FR2528832A1 - NOVEL BENZENE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

THE OBJECT OF THE INVENTION IS THE 1-AMINO-4-OXY-3-MERCAPTO-ALKYL (LINEAR CHAIN) BENZENES, AS WELL AS THEIR S-ACYL DERIVATIVES AND THEIR S-S DIMERS AND THEIR ACID ADDITION SALTS. THE SAID COMPOUNDS HAVE A PHARMACEUTICAL ACTION, AND IN PARTICULAR ANALGESIC ACTION.

Description

The present invention relates to 1,3,4-trisubstituted benzenes and

  their derivatives, their preparation and their use in therapeutics,

  as active ingredients of drugs.

  The invention relates to 1-amino-4-oxy-3-mercaptoalkyl- (linear chain) benzenes, their S-acyl derivatives, their S-S dimers, and salts thereof.

  acid addition of these compounds.

  In the compounds of the invention, the group

  amino may be unsubstituted or mono or di-substituted.

  Preferred substituents are alkyl and acyl as

the remainder of a carboxylic acid.

  The straight chain alkyl radical can contain up to 5 carbon atoms; preferably,

  it contains 2 or 3 carbon atoms and more preferably

  it contains 3 carbon atoms.

  The preferred compounds of the invention are those of formula I N f R

A S R 3

  OR 2 in which R, R 'and R 2 each independently of one another is hydrogen or a C 1 -C 6 alkyl group, R' may also mean a group -COR 1 o R means hydrogen or a C 1 -C 6 alkyl group, A denotes a straight-chain alkylene radical containing up to 5 carbon atoms, and R 3 is hydrogen, an acyl group or a group of formula (a) R '(a) -SA OR 2 in which R, R ', R 2 and A are as defined above and are identical to or different from R, R', R 2 and A as defined for formula I, and their esters,

  and the acid addition salts of these compounds.

  When R 3 is acyl, it is preferably an acyl radical containing up to 8 atoms

  of carbon and derived from a carboxylic acid.

  The compounds of the invention, for example the compounds of formula I and their esters, having in position 1 a nonacylated amino group form salts

of acid addition.

  Exemplary esters of the compounds of formula I, that is compounds of formula I where R 2 is acyl, include physiologically hydrolysable and physiologically acceptable esters, i.e., esters which are hydrolyzable under physiological conditions to give the corresponding 4-hydroxy analog and an acid which is itself physiologically acceptable, i.e. nontoxic

at the doses administered.

  Preferred esters are, for example, esters with carboxylic acids containing up to 8 carbon atoms. The preferred compounds of formula I are those of ethylene or propylene, preferably propylene, and / or R is hydrogen, and / or R 'is -COR 1, and / or R 2 is hydrogen or a C 1 -C 6 alkyl group, and / or

  R 3 means hydrogen or a group R 4 CO-o R 4 represents

  hydrogen or a C 1 -C 6 alkyl group.

  The preferred compounds of the invention are those corresponding to formula IA

NH-CO-R 1

CH 2 -CH 2 -CH 2 S R (IA)

R 20

CH 2 'CH 2' CH 2 'S R 3

  R.2 wherein R 1 is hydrogen or C 1 -C 6 alkyl, R 2 is hydrogen or C 1 -C 6 alkyl, and R 3 is hydrogen or R 4 CO-o R 4 means

hydrogen or C 1 -C 6 alkyl.

  The present invention also relates to a

  process for the preparation of 1-amino-4-oxy-3-mercapto

  alkyl (linear chain) benzenes, their S-acyl derivatives, their SS dimers, and the acid addition salts thereof, wherein (a) hydrolyzing 1-amino-4-oxybenzene (other than a 1-amino-4acyloxybenzene) substituted at the 3-position of the benzene ring by a linear-chain RS-thioalkyl group R 5 corresponds to formula b)

-C Z

  Where X is = S and Z is -OR 5 where R 5 is C 1 -C 4 alkyl, or X is = NH and Z is -NH 2, to prepare a l-amino-4-oxy-3-mercaptoalkyl- (to

  linear chain) benzene (other than 1-amino-4-

  acyloxy-3-mercaptoalkyl (linear chain) benzene),

and or-

  b) a free hydroxy group and / or a group are acylated

  free mercapto in 1-amino-4-oxy-3-mercaptoalkyl

  (linear chain) benzene or its S-acyl derivative or its S-S dimer, to prepare an S-acyl derivative

  1-amino-4-oxy-3-mercaptoalkyl (linear chain) -

benzene, or

  1-amino-4-acyloxy-3-mercaptoalkyl (chain link)

  benzene or its S-acyl derivative or its SS dimer, and / or c) a benzylated 1-amino-4-oxy-3-mercaptoalkyl (linear chain) is subjected to SS dimerization, to obtain the corresponding SS dimer ,

  d) and then, if desired, transform a

  of the invention thus obtained into another compound

  of the invention, for example according to the further steps

  d 1 to d 6 below, and recovering the compound thus obtained in the form of

  free base or as an acid addition salt.

  In a more specific embodiment, the present invention relates to a process for the preparation of compounds of formula I and their esters, and their acid addition salts, wherein (a) a compound of formula II / R is hydrolyzed;

X A-S-C-Z ()

  Wherein R, R ', R 2 and A are as defined for Formula I, and

  X and Z are as defined for formula (b) below.

  above, and / or b) a compound of formula I in which R 2 and / or R 3 'is hydrogen is used to give an ester of this compound or a compound of formula I wherein R 3 is an acyl group as defined for formula I, and / or c) a compound of formula I wherein R 3 is hydrogen is subjected to SS dimerization to prepare a compound of formula I wherein R 3 is a group of formula ( a) as defined above, and recovering the compounds of formula I thus obtained,

  as a free base or as an additive salt

acid.

  In the compounds of formula II, X is preferably = S and Z is -OR 5 More preferably, in compounds of formula II R 2 means

  a C 1 -C 6 alkyl group.

  the process involving compounds of formula II having the meanings of formula IA for R and A, especially those where R 'means

-COR 1.

  The process a) can be carried out according to known methods, for example by alkaline hydrolysis using amoniac in an aqueous alkanolic medium

  or sodium hydroxide in aqueous or alkaline

  The alkanol is preferably ethanol

  reaction is carried out appropriately at a temperature

  gap between about room temperature

and the reflux temperature.

  Process b) can be used for acylating

  lation of the mercapto residue of the 3-mercaptoalkyl groups

  and / or for the acylation of 4-hydroxy groups, that is,

  say to get the corresponding esters acylate

  The reaction may be carried out by conventional methods, for example by reaction with the appropriate acid or a reactive derivative thereof, in the presence of an inert diluent or solvent and at room temperature or at a slightly higher temperature. The mercapto group are both present in the starting material and may, if desired, be selectively acylated by selecting appropriate reaction conditions or by temporary use of a suitable protecting group.

  on the oxygen or nitrogen atom that is eliminated

after acylation.

  Process c) can be carried out according to known methods, for example by oxidation, suitably by exposing the product to the action of atmospheric oxygen in a slightly alkaline medium,

  at room temperature or at a light temperature-

higher level.

  Unless the reaction is carried out

  under an inert atmosphere, it can occur spontaneously

  Some degree of oxidation is achieved by the process a), S-S dimer being produced in small amounts as a by-product by

  example as described in the examples below.

  The starting materials of formula II are themselves new and are also part of the present invention. A particular group of starting materials are the compounds of formula IIA

NH.CO R 1

O 2 H-CH 2 -CH 2 -S-C-OR 5 (LIA)

  Wherein R represents a C 1 -C 6 alkyl group, preferably

the ethyl group.

  The preparation of the starting materials of formula II can, for example, be carried out according to the following reaction schemes in which: compound VII can be prepared, for example, according to the method described in Ind J Chem 3, 74 (1965); and the compound IX 'can be prepared according to the method

  described in J Amer Chem Soc 80, 3271 (1958).

1 2 (53

- A-OH

  HO (Vil) 2 na 252 04 N, O-diacylation

A-0-COX 1

LA-OH (VA)

  lXi 1 R 1 or alkoxy) (VI) 0-deacylation selective

NH-COX 1

  or from the compound (VIII ') in the scheme HO etherification t NHCOX 1

2 N NA-OH

R O 9

$ RCSOR,

  lR 6 = For example methyl-, tolyl; 1R 1 = halogen, for example NH-COX 1 Cl, B xs -cRRiRiRR R 'OR P see diagram 3

O R 5

  ## STR2 ## Example of preparation of starting materials of formula II where X is es and Z is -OR 5 SCHEM 1A i (IV) 1R = alkyl) EX 1 = R 1 or alkoxyl or coiipose IV

the scheme i-

  for example with o 3 / N Ia SH 4 (A = (CH 2) 2)) or with the formula lix ') lR' R '2 ri

BH 3 CH 35 CH 3

  NHCOX I I (VI II I ') optionally chain extension V eg ICN -> COOH -> CH 2 (OH-> CH 2 R 7 l

-NHC O X

A R 7 (VIII)

  halogen by 0 example II see diagram 3

= I NH 2

= c -

NH I 2

A S C NH-2

  EXAMPLE 1 Preparation of starting materials of formula II in which X = NH and Z = -NH 2 SC HI E MA 2 = alkyll R 12 i.e. compounds VIII or II II or KS -C-OR 5 (Scinema 1) C z M x te reactions - up) plemen tary

A S C Z

RI ', to

  Example of reaction sequence at (C) I

eg when X = alkoxy, spe-

cialenient tert-butoxy, N-hydro-

  lysis. Possibly N-alkylation and / or N-acylation and / or cleavage of the

ether bond in position 4.

  (He) the penultimate step of diagrams 1

S CH E MA 3

(AT)

S = C-, H

  <scheme 2) N Hf COX 1 and 2 1 l It should be noted that it is not necessary, as is frequent in chemistry, to isolate each intermediate product or starting product and it is equally possible to subject In this case, for example, the starting materials of formula II "(Scheme 2) can be hydrolyzed in situ to the corresponding compound of formula I. It will be readily understood that in the reaction schemes above, the preparation of the compounds

  of formula I has been indicated for reasons of simplicity

  cited but that other l-amino-4-oxy-3-mercaptoalkyl-

  (straight chain) benzenes of the invention can be prepared analogously In addition, it has been found

  that the corresponding S-S dimers of the invention can

  can be obtained as by-products of the above reactions, since the monomer can oxidize

  in dimer under the usual reaction conditions.

  On the other hand, the preparation of the compounds of the invention may comprise one or more of the following steps d1 to d below, in which a compound of the invention is converted into another desired compound of the invention, according to the

  conventional methods known in the field of chemistry.

  The following subsequent steps, as before, relate for simplicity to the compounds of formula I, but it goes without saying that other compounds of the invention may be

prepared in a similar manner.

  Therefore, the method of the invention may also include:

  d) deacylation of a compound of formula I in

  which R 'means -COR 1 and / or R 3 means R 4 CO-

  as defined in relation to formula 1, for preparing a compound of formula I wherein R and / or R 3 are hydrogen, and / or d) splitting the ether linkage in a compound of formula I wherein R 2 has a meaning other than hydrogen, for preparing a compound of formula 1 in which R 2 is hydrogen, and / or 3) splitting of the SS group, for example in a

  compound of formula I, or its ester, in the

  which R 3 denotes a group of formula (a) as defined above, for preparing a compound of formula I, or its ester, in which R 3 is hydrogen, and / or d) reduction, for example a compound of formula I wherein R 'is RICO, for preparing a compound of formula I wherein R' is a CC 6 alkyl group, and / or d) N-alkylation or N-acylation, e.g. a compound of formula I, or its ester, wherein R and / or R 'signify hydrogen, to prepare a compound of formula I, or its ester, wherein R and / or R signify a group

  C 1 -C 6 alkyl or wherein R 'means -COR 1.

  All the above processes can be carried out according to conventional methods in the field of chemistry, for example as described in

the examples below.

  The following examples illustrate this

  invention without in any way limiting its scope.

  All temperatures are given in degrees Celsius.

  Preparation of starting materials

Example A

  N-1 4-Ethoxy-3- (3-ethoxythiocarbonylthiopropyl) phenyl

  acetamide (Reaction Scheme 1) a) To a solution of 64.7 g of sulphanilic acid and 19.8 g of sodium carbonate in 400 ml of water is added between 0 and 10 a solution of 27, 9 g

  of sodium nitrite in 150 ml of water while stirring

  The yellow reaction solution is poured into a mixture of 78.2 ml of 37% hydrochloric acid and 500 g of ice and stirred for a further 10 minutes. The orange solution of the diazonium salt is added dropwise. while cooling between and with ice, to a cooled solution

  beforehand and consisting of 56.9 g of 3- (2-hydroxy-

  phenyl) -1-propanol and 82.3 g of sodium hydroxide

  in 700 ml of water After shaking for 15 hours

  at room temperature, 232 g of hydrosulfite

  of sodium are added in portions to 70

  red mixture and the mixture is stirred for 15 hours at room temperature.

  3- (5-amino-2-hydroxyphenyl) -1-propanol, which

  precipitated and dried (F = 116-118 after

  in a mixture of methanol and ether) 3- (5-Amino-2-hydroxyphenyl) -1-propane is dissolved in 6 times its amount of a mixture in equal parts

  acetic anhydride and pyridine and stirred

  15 minutes, giving the N-1 3- (3-acetoxypropyl)

  pyl) -4-hydroxyphenylacetamide in the crude state This product is dissolved in methanol and is treated for 2 hours at room temperature with

  excess of aqueous sodium hydroxide 2 N After acid

  at pH 4 with 2N hydrochloric acid, N-1 4-hydroxy-3- (3-hydroxypropyl) phenylacetamide

  precipitate; it melts at 156-158 after crystallization

in water.

  (b) With stirring, a mixture of 31.9 g of Nl 4-hydroxy-3- (3-hydroxypropyl) phenylacetamide, 74.0 g of potassium carbonate and 43, was heated under reflux for 48 hours. 0 ml of ethyl iodide in 10 ml of acetone After separating the inorganic products by filtration, the filtrate is concentrated by evaporation, which

  gives N-1 4-ethoxy-3- (3-hydroxypropyl) phenyl-

  acetamide; it melts at 94-96 after crystallization

in ethyl acetate.

  c) The alkoxylated compound described above is reacted between -10 and 0 with a 1: 1 mixture of methanesulfonyl chloride and triethylamine (50% excess) in methylene chloride;

  which gives N-1 4-ethoxy-3- (3-methylsulphonyloxy)

  propyl) phényllacétamide; it melts at 13-115 after

  crystallisation in a mixture of ethyl acetate

and hexane.

  d) The mesylate is converted to N-1,4-ethoxy-

  3- (3-ethoxythiocarbonylthiopropyl) phenylacetamide (F = 78-80 after crystallization from a mixture

  toluene and hexane) by reaction for 3 hours.

  to 50 with potassium xanthate (excess of

%) in methanol.

Example B

  N-1 3- (3-ethoxythiocarbonylthiopropyl) -4-methoxyphenyl

  acetamide (scheme 1) a) and b) in a manner analogous to that described in Example A) and using the iodide of

  methyl, N-1 3- (3-hydroxypropyl) is obtained

  4-méthoxyphényllacétamide; F = 84-86 after

  crystallization in ethyl acetate.

  (c) Similarly, N-1 4- is prepared

  methoxy-3- (3-methylsulfonyloxypropyl) phenyl

  acetamide; Mp 94-96 after crystallization from

mixture of acetone and ether.

  (d) The title compound is prepared in such a way

  analogous and is obtained in the form of an oil

  The other starting materials are prepa-

  res in a manner similar to that described in the examples

A) and B).

Example C

  Preparation of the starting material for Example 2 (Scheme 2)

  a) To a solution of 390 g of N-1 4-ethoxy-

  3- (prop-2-enyl) phenyl-acetamide in 2500 ml of tetrahydrofuran, 5 ml of a borane-dimethylsulfoxide complex are added dropwise, with stirring and under a nitrogen atmosphere, and the mixture is stirred for a period of one hour. hour after

  have added 451 g of iodine, add drop by drop

  a freshly prepared solution of sodium methoxide (from 40.4 g of sodium and 700 ml of methanol) and stirring is continued for 24 hours.

  hours at room temperature Then treat

  the gray reaction mixture with a solution of sodium thiosulphate (about 1 liter) and

  the extract with ethyl acetate

  poration gives Nl-1,4-ethoxy-3- (3-iodopropyl) -

  crude phenyllacetamide in the form of a brown oil

  red, which can be used directly for

next reaction.

  (b) A refluxing period of 17 hours is

  solution of 549 g of N-1,4-ethoxy-3- (3-iodopropyl) -

  phenyllacetamide and 120 g of thiourea in 1500 ml of 95% ethanol.

  form of a red solution, the compound of formula

  II "of Scheme 2 (R = H, R '= COCH 3, R 5 = C 2 H 5, A = (CH 2) 3) The product is not isolated but is

  used directly in the process of Example 2.

Examples D to J

  Preparation of starting materials for Examples 3 to 6 (Schemes 1 and / or 2) In a manner analogous to that described in Examples A and C, the starting materials can be prepared.

  of formula II described in the following table.

BOARD

Ex R 'R R A X Z

D COCH 3 H CH 3 (CH 2) 3 NH NH 2

  E CO (t-C 4 Hg) H C 2115 (CH 2) 3 S OC 2 H 5 CO (t-C 4 H 9) H C 2 H 5 (CH 2) 3 NH NH 2

  G COCH 3 H C 2 H 5 (CH 2) 2 S OC 2 H 5

  H COCH 3 HC 2 H 5 (CH 2) 2 N H 2 NH 2 I 25i CO (nC 3 H 7) HC 2 H 5 (CH 2) 3 S OC 2 H 5 CO (nC 3 H 7) HC 2 H 5 (CH 2) 3 N Hil NH 2

Example 1

  N-1 4-ethoxy-3- (3-mercaptopropyl) phenylacetamide and its dimer SSlprocedure a)

  The mixture is stirred for 15 hours at room temperature.

  27 g of N-1 4-ethoxy-3- (3-ethoxythiocarbonyl)

  thiopropyl) phenyllacetamide (prepared, for example, according to Example A) and 90 ml of aqueous ammonia in 300 g of ethanol, while

  through the solution a current of CO After evapo-

  ration, the title compound is obtained; it melts at 70-

  720 and its dimer melts at 112-114 (after crystallization

  in a mixture of ether and hexane).

Example 2

  Nl 4-ethoxy-3 - (- 3-rercaptopropyl) phenyllacetamide and its SS dimer The procedure a) The red solution obtained under b) is treated in Example C with 10% sodium hydroxide and maintained at room temperature. The mixture is then refluxed for 2 hours. The mixture is then cooled and extracted with ethyl acetate. The organic phase is washed once with dilute sulfuric acid and once with a sodium chloride solution. and evaporated. The title compound is thus obtained in the form of a resin.

  The product is purified in 5 portions by chromato-

  The title compound, its dimer and a mixed fraction are thus obtained on column with ethyl acetate. The title compound is recrystallized from a mixture of ethyl acetate and hexane, which gives

  slightly impure white crystals After recreating

  additional tallification, it melts at 85-87.

  Examples 3 to 6 Procedure (a) In a similar manner to that described in Examples 1 and 2, according to Schemes 1 and 2 above, the following compounds of formula I are obtained. (See table on next page)

BOARD

* Ex point R 'R? A _ fusion

3 COCH 3 H CH 3 (CH 2) 3 H 78-81 '

  4 CO (t-C 4 H 9) H C 2 H 5 (Cl 2) 3H 117-118 '

COCH 3H C 2H 5 (CH 2) 2H 124-125 '

  This compound can be used in the process of Example 19 without prior isolation and purification.

Example 7

  N-1-3- (3-acetylthiopropyl) -4-ethoxyphenylacetamide

  It is stirred for one hour at room temperature.

  ambient temperature a mixture of 4.1% N-1,4-ethoxy-

  3- (3-mercaptopropyl) phenylacetamide (prepared in Example 1), 30 ml of pyridine and 30 ml

  of acetic anhydride After evaporation,

  holds the title compound; it melts at 72-74 after

  crystallisation in a mixture of ethyl acetate

and hexane.

  B To a solution of 50 g of N-1 4-ethoxy-

  3- (3-mercaptopropyl) phenyllacetamide (prepared in Example 2) in 500 ml of pyridine, 500 ml of acetic anhydride are added. After stirring overnight, the mixture is evaporated in a rotary evaporator to give the mixture. composed of slightly impure title The product is purified by

  column chromatography with acetate acetate

  thyle, which gives the title compound, a fraction

combination and a by-product.

  The by-product is identical to the product

  Starting from Example C, namely N-1 4-ethoxy-3-

  (prop-2-enyl) phenyllacetamide, which by extraction can be used in the crude state for subsequent reactions, for example as described in Example C. The title compound recrystallized from a

  mixture of ether and hexane melts at 62-64

  slow solution in a mixture of ethyl acetate and

  hexane gives the title compound which melts at 72-

O 74 as in A above.

  EXAMPLES 8 TO 14 PROCEDURE B) In a manner analogous to that described in Example 7 A or 7B, or using the appropriate acyl chloride in place of the acid anhydride, the compounds of wherein the substituents are those of the starting material, with the exception of R 3 which has the meaning indicated in

following table.

  Example Ex of Preparation Point of No of the starting material R 3 fusion

8 3 COCH 3 68-69

  9 1,2 CO (i-C 3 H 7) 82-83 '1,2 CO (t-C 4 H 9) 106-107

11 1.2 COC 6 H 5 96-98 '

12 1.2 CSOC 2 '5 78-80'

13 1,2 C O O foam N i F

14 6 COCH 3 56-53

Example 15

  N-1 4-hydroxy-3- (3-mercaptopropyl) phenylacetamide (method d 2)

  To a solution of 6.0 g of N-1 4-methoxy-

  3- (3-mercaptopropyl) phenylacetamide (prepared in the example

  3) in 250 ml of methylene chloride, 7.56 ml of boron tribromide is added. The mixture is warmed to room temperature, stirred overnight, evaporated, added to 120 ml of boron tribromide. ml of ethanol and heated at reflux for 2 hours.

  ethanol, the resulting oil is taken up in acetone.

  ethyl acetate and washed with a bicarbonate solution

  sodium nate After evaporation of the organic phase,

  the product is isolated by gel chromatography

  and recrystallized from a mixture of ethyl acetate

and ether It melts at 74-77.

Example 16

  N-1 4-ethoxy-3- (3-mercaptopropyl) phenylamine (method dl

  70% of N-1,4-ethoxy-3- (3-mercapto)

  propyl) phenyllacetamide (prepared, for example, according to the

  1) in 350 ml of ethanol and 350 ml of hydrochloric acid.

  concentrated and refluxed for 3 hours.

  The solvent is evaporated and the title compound can be

  crystallized as hydrochloride in a mixture

  ethanol and ether; M = 137-139 o.

Example 17

  S-S dimer of N-1 4-ethoxy-3- (3-mercaptopropyl) phenyl

aminelprocedure c) l

  60 g of N-1,4-ethoxy-3- (3-mercapto)

  propyl) phenyllamine (prepared for example from the salt of Example 16) in 500 ml of methanol, 300 ml of 2 N sodium hydroxide are added and the mixture is stirred for 48 hours at room temperature in a flask of which

  the neck is kept open After addition of water, it is

  The mixture is washed three times with ethyl acetate. The organic phase is evaporated and the product is purified by chromatography on silica gel. The title compound is thus obtained in the form of a brown oil. Examples 18 to 20 Procedure c) The following dimers of formula I can also be prepared by a method analogous to that described in Example 17 or as by-products of the processes described in Examples 1 and 2 In the following table, R 3 means a group of formula (a) as defined above and R, R ', R 2 and A have the meanings

given in the following table.

BOARD

  Ex. Melting Point Ex R R '_ _ A

  18 H COCH 3 C 2 H 5 (CH 2) 3 112-114

  19 H CO (n-C 3 H) C 2 H 5 (CH 2) 3 96-98 H CO (t-C 4 H 9) C 2 H 5 (CH 2) 3 136-137 Example 21

  S-S dimer of N-1 4-ethoxy-3- (3-mercaptopropyl) phenyl

  pivalamide method (5) To a solution of 2.5 g of S-S dimer of N-1,4-ethoxy-3- (3-mercaptopropyl) phenylamine (prepared in Example 17) in a mixture of 60 ml of choroform and

  of 10 ml of pyridine, 6.1 ml of

  in 10 ml of chloroform. The mixture is stirred

  in 3 hours at room temperature, evaporated, the evaporation residue is taken up in 1N hydrochloric acid and extracted three times with methylene chloride. After evaporation of the organic phase, the residue is recrystallized. title compound in a mixture of ether and hexane; F = 136-

  The product is the same as that of Example 20.

  Examples 22 to 26 Procedure 5 (5) In a manner analogous to that described in Example 21, the following compounds can be prepared in which the substituents are those of the starting material, with the exception of R 'which has the meaning

given in the following table. Example of Preparation of Example Pro R 'prepared for melting

  Starting No. Example 22 17 COCH 3 Ex 1,2 (dimer) 112-114 '23 17 CO (n-C 3 H 7) Ex 19 (dimer) 96-96'

  24 16 CO (t-C 4 hg) Example 4 117-118-

  COCH 3 Example 1 70-72 '26 16 CO (n-C 3 H 17) Example 6 Oil This compound can be used in the process of Example 19 without prior isolation and purification.

Example 27

  Preparation of N-1 4-ethoxy-3- (3-mercaptopropyl) phenyl

  pivalamide from its dimer method d) 1) 2.25 g of the SS dimer prepared in Example 21 are dissolved in 200 ml of liquid ammonia and 130 ml of tetrahydrofuran. A piece of sodium is immersed in the mixture. until it develops a blue color and then we add

  3 g of ammonium chloride and the solvents are evaporated.

  The reaction mixture is taken up in water and extracted with methylene chloride. After evaporation of the organic phase, the compound is isolated

  by chromatography on silica gel; F = 116-

117.

  Examples 28 to 29 (Method d 3) In a manner analogous to that described in Example 27, the following compounds can also be prepared. Example Starting product Compound of title No No of the example as for

example

28 22 1.2

29 23 6

Example 30

  Nl 4-ethoxy-3- (3-mercaptopropyl) phenyllethylamine Method d) To a suspension of 4.5 g of lithium aluminum hydride in 200 ml of tetrahydrofuran is added to -5 a solution of 3.08 1 ml of 100% sulfuric acid in 30 ml of tetrahydrofuran is stirred for 5 minutes. A solution of N-4-ethoxy-3- (3-mercaptopropyl) phenylacetamide is added to 0.

  (Examples 1, 2, 25, or 28) in 200 ml of tetrahydrofuran.

  Allowed to react for 2 hours at room temperature, the mixture is poured on water

  iced and extracted with methylene chloride.

  After evaporation of the organic phase, the resulting oil is chromatographed on silica gel with a mixture of hexane and ethyl acetate (3: 1) as eluent. The product can be isolated as 1.5-naphthalene. -disulfonate and recrystallize it from a mixture of methanol and ether;

F = 145-149

  The 1-amino-4-oxy-3-mercapto-alkyl (linear chain) benzenes, their S-acyl derivatives and their SS dimers according to the invention, in particular the compounds of formula I and their esters, and their salts addition of pharmaceutically acceptable acids, are distinguished by interesting pharmacological properties and can therefore be used therapeutically as medicaments. In particular, they exert an analgesic action, as can be seen from, for example, A) pain testing. arthritis in rats based on the method of AW Pircio et al., described in Eur J Pharmacol, 31, 207-215 (1975) after oral administration at doses of between 5 and 200 mg / kg and B ) of Randall-Selitto's test on the hind paw

  rat inflammation, described in Arch Int Pharmacodyn.

  61, 409-419 (1957), after oral administration

  at doses between 40 and 200 mg / kg.

  The compounds of the invention can

  therefore be used therapeutically as analgesic agents

  eg for the treatment of pain For this indication, they will be administered at a daily dose

  from about 50 to 300 mg, preferably administered

  The appropriate unit doses, for example for oral administration, contain from about 12 to about 1 mg of active substance in the form of a controlled dose of 2 to 4 times daily or in a delayed-release form. free base or in the form of a pharmaceutically acceptable acid addition salt, in combination with a diluent or vehicle

pharmaceutically acceptable.

  The compounds of the invention also possess antipyretic properties as is apparent from, for example, the Takesue et al. Test described in US Pat.

  Arch Intern Pharmacodyn 221, 122-131, (1976).

  The invention thus relates to 1-amino

  4-oxy-3-mercapto-alkyl (linear chain) benzenes, their Sacyl derivatives and their S-S dimers, in particular the compounds of formula I and their esters, for use

  as drugs, especially as analgesic agents.

  The invention also relates to a medicament containing, as the active ingredient, a 1-amino-4-oxy-3-mercapto alkyl (linear chain) benzene, or its S-acyl derivative or its SS dimer, in particular a compound of formula I or its ester, in free base form or in the form of a

  acid addition salt acceptable from the pharmaceutical point of view

  ceutical. As drugs, the compounds of

  the invention may be used in the form of

  pharmaceutical compositions containing a compound of the invention

  in free form or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent

  such pharmaceutical compositions, which also

  part of the present invention, can be

  prepared according to the usual methods and

  for example in the form of solutions, capsules

or tablets.

Claims (1)

  l) 1-amino-4-oxy-3-mercapto-alkyl (linear chain) benzenes, their S-acyl derivatives and their S-S dimers.   2) A compound according to claim 1, characterized in that it corresponds to the formula I y R N-R, I A A-S R 3   Wherein R, R 'and R 2 each independently of one another is hydrogen or C 1 -C 6 alkyl, R' may also be -COR 1 o R 1 means hydrogen or a C 1 -C 6 alkyl group, A denotes a straight-chain alkylene radical containing up to 5 carbon atoms, and R 3 signifies hydrogen, an acyl group or a group of formula (a) R IR SA OR (a   wherein R, R ', R 2 and A are as defined above.   above and are identical or different from R, R ', R 2 and A as defined for formula I, and the esters of these compounds. 3) A compound according to claim 2, characterized in that it corresponds to formula IA NH CO-R 1 CH 2 CH 2 -CH 2 -SR 3   R 20 (IA) wherein R 1 is hydrogen or C 1 -C 6 alkyl, R 2 is hydrogen or C 1 -C 6 alkyl, and R 3 is hydrogen or a group R 4 CO-o R 4   means hydrogen or a C1-C6 alkyl group.   4) A compound according to claim 3, characterized in that R 1 is CH 3, R 2 is C 2 H 5 and R 3 is CH 3 CO.   A compound according to claim 3, wherein R 1 is CH 3, R 2 is C 2 H 5 and R 3 is H, or R 1 is CH 3, R 2 is CH 3 and R 3 is H or   R 1 is CH 3, R 2 is CH 3 and R 3 is CH 3 CO.   6) A compound according to claim 3, characterized in that R 1 is tert-C 4 H 9 or nC 3 H 7, R 2 is C 2 H 5 and R 3 is H. 7) A compound according to claim 2, characterized in that it is selected from the compounds of formula I wherein R 'is CH 3 CO-, R is H, R 2 is C 2 H 5, A is (CH 2) 2 and R 3 is H, R is CH 3 CO, R is H, R 2 is C 2 H 5, A is (CH 2) 3 and R 3 is (C 3 H 7) C 0-, (tC 4 Hg) C 0-, / CO-, C 2 H 50-CS or S <L o 4 1 CO-   HR 'is (nC 3 H 7) CO-, R is H, R 2 is C 2 H 5, A is (CH 2) 3 and R 3 is CH 3 CO-, R' is CH 3 CO-, R is HR 2 is H, A is (CH 2) 3 and R 3 is H, R 'is HR is HR 2 is C 2 H 5, A is (CH 2) 3 and R 3 is H, is H, R' is C 2 H 5, R is H, R 2 is C 2 H 5, A is (CH 2) 3 and R 3 is H, and the SS dimers of the compounds of formula I, wherein R 'is CH 3 CO-, (tert-C 4 H 9) CO or (nC 3 H 7) CO-, R is HR 2 is C 2 H 5, A is (CH 2) 3 and R 3 is H, R 'is CH 3 CO-, R is H, R 2 is CH 3, A is (C 1 2) 3 and R 3 is H, R 'is CH 3 CO-, R is H, R 2 is C 2 H 5, A is (CH 2) 2 and R 3 is H, R 'is H, R is H, R 2 is C 2 H 5, A is (CH 2) 3 and R 3 is H. 8) The compounds specified in any one of   Claims 1 to 7, characterized in that they   present in free base form or in the form of salts of acid addition.   9) Process for the preparation of the specific compounds   compounds as claimed in claim 1, and their acid addition salts, characterized in that a) a 1-amino-4-oxybenzene (other than a 1-amino-4-acyloxybenzene) substituted in position is hydrolyzed. 3 of the benzene ring by a R 3 '-thio-alkyl (linear chain) group where R 3' corresponds to the formula (b) -C -Z (b) where x X is = S and Z is - OR 5, where R 5 is a C 1 -C 4 alkyl group, or X is = NH and Z is -NH 2, to prepare a 1-amino-4-oxy-3mercapto-alkyl (chain   linear) benzene (other than 1-amino-4-acyloxy-   3-mercapto-alkyl (linear chain benzene), and / or b) a free hydroxy group and / or a group   free mercapto in a 1-amino-4-oxy-3-mercapto-alkyl-   (linear) benzene or its S-acyl derivative or SS dimer thereof, to prepare an S-acyl derivative of a 1-amino-4-oxy-3-mercapto-alkyl (linear chain) benzene or a aryl-4-acyloxy-3-mercaptoalkyl (linear chained) benzene or its S-acyl derivative or SS dimer, and / or c) a 1-amino-4-oxy-3-mercapto-alkyl is obtained (line chain) benzene to a dimerization SS, to obtain the corresponding SS dimer,   d) and then, if desired, transform the 1-amino   4-oxy-3-mercapto-alkyl (linear chain) benzenes,   their S-acylated derivatives or their S-S dimers thus ob-   contained in another compound of the invention, and the 1-amino-4oxy-3-mercapto-alkyl (linear chain) benzenes, their S-acyl derivatives or their SS dimers thus obtained, are recovered in the form of a free base or form an acid addition salt.   Process for the preparation of the compounds of the formula I and their esters, as specified in claim 2, and their acid addition salts, characterized in that a) a compound of the formula II R is hydrolyzed A-S -C-Z   wherein R, R ', R 2, A, X and Z have the meanings given in claim 2, for preparing a compound of formula I wherein R 3 is hydrogen, and / or b) a compound is acylated; of formula I wherein R 2 and / or R 3 signify hydrogen, to prepare its ester or a compound of formula I wherein R 3 is acyl, and / or c) a compound of formula I wherein R 3 is signifies hydrogen at dimerization SS, to obtain a compound of formula I wherein R 3 is a group of formula (a) as defined in claim 2, d) and then, if desired, converting a compound of formula I thus obtained in another compound of formula I, and the compound of formula I or its ester thus obtained, in the form of a free base or in the form of a salt, is recovered. acid addition.   11) A process according to claim 10, characterized in that the transformation of a compound of   formula I to another compound of formula I according to   assigned d), comprises dl) deacylating a compound of formula I, or its ester wherein R 'is -COR 1 and / or R 3 is acyl, to give a compound of formula I   or its ester in which R and / or R 3 signify hydro-   gene, and / or d) splitting the ether linkage in a compound of formula I wherein R 2 is C 1 -C 6 alkyl to give a compound of formula I wherein R 2 is hydrogen, and / or d) splitting the SS group into a compound of formula I, or its ester, wherein R 3 is a group of formula (a), to obtain a compound of formula 1, or its ester, wherein R 3 means hydrogen, and / or d 4) reducing a compound of formula I wherein R 'is -COR 1, to produce a compound of formula I wherein R' is C 1-4 alkyl C 6, and / or d S) N-alkylation or N-acylation of a compound of   formula I in which R and / or R 'signifies hydro-   gene, to obtain a compound of formula I, or its ester, wherein R and / or R are C 1 -C 6 alkyl or wherein R 'is a group -COR 1.   12) 1-Amino-4-oxy-3-mercapto-alkyl (linear chain) benzenes, their S-acyl derivatives and their S-S dimers, as specified in any one of   Claims 1 to 7, in the form of a free base or a   acid addition salt acceptable from the pharmaceutical point of view   for use as medicines.   13) 1-amino-4-oxy-3-mercapto-alkyl (linear chain) benzenes, their S-acyl derivatives   and their S-S dimers, as specified in any one   conque of claims 1 to 7, in free base form   or an acid addition salt acceptable from the point of view   for use as analgesics   gésiques. 14) A drug, characterized in that   contains, as an active ingredient, a 1-amino-4-oxy   3-mercapto-alkyl (linear chain) benzene, or its S-acyl derivative or S-S dimer, as specified   in any one of claims 1 to 7 in the form of   free base or as an acid addition salt   acceptable from a pharmaceutical point of view.   ) A pharmaceutical composition, characterized   in that it contains 1-amino-4-oxy-3-mercapto   alkyl (linear chain) benzene, or its S-acyl derivative or SS dimer thereof, as specified in any one of   Claims 1 to 7, in the form of a free base or   in the form of a pharmaceutically acceptable acid addition salt in combination with pharmaceutically acceptable diluents or carriers.