WO1984000032A1

WO1984000032A1 - Amino-oxy-(mercapto-alkyl)-benzenes, method for the preparation thereof and pharmaceutical products containing them

Info

Publication number: WO1984000032A1
Application number: PCT/CH1983/000075
Authority: WO
Inventors: Roland Achini; Laszlo Revesz
Original assignee: Sandoz Ag
Priority date: 1982-06-17
Filing date: 1983-06-14
Publication date: 1984-01-05
Also published as: IT8348521A0; FI832097A0; GB2121800A; FR2528832A1; DK279383A; BE897034A; JPS5916872A; IT1197665B; DE3320746A1; IL68974A0; SE8303410L; PT76877B; GB2121800B; SE8303410D0; FR2528832B1; PT76877A; GB8316053D0; DK279383D0; ES523333A0; NL8302108A

Abstract

1-amino-4-oxy-3-(mercapto-alkyl)-(unbranched chain)-benzenes, having particularly the formula (I) wherein R and R2 are hydrogen or an alkyl residue with 1 to 6 atoms of carbon, R' is hydrogen, an alkyl residue with 1 to 6 atoms of carbon or the group -COR1 wherein R1 is hydrogen or an alkyl residue with 1 to 6 atoms of carbon, and A is an unbranched alkyl chain with 5 atoms of carbon at the most, as well as their S-acylated derivatives, S-S-dimers derivatives and salts thereof. Those compounds have a pharmacological activity, particularly an analgesic activity.

Description

Amino-oxy-mercaptoalkylbenzenes, manufacture, and pharmaceutical preparations.

The present invention relates to positions 1, 3 and 4 substituted benzenes and derivatives thereof, their preparation, pharmaceutical preparations which contain them, and their pharmaceutical, in particular analgesic and antipyretic, use.

The invention relates in particular to 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzenes, their S-acyl derivatives, their S-S diraers; as well as the acid addition salts of these compounds.

In the compounds according to the invention, the amino group can be substituted (mono- or disubstituted) or unsubstituted. Preferred substituents are alkyl residues and acyl residues, e.g. the acyl residue of a carboxylic acid.

"Oxy" in position 4 means all residues which are bonded to the benzene ring via an oxygen atom, e.g. Hydroxy, alkoxy, acyloxy.

The straight-chain alkyl group can contain up to five carbon atoms, preferably it contains 2 or 3, in particular 3, carbon atoms.

Preferred compounds are those of the formula I and their esters, and also the acid addition salts of these compounds.

wherein

R, R 'and R ₂ independently of one another represent hydrogen or alkyl having 1 to 6 carbon atoms

R 'can also represent a -COR ₁ group, in which R _{1 represents} hydrogen or alkyl having 1 to 6 C atoms, A represents an alkylene radical having up to five C atoms and R _{3 represents} hydrogen, an acyl group or one Group of formula (a)

wherein

R, R ', R ₂ and A have the same meaning and are identical to or different from the radicals R, R', R ₂ and A, as defined in the formula I, are.

If R _{3 is} acyl, it is preferably the acyl radical of a carboxylic acid having up to 8 carbon atoms.

The compounds according to the invention, for example the compounds of the formula I and their esters which have an unscylated amino group in position 1, can form acid addition salts. The esters of the compounds of the formula I (ie compounds of the formula I in which R ₂ stands for acyl) comprise physiologically hydrolyzable and physiologically acceptable esters: ie those esters which are hydrolyzable under physiological conditions, the corresponding 4-hydroxy derivative being formed, and an acid that is itself physiologically acceptable, ie non-toxic at the desired dosages. Esters with carboxylic acids which contain up to 8 carbon atoms are preferred.

Preferred compounds of formula I are those in which

A is ethylene or propylene, especially propylene, and / or R is hydrogen, and / or R 'is a -COR ₁ group, and / or

R ₂ is hydrogen or alkyl having 1 to 6 C atoms, and / or R ₃ is hydrogen or an R ₄ CO group, in which R _{4 is} hydrogen or alkyl having 1 to 6 C atoms.

Preferred compounds of the invention are those of the formula IA

wherein

R _{1 is} hydrogen or alkyl with 1 to 6 C atoms R _{2 is} hydrogen or alkyl with 1 to 6 C atoms and R _{3 is} hydrogen or an R.CO group, in which R _{4 is} hydrogen or alkyl with 1 to 5 C atoms Atoiaen stands

mean. The present invention further relates to processes for the preparation of the 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzcle, their S-acyl derivatives and their SS dimers, and the acid addition salts of these compounds.

These processes comprise a) the hydrolysis of a 1-amino-4-oxybenzene (apart from a 1-amino-4-acyloxybenzene) which is substituted in position 3 of the ring by an R ' ₃ -thio (straight-chain) alkyl group, where R' _{3 represents} a group of formula (b)

wherein X is either = S and Z -OR ₅ , wherein R _{5 is} alkyl with 1 to

4 carbon atoms, or

X = NH and Z -N ₂ mean

for the preparation of a 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene (apart from a 1-amino-4-acyloxy-3-mercapto (straight-chain) alkylbenzene), and / or b) the acylation of a free OH- and / or SH group in a 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene or in an S-acyl derivative or SS dimer thereof, for the preparation of the S-acyl derivative of a 1-amino-4-oxy- 3-merkaρto (straight-chain) alkyl benzene, or a 1-amino-4-acyloxy-3-mercapto (straight-chain) alkylbenzene or an S-acyl derivative or SS dimer thereof, and / or c) the SS dimerization of a 1-amino -4-oxy-3-merkapto (straight chain) alkylbenzene to the corresponding SS dimer. d) if appropriate, the subsequent conversion of a compound according to the invention thus obtained into another compound according to the invention (for example in accordance with the following) carried out subsequent stages d ¹ to d ⁵ ), and the maintenance of the compound thus prepared, if appropriate as a free base or as an acid addition salt of such a base.

More specifically, the compounds of formula I or their esters, as well as the acid addition salts of these compounds can be prepared according to the invention by a) a compound of formula II

wherein R, R ', R ₂ and A have the meanings given for the formula I, and

X and Z have the meanings given for the formula (b), hydrolyzed to produce the corresponding free mercapto compounds, and / or

b) a compound of the formula I in which R ₂ and / or R _{3 are} hydrogen, acylated for the preparation of an ester thereof or for the preparation of a compound of the formula I in which R _{3 is} acyl, and / or c) a compound in the Formula I, wherein R _{3 is} hydrogen, undergoes SS dimerization to produce a compound of formula I, wherein R _{3 is} a group of formula (a) as defined above

and the compound of formula I if necessary. as a free base or as an acid addition salt of such anase.

In formula II, X preferably stands for = S, Z for -OR ₅ and R ₂ for alkyl having 1 to 6 carbon atoms. Ver is particularly preferred drive when in formula II R and A have the same meanings as in formula IA, especially when R 'is -COR ₁ .

Method a) can according to. known methods are carried out e.g. by alkaline hydrolysis with KH in an aqueous-alcoholic environment or with NaOH in an aqueous α or aqueous-alcoholic environment. Ethanol is preferably used as the alcohol. Suitable reaction temperatures range from room temperature to the reflux temperature.

Process b) can be used for the acylation of the free SH group of the 3-mercaptoalkyl radical and / or the acylation of the free 4-hydroxy group to produce the corresponding esters. The acylation can be carried out according to standard methods, e.g. by reaction with a suitable acid or a reactive derivative thereof in the presence of an inert solvent or diluent at room temperature or at a slightly elevated temperature. If both free OH and free SH groups are present in the starting compound, these can, if desired, be selectively alkylated under suitable reaction conditions or by the intermediate application of suitable protective groups on the O or S atom and removal of these protective groups after Acylation.

Process c) can also be carried out according to methods known per se, e.g. by oxidation, preferably with atmospheric oxygen, in a slightly alkaline environment at room temperature or at a slightly elevated temperature.

When carrying out process a), if the reaction does not take place with the exclusion of air, spontaneous oxidation will result in a certain amount of S-S dimer as a by-product, as described in the examples below.

The starting products of formula II are new per se and belong to the invention. A special group of the starting compounds are those of the formula ITA

wherein R _{5 is} alkyl with 1 to 4 carbon atoms, especially ethyl.

The starting compounds of the formula II can be prepared, for example, as set out in the reaction schemes below. The preparation of starting materials of the formulas VII and IX 'can be described, for example, by the methods described in Ind. J. Chem. 3, 74 (1965) and J. Amer. Chem. Soc. 80, 3271 (1958).

Example for the preparation of starting compounds of the formal II if X

= S and Z -OR evaluates. SCHEME 1 5 mean

Example for the preparation of the starting compounds of formula II, wherein

X = NH and Z -NH ₂ mean

SCHEME 2

Example of the reaction sequence for the penultimate stage of schemes 1 and 2

SCHEME 3 It is pointed out that, as is customary in the case of such reaction sequences, it is not necessary to isolate every intermediate or starting product. The end product of a reaction stage can thus be reacted directly in the same medium without isolation, for example compounds of the formula II "(Scheme 2) can be hydrolyzed immediately after their preparation in the same reaction medium to give corresponding compounds of the formula I.

For the sake of simplicity, the above reaction schemes only describe the preparation of the compounds of the formula I, but it goes without saying that further 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzenes can be prepared in an analogous manner. It is also pointed out that the corresponding S-S dimers according to the invention are by-products of the abovementioned. Reaction can be obtained because the monomer can be oxidized to the dimer under the usual reaction conditions.

The preparation of the compounds according to the invention can further comprise one or more of the subsequent reaction stages d ¹ to d ⁵ , as listed below. In these reaction stages, a compound according to the invention can be converted into another desired compound according to the invention by conventional methods known per se.

For the sake of simplicity, the following subsequent reaction stages are formulated only for compounds of the formula I, but other compounds according to the invention can also be prepared in an analogous manner.

The production process according to the invention can therefore also comprise: d ¹⁾ the deacylation of a compound of the formula I in which R 'is -COR ₁ and / or R _{3 is} R ₄ CO, as defined for formula I, for the preparation of compounds of the formula I in which R 'and / or R _{3 are} hydrogen, and / or d ²⁾ the ether cleavage of a compound of the formula I in which R _{2 is} alkyl having 1 to 6 C atoms for the preparation a compound of the formula I in which R _{2 is} hydrogen and / or d ³⁾ SS cleavage, for example a compound of the formula I or an ester thereof, in which R _{3 is} a group of the formula (a) as above, defines, for the preparation of a compound of the formula I or an ester thereof in which R _{3 is} hydrogen and / or d ⁴⁾ the reduction, for example a compound of the formula I in which R 'is R ₁ CO, for the preparation a connection of the

Formula I, in which R 'is alkyl having 1 to 6 carbon atoms, and / or d ⁵⁾ N-alkylation or N-acylation, for example a compound of the formula I or an ester thereof, in which R and / or R' is Hydrogen represents the preparation of a compound of formula I or an ester thereof, in which R and / or R 'represents alkyl having 1 to 6 carbon atoms or in which R' represents -COR ₁ .

All of the above processes can be carried out according to methods known per se, for example as set out in the descriptions and examples below, in which all the temperatures are given in degrees Celsius.

Descriptions 1-10: Manufacture of raw materials

Description 1: N- [4-ethoxy-3- (3-ethoxythiocarbonylthiopropyl) phenyl] acetamide (Scheme 1)

a) A solution of 64.7 g of sulfanilic acid and 19.8 g of sodium carbonate in 400 ml of water is mixed at 0-10 ° with a solution of 27.9 sodium nitrite in 350 ml of water. The yellow reaction solution is poured onto a mixture of 78.2 ml of 37% HCl and 500 g of ice with stirring and stirred for a further 10 minutes. The orange solution of the diezonium salt is added dropwise with ice cooling (5-10 °) to a precooled solution of 56.9 g of 3- (2-hydroxyphenyl) -1-propanol and 82.3 g of sodium hydroxide in 700 ml of water. After stirring for 15 hours at room temperature, 232 g of sodium hydrosulfite are added in portions at 70 ° and stirring is continued for 15 hours at room temperature. The precipitated 3- (5-amino-2-hydroxyphenyl) -1-propanol is filtered off, dried (mp. 116-118 °, from methanol / ether) and by dissolving and stirring for 15 minutes in 6 times the amount of acetic anhydride. Pyridine- (1: 1) converted to the crude N- [3- (3-acetoxypropyl) -4-hydroxyphenyl] acetamide. This is dissolved in methanol and treated for 2 hours at room temperature with an excess of aqueous 2 N NaOH. After acidification with 2 N HCl to pH 4, the N- [4-hydroxy-3- (3-hydroxypropyl) phenyl] acetamide precipitates, mp. 156-158 ° (from water).

b) A mixture of 31.9 g of N- [4-hydroxy-3- (3-hydroxypropyl) phenyl] acetamide, 74.0 g of potassium carbonate, 43.0 ml of ethyl iodide in 100 ml of acetone is heated for 48 hours with stirring and reflux. After filtering off the inorganic parts and evaporating the filtrate, N- [4-ethoxy-3- (3-hydroxypropyl) phenyl] acetamide, mp. 94-96 ° (from ethyl acetate) results. c) The compound described above is with methanesulfochloride triethylamine - (1: 1) (50% excess) in methylene chloride at -10 to 0 ° to N- [4-ethoxy-3- (3-methylsulfonyloxypropyl) phenyl] acetamide, mp 113-115 ° (from ethyl acetate / hexane). d) The mesylate is treated with potassium xanthate (50% excess) in methanol at 50 ° for three hours to give N- [4-ethoxy-3- (3-ethoxythiocarbonylthiopropyl) phenyl] acetamide, mp. 78-80 ° (from toluene / Hexane) implemented.

Description 2: N- [3- (3-ethoxythiocarbonylthiopropyl) -4- methoxyphenyl] acetamide (Scheme 1)

a) and b) Analogously to description 1, N- [3- (3-hydroxypropyl) -4-methoxyphenyl] acetamide is obtained with methyl iodide, mp. 84-86 ° (from ethyl acetate). c) Analogous to description 1, N- [4-methoxy-3- (3-methylsulfonyloxypropyl) phenyl] acetamide, mp. S4-96 ° (from acetone / ether) is also obtained. d) The title compound is obtained as an oil in an analogous manner.

Other starting products can also be obtained analogously to the descriptions 1) and 2).

Description 3: Starting product for example 2 (scheme 2)

a) To a solution of 390 g of N- [4-ethoxy-3-prop-2-enylphenyl] acetamide in 2.5 L of tetrahydrofuran, 60.5 ml of borane dimethyl sulfide complex are added dropwise with stirring and N ₂ at 0 ° and 1 Hours stirring. 12 ml of methanol are added dropwise to destroy excess BH ₃ . After the addition of 451 g of iodine, a freshly prepared CH ₃ ONa solution consisting of 40.4 g of sodium and 700 ml of methanol is added dropwise and the mixture is subsequently stirred at room temperature for 24 hours. After that the Gray reaction solution with about 1 L Na ₂ S ₂ 0 ₃ solution and extracted with ethyl acetate. After drying and evaporation, the N- [4-ethoxy-3- (3-iodopropyl) phenyl] acetamide is obtained as a red-brown oil, which is processed directly.

b) A solution of 549 g of the product obtained under a) and 120 g of thiourea in 1.5 L of 95% ethanol is boiled under reflux for 17 hours (overnight).

The resulting compound of formula II '' in Scheme 2 (R = H, R '= COCH ₃ , R ₂ = C ₂ H ₅ , A = (CH ₂ ) ₃ ), which is obtained as a red solution, is not isolated , but used directly in the procedure of Example 2.

Descriptions 4-10: Starting products for Examples 3-6

(Scheme 1 and / or 2)

The following starting products of the formula II can also be prepared analogously to the descriptions 1 and 3:

Example 1: N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] acetamide and its SS dimer (method a)

A solution of 27.0 g of N- [4-ethoxy-3- (3-ethoxythiocarbonylthiopropyl) phenyl] acetamide (prepared as set forth in Description 1) and 90 ml of 25% aqueous ammonia in 300 ml of ethanol is passed through under a CO stream stirred for 15 hours at 25 °. After evaporation, the title compound mp 70-72 ° (from ether / hexane) and the corresponding S-S dimer, mp 112-114 ° (from ether / hexane) result.

Example 2: N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] acetamide and its S-S dimer (method a)

The red solution obtained in description 3b) is mixed with 1 L of 10% NaOH and kept under reflux for a further 2 hours. After cooling, the mixture is extracted with ethyl acetate. The organic phase is washed once with dilute H ₂ SO ₄ and once with brine, dried and evaporated. The result is 367 g of brown resin, which is chromatographed for cleaning in 5 portions on a flash column Ø 15 cm with ethyl acetate. The title compound, its dimer and a mixed fraction are obtained. Recrystallization of the title compound from ethyl acetate / hexane gives a white crystallizate which is still slightly contaminated. Recrystallizing again gives a product with mp = 85-87 °.

Examples 3-6 (Method a)

The following compounds can be prepared analogously to the processes of Examples 1 and 2 and in accordance with Schemes 1 and 2:

* This compound can be used in the procedure of Example 19 without isolation and purification.

Example 7: N- [3- (3-Acetylthiopropyl) -4-ethoxyphenyl] acetamide (Method b)

A. A mixture of 4.1 g of N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] acetamide, 30 ml of pyridine and 30 ml of acetic anhydride is stirred at room temperature for 1 hour. Evaporation gives the title compound, mp 72- 74 ° (from ethyl acetate / hexane).

B. 500 ml of acetic anhydride are added to a solution of 50 g of the product prepared in Example 2 in 500 ml of pyridine with stirring at room temperature. After standing overnight, the mixture is evaporated on a rotovapor. The slightly contaminated title compound is obtained, which is flash-chromatographed again with ethyl acetate. The title compound, a mixed fraction and a by-product are obtained.

The by-product is identical to the starting product of description 3) and can be used as a raw product again in the process of description 3).

The title compound is recrystallized from ether / hexane, mp. 62-64 ° (slow crystallization from ethyl acetate / hexane gives mp. 72-74 °, as above under A). Examples 8-14 (Method b)

The following compounds can be prepared analogously to Example 7 (A or B), optionally using the corresponding acyl chlorides instead of the acid anhydrides. The substituents on the benzene ring are the same as for the corresponding starting product with the exception of the R ₃ group, which is defined in the table.

Example 15: H- [4-Hydroxy-3- (3-mercaptopropyl) phenyl] acetamide

(Method d ² )

7.56 ml of boron tribromide are added at -60 ° to a solution of 6.0 g of N- [4-methoxy-3- (3-mercaptoprcpyl) phenyl] acetamide (Example 3) in 250 ml of methylene chloride. The mixture is brought to room temperature by heating and stirred overnight, evaporated, 120 ml Ethanol was added and heated under reflux for 2 hours. The ethanol is distilled off, the remaining oil is taken up in ethyl acetate and washed with sodium bicarbonate solution. After evaporating the organic phase, the title compound is isolated by column chromatography on silica gel and recrystallized from ethyl acetate / ether. M.p .: 74-77 °

Example 16: N- [4-Ethoxy-3- (3-mercaptopropyl) phenyl] amine (Method d ¹ )

A solution of 70 g of N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] acetamide (from Example 1) in 350 ml of ethanol and 350 ml of conc. Hydrochloric acid is heated under reflux for 3 hours. After evaporation, the title compound is recrystallized as an HCl salt from ethanol / ether. M.p .: 137-139 °.

Example 17: S-S dimer of N- [4-ethoxy-3- (3-mercaptoproρyl) phenyl] amine (method c)

To a solution of 60 g of N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] amine (made from the HCl salt of the compound of Example 16). 300 ml of 2N NaOH solution are added to 500 ml of methanol and the mixture is stirred in an open round-bottom flask for 48 hours at room temperature. Afterwards water is added and the mixture extracted 3 times with Essigestεr. After the organic phase has been evaporated off, the title compound is isolated as a brown oil by column chromatography on silica gel.

Example 18-20 (Method c)

The following dimers are known analogously to Example 17 or as by-products of process a), as in Examples 1 and 2 described. In the compounds in the table below, R _{3 represents} a group of the formula (a) as defined above and R, R ', R ₂ and A have the meanings given below.

Example 21: SS dimer of N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] pivalamide (method d ⁵ )

6.1 ml of pivalic anhydride are added to a solution of 2.5 g of the dimer of N- [4-ethoxy-3- (3-mercapto propyl) phenyl] amine (from Example 17) in 60 ml of chloroform + 10 ml of pyridine 10 ml chloroform. The mixture is stirred for 3 hours at room temperature, evaporated, taken up in 1N hydrochloric acid and extracted 3 times with ethylene chloride. After evaporating the organic phase, the title compound is recrystallized from ether / hexane. M.p .: 136-137 °.

Examples 22-26 (Method d ⁵ )

Analogously to Example 21, the following compounds can also be prepared; where the substituents on the Eenzolring die are the same as in the corresponding starting product with the exception of the group R ', which is defined in the table.

Example 27: N- [4-Ethoχy-3- (3-mercaptopropyl) phenyl] pivalamide (method d ³ )

2.25 g of the S-S dimer of the title compound (from Example 21) is dissolved at -70 ° in 200 ml of liquid ammonia and 130 ml of tetrahydrofuran. Subsequently, a piece of sodium is immersed in this genetic until a blue color develops, then 3 g of ammonium chloride are added and the mixture is evaporated. The residue is taken up in water and extracted with methylene chloride. After the organic phase has been evaporated off, the title compound is isolated by column chromatography on silica gel. M.p. 116-117 °.

Examples 28-29 (Method d ³ )

The following compounds can also be produced analogously to example 27:

Example 30: N- [4-Ethoxy-3- (3-mercaptopropyl) phenyl] ethylamine (Method d ⁴ )

A solution of 3.08 ml of 100% H ₂ SO ₄ in 30 ml of tetrahydrofuran is added to a suspension of 4.5 g of LiAlH ₄ in 200 ml of tetrahydrofuran at -5 °. This mixture is stirred at -5 ° for 30 minutes and a solution of 10 g of N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] acetamide (for example from Example 1) in 200 ml of tetrahydrofuran is added at 30 ° at 30 ° . The mixture is left to stand at room temperature for 2 hours and poured on. Ice water and extracted with methylene chloride. After evaporation, the remaining oil is chromatographed on silica gel with hexane / ethyl acetate (3: 1) as the eluent. The title compound is isolated as 1,5-naphthalene disulfonate and recrystallized from methanol / ether. M.p. 145-149 °

The 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzenes according to the invention, their S-acyl derivatives and their SS dimers, in particular the compounds of the formula I and their esters, and the pharmaceutically acceptable acid addition salts thereof, have valuable pharmacological, especially analgesic properties, as can be seen, for example, from their effect in the following tests: A) in the arthritis pain test (based on the test described by AW Pircio et al. In Eur.J. Pharmacol. 31, 207-215, 1975) at doses of 5 to 200 mg / kg po and

B) in the Randall-Selitto test on the inflamed hind paw of the rat (Arch. Int.Pharmacodyn. 61, 409-19, 1957) at doses of 40 to 200 mg / kg p.o.

The compounds according to the invention can consequently be used as analgesics, e.g. to treat pain. A suitable daily dose for this application is about 50 to 300 mg, expediently divided into 2 to 4 parts or administered as a slow-release form. For example, for oral administration, the partial nozzles 12.5 to 150 mg of the compounds according to the invention, optionally as free base or acid addition salt in addition to pharmaceutically acceptable diluents or carrier substances.

The compounds according to the invention also have antipyretic properties, such as e.g. from their effect in that of E.I. Takesue et al. in Arch. Intern. Pharmacodyn. 221, 122-31, 1976.

The invention also includes

1) 1-Amino-4-oxy-3-mercapto- (straight-chain) alkylbenzenes, their S-acyl derivatives and SS dimers, especially compounds of the formula I or their esters, or their pharmaceutically acceptable acid addition salts for use as medicaments, for example for Use as analgesics or antipyretics. 2) A method for the treatment (eg relief) of pain, which consists in administering an analgesically effective amount of a compound mentioned under 1), optionally in the form of the free base or a pharmaceutically acceptable acid addition salt.

3) Pharmaceutical preparations containing a compound as defined under 1) above, optionally as free base or as a pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable diluent or carrier.

The pharmaceutical preparations mentioned under 3) can be prepared by galenic methods known per se. Suitable galenical forms of administration are e.g. Tablets and liquid preparations.

Claims

Claims:

1. 1-amino-4-oxy-3-mercapto (straight-chain) alkyl-benzenes, their S-acyl derivatives, their S-S dimers; as well as the acid addition salts of these compounds.

.

2. Compounds according to claim 1 of formula I.

wherein

R 'can also represent a -COR ₁ group in which R _{1 is} hydrogen or alkyl having 1 to 6 carbon atoms,

A for an alkylene radical with up to five carbon atoms and

R _{3 represents} hydrogen, an acyl group or a group of the formula (a)

wherein

R, R ', R ₂ and A have the same meaning and the same at or ver differ from the radicals R, R ', R ₂ and A, as defined in the formula I, as well as their esters and the acid addition salts of these compounds.

3. Compounds according to claim 2 of formula IA

wherein

R _{1 is} hydrogen or alkyl having 1 to 6 carbon atoms

R _{2 is} hydrogen or alkyl having 1 to 6 carbon atoms and

R _{3 is} hydrogen or an R ₄ CO group, in which R _{4 is} hydrogen or alkyl having 1 to 5 carbon atoms.

4. As a compound according to claim 3, the compound of formula IA, wherein R _{1 is} CH ₃ , R _{2 is} C ₂ H ₅ and R _{3 is} CH ₃ CO.

5. A process for the preparation of 1-amino-4-oxy-3-mercapto- (straight-chain) alkylbenzenes, their S-acyl derivatives and their SS dimers, and the acid addition salts of these compounds, for example for the preparation of a compound of the formula I according to Claim 2 or their esters or the acid addition salts of such a compound, characterized in that a 1-amino-4-oxybenzene (apart from a 1-amino-4-acyloxybenzene) which is substituted in position 3 of the ring by an R ₃ 'thio (straight-chain) alkyl group, where R ₃ ' represents a group of the formula ( b) stands

wherein X is either = S and Z -OR ₅ , wherein R _{5 is} alkyl with 1 to

4 carbon atoms, or

X = NH and Z -NH ₂ mean hydrolyzed to produce a 1-amino-4-oxy-3-mercapto (straight chain) alkylbenzene (except for a 1-amino-4-acyloxy-3-mercapto (straight chain) alkylbenzene), for example a compound of formula II

wherein R, R ', R ₂ and A have the meanings given for the formula I, and

X and Z have the meanings given for the formula (b), hydrolyzed, and / or b) a free OH and / or SH group in a 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene or in an S-acyl derivative or SS dimer thereof acylated to produce the S-acyl derivative of a 1 -Amino-4-oxy-3-mercapto (straight-chain) alkylbenzene, or a 1-amino-4-acyloxy-3-mercapto (straight-chain) alkylbenzene, or an S-acyl derivative or SS dimer thereof, for example a compound of the formula I, according to claim 2, wherein R and / or R are hydrogen, acylated to produce an ester thereof or to prepare a compound of formula I, wherein R _{3 is} acyl, and / or

c) a 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene is subjected to an SS dimerization to produce the corresponding SS dimer, for example a compound of the formula I in which R _{3 is} hydrogen is subjected to an SS dimerization for the preparation of a compound of formula I according to claim 2, wherein R _{3 represents} a group of formula (a) as defined above, and if desired ge

d) a 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene thus obtained, an S-acyl derivative or S-S-dimer thereof is converted into another such compound, e.g.

d is a compound of formula I according to claim 2, wherein R 'is

-COR ₁ and / or R are R ₄ CO, as defined for formula I, are desacylated for the preparation of compounds of formula I, wherein R 'and / or _R 3 are hydrogen, and / or d ²⁾ a compound of the formula I in which R _{2 is} alkyl with 1 to 6

C atoms, subject to ether cleavage, for the preparation of a compound of the formula I in which R _{2 is} hydrogen and / or

d ³⁾ subjecting a compound of the formula I or an ester thereof, in which R is a group of the formula (a), as defined above, to SS cleavage, to prepare a compound of the formula I or an ester thereof, in which R ₃ stands for V-hydrogen, and / or

d ⁴⁾ a compound of the formula I in which R 'is R ₁ CO, reduced to produce a compound of the formula I in which R' is alkyl having 1 to 6 carbon atoms, and / or

d ⁵⁾ a compound of the formula I or an ester thereof, in which R and / or R 'are hydrogen, N-alkylated or N-acylated for the preparation of a compound of the formula I or an ester thereof, in which R and / or R' represent alkyl having 1 to 6 carbon atoms or where R 'represents -COR ₁ ,

and the 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzenes thus obtained, their S-acyl derivatives. or S-S dimers, e.g. the compounds of formula I or their esters, optionally as free base or acid addition salt.

6. Pharmaceutical preparations containing a 1-amino-4-oxy

3-mercapto (straight chain) alkylbenzene, or an S-acyl derivative or SS dimer thereof or a pharmaceutically acceptable acid addition salt thereof according to claims 1 to 4 together with a pharmaceutically acceptable diluent or carrier.

7. 1-Amino-4-oxy-3-mercapto (straight chain) alkylbenzenes, their S-acyl derivatives or S-S-dimers or pharmaceutically acceptable acid addition salts thereof according to Claims 1 to 4 for use as medicaments, especially as analgesics.

8. Compounds of formula II

wherein R, R ', R ₂ and A have the meanings given in claim 2, and

X either = S and Z -OR ₅ , where R _{5 is} alkyl with 1 to 4

C atoms, or X = NH and Z -NH ₂ mean.