DE3320746A1 - BENZENE DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL PREPARATIONS WHICH THEY CONTAIN - Google Patents

Description

■ ro «·· Q

100-5808

Benzene derivatives, their manufacture and pharmaceutical Preparations containing them.

The present invention relates to benzenes substituted in positions 1, 3 and 4 and derivatives thereof, their preparation, pharmaceutical preparations containing them, as well as their pharmaceutical, in particular analgesic and antipyretic Use.

The invention relates specifically to l-amino-A-oxy-S-merkapto (straight chain) alkyl benzenes, their S-acyl derivatives, their S-S dimers; as the acid addition salts of these compounds.

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

Under "oxy" in position 4 are all radicals which have an oxygen atom are bound to the benzene ring, e.g. hydroxy, alkoxy, acyloxy.

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

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

8th -

100-5808

-A-S-R,

(D

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

R 'also stands for a -COR group, in which R is hydrogen or alkyl with 1 to 6 carbon atoms means, can stand, A is an alkylene radical with up to five carbon atoms and

R. for hydrogen, an acyl group or a group of the formula (a)

(a)

-S-A

R, R ¹ , R and A have the meanings given above and are identical to or different from the radicals R, R ¹ , R _? and A, as defined in formula I, are

stand.

If R is acyl, it is preferably the acyl radical Carboxylic acid with up to 8 carbon atoms.

The compounds according to the invention, for example the compounds of Formula I and its esters, which have a non-acylated amino group in position 1 can form acid addition salts.

~ ⁹ ~ 100-5808

The esters of the compounds of the formula I (ie compounds of the formula I in which R _? Stands for acyl) include physiologically hydrolysable and physiologically acceptable esters: ie those esters which are hydrolysable under physiological conditions, the corresponding 4-hydroxy derivative being formed, as well as a Acid which is itself physiologically acceptable, ie is non-toxic at the desired dosages. Esters with carboxylic acids which contain up to δ carbon atoms are preferred.

Preferred compounds of the formula I are those in which

A is ethylene or propylene, especially propylene, and / or

R is hydrogen, and / or

R 'is a -COR - group, and / or

R- is hydrogen or alkyl with 1 to 6 carbon atoms, and / or

R, is hydrogen or an R.CO group, where R, is hydrogen

or is alkyl having 1 to 6 carbon atoms.

Preferred compounds of the invention are those of the formula IA

NHtCO-R ₁

(IA)

wherein

R ^ hydrogen or alkyl with 1 to 6 carbon atoms 20 "^ ₂ hydrogen or alkyl with 1 to 6 carbon atoms and

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

mean.

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100-5808

The present invention further relates to methods of manufacture the l-amino-4-oxy-3-nierkapto (straight-chain) alkylbenzenes, their S-acyl derivatives and their S-S dimers, as well as the acid addition salts of these connections.

These procedures include

a) the hydrolysis of a l-amino-4-oxybenzene (except for a 1-amino-4-acyloxybenzene) _y which is substituted in position 3 of the ring by an R'-thio (straight-chain) alkyl group, where R 'is a group of Formula (b) stands

-CZ
YY (b)

where X either = S and Z -OR ^, where R is alkyl with 1 to

4 carbon atoms, or X = NH and Z mean _{-NH 2,}

for the production of a l ~ amino-4-oxy-3-inerkapto (straight-chain) -alkylbenzenes (except for a l-amino-4-acyloxy-3-merkapto (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 into an S-acyl derivative or S-S-dimer thereof to produce the S-acyl derivative of a l-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene s, or a l-amino-4-acyloxy-3-mercapto (straight-chain) alkylbenzene or an S-acyl derivative or S-S dimer thereof and / or

c) the SS-di; aerization of a l-amino-4-oxy-3-merkapto (straight-chain) -alkylbenzene to the corresponding SS-dimer _t

d) if necessary, the subsequent reaction of a product according to the invention obtained in this way Connection into another connection according to the invention (for example in accordance with the following

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: ·. "Led to subsequent stages d to d), j

■. ι

and the preservation of the connection established in this way, possibly as free j

Base or as an acid addition salt of such a base. ·,

. More specifically, the compounds of the formula I or their j Esters and the acid addition salts of these compounds according to the invention be made by one

a) a compound of the formula II

• Asez ^1τ

Il

wherein R, R ¹ , R and A have the meanings given for formula I, and

X and Z are the meanings given for formula (b)

have hydrolyzed to produce the corresponding free mercapto compounds, and / or

b) a compound of the formula I in which R_ and / or R is hydrogen are acylated to produce an ester thereof or to produce a compound of formula I wherein R stands for acyl, and / or

c) a compound of the formula I in which R_ is hydrogen, subjected to S-S dimerization to produce a compound of formula I, wori

as defined above, stands,

bond of the formula I, in which R «represents a group of the formula (a),

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

In the formula II, X preferably stands for = S ', Z for -OR ₅ and R ₂ for alkyl having 1 to 6 carbon atoms. Particularly preferred is the

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'-> drive if in formula II R and A have the same meanings as in formula IA, especially if R' stands for -COR.

Process a) can be carried out according to methods known per se, e.g. by alkaline hydrolysis with NH in aqueous-alcoholic Medium or with NaOH in an aqueous or aqueous-alcoholic medium. Ethanol is preferably used as the alcohol. Suitable reaction temperatures start from room temperature to 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 for the preparation of the corresponding ester. 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 solution or Diluent at room temperature or at a slightly elevated temperature. If both free OH and free SH groups in the Starting compounds are present, these can, if desired, be selectively acylated under suitable reaction conditions or by the intermediate use of suitable protective groups on the O or S atom and removal of these protective groups the acylation.

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

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

j) i _e starting products of the formula II are new per se and belong to the invention. A special group of the starting compounds are those of the formula HA

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NH-CO-R _n
ι 1

CH-CH-CH-S-C-OR (IIA)

i. ί λ " D

K ₂ O

where Β. _{ς stands} for alkyl with 1 to 4 carbon atoms, especially for ethyl,

The preparation of the starting compounds of the formula II can take place, for example, as set out in the reaction schemes below. Starting materials of the formula VII and IX ¹ can be prepared, for example, by the methods described in Ind. J. Chem. J ^, 74 (1965) or J. Amer. Chem. Soc. j30, 3271 (1958).

A-OH

HO (VII)

Ν, Ο-diacylation

"NH-COX ₁

A-O-COX

HO

[Χ ·, = R, ^or alkoxy]

selective O-deacylation

NH-COX

A-OH

HO etherification

NH-COX

or from compound (IX ¹ ) or (VIII ¹ ) in scheme 2

A-OH

LR ₆ SO ₂ R [R ₆ = ZB ^ψ CR = halo

NH-COX

₆ methyl, toluyl "; J CR ₇ = halo e.g." Cl, Br]

(III)

R-JO

s ". Scheme 3

KS-C-OR,

ASC-OR ₅ (II ¹ )

R ₂ O

Example of the preparation of starting compounds of the formula II, if X

= S and Z means -OR ₅ .

SCHEME I

or to compound (IV) -in scheme 1

[e.g. with 0 / NaBH ^

A A "* ft
«T * Λ Λ Λ * Λ *
α «« tea - [X, : 3320746 η ft ο
ΛΑ AA .X ₁ - 15 100-5808 NH. CO.
JL = J3 or alkoxy]

or to scheme 1

[IX ')

(VIII ¹ )

chain extension if necessary [e.g.! - _{> CN}

NHCOX ₁

(VIII)

[P. = Halo e.g.

see scheme 3 ι S = C

A-S-

C -Il

NH

Example of the preparation of the starting compounds of formula II, wherein X = NH and Z -2TIi-

SCHEME 2

»WW ν V WUw .. · · ·

• W W if * W WW »ί · · · ·

• W MF «r V <« ^ W · · · ·

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NHCOX ₁

A-X

(Scheme 2)

NHCOX ₁

(A) ['= compound VIII or III)

or

(Scheme 1)

A-S-C-Z (C)

■ I

More [e.g. if X = alkoxy ",". bes. tert. Reactions butoxy, N-hydrolysis.

If necessary, N-alkylation and / or N-acylation

and / or 4-ether splitting]

(II)

Example of reaction sequence in the penultimate stage of schemes 1 and

SCHEME 3

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J It should be noted that, as is usual with such reaction sequences, it is not necessary to isolate every intermediate or starting product. Thus, the end product of a reaction stage can be used further directly in the same medium without isolation, for example compounds of the formula II (Scheme 2) can be hydrolyzed to corresponding compounds of the formula I immediately after their preparation in the same reaction medium.

In the above reaction schemes, for the sake of simplicity, ^only the preparation of the compounds of the formula I is described, but it goes without saying that further 1-amino-4-oxy-3-mercapto (straight-chain) alkylbenzenes according to the invention can be prepared in an analogous manner. It will also be noted that the inventive appropriate SS-dimers can be _s can be obtained as by-products of the reaction oe since the monomer under the usual reaction conditions oxidized to the dimer.

The preparation of the compounds according to the invention can also be carried out one or more of the subsequent reaction stages d to d, as listed below, comprise. In these reaction stages can a compound according to the invention into another desired compound according to the invention according to conventional methods known per se Methods are implemented.

The following subsequent reaction steps are, as before, for the sake of simplicity formulated only for compounds of the formula I, but other compounds according to the invention can also be used in analogous Way to be made.

The manufacturing method according to the invention can also include:

d the deacylation of a compound of the formula I in which R ^{1 is} -COR. and / or R for R.CO, as defined for formula I,

100-5808

for the preparation of compounds of the formula I in which R ¹ and / or R ^ are hydrogen and / or

2)

d the ether cleavage of a compound of the formula I in which R_ stands for alkyl having 1 to 6 carbon atoms, for the production of a compound

and or

Compound of the formula I in which R is hydrogen,

3)

d the S-S cleavage, for example of a compound of the formula I. or an ester thereof, in which R "represents a group of the formula (a), as defined above, for the preparation of a compound of the formula I or an ester thereof, in which R_ is hydrogen stands, and / or

d 'the reduction, for example of a compound of the formula I in which R ^{1 is} R CO, for the preparation of a compound of the formula I in which R ^{1 is} alkyl having 1 to 6 carbon atoms, and / or

d N-alkylation or N-acylation, for example a compound of the formula I or an ester thereof, in which R and / or R ^{1 are} hydrogen for the preparation of a compound of the formula I or an ester thereof, in which R and / or R ^{1 are} Alkyl having 1 to 6 carbon atoms or in which R ^{1 is} -COR.

All o.e. Processes can be carried out according to methods known per se are, for example, as in the following descriptions and examples, in which all temperatures are in degrees Celsius take place, set out.

¹⁹ "100-5808

Descriptioneta 1-10: Manufacture of raw materials

Description 1: N - [/ j-Ethoxy-3- (3-ethoxythiocarbonylthiopropyl ·) -phenyllacetamide (Scheme 1)

a) A solution of 64.7 g of sulfanilic acid and 19.0 g of sodium carbonate

in 400 ml of water at 0-10 ° with a solution of 27.9 sodium • nitrite in 150 ml of water. The yellow reaction solution is poured into a mixture of 78.2 ml of 37% HCl and 500 g while stirring Poured ice and stirred for another 10 minutes. The orange solution of the diazonium salt is cooled with ice (5-10 °) to form a

cooled solution of 56.9 g of 3- (2-hydroxyphenyl) -l-propanol and 82.3 g of sodium hydroxide in 700 ml of water were added dropwise. After 15 hours Stirring at room temperature, 232 g of sodium hydrosulfite are added in portions to the red solution at 70 ° and at room temperature for 15 hours stirred. The precipitated 3- (5-amino-2-hydroxyphenyl) ~ - 1-propanol is filtered off, dried (melting point 116-118 °, from methanol / Ether) and by dissolving and stirring for 15 minutes in 6 times the amount of acetic anhydride-pyridine- (Ιίΐ) to the crude N- [3- (3-AcetoxypiOpyl) -4-hydroxyphenyl] acetamide implemented. This is dissolved in methanol and treated with an excess for 2 hours at room temperature treated aqueous 2N NaOH. After acidification with 2N HCl to pH 4, the N- [4-hydroxy-3- (3-hydroxypropyl) phenyl] acetamide precipitates, M.p. 156-158 ° (from water).

b) A mixture of 31.9 g of N- [4-hydroxy-3- (3-hydroxypropyl) phenyl j acetamide, 74.0 g potassium carbonate, 43.0 ml ethyl iodide in 100 ml Acetone is heated with stirring and reflux for 48 hours. After filtering off the inorganic parts and evaporating the The filtrate results in N- [4-ethoxy-3- (3-hydroxypropyl) phenyl! Acetamide, M.p. 94-96 ° (from ethyl acetate).

" ²⁰ " 100-5808

c) The compound described above is treated with Methanesulfochlorid-Triethylainin - (1: 1) (50% excess) in methylene chloride at -10 to 0 ° to the N- [4-ethoxy-3- (3-methylsulfonyloxypropyl) phenyl] acetamide, Mp. 113-115 ° (from ethyl acetate / kexane) implemented.

d) The mesylate is treated with potassium xanthate for three hours (50% excess) in methanol at 50 ° to the 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, methyl iodide is used N- [3- (3-hydroxypropyl) -4-methoxyphenyl] acetamide obtained, M.p. 84-86 ° (from ethyl acetate).

c) Analogously to description 1, N ~ [4-methoxy ~ 3- (3-methylsulfonyloxypropyl) phenyl] acetamide is also used, M.p. 94-96 ° (from acetone / ether) obtained.

d) The title compound is obtained as OeI in an analogous manner.

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

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

a) To a solution of 390 g of N- [4-ethoxy-3-prop-2-enyl-phenyl] -acetamide in 2.5L tetrahydrofuran are _{added dropwise with stirring and N 9} at 0 ° 60.5 ml of boranediraethyl sulfide complex and Hours after stirring. To destroy excess BH_, 12 ml of methanol are added dropwise. After 451 g of iodine have been added, a freshly prepared CH “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

33 2074

100-5808

1 L Na ₇ S ₉ O solution is added to the gray reaction solution and the mixture is 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 further processed directly.

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

The resulting compound of the formula II ¹ 'in scheme 2 (R = H, R "= COCH, R = CX, Λ = (CH)), which is obtained as a red solution, is not isolated, but directly in the process of the example 2 used.

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

(Scheme 1 and / or 2)

Analogous to the descriptions 1 and 3, the following Starting products of the formula II are produced:

description R ¹ R. R ₂ In A. Formula (11) Z No. COCH H CH ₃ - .. (CH ₂ ) ₃ NH ₂ CO (tC ₄ H ₉ ) H ^C 2 ^H 5 (CH ₂ ) ₃ X OC ₂ Il ₅ 4th CO (tC ₄ H ₉ ) H C ₂ H ₅ (CH ₂ ) ₃ . NH NH ₂ 20 5 COCH ₃ H C ₂ H ₅ (CH ₂ ) ₂ CO OC ₂ H ₅ 6th COCH H C ₂ H ₅ (CH ₂ ) ₂ NH NH ₂ 7th CO (UC ₃ H ₇ ) H C ₂ H ₅ (CH ₂ ) 3 S. OC ₂ Il ₅ δ C0 (nC ₃ H _y ) H C ₂ H ₅ (CH ₂ ) 3 NH NH ₂ 9 S. 25 10 NH

332074

" ²² " 100-5808

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

A solution of 27 g _S O N- [4-ethoxy-3- (3-ethoxythiocarbonylthiopropyl) -phenyl] -aceLamid (prepared as outlined in Description 1) and 90 ml of 25% aqueous ammonia in 300 ml of ethanol is by passing a CO stream for 15 hours at 25 °. Evaporation results in the title compound, mp 70-72 ° (from ether / hexane), and the corresponding SS dimer, mp 112-114 ° (from ether / hexane).

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% strength NaOH and refluxed for a further 2 hours. After cooling, the geraisch is extracted with ethyl acetate. The organic phase washed 1 χ with dilute H ₉ SO, and 1 χ with brine, dried and evaporated. This results in 367 g of brown resin which, for purification, is chromatographed in 5 portions on a flash column of 0 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 white crystals which are still slightly contaminated. Recrystallization again gives a product with melting point = 85-87 °.

Examples "3-6 (method a)

In analogy to the process of Examples 1 and 2 and accordingly Schemes 1 and 2, the following connections can be made will:

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Example ..- compound of formula I m.p.

R ' R. ^R 2 A. ^R 3 78-81 ° 3 COCH ₃ H CH ₃ (CH ₂ ) ₃ H 117-118 ° 4th COCt-C ₄ H ₉ ) H C ₂ H ₅ (CH ₂ ) 3 H 124-125 ° 5 COCH H ^C 2 ^H 5 (CH ₂ ) ₂ H OeI * 6th COCn-C ₃ H ₇ ) H ^C 2 ^H 5 (CH ₂ ) 3 H

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

Example 7: N- [3- (3-Acetylthiopropyl) -4-ethoxyphenyl1acetamide (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 1 Stirred for one hour at room temperature - after evaporation the result

.15 benefits the title compound, m.p. 72-74 ° (from ethyl acetate / hexane).

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

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

The title compound is recrystallized from ether / hexane M.p. 62-64 ° (slow crystallization from ethyl acetate / kexane gives melting point 72-74 °, as above under A).

. "" * .- ** »." Ico-503320748

Be js piele 8-14 (method b)

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

Example no. Starting product
Example no. ^R 3
(in formula I) COCH M.p. 8th 3 COCH 68-69 ° 9 1.2 COd-C ₃ H ₇ ) 82-83 ° 10 1.2 (XXt-C ₄ H ₉ ) 106-107 ° 11th 1.2 COC H
6 5 96-98 ° 12th 1.2 CS.OC H 78-80 ° 13th 1.2 foam I.
H 14th 6th 56-58 °

Example 15 : N- [4-Hydroxy-3- (3-mercaptopropyl) phenyl] acetamide ( method d ² )

To a solution of 6.0 g of N- [4-methoxy-3- (3-mercaptopropyl) phenyl] ■ Acetamide (Example 3) in 250 ml of methylene chloride is added 7.56 ml of boron tribromide at -60 °. The mixture is made by heating to room temperature brought and stirred overnight, evaporated, 12O ml

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Ethanol was added and the mixture was refluxed for 2 hours. The ethanol is distilled off / the remaining oil in ethyl acetate taken up, and washed with sodium bicarbonate solution. After evaporation of the organic phase, the title compound is purified by column chromatography isolated 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)

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 refluxed for 3 hours. After evaporation the title compound is recrystallized as HCl salt from ethanol / ether. M.p .: 137-139 °.

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

To a solution of 6O g of N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] amine (prepared from the HCl salt of the compound of Example 16) in 500 ml of methanol are added to 300 ml of 2N NaOH solution and the mixture is stirred 48 hours at room temperature in an open round bottom flask. Then water is added and the mixture is extracted 3 times with ethyl acetate. After evaporation of the organic phase, the title compound is isolated as a brown oil by column chromatography on silica gel.

Example 18-20 (method c)

The following dimers can analogously to Example 17 or also as By-products of process a), as in Examples 1 and 2

described, can be obtained. In the compounds of the table below, R stands for a group of the formula (a) as defined above and R, R ¹ , R and A have the meanings given below.

example
No. R. Dimer the
Formula (I) and (a) ■ - M.p. H R ¹ R A. 18th H COCH ■ CH (C V ₃ 112-114 ° 19th H COCn-C ₃ H ₇ ) C ₃ H ₅ (C V ₃ 96-98 ° 20th CO Ct-C ₄ H ₉ ) C ₃ H ₅ (C V ₃ 136-137 °

Example 21 : SS dimer des N- f 4-ethoxy-3- (3-merkaptopropy1)

phenyl] pivalamids ( method d)

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

Examples 22-26 (method d)

The following compounds can also be prepared analogously to Example 21 where the substituents on the benzene ring are the

«Λ Λ *

332074

1OO-ÜÖO8

are the same as in the corresponding starting product with the exception of the Gx'uppe R ¹ / which is defined in the table.

Example starting product
No. Example No. link 17th _Ri too the Formula I. 6th (Dimer) M.p. 17th COOCH Ex. made in (Dimer) 22nd 16 CO (HC ₃ H ₇ ) Ex. 1.2 332-114 ° 23 16 C0 (tC H _g ) Ex. 19th 96-98 ° 24 16 COCH Ex. 4th 117-118 ° 25th CO (n-CHJ ex. 1 70-72 ° 26th OeI *

* This compound can be used without isolation and purification during the process of Example 19 can be used.

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

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

Example e 28-29 ( method d)

Analogously to example 27, the following connections can also be made:

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example

Starting product example Kr.

End product as in example no.

28
29

22 23

1.2
6th

Example 30 : N- [4-ethoxy-3- (3-mercaptopropyl) phenyl3-ethylamine

4 [method d)

A solution of 3.08 ml of 100% H SO in 30 ml is added at -5 ° to a suspension of 4.5 g of LiAlH in 200 ml of tetrahydrofuran Tetrahydrofuran. This mixture is stirred for 30 minutes at -5 ° and a solution of 10 g of N- [4-ethoxy-3- (3-mercaptopropyl) phenyl] acetamide (e.g. from Example 1) in 200 ml of tetrahydrofuran was added within 30 minutes at 0 °. The mixture is left for 2 hours stand at room temperature, pour it onto ice water and extract with methylene chloride. After evaporation, the remaining Oil over silica gel with hexane / ethyl acetate (3: 1) as the eluent chromatographed. The title compound appears as 1,5-naphthalene disulfonate isolated and recrystallized from methanol / ether. M.p. 145-149 °

The inventive l-amino-4-oxy-3-mercapto (straight-chain) -alkylbenzenes, their S-acyl derivatives and their S-S dimers, in particular the compounds of formula I and their esters, as well as 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:

- 29 - 100 - '"> 000

A) in the arthritis pain test (based on that of AV, ^7th Pircio

et al. in Eur.J.Pharmacol. J33 ^ _r 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 po

The compounds according to the invention can consequently be used as analgesics can be used, e.g. for the treatment of aprons. A suitable daily dose for this application is around 50 to 300 mg, expediently share in 2 to 4 An or administered as a sustained-release form. For example, for oral administration, the partial doses contain 12.5 to 15Ο mg of the compounds according to the invention, optionally as free base or acid addition salt besides pharmaceutically acceptable ones Diluents or carriers.

The compounds according to the invention also have antipyretic properties, such as, for example, from their action in the method described by EI Takesue et al. in Arch. Intern. Phariaacodyn. 221 , 122-31, 1976 appears.

The invention also includes

1) l-Amino-4-oxy-3-mercapto (straight-chain) alkylbenzenes, their S-acyl derivatives and S-S dimers, especially compounds of formula I or their esters, or their pharmaceutically acceptable acid addition salts for use as medicaments, e.g. for use as analgesics or antipyretics.

ν. ..ν, ΟΟΔΌ I HO - 30 - 100-5808

2) A method of treating (e.g. relieving) pain, consisting in having an analgesic effective amount a compound listed above under 1), optionally in the form of the free base or a pharmaceutically acceptable one Acid addition salt administered.

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

The pharmaceutical preparations mentioned above under 3) can according to at . known galenic methods are produced. Suitable galenic administration forms are, for example, tablets and liquid preparations.

Claims (8)

SANDOZ Patent GmbH. ] OO-5808 Loerrach claims; 1. l ~ Amino-4-oxy ~ 3-mercapto (straight-chain) alkyl-benzenes, their S-acyl derivatives, their S-S dimers ^ and the acid addition salts of these connections. 2.y Compounds according to claim 1 of the formula I. R. (I) wherein R, R * and R independently of one another represent hydrogen or alkyl with 1 to 6 carbon atoms R ^{1 can} also stand for a -COR group in which R is hydrogen or alkyl with 1 to 6 carbon atoms, A for an alkylene radical with up to five carbon atoms and R for hydrogen, an acyl group or a group of the formula (a) (a) wherein R »R ¹ ι R„ and A have the meaning mentioned above and are identical to or different - ² - 100-5808 separated from the radicals R, R ¹ , R and A, as defined in formula I, stand, as well as their esters and the acid addition salts of these compounds. 3. Compounds according to claim 2 of the formula IA NHtCO-R. R ~ 0 wherein R is hydrogen or alkyl having 1 to 6 carbon atoms R is hydrogen or alkyl having 1 to 6 carbon atoms and R is hydrogen or an R CO group, where R is hydrogen or alkyl with 1 to 5 carbon atoms, mean. 4. As a compound according to claim 3, the compound of the formula IA, wherein R is CH, R is CH and R is CH CO. 5. Process for the preparation of l-amino-4-oxy-3-mercapto- (straight-chain) alkylbenzenes, their S-acyl derivatives and their S-S dimers, as well as the acid addition salts of these compounds, e.g. for the preparation of a compound of the formula I according to claim 2 or its esters or the acid addition salts of such a compound, characterized in that one ³ 1ΟΟ-58Ο8 a) a l-amino-4-oxybenzene (except for a l-amino-4-acyloxybenzene), which in position 3 of the rank by an R'-thio (straight chain) alkyl group, where R 'is a group of the formula (b) where X either = S and Z -OR_, where R_ is alkyl with 1 to b 5 4 carbon atoms, or X = NH and Z mean -NH, hydrolyzed for the production of a l-amino-4-oxy-3-mercapto (straight-chain) -alkylbenzenes (except for a l-amino-4-acyloxy-3-mercapto (straight-chain) alkylbenzene),
for example a compound of formula II II wherein R, R ¹ , R and A have the meanings given for formula I, and X and Z have the meanings given for formula (b) have, hydrolyzed, and / or _ 4 - 100-5808 b) a free OH and / or SH group in a l-amino-4-oxy-3-merkapto (straight-chain) alkylbenzene or acylated in an S-acyl derivative or S-S-diraer thereof to produce the S-acyl derivative a l-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene, or a l-amino-4-acyloxy-3-mercapto (straight-chain) alkylbenzene, or an S-acyl derivative or S-S-dimer thereof, e.g. a compound of the formula I according to claim 2, wherein R and / or R represent hydrogen, acylated for preparation an ester thereof or for the production of a 3.0 bond of the formula I, in which R is acyl, and / or c) a l-amino-4-oxy-3-merkapto (straight chain) alkylbenzene one Subjects S-S dimerization to produce the corresponding S-S dimer, e.g. a compound of formula I wherein R is hydrogen is, subjected to an S-S dimerization to prepare a compound of the formula I, according to claim 2, wherein R is a Group of formula (a) as defined above, and if desired d) a l-amino-4-oxy-3-mercapto (straight-chain) alkylbenzene obtained in this way, converting an S-acyl derivative or S-S dimer thereof into another such compound, e.g. d a compound of the formula I according to claim 2, wherein R ^{1 is} -COR, and / or R for R CO, as defined for formula I, 1 3 4 deacylated for the preparation of compounds of the formula I in which R ¹ and / or R are hydrogen, and / or r * e, »* β» Λ Ο Λ aa t> · ~ ⁵ ~ 100-5808 2)
d a compound of the formula I, in which R is alkyl having 1 to 6 carbon atoms, is subjected to an ether cleavage to produce a Vei and or a compound of the formula I in which R is hydrogen, d a compound of the formula I or an ester thereof, in which R is a group of the formula (a), as defined above, is subjected to SS cleavage to produce a compound of the formula I or
stands, and / or of the formula I or an ester thereof, in which R is hydrogen 4) ö a compound of the formula I in which R 'is R CO, reduced to produce a compound of the formula I in which R ^{1 is} alkyl having 1 to 6 carbon atoms, and / or d a compound of the formula I or an ester thereof, v / orin R and / or R ^{1 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 ' stand for alkyl with 1 to 6 carbon atoms or in which R 'stands for -COR, and the l-amino-4-oxy-3-mercapto (straight-chain) alkylbenzenes thus obtained, their S-acyl derivatives. or S-S diiners, e.g., the compounds of formula I or their esters, optionally as a free base or acid addition sal wins. 6. Pharmaceutical preparations containing a l-amino-4-oxy-3-merkapto (straight-chain) alkylbenzene, or an S-acyl derivative or S-S dimer thereof or a pharmaceutically acceptable acid addition salt thereof according to claims 1 to 4 together with a pharmaceutically acceptable diluent or carrier. • m * · - ⁶ "10O-5808 7. 1-Ami.no-4-oxy-3-Qerkapto (straight-chain) alkylbenzenes, theirs S ~ acyl derivatives or S-S dimers or pharmaceutically acceptable acid addition salts thereof according to claims 1 to 4 for use as drugs, especially as analgesics. 8. Compounds of the formula II II wherein R, R ¹ , R and A have the meanings given in claim 2, and X either = S and Z -OR, where R is alkyl with 1 to 4 5 5 C atoms, or X = NH and Z mean -NH.