FR2473512A1 - NOVEL 2-AMINOMETHYL-6-HALOGENO-PHENOLS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS - Google Patents

Abstract

The subject of the invention is novel 2-amino-methyl-6-halo-phenols of formula: (CF DRAWING IN BOPI) in which one of the symbols A and B represents a bromine or iodine atom and the other means an optionally substituted aminomethyl group and n means 1 or 2, and their preparation. These compounds can be used therapeutically as active principles of medicaments.

Description

The subject of the present invention is new 2-

  aminomethyl-6-halogenophenols, their preparation and their therapeutic application, as active ingredients

of drugs.

  - British Patent Application No. 2,013,655A

  describes a class of 2-aminoethyl-6-halogenophenols com-

  carrying a string a1ky1gne possibly substituted by ----

  an alkyl group and attached to positions 3 and 4 or 4 and 5

  of the cycle, and whose amino group is

  tituated by an alkyl group. These compounds have

  anti-inflammatory, analgesic, antipyretic, diuretic and hypotensive properties.The Applicant has now

  found that certain compounds of this class, in parti-

  those having a bromine atom in position 6 and / or an α,--disubstituted trimethylene chain

  by alkyl groups and a non-substituted amino group

  killed, compounds not specifically described or mentioned in this patent, and their derivatives,

  have remarkable pharmacological properties.

  The invention relates more particularly to the compounds corresponding to the formula I R 3 (CH 2) n R 3 n A j B

OH

  in which one of the symbols A or B means X and the other represents a remainder R1

-C-N

_CNH2,

  R2 X represents a bromine atom and, in this case, n means 1 or 2, and R2 represents each a hydrcgene atom or a

  methyl group or one of the symbols R1 and R2 signifies

  hydrogen and the other a methyl group, and the two symbols R3 each signify a hydrogen atom or a linear alkyl group containing from 1 to 4 carbon atoms, or X signifies an iodine atom and, in this case, n is 1 and

  R 1 and R 2 each represent a hydrogen atom and the symbols

  R 3 groups each means an alkyl group containing from 1 to 4 carbon atoms, or R 1 and R 2 each represent a methyl group or one of the symbols R 1 and R 2 represents a hydrogen atom and the other a methyl group. and the

  two R3 symbols each signify a hydrogen atom

  a gene or an alkyl group containing from 1 to 4 carbon atoms, ie n means 2 and one of the symbols R1 and R2 represents a hydrogen atom and the other a methyl group or R1 and R2 each represent a methyl group and the R3 symbols each denote a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and the salts that these compounds form with acids

organic or mineral.

  Among the compounds of formula I, the invention comprises the compounds of formula Ia R '3 (CH 2) n R 3 (la) / R 1 X C - Nil

2

  one in which R 1, R 2, X and n have the meanings already given, and the R symbols each represent a hydrogen atom

or a methyl group.

  Another group of compounds of formula I include those wherein A is a radical of formula / R1

-C- NH2

2

  B represents X and R1, R2, R3, X and n have the meanings

already given.

  A third group of compounds of formula I comprises the compounds of formula Ib

_

X

XI C --NIH2

  R 'o! R 2 in which the symbols R1 and R' each signify a hydrogen atom or one of the symbols R1 and R 'signify a hydrogen atom and the other a methyl group, the R symbols represent each.a hydrogen atom or

  a methyl group, and X and n have the already defined meanings.

  As the fourth group of compounds of formula I, there may be mentioned compounds of formula Ic (formula Ic see next page) C13 (c) R '

11W --- C X

2 / X

R '

2 OH

  in which R 1, R 'and X have the meanings already given. A fifth group of compounds of formula I

  includes those in which A, B, R3 and n have the meanings

  cations already given and R1 and R2 represent a methyl group or one of the symbols R1 or R2 means hydrogen

and the other a methyl group.

  In the compounds of formula I, X is preferably a bromine atom; n preferably means 1; the symbols R 3 preferably represent a methyl group and at least one of the symbols R 1 and R 2 preferably signifies hydrogen. The compounds of formula I which are particularly preferred are those in which X, n, R 3, R 1 and R 2 have

these preferred meanings.

  According to the process of the invention, a) to prepare compounds of formula I where B is a radical of formula R 1 C -NH 2, A is X, and R 1, R 2, R 3, n and X R

R2

  have the meanings already given, a compound of formula II (formula II see next page) is brominated or iodinated (CH2) n3 S9 n (II) C-N12 R \ R

OH 2

  in which n, R1, R2 and R3 have the meanings

already given.

  Bromination or iodination may be effected

  killed by known methods. We can operate at a

  temperature between about -10 and +500, preferably

  between about 0 ° and room temperature. The

  bronzing and iodization can be carried out

  by direct reaction with bromine or iodine chloride (IC1). Jhromation. preferably carried out in an inert solvent under the conditions of the reaction as

  methylene chloride, chloroform, tetra-

  carbon chloride or glacial acetic acid.

  The iodination is preferably carried out with iodine chloride, in glacial acetic acid or in water, optionally in the presence of a solvent which is miscible with water and inert under the conditions of the reaction, such as than dioxane. It is advantageously carried out under acidic conditions. b) To prepare the compounds of formula I where B is X, A represents a residue of formula R -C - N12, R 2 and R 3 each signify hydrogen, R 2 and R 3, n and X have the meanings already given, hydrolyzing a compound of formula III 13

(CH2 [R3

| | R (III)

Acyl- NH-

CH2 X

  In which R3, X and n have the meanings already given. The reaction can be carried out according to the methods usually used for the hydrolysis of analogous acylamino compounds, preferably by acid hydrolysis in the presence of a strong acid such as

  concentrated hydrochloric acid or sulfuric acid.

  preferably operates in a lower alcohol such as ethanol or in a water-miscible solvent, for example

  dioxane, at the reflux temperature.

  c) To prepare compounds of formula I where B is X, A represents a radical of formula R

-C- NI

R2

  one of the symbols R1 or R2 represents a hydrogen atom

  gene and the other a methyl group, and R3 and n have the meanings already given, is reduced a compound of formula IV (formula IV see next page) R3 (CH2) n R

I (IV)

  In which R3, X and n have the meanings already given. The reaction can be carried out according to the methods usually used for the reduction of imino analogues, for example by reaction with complex metal hydrides such as sodium borohydride, lithium aluminum hydride,

  diborane or the borane-dimethylsulfide complex.

  The reaction is carried out in a suitable solvent for the reducing agent.

  chosen, such as tetrahydrofuran, methanol, ethanol or ether, at a temperature

  about 0 and 70, for example as described in Example 2c.

  d) To prepare compounds of formula I where B is X, A represents a radical of formula R1

-C - NH2

  R2 R1 and R2 each signify a methyl group, and R3 and n have the meanings already given, catalytically hydrogenated a compound of formula V (formula V see next page) R3 (CH2) n3 (V) CH3 CH3

C3 OH

  wherein R3, n and X have the meanings already given, and the substituent X is brominated or iodinated if it has been removed during the hydrogenation. The catalytic hydrogenation can be carried out according to known methods used for the catalytic hydrogenation of analogous azido compounds. As catalyst, for example, palladium or platinum and, as a solvent, preferably an alcohol. It operates at a temperature between about 20 and 60, and at a pressure between 5 and 20 atmospheres, by

  example as described in Example 6c). Where the substitute

  killing X is eliminated during the hydrogenation, it can be reintroduced by reaction with a brom-ation agent

  or iodination, for example as described under a) above.

  The compounds of formula I thus obtained can

  then be isolated and purified according to known methods.

  The compounds used as starting materials can be prepared in several steps from an indanol or a 5,6,7,8-tetrahydronaphthol of formula IX, as shown in both reaction schemes I and II below. The first substitution of the compound of formula IX, whether by acylaminomethylation, acetylation or halogenation, takes place mainly at the 6-position in the case of an indanol or at the 3-position in the case of a tetrahydronaphthol and in small proportions, at

  position 4 of indanol or position 1 of tetrahydro-

  naphthol. The second substitution is then carried out on

  the second ortho position of the phenolic residue. The substitute

  The main scheme is shown in Figures I and II. The starting materials used in the reactions of the invention can be obtained according to three different processes depending on whether the aminomethylene group located in the ortho position of the phenolic residue is unsubstituted or

  substituted with one or two methyl groups.

Reactional scheme I R3

(CH) --- R3

  (X), .. Nhb-Acyl ayurcayse - '0t1i / cyl a minomethyl ation

R3 R3

(CH 2) R 3 (C

  (XIlll) II "(XI) n CH 3 CH 2 CH 3 MgH 1 (Ix) R (IIa) NH 2 O 2 R 2 O and Nil-CH 3 Reduction (II 1b) Azide R 3 (C 7) n 3 (C 1)

> J CH3 -

  N 0 3 Hydrogenation (XII) C-N3 catalytic Cl3 (11 R3

C - NH2

  ## STR1 ## wherein R 2 -N 3 R 3 R 3 R 3 R 3 R 3 R 3 R 3

(III) H

R3

(IX) 011 (VIII)

  (V CI C l1 (VI) cl oi O3i R ú3 (CHIv) M (IV) tW11 or CH 3MgHa R3 tC2C) R3 v HO-C UiX (VII) ilvC Azide R3

(CH2) 3

h3c%

N-C X

  ## STR2 ## The compounds of formulas VI and XIII and of formulas VIII and IX R3 R3 t () m = (VIII)

OH OH

  in which the symbols R3 each signify a hydrogen atom or a linear alkyl group containing from 1 to 4 carbon atoms, X represents a bromine or iodine atom and the R "symbols each represent a methyl or ethyl group,

  are new and part of the present invention.

  The other compounds of formula IX are known or can be prepared according to known methods, for example as described in the examples below. When the preparation of the starting materials is not described, these are known or can be prepared in a

  known or according to the methods described in this application.

  The compounds of formula I, the starting materials of basic character as well as the intermediate products obtained in the free base state can be converted into acid addition salts according to the usual methods by reaction with inorganic or organic acids; from the salts, the bases can be liberated according to known methods. As suitable acids for the formation of

  salts, mention may be made of hydrochloric acid, fumaric acid and

  that, oxalic acid or hydrobromic acid.

  The following examples illustrate this

  invention without in any way limiting its scope. Temperatures

  eratures are all indicated in degrees Celsius and are not

not corrected.

Example 1

  6-Aminomethyl-4-bromo-1,1-dimethylindan-5-ol a) 1 H -dimethylindan-5-ol With stirring, a solution of 10.3 g of sodium nitrite is added dropwise at 0-5. in 80 ml of water at 20 g of 6-amino-1,1 dimethylindane in 100 ml of water and 25 ml of concentrated sulfuric acid. We add

  dropwise the resulting solution to a solution

  boiling point of 40 ml of concentrated sulfuric acid

  150 ml of water. 1,1-Dimethylindan-5-ol is separated from the

  reaction mixture by distillation of the water and, after

  crystallization in petroleum ether, we get

  white crystals melting at 96-98.

  b) 6-chloroacetylaminomethyl-1,1-dimethylindan-5-ol 8.1 g of 1,1-dimethylindan-5-ol are dissolved in a mixture of 60 ml of glacial acetic acid and 6 ml of sulfuric acid. concentrated and added in portions

  at 10, a total of 6.2 g of 2-chloro-N-hydroxymethylacetate

  amide. After stirring the reaction mixture for two hours at 1520, it is poured onto a mixture of water and ice and the reaction product is extracted.

  with ethyl acetate. 6-chloroacetylamino

  crude methyl-1,1-dimethylindan-5-ol thus obtained is used as it is without further purification for step c)

next.

  c) 6-Aminomethyl-11-dimethylindan-5-ol The crude product obtained under b) is refluxed for 4 1/2 hours in a mixture of

  ml of ethanol and 80 ml of concentrated hydrochloric acid.

  After the ethanol has been removed under reduced pressure, dilute ammonia is poured into the residue, the mixture is extracted with methylene chloride, and the phase is dried.

  organic and evaporated. The resulting base can be purified

  aunt obtained in the raw state by transforming it into bromhyn-

  crystalline drate by reaction with hydrobromic acid

  in ethanol. The hydrobromide of 6-aminomethyl-1, 1-

  dimethylindan-5-ol melts at 220-224.

  d) 6: -aminomethyl-4-bromo-1,1-dimethylindan-5-ol

  1 g of 6-aminomethyl-1,1-dimethyl-

  indan-5-ol in 10 ml of glacial acid and, while stirring at room temperature, a solution of 1.1 g of bromine in 2 ml of glacial acetic acid is added dropwise. After having carefully evaporated under pressure

  reduced the volatile components, 6-amino-

  methyl-4-bromo-1,1-dimethylindan-5-ol in the form of a

  crude crystalline product which can be purified by recrystallization

  in a mixture of ethanol and ether. Brom-

  6-Aminomethyl-4-bromo-1,1-dimethylindan-5-ol hydrate

background 197-198.

Example 2

  6- (1-aminoethyl) -4-bromo-indan-5-ol a) 6-actylindan-5-ol 100 mg of indanol are heated at 60 for 4 hours in a mixture of 200 ml of acetic anhydride and 200 ml of pyridine. After eliminating

  volatile components by evaporation under high pressure

  113 g of aluminum chloride are added in portions.

  minium and heated to 140 for 2 hours. The mixture is then decomposed by addition of ice water, extracted with methylene chloride and concentrated

  the organic phase by evaporation, which gives the 6-

  acetylindan-5-ol as a slowly crystallizing mass; this product can be used as is for

  the next step (b) without further purification.

b) 6- (1-iminoethyl) indan-5-ol

  Let stand for one night at room temperature

  20 g of the crude ketone obtained under a) in 150 ml of methanol saturated with ammonia; the imine precipitates in the form of yellow crystals which can be filtered. The 6- (1-iminoethyl) indan-5-ol thus obtained

at 229-230.

  c) 6- (1-aminoethyl) indan-5-ol 24h.73512 3.5 g of 6- (1iminoethyl) indan-5-ol are dissolved in 30 ml of methanol. To this solution is added, portionwise and at room temperature, 2 g of borohydride

  of sodium and allowed to stand for one hour.

  Excess sodium borohydride is then decanted by the addition of a small amount of dilute hydrochloric acid. After evaporating the mixture under reduced pressure, the evaporation residue is diluted. with water, we extract

  the alkaline reaction mixture with methylene chloride

  The organic phase is dried, evaporated and the yellow oil obtained is recrystallized from ether. The

  6- (1-aminoethyl) indan-5-ol thus obtained melts at 114-115.

  d) 6- (1-aminoethyl) -4-bromoindan-5-ol

  Brominated: as described in Example 1.

  tallizes 6- (1-aminoethyl) -4-bromoindan-5-ol in ethanol The product obtained in the free base state melts

at 153-154.

Example 3

  6- (1-aminoethyl) -4-bromo-1,1-dimethyl-indan-5-ol The following compounds are prepared successively as in Example 2: a) 6-acetyl-1,1 dimethylindan-5-ol prepared from 14 g of 1,1-dimethylindan-5-ol; yellow oil; b) 6- (1-iminoethyl) -1,1-dimethylindan-5-ol; it melts at 172-174 after recrystallization from methanol; c) 6- (1-aminoethyl) -1,1-dimethylindan-5-ol; He created

134-136;

  d) 6- (1-Airoethyl) -4-bromo-1,1-dimethylindan-5-ol

  the free base state, it melts at 120-121 hours after recrystallization

  in ether; this compound is transformed into bromine

hydrate.

Example 4

6- (1-aminoethyl) -4-iodoindane-5-ol

  To a solution of 1.8 g of 6- (1-aminoethyl) indane

  5 g in iodine chloride (20 ml of glacial acetic acid), 1.9 g of iodine chloride are added over a period of 10 minutes and the reaction mixture is stirred at room temperature for 3 hours. After removing the volatile components under reduced pressure, the mixture is basified with a dilute aqueous ammonia solution and extracted with methylene chloride. After drying and evaporation of the organic phase, a brown oil is obtained from

  which the title compound is collected by crystallization

  in ethanol. The compound obtained in the basic state

free background at 119-121.

  Example 5 4-Aminomethyl-6-bromo-1,1-dimethylindan-5-ol a) 4- (3-methoxyphenyl) -2-methyl-2-butanol

  To a solution of 25.8 g of 3- (3-methoxyphenyl)

  methyl propionate in 300 ml of anhydrous ether,

  add dropwise, with stirring and while cooling

  with ice, 200 ml of a 1.5 molar solution of methyl magnesium bromide in ether. After allowing the mixture to stand at room temperature for one hour, it is poured into ice water and then acidified with dilute hydrochloric acid. The organic phase is then separated, dried over sodium sulphate and

  concentrated by evaporation. 4- (3-Methoxyphenyl) -2-ethyl-2- is obtained.

  butanol by distillation under high vacuum to about (Kugelrohr distillation), in the form of a

colorless liquid. -

  b) 5-methoxy-1,1-dimethylindane While stirring, add dropwise at 100

  and within 30 minutes, 29 g of 4- (3-methoxyphenyl)

  2-methyl-2-butanol to 45 ml of 85% phosphoric acid.

  After stirring this mixture for a further hour, it is poured into ice water and extracted with ethyl acetate. After drying and evaporation of the organic phase, 5-methoxy-1,1-dimethylindane is obtained by distillation under high vacuum at 80-90, under

form of a colorless oil.

  c) 1,1-dimethylindan-5-ol A mixture of 8.5 g of 5-methoxy-1,1-dimethylindane and 80 ml of 63% hydrobromic acid is heated under reflux for 2 hours and then, after poured this mixture on ice water, extracted with methylene chloride. After drying and evaporation of the organic phase, the crude 1,1-dimethylindan-5-ol is obtained in the form of a crystalline residue which can be

  purify by crystallization from hexane; he melts at 98.

  d) 6: bromo-11-dimethylindan-5-ol To a solution, cooled with ice, 40 g of 1,1-dimethyl-5-indanol in 400 ml of tetrachloride.

  carbon is added dropwise with vigorous stirring.

  and within one hour, 15 ml of bromine in 70 ml of carbon tetrachloride. After evaporating the reaction mixture to dryness under reduced pressure, the mixture is distilled

  the product obtained under vacuum pushed to 110.

  e) 6-bromo-4-chloroacetylaminomethyl-11-dimethylindane

- 1

  55.8 g of 6-bromo-1,1-dimethylindan-5 are dissolved

  ol in a mixture of 60 ml of concentrated sulfuric acid and 560 ml of glacial acetic acid. To this mixture, we

  add in portions 35 g of 2-chloro-N-hydroxymethyl

  acetamide while stirring and cooling with ice. After allowing the mixture to stand for 2 hours at room temperature, it is poured on 2 liters

  of a mixture of water and ice and is allowed to crystallize

  be at night. After filtration and drying,

  obtains 6-bromo-4-chloroacetylaminomethyl-1,1-dimethyl-

  indan-5-ol crude that can be used as is, without

  further purification, for the next reaction.

  f) 4-Aminomethyl-6-bromo-1-dimethylindan-5-ol The mixture is boiled under reflux for 3 hours.

  hours 78 g of 6-bromo-4-chloro-acetylaminomethyl-1, 1-

  dimethylindan-5-ol crude in a mixture of 400 ml of ethanol

  and 300 ml of concentrated hydrochloric acid. We evaluate

  completely pore the clear solution under reduced pressure to expel the alcohol. After standing cold, the hydrochloride of 4-aninanmethyl-6-bromo-1,1-dimethylindan-5-ol crystallized as beautiful white crystals, mp 204-207. After addition of dilute ammonia to the aqueous solution of the hydrochloride, the free base of this hydrochloride is obtained.

compound melting at 167-168.

Example 6

  6- (1-amino-1-methylethyl) -4-bromo-1,1-dimethylindan-5-ol a) 6- (1-hydroxy-methylmethyl) -1,1-dimethylindan-5-ol

  To a solution of 12.9 g of 6-acetyl-1,1-dimethyl-

  indan-5-ol in 150 ml of anhydrous ether, 90 ml of a 1.6 molar solution of methyllithium in ether are added dropwise at room temperature and under a nitrogen atmosphere. The reaction mixture is stirred for one hour and then poured onto a mixture of ice and dilute hydrochloric acid. The organic phase is then separated off, dried and concentrated to give 6- (1-hydroxy-1-methyl-ethyl) -1,1-dimethylindan-5-ol by recrystallization of the evaporation residue from

hexane; he melts at 94-95.

  b) 6- (1-azido-1-methylethyl) -1,1-dimethylindan-5-ol

  To a solution of 8.5 g of 6- (1-hydroxy-1-methyl-

  ethyl) -1,1-dimethylindan-5-ol in 100 ml of chloroform, 5 g of sodium azide are added and the suspension is then cooled to -8. 15 ml of trifluoroacetic acid are added dropwise over a period of 30 minutes while

  shaking vigorously. After stirring the reaction mixture

* at room temperature for 2 hours, alkalinize with concentrated ammonia, separate

  the organic phase, washed with water and evaporated

  pore to dryness. This gives 6- (1-azido-1-methyl)

  ethyl) -1,1-dimethylindan-5-ol as a yellow oil. c) 6- (1-amino-1-methylethyl) -4- (1-dimethylindan-5-ol) 8.9 g of 6- (1-azido-1-methylethyl) -1,1-diol is hydrogenated at 50 ° and under 5 atmospheres. -dimethylindan-5-ol in

  220 ml of ethanol in the presence of a platinum catalyst.

  The catalyst is then removed by filtration and the solution is evaporated to dryness. 6- (1-Amino-1-methylethyl) -1,1-dimethylindan-5-ol is then recrystallized from hexane; in the free base state, it melts at 115-117.

  In the form of hydrochloride, it melts at 180-185.

  d) 6- (1-aminoiminophenyl) -4-bromo-1,1-dimethylindan

  ol. Bremation is performed by proceeding as described in

  Example 1. The compound obtained in the form of bromine

  drate melts at 219-220; in the free base state, it melts at 109-111.

Example 7

  4-aminomethyl-6-bromo-1,1-diethylindan-5-ol Proceeding as described in Example 5, the following compounds are prepared successively: a) 1,1-diethylindan-5-ol in the form of a viscous colorless oil; b) 6-bromo-1,1-diethylindan-5-ol; it boils at 120-130 at 0.1 mm Hg,

  c) 6-Bromo-4-chloroacetylaminamethyl-1,1-diethylindan

  -ol in the form of a yellowish oil, d) 4-aminomethyl-6-bromo-1,1-diethyl-indan-5-ol; he

background at 165-166.

  By proceeding as described in the previous examples, the following compounds of formula I can be prepared: AB n R Process Point n = 3 fusion i)] 8 I -CH (CH 3) NH 2 1 CH 3 132-133 a 9 I-CH 2 NH 2 1 CH 3 137-138 a I -C (CH 3) 2 -NH 1 CH 141 -142 a

-_____ -_1C3 142 2 3

35 ...

1) Free base form.

  In tests carried out on laboratory animals, the compounds of formula I are distinguished by

  interesting pharmacodynamic properties.

  In particular, they exert a salidiuretic action which has been demonstrated during standard tests.

  performed on the rat as described in Schweiz.Med.

  Wochenschrift, 93, (1963), 1232-1237. When administered orally at a dose of between 1 and 100 mg / kg, the compounds of formula I exhibit, in this test, a

significant saliuretic effect.

  Thanks to this property, the compounds of formula I can be used therapeutically as

salidiuretic agents.

  In addition, the compounds of formula I

  also antihypertensive action. This anti-activity

  Hypertensive was demonstrated by standard tests performed on the spontaneously hypertensive rat, according to the method described in Proc.Soc. Exptl.Biol. and Med. 57, (1944), 102. When administered orally at a dose of between 1 and 100 mg / kg, the compounds of formula I decrease,

  during this test the blood pressure.

  Owing to this property, the compounds of formula I can be used therapeutically as antihypertensive agents. They will be prescribed at doses

  daily doses of between 1 and 150 mg of

  active ingredient which will advantageously be administered in several unit doses each containing approximately 0.25 to 75 mg of active substance at a rate of 2 to 4 times per day, or

in the form of delay.

  The compounds of formula I in which R 1 and R 2 each represent a hydrogen atom and R 3 signifies a hydrogen atom or a methyl group, are indicated by a particularly advantageous pharmacological activity. These compounds are in particular well tolerated and well absorbed after oral administration; moreover, they cause only a small excretion of potassium ions and / or

lasting antihypertensive effect.

  The compounds of formula I can be administered

  very much in the form of free bases as well as in the form of pharmaceutically acceptable acid addition salts; the activity of these salts is of the same order as

  that of the corresponding free bases.

  The compounds of formula I and their salts

  addition of pharmaceutically acceptable acids can be used as medicaments either alone or

  form of pharmaceutical compositions

  appropriate for oral administration, rec-

  tale or parenteral. To prepare pharmaceutical compositions

  The active substances are processed using inorganic or organic excipients which are pharmacologically inert. As excipients, it may be used for example: for tablets and dragees: lactose, starch, talc, stearic acid etc .; for syrups: solutions of sucrose, invert sugar, glucose etc .; for injectable preparations: water, alcohols, glycerol, vegetable oils etc .; for suppositories: natural or hardened oils,

waxes etc ...

  The pharmaceutical compositions may further contain preservatives, stabilizers,

  wetting agents, auxiliaries of dissolution,

  corants, colorants, flavorings, etc., suitable.

  The compounds of formula I particularly

  Preferred are the compounds of Examples 3 and 5.

Claims (23)

  1. New 2-aminomethyl-6-halogenophenols, characterized in that they correspond to the formula I R3 A (I) B OH in which one of the symbols A or a remainder B means X and the other represents R- / 1 -C-NH2   R2 X means a bromine atom and in this case n means 1 or 2, F and R2 each represent a hydrogen atom or a   methyl group or one of the symbols R1 and R2 signifies   hydrogen and the other a methyl group, and the two symbols R3 each signify a hydrogen atom or a linear alkyl group containing from 1 to 4 carbon atoms, or X signifies an iodine atom and, in this case, n is 1 and   R1 and R2 each represent an atore d 'aging and s.-.-   R 3 each means an alkyl group containing 1 to 4 carbon atoms, or R 1 and R 2 are each methyl or one of R 1 and R 2 is hydrogen and the other is methyl, and   two R3 symbols each signify a hydrogen atom   gene or an alkyl group containing 1 to 4 carbon atoms, n is 2 and one of R 1 and R 2 is hydrogen and the other is methyl or R and R are each methyl and the R 2 symbols R 3 each signify a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and the salts that these compounds form with acids organic or mineral.   2. New 2-aminomethyl-6-halogenophenols, characterized in that they correspond to the formula Ia R '(CH 2) n -RI 3 (Ia) R 1 X | C-4H2 R2 OH 2   wherein X is bromine and in this case n is 1 or 2, R and R 2 are each hydrogen or   methyl group or one of the symbols R1 and R2 signifies   hydrogen and the other a methyl group, and the symbols R3 'each signify a hydrogen atom or a methyl group, or X signifies an iodine atom and, in this case, n means 1 and R1 and R are each an atom of hydrogen and the symbols R1 2-   each means a metiyl group, or R and R2   each has a methyl group or one of the symbols R1 and R2 represents a hydrogen atom and the other a methyl group and the two symbols R1 each signify a hydrogen atom or a methyl group, ie n means 2 and 1 R 1 and R 2 are hydrogen and the other is a nithyl groove, or R 1 and R 2 are each methyl and R 'are each hydrogen or methyl, and the salts are these compounds form with acids organic or mineral.   3. New 2-aminomethyl-6-halogenophenols, characterized in that they correspond to the formula Ib R '(Ci) R'3 (Ib) X C -NIl2 I- R ' O01 2 in which   the symbols R and R2 each signify a hydrogen atom   gene or one of the symbols R1 and R represents a hydrogen atom and the other a methyl group, the R 'symbols each represent a hydrogen atom or a methyl group, X and n have the meanings given to the claim 1, and the salts which these compounds form with acids organic or mineral.   4. New 2-aminomethyl-6-halogenophenols, characterized in that they correspond to the formula Ic CH3 CH (Ic) R'1 HN-C X R ' 2 OH in which   the symbols R 'and RI each signify a hydrogen atom   gene or one of the symbols R1 and R2 represents a hydrogen atom and the other a methyl group, and X represents a bromine and iodine atom, and the salts that these compounds form with acids organic or mineral.   5. The 2-aminomethyl-6-halogenophenols of formula I according to claim 1, characterized in that A signifies a residue / R1 - C - NH2 1 21   R2 B represents X and R1, R2, R3, X and n have the meanings data in claim 1.   6. The 2-aminomethyl-6-halogenophenols of formula I according to claim 1, characterized in that A, B, R3 and n have the meanings given in claim 1 and R1 and R2 each represent a methyl group, one of the symbols R1   and R2 is hydrogen and the other is methyl.   7. New 2-aminomethyl-6-halo-phenols,   characterized in that they are selected from 6-amino   methyl-4-bromo-1,1-dimethylindan-5-ol, 6- (1-aminoethyl) -   4-bromoindan-5-ol, 6- (1-aminoethyl) -4-iodoindan-5-ol,   6- (1-amino-1-methylethyl) -4-bromo-1,1-dimethylindane;   -ol, 6- (1-aminoethyl) -4-iodo-1,1-dimethyl-indan-5-ol,   6-aminomethyl-4-iodo-1,1-dimethyl-indan-5-ol, 4-   amino-6-bromo-1,1-dimethylindan-5-ol and 6- (1-amino)   1-methyl-ethyl) -4-iodo-1,1-dimethylindan-5-ol, and the salts that these compounds form with acids organic or mineral.   8. 6- (1-aminoethyl) -4-bromo-1,1-dimethyl-   indane-5-ol, and the salts that this compound forms with organic or mineral acids.   9. 4-Aminomethyl-6-bromo-1,1-dimethylindan   -ol and the salts that this compound forms with acids organic or mineral.   10. A process for the preparation of 2-aminomethyl   6-halogenophenols of formula I specified in claim   cation 1 and in which B means a remainder R1 - C-NH2   R2 and A represents X, and salts thereof, characterized in that a compound of formula II R3 (CH2) n 3 (II) R 1 is brominated or iodinated; C 'NH2 R2   In which n, R 1, R 2 and R 3 have the meanings given in claim 1, and, if appropriate, converting the compounds of formula I thus obtained, where B denotes a radical R 1 - C-NH   -R2 and A represents X, in their salts by reaction with organic or mineral acids.   11. A process for the preparation of 2-amino   methyl-6-halogenophenols of formula I specified in claim 1 and wherein B is X, A represents a remainder -   R1 -C-NH R2 and R and R2 each represent a hydrogen atom, and their salts, characterized in that a compound of formula III R3 R3 (Cl2) n <Acyl-NH is hydrolyzed CH2 X (III) -25 OH   in which R 3, X and n have the meanings given in claim 1, and, if appropriate, converting the compounds of formula I thus obtained where A means a residue R   B 2 R 2 represents X and R 1 and R 2 each signify a hydrogen atom, in their salts by reaction with organic or mineral acids.   12. A process for the preparation of 2-amino   methyl-6-halogenophenols of formula I specified in claim 1 and wherein B is X, A is a residue - 5 iR - C - NH2 R2   and one of the symbols R1 or R2 represents an atom   hydrogen and the other a methyl group, and their salts, characterized in that a compound of formula IV R3 is reduced (CH2) R (IV) CH3 C X IIX NH   In which R 3, X and n have the meanings given in claim 1, and, if appropriate, converting the compounds of formula I thus obtained or B means X, A represents a residue R - C - NH R2   and one of R or R2 represents a hydrogen atom   gene and the other a methyl group, in their salts by reaction with inorganic or organic acids.   13 ..- A process for the preparation of 2-aminomethyl   6-halogenophenols of formula I specified in the claim   1 and where B is X, A is a radical R - C - NH2   R 2 and R 1 and R 2 each signify a methyl group and their salts, characterized in that a compound of formula V R 3 is catalytically hydrogenated; (CH2) R R3- 'CH3 N3-% C X   Wherein R3, n and X have the meanings given in claim 1, and or reintroduced by bromination or iodination the substituent X if the latter has been removed during the hydrogenation, and, if appropriate, the compounds are converted of formula I thus obtained where B is X, A represents a radical R - C - NH2   R2 and R1 and R2 each signify a methyl group, in their salts by reaction with organic acids or minerals.   14.- The therapeutic application of 2-amino-   methyl-6-halogenophenols specified in any one of   Claims 1 to 9 as Active Ingredients of drugs.   15.- A drug, characterized in that   contains, as active principle, a 2-aminomethyl-   6-halogenophenol corresponding to formula I R3 (Ci2) n I3 (R3 A B   OH in which one of the symbols A or B means X and the other represents a remainder R1 -C-NH2   R2 X represents a bromine atom and in this case n means 1 or 2, and R2 each represents a hydrogen atom or a   methyl group or one of the symbols R1 and R2 signifies   hydrogen and the other a methyl group, and the two symbols R3 each signify a hydrogen atom or a linear alkyl group containing from 1 to 4 carbon atoms, or X signifies an iodine atom and, in this case, n is 1, and R1 and R2 are a hydrogen atom and the M-positions each signify an alkyl group containing from 1 to 4 carbon atoms, or R 1 and R 2 each represent a methyl or l-group. one of the symbols R1 and R2 represents a hydrogen atom and the other a methyl group and the   two R3 symbols each signify a hydrogen atom   gene or an alkyl group containing 1 to 4 carbon atoms, n is 2 and one of R 1 and R 2 is hydrogen and the other is methyl or R 1 and R 2 are methyl and the symbols R3 each signify a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, in the free state or in the form of an acceptable salt of pharmaceutical point of view.   16.- A drug, characterized in that   contains, as active ingredient, a 2-aminomethyl-6-   Halo-phenol O10 as specified in any of the   Claims 2 to 7, in the free state or in the form   a pharmaceutically acceptable salt.   17.- A drug, characterized in that   contains, as active principle, 6- (1-aminoethyl) -4-   bromo-1,1-dimethyl-indan-5-ol, in the free state or in the   form of a pharmaceutically acceptable salt.   18.- A drug, characterized in that   contains, as active substance, 4-aminomethyl-6-   bromo-1,1-dimethylindan-5-ol, in the free state or in the   the form of a pharmaceutically acceptable salt.   19.- A pharmaceutical composition, characterized   in so far as it contains at least one of the   assets specified in any of claims 15   at 1l, in combination with excipients and vehicles   acceptable from the pharmaceutical point of view.   20. New bicyclic compounds, characterized in that they correspond to the formula XIII R3 (CH2) n R3 (XIII)   Wherein n is 1 or 2, and R 3 are each hydrogen or linear alkyl containing 1 to 4 carbon atoms. 21. New bicyclic compounds, characterized in that they correspond to the formula IX R "3 3 (IX) OH   in which the symbols R "each represent a methyl or ethyl group.   22.- New bicyclic compounds, characterized in that they correspond to formula VI R3 (C R   C2) n 3 (VI) 13C OT 0I wherein X is bromine or iodine, n is 1 or 2, and R3 is a hydrogen atom or a linear alkyl group containing from 1 to 4 carbon atoms.   23.- New bicyclic compounds, characterized in that they correspond to formula VIII R3 (VIII)   X wherein OH X is bromine or iodine, and R3 are each hydrogen or linear alkyl containing from 1 to 4 atoms of carbon.