- (2) is therefore clinically suitable as an appetite moderator.

   As shown in Table II, Y 194 has a greater anorectic effect than Ip l-p.ah1oro.phdn11.a. edthyl-propylamite .- (2) and an activity of stimulating the central nervous system and dilating the pupil even lower, so that it can be considered in practice to be quite free of side effects pierces that the value of its quotient is close to 1 (normal state).

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   The F 394 being the least toxic, see Table III, is clearly superior to the comparison compounds * The new compounds can be prepared by the Qrignard reaction of
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 2-phdnyl-butatione- (3) of formula
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 with a metbyl-m & snés1wn halide, reaction of 2-phdnyl-3- ethyl-butanol- (3) of formula
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 formed with a metal cyanide in the presence of sulfuric acid and an ac1 (1 lower aliphatic monoeurboxylic according to RITTER and ± ÂL16d # J. au Cheme bocoo, 20, 4048 (1948), oorres- pondant formamide of formula
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 and cleavage of the formyl radical by treatment in an acid or alkaline solution, followed if necessary by salification.



   The products obtained according to the invention are, in the form of free base., Colorless liquids which form salts.
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 taoi1e # ent soluble in water with inorganic and organic acids * Suitable physiologically compatible acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid
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 ric, phosphoric, tartaric, succinic, malefic, fumaric and cinnamic.! The salts with organic aciaes are particularly interesting and, indeed, it has been surprisingly found that they are more active than the corresponding salts of inorganic acids. *
The compounds according to the invention can,

   if they occur as racemates, be easily split into

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 optical isomers. they can be separated by olastric procedures, such as fractional crystallization of sala from raceaic bases with optically active acids. Suitable optically active acids are, for example, 11 .. or L-tortric or U acids. -oa # pbo8ulfon1que'e
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 The optically active forces of the compounds according to the invention have shown varying effects in experiments.
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 driving on animals.

   thus L- '394 (D-tartrate) is
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 anoreetic, but it has greater effects in trials of
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 utility and dilation of the pupil as the raceralque or the levorotatory form (L-tartrute)
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 The compounds according to the invention have not yet been
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 described in the literature.

   German patent no. 9.65 indicates
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 that the compound described here can be obtained from 1-phenyl-
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 1-cbloro-2-methyl-propylamine- (2) in atetbanolic solution by
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 the action of hydrogen in the presence of a palladium catalyst
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 and that the hydrochloride has a melting point of 2UO-2010U $ but it
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 is possible to show that the compound obtained according to this patent
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 German is not 2-phenyl -> - methyl-butylamine- (3), but o, a-dimethyl-phenethylamine of the formula
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 The latter compound has been described several times in the
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 l-J literature. Am. Chem. boa. 12, 955-57 (1948), hydrochloride, m.p. 199-00 ° C. J. zum. Chem. Co 22 4t 48-5O (1948), hydrochloride, melting at 198-199.5 C-j.

   The melting points of the hydrochlorides of 1 # apa-dimethyl-phenethyluUne and of the compound obtained according to the German patent n 849 * 695 (198-2uU C and 200-201 * Cf respectively-
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 ment) are practically identical, while the hydrochloride of
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 2-Phenyl-3-methyl-butylamine- (3) -Y 360¯7 melts at <4-166 ° C.

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 besides, the information! data in the patent 1111 .. a * "9¯695 were studied Mperiwetttalotont and the obtained ecmpeté has it to seize with the hydrochloride of a.a-cU.a'th71..pb1af ,, 1.t1 \ 8 ( following lû'1. "J: ± d and & AH6M, J. âm. th <. 8oe., .m. -OH8-5O (1->).



  These experiments showed not 18Ul88eD \ that the emotions ..PO '"are anâlytlqueaunt Identical and have the $% * point of ft ICMD 1 namely 2UU - ..' U18C, but also that the melting point ixtw is not
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 lowered. The Identity of the two eopet eg% doue 4MMLiw. By bzz
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 the synthesis described in the German patent a. * .I "9.fr9 'is not clear and, indeed, according to the knowledge aoC; uell88, the atom of color of an aralkyl chloride does not can be replaced only by an atone of nyaroiene in the presence of a process catalyst which the chemical terminology gives the dm 4'RD, 1dI'o .'- \ 1 "..



  This fact is supported by the finding of US Patent No. 8 * # 597,445 that the reaction of 1phIl "aéttlyl-proPll-lIIétbll & a1ne (i.e. the derivative ... 'th71' of the starting compound employed in German Patent No. 849 * 695) with hydrogen in the presence of a palladium catalyst leads to the
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 1-phyl-x-adtnyl-propyl-2 methylcaine.



   The invention is further illustrated by the following examples! EXAMPLE 1. -
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 2-PhenYl-3-meth11-butyamine- (3l. To 19.4 g of oagnéslua clippings is added, dropwise, with stirring, a solution of 94 7 g of sebthyl wheat in 400 carats. of anhydrous ether so that the ether reaches the boiling temperature The mixture is heated towards the end until the last traces of Magnesium are dissolved.
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 A solution of 105 # bu 4-phenyl-butanone- (3) in 110 car of ether is then added, dropwise, over 60 to 90 minutes, and the mixture is kept at the boil for a further 1 hour.



  After cooling, the contents of the flask are poured onto

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 ice and mixed with a quantity of diluted H2SO4 such that the disturbance disappears. After separation of the obese phase, the aqueous phase is stirred several times with ether. The ethereal extracts are combined, dried over Na2SO4, the solvent is removed and the reaction product is fractionated.
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  Boiling point / 20 to Rg "116-118 * Co 105 g of 2-phenyl-3methyl-butanol- (3), colorless liquid are obtained with a refractive index nD22 = 1.5152.
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 At 2 $., $ G of HaCn (at 96) in a flask cooled externally with ice-water is added, dropwise, and with vigorous stirring, 64 cm of glacial acetic acid so that the temperature reaction temperature remains between 10 and 20 ° C. After that, a mixture of 70 cm3 of concentrated H2SO4 and 64 cm3 of concentrated acetic acid is added dropwise, the internal temperature being kept below 20 ° C.

   After replacing the ice water with a water bath at 20-25 C, 82 g of 2-phenyl-
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 . -methyl-butanol- (3) with a flow rate chosen so that the reaction temperature rises to about 45-50 ° C. (time required: about 10 to 15 minutes).



   The reaction mixture is then heated to 70 ° C. and then cooled slowly with stirring.



   The reaction product is mixed with 750 cm3 of water and the free acid is neutralized by adding solid Na2CO3.



   The oil which separates is taken up in 200 cm3 of ether and the aqueous phase is stirred well with ether. The solvent is removed from the combined and dry ether extracts and the residue is fractionated.
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  Boiling point / 9 mmtig - 17> -17b * Co Melting point * 63-6500 # Un obtains - '. DimétnylbenZflcMrb1nfl.7-tormam1d. with a yield of 63.0 g, ie ae 66.0. theoretical yield.



   To carry out the saponification, it is boiled for

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 for 6 hours, 52.3 g of formamide with 245 carbohydrate concentrated acid (density = 1.19) and 196 car water. After cooling, the solution is freed of unchanged compounds by extraction with ether. The solution is made strongly alkaline by addition of solid NaOH and the free amine is extracted with ether.



  After solvent distillation, the residue is fractionated.
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  Boiling point / 2ùmmag = 109-111 $ Co 48.2 g, that is to say a yield of µ9p2% of the theoretical yield, of D, ii-2-phenyl-3-methyl-butylamino is obtained under the form of a colorless liquid, Point de tuai on auh1orhldr & tll 164-loo'C (F 360), EXAMPLE 2. -
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 Tartrate brakes de -DhÓnYl -) - m61DUYl1ne- (3) (sol. Of, -Past cém1gue with, 3, 'bought U-tartr1aue One dissolved in 500 friend of water, l, 0 5 of 2-phenyl-3 methyl-buty3.waine- (3) ragealic and 5 g of O-tartaric acid and most of the solvent removed by vacuum distillation.



  The product which crystallizes is filtered carefully under vacuum and dried. A new concentration of the zero liquor gives a new crop of the compound of equal purity.
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  Yield: 7 ', of 2-phenyl-3-aethyl-butylaNine- (3) acid tartrate (F 394). feint fusion = 100-162 C
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 {.ā7o 18 +1), 4 (0 18 O, 8jIJ QW1S water, 20 on Q8 tube length). u4t11Jt. J, - Acid tartrate aes - et b - nnënv-5-inethyl.butyls- (3l On u1uQUS in 3tjU co of boiling methanol, 80 t of tph4nyl..muthyl-'butylumint (3) raoemic and 78.1 g of diacid D-tartaric The crystals which separate from the cooled solution are collected. 65.5 g of a compound which has no potency is obtained.
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 rotary '-Q.7u of 1 * 4 * The concentrated mother liquor gives 68, fi i of crystals having a / -0. 7 '? of 104 '.

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  As the salt of D-tartaric acid with 2phn, i3 ..



  86th²1-butflam1nt- (}) is somewhat less soluble in 4th & nQl than its L form, the two compounds obtained are separated, Muait to fractional recrystallization from a little ethanol and the separation is controlled by determining the potency. rotation of the substances obtained. In this way two salts are finally obtained, the angle of rotation of which no longer changes after a new recrystallization.



  Products obtained: 1) 22.4 g of base D salt and D tartaric acid
Melting point at 167-169 C.
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  -ā7o + 17'5O 2) 35 g of base salt L and tartaric acid D
Melting point at 164-166 C.
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  L-Q¯7o. +3.4.
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  '"**" ** "' <* * m <t <mmK t <e <ii # ** rw-r-wrl7ryr 1. D, L-, h- and L-2-phenyl-3-methyl- btttgmines. (3) and their salts with physiologically compatible acids. t Salts of Dplï- # y. and Le.phry1 - t6ttyl-butylam, ret- (3) with physiologically compatible organic acids.



  3 ". Put of Pà4-, 4) - and 1 - phnyl-jrmtt, yl-butylaainea (3) with tartri acid (iuiet 4.2'artrata acid de V $ L-9-phinyl-3-methyl -butylaclne- (3).



  5. Ae -2-phMyl''3''metyl-butylMine- tartrate (3). be t-2-phenyl-thYl-buty tartrate aciae, atx.ne-3).



  7. Process for preparing these DOL-J D- and L-X-phenyl-3-methyl-butylaminea- () and their salts with physiologically compatible acids, characterized in that reacting
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 2-phenyl-butanone- (3) with a methyltagnenium halide # 'we convert the s-pnenyl-3-methyl-butanol- (3) formed using a

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 -metal cyanide, sulfuric acid and a lower aliphatic monocarboxylic acid in 2-phenyl-3-methyl-butyl- (3-) formyla- alaine and the formyl radical is removed by treatment with 4 ' an acidic or alkaline solution.



   8. Process for the preparation of D, L-, D- and L-2-phznyl- 3-methyl-butylamines- (3) and their salts, with physiologically compatible acids, characterized in that reactirla 2-phenyl-butanone- (3) with a methylmagnesium halide, the 2-phenyl-3-methyl-butanol- (3) obtained is converted using a metal cyanide, sulfuric acid and a monocarboxyli acid. - As a lower aliphatic in 2-phenyl-3-methyl-butyl- (3) -formylamis, the formyl radical is removed by treatment with an acid or alkaline solution, and the base obtained is converted into a salt with a physiologically compatible acid.