DE2458222A1 - PROCESS FOR THE PRODUCTION OF NEW PHENYLAETHYLAMINE DERIVATIVES - Google Patents

Description

S ANDOZ-PATENT-GmbH. ·, _ΛΛ , · ,, "

785O Loerrach Case '100 ^ 4114

Process for the production of new phenylethylamine derivatives

The present invention relates to new phenylethylamine derivatives (formula I ₇ see formula sheet), in which R. and R _{2 are} hydrogen or lower alkyl / their salts with inorganic and organic acids, and processes for their preparation.

If R. or R ₃ denotes lower alkyl, this contains 1 to 5, preferably 1 to 3, carbon atoms and is, in particular, methyl.

According to the invention one arrives at 'the new compounds of the formula I and their acid addition salts by

a) in compounds of the formula II in which R _{1 and R 2 are} hydrogen or lower alkyl and R _{3 is} an acidolytically or hydrogenolytically removable radical, the ether groups are converted into hydroxyl groups ° ^der 5098-27 / 0974

- 2 - Case 100-4114

b) Compounds of the formula III in which R and R- are hydrogen or mean lower alkyl, reduced

and the compounds of formula I thus obtained Reaction with inorganic or organic acids converted into the corresponding salts.

Process a) according to the invention can in itself be used to convert ether groups into hydroxyl groups usual methods are carried out.

In compounds of the formula II R stands for an acidolytically removable residue, such as. B. methyl, ethyl or benzyl, the ether cleavage is carried out by the usual methods. For example, compounds of the formula II in which R-. stands for an acidolytically removable radical, with Lewis acids, e.g. B. with boron tribromide, in an inert organic solvent under the reaction conditions, e.g. B. a halogenated hydrocarbon such as methylene chloride or carbon tetrachloride or aromatic hydrocarbons at -80 ° to + 70 ° or react briefly with strong mineral acids, such as. B. with hydrobromic or hydroiodic acid optionally at elevated temperature at 20 to 100 °, or on compounds of the formula II in which R _{3 is} an acidolytically removable radical, hydrochlorides, bromides or iodides of organic bases such as aniline or pyridine at increased Let the temperature take effect.

509827/0974

- 3 - ■ Case 100-4114

_{If R 3} in compounds of the formula II is a hydrogenolytically removable residue, the treatment is carried out with catalytically excited hydrogen. An optionally substituted benzyl and benzhydryl radical can be used as a hydrogenolytically removable radical. The catalytic hydrogenation can be carried out in a solvent which is inert under the reaction conditions, e.g. B. ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide or in a lower alcohol such as methanol or ethanol. The hydrogenation is preferably carried out at temperatures between 0 and 100 ° at 1 to 100 atmospheres hydrogen pressure. The usual noble metal catalysts, preferably palladium, are suitable as catalysts. The noble metal catalysts can, for example, as supported catalysts, such as. B. palladium on charcoal.

Process b) according to the invention can be carried out by mixing compounds of the formula III with organometallic reducing agents, such as diborane, ethoxy-methoxy-sodium aluminum hydride, Sodium aluminum hydride or lithium aluminum hydride in a solvent, preferably cyclic, which is inert under the reaction conditions or open-chain ethers, such as. B. tetrahydrofuran, dioxane, diethyl ether, diglyme or dibutyl ether, treated. The reduction is preferably carried out at temperatures between approximately 0 and 80 °. The response time varies depending on the reaction temperature between about 15 minutes and several hours. The decomposition of the The reaction complex is made in a manner known per se carried out the reaction mixture.

509827/0974

- 4 - Case 100-4114

The compounds of the formula I can be known per se Way can be isolated from the reaction mixture and purified, the free bases can be used in the usual way Wise convert them into their acid addition salts and vice versa.

The previously unknown compounds of the formula II used as starting material are prepared by reacting 2,4,5-trichlorophenol with adipic acid, reacting the mono-2,4,5-trichlorophenyl adipate (formula IV) with hexamethylenediamine, and the amide (formula V) reacts without isolation with 2,4,5-trichlorophenol, the resulting reactive ester (formula VI) without isolation with a compound of the formula VII, wherein R. and R _? Mean hydrogen or lower alkyl and R _{3 stands} for an acidolytically or hydrogenolytically removable radical, condensed and the resulting compounds of the formula VIII, in which R ₁ and R _{2 represent} hydrogen or lower alkyl and R stands for an acidolytically or hydrogenolytically removable radical, with a reducing agents that selectively attack the carbonyl groups, ζ. Β. Lithium aluminum hydride reduced.

The previously unknown compounds of the formula III used as starting material are obtained by a compound of formula IX wherein R and R ^ are hydrogen or mean lower alkyl, with hexamethylene-Ν, Ν'-l-bromocaproic acid diamide (Formula X) implements.

The new phenylethylamine derivatives and their acid addition salts stand out in the pharmacological

509827/0974

Case 100-4114

Testing through circular effects and can therefore find use as a remedy.

They show dopamine receptor stimulation, as in the anesthetized dog by increasing the blood flow in the Mesenteric artery and a decrease in blood pressure in doses of 0.01 mg / kg could be determined.

They also show beta adrenergic stimulation, as shown in vitro on the isolated, spontaneously beating guinea pig vestibule by positive inotropes and Chronotropic effects could be shown in doses of 2 mg / 1.

The doses to be used for this naturally vary depending on the type of substance, the administration and the condition to be treated. In general, however obtain satisfactory results with a dose of approx. 0.01 'to 3 mg / kg body weight.- This dose can if necessary, be administered in 2 to 4 portions or as a sustained-release form. For larger mammals lies the daily dose is around 1 to 200 mg. So contain z. B. for oral applications the partial doses about 1 up to 50 mg of the compounds of the formula I in addition to solid or liquid carrier substances.

5.09827 / 0974

- 6 - Case 100-4114

The new compounds or their water-soluble, physiologically compatible salts can be used as medicinal products be administered alone or in a suitable drug form with pharmacologically inert adjuvants.

In the following examples, which explain the invention in more detail, but in no way its scope should restrict, all temperatures are given in degrees Celsius.

509827/097 4

ORIGINAL INSPECTED

Case 100-4114

NH- (CH ₂ ) ₆ -NH- (CH ₂ ) -jj-

IR-O

NH- (CH ₂ ) ₆ -NH- (CH ₂ ) ₃ ~ -J-

II

NH- (CH ₉ ) _-CO-NH- (CH ₂ ) ₃ ~

III

Cl

Cl-

0-C- (CH)

-COOH

Cl

IV

HO-C- _{(CH2) 4} -C0-NH- (CH ₂₎ 0

Cl

Cl

0-C- (CH ₉ )

Il ^

-NH- (CH ₂ )

Cl

VI

5 0 9827/0974

2451212

VII

R ₃ O.

^R 3 ^Ö

NH-C- (CH) -C- ^ NH- (CH ^) _- 1 OO

VIII

HO HO

(CH ₂ ) ^ CO-NH-

^{2) 3} J;

509827/0974

ORIGINAL INSPECTED

- ⁹ ■ - 'Case 100-4114

Example "1; N, N'-Bis {β- [(3, 4-dihydroxyphenyl) ethylamino] hexylYhexamethylenediamine

1 g of N, N'-BXS-C6- [(3,4-dimethoxyphenyl) ethylamino] hexyl} · hexamethylenediamine is suspended in 50 ml of methylene chloride and 1.3 ml of boron tribromide in 5 ml of methylene chloride is added dropwise at 0 °. Stirring is continued for 45 minutes at room temperature and the complex is destroyed by adding methanol. After evaporation several times with methanol, the residue is treated with isopropanol and ether. The title compound is obtained in the form of the tetrahydrobromide.
C ₃₄ H ₅₈ N ₄ O ₄ + 4HBr; M.p .: 200 °.

The N, N'-BIs- (Id - [(3,4-dimethoxyphenyl) ethylamino] hexyl} · hexamethylenediamine is obtained as follows:

59 g of 2,4,5-trichlorophenol and 44 g of adipic acid are dissolved and 62 g of dicyclohexylcarbodiimide in 600 ml of tetrahydrofuran and left for 16 hours at room temperature stand. The urea which has separated out is filtered off and the tetrahydrofuran is evaporated off in vacuo. Of the The residue is fractionated from ethanol / water, the title compound being obtained; M.p. 80-82 °.

2. N ₀ , N '- bis (3,4-dimethoxyphenylethyl) -N ₁ N' -hexamethylene

325 g of adipic acid mono- 2,45-trichlorophenyl ester and 58 g of hexamethylenediamine are dissolved in 5 l of dimethyl formamide. It is left at room temperature for 16 hours

509827/0974

- ^lö ~ Case 100-4114

stand and add 20 g of 2,4,5-trichlorophenol and 206 g of dicyclohexylcarbodiimide to the adipic acid-NjN'-hexamethylenediamide formed in this way, but not isolated, and leave to stand for 16 hours at room temperature. The resulting suspension containing tend mipic acid 2 _/ 4,5-trichlorophenyl _{ester-N /} N ^l -hexamathylendiaitiid is heated to 50 ° and added 181 g of homoveratrylamine. First a solution is obtained from which a suspension soon forms. After a further 6 hours, the title compound is filtered off with the urea and the residue is dissolved in methylene chloride / methanol (8: 2). Isopropanol is then added and the solution is then concentrated in vacuo, the title compound being obtained; 192-194 °.

³ * N ^ Nj ^

hexamethylenediamine

One puts abs in 200 ml. Tetrahydrofuran 3.4 g lithium aluminum hydride before. A suspension of 8 g of N ₃₇ N ^ -BiS (3,4-dimethoxyphenylethyl) -N ,, N'-hexamethylene-bis (adipic acid diamide) in 100 ml of tetrahydrofuran is added dropwise with stirring and nitrogen flow. The resulting solution is refluxed for 3 hours. After cooling to 0 °, 10 ml of water are added. The resulting pulp is filtered off through Hyflo and the solution is precipitated with an ethereal hydrochloric acid solution. It is suction filtered and the crystals are crystallized from isopropanol / methanol. The title compound is obtained with melting point 298-300 (decomp.).

509827/097 4

"■ '■ ^{-': -:} - Xl - *" Gases 100-4114

Example 2: NyN'-Bis- £ β -ΐ (3 ", 4-dihydr axyphenyiypropy 1- ^:

yl ^ ^:

N, N ^l -to- € ^ t3. _i; 4y hexyl-hexamethylenediamine is reacted with boron tribramide according to the method described in Example 1 ".

Example 3; N, H * -BIs - ^ - [2- (2-methyl-4,5-dihydroxy-

phenyl ') ethylamino] -l-hexyl ^ -hexamethylene ^ dianvin

N, N ¹ -bis- {6 ~ £ 2- (2-methyl-4, 5-dimethoxyphenyl) ethylamino] -1-hexy! ^ Hexamethylenediamine is reacted according to the procedure described in Example 1 with boron tribromide. "

Example 4; N, N '-Bis- ^ 6- [3- (2-methyl - 4 ', 5-dihydroxyphenyl) propy1-2-amino3 -l ~ hexy ^ -hexamethylene diamine tetra-hydrobromide .

30 g of N , H '-BiS - ^ - [3- ■ (2-methy 1-4,5-dimethoxyphenyl) propyl-2-amino] -l-hexy ^ -hexamethylene diamine. are refluxed for 8 hours in 300 ml of 48% aqueous hydrogen bromide solution with the introduction of nitrogen.

After evaporation in vacuo and repeated digestion with ethanol and ether is suction filtered and the Title compound obtained; M.p. 130 °.

The N _i N'-bis-6- [3- (2-methyl-4,5-dimethoxyphenyl) propy1-2-amino] -1-hexylhexamethylenediamine used as starting material is prepared as follows:

509827 / 0-974

ORIGINAL INSPECTED

~ 12 - Case 100-4114

1. Hexamethylene-N_, N2-1-bromocaproic acid diamide

12 g hexamethylenediamine, 43 g bromocaproic acid chloride are dissolved in 400 ml of ethyl acetate at 0 ° and treated with 200 ml of 1 η sodium hydroxide solution. One lets Stand for 12 hours at a pH of 9 to 10 and then filtered off. The organic phase is with Washed water and, after drying over sodium sulfate, filtered off and evaporated. After recrystallization the title compound is obtained from hot chloroform; 117 °.

2. N_, N ^ _ |
2 — amino—! "

34 g of 3 ^ -dimethoxy-e-methyl-oc-methylphenylethylamine are added and 19 g of hexamethylene ~ N, N'-1-bromocaproic acid diamide in 500 ml of ethanol and boils for 5 hours at reflux. It is cooled and washed repeatedly with dilute sodium hydroxide solution. It will evaporated and taken up in ethyl acetate, dried over sodium sulfate and evaporated in vacuo. The residue is treated with ether and then pulverized. 33 g of the amide derivative of the above are obtained named title compound, which is immediately further reduced. The amide derivative of the above The title compound is placed in 500 ml of absolute tetrahydrofuran and 10 g of lithium aluminum hydride added dropwise in absolute ether. It is refluxed for 16 hours, cooled and destroyed at 0 ° the excess lithium aluminum hydride by adding water.

50982 7/0974

Case 100-4114

The solvent is distilled off in vacuo and the residue is extracted with ethyl acetate. The dried one The ethyl acetate phase is mixed with ether / 4 η hydrochloric acid solution. After filtering off with suction and drying, the Title compound as the hydrochloride salt; Snp. 208 ° (decomp.).

Example 5: N, N'-bis (~ 6- [Q, 4 ~ dihydroxyphenyl) ethylamino] hexyl hexamethylenediamine tetrahydrobromide

5.5 g of bis [6- (N-3,4-dihydroxyphenylethyl) aminocaproic acid] -N, N ¹ -hexamethylene amide is dissolved in 500 ml of tetrahydrofuran abs. stirred in suspension. While passing in nitrogen, 120 ml of 1 η diborane in tetrahydrofuran are added dropwise and then refluxed for 3 hours. The complex is then destroyed with dilute hydrochloric acid solution and the solution is evaporated in vacuo. After repeated evaporation with methanol, the residue is recrystallized from isopropanol / hydrogen bromide. The title compound is obtained; M.p. 200 °.

The bis-f6- (N-3,4-dihydroxyphenylethyl) used as starting material -amino-caproic acid- ^ N'-hexamethylene amide is made as follows:

30 g of 3,4-dihydroxyphenylethylamine and 47 g of hexamethylene-N, N ¹ -1-bromocaproic diamide are refluxed in a mixture of 500 ml of ethanol and 50 ml of pyridine for 8 hours. The residue is digested with isopropanol and ether. It is then suction filtered and the residue is dried.

509827/0974

Claims (4)

- 14.- Case 100-4114 Claims; Tl .. New Phenyl.athylaminderi.vate of the formula I (see formula sheet), where R ₁ and R ~ are hydrogen or lower alkyl, their salts with inorganic and organic acids. 2. Process for the preparation of new phenylethylamine derivatives of the formula I, in which R ₁ and R_ denote hydrogen or lower alkyl, and their acid addition salts, characterized in that one a) in compounds of the formula II , in which R .. and R _? Denotes hydrogen or lower alkyl and R denotes an acidolytically or hydrogenolytically removable radical which converts the ether groups into hydroxyl groups or b) Compounds of the formula III in which R _{1 and R 2 are} hydrogen or lower alkyl, reduced. and the compounds of the formula I obtained by reaction with inorganic or organic acids converted into the corresponding salts. 3. N, N ¹ -bis- (β- [3,4-dihydroxyphenyl) ethylamino] hexyl ·} - hexamethylenediamine and its acid addition salts. 4. Remedies characterized in that they have compounds of the formula I and / or their acid addition salts. 509877 / G97A
3700 / BA / ER '"' SANDOZ-PATENT-GMBH