FI62051C - FRAMEWORK FOR HYDROXYHALOGENBENYLAMINING OF HYDROXYHALOGENBENYLAMIN WITH MEDICINAL SECRETOLIC CHARACTERISTICS OF A YTAKTIVA AEMNEN UNDERLAETTANDE VERKAN - Google Patents

Description

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Patent ·) a Board of Registration .... _ ... _. . .....

_ '(44) Date of entry into force of the contract. -

Patent · och registrstyrelsen 'Antoktn utit (d odi uti.tkrift * n pubiicmd 30.07.82 (32) (33) (31) Oil.73, 26.07.73, 17.09.73

Federal Republic of Germany-Förbundsrepubliken lysklandiDE) P 2251891.8, P 2310325-9. p 2320967.8, P 2337932.0, p 23 ^ 671 + 3.8 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, Biberach an der Riss, Federal Republic of Germany Tyskland (DE) (72) Johannes Keck, Biberach / Riss, Sigfrid Puschmann, Biberach / Riss,

Gerd Kruger, Biberach / Riss, Klaus-Reinhold Noll, Warthausen-Oberhöfen, Federal Republic of Germany-Förbundsrepubliken lyskland (DE) (7I +) Leitzinger Oy (5I +) Process for the preparation of - For the preparation of hydroxyl-halobenzylamines with a host, secretory and imaging function in the host network

The present invention relates to a process for the preparation of hydroxyhalobenzylamine derivatives having a cough-relieving, secretolytic and surfactant-promoting effect, the compound of formula I being

(Hali OH

k where

Hai is a chlorine or bromine atom, is a hydrogen, chlorine or bromine atom, R2 is a branched alkyl group having 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups, or a group of the formula 2,62051 R3 wherein a hydrogen atom, a hydroxy group or an alkyl group, having 1 to 4 carbon atoms, n is 0, 1 or 2 R 1 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 or 4 carbon atoms or also a hydrogen atom if R 1 is not a hydrogen atom or a branched alkyl group having 3 to 5 carbon atoms optionally substituted by R2 or 1 to 3 hydroxyl groups, and k represents 1 or 2, and their physiologically acceptable acid addition salts with inorganic or organic acids.

The compounds of the general formula I above and their physiologically acceptable acid addition salts with inorganic or organic acids have valuable pharmacological properties, in particular, in addition to their action on surfactant formation or on the antiatelectasis factor of alveoli, a secretolytic and antitussive effect.

According to the invention, the compounds of the formula I can be prepared by the following methods: a) The compound of the general formula II 3 62051

^ \ / Cn2 'R6 (Hal) k OH

In J, R 1, Hal and k have the same meaning as above and

Rg is a hydroxyl group, a chlorine, bromine or iodine atom, an acyloxy, sulfonyloxy, alkoxy, aryloxy or aralkoxy group, is reacted with an amine of the general formula III H - ή '' 2 (III) wherein

R 1 and R 2 have the same meaning as above.

The reaction is conveniently carried out in a solvent such as acetone, carbon tetrachloride, chloroform * ethanol, tetrahydrofuran, benzene, toluene, dioxane, tetralin, or an excess of the amine of general formula III and, depending on the reactivity of the group Rg, at temperatures between -70 ° C and 200 ° C. . However, the reaction can also be carried out without a solvent.

If Rg represents a halogen atom, the reaction is best carried out at temperatures between 0 and 150 ° C, for example at the boiling point of the solvent used, and suitably in the presence of a hydrogen halide binding agent such as inorganic bases such as sodium carbonate or sodium hydroxide, ion exchangers, tertiary organic or pyridine. In this case, the tertiary organic base used can also act simultaneously as a solvent.

If Rg represents a sulfonyloxy group such as U-methylphenylsulfonyloxy group, then the reaction is best carried out at temperatures between -70 ° and 50 ° C.

If Rg represents an acyloxy group such as an acetoxy or · 62051 benzoyloxy group or an alkoxy, aryloxy or aralkoxy group, then the reaction is optionally carried out in the presence of an acid catalyst such as ammonium chloride at temperatures between 0 and 200 ° C.

If R "represents a hydroxyl group, the reaction is optionally carried out in the presence of an acid catalyst such as hydrobromic acid, p-toluenesulfonic acid, butyric acid or optionally an alkaline catalyst such as potassium hydroxide or magnesium oxide, preferably at temperatures of 120 and 180 ° C. However, the reaction can also be carried out without a solvent.

b) An aldehyde of general formula IV is obtained

CHO

'' ICT

(Hai), OH k in R 1, L 1 and k have the same meaning as above, to react with the amine of general formula III m 2 R 2 (III)

ti - N

wherein and R 1 are as defined above, or with the corresponding formamide, in the presence of formic acid.

The reductive amination is best carried out at temperatures between 50 and 250 ° C, optionally in a solvent and optionally by distilling off the water formed at the same time; however, it is particularly preferred when the amine and / or formic acid used according to the general formula III simultaneously acts as a solvent in the reaction. If R 1 in the compound of the general formula III represents a hydrogen atom, then after the reaction, the resulting reaction mixture is heated to reflux with a dilute acid such as 2N hydrochloric acid.

s 62051 c) For the preparation of compounds of general formula I in which a hydrogen atom is present:

The compound of general formula V is reduced

^, CH = N

iCT! (Hal OR? Or a compound of general formula Va

XiT'V CH2 '* Z

(Hal) ° R 7 k wherein R 1, R 2, Hal and k are as defined above, Z is optionally substituted by a hydroxy or alkyl group having 1 to 4 carbon atoms, a substituted cyclohexylidene group or a branched alkylidene group having 3 to 5 carbon atoms, and Rη is a hydrogen atom or a carboxylic acid group.

The reduction is conveniently carried out with catalytic activated hydrogen if R? is a hydrogen atom, for example hydrogen in the presence of Raney nickel or Raney cobalt, evolving hydrogen, for example activated metallic aluminum or water, sodium amalgam and ethanol, zinc and hydrochloric acid, or particularly preferably a complex metal hydride such as lithium aluminum hydride or sodium borohydride, for example methanol, ethanol, ethanol / water, tetrahydrofuran, dioxane, dioxane / water, pyridine or ether, and up to the boiling point of the solvent used, for example at temperatures between -50 and 100 ° C. If R7 in the compound of the general formula 6 62051 V or Va represents a carboxylic acid group, then a "development" during hydrogen or complex metal hydride reduction occurs at the same time.

d) For the preparation of compounds of general formula I in which no hydrogen atom is indicated and the groups R e and R 2 do not mean a group substituted by a hydroxy group:

The compound of general formula VI is alkylated

B

CH - N (VI) n- ·

(Hai) k OH

wherein R 1, H 2 and k are as defined above and R 21 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or the same as a group R 0 above except for a branched 4 mt alkyl group having 3 to 5 carbon atoms and a group substituted by a hyroxyl group, With the compound of formula VII, R 4 '- W (VII) in I <4' represents a branched alkyl group having 3 to 5 carbon atoms, a cyclohexyl group and the same as R 1 except hydrogen and W represents a halogen atom and a sulfonic acid group.

The reaction is conveniently carried out in a solvent such as methanol, dioxane or dimethylformamide, and conveniently at temperatures between -20 ° C and 150 ° C, but most preferably at the boiling point of the solvent used. The methylation can also take place with formaldehyde in the presence of formic acid at elevated temperatures, for example at the boiling point of the reaction mixture.

e) Phenol of general formula VIII 7 62051 "-Cl

'OH

(Hal) k joSSd, Hal and k have the same meaning as above, wherein one nal group is in the 2-position of the compound of general formula VIII, is reacted with formaldehyde or paraformaldehyde and an amine of general formula III in K - (III) hj in R2 and has the same meaning as above.

The reaction is conveniently carried out in the presence of a solvent such as water, methanol, ethanol or dioxane at temperatures between 0 and 100 ° C, however, most preferably in the boiling point of the solvent used.

The reaction can also be carried out in such a way that, if appropriate, a compound of the general formula IIIa is formed in situ

Alk - O - Ch „- N ^ 2 (Ula) * \ R4 where R2 has the same meaning as above and

Alk represents a lower alkyl group, is reacted with a compound of general formula VIII.

f) Halogenating a compound of general formula IX β 62051/2 (IX) C, 12 - Ν \ -Μ 0 Η wherein.

, mean the same as above.

The halogenation is carried out with a halogenating agent, for example chlorine, bromine, phenyl iodide dichloride or tribromophenol hydrochloride, preferably in solution, for example in 50-100% acetic acid, methylene chloride or in the presence of a tetrahydrofuran in the presence of a tertiary organic base. and 50 ° C. Suitably 1 or 2 moles or a small excess of halogenating agent are used per mole of the compound of general formula IX which can be used as a base or a salt, for example the hydrochloride. If a hydrogen halide salt is formed in the reaction, this can be isolated as such directly or, if desired, further purified via a base.

g) Cleavage of one or two protecting groups from a compound of general formula X.

X

'J Vii' Ci (Hal), OY in R 1, R 6, Hal and k have the same meaning as above, X is an amino group protecting group or means the same as above, R and Y are a hydroxyl group protecting group or a hydrogen atom, however, at least the second group X or Y must be a protecting group of an amino or hydroxyl group.

If X and / or Y represents an arbitrary acyl group, for example an acetyl, benzoyl or p-toluenesulphonyl group, its cleavage into 9 62051 groups takes place hydrolytically in the presence of a solvent, for example with ethanolic hydrochloric acid or aqueous-alcoholic sodium hydroxide. .

If X and / or Y represents a benzyl group, the cleavage of this group takes place hydrogenolytically, for example with hydrogen in the presence of a catalyst, preferably in a solvent such as ethanol, methanol / hydrochloric acid, water / hydrochloric acid, and at room temperature. Upon determination of the group, said alkenyl groups may be simultaneously converted into the corresponding alkyl groups in the reaction.

If Y represents an alkyl, aryl or aralkyl group, then the cleavage of these groups takes place best with hydrogen bromide or hydrogen iodine at elevated temperatures. However, it can also be carried out with acid halides, phosphorus oxyhalides, phosphorus pentahalides, alurcinin halides, sulfuric acid or organometallic compounds.

If Y represents a carbo, xylic acid residue, for example an acetyl or benzyl group, the cleavage of this group can also be carried out with complex metal hydrides, for example sodium borohydride in pyridine or lithium aluminum hydride in an inert solvent such as ether or tetrahydrofuran at temperatures between 0 ° C and If X then represents a formyl or acetyl group, this is simultaneously reduced to a methyl or ethyl group.

h) Reduction of a compound of general formula XI 0 II / Ro * N "(Hai) 0R ~ k 7 wherein ίο 62051 R ^ 5 · Hal and k have the same meaning as above, '' is a formyl or acetyl group or means the same as above r4 ia R 7 is a hydrogen atom or a carboxylic acid group.

The reduction is conveniently carried out with catalytically activated hydrogen if R? means a hydrogen atom or a developing hydrogen, for example an alkali metal in an alcohol such as sodium in ethanol, at temperatures between room temperature and the boiling point of the solvent used; however, particularly preferably the reaction is carried out with a complex metal hydride, for example sodium borohydride in pyridine or lithium aluminum hydride in ether or tetrahydrofuran. If R 1 'represents a formyl or acetyl group in the compound of general formula XI, then upon reduction it is reduced to the corresponding alkyl group, and / or R 1 represents a carboxylic acid group, this is cleaved off during the reaction if the reduction is carried out with evolving hydrogen or complex metal hydride.

i) For the preparation of compounds of general formula I having a hydroxyl group in the 2-position and R 1 is a hydrogen atom:

Hydrolysing a compound of general formula XII R1 to M? "R2 (XII) 0'c = 0 (Hal j

R 1> R 2, Hai and k have the same meaning as above.

The hydrolysis is conveniently carried out in the presence of an acid such as hydrochloric acid or sulfuric acid and particularly preferably in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol, isopropanol, tert-butanol, acetone or dioxane and the boiling point of the solvent used. .

11 62051 j) A compound of general formula XIII

ί ^ Υ CH2 · ° H

(Hai) 0R „k ö where

, Hai and k have the same meaning as above and R „is an organic acyl group, is reacted with the formula III

O

with the amine according to / R 2 H "N \ (III) R 4 wherein R and Ru have the same meaning as above.

The reaction is conveniently carried out in a solvent such as tetralin or an excess of the amine of general formula III used at temperatures between 100 and 220 ° C, but most preferably at temperatures between 120 and 180 ° C. However, the reaction can also be carried out without a solvent.

In the definition of the group Rg, acetyl, butyryl, benzoyl or 4-chlorobenzoyl is particularly suitable as the above-mentioned organic acyl groups.

k) For the preparation of compounds of general formula I in which the hydroxyl group is in the 2-position:

A compound of general formula XIV 12 62051 (Hal) is obtained, in which R 1> rial and k have the same meaning as above, and

R 9 is an alkyl, aryl or aralkyl group, to react with an amine of general formula III in R 2 and is as defined above, and then the reaction product is hydrolyzed.

The reaction is conveniently carried out in a solvent such as tetralin or an excess of the amine of general formula III used at temperatures between 100 and 200 ° C, but most preferably at temperatures between 120 and 180 ° C. However, the reaction can also be carried out without using a solvent.

Subsequent hydrolysis is best performed in the presence of an acid such as hydrochloric acid or sulfuric acid in a polar solvent such as hydrogen, ethanol / water or dioxane / water and at temperatures up to the boiling point of the solvent used.

When determining the group Rg, the methyl groups mentioned above are, in particular, a methyl, phenyl or benzyl group.

1) For the preparation of compounds of general formula I having a hydrogen atom and a hydroxyl group in the 2-position:

Hydrolysing a compound of general formula XV; 1 13 62051

R1-f ^ YCh2'N - r2 l ^ A O / Ch2 CXV) (Hal) k where R »R2, Hal and k have the same meaning as above.

The hydrolysis may optionally take place in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid, but preferably without acid in a polar solvent such as water, methanol / water or dioxane / water, and at temperatures between 0 ° C and the boiling point of the solvent used.

m) For the preparation of compounds of general formula I in which a cyclohexyl group and an R 1 methyl group are represented by:

Compound of general formula Ha H-CT '"

So <r (IIa) (Hai), OH k wherein, rial and k are as defined above, is reacted with an amide of general formula XVI f / R2 \ 0 = P t NI (XVI) V R4 / 3 or an amide of general formula XVIa with, 11 (62051

0 R

Κ10 - C - N ^ <XVIa> where

R 1 and R 1 + have the same meaning as above and R 10 is an alkyl, aryl or aralkyl group.

The reaction is conveniently carried out in a solvent such as tetalin in temperatures between 100 and 250 ° C, but preferably at temperatures between 120 and 180 ° C. However, the reaction can also be carried out without a solvent.

The compounds of the general formulas II-XVIa used as starting materials in processes a-m are partly known from the literature or can be prepared by methods known in the literature.

Thus, for example, benzyl halides of general formula II can be prepared from the corresponding toluene derivatives by reacting them with N-bromosuccinimide or halogen under UV radiation.

Thus, a benzyl alcohol derivative of the general formula II is obtained, for example, by reacting the corresponding benzyl alcohol with the corresponding acid in the presence of hydrochloric acid or by reacting the corresponding benzyl halide with the corresponding alcohol in the presence of barium carbonate and halogenating the corresponding benzyl alcohol.

The aldehyde of general formula IV is obtained, for example, by halogenation of the corresponding benzaldehyde, and the amines of general formulas V and Va are obtained from the corresponding primary amines and the corresponding carbonyl compounds. Reduction of the compound of general formula V or Via thus obtained, for example with sodium borohydride, gives a compound of general formula VI.

The benzylamines of the general formulas IX and X are obtained, for example, by reacting the corresponding benzyl halides with the corresponding amines and optionally then acylating.

The benzamides of the general formula XI used as starting materials can be prepared, for example, by reacting the corresponding naphthalides with the corresponding amines and optionally then acylating.

The compounds of general formula XII used as starting materials are obtained, for example, by halogenation of the corresponding benzoxazines.

The compound of general formula XIII is obtained, for example, by reducing the corresponding benzaldehyde with hydrogen and using Raney nickel as a catalyst.

The compound of general formula XIV is obtained, for example, by halogenation of the corresponding compounds.

The compound of general formula XV is obtained by condensing the corresponding phenol and the amine of general formula III with an excess of formaldehyde.

The acid amine of general formulas XVI or XVIa is obtained, for example, by reacting the corresponding acid halide with the corresponding amine in the presence of pyridine.

The compounds of the general formula I obtained can be converted into their physiologically acceptable salts with inorganic or organic acids, for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid have proved to be suitable.

As already mentioned, the novel compounds of the general formula I have valuable pharmacological properties, in particular they have a secretolytic and cough-suppressing effect, in addition to an increasing effect on the formation of a surfactant or an antiatelectase factor.

For example, the biological efficacy of the following compounds was studied: Λ = M-ethyl-N-cyclohexyl-η 3,5-dibromo-2-hydroxy-benzylamine hydrochloride, B = N-ethyl-N-cyclohexyl-3,5-dibromo-L-hydroxy -benzylamine hydrochloride, 1C 62051 lb C = 3,5-dibromo-t-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride, D = 3-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride, E = 3-bromo-5-chloro-N-cyclohexyl-4-hydroxy-H-methyl-benzylamine hydrochloride, F = 3 3 5- dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylalanine hydrochloride, G = 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylanine hydrochloride, H = 3,5-dichloro-N- (dihydroxy-tert-butyl) -4-hydroxy-benzylanine hydrochloride and 1 = 3,5-dibromo-2-hydroxy-N-tert-pentyl-benzylamine-hydro -chloride.

1. Cough suppressant effect:

In groups of 10 alert white rats given 50 mg / kg p.o. test substance, triggered by cough irritation by inhalation of a 7.5% aqueous citric acid spray. Thirty minutes after administration of the test compounds, the mean percentage change in the number of coughing episodes compared to the control group of 10 animals was measured (see Engelhorr. And Puschman, Arzneimittelforschung 13 ^ 474-480 (1963)): --- 1 .......— - - '- ---------- -

Mean Percentage change in the number of coughing episodes 30 min. On the administration of a dose of 50 mg / kg p.o._____ A - 38 3 - 34 C - 35

_________________________J

2. Effect against sputum:

Sputum removal experiments were performed after administration of 8 mg / kg p.o. test substances for 8-10 anesthetized rabbits or 5 anesthetized guinea pigs. The calculation of the 2-hour increase in secretion occurred before and after administration of the agents (see Perry and 3oud, Pharmakol. Exp. Thaap. 7_3> 65 (1941)).

I? 62051

The effect of the compounds on the circulation of cats under chlorolose-urethane anesthesia after intravenous administration was studied (3 animals per dose):

Experiments in rabbits:

Substance Increased excretion Circulatory effect A + 81% '4 mg / kg: no effect 8 mg / kg: short-term small decrease in blood pressure B + 87% 8 mg / kg: no effect 3. Acute toxicity:

Oriented acute toxicity was determined in groups of 5 white mice after an animal dose of between 500 and 5000 mg / kg p.o. (observation time: 72 hours).

Pharmacological comparative tests

The above-mentioned compounds A-I and the compounds K-0 and DE prepared according to the invention are disclosed in DE 593 579 (compounds P, Q and R) and Chim. Therap. 3, 97 (1968) (S and T), the pharmacological properties of the known compounds are compared in the following table with respect to the antitussive effect of the compounds and their toxicity. The antitussive effect was performed as described in 2. above, using guinea pigs as experimental animals.

The compounds are, in addition to the above-mentioned compounds A1, the following compounds: K = 3,5-dibromo-2-hydroxy-N- (hydroxy-tert-butyl) -benzylamine hydrochloride, L = 3,5-dibromo-N- (dihydroxy-tert-butyl) (butyl) -4-hydroxy-benzylamine hydrochloride, M = 3,5-dichloro-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, N = 3,5-dichloro-2- hydroxy-N- (trihydroxy-tert-butyl) -benzylamine hydrochloride and Ιβ 620550 = 3,5-dichloro-4-hydroxy-N- (hydroxy-tert-butyl) -benzylamine hydrochloride

Reference compounds: P = 2-amino-3,5-dibromo-N- (cis-3'-hydroxycyclohexyl) -benzylamine hydrochloride, Q = 2-amino-3,5-dibromo-N- (trans-3 ' -hydroxycyclohexyl) -benzylamine hydrochloride, R = 2-amino-3,5-dibromo-N- (trans-3'-hydroxycyclohexyl) -N-methyl-benzylamine hydrochloride, S = 3,5-dichloro-2 -hydroxy-N- (n-2-hydroxypropyl) -benzylamine hydrochloride and T = 3,5-dichloro-2-hydroxy-N-cyclohexyl-benzylamine hydrochloride.

The experiments gave the values shown in the following table

Compound Increase in secretion Toxicity (mouse) A + 67%> 10 g (dead in animals 1) B + 61%> 10 g ("" 1) C + 71%> 5 g ("0) D + 88%> 5 g ( ”0) E + 67%> 10 g (" "0) F + 88%> 4 g (" 0) G + 64%> 4 g ("0) H + 61%> 4 g (" 0) I + 80%> 1 g ("0) K + 66%> 4 g (" 0) L + 62%> 4 g ("0) M + 75%> 4 g (" 0) N + 62%> 4 g ( "0) 0 + 61%> 4 g (" 0) P + 24% <4 g ("5) Q + 29% <3 g (" 3) R + 18% <2.5 g ("3) S + 38% <5 g ("3) T + 19%> 4 g (" "0) 19 62051

Substance Acute toxicity A> 1000 mg / kg p.o. (5 animals dead 0) B> 1000 mg / kg p.o. (5 animals dead 0) C> 1000 mg / kg p.o. (& animal dead 0) D> 500 mg / kg p.o. (5 animals dead 0) E> 500 mg / kg p.o. (5 animals dead 0) F> 5000 mg / kg p.o. (5 animals dead 0) G> 5000 mg / kg p.o. (5 out of 5 animals dead)

B

I> 5000 mg / kg p.o. (5 of the 5 dead)

The compounds of the general formula I prepared according to the invention, optionally in combination with other active ingredients, are processed into conventional pharmaceutical preparations in a single dose of 1 to 20 mg, but preferably 2 to 10 mg.

The following examples further illustrate the invention:

The compounds of the present invention can, of course, be prepared by any method, taking into account the limitations of the various methods.

Example 1 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride 17 g of 3,5-dibromo-2-hydroxy-benzyl bromide and 12.7 g of N-ethyl-cyclohexylamine are heated under reflux for 3 hours. In 150 ml of ethanol. The residue, 150 ml of chloroform and 200 ml of water are then shaken. The chloroform phase is separated, filtered and evaporated to dryness. The residue is dissolved in ethanol and acidified with ethanolic hydrochloric acid. In this case, N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxybenzylamine hydrochloride crystallizes. Melting point: 193 - 19U ° C (decomposes).

20 62051

Example 2 N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-Benzylamine hydrochloride 21 g of 3,5-dibromo-salicylaldehyde, 565 g of N-methyl-cyclohexylamine and 23 g of formic acid are heated 6 hours at 70-80 ° C. After cooling, the reaction product is shaken together with chloroform and dilute ammonia. The chloroform phase is separated and evaporated to dryness. The residue is chromatographed on 800 g of silica gel using ethyl acetate / chloroform (1: 1). After 0.5 l of the stock solution, the next 0.5 L is collected and evaporated to dryness. The residue is dissolved in 50 ml of ethanol and acidified with ethanolic hydrochloric acid. N-cyclohexyl-3,5-dibromo-2-hydroxy-N ** methyl-benzylamine hydrochloride, m.p. 189-191 ° C, decomposes (decomposes).

Example 3 3,5-Dibromo-H-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride ______ 19 g N- (3,5-dibromo-α-hydroxy-benzylidene) -cis-3-amino -cyclohexanol (melting point 231-233 ° C) (decomposes)) is slurried in 0.5 liter of ethanol and 2 g of sodium borohydride are added. The mixture is stirred at room temperature for 1.5 hours. 200 ml of 2N sodium hydroxide are then added and the ethanol is distilled off in vacuo. Ammonium chloride is added to the remaining solution, whereupon a crystalline precipitate precipitates. This is filtered off with suction, washed with water and dissolved in 100 ml of 2N hydrochloric acid with heating. After a short time, 3,5-dibromo-H-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride crystallizes out, which is filtered off with suction and washed with acetone. Melting point 216-218 ° C (decomposes).

Example 4 N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hyarochloride __-3.6 g of N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine, 3.6 g of 21,62051 sodium bicarbonate and 3.6 g of methyl iodide are refluxed for 16 hours in a mixture of 25 ml of tetrahydrofuran and 50 ml of methanol. It is then filtered and the filtrate is evaporated to dryness. The residue is shaken with chloroform and dilute ammonia and the chloroform phase is evaporated to dryness. The remaining residue is boiled with ethyl acetate and, after cooling, a small amount of insoluble matter is filtered off. The filtrate is acidified with ethanolic hydrochloric acid to crystallize the hydrochloride, mp 189-191 ° C (decomposes).

Example 5 N-Cyclohexyl-3,5-dibromo-H-hydroxy-N-methyl-benzylamine hydrochloride 7.2 g of N-cyclohexyl-3,5-dibromo-α-hydroxy-benzylamine are dissolved in 20 ml of formic acid and added. 2 ml of 10% formaldehyde. The solution is heated for 3 hours in a boiling water bath, then diluted with water and made alkaline with concentrated ammonia. The precipitated base is filtered off with suction, washed with water and the hydrochloride is crystallized from ethanol by adding a little ether. Melting point 168-170 ° C (decomposes).

Example 6 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride 51 51 g of N-ethyl-cyclohexylamine and 12 g of paraformaldehyde are dissolved with heating in 200 ml of ephenol. After cooling, 100 g of 2,4-dibromo-phenol are added, the mixture is allowed to stand for 1 hour at room temperature and refluxed for 7 hours. The solution is evaporated on the images. The residue is dissolved in ether and shaken with 2N ammonia and then with water. With vigorous stirring, 2N hydrochloric acid is added to the ether phase until the mixture reacts strongly acidically.

After a short time, the hydrochloride crystallizes. This is filtered off with suction, washed with water and then with acetone. After recrystallization from ethanol / ether, the melting point is 193-194 ° C (decomposes).

22 62051

Example 7 N- (4-tert-Butyl-cyclohexyl) -3,5-dibromo-β-hydroxy-Benzene 1 m.p. Hydrochloride melting point: 229-231 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and 4-tert-butyl-cyclohexylamine.

Example 8 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzyl-ε-βyl ___________-______________________ ^ ____-____________________

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and trans-4-amino-cyclohexanol.

Example 9 3,5-Dibromo-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine_________

Melting point of the hydrochloride 128-136 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and cis-3-amino-cyclohexanol.

Example 10 3,5-Dibromo-2-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine_________

Melting point: 203-204.5 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and trans-3-amino-cyclohexanol.

Example 11 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-Benzyl 1 Jamine _______ Hydrochloric acid Melting point: 120 ° C (decomposes).

Prepared according to Example 2 from 3,5-dibromo-salicylaldehyde, trans-4-methylaminocyclohexanol and formic acid.

„62051

Example 12 Melting point of 3,5-dibromo-2-hydroxy-N- (cis-3-hyaroxy-cyclohexyl) -h-methyl-benzyl 1 hydrochloride hydrochloride: 80-83 ° C (decomp.).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl-bromide and cis-3-methylamino-cyclohexanol.

Example 13 Melting point of N-ethyl-3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine (hydrochloride as ethanolate: 135-137 ° C (Chajoa)). Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and trans-4-ethylamino-cyclohexanal.

Example 14 N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine hydrochloride Melting point: 17-180 ° C.

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and E-propyl-cyclohexylamine.

Example 15 N-allyl-N-cyclohexyl-3. 5-Dibromo-2-hydroxy-bercyl-amine Melting point of the hydrochloride: 176-178 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-allyl-cyclohexylamine.

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Example 16 N-Cyclohexyl-3,5-dibromo-2 'hydroxy-N-isopropylbenzylamine; Melting point: 108-110 ° C.

Prepared according to Example 1 from 3,5-dibrono-2-hydroxybenzyl bromide and N-isopropylcyclohexylanine.

Example 17 N-Cyclohexyl-N-cyclopropyl-3,5-dibromo-2-hydroxy-benzylic acid · Melting point of the hydrochloride: 204-208 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl 4-bromide and ii-cyclopropyl-cyclohexylamine.

Example 18 N- (4-tert-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy'N-methyl-benzylamine ______

Melting point of hydrochloride: 209-211 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-fluoro-benzyl bromide and N-methyl-4-tert-butyl-cyclohexylamine.

Example 19 N-Ethyl-N- (trans-4-tert-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylamine________

Melting point of hydrochloride: 175-176 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-4-tert-butyl-cyclohexylamine. The isomer mixture is separated by column chromatography.

Example 20 N-Ethyl-N- (cis-4-tert-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylamine ____

Melting point of hydrochloride: 168-169 ° C (decomposes).

Prepared according to Example 19 from 3,5-dibromo-2-hydroxy-benzyl-ibromide and N-ethyl-4-tert-butyl-cyclohexylamine.

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Example 21 N- (trans-4-tert. ** butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-u-propyl-benzylamine ___

Melting point of the hydrochloride: 173-174 ° C (decomposes).

Prepared according to Example 19 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-4-tert-butyl-cyclohexylamine.

Example 22 N- (cis-4-tert-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-N-propyl-pentylamine

Hydrochloride melting point: 148-150 ° C (decomposes).

Prepared according to Example 19 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-4-tert-butyl-cyclohexylamine.

Example 23 N- (4-tert-Butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine_

Melting point of the hydrochloride: 152-154 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibro-2-hydroxy-benzyl bromide and N-isopropyl-4-tert-butyl-cyclohexylamine.

Example 24

N-cyclopentyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine Melting point: 61-63 ° C

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-methyl-cyclopentylamine according to Example 1.

Example 25 62051 26 M-ethyl-N-cyclopentyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride melting point: 12U to 128 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethylcyclopentylamine.

Example 26 Melting point of N-cyclopentyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine hydrochloride: 113-120 ° C.

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propylcyclopentylamine.

Example 27 N-Cyclopentyl-3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine Melting point of the hydrochloride: 151 DEG-157 DEG C. (decomposition).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopropylcyclopentylamine according to Example 1.

Example 28 N-cycloheptyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride melting point: 196-198 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-methylcycloheptylamine.

Example 29 N-ethyl-N-cycloheptyl-3,5-dibromo-2-hydroxy-benzylamine Hydrochloride melting point: 180-183 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-cycloheptylamine.

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Example 30 N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine Hydrochloride melting point: 13 * 1-139 ° C.

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-cycloheptylamine.

Example 31 N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-iropropyl-benzylamine Melting point of the hydrochloride: 156-159 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopropyl-cycloheptylamine.

Example 32 3,5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine_

Melting point of the hydrochloride: 220-225 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-N-hydroxy-benzyl bromide and trans-4-amino-cyclohexanol.

Example 33 3,5-Dibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine__

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hyaroxy-benzyl bromide and trans-3-amino-cyclohexanol.

Example 3U

H-cyclohexyl-3,5-dibromo-U-hydroxy-N-methyl-benzylamine Melting point of the hydrochloride: 168-170 ° C (decomposes).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cyclohexylamine according to Example 1.

Example 35 28 62051 3,5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-benzyl wamine melting point hydrochloride: 160-162 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and trans-4-methylamino-cyclohexanol.

Example 36 3,5-Dibromo-E-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -N-methyl-benzylamine

Melting point: 133-136 ° C.

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and cis-3-methylamino-cyclohexanol.

Example 37 N-Ethyl-3,5-dibromo-E-hydroxy-β- (trans-β-hydroxy-cyclohexyl) -benzylamine

Melting point of hydroclave: 176-178 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and trans-H-ethylaminocyclonexanol.

Example 38 N-Ethyl-3,5-dibromo-E-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine ___

Melting point: 13E - 136 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and cis-3-ethylamino-cyclohexanol.

Example 39 ^ _ ~ cyclohexyl-3? 5-dibromo-H-hydroxy-n-propyl-benzylamine

Melting point: 115-116 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-cyclohexylamine.

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Example 40 N-Allyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine melting point of the hydrochloride: 184-186 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-allyl-cyclohexylamine.

Example 41 N-Cyclohexyl-N-cyclopropyl-3,5-dibromo-4-hydroxy-benzylamine. Melting point of the hydrochloride: 197-198 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-cyclopropyl-cyclohexylamine.

Example 42 N- (4-tert-Butyl-cyclohexyl) -3,5-dibrono-4-hydroxy-N-methyl-benzylamine _____

Melting point of hydrochloride: 158-159 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-4-tert-butyl-cyclohexylamine.

Example 43 N-Ethyl-N- (4-tert-butyl-cyclohexyl) -3,5-dibromo-4-hydroxy-Benzene 1 Jamine ______

Melting point of the hydrochloride: 170-170.5 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-4-tert-butyl-cyclohexylamine.

Example * + * + 30 62051 N- (4-tert-butyl-cyclohexyl) -3,5-dibromo-4-hydroxy-N-propyl-benzylamine _________ hydrochloride melting point: 159-160 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-U-hydroxybenzyl bromo and N-propyl - * + - tert-butyl-cyclohexylamine.

Example Ho N-cyclopentyl-35-dibromo-U-hydroxy-K-methyl-benzylamine melting point of the hydrochloride: 185-188 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cyclopentylamine.

Example M-6 N-ethyl-H-cyclopentyl-> 3> Sdibromo-U-hydroxy-benzylamine hydrochloride melting point: 16 * + - 165 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-U-hydroxy-benzyl bromide and N-ethyl-cyclopentylamine.

Example +7 N-Cyclopentyl-3,5-dibromo-U-hydroxy-M-propyl-benzylamine Melting point of the hydrochloride: 156-158 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-U-hydroxy-benzyl bromide and N-propyl-cyclopentylamine.

Example 48. N-Cyclopentyl-3,5-jibromo-4-hydroxy-N-isopropyl-;

Melting point of the hydrochloride: 151-152 ° C (decomposes).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromo and N-isopropyl-cyclopentylamine according to Example 1.

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Pre. Example 49_ N-cycloheptyl ·· 3,5-dibromo-4-hydroxy-N-methylbenzyl,

Melting point of hydrochloricline: 17 5 -, 179 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cycloheptylamine.

L 50% N-ethyl-N-cycloheptyl-3,5-dibromo-4-hydroxy-benzylamine Hyalochloride melting point: 176-177 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl-bromide and N-ethyl-cycloheptylamine.

N-cycloheptyl-3,5-dibrol-4-hydroxy-N-propyl-benzylamine Aml. hydrochloride melting point: 135-166 ° C.

Prepared according to Example 1 from 3,5-albromo-4-hydroxy-benzyl bromide and N-propyl-cycloheptylamine.

Example 52 N- (2-Bicyclo [2.2.1] heptyl) -3,5-dibromo-4-hydroxy-1'-methyl-benzylamine _________ Hydrochlorine Melting Point: 181-182 ° C (decomposes) .

Prepared according to Example 1 from 3,5-dibromo-4-hyuroxy-benzyl bromide and 2-methylamino-bicyclo [2.2.1] heptane.

Example 53 N-Cyclonexyl-3,5-diphalo-2-hydroxy-1'-methyl-benzylanine Hyalochloride melting point: 174-178 ° C.

Prepared according to Example 1 from 3,5-dichloro-2-hydroxy-benzyl bromide and N-methyl-cyclohexylamine.

Example 5H

32 62051 N-ethyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine Melting point of the hydrochloride: 185-188 ° C (decomposes).

Prepared according to Example 1 from 3,5-dichloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

Example 55 N-Ethyl-3,5-dichloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine

Melting point of the hydrochloride: 147-152 ° C.

Prepared according to Example 1 from 3,5-dichloro-2-hydroxy-benzyl bromide and trans-4-ethylamino-cyclohexanol.

Example 56 N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-propyl-benzyl amide Hydrochloride melting point: 168-170 ° C.

Prepared according to Example 1 from 3,5-dichloro-2-hydroxy-benzyl bromide and N-propyl-cyclohexylamine.

Example 57 N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-isopropyl-benzylamine Melting point: 86-89 ° C.

Prepared according to Example 1 from 3,5-dichloro-2-hydroxy-benzyl bromide and N-isopropyl-cyclohexylamine.

Example 58 N-ethyl-N-cyclohexyl-3,5-dichloro-4-hydroxy-benzylamine Melting point of the hydrochloride: 190-191 ° C (decomposes).

Prepared according to Example 1 from 3,5-dichloro-4-hydroxy-benzyl bromide and N * => ethyl-cyclohexylamine.

Example 59 33 6 2 0 51 N-ethyl-3-bromo-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine

Melting point of the hydrochloride: 194-197 ° C (decomposes).

Prepared according to Example 1 from 3-bromo-5-chloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

Example 60 N-Ethyl-5-bromo-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine

Melting point of the hydrochloride: 188-19 ° C (decomposes).

Prepared according to Example 1 from 5-bromo-3-chloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

Example 61 5-Bromo-N-cyclohexyl-2-hydroxy-N-methyl-benzylamine Melting point of hydrochloride: 194-179 ° C.

Prepared according to Example 2 from 5-bromo-salicylaldehyde, N-methyl-cyclohexylamine and formic acid.

PPexample 6 2 N-ethyl-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine Melting point of the hydrochloride: 175-178 ° C.

Prepared according to Example 2 from 5-bromo-salicylaldehyde, N-ethyl-cyclohexylamine and formic acid.

Example 63 N-Ethyl-5-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylline _________

Melting point of the hydrochloride: 190-193 ° C (decomposes).

Prepared according to Example 2 from 5-bromo-salicylaldehyde, trans-4-ethylamino-cyclohexanol and formic acid.

Example 64 3 * 62051 5-Bromo-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine Hydrochloride melting point: 166-169 ° C (decomposes).

Prepared according to Example 2 from 5-bromo-salicylaldehyde, II-propyl-cyclohexylamine and formic acid.

Example 65 5-Bromo-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine Melting point: 90-93 ° C.

Prepared according to Example 2 from 5-bromo-salicylalehyde, N-isopropyl-cyclohexylamine and formic acid.

Example 66 5-Chloro-N-cyclohexyl-2-hydroxy-N-methyl-benzylamine Melting point of hydrochloride: 194-198 ° C.

Prepared according to Example 2 from 5-chloro-salicylaldehyde, N-methyl-cyclohexylamine and formic acid.

Example 67 N-ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine Melting point of the hydrochloride: 169-171 ° C.

Prepared according to Example 2 from 5-chloro-salicylaldehyde, M-ethyl-cyclohexylamine and formic acid.

Example 68 5-Chloro-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine Melting point of hydrochloride: IHO - 142 ° C.

Prepared according to Example 2 from 5-chloro-salicylaldehyde, H-propyl-cyclohexylamine and formic acid.

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Example 69 5-Chloro-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine Melting point: 85-88 ° C.

Prepared according to Example 2 from 5-chloro-salicylaldehyde, N-isopropyl-cyclohexylamine and formic acid.

Example 70 3-Bromo-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine

Melting point of the hydrochloride: 165-169 ° C (decomposes).

Prepared according to Example 1 from 3-bromo-H-hydroxy-benzyl bromide and N-methyl-cyclohexylamine.

Example 71 N- (4-tert-Butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylamine ___

Melting point: 188-191 ° C.

Prepared according to Example 1 from 3,5-dibromo-2-hydroxy-benzyl-4-bromide and 4-tert-butyl-cyclohexylamine.

Example 72 N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine Melting point of the hydrochloride: 180-181 ° C (decomposes).

Prepared according to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

Example 73 N-ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzylamine To 54 g of 2-bromo-5-hydroxy-benzyl bromide in 800 ml of carbon tetrachloride is added 51 g of N-ethyl-cyclohexylamine and boiled 1 hour at reflux. The reaction mixture is then shaken twice with 36,62051 times with water, the organic phase is dried over sodium sulfate and evaporated. The residue is purified by column chromatography on silica gel using ethyl acetate. The crude base is dissolved in ethyl acetate and acidified with absolute ethanolic hydrochloric acid, after which N-ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzylamine hydrochloride crystallizes.

Melting point: 183-188 ° C (decomposes).

Example 7k 2,4-Dibromo-5-hydroxy-N- (trans-s-4-hydroxy-cyclohexyl) -benzylamine to 3.5 g of N- (2,4-dibromo-5-hydroxy-benzylidene) -trans -4-Amino-cyclohexanol in 70 ml of ethanol is added dropwise with stirring a solution of 0.1 g of sodium borohydride in 5 ml of water.

After stirring for 1 hour, 10 ml of 2N sodium hydroxide and 30 ml of water are added and the solution is evaporated to about half volume. Saturated ammonium chloride solution is then added to the solution, whereupon 2,4-dibromo-5-hydroxy-N- (trans-β-hyaroxy-cyclohexyl) -benzylamine precipitates. The precipitate is filtered off with suction, suspended in acetone, heated and acidified with absolute ethanolic hydrochloric acid, whereupon the base dissolves and the hydrochloride precipitates soon.

Melting point: 268-270 ° C (decomposes).

Example 73 3-Bromo-5-chloro-N-cyclohexyl-N-hydroxy-N-methyl-benzylamine 3.6 g of 3-bromo-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine hydrochloride are dissolved in 50 ml of 90 % acetic acid and a solution of 0.75 g of chlorine in 15 ml of glacial acetic acid is added under ice-water. After stirring for a while, the solution is poured into a mixture of ice and 10 N sodium hydroxide, shaken three times with methylene chloride and the organic phase is evaporated to dryness. The residue is purified by column chromatography on silica gel using ethyl acetate, and the resulting 3-bromo-5-chloro-N-cyclohexyl-k-hydroxy-N-methyl-benzylamine is crystallized from ethanol-ether.

Melting point: 136-138 ° C.

Example 76 37 6 2 0 51 N-ethyl-S-bromo-U-cyclohexyl-3-chloro-H-hyoxy-benzylamine 2,3 g of ethyl-3-chloro-N-cyclohexyl-4-hyroxy- benzylamine is dissolved in 20 ml of 75% acetic acid and 1.6 g of bromine are added dropwise with stirring. The solution is diluted with water, made alkaline with concentrated ammonia and shaken twice with chloroform. The organic phase is dried over sodium sulfate and evaporated. The residue is dissolved in absolute ethanol, acidified with absolute ethanolic hydrochloric acid and crystallized from N-ethyl-S-bromo-N-cyclohexyl-5-chloro-.alpha.-hydroxy-benzylismine hydrochloride by adding ether.

Melting point: 165-168 ° C (decomposes).

Example 77 N-ethyl-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine 13 g of ii-ethyl-cyclohexylamine and 3 g of paraformaldehyde are dissolved in 100 ml of ethanol by heating, recooled, 13 g of 2-chloro-chlorine are added. -f enol, allow to stand for 1.5 hours at room temperature and finally reflux for a further 3 hours. The solution is then evaporated and the residue is purified by column chromatography on silica gel using ethyl acetate. The crude base is dissolved in absolute ethanol, acidified with absolute ethanolic hydrochloric acid and crystallized from N-ethyl-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride by adding ethyl acetate.

Melting point: 177-178 ° C (decomposes).

Example 78 3,5-Dichloro-2-hydroxy-N- (trans-b-hydroxy-cyclohexyl) -benzyl-amino ____________________

Hydrochloride melting point: 216-222 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

38 62051

Example 79 to 3,5-Dichloro-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine _______________

Melting point of the hydrochloride: 222-225 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3,5-dichloron-4-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 80 3-Bromo-5-chloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine____

Hydrochloride melting point: 214-221 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3-bromo-5-chloro-2-hydroxy-bicylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 81 5-Bromo-3-chloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine

Melting point of the hydrochloride: 193-197 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (5-bromo-3-chloro-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 82 Melting point of 5-bromo-3-chloro-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride: 220-226 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (5-bromo-3-chloro-4-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 33 39 f 62051 Melting point of 5-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride: 22 2-230 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (5-bromo-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 8H

2-Bromo-5-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine Hydrobromide melting point: 220-225 ° C (decomposes).

Prepared according to Example 73 from 2-bromo-5-hydroxy-benzyl bromide and trans-4-amino-cyclohexanol.

Example 85 3-Bromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine

Melting point of the hydrochloride: 225-227 ° C (decomposes).

Prepared according to Example 7 by reduction of N- (3-bromo-f) -hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 86 Melting point of 3-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride: 194-196 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3-bromo-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 87 2,6-Dibromo-3-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine ____ 40 62051

Melting point of hydrochloride: 269-271 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (2,6-dibromo-3-hydroxy-benzylidene) -tr, ans-4-amino-cyclohexanol.

Example 88 3,5-Dichloro-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine___________

Melting point of hydrochloride: 209-214 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 89 3,5-Dichloro-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine_______________

Melting point of hydrochloride: 219-224 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3,5-dichloro-4-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 90 3-Bromo-5-chloro-2-hydroxy-N- (cis-3-hyuroxy-cyclohexyl) -benzylamine

Melting point of hydrochloride: 197-201 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3-bromo-5-chloro-2-hyuroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 91 5-Bromo-3-chloro-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine_______________ hydrochloride melting point: 219-222 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (5-bromo-3-chloro-2-hydroxy-benzylene) -cis-3-amino-cyclohexanol.

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Example 92 5-Bromo-3-chloro-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine ___________

Hydrochloride melting point: 216-218 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (5-bromo-3-chloro-4-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 93 5-Bromo-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine

Melting point of the hydrochloride: 148-151 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (5-bromo-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 94 2-Bromo-5-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine

Melting point of the hydrochloride: 245-250 ° (decomposes).

Prepared according to Example 74 by reduction of N- (2-bromo-5-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 95 2,4-Dibromo-5-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine Starting point for the hydrochloride: 278-280 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (2,4-dibromo-5-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 96 3-Bromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine Melting point of the hydrochloride: 214-220 ° C (decomposes).

Prepared according to Example 7 by bromination of 4-hydroxy-H- (cis-3-hydroxy-cyclohexyl) -benzylamine.

42 62051

Example 97 3-Bromo-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine

Melting point of the hydrochloride: 163-167 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3-bromo-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 98 2,6-Dibromo-3-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine _______

Melting point of the hydrochloride: 255-259 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (2,6-dibromo-3-hydroxy-benzylidene) -cis-3-amino-cyclohexanol.

Example 99 N-ethyl-2-bromo-4-chloro-N-cyclohexyl-5-hydroxy-benzylamine Melting point of the hydrochloride: 132.5-137 ° C (decomposes).

Prepared according to Example 7 by bromination of N-ethyl-4-chloro-1H-cyclohexyl-3-hydroxy-benzylamine.

Example 100 N-ethyl-4-chloro-N-cyclohexyl-3-hydroxy-benzylamine Melting point of the hydrochloride: 128-132 ° C (decomposes).

Prepared according to Example 73 from 4-chloro-3-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

Example 101 N-ethyl-2-chloro-N-cyclohexyl-5-hydroxy-benzylamine Melting point of the hydrochloride: 210-211 ° C.

Prepared according to Example 73 from 2-chloro-5-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

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Example 102 N-ethyl-N-cyclohexyl-2H-dichloro-5-hydroxy-benzylamine Hydrochloride melting point: 179-186 ° C (decomposes).

Prepared according to Example 75 by chlorination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine.

Example 103 N-ethyl-3-bromo-N-cyclohexyl-U-hydroxy-benzylamine melting point of nyarochloride: 185-190 ° C (decomposes).

Prepared according to Example 77 from 2-bromo-phenol, paraformaldehyde and N-ethyl-cyclohexylamine.

Example 104 Melting point of N-ethyl-4-chloro-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride: 144-146 ° C.

Prepared according to Example 77 from 3-chloro-phenol, para-formylhydro and U-ethyl-cyclohexylamine.

Example 105 N-ethyl-3-bromo-N-cyclohexyl-2-hydroxy-benzylamine Melting point of hydrochloride: 171-173 ° C.

Prepared according to Example 77 from 2-bromo-phenol, praformaldehyde and N-ethyl-cyclohexylamide.

Example 106 N-Ethyl-ε-bromo-β-cyclohexyl-2-hydroxy-Benzene 1 Jamine hydrochloride Melting point: 175-177 ° C.

Prepared according to Example 77 from 3-bromo-phenol, paraformaldehyde and k-ethyl-cyclohexylamine.

Example 107 ** 62051 N-Ethyl-3-chloro-N-cyclohexyl-1'-hydroxy-Benzene 1 to 1 melting point: 181-183 ° C.

Prepared according to Example 75 by chlorination of N-ethyl-N-cyclohexyl-H-hydroxy-benzylamine.

Example 108 N-ethyl-N-chloro-N-cyclohexyl-N-hydroxy-benzylamine Hyperchloride melting point: 165-166.5 ° C.

Prepared according to Example 77 from 3-chlorophenol, paraforn aldehyde and N-ethyl-cyclohexylamine.

im imijj 10 9 H-Ethyl-2-bromo - * 4-chloro-N-cyclohexyl-1-3-hydroxy i-Bent cause 1 jam

Hydrochloride in melting point: 130-137 ° C (decomposes).

Prepared by bromination of N-ethyl-4-chloro-N-cyclohexyl-3-hydroxy-benzylamine according to Example 76.

Example 110 N-ethyl-N-cyclohexyl-2,6-dibrol-3-hydroxy-benzylamine Melting point: 123-126 ° C.

Prepared by bromination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine according to Example 76.

Example 111 N-Ethyl-N-cyclohexyl-2H-dichloro-3-hydroxy-benzyl} -amine Amine hydrochloride Melting point: 127-132 ° C (decomposes).

Prepared according to Example 75 by chlorination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine.

Example 112 45 62051 3,5-Dibromo-2-hydroxy-N-methyl-N-morpholinocarbonylmethylbenzylamine

Melting point of hydrochloride: 196-201 ° C.

Prepared according to Example 73 from 3,5-dibromo-2-hydroxy-benzyl bromide and sarcosine morpholide.

Example 113 2,5-Dibromo-4-hydroxy-N-methyl-N-morpholinocarbonylmethylbenzylamide

Melting point of the hydrochloride: 214-218 ° C.

Prepared according to Example 73 from 3,5-dibromo-H-hydroxy-benzyl bromide and sarcosine morpholide.

Example 114 4-Chloro-2-hydroxy-N-methyl-N-morpholinocarbonylmethyl-benzylamine_____

Melting point of the hydrochloride: 210-213 ° C (decomposes).

Prepared according to Example 7 from 3-chlorophenol, paraform aldehyde and sarcosine morpholide.

Example 115 2-Chloro-4-hydroxy-N-methyl-N-morpholinocarbonylmethyl-benzylamine _______.

Melting point of the hydrochloride: 216-217 ° C (decomposes).

Prepared according to Example 77 from 3-chlorophenol, paraformaldehyde and sarcosine morpholide.

Example 11G

46 62051 N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine

Hydrochloride melting point: 180-181 ° C (decomposes).

Prepared according to Example 76 from N-ethyl-N-cyclohexyl-4-hydroxy-benzylamine and bromine.

Example 117 N-ethyl-β-chloro-N-cyclohexyl-4,4-dibromo-3-hydroxy-benzylamine

Melting point: 138-140 ° C.

Prepared according to Example 76 from N-ethyl-2-chloro-N-cyclohexyl-5-hydroxy-benzylamine hydrochloride and bromine.

Example 118 Melting point of N-ethyl-4-chloro-N-cyclohexyl-2,6-dibromo-3-hydroxy-benzylamine hydrochloride: 183-190 ° C (decomposes).

Prepared from N-ethyl-U-chloro-N-cyclohexyl-3-hydroxy-benzylamine hydrochloride and bromine according to Example 76.

Example 119 N-ethyl-N-cyclohexyl-3-hydroxy-2,4,6-tribromo-benzylamine Melting point: 172-175 ° C.

Prepared according to Example 76 from N-ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzylamine and bromine.

Example 120 3-Hydroxy-N- (cis-3-hydroxy-cyclohexyl) -2,4,6-tribromo-benzylamine ___________ ____ 47 6 2 0 51

Melting point of hydrochloride: 228-228.5 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3-hydroxy-2,4,6-tribromo-benzylidene) -cis-3-amino-cyclohexanol with sodium borohydride.

Example 121 3-Hyaroxy-N- (trans-4-hydroxy-cyclohexyl) -2,4,6-tribromo-benzylamine ___

Hydrochloride melting point: 259-261 ° C (decomposes).

Prepared according to Example 74 by reduction of N- (3-hydroxy-2,4,6-tribromo-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 122 N-Ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine 3.5 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride are dissolved in 50 parts of glacial acetic acid. With vigorous stirring, a solution of 0.85 g of chlorine in 10 ml of glacial acetic acid is poured into the solution at room temperature. Stir for a further 1 minute and then pour over ice, then add 10 N sodium hydroxide until the reaction is slightly basic and extract twice with 100 ml of chloroform. The combined chloroform solutions are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo, the sticky residue being taken up in a small amount of absolute ethanol. Ethereal hydrochloric acid is added until the reaction is clearly acidic, whereupon colorless crystals separate. The hydrochloride is filtered off with suction and crystallized twice from isopropanol.

Melting point: 159-171 ° C.

Example 123 N-Ethyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine 3.1 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine are dissolved in 100 ml of azaolytic tetrahydrofuran and 4 ml of: pyridine. The solution is cooled to -5 ° C. At this temperature, 7.2 g of phenyl iodide dichloride are added with vigorous stirring and portionwise portions and the mixture is stirred for a further 2 hours at -5 to 0 ° C. After evaporation, the mixture is evaporated to dryness in vacuo and the residue is partitioned between water and chloroform. The combined chloroform phases are dried over sodium sulfate and evaporated to dryness in vacuo. The oily residue is dissolved in a small amount of absolute ethanol. After addition of the ethereal solution until the reaction is clearly acidic, colorless crystals separate which are filtered off with suction and recrystallized from isopropanol.

Melting point of the hydrochloride: 185-188 ° C (decomposes).

Example 124 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 2.7 g of n-ethyl-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride are dissolved in 50 ml of glacial acetic acid. With vigorous stirring, a solution of 1 ml of bromine in 10 ml of glacial acetic acid is slowly added dropwise at the temperature of the solution. After the addition, it is poured onto ice, made slightly alkaline with 10 N sodium hydroxide and extracted three times with 100 ml of chloroform. The combined chloroform solutions are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The oily residue is taken up in a small amount of absolute ethanol. Add ethereal hydrochloric acid until the reaction is clearly acidic, whereupon colorless crystals separate, which are separated by suction and recrystallized from absolute ethanol, melting point: 193-194 ° C (decomposes).

Example 125 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxybenzylamine 3 g of N-ethyl-N-cyclohexyl-2-hydroxybenzylamine are dissolved in 50 ml of methyl anhydride. The solution is cooled to -5 ° C. At this temperature, a solution of 10 g of tribromophenol bromide in 200 ml of methylene chloride is slowly added dropwise with vigorous stirring, the mixture is stirred for a further 2 hours after the addition has ceased and is evaporated to dryness in vacuo. The residue is purified by column chromatography on 49 62051 silica gel using a chloroform. After subsequent fractionation, the solvent is evaporated off in vacuo. The residue is dissolved in a small amount of absolute ethanol. Ethereal hydrochloric acid is added until the reaction is clearly acidic, whereupon colorless crystals separate which are separated by suction and recrystallized absolutely from ethanol.

melting point of the hydrochloride: 193-194 ° C (decomposes).

Example 126 N-Ethyl-h-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 0.15 g of 2-acetoxy-N-ethyl-N-cyclohexyl-3,5-dibromo-benzylamine and 10 ml of 4n the ethanolic hydrochloric acid is boiled for one hour. Cool, pour onto ice, make alkaline with concentrated ammonia, shake with chloroform, dry the chloroform extract over sodium sulfate and evaporate in vacuo. The residue is dissolved in ethanol and ethanolic hydrochloric acid is added, whereupon the hydrochloride precipitates.

Melting point: 193-194 ° C (decomposes).

Example 127 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine 4.7 g of E-benzyl-3,5-dibromo-2-hydroxy-N- (trans-4- hydroxy-cyclohexyl) -benzylamine is dissolved in a mixture of 350 ml of methanol and 6 ml of 2N hydrochloric acid. The solution is hydrogenated with 50 mg of palladium (10%) on carbon. The hydrogenation is stopped after 1 mol of hydrogen has been consumed; the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is recrystallized from ethanol; 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride with a melting point of 212-218 ° C (decomposes) is obtained.

Example 128 N-Ethyl-E-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 0.2 g of N-ethyl-h-cyclohexyl-3,5-dibromo-2-methoxy-benzylamine-62051 hydrochloride and 3 ml of a 40% solution of hydrogen bromide in glacial acetic acid is boiled for 3 hours. Cool, pour onto ice, basify with ammonia, extract with chloroform, dry the chloroform extract over sodium sulfate and evaporate in vacuo. The residue is dissolved in a small amount of ethanol and the hydrochloride is crystallized by adding ethanolic hydrochloric acid.

Melting point: 193-194 ° C (decomposes).

Example 129 N- (4-tert-Butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylanane ______ 2.3 g of 3,5-dibromo-2-hydroxy-benzylamine and 1.6 g of 4-tert. -bu-cyclohexanone is heated under reflux for 4 hours in 250 ml of toluene. After cooling, it is diluted with 250 ml of methanol and 2.8 g of sodium borohydride are added portionwise with stirring. After one hour, evaporate to dryness in vacuo. The residue is shaken with 2N sodium hydroxide. The material is filtered off with suction, washed with water and recrystallized from methanol. The isomer mixture can be separated by column chromatography on silica gel. using chloroform / ethyl acetate (2: 1).

melting point of the cis form: 159-160 ° C; melting point of the trans form: 186-189 ° C (decomposes).

Example 130

N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 0.4 g of ΐϊ-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzamide and 0.12 g of sodium borohydride in 20 ml dry pyridine is boiled for 5 hours. To remove excess sodium borohydride, a little acetone is added, then the pyridine is distilled off in vacuo, the residue is partitioned between water and chloroform, the chloroform phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed for purification on silica gel using ethyl acetate. An oil is obtained which is dissolved in ethanol and converted into N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylarine hydrochloride with ethanolic hydrochloric acid.

Melting point: 193-194 ° C (decomposes).

Example 131 si 62051 N-ethyl-N-cyclohexyl-3,5-dilbromo-2-hydroxy-benzylamine 1 g of N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzamide and 0.17 g of lithium aluminum hydride Boil in 80 ml of absolute tetrahydrofuran for one hour. Cool, carefully decompose with water, separate the precipitate, boil with tetrahydrofuran, evaporate the tetrahydrofuran solution, evaporate the solution in vacuo, partition the residue between water and chloroform, dry the chloroform phase over sodium sulphate and evaporate in vacuo. An oil is obtained which is dissolved in ethanol and converted into N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride with ethanolic hydrochloric acid.

Melting point: 193-194 ° C (decomposes).

Example 132 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 2.25 g of 2-acetoxy-N-ethyl-N-cyclohexyl-3,5-dibromo-bermsmid are dissolved in 30 ml of: absolute tetrahydrofuran and added dropwise with stirring to a suspension of 0.8 g of lithium aluminum hydride in 120 ml of absolute tetrahydrofuran. The mixture is boiled for 75 minutes, then cooled to 10 ° C and quenched with water. The precipitate formed is filtered off with suction and washed once with tetrahydrofuran. The combined aqueous tetrahydrofuran solutions are evaporated to remove the organic solvent. The aqueous solution thus obtained is extracted three times with chloroform, the combined chloroform extracts are dried over sodium sulfate and evaporated. N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine is obtained as an oil, which is dissolved in ethanol and converted into the hydrochloride with ethanolic hydrochloric acid.

Melting point: 193-194 ° C (decomposes).

52 62051

Example 133 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 1.2 g of 2-acetoxy-N-acetyl-N-cyclohexyl-3,5-dibromo-benzylamine and 0.5 g of g of lithium aluminum dyride in 100 ml of absolute tetrahydrofuran is boiled for about 1 hour; the excess lithium aluminum hydride is decomposed by careful addition of water. The precipitate formed is filtered off with suction and washed with tetrahydrofuran. The combined tetrahydrofuran solutions containing water are evaporated and the remaining aqueous residue is extracted with chloroform.

The chloroform solution is dried over sodium sulfate and evaporated. The oil thus obtained is dissolved in ethanol, and the addition of ethanolic hydrochloric acid gives N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, melting point 193-194 ° C (decomposes).

Example 134 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine-1.0 g of 6,8-dibromo-3- (trans-4-hydroxy-cyclohexyl) -3 The 4-dihydro-2H-1,3-benzoxazin-2-one is refluxed for 1 hour in a mixture of 30 ml of tert-butanol and 25 ml of 2N sodium hydroxide. After cooling, 30 ml of 2N hydrochloric acid are added, followed by an excess of sodium hydrogen carbonate solution. The alcohol is distilled off in vacuo and the aqueous phase is extracted twice with a mixture of tetrahydrofuran and ether (1: 1). The organic extracts are dried over magnesium sulfate and evaporated in vacuo to a small volume. Add light petroleum while heating until the solution begins to cloud and allow the above product to crystallize in the cold,

Melting point: 191-193 ° C.

Melting point of the hydrochloride: 212-218 ° C (decomposes).

Example 135 zl-Bromo-N-cyclohexyl-2-hydroxy-benzylamine Hydrochloride melting point: 175-178 ° C.

Prepared according to Example 124 from N-ethyl-N-cyclohexyl-2-hyuroxy-benzylamine hydrochloride and bromine.

53 62051

Example 136 N-ethyl-3-bromo-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine Hydrochloride melting point: 194-179 ° C (decomposes).

Prepared according to Example 124 from N-ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride and bromine.

Example 137 N-ethyl-N-cyclohexyl-3,5-dichloro-4-hydroxy-benzylamine

Melting point of the hydrochloride: 190-191 ° C (decomposes).

Prepared according to Example 122 from N-ethyl-N-cyclohexyl-4-hydroxy-benzylamine and chlorine.

Example 138 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine

Melting point of hydrochloride: 216-218 ° C (decomposes).

Prepared according to Example 124 from 4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine.

Example 139 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine________

Melting point of the hydrochloride: 212-1188 ° C (decomposes).

Prepared according to Example 124 from 2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine.

Example 140 3,5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine-54 62051

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 12¼ from 4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -hexylamine hydrochloride and bromine.

Example 141 3,5-Dibromo-2-hyaroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamino _______

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 128 by cleavage of 3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl) -2-methoxy-benzylamine hydrochloride with 40% hydrogen bromide in glacial acetic acid.

Example 142 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine_______

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 129 from 3,5-dibromo-2-hydroxy-benzylamine, 4-hydroxy-cyclohexanone and sodium borohydride.

Example 143 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine__

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 131 by reduction of 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzamide with lithium aluminum hydride.

Example 144 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine mp 5522051 Melting point: 212-218 ° C (decomposes).

Prepared according to Example 132 by reduction of 2-acetoxy-3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl) -benzamide with lithium alunin hydride.

Example 145 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine ____ hydrochloride Melting point: 216-218 ° C (decomposes).

Prepared by removing the benzyl group from k-benzyl-3,5-dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride according to Example 127 with hydrogen in the presence of palladium on activated carbon.

Example 146 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylanine Melting point of __________-1-fluorochloride: 216-213 ° C (decomposes).

Prepared according to Example 128 by cleavage of 3,6-dibrono-E- (cis-3-hydroxy-cyclohexyl) -4-methoxy-benzylienine-nyorochloride with 40% hydrogen bromide in glacial acetic acid.

Example Im 7 3,5-Dibrono-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamino 1___________________________________: melting point of yuro> chloride: 216-213 ° C (decomposes).

It is quenched from 3,5-dibromo-4-hydroxy-benzylanine, 3-hydroxy-cyclohexanone and sodium borohydride according to Example 129.

56 62051

Example 146 3,5-Dibroin-b-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -Bent Cause Ilarin_____

Melting point of the hydrochloride: 216-218 ° C (decomposes).

Prepared according to Example 131 by reduction of 3,5-dibrono-γ-aryroxy-N- (cis-3-hydroxy-cyclohexyl) -benzamide with 1-lithium aluminum hydride.

Example 149 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine]

Melting point of hydrochloride: 216-218 ° C (decomposes).

Prepared by reduction of 4-acetoxy-3,5-dibrono-b- (cis-3-hydroxy-cyclohexyl) -benzamide with 1-lithium aluminum hydride according to Example 132.

Example 150 3,5-Dibromo-U-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzyl ”amine______________

Melting point of the hydrochloride: 215-215.5 ° C (decomposes).

Prepared by removing the Bentyl group from N-benzyl-3,5-cyano-4'-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylanine hydrochloride with hydrogen according to Example 127 when the earth is palladium on activyl.

Example 151 3,5-Dibrono-4-hydroxyl-N- (trans-3-hydroxy-cyclone-yl) -benzyl] anine________________________

Melting point of the hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 128 by cleavage of 2,5-dibromo-n- (trans-3-hydroxy-cyclohexyl) -4-methoxy-benzylamine hydrochloride with 40% hydrogen bromide in glacial acetic acid.

Example 152 57 62051 3,5-Dihroin-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine ___________

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 129 from 3,5-dibromo-4-hydroxy-benzyl-amine, 3-hydroxy-cyclohexanone and sodium borohydride.

Example 153 3,5-Dibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine__________

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 131 by reduction of 3,5-dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzamide with lithium aluminum hydride.

Example 154 3,5-Dichrome-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine___

Melting point of the hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 132 by reduction of 4-acetoxy-3,5-dibromo-N- (trans-3-hydroxy-cyclohexyl) -benzamide with lithium aluminum nitride.

Example 155 3,5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine ______-hydrochloride Melting point: 220-225 ° C (decomposes).

Prepared according to Example 124 from 4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine.

Example 156 58 6 2 0 51 3 j 5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-benzylamine 1 __________

Melting point of the hydrochloride: 160-162 ° C (decomposes).

Prepared according to Example 124 · from 4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-benzylamine hydrochloride and bromine.

Example 157 N-ethyl-5-bromo-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine Hydrochloride melting point: 188-191 ° C (decomposes).

Prepared according to Example 122 from N-ethyl-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride and chlorine.

Example 158 N-Ethyl-3,5-dichloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine ______ hydrochloride Melting point: 147-152 ° C.

Prepared according to Example 123 from N-ethyl-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine and phenyl iodide dichloride.

Example 159 N- (4-tert-Butyl-cyclohexyl) -3,5-dibromo-4-hydroxy-benzylamine _________

Melting point of the hydrochloride: 1S8 - 159 ° C.

Prepared according to Example 124 from N- (4-tert-butyl-cyclohexyl) -4-hydroxy-benzylamine hydrochloride and bromine.

Example 160 N-ethyl-5-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine ____ hydrochloride melting point: 190-193 ° C Decomposes).

59 62051

Prepared according to Example 124 from N-ethyl-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine.

Example 161 5-Bromo-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine Melting point: 90-93 ° C.

Prepared according to Example 124 from N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine and bromine.

Example 162 N-Cyclofrentyl-3,5-dibromo-H-hydroxy-N-methyl-benzylamine Hydrochloride melting point: 185-188 ° C (decomposes).

Prepared according to Example 124 from N-cyclopentyl-4-hydroxy-N-methyl-benzylamine hydrochloride and bromine.

Example 163 N-ethyl-N-cyclopentyl-3,5-dibromo-2-hydroxy-benzylamine Melting point of the hydrochloride: 124-128 ° C (decomposes).

Prepared according to Example 124 from N-ethyl-N-cyclopentyl-2-hydroxy-benzylamine hydrochloride and bromine.

Example 164 H-Cycloheptyl-3,5-dibromo-4-hydroxy-N-propyl-benzylamine Melting point of hydrochloride: 176-177 ° C (decomposes).

Prepared according to Example 124 from N-cycloheptyl-4-hydroxy-N-propyl-benzylamine hydrochloride and bromine.

Example 1G5 N Cycloheptyl-3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine mixture 62051

Melting point of the hydrochloride: 156-159 ° C (decomposes).

Prepared from N-cycloheptyl-2-hydroxy-N-isopropyl-benzylamine hydrochloride and bromine according to Example 124.

Example 166 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 6 g of acetic acid (3,5-dibromo-2-hydroxy-benzyl) ester and 7 g of N-ethyl-cyclohexylamine are heated 1 hour at 140 ° C. The reaction product is mixed with 2N hydrochloric acid and ether, whereupon N-ethyl-N-cyclohexyl-3,6-dibromo-2-hydroxy-benzylamine hydrochloride crystallizes. It is separated by suction and washed with water and acetone. Melting point: 193-194 ° C (decomposes).

Example 167 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine? g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 2.8 g of a dispersion of sodium hydride (50% in oil) are refluxed for 6 hours in 150 ml of absolute tetrahydrofuran. It is then cooled to -60 to 70 [deg.] C. and 9.5 g of p-toluenesulphonic acid chloride in 100 ml of absolute tetrahydrofuran are added dropwise with stirring. Allow to warm to -30 ° C and re-cool to -70 ° C. 12.7 g of N-ethyl-cyclohexylamine in 100 ml of ether are then added dropwise. Stir further, allow the reaction mixture to slowly warm to room temperature and shake twice with 200 ml of water. The combined aqueous phase is shaken once with chloroform. The chloroform phase is purified with the ether-tetrahydrofuran phase and evaporated to dryness. For purification, chromatograph on silica gel using chloroform-ethyl acetate (9: 1). The corresponding fractions are combined and evaporated to dryness. The residue is mixed with 2N hydrochloric acid and ether to precipitate N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. It is separated by suction and washed with water and acetone.

Melting point: 193-194 ° C (decomposes).

«1 62051

Example 168 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 1.3 g of 2-benzoyloxy-3,5-dibromo-benzyl alcohol and 1.3 g of N-ethyl-cyclohexylamine are heated for 1 hour 14 -0 ° C. The reaction product is mixed with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylalimine hydrochloride. It is separated by suction and washed with water and acetone.

Melting point: 193-194 ° C (decomposes).

Example 169 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 1 g 2.8 g of 3,5-dibromo-2-hydroxybenzyl alcohol and 3.8 g of N-ethylcyclohexylamine heated at 140 ° C for 1 hour. The reaction product is stirred with 2N hydrochloric acid and ether, whereupon N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride crystallizes. It is separated by suction and washed with water and acetone. Melting point: 193-194 ° C (decomposes).

Example 170 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 2.8 g of 3,5-dibromo-2-hydroxy-benzyl alcohol, 3.8 g of N-ethyl-cyclohexylamine and 1.2 ml of 48 % hydrobromic acid is heated at 140 ° C for 1 hour. The reaction mixture is shaken with chloroform and water. The chloroform phase is separated and evaporated to dryness. The residue is mixed with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. It is separated by suction and washed with water and acetone.

Melting point: 193-194 ° C (decomposes).

Example 171 62 6 2 0 51 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 5.6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol, 3.8 g of butyric acid and 12.7 g The N-ethyl-cyclohexylamine is heated for 1 hour at 140 ° C, then cooled, dissolved in 200 ml of ether and shaken four times with water. The organic phase is dried over sodium sulfate and evaporated. The residue is dissolved in a small amount of absolute ethanol, the solution is acidified with ethanolic hydrochloric acid and the crystallization of N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride is completed by adding ether.

Melting point: 193-194 ° C (decomposes).

Example 172 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 5.6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol, 12.7 g of N-ethyl-cyclohexylamine and 0.4 g of magnesium oxide heated at 120 ° C for 3 hours, then add ether and water, acidified with 2N hydrochloric acid and again made alkaline with concentrated ammonia. The mixture is shaken, the organic phase is separated, washed four times with water, dried over sodium sulfate and evaporated. The residue is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and, with the addition of ether, N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride is mixed,

Melting point: 193-194 ° C (decomposes).

Example 173 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine ____ 0.9 g of 6,8-dibromo-2-methyl-1,3-benzodioxane and 1 0.0 g of trans-4-aminocyclohexanol is heated for 17 hours at 140 ° C. The reaction product is then boiled with 100 ml of dilute hydrochloric acid.

The solution is treated with activated carbon and evaporated in vacuo to about 63,62051 to 5 ml. In this case, 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride precipitates. It is filtered off with suction, washed with water and acetone and dried in vacuo at 80 ° C. Melting point: 212-218 ° C (decomposes).

Example 17 4 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine 2.9 g of 3,5-dibroine-α-methoxy-o-cresol and 3.8 g of N-ethyl-cyclohexylamine the lamine is heated for 1 hour at 140 ° C. The reaction product is mixed with 2N hydrochloric acid and ether to crystallize N-ethyl-1 H -cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. Separate with suction and wash with water and cetone.

Melting point: 193-194 ° C (decomposes).

Example 175 N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine 1.4 g of 3,5-O-bromo-2-hydroxy-benzyl alcohol and 11.5 g of Ν, Κ ', Ν "-tricyclohexyl The -N, N ', N "-trimethyl-phosphoric acid triamide is heated for 10 hours at 150 ° C and the reaction product is chromatographed on a silica column using chloroform-ethyl acetate (1: 1). The corresponding fractions are combined, evaporated, the residue is dissolved in Petro-ether, acidified with ethanolic hydrochloric acid, shaken and decanted, the oily residue is taken up in a small amount of absolute ethanol and ether is added to give N-cyclohexyl-3,5-dibromo-2-hydroxy N? ** methylmethylamine hydrochloride crystallizes.

Melting point: 189-191 ° C.

Example 176 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine 2 g of 6,8-dibromo-3,4-dihydro-3- (trans-4-hydroxy- cyclohexyl) -2H-1,3-benzoxazine is dissolved in 20 ml of methanol at room temperature and 5 ml of water are added. After 15 minutes, a further 10 ml of methanol are added, the crystalline precipitate formed is filtered off with suction and washed with methanol. The base is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, whereupon 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride crystallizes.

Melting point 212-218 ° C (decomposes).

Example 177 3,5-Dibromo-2-hydroxy-N- (trans-α-hydroxy-cyclohexyl) -benzylamine____

Melting point of the hydrochloride: 212-218 ° (decomposes).

Prepared according to Example 166 from acetic acid (3,5-dibromo-2-hydroxy-benzyl) -ester and trans-4-amino-cyclohexanol.

Example 178 N-ethyl-N-cyclohexyl-3,5-dibromo-α-hydroxy-benzylamine Melting point of the hydrochloride: 180-181 ° C (decomposes).

Prepared according to Example 166 from acetic acid (3,5-dibromo-4-hydroxy-benzyl) -ester and N-ethyl-4-cyclohexylamine.

Example 179 3,5-Dibromo-α-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine Melting point of the hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 166 from acetic acid (3,5-dibromo-4-hydroxy-benzyl) -ester and cis-3-amino-cyclohexanol.

Example 180 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine

Melting point of hydrochloride: 193-194 ° C (decomposes).

Prepared according to Example 166 from benzoic acid (3,5-dibromo-2-hydroxy-benzyl) -ester and N-ethyl-cyclohexylamine.

65 62051

Example 181 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine__________

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 168 from 2-benzoyloxy-3,5-dibromo-benzyl alcohol and trans-4-amino-cyclohexanol.

Example 182 N-Ethyl-N-cyclohexyl-3,5-dibromo-H-hydroxy-benzylamine

Hydrochloride melting point: 180-181 ° C (decomposes).

Prepared according to Example 168 from U-acetoxy-3,5-dibromo-benzyl alcohol and N-ethyl-cyclohexylamine.

Example 183 3,5-Dibromo-1-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylanine Melting point of the hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 168 from “i-astoxy-S, 5-dibromo-benzyl alcohol and cis-3-amino-cyclohexanol.

Example 18U

3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine__

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 169 from 3,5-dibromo-2-hydroxy-benzyl alcohol and trans-4-amino-cyclohexanol.

Example 185 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine-62051

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 169 from 3,5-dibromo-U-hydroxy-benzyl alcohol and cis-3-amino-cyclohexanol.

Example 186 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine Melting point of the hydrochloride: 193-19 ° C (decomposes).

Prepared according to Example 170 from 3,5-dibromo-2-hydroxy-benzyl alcohol, N-ethyl-cyclohexylamine and p-toluenesulfonic acid.

Example 187 N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine Hydrochloride melting point: 180-181 ° C (decomposes).

Prepared according to Example 171 from 3,5-dibromo-4-hydroxy-benzyl alcohol, N-ethyl-cyclohexylamine and butyric acid.

Example 188 3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine______

Hydrochloride melting point 212-218 ° C (decomposes).

Prepared according to Example 171 from 3,5-dibromo-2-hydroxy-benzyl alcohol, butyric acid and trans-4-amino-cyclohexanol.

Example 189 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine_______

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 171 from 3,5-dibromo-4-hydroxy-benzyl alcohol, cis-3-amino-cyclohexanol and butyric acid.

67 62051

Example 190 3,5-Dibromo-2-hydroxy-N- (trans - * + - hydroxy-cyclohexyl) -benzylamine________________________

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared from 3,5-dibromo-2-hydroxy-benzyl alcohol, trans-4-amino-cyclohexanol and magnesium oxide according to Example 172.

Example 191 N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine Melting point of the hydrochloride: 193-19 ° C (decomposes).

Prepared according to Example 172 from 3,5-dibromo-2-hydroxy-benzyl alcohol, N-ethyl-cyclohexylamine and potassium hydr. hydroxide.

Example 192 3,5-Dibromo-β-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine_______

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 172 from 3,5-dibromo-M-hydroxy-benzyl alcohol, cis-3-amino-cyclohexanol and magnesium oxide.

Example 193 N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine

Melting point of the hydrochloride: 193-19 U ° C (decomposes).

Prepare from Example 173 6,8-dibromo-2-methyl-1,3-benzodioxane and N-ethylcyclohexylamine.

Example 19H

3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine_______ 68 62051

Hydrochloride melting point: 212-218 ° C (decomposes).

Prepared according to Example 17 * + from 3,5-dibromo-α-methoxy-o-cresol and trans-4-amino-cyclohexanol.

Example 195 N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine

Hydrochloride melting point: 180-181 ° C (decomposes).

V% is expressed according to Example 17 4 from 3,5-dibromo-α-methoxy-p-cresol and N-ethyl-cyclohexylamine.

Example 196 3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine _________

Melting point of hydrochloride: 215-215.5 ° C (decomposes).

Prepared according to Example 174 from 3,5-dibromo-α-methoxy-p-cresol and cis-3-amino-cyclohexanol.

Example 197 N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine Melting point of hydrochloride: 189-191 ° C.

Prepared according to Example 17S from 3,5-dibromo-2-hydroxy-benzyl alcohol and N-cyclohexyl-N-methyl-acetic acid amide.

Example 198 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 5.6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 6.3 g of dihydroxy-tert-butylamine are heated for 1 hour. hour at 140 ° C, then the melt is dissolved in absolute concrete, acidified with ethanolic hydrochloric acid and 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride is crystallized by adding ether.

Melting point: 187-189 ° C (from absolute ethanol-ether).

Example 199 69 62051 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylarine 21.6 g of 3,5-dibromo-2-hydroxy-benzyl bromide dissolved in 0.5 liters of carbon tetrachloride, a solution of 26.4 g of dihydroxy-tert-butylamine in 100 ml of ethanol is added and the mixture is refluxed for 30 minutes. This precipitates, which is separated by suction and washed with carbon tetrachloride and water. The crude product is dissolved in absolute ethanol, the solution is acidified with ethanolic hydrochloric acid and 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride is crystallized by adding ether. Melting point: 187-188 ° C.

Example 200 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 4.0 g of acetic acid (3,5-dibromo-2-hydroxy-benzyl ester) and 4.0 g of dihydroxy-tert. -butylamine is heated at 140 ° C for 1 hour. The reaction product is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride is crystallized by adding ether.

Melting point: 187-189 ° C.

Example 201 3,5-Dibro-2-hydroxy-N-tert-pentyl-benzylamine 3.5 g of 3,5-dibromo-2-hydroxybenzyl alcohol and 1.4 g of a dispersion of sodium hydride in C50% oil) are refluxed. 6 hours in 100 ml of absolute tetrahydrofuran. It is then cooled to -60 to -70 [deg.] C. and 4.8 g of p-toluenesulphonic acid chloride in 50 ml of absolute tetrahydrofuran are added dropwise with stirring.

Allow to warm to -30 ° C and re-cool to -70 ° C.

4.4 g of tert-pentylamine in 50 ml of ether are then added dropwise and the mixture is stirred until the reaction mixture is warmed to room temperature. It is then shaken twice with water, the aqueous phase is extracted with chloroform, the organic phases are combined and evaporated. The crude product is purified by column chromatography on silica gel using chloroform-ethyl acetate (2: 1), after which 3,5-dibromo-2-hydroxy-N-tert-pentyl-benzylamine hydrochloride is crystallized from aston-ether after acidification. with ethanolic hydrochloric acid.

Melting point: 202-206 ° C (decomposes from water).

Example 202 3,5-Dibromo-N- (trifluoro-tert-butyl) -2-hydroxy-benzylamine 2.9 g of 3,5-dibromo-2-hydroxy-benzylmethyl ether and 3.3 g of dihydroxy-tert. -butylamine is heated at 140 ° C for 1 hour. The crude product is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and ether is added until 3,5-dibromo-1H-dihydroxy-tert. -butyl) -2-hydroxy-benzylamine hydrochloride begins to crystallize.

Melting point: 187-189 ° C.

Example 203 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 7 g of 3,5-dibromo-salicylaldehyde, 17.5 g of dihydroxy-tert-butylamine and 7.7 g of formic acid heated for 6 hours at 70-80 ° C.

Then add 2 N ammonia, shake vigorously and separate the precipitate with suction. The residue is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and added aster for crystallization. Recrystallization from absolute ethanol / ether gives melting of 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride at 187-189 ° C.

Example 20- [3,5-Dibrora-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 7.3 g of N- (3,5-dibro-2-hydroxy-benzylidene) -dihydroxy-tert-butyl- butylamine and 1 g of sodium borohydride are stirred for 2 hours in 200 ml of ethanol. A little acetone is then added to decompose the excess sodium borohydride, acidified with 2N salt 7i 62051 acid and evaporated to a small volume. Add 2 N ammonia until the reaction is alkaline and separate the yellowish precipitate by suction. The residue is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and ether is added to crystallize 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride.

Melting point: 187-189 ° C.

Example 205 3,5-Dibromo-2-hydroxy-N-isopropyl-benzylamine To 16 g of N-isopropylidene- (3,5-dibromo-2-hydroxy-benzylamine) in 120 ml of ethanol is added 2 g of sodium borohydride, stirred for 3 hours, then filtered, 40 ml of 2N sodium hydroxide and 200 ml of water are added and evaporated to about half volume. Saturated ammonium chloride solution is added to the solution, whereupon the crude base precipitates. The precipitate is filtered off with suction and washed well with water. The product is dissolved in acetone and acidified with ethanolic hydrochloric acid. In this case, 3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine hydrochloride crystallizes.

Melting point: 195-199 ° C (decomposes).

Example 206 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 4.2 g of dihydroxy-tert-butylamine and 1.2 g of paraformaldehyde are dissolved with heating in 20 ml of absolute ethanol, added at room temperature. 10.0 g of 2,4-dibromo-phenol and, after standing for one hour, boiling for a further 7 hours at reflux. The reaction solution is then acidified with ethanolic hydrochloric acid and 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride is crystallized by adding ether.

Melting point: 187-189 ° C (from absolute ethanol-ether).

Example 207 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 72 6 2 0 51 2.5 g of N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride is dissolved in a mixture of 50 ml of glacial acetic acid and 5 ml of water, while adding 3.2 g of bromine in 10 ml of glacial acetic acid dropwise with stirring. The reaction mixture is then diluted with water, basified with concentrated ammonia and the crude base precipitated is filtered off with suction. The base is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and ether is added until 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride begins to crystallize.

Melting point: 187-189 ° C (from absolute ethanol-ether). Example 208 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 2.5 g of N-benzyl-3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy -Benzylamine hydrochloride is dissolved in 200 ml of methanol and hydrogenated in the presence of about 0.1 g of palladium (10%) on carbon.

After the calculated amount of hydrogen has elapsed, the hydrogenation is stopped, the catalyst is filtered off and the solution is evaporated. Recrystallize twice from absolute ethanol-ether to give pure 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, m.p. 187-189 ° C.

Example 209 3,5-Dibromo-2-hydroxy-tert-pentyl-benzylamine 0.8 g of 3,5-dibromo-2-hydroxy-N-tert-pentyl-benzamide and 0.3 g of sodium borohydride in 30 ml of dry pyridine boil at reflux for 5 hours. To decompose the excess sodium borohydride, a little acetone is added and the pyridine is distilled off in vacuo.

The residue is taken up in hot 2N hydrochloric acid, filtered, made alkaline with 2N ammonia and shaken three times with chloroform. The organic phase is dried over sodium sulfate and evaporated. For further purification, the crude product is chromatographed on silica gel using chloroform-ethyl acetate (2: 1). The base obtained is dissolved in a small amount of acetone, acidified with ethanolic hydrochloric acid and crystallized from ether by adding 3,5-di-73,62051 bromo-2-hydroxy-tert. -pentyl-Bentylamine hydrochloride. Melting point: 202-206 ° C (decomposes, from water).

Example 210 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 1.8 g of 6,8-dibromo-3,4-dihydro-3- (dihydroxy-tert-butyl) -2H-1 The 3-benzoxazin-2-one is refluxed for 1 hour in a mixture of 50 ml of tert-butanol and 40 ml of 2N sodium hydroxide. Cool, add 50 ml of 2N hydrochloric acid, distill off the alcohol in vacuo and then add excess sodium hydrogen carbonate solution. The precipitated base is filtered off with suction and washed with water. The residue is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and crystallized from 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride by adding ether.

Melting point: 187-189 ° C.

Example 211 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 0.9 g of 2-benzoyloxy-3,5-dibromo-benzyl alcohol and 0.6 g of dihydroxy-tert-butylamine are heated for 1 hour. hour at 140 ° C. The reaction product is dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and ether is added to crystallize 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride.

Melting point: 187-189 ° C (from absolute ethanol-ether). Example 212 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 1.8 g of 6,8-dibromo-2-methyl-1,3-benzdiosane and 1.8 g of dihydroxy-tert-butylamine heated at 140 ° C for 20 hours. The reaction product and 100 ml of 2N hydrochloric acid are then boiled, activated carbon is added, filtered and evaporated. To purify 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxybenzylamine hydrochloride 74 62051, the residue is recrystallized twice from absolute ethanol-ether.

Melting point: 187-189 ° C.

Example 213 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine 3 g of 6,8-dibromo-3,4-dihydro-3- (dihydroxy-tert-butyl) -2H 1,3-Benzoxazine is dissolved in 30 ml of methanol and 10 ml of water are added. This starts to separate the precipitate. After one hour, the precipitate is filtered off with suction and washed with a small amount of methanol. The base is dissolved in a small amount of absolute ethanol, acidified with ethanolic hydrochloric acid and ether is added to crystallize 3,5-dibromo-AT- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride.

Melting point: 187-189 ° C.

Example 21 3,5-Dichloro-2-hydroxy-N-isopropyl-benzylamine Melting point of ethyl chloride: 188-189.5 ° C.

Prepared according to Example 199 from 3,5-dichloro-2-hydroxy-benzyl bromide and isopropylamine.

Example 215 N-tert-Butyl-3,5-dibromo-4-hydroxy-benzylamine

Melting point of the hydrochloride: 234-236 ° C (decomposes).

Prepared according to Example 199 from 3,5-dibromo-U-hydroxy-benzyl bromide and tert-butylamine.

Example 21G

N-tert-butyl-3,5-dichloro-2-hydroxy-benzylamine Melting point: 172-174 ° C.

Prepared according to Example 199 from 3,5-dichloro-2-hydroxy-75,62051 benzyl bromide and tert-butylamine.

Example 217 N-tert-butyl-3,5-dichloro-4-hydroxy-benzylamine

Melting point of hydrochloride: 222-223 ° C (decomposes).

Prepared according to Example 199 from 3,5-dichloro -> + - hydroxy-benzyl bromide and tert-butylamine.

Example 218 3,5-Dibromo-N-hydroxy-N-tert. -pentyl-bentsyyliarniini

Melting point of hydrochloride: 176-180 ° C (decomposes).

Prepared according to Example 199 from 3,5-dibromo-N-hydroxybenzyl bromide and tert-pentylamine.

Example 219 3β-Dichloro-4-hydroxy-N-tert-pentyl-benzylamine

Hydrochloride melting point: 203-207 ° C (decomposes).

Prepared according to Example 199 from 3,5-dichloro-U-hydroxy-benzyl bromide and tert-pentylamine.

Example 220 3,5-Dibromo-2-hydroxy-N- (hydroxy-tert-butyl) -benzylamine Melting point of the hydrochloride: 189-191 ° C.

Prepared according to Example 199 from 3,5-dibromo-2-hydroxy-benzyl bromide and hydroxy-tert-butylamine.

Example 221 3,5-Dibromo-1-H-hydroxy-N- (hydroxy-tert-butyl) -benzylamine Melting point of the hydrochloride: 200-202 ° C.

76 62051

Prepared according to Example 199 from 3,5-dibromo-4-hydroxy-benzyl bromide and hydroxy-tert-butylamine.

Example 222 3,5-Dichloro-N-hydroxy-N- (hydroxy-tert-butyl) -benzyl, η · Hydrochloride melting point: 208-212 ° C (decomposes).

Prepared according to Example 199 from 3,5-dichloro-4-hydroxy-benzyl bromide and hydroxy-tert-butylamine.

Example 223 3,5-Dibromo-N- (dihydroxy-tert-butyl) -4-hydroxy-benzylamine

Melting point of the hydrochloride: 182-183.5 ° C.

Prepared according to Example 199 from 3,5-dibromo-4-hydroxy-benzyl-libromide and dihydroxy-tert-butylamine.

Example 224 3,5-Dibromo-4-hydroxy-N- (trihydroxy-tert-butyl) -benzylamine Hydrochloride melting point: 189-191.5 ° C.

Prepared according to Example 199 from 3,5-dibromo-U-hydroxy-benzyl libromide and trihydroxy-tert-butylamine.

Example 225 3,5-Dichloro-N- (dihydroxy-tert-butyl) -N-hydroxy-benzylamine Melting point of the hydrochloride: 166-169 ° C (decomposes).

Prepared according to Example 199 from 3,5-1-dichloro-'+ - hydroxy-benzyl bromide and dihydroxy-tert-butylamine.

„62051

Example 226 3,5-Dibromo-2-hydroxy-N- (trihydroxy-tert-butyl) -benzylamine Melting point of the hydrochloride: 185-187 ° C (decomposes).

Prepared according to Example 199 from 3,5-dibromo-2-hydroxy-benzyl libromide and trihydroxy-tert-butylamine.

Example 227 3,5-Dichloro-4-hydroxy-N- (trihydroxy-tert-butyl) -benzylamine Melting point of the hydrochloride: 170-174 ° C (decomposes).

Prepared according to Example 199 from 3,5-dichloro-4-hydroxy-benzyl bromide and trihydroxy-tert-butylamine.

Example 228 N-tert-butyl-3,5-dibromo-2-hydroxy-benzylamine Melting point of hydrochloride: 216-220 ° C (decomposes).

Prepared according to Example 203 from 3,5J-dibromo-salicylaldehyde, tert-butylamine and formic acid.

Example 229 3,5-Dibromo-4-hydroxy-N-isopropyl-benzylamine Melting point of hydrochloride: 229-233 ° C (decomposes).

Prepared by reduction of N- (3,5-dibromo-4-hydroxy-benzylidene) -isopropylamine with sodium borohydride according to Example 204.

Example 230 3a 5-Dichloro-4-hydroxy-N, N-propyl-benzylamine

Melting point of hydrochloride: 223-231 ° C (decomposes).

Prepared according to Example 204 by reduction with sodium borohydride N- (3,5-dichloro-4-hydroxy-benzylidene) -isopropylamine.

78 62051

Example 231 3,5-Dichloro-2-hydroxy-N-tert-pentyl-benzylamine Melting point of hydrochloride: 211-213 ° C (decomposes).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -tert-pentylamine with sodium borohydride according to Example 204.

Example 232 3 - 5-Dichloro-2-hydroxy-N- (hydroxy-tert-butyl) -benzylamine

Melting point of the hydrochloride: 200-204.5 ° C (decomposes).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -hydroxy-tert-butylamine with sodium borohydride according to Example 204.

Example 233 3,5-Dichloro-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine Melting point of hydrochloride: 184-188 ° C (decomposes).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -dihydroxy-tert-butylamine with sodium borohydride of Example 204. in accordance with.

Example 234 3,5-Dichloro-2-hydroxy-N- (trihydroxy-tert-butyl) -benzylamine Hydrochloride melting point: 172-176 ° C (decomposes).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -trihydroxy-tert-butylamine with sodium borohydride according to Example 204.

Example 235 5-Bromo-N-tert-butyl-2-hydroxy-benzylamine 79,62051

Hydrochloride melting point: 2S5 - 258 ° C (decomposes).

Prepared by reduction of N- (5-bromo-2-hydroxy-benzylidene) -tert-butylamine with sodium borohydride according to Example 204.

Example 236

Syrup containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride

Composition: 100 ml contains:

0.04 g of active ingredient

Tartaric acid 0.5 g

Benzoic acid 0.2 g

Ammonium chloride 0.4 g

Glycerin 10.0 g

Sorbitol 50.0 g

Edible red 0.01 g

Raspberry flavor 4824 0.25 g (Fa. Boake, Roberts & Co.)

Ethanol 10.0 g

Distilled water ad 100.0 ml

Method of preparation:

About 45 g of distilled water are heated to 80 ° C and tartaric acid, benzoic acid, active ingredient, colorant and sorbitol are dissolved in succession. Glycerin and a 20% solution of ammonium chloride are then added. Ethanol and raspberry aroma are mixed with the mixture cooled to room temperature. The syrup is filled to a given volume and performed as appropriate.

10 ml of syrup contains 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride.

Example 237

Drops containing 4 mg of N, N-cyclohexyl-S, 5-dibromo-4-hydroxy-benzylamine hydrochloride 62051

Composition: 100 ml of drip solution contains:

Active substance 0.4 g p-oxybenzoic acid methyl ester 0.07 g p-oxybenzoic acid propyl ester 0.03 g

Polyvinylpyrrolidone 5.0 g

Anise oil 0.01 g

Fennel oil 0.001 g

Ethanol 10.0 g

Distilled water ad 100.0 ml

Method of preparation: p-oxybenzoic acid esters, polyvinylpyrrolidone and the active ingredient are successively dissolved in water heated to 80 ° C. The solution is cooled "and then the aroma and ethanol are mixed in a mixture. Make up to volume with water and filter through a suitable filter.

1 ml of drop solution contains H mg of N-ethyl-N-cyclohexyl-3,5-dithrom: 4-hydroxy-benzylamine hydrochloride.

Example 238

Tablets containing 4 mg of L-ethyl-N-cyclohexyl-3,5,5-dibroxyl-benzylamine hydrochloride ______

Composition: 1 tablet contains:

4.0 mg of active ingredient

Milk sugar 60.0 mg

41.0 mg of potato starch

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate 1.0 mg 110.0 mg

Method of production: no 62051

The active ingredient is mixed with milk sugar and potato starch and granulated with a 20% aqueous solution of polyvinylpyrrolidone through a 1 mm sieve. The wet granulate is dried at 40 ° C, sieved once more through said sieve and mixed with crude stearate. The mixture is compressed into tablets.

Tablet weight: 110 mg Tail: 7 mm

Example 239 Medicinal granules containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride__

Tablets prepared according to Example 238 are coated in a known manner with a shell consisting essentially of sugar and talc. The finished drug granules are polished with beeswax.

Weight of drug granule: 200 mg.

Example 240 Suppositories containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride

Composition: 1 stick contains:

4.0 mg of active ingredient

Stick pulp (e.g. Witepsol W 45) 1696.0 mg 1700.0 mg

Method of preparation:

The finely ground material is mixed with the melted and pulp mass cooled to 40 ° C and homogenized. The mass is poured into molds slightly pre-cooled at about 35 ° C.

Example 241

Ampoules containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride --- 82 62051

Composition: 1 ampoule contains:

Active ingredient * +, 0 mg

Tartaric acid 2.0 mg

Grape sugar 95.0 mg

Distilled water ad 2.0 ml

Prepare by methods:

Distilled water is heated to 80 ° C and dissolved in tartaric acid and the active ingredient with stirring. After cooling to room temperature, the grape sugar is dissolved and made up to volume. The solution is filtered sterile.

Filling: white 2 ml ampoules

Sterilization: 20 minutes at 120 ° C.

Claims (2)

A process for the preparation of hydroxyhalobenzylamine derivatives having cough-relieving, secretolytic and surfactant-promoting activity and having the general formula I or <wherein Hai is a chlorine or bromine atom, is a hydrogen, chlorine or bromine atom, R2 is a branched alkyl group having 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups, or a group of the formula V 1 (R 2) n R 3 wherein R 1 is a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms, n is a number 0, 1 or 2 62051 84 R 1 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 or 4 carbon atoms or also a hydrogen atom if R 1 is not a hydrogen atom or R 2 is optionally substituted by 1 to 3 hydroxyl groups an alkyl group having 3 to 5 carbon atoms and k represents 1 or 2, and their physiologically acceptable acid addition salts with inorganic or with organic acids, characterized in that a) a compound of the general formula II * '- Q (Hal) OH k in which R 1, Hal and k have the same meaning as above and R 8 is a hydroxyl group, a chlorine, bromine or iodine atom, acyloxy, sulfonyloxy, alkoxy, aryloxy or aralkoxy group, is reacted with an amine of general formula III / 2 H - N 2 - (III) R 4 wherein r and R 4 are as defined above, or «* 1 b) an aldehyde of general formula IV 85 6205 CH 2 (Hal) OH k wherein R, hal and k are as defined above is reacted in the presence of formic acid with an amine of general formula III wherein R 2 is H (N) ) for the preparation of compounds of general formula I in which a hydrogen atom is represented by a compound of general formula V R1- + j R2 (V) (Hal) OR7 k! or the general formula Va. CH 6; , a substituted cyclohexylidene group or a branched alkylidene group having 3 to 5 carbon atoms and Ry is a hydrogen atom or a carboxylic acid group is reduced, or d) for the preparation of compounds of general formula I wherein R 4 does not represent a hydrogen atom and R 2 and R 4 compound / H CH1 'N \ (VI) - CT - (Hal) k OH wherein R1, Hal and k are as defined above and R2' is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms or the same as mentioned above for With respect to R 2, except for a branched alkyl group having 3 to 5 carbon atoms and a group substituted by a hydroxyl group, is alkylated by a compound of general formula VII V - w (VII) wherein R 4 'represents an alkyl group having 3 to 5 carbon atoms, a cyclohexyl group and the same as R4 except for hydrogen, and W is a halogen atom or a sulfonic acid group, or e) a phenol of general formula VIII KaiιΪΛ <vni> (Kai) 0H k g7 62051 j the same as above, wherein one of the Hal groups in the 2-position of the compound of the general formula VIII is reacted with formaldehyde or paraformaldehyde and an amine of the general formula III R 2 H - N wherein R 2 and R 2 have the same meaning as above, or f) Compound of formula IX / R 2, ch 2 -IK (IX) "• in C 1 OH 2 R 1> R 2 and R 1 + have the same meaning as above, are halogenated, or g) from a compound of general formula X 'NX R 1 -p-H h (x) (Hal) O in R 1, R 2, Hal and k have the same meaning as above, X is an amino group protecting group or means the same as above R 1 and Y is a hyaroxyl group protecting group or a hydrogen atom, wherein at least one of X or Y must be an amino group. or a hydroxyl protecting group, cleaving one or two protecting groups, or h) a compound of general formula XI 88 62 0 51 0 R <X1) “‘ CT V (Hal) ^ OR? wherein R 1, R 2, hal and k are as defined above, R 1 is a formyl or acetyl group or the same as R 1, and Ry is a hydrogen atom or a carboxylic acid group, is reduced, or i) for the preparation of compounds of general formula I in which the hydroxyl group is In the 2-position and R 1 is an atom, a compound of general formula XII 0112 v R 1 -L 11 R 2 (XII) (hal) in R 1, Hal and k have the same meaning as above, is hydrolyzed, or j) Compound XIII R1_f J <XIII) (Hal) ORβ in kbj R1, nai and k have the same meaning as above and Rg is an organic acyl group, is reacted with an amine of general formula III 89 62051 R2 n - (III) wherein) a has the same meaning as above, or k) for the preparation of compounds of general formula I in which the hydroxyl group is in the 2-position, a compound of general formula XIV '* - E 0 -, (hai) k where R a, hai and k have the same meaning as above and Rg is alkyl, aryl or a a alkyl group, is reacted with an amine of general formula III / R 2 in N (III) and R 1 - and R have the same meaning as above, and the resulting reaction reaction is then hydrolyzed, or l) for the preparation of compounds of general formula I having a hydrogen atom and the hydroxyl group is in the 2-position, a compound of general formula XV -f T t; (R), R, hai and k are as defined above, hydrolysed or m) for the preparation of compounds of general formula I in which 1 * 2 is a cyclohexyl group and is methyl a group, a compound of the general formula Ha ^ w-ch2-oh R1HLjJ (Hal) k OH in which r ^, Hal and k have the same meaning as above, is reacted with an amide of the general formula XVI 1 \ O = PNV / N / 3 (XVI) or with an amide of general formula XVIa * / 2 R c N '(XVIa) \ r4 in which R2 and have the same meaning as above and R1q is an alkyl, aryl or aralkyl group, and the compound of general formula I obtained by methods a to m is subsequently converted if desired physiologically acceptable salts with inorganic or organic acids. 91 62051 For the preparation of hydroxyhalobenzylamines with a host, secretolytic and imaging activity in the form of an underlying solution, and with the formulation I ^ R2 (Hai) OH ki vilken Hai är en chlor- eller bromatom, R ^ är en vä chloro-bromine, R2 is optionally substituted with 1-3 hydroxyl groups substituted by 3-5 alkyl groups, having 3-5 cholatomers, or with a group of stem formulas * 3 colors R3 is not a hydrogen atom, with a hydroxyl group or an alkyl group of 1-4 cholatomers , n is or 0, 1 or 2 R 4 is an alkyl group having a alkyl group of 1 to 4 chapters, an alkenyl group having 2 to 4 cholatomers, a cycloalkyl group having 3 to 4 mole atoners or a single atom, to R 3 or a lower atom wherein R2 and optionally 1-3 hydroxyl groups are substituted by a preferred alkyl group, which is 3-5 cholatomers, and in particular 1 or 2, the same as the physiologically acceptable radical addition salt with an organic or organic weight, in which case a further Form II II ^^ ch2-r6 <rI> (HQl) k OH 62051 92 i vilken R ^, Hal och k har ovan angiven betydelse och Rg är en hydroxylgrupp, en chloro-, brom- eller iodatom, en acyloxy-, sulfonyl- oxy-, alkoxy-, aryloxy- or aralkoxy groups, rings of a reagent with an amine having the formula III r2 H 'N (III) R4 i are valence R2 and R ^ har ovan angiven betydelse, or b) en aldehyde with the formula IV CH0 (Hal) OH, which is R ^, Hal och k har ovan angiven betydelse, bringas att reagera i närvaro av myrsyra med en Amin med den allmänna formuleln III R, / 2 H - N (III) * 4 i vilken R2 and in the case of an aqueous formulation, or in the case of a compound formulation, or (c) for the purpose of reducing the formulation of all the formulas I, i and then the R4 formulation is reduced, reducing the formulation with the formulation V h _rfVCH = N 'w ? or in the case of all the compounds of the formula Va i ^ V 'v "' '(Hey) 0R„ k 1 k 93 62051 1 vilka R] ^ ^ 2, Hal and k har ovan angivna betydelser, Z är en eventuellt med en hydroxi- eller an alkyl group having 1-4 cholaters, a substituent of a cyclohexylidene group or a preferred alkylidene group, having 3-5 cholatomers and a substituent of a cyclohexyl radical group, or d) for the purpose of the reaction with an alkyl compound this is a substituent and a group R2 and R4 and a group having a hydroxyl substituent, alkylated with the group * H in Formula VI ^ CH. - N 'v CVI) • CHaX> ^ OH i vilken R ^, Hal och k har ovan angiven betydelse and R2 * är en väteatom eller en alkygrupp somar 1-4 kolatomer, eller Decamma som ovan nämnts om R2 med undantag av förgrenad alkylgrupp, at har 3-5 cycatomer, och en med en hydroxvlgrupp substituerad grupp, med en förening med of all formulas VII r »W (VII) i vilken R4 'betecknar en alkylgrupp som ha r is 3-5 cholatomers, in which the cyclohexyl group and the same moiety are taken from R4 and in which the halogen atom or the sulfonyl group is used, or e) phenol in the form of a compound VIII% - {£ X (Hai) ° H ki vilken Rj ^ Hai OCh ^ har ovan angiven betydelse, varvid en av Hal-grupperna är i föreningens med almänna formulin VIII 2-stinging ring to react with formaldehyde or paraformaldehyde and en Amin med denemänna Formula III H - »^ "4 ^ Ru (III) 62051 94 in the form of R2 and R4 in the form of an active compound, or f) in the case of a compound of formula IX / * 2 y CH- - IL (IX) --Of" OH in the form of R] ^ and with an angular process, halogenated, or g) a compound having the formula X ^ r ^ CH2 - nn Rx _ £ _ HR |. «> (Hal) ° Y ki vilken R] ^ ^ Hal och ^ ^ ar ovan angiven betydelse, X är en skyddsgrupp för aminoamino eller harra samma betettelse som R4 i det föregAende, och Y Mr hydroxylgruppens skyddsgrupp eller en vMteatom, varvid Atminstone den in which the group X or Y is selected from the group consisting of amino or hydroxyl groups, the group consisting of the group or the group of the group, or h) in the form of a group X 0 ^ R2, ^ Vc. / <XI) Xv (Hal) k 0R? in which R 1, R 8, Hal and k are angiven betydelse, R 4 "is a formyl group or an acetyl group or a group of R 4 groups, and R 7 is a group or a carboxyl group, a reducing agent or i) for a compound of the same nature in which all the compounds of formula I, i and the hydroxyl group are 1 2-stSllning and R4 Sr en väteatom> hydrolvers 62051 95 for which all the compounds of formula XII R1 - i R2 ”R2 (XII)> ^ A0 ^ CS0 (Hai) j, i vilken R ^, R2 / Hai och k har ovan angiven betydelse, eller i) föreningen med den allmänna formuleln XIII ^ \ / CH2'0H ··, Γ TT (Xixi) (Hai) 0Rr k 8 i vilken, Hai och k har an anhydrous bethel and an RB is an organic acyl group, the ring is reacted with an amine having the formula III H - N <"CU1) and R 2 and R anh are an orthoglyl, or k) with all of the compounds of formula I, i having a hydroxyl group in the 2-ring, the ring of which is formed by all of the compounds of formula XIV Cha *! - | T 9 CXIV> Ι? ίϊ <Λθ - <: Η- * 9 (Hal) k in which R ^ / Hai and k har ovan angiven betydelse, och Rg is an alkyl-aryl- or aralkyl group, which react with the amine with all the compounds of formula III K - <* 2 (III>