DE1543647C - Process for the preparation of 2 (1 methylpropylamino) 1 square bracket on 5,6,7,8 tetrahydronaphthyl (2) square bracket to ethanol and its stereoisomers - Google Patents

Description

The invention relates to a process for the preparation of 2- (1-methylpropylamino) -1 - [5,6,7,8-tetrahydronaphthyl (2)] ethanol of the formula. · ■. . _;

α β

-CH-CH ₂ -NH-CH-CH ₂ -CI-Ij

OH

CH ₃

as well as its four stereoisomers and the corresponding non-toxic acid addition salts, which is characterized in that 5,6,7,8 - tetrahydro - α - bromoacetyl - naphthyl - 2 - ketone in a manner known per se with 1 -Methylpropylamine condensed in an inert solvent and the condensation product is reduced catalytically in the presence of a Pd-, Ft- oiler Ni-catalyst, whereby one for the production of the (+) (fiS: / i'S) - and the (-) (r (R: / iS) - or des (- | -) ( ₍₁ S: // R) - and des (-) (uR: // R) -2- (I-methylpropylainino) -1 - [5,6,7, 8-tetrahydronaphthyl (2)] - ethanol carries out the condensation with (S) - or with (R) -I-methylpropylamine and the resulting mixture of the pairs of stereoisomers is converted into the optical antipodes by fractional crystallization of the hydrochloride from an ethyl acetate-ethanol mixture separates.

Suitable acid addition salts are obtained with inorganic acids, e.g. B. in the form of hydrochloride!), • Hydrobromides, phosphates or sulfates or with organic acids, e.g. B. in the form of citrates, Tartrates, darbiturates or theophylin-7-acetates.

The 2 - (1 - methylpropylamino) -1 - [5,6,7,8 - tetrahyilronaphthyl (2) j-ethanol has particularly interesting properties in the therapeutic field as a medicine for angina and arrhythmia. It is characterized by increased effectiveness, in particular J5 in ile ischemic heart diseases and cardiac arhythmies. This Medicines fills a gap in the field of adrenergic substances with an antagonistic effect Amines, as it is known that previously used for therapy. used inhibitors of adrenergic amines on the heart muscle are not free from various side effects. 2- (1-methylpropylamino) -l- [5,6,7,8-tetrahydronaphthyl (2)] ethanol on the other hand, has a considerable effect, but without showing the previous side effects.

Therefore, its administration is not only very effective in therapy even for long periods of time, but also very safe. \ 50 '

The 2- (I -methylpropylamino) -1 - [5,6,7,8-tetrahydronaphthyl (2)] - ethanol can by condensation of 5,6,7,8 - tetrahydro - α - bromoacetyl - naphthyl-2-ketone with 1-methylpropylamine in an inert solvent, e.g. B. in ether, alcohol or a ketone at a temperature between 0, and 25 ° C; about 2 moles of amine per mole of bromoketone or a stoichiometric ratio of 1: 1 are used if a hydrobronic acid acceptor is used.

After the end of the reaction, the amine hydrobromide becomes filtered off and the end product by evaporation of the solvent and the unreacted recovered excess amine. The residue thus obtained is dissolved in a solvent (e.g. ether or acetone) dissolved and treated with a mineral acid (ζ. Β. gaseous hydrogen chloride), being the hydrochloride of 1-methylpropylaminomethyl - 5,6,7,8 - tetrahydronaphthyl - 2 - ketones. -

This hydrochloride can by catalytic hydrogenation .. or, with sodium borohydride or aluminum isopropylate. to 2 - (1; * methylpropylamino) - ! - [S ^ JjS-tetrahydronaphthyl ^ Jj-ethanol hydrochloride be reduced. Among the abovementioned reduction processes, the catalytic one is preferred Hydrogenation in alcoholic solution using conventional hydrogenation catalysts, z. B. palladium on activated carbon, platinum or Raney nickel, preferably temperatures between 0 and 30'C and pressures between atmospheric and 8 atm. "

After the calculated amount of hydrogen has been absorbed, the catalyst is filtered off and the solution evaporated; the remaining residue is removed from a solvent, e.g. B. an alcoholic ether mixture, Recrystallized acetone or ethyl acetate.

As can be seen from the formula for 2- (l-methylpropylamino) -1- [5,6,7,8-tetrahydronaphthyl (2)] ethanol, the compound has two asymmetric carbon atoms ^ which in the formula with α and // Marked are. Theoretically, four stereoisomers correspond to these two carbon atoms, depending on the configuration of the two asymmetric carbon atoms. The following combinations are therefore possible: A connection with the configuration R on both asymmetric carbon atoms (<tR: // R), a connection with the configuration S on both asymmetric carbon: atoms (αS: // S), a connection with the configuration R aiii asymmetric carbon atom u and the configuration S on the asymmetric carbon atom // ((/ R: // S) and a compound with the configuration S on the asymmetric carbon atom α and the configuration R on the asymmetric carbon atom // («S: // R ) .: ^f

It has now been shown that by separating off the individual stereoisomers, compounds with different pharmacological effects' obtained from those of the total mixture, obtained by the conventional synthesis method.

It was found exactly that the. (-) («R: // R) -2- (1-methylpropylamino-1- [5,6,7,8-tetrahydronaphthyl (2) I-ethanol and the (-) («R: / fS) -2- (l-methylpropylamino-1 - [5,6,7,8-letrahydronaphthyl (2)] - ethanol the only active compounds as inhibitors the // - represents adrenergic receptors; in particular, the former compound is the most effective. · ..... '

In addition, the toxicity of these compounds is remarkably lower than that of the mixture as a whole and that of the other individual stereoisomers contained in the mixture.

The compound (-) {«R: / iR) -2- (l-methylpropylamino - 1 - [5,6,7,8 - tetrahydronaphthyl (2)] - ethanol also has a lower anesthetic effect than that of the overall mixture and the other individual stereoisomers.

As a result of the decrease in specific toxicity and the decrease in the required doses as a result the greater the effectiveness, the greater the safety factor results from the use of the most effective stereoisomer.

The separation of the individual stereoisomers from the Gesanit mixture is particularly difficult because it

because of the similar physical _: chemical properties it is not possible to separate the two pairs of diastereoisomers and then to subject them to an optical antipodal separation, which would probably also be very difficult.

It has now been found that the stereoisomers can be obtained separately if one in the first step of the synthesis an optically active intermediate introduces, where one. a mixture is obtained which contains only 2 stereoisomers instead of 4. V

It has also been found that these two stereoisomers are not enantiomeric and can therefore be separated by fractional crystallization from ethyl acetate. Thus, the (R) -l-methylpropylaminomethyl-5,6,7,8-tetrahydronaphthyl-2-ketone hydrochloride was prepared from the (R) -l-methylpropylamine by the method described above for the racemic compounds. By hydrogenating this compound, a mixture of (-) (rxR: [IR) -I- (I- methylpropylamino-1 - [5,6,7,8-te- 'trahydronaphthyl (2)] - ethanol hydrochloride and (+) («S: // R) -2- (1-methylpropylamino-1- [5,6,7,8-part trahydronaphthyl (2)] ethanol hydrochloride.

The two compounds were first using fractional crystallization from ethyl acetate containing small amounts of alcohol and then obtained in pure form.

Similarly, (S) became -3-methylpropylamine the (- (-) («S: // S) -2- (l-methylpropylamino-1 - [5,6,7,8 - tetrahydronaphthyl (2)] - ethanol hydrochloride and the '(-) (uR: / iS) -2- (l - methylpropylamino- 1 - [5,6,7,8 - tetrahydronaphthyl (2)] - ethanol obtained, in turn by fractional crystallization were separated. '. ·

. Comparison attempts:

... Pharmacological studies have been carried out to determine the effectiveness of two tetrahydronaphthalene derivatives, namely that according to the documents laid out in Belgian patent 630 210 known isopropylamino derivative and the secondary butylamino derivative to be produced according to the invention, as inhibitors of the / f receptors after oral administration.

The formulas of the two compounds are as follows: ·, - ■;

OH

CH-CH ₂ -NH-CH-CH ₂ -CHj · HCl

2-sec-butylamino-1- (5,6,7,8-tetrahydro-. "2-naphthylj-ethanol. HCl

OH

CH-CH ₂ -NH ₂ -CH

V /

CH ₃

CH,

Isopropylamino-1- (5,6,7,8-tetrahydronaphthyl) ethanol · HCl

The effectiveness of the two compounds was studied based on their ability to produce the effects of noradrenaline and isopropyl noradrenaline on the force of contraction of the heart of dogs to inhibit under anesthesia and with the thorax open. The force of contraction was with a Wa It on strain gauge sewn onto the epicardium of the right ventricle was measured. The procedure used was described in "Arzneimittel-Forschung", 18, 43 (1968), described in detail by M a r c h e 11 i et al. In the same report is the pharmacological examination of the two substances, along with others

ίο similar. Connections, reproduced. The said Investigation has proven that daV'2-sec-butylamino derivative after parenteral administration a stronger and longer lasting one. Effectiveness as an inhibitor of the // receptors against the isopropylamino derivative owns. However, this difference is not very noticeable.

Another (unpublished) investigation

allowed it to be established that between the two. Compounds show a remarkable difference in pharmacological activity when administered orally. Under the test conditions mentioned, the two substances were administered to dogs under anesthesia in doses of 3 mg / kg via a gastric tube. After about 15 minutes, both caused a clear reduction in the frequency of cardiac contractions and the force of contraction. The negative inotropic and chronotropic effect reaches its maximum after 30 minutes and remains almost unchanged for about 2 hours, and then it does so

jo tend to gradually disappear. This Effect is not significantly different for the two derivatives, provided that one considers the intensity, since this lasts longer with the 2-sec-butyl derivative. The intravenous administration of norepinephrine

and isopropyl noradrenaline has shown that the positive inotropic effect of the two amines of the two tetrahydronaphthalene derivatives is clearly reduced. Nevertheless, isopropyU does this aminoderivat 30 minutes after administration an inhibition of 35% and 28% of the effect of the Noradrenaline or isopropyl noradrenaline, whereas the 2-sec-butyl derivative 30 minutes later the administration a 66% inhibition of the action of noradrenaline and a 45% inhibition

the effect of isopropyl noradrenaline. Furthermore, the effect of the 2-sec-butyl derivative is still clearly present after 120 minutes, especially since the inotropic activity of the adrenergic amines is still 37% (noradrenaline) or 25% (isopropylnoradrenaline) inhibited, while the effect of the isopropyl derivative of tetrahydronaphthalene is inhibited after 2 Hours is no longer worth mentioning. > _:

These results show that if /. On the one hand the two derivatives in question have a qualitatively similar effect on the / i-adrenergic receptors, on the other hand. the 2-sec-butyl derivative has a clearly more intensive and longer-lasting effect, which in turn proves that its absorption through the gastrointestinal canal is significantly better and more complete than that of the isopropyl derivative. . .. ■■ · ..: -;,:. ^:: '.- ■' ■ ·. ., - "■ '-:, - ·;, λ

For pharmaceutical purposes, the new compounds prepared according to the invention can be mixed with suitable Binders for oral administration in

Form of tablets or capsules mixed or in solvents for intramuscular or intravenous use Injection can be dissolved or sold as suppositories.

1 O43

In addition, the compounds prepared according to the invention can advantageously be used together with Substances that have a sedative effect are used; Examples are phenylethylbarbituric acid, Meprobamate or reserpine.

B is ρ ie 1 1. '-L

a) 74.5 g of 1-methylpropylamine in 200 ml of anhydrous ether were added to a solution of 120 g 5,6,7,8 - Tetrahydro-α - bromoacetylnaphthyl - 2-ke-

■ ... ·:. '■! clay given in 700 ml of anhydrous ether. The temperature of the mixture was ^{kept at 10 °} C. for 15 to 20 hours, it was then filtered and the solvent and excess 1-methylpropylamine were then removed in vacuo. The remaining residue was dissolved in anhydrous ether and acidified with dry gaseous hydrogen chloride. Here, the l-methylpropylaminomethyl-So ^ S-tetrahydronaphthyl-2-ketone with a melting point of 182

. :, obtained up to 184 ° C (from alcohol — ether).

b) An alcoholic solution of 50 g of 1-methylpropylaminomethyl - 5,6,7,8 - tetrahydronaphthyl-2-ketone hydrochloride was added under hydrogen pressure hydrogenated from 2 to 5 atmospheres and in the presence of 2 g of 10% palladium charcoal.

• After the catalyst has been separated off Evaporation of the solution gave the 2- (l-methylpropylamino-1 - [5,6,7,8 - tetrahydronaphthyl (2)] - ethanol in the form of the hydrochloride with a melting point to 120 "C (from alcohol — ether) obtained.

Example2

a) The procedure described in Example 1 was repeated with the modification that (S) -l-methylpropylamine was used as starting material. In this case, (S) -l-Methylpropylaminomethyl - 5,6,7,8 - tetrahydronaphthyl - 2 - ketonhydrochlorid a melting point of 182 to '184 ⁰ C after recrystallization from ether alcohol obtained _': -; V _v ■

■■■ ·, If the 'condensation' is used (R) - 1-methylpropylamine this gives (R) -1 - methylpropylaminomethyl - 5,6,7,8 - tetrahydronaphthyl-2-ketone hydrochloride, which also has a melting point of 182 to 184 ° C.

b) An alcoholic solution of 50 g of (S) -l-methylpropylaminomethyl-5,6,7,8-tetrahydronaphthyl-2-ketone hydrochloride was hydrogenated under a hydrogen pressure of 2 to 5 atmospheres in the presence of 2 g of 10% palladium charcoal . , _: ,

After the absorption of water had ceased, the mixture was filtered and the solution was evaporated. A mixture of (+) (aS: / fS) -2- (l-Methyipropylamino -1 - [5,6,7,8 - tetrahydronaphthyl (2)] - ethanol hydrochloride and (-) (aR: / JS) -2- <1-methylpropylamino-1 - [5,6,7,8-tetrahydronaphthyI (2)] -etha- <

; nol hydrochloride obtained. The product was in warm ethyl acetate, which contained 5% alcohol,

. dissolved and the solution crystallize at room temperature leave. The deposited crystals were filtered off and recrystallized twice from ethyl acetate.

The (+) (<iS: /? S) -2- (l-methylpropylamino -1 - [5,6,7,8 - tetrahydronaphthyl {2)] - ethanol hydrochloride had a melting point of 170 up to 172 ° C and the rotation value [a] g ". = + 46.9 ° (1%, Alcohol). It consisted of needle-shaped crystals. By displacement with ammonia one can get out the base obtained from the hydrochloride, which has a melting point of 61 to 62 ° C. '

The obtained in the crystallization mother: - _r leach wBrden 'then strongly gekühltf case. one obtains a further crystal fraction consisting of a mixture of the two stereqi ^ bers, which can then be reused in a subsequent approach. The new mother liquors are evaporated to dryness. After recrystallizing twice from ethyl acetate, (-) (aR: // R) -2- (l-methylpropylamino) -15 is obtained from the residue. 1 - [5,6,7,8 - tetrahydronaphthyl (2)] - äthanolhydrochlorid of melting point 129-130 ⁰ C. and the rotation value of [α]? = -46 ° (1%, alcohol) as lamellar crystals. ^ V

The base is obtained from the hydrochloride by displacement with ammonia, which has a melting • point of 66 to 67 ° C.

B e i s ρ i e 1 3

The procedure according to Example 2 was repeated, with the modification that instead of (S) -l-methylpropylaminomethyl-S ^ J ^ -tetrahydronaphthyl ^ -ketone hydrochloride vom (R) -1 - methylpropylaminomethyl - 5,6,7,8 - tetrahydronaphthyl - 2 - ketone hydrochloride was started, a mixture of stereoisomers was obtained. This was in analogously separated by fractional crystallization and here the two stereoisomers

trahydronaphthyl (2)] - ethanol hydrochloride with a melting point of 170 to 172 ° C and the rotation value • [α]? = 46.7 ° (1%, alcohol) as needle-shaped crystals and the (+) (aS: #R) -2- (l - methylpropylamino) -1- [5,6,7,8-tetrahydronaphthyl (2)] Ethanol hydrochloride with a melting point of 129 to 130 ⁰ C with the rotation value MS ¹ = + 47 ° (1%, alcohol) obtained as lamellar crystals. \ _; '; ν:.

Claims (1)

Claim:, ^, -; Process for the preparation of 2- (1-Methy 1-propylamino) - 1 - [5,6,7,8 - tetrahydronaphthyl (2)] - ethanol and its stereoisomers of the formula CH - CH ₂ - NH - CH - CH ₂ - CH ₃ on ' ^::: / y. ^ CH ₃ ; 'J; ^ I ^ι ;'".;:'■ and its pharmacologically usable acid addition salts, characterized in that 5,6,7,8-tetrahydroa-bromoacetylnaphthyl-2-ketone is condensed in a known manner with 1-methylpropylamine in an inert solvent and the condensation product is catalytically in the presence of a Pd, Pt. öder Ni catalyst reduced, whereby one has to produce the (+) (aS: ßS) - and the (-) (oR: /? SK or the (+) (aS : ßR) - and the (-) (aR : ^ R) -2- (l-Methylpropylaniino) -1 - [5,6,7,8-tetrahydronaphthyl (2)] -ethanol carries out the condensation with (S) - or with (R) -1-methylpropylamine and the mixture of the pairs of stereoisomers obtained in each case is separated into the optical antipodes by fractional crystallization of the hydrochloride from an ethyl acetate-ethanol mixture.,